Compound, pharmaceutical composition, and methods for visualizing deposits of alpha-synucleiin in a human patient and for measuring the clinical efficacy of therapeutic agents for parkinson's disease

Description

[001] This patent application claims the benefit or priority of this patent to U.S. Provisional Patent Application No. 63 / 485 159, filed February 15, 2023, the contents of which are incorporated herein in their entirety. Fundamentals of the invention

[002] Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD), Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, are debilitating diseases that affect cognition and / or muscle control. These diseases constitute a subset of diseases associated with protein misfolding. Protein folding is an essential process for protein function in all organisms, and conditions that disrupt protein folding pose a threat to cell viability. In some cases, the disease arises because a specific protein is no longer functional when it adopts a misfolded state. In other diseases, the pathological state originates because misfolding occurs concomitantly with aggregation, and the underlying aggregates are detrimental.Although neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are caused by different proteins, both involve the accumulation of insoluble fibrous protein deposits called amyloids. For example, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively referred to as "synucleinopathies," have been linked to the accumulation of aggregated forms of the alpha-synuclein protein in neurons in the brain (see Nat. Rev. Neuro. 2013, 9, 13-24 and J. Parkinson's Disease 2013, 3, 565-567). Petition 870260070497, dated 07 / 16 / 2026, page 10 / 214 / 205 As the primary neuropathological alteration in PD, the degeneration of dopaminergic neurons occurs in the substantia nigra, as well as Lewy bodies (LB) and Lewy neurites (NL). To date, the pathogenic mechanism of PD has not been fully revealed.

[003] Alpha-synuclein is a protein present in presynaptic terminals and consists of a 140-amino acid protein with an important function in the central nervous system, including the recycling and synthesis of synaptic vesicles, vesicular storage, and the release of neurotransmitters. It is specifically upregulated in a distinct population of presynaptic terminals in the brain during synaptic rearrangement related to acquisition. Alpha-synuclein naturally exists in an unfolded, highly soluble state. Evidence suggests that filamentous aggregates of alpha-synuclein accumulate in the presynaptic membrane and trigger synapse dysfunction and neuronal cell death in synucleinopathies, and may be the cause of Parkinson's disease and MCI.Alpha-synuclein aggregation has been identified, through immunohistological studies with antibodies, as the main component of Lewy bodies, which are microscopic protein deposits in deteriorating nerve cells. The accumulation of fibrillar, misfolded alpha-synuclein in Lewy bodies (LB) and Lewy neurites (NL) is considered a hallmark of Parkinson's disease (PD).

[004] The diagnosis of PD is primarily based on clinical symptoms such as resting tremor, bradykinesia, and rigidity, although these methods have their limitations (see J. Neurology 2019, 266, 1927-1936). The current desired treatment for PD is to slow the progression of the disease and minimize the symptoms of the disease in patients. Therefore, a method for diagnosing PD at a very early stage could greatly help physicians design the therapeutic paradigm accordingly and slow the progression of the disease. There is still a need for improved diagnostic methods to identify aggregations of malformed proteins.Petition 870260070497, dated 07 / 16 / 2026, page 11 / 214 / 205, including alpha-synuclein, for early detection and continuous monitoring of PD in individuals (see J. Parkinson's Disease 2013, 3, 565-567).

[005] An alpha-synuclein tracer on positron emission tomography (PET) would be a valuable non-invasive diagnostic biomarker for spatial and temporal quantification of pathologically aggregated alpha-synuclein in the human brain as a biomarker of Parkinson's disease. Furthermore, an alpha-synuclein tracer on PET scans could be useful in selecting patients for PD clinical trials. Thus, an alpha-synuclein tracer could be developed as a complementary diagnostic tool for the registration of a therapeutic agent.Furthermore, an alpha-synuclein tracer in PET scans could be a critically relevant disease tool for quantifying a stabilization or decrease in alpha-synuclein formation for disease-modifying therapy in Parkinson's disease.

[006] Therefore, there is a need for neuroimaging radiotracers that would allow in vivo imaging of alpha-synuclein pathology, thus providing insight into the deposition of alpha-synuclein aggregates in the human brain. A successful neuroimaging radiotracer should cross the blood-brain barrier, exhibit rapid clearance from tissues and plasma, and possess high affinity and specificity for alpha-synuclein aggregates with high selectivity for binding to beta-amyloid and aggregated tau proteins due to co-expression in many PD patient populations (see Biol Psychiatry 2015, 78, 672-683 and J Neuropath Exper Neurol 2003, 62, 389-397).Although alpha-synuclein-binding ligands with reduced selectivity for aggregated beta-amyloid have been described (WO 2019 / 121661), there is a need for compounds with high levels of selectivity for aggregated proteins co-expressed in PD in order to quantify a specific alpha-synuclein signal in an in vivo imaging study for PD patients. Petition 870260070497, dated 07 / 16 / 2026, page 12 / 214 / 205

[007] The present invention advances these interests by providing compounds of Formula I, as ligands for binding alpha-synuclein aggregates, with high selectivity over the binding of pathological beta-amyloid aggregates. The present invention also relates to a method for using the compounds of Formula I as tracers in PET imaging to study alpha-synuclein deposits in the brain in vivo and to allow the diagnosis of neurodegenerative diseases that are distinguished by alpha-synuclein pathology. The invention further relates to a method for measuring the clinical efficacy of therapeutic agents targeting alpha-synuclein pathology. Summary of the invention

[008] The invention is directed to compounds of Formula I, pharmaceutical salts thereof, pharmaceutical compositions comprising them, diagnostic and therapeutic uses, and processes for producing such compounds. One embodiment of the invention provides a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 -alkyl, OR or halo, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl, OR or halo groups; Raé is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rbé selected independently from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or Petition 870260070497, dated 07 / 16 / 2026, page 13 / 214 / 205 -O(CH2)nhalo; Rcé is independently selected from H or C1-6 -alkyl, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl groups, OR or halo; Rdé selected independently from either H or C1-6 alkyl; R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, Orc, NO2, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, imidazopyridinyl, 3,4-dihydro-2Hpyrido[3,2,b][1,4]oxazine or phenyl; Ring B is selected from: (Ra)m ^-h / a) , Petition 870260070497, dated 07 / 16 / 2026, page 14 / 214 / 205 b) or w)\; ; m is selected from 1, 2 or 3; n is selected independently from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, or 3; eq is selected from 1, 2, or 3.

[009] The present invention is also directed to isotopically labeled compounds of Formula I. In addition, the present invention provides pharmaceutical compositions comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.

[0010] The present invention is directed to compounds of Formula I that may be useful for binding aggregated alpha-synuclein proteins and / or aggregated tau proteins and, consequently, are useful in binding and visualizing aggregated alpha-synuclein protein pathology in patients with PD or other synucleinopathies different from PD, as well as patients with Alzheimer's disease (AD) with tau protein pathology and non-AD tauopathy by means of PET imaging techniques commonly known in the field (see J. Nucl. Med. 2019, 60, 93-99 and 107-114). This invention also relates to methods for using the compounds of Formula I to identify patients with abnormal levels of pathological aggregated alpha-synuclein in the brain. This invention also relates to methods for using a compound of Formula I to measure the progression of alpha-synuclein pathology over time as a biomarker in Petition 870260070497, dated 07 / 16 / 2026, page 15 / 214 / 205 clinical evaluation of potential therapeutic agents that may modify the progression of Parkinson's disease.

[0011] Compounds of this invention may also be useful for imaging and detection of other neurodegenerative diseases that are distinguished by the deposition of alpha-synuclein aggregates, such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Brief description of the drawings

[0012] Figure 1: Saturation binding experiment in DA tissue homogenate rich in beta-amyloid aggregated for [3H]-105.

[0013] Figure 2: Saturation binding experiment in the insoluble fraction in Triton of DP tissue homogenate enriched with alpha-synuclein aggregated to [3H]-1.

[0014] Figure 3: Saturation binding data of the radioligand [3H]-1 in pathologically aggregated DP human cortical tissue homogenate.

[0015] Figure 4: Saturation binding data of the radioligand [3H]-1 in Ae-enriched human cortical tissue homogenate.

[0016] Figure 5: Saturation binding data of the radioligand [3H]24 in pathologically aggregated DP human cortical tissue homogenate.

[0017] Figure 6: Saturation binding data of the radioligand [3H]24 in Ae-enriched human cortical tissue homogenate of DA. Detailed description of the invention

[0018] The present invention provides novel substituted heterocyclic piperazine amide compounds, synthetic methods for producing the compounds, pharmaceutical compositions containing them, compounds Petition 870260070497, dated 07 / 16 / 2026, page 16 / 214 / 205 isotopically labeled and methods for using the compounds as contrast agents.

[0019] In one embodiment, the present invention is directed to a compound of Formula I: I or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 -alkyl, OR or halo, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl, OR or halo groups; Raé is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or -O(CH2)nhalo; Rcé is independently selected from H or C1-6 -alkyl, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl groups, OR or halo; Rdé selected independently from either H or C1-6 alkyl; R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; Petition 870260070497, dated 07 / 16 / 2026, p. 17 / 214 / 205 R2 is selected from hydrogen, Orc, NO2, halo or -alkyl C1-6; Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, imidazopyridinyl, 3,4-dihydro-2Hpyrido[3,2,b][1,4]oxazine or phenyl; Ring B is selected from: (Ra)m —^-N^ \l-\-a) b) or w) ; m is selected from 1, 2 or 3; n is selected independently from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, or 3; eq is selected from 1, 2, or 3. Petition 870260070497, dated 07 / 16 / 2026, page 18 / 214 / 205

[0020] In a further embodiment, the present invention is directed to a compound of Formula IA, IA or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, OR or halo; Raé is independently selected from unsubstituted or substituted C1-6 alkyl or -(CH2)1-3O-(CH2)0-3R, said alkyl optionally substituted with 1 to 3 R groups; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or -O(CH2)nhalo; Rc is independently selected from H or C1-6 -alkyl, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl groups, OR or halo; Rdé selected independently from either H or C1-6 alkyl; R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, -NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; r2 is selected from hydrogen, Orc, halo or C1-6 alkyl; Petition 870260070497, dated 07 / 16 / 2026, p. 19 / 214 / 205 Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2, b][1,4]oxazine or phenyl; m is selected from 1, 2 or 3; n is selected independently from 0, 1, 2, 3, or 4; ep is selected from 0, 1, 2, or 3.

[0021] In a further embodiment, the present invention is directed to a compound of Formula IA, or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 -alkyl, OR or halo, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl, OR or halo groups; Raé is independently selected from unsubstituted or substituted C1-6 alkyl or -(CH2)1-3O-(CH2)0-3R, said alkyl optionally substituted with 1 to 3 R groups; Rbé is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or -O(CH2)nhalo; Rcé is independently selected from H or C1-6 -alkyl, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl groups, OR or halo; Rdé selected independently from either H or C1-6 alkyl; R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, -NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, cycloalkyl Petition 870260070497, dated 07 / 16 / 2026, p. 20 / 214 / 205 C3-C10 unsubstituted or substituted, heteroaryl unsubstituted or substituted, or heterocyclyl unsubstituted or substituted, wherein said alkyl, cycloalkyl, phenyl, heteroaryl, or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, ORC, -NO2, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, imidazopyridinyl, 3,4-dihydro-2Hpyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 1, 2 or 3; n is selected independently from 0, 1, 2, 3, or 4; p is selected from 0, 1, 2, or 3; eq is selected from 1, 2, or 3.

[0022] In a further embodiment, the present invention is directed to a compound of Formula IA, or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 -alkyl, OR or halo, wherein said alkyl is optionally substituted with one to three C1-6 -alkyl, OR or halo groups; Raé is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Petition 870260070497, dated 07 / 16 / 2026, page 21 / 214 / 205 Ring A1 is selected from pyridyl, pyrazinyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl or pyridyl, wherein said pyrimidinyl, phenyl or pyridyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl or phenyl; m is selected from 1 or 2; p is selected from 0, 1, or 2; and all other substituents and variables are as defined above in Formula I.

[0023] In another embodiment, the present invention is directed to compounds of Formula IB: IB or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, OR or halo; Rae - unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rbé is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -(CH2)nhalogen or -O(CH2)nhalo; Rcé is selected independently from either H or C1-6 alkyl; R1 is selected from -(CH2)nORc, -(CH2)nO(CH2)nR, (CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, Petition 870260070497, dated 07 / 16 / 2026, p. 22 / 214 / 205 unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, Orc, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, pyrrolpyrazinyl, oxadiazolyl, 3,4-dihydro-2Hpyrido[3,2,b][1,4]oxazine or phenyl; n is selected independently from 0, 1, 2, 3, or 4; ep is selected from 1 or 2.

[0024] In another embodiment, the present invention is directed to compounds of Formula IC: or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, OR or halo; Raé is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Petition 870260070497, dated 07 / 16 / 2026, pages 23 / 214 / 205 Rbé seleciomdo independente entre -alquila C1-6, halo, -(CH2)nORc, -CN, -(CH2)nhalogênio ou -O(CH2)nhalo; Rcé is selected independently from either H or C1-6 alkyl; R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, Orc, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2, b][1,4]oxazine or phenyl; n is selected independently from 0, 1, 2, 3, or 4; ep is selected from 0, 1, 2, or 3.

[0025] In another embodiment, the present invention is directed to compounds of Formula IC, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, OR or halo; Petition 870260070497, dated 07 / 16 / 2026, page 24 / 214 / 205 Raé is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rbé is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -(CH2)nhalogen or -O(CH2)nhalo; Rcé is selected independently from either H or C1-6 alkyl; R1 is selected from -(CH2)nORc, -(CH2)nO(CH2)nR, -NR2, pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl or furyl, wherein said pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl or furyl may optionally be replaced with one to three Rb groups; R2 is selected from among hydrogen, Orc, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, pyrimidinyl, thiazolyl or pyrazolyl; Ring A2 is selected from pyrimidinyl, pyridyl or pyrazinyl, wherein said pyrimidinyl, pyridyl or pyrazinyl is optionally replaced with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl or phenyl; n is selected independently from 0, 1, 2, 3, or 4; ep is selected from 0, 1, 2, or 3.

[0026] In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein Ring A1 is selected from pyridyl, pyrazinyl, pyrimidinyl, thiazolyl or pyrazolyl. In another embodiment, Ring A1 is selected from pyridyl, pyrazinyl, pyrazolyl or pyrimidinyl. In yet another embodiment, Ring A1 is selected from pyridyl or pyrazinyl.

[0027] In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein Ring A2 is selected from pyrimidinyl, pyridyl or pyrazinyl, wherein said pyrimidinyl, pyridyl or pyrazinyl is optionally substituted with 1 to 3 R groups. In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein Ring A2 is Petition 870260070497, dated 07 / 16 / 2026, p. 25 / 214 / 205 selected from pyrimidinyl or pyrazinyl, wherein said pyrimidinyl or pyrazinyl is optionally replaced with 1 to 3 R groups. In a further embodiment, Ring A2 is pyrimidinyl, which is optionally replaced with 1 to 3 R groups. In a further embodiment, Ring A2 is pyrazinyl, which is optionally replaced with 1 to 3 R groups.

[0028] In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl or phenyl. In another embodiment, Ring A3 is selected from pyridyl, pyrazinyl or phenyl.

[0029] In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein R is independently selected from H or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three C1-6 alkyl groups, OR or halo. In another embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein R is independently selected from H or C1-6 alkyl.

[0030] In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, in which R1 is selected among -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, -NR2, -alquila C1-6, cyclopropyl, imidazolila, pyridila, indolila, pyrazolila, triazolila, azetidinila, phenyl, azepanila, pyrrolpirazinila, pirrolidinila, azabiciclo-heptanila, furila, tiazolila, pirimidinila, oxa-azabiciclo-heptanila, piridazinila, tienila, isoxazolila, oxazolila, dihidropirrolilpirazolila, morpholinila, tetrazolila ou piperazinila, em que o dito alquila, ciclopropila, imidazolila, piridila, indolila, pirazolila, triazolila, azetidinila, fenila, azepanila, pirrolpirazinila, pirrolidinila, azabiciclo-heptanila, furila, tiazolila, pyrimidinila, oxa-azabiciclo-heptanila, piridazinila, tienila, isoxazolila, oxazolila, dihidropirrolilpirazolila, morpholinila, tetrazolila, piperazinila pode ser opcionalmente substituído com um a três grupos de Rb. Petition 870260070497, dated 07 / 16 / 2026, page 26 / 214 / 205

[0031] In one embodiment, the invention provides a compound of Formula I, IA, IB or IC, wherein R1 is selected from -(CH2)nORc, (CH2)nO(CH2)nR, -NR2, pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl, furyl, wherein said pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl, or furyl may optionally be substituted with one to three Rb groups.

[0032] Representative compounds of the present invention include compounds selected from: Table 1 Ex. in Structure Name 1 ? O / =N / \y—N Xn—(\ nhY^ \=NX—N N-^ (S)-6-methoxy-N-(2-(2-methyl-4- (pyridin-2-yl)piperazine-1yl)pyrimidine-5-yl)nicotinamide 2 YT o N-[2-[(3S)-3-ethyl-4-(5-methyl-2pyridyl)piperazine-1-yl]pyrimidine-5yl]-6-imidazol-1-yl-pyridine-3carboxamide 3 0 0 Λ 'X) N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazine-1-yl]pyrimidine-5yl]-4-(3-pyridyl)benzamide 4 Cp c 5-fluoro-N-[5-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrazin-2-yl]1H-indol-2-carboxamide 5 α YT 6-imidazol-1-yl-N-[2-[4-(3-(3-methyl)2,-2- trifluoroethyl)piperazine-1yl]pyrimidine-5-yl]pyridine-3carboxamide 6 Λ X) 6-methoxy-N-[2-[(2S)-2-methyl-4-(6methyl-2-pyridyl)piperazine-1yl]pyrimidine-5-yl]pyridine X7, YCarboxy 6-imidazol-1-yl-N-[2-[(2S)-2-methyl4-(6-methyl-2-pyridyl)piperazine-1yl]pyrimidine-5-yl]pyridine-3carboxamide 8 í YY 6-methoxy-N-[2-[(2S)-2-methyl-4-(5methyl-2-pyridyl)piperazine-1yl]pyrimidine-5-yl]pyridine-3carboxamide Petition 870260070497, dated 07 / 16 / 2026, p. 27 / 214 / 205 Ex. no Structure Name 9 Y $ 5-(2-fluoroethoxy)-N-[2-[(2S)-2methyl-4-(6-methyl-2-pyridyl)piperazin-1-yl]pyrimidin-5yl]pyrazine-2-carboxamide 10 6-methoxy-N-[2-[(2S)-4-(5-methoxy2-pyridyl)-2-methyl-piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 11 $ AA 4-(2-fluoroethoxy)-N-[2-[(2S)-2methyl-4-(6-methyl-2-pyridyl)piperazin-1-yl]pyrimidin-5yl]benzamide 12 X íít 6-methoxy-N-[2-[(2S)-2-methyl-4pyrazin-2-yl-piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 13 Cp V N-[5-[(2S)-2-metil-4-(2pyridyl)piperazin-1-yl]pyrazin-2-yl]5H-pyrrol[2,3-b]pyrazina-6carboxamida 14 9 9' T 4-(2-fluoroethoxi)-N-[2-[(2S)-2metil-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]benzamide 15 AAO 6-methoxy-N-[2-[(2S)-2-metil-4pyrimidin-4-yl-piperazin-1il]pyrimidin-5-yl]pyridina-3carboxamida 16 AAA} o 6-(2-hidroxietoxi)-N-[2-[(2S)-2metil-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridina-3carboxamida 17 AAA: à 6-methoxy-N-[2-[(2S)-2-methyl-4-(4pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 18 o...VT 6-chloro-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 19 Λ Ó 4-(1-cyanocyclopropyl)-N-[5-[(2C)2-methyl-4-(2-pyridyl)piperazin-1yl]pyrazine-2-yl]benzamide. Petition 870260070497, of 16 / 07 / 2026, p. 28 / 214 / 205 Ex. no Structure Name 20 — CD V / / 6-bromo-N-[2-[(2S)-2-methyl-4-(2piridil)piperazin-1-yl]pirimidin-5- il]pmdina-3-carboxamide 21 A x: ΆΜΑ N-[2-[(2S)-2-methyl-4-(2piridil)piperazin-1-yl]pirimidin-5yl]-5-phenyl-pyrazine-2-carboxamide 22 — x__ / ~ — 6-methoxy-N-[2-[(2R)-2-methyl-4-(2piridil)piperazin-1-yl]pirimidin-5yl]pyridine-3-carboxamide 23 — C1,.V x— _ 6-(2-fluoroethoxy)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 24 Λ c 2-methoxy-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-4-carboxamide 25 ò A: C 6-methoxy-N-[2-[(2S)-2-methyl-4-(4methyl-2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 26 — ô A: V--7 ' 4-(1 -cyanocyclopropyl)-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazin-1- yl]pyrimidin-5-yl]benzamide 27 Δ A) N-[2-[(2S)-4-(6-fluoro-2-pyridyl)-2methyl-piperazin-1-yl]pyrimidin-5yl]-6-methoxy-pyridine-3-carboxamide 28 — C λ YC 6-(difluoromethoxy)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 29 c λ 4-methoxy-N-[5-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrazin-2yl]pyridine-2-carboxamide. Petition 870260070497, de 16 / 07 / 2026, pág. 29 / 214 / 205 Ex. no Structure Name 30 x: 1 6-(2-fluoroethoxy)-N-[6-[(2S)-2- methyl-4-(2-pyridyl)piperazin-1-yl]-3pyridyl]pyridine-3-carboxamide 31 '— — —— 4-methoxy-N-[5-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl]-2- pyridyl]pyridine-2-carboxamide 32 1 X” 2-(2-fluoroethoxy)-N-[5-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrazin-2-yl]pyrimidine-5carboxamide 33 — —— — 6-methoxy-N-[2-[(3R)-3-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 34 — —— — 6-methoxy-N-[2-[(3S)-3-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 35 —(\ X*- aX N-[2-[(3S)-3-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-5H-pyrrole[2,3-b]pyrazine-6carboxamide 36 — —— / 2-methoxy-N-[2-[(3S)-3-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]pyrimidine-5-carboxamide 37 1 X 1 -- X^J^] N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-pyrazol-1 -yl-pyridine-3carboxamide 38 1 cx„ 1 λ \^X 6-(4-methoxypyrazol-1-yl)-N-[2- [(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 39 1 X) 1 \_ v \^X. 6-(4-fluoropyrazol-1-yl)-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide, Petition 870260070497, de 16 / 07 / 2026, pág. 30 / 214 / 205 Ex. no Estrutura Nome 40 ίΪΊ X) 1 .MA- Ά 6-(3 -methoxypyrazol-1-yl)-N-[2- [(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 41 CD Γ. N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-(triazol-1-yl)pyridine-3-carboxamide 42 ίΪΊ 1 6-(3-methylpyrazol-1-yl)-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 43 1 C λ, ô T 6-(2-methylimidazol-1 -yl)-N-[2- [(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 44 1 c i...O1 [Z^ 1 (S)-N-(2-(2-methyl-4-(pyridin-2yl)piperazin-1-yl)pyrimidin-5-yl)-6(2H-1,2,3-triazol-2-yl)nicotinamide 45 XJ 1 —ZZ^- 6-(3,5-dimethylpyrazol-1-yl)-N-[2[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 46 ηΊ X 1 6-(3,3-difluoroazetidin-1-yl)-N-[2 [(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 47 1 cx, [H _^a 6-[(3R)-3-fluoropyrrolidin-1-yl]-N- [2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 48 1 o,, . ZZ^- \Ã^ 6-[rac-(4S)-2- azabicyclo [2.2.1]heptan-2-yl]-N-[2- [rac-(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5- yl]pyridine-3-carboxamide 49 AX: 1 a 6-[(3S)-3-fluoropyrrolidin-1-yl]-N[2-[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 50 \___ / —CZ^- cZ” 6-(3,3-dimethylpyrrolidin-1-yl)-N-[2[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide. Petition 870260070497, de 16 / 07 / 2026, pág. 31 / 214 / 205 Ex. no Estrutura Nome 51 — 1 Ύ D Λ v / / — 6-(3-fluoroazetidin-1-yl)-N-[2[(2S)-2-methyl-4-(6-methyl-2pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 52 — C1, 1 - 6-(3-methylazetidin-1-yl)-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridin-3carboxamide 53 — CX, 1 a 3^· \\ / / Q 6-(azepan-1-yl)-N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl] yl]pyrimidin-5-yl]pyridine-3carboxamide 54 — CX, 1 Á / / -χ 6-(2-oxa-5-azabiciclo [2.2.1]heptan-5-yl)-N-[2- [rac-(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 55 — C 1. / / / \ 6-[methyl(propyl)amino]-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 56 — c λ — VZ / 6-(azetidin-1-yl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 57 / \ / Ά / / \ 6-(methylamino)-N-[2-[(2S)-2-methyl4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 58 C1., —Z— / v — 6-(dimethylamino)-N-[2-[(2S)-2methyl-4-(6-methyl-2- pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 59 — C X. 1 \ \χ~ \ 6-[ethyl(2-hydroxyethyl)amino]-N-[2[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 60 — CX, 1 Á / / — 6-(3 -hydroxyazetidin-1-yl)-N -[2[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 61 — c λ, 1 -x - / / 6-[isobutyl(methyl)amino]-N-[2[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide. Petition 870260070497, de 16 / 07 / 2026, pág. 32 / 214 / 205 Ex. no Structure Name 62 — CX, 1 XZX- 0 N-[2-[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-pyrrolidin-1-yl-pyridine-3carboxamide 63 — c X. 1 / = / = / 6-(3-fluorophenyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 64 — c X. 1 -λ ZX- —C=x 6-(4-methyl-3-furyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 65 c:..... ΗχΧ-Χυ N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-thiazol-5 -yl-pyridine-3carboxamide 66 — 1 N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-pyridazin-4-yl-pyridine-3carboxamide 67 — c x.„ C \íX N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-(3-thienyl)pyridine-3carboxamide 68 — CX, 1 o ao 6-(4-fluorophenyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 69 — c x.„ 1 X\ vv X N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]-6-(3-pyridyl)pyridine-3-carboxamide 70 — C).....1 a 3^· N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-(4-pyridyl)pyridine-3-carboxamide 71 — 1 X: \\ —\t # N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-phenyl-pyridine-3-carboxamide 72 — c x. 1 λ 3^- XL_ --CíX 6-(3-furyl)-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide. Petition 870260070497, de 16 / 07 / 2026, pág. 33 / 214 / 205 Ex. no Structure Name 73 — X Λ X) 6-(4-cyanophenyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 74 o... T 1 6-(5,6-dihydro-4H-pyrrolo[1,2b]pyrazol-3-yl)-N-[2-[(2S)-2-methyl4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 75 o... $ -γΠι / 6-(2-methylpyrazol-3-yl)-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 76 o..,„ $ N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5yl]-6-pyrimidin-5-yl-pyridine-3carboxamide 77 — C 1, YX / / 6-(2-methyl-4-pyridyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 78 Λ .....c: 6-(5-fluoro-3-pyridyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 79 — c X. YX ___ / J 6-(3-fluoro-4-pyridyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3carboxamide 80 — : X.YT \χ / / 6-(6-fluoro-2-pyridyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3-carboxamide 81 — 0 Λ X 3 1 6-(3,5-dimethyl-isoxazol-4-yl)-N-[2[(2S)-2-methyl-4-(2- pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 82 — X Λ ___ / J 6-(3-methyl-4-pyridyl)-N-[2-[(2S)-2methyl-4-(2- pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3-carboxamide. Petition 870260070497, de 16 / 07 / 2026, pág. 34 / 214 / 205 Ex. no Structure Name 83 HJ 0 Al Ύ D N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazine-1-yl]pyrimidine-5yl]-6-(2-methylpyrimidine-5yl)pyridine-3-carboxamide 84 / Λ 0 AX: 6-(1-methylpyrazol-4-yl)-N-[2-[(2S)2-methyl-4-(2-pyridyl)piperazine-1yl]pyrimidine-5-yl]pyridine-3carboxamide 85 0 A [^JJ 6-(3-methyl-isoxazol-4-4-yl-2)-N pyridyl)piperazine-1-yl]pyrimidine-5yl]pyridine-3-carboxamide 86 0 AX: 4-(3-cyanophenyl)-N-[2-[(2S)-2methyl-4-(2-pyradyl)piperazine-1yl]pyrimidine-5-yl]V 7 [87 I).…. (S)-6-(3,3-difluoroazetidine-1-yl)-N(2-(4-(4-fluoropyridin-2 -yl))-2methylpiperazine-1-yl)pyrimidine-5yl)nicotinamide 88 9 Λ AA (S)-6-(3,3-difluoroazetidine-1-yl)-N(2-(2-methyl-4-(4-nitropyridine-2yl)piperazine- 1-yl)pyrimidine-5yl)nicotinamide 89 DAX) Òl (S)-N-(2-(4-(2-fluoropyradine-4-yl)2-methylpiperazine-1-yl)pyrimidine-5 yl)-6-(1H-pyrazol-1-yl)nicotinamide 90 C λ. V Λ o (S)-N-(2-(2-methyl-4-(2-nitropyridine4-yl)piperazine-1-yl)pyrimidine-5-yl)6-(1H-pyrazol- 1-yl)nicotinamide 91 9 C X.V or (S)-6-(1H-imidazol-1-yl)-N-(2-(2methyl-4-(pyridine-2-yl)piperazine-1yl)pyrimidine-5-yl)nicotinamide 92 Φ „..c λ V ó N-(2-((2S,6R)-2,6-dimethyl-4-(5methylpyridine-2-yl)piperazine-1yl)pyrimidine-5-yl)-5'-fluoro-[2,3'bipyridine]-5-carboxamide AL. Petition 870260070497, dated 07 / 16 / 2026, p. 35 / 214 / 205 Ex. in Structure Name 93 Φ C 1,. ¥ 'í> P N-(2-((S)-4-(5-fluoropyperazine-2-yl)2-methylpiperazine-1-yl)pyrimidine-5yl)-6-((R)-3-fluoropyrrolidin-1yl)nicotinamide 94 / \ (R)-6-(1H-imidazol-1-yl)-N-(2-(2(methoxymethyl)-4-(pyridine-2yl)piperazine- 1-yl)pyrimidine-5-yl)nicotinamide 95 7 r. í V (.1 (S)-N-(2-(4-(4-fluoropyradine-2-yl)2-methylpiperazine-1-yl)pyrimidine-5 yl)-6-morpholinonicotinamide Petition 870260070497, dated 07 / 16 / 2026, p. 36 / 214 / 205 Ex. no Structure Name 96 9 c ¥ 9 Y (S)-6-(3-fluoroazetidine-1-yl)-N-(2(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-1-yl)pyrimidine-5yl)nicotinamide 97 9 t 9 -j 97 (S)-6-(3-methoxy-1H-pyrazol-1-yl)N-(2-(2-methyl-4-(pyridin-2yl)piperazine- 1-yl)pyrimidine-5yl)nicotinamide 98 9 : J, V or ¥ (S)-6-(3-fluoro-1H-pyrazol-1-yl)-N(2-(2-methyl-4-(pyridin-2yl)piperazine- 1-yl)pyrimidine-5yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, p. 37 / 214 / 205 Ex. no Structure Name 99 LT CX, V í o 1 (S)-N-(2-(4-(4-(6-fluoropyrimidine-4yl))-2-methylpiperazine-1-yl)pyrimidine5-yl)-6-(4-methylpiperazine-1yl)nicotinamide 100 / \ (R)-6-(2-fluoropyrimidine-5-yl)-N(5-(2-(methoxymethyl)-4-(pyridin-2yl)piperazine-1-yl)pyrazine-2yl)nicotinamide 101 c 5 Ό (S)-N-(2-(2-methyl-4-(thiazol-2yl)piperazine-1-yl)pyrimidine-5-yl)-6- (1H-pyrazol-1-yl)nicotinamide 102 t> V 6-(dimethylamino)-N-(2-(5-(6fluoropyrimidine-4-yl)-2,5diazabicyclo[4.1.0]heptane-2yl)pyrimidine-5-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, p. 38 / 214 / 205 Ex. from Structure Name 103 ir y C λ Y (S)-6-(dimethylamino)-N-(2-(4-(6fluo ropyrimidine-4-yl)-2methylpiperazine-1-yl)pyrimidine-5yl)nicotinamide 104 \ c 1... Y $ (S)-N-(2-(2-methyl-4-(1-methyl-1Hpyrazol-3-yl)piperazine-1- il)pyrimidine-5-yl)-6-(1H-pyrazol-1yl)nicotinamide 105 g -<2h ç (S)-N-(2-(4-(3-fluoropyrazine-4-yl)2-methylpiperazine-1-yl)pyrimidine-5yl)-6-morpholinonicotinamide 106 çf V í 6-(3 -fluoro-3-methylazetidin- 1-yl-yl-pyri-(2-din-4-flu- 2,5-diazabicyclo[2.2.2]octan-2yl)pyrimidine-5-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, p. 39 / 214 / 205 Ex. from Structure Name 107 and ύ C 1,. V ά / (S)-N-(2-(4-(6-fluoropyrimdin-4yl)-2-methylpiperazine-1-yl)pyrimdin5-yl)-3-methyl-3H-imidazo[4,5b]pyridine-6-carboxamide 108 0 7: V í N-(2-((2S,5R)-2,5-dimethyl-4-(5methylpyridine-2-yl)piperazine-1yl)pyrimidine-5-yl)-6-(1H-pyrazol-1yl)nicotinamide 109 (S)-N-(2-(4-(5-5-fluoropyrizidine)2methyl-2 IL)-4-(pyridin-3-yl)benzamide 110 7 α V 0 6-(3,3-difluoroazetidine-1-yl)-N-(2 ((2R,3R)-4-(4-fluoropyrazine-2-yl)2,3 -dimethylpiperazine-1-myl)pyrimide Petition 870260070497, dated 07 / 16 / 2026, p. 40 / 214 / 205 Ex. no Structure Name 111 Οι: 1-, Y o (S)-N-(2-(4-(2-fluoropyridin-3-yl)2-methylpiperazin-1-yl)pyrimidin-5 yl)-6-morpholinonicotinamida 112 d (S)-6-(3,3-difluoroazetidin-1-yl)-N(5-(4-(6-fluoropyridin-4-yl)-2methylpiperazin-1-yl)pyrazin-2yl)nicotinamida 113 X] φ1 (S)-6-(azetidin-1-yl)-N-(2-(4-(5fluoropyridin-2-yl)-2- methylpiperazin-1-yl)pyrimidin-5yl)nicotinamida 114 A .....C |^J| (R)-6-(4-(fluoromethyl)-1H-pyrazol1-yl)-N-(2-(2-(methoxymethyl))-4(pyridin-2-yl)piperazine-1yl)pyrimidine-5-yl)nicotinamide 115 Yk -O- _ (S)-N-(5-(4-(6-fluoropyrimidine-4yl)-3-methylpiperazine-1-yl)pyrazine-2yl)-6-(1-methyl-1H-pyrazol-4yl)nicotinamide 116 ( S )-6-(3-fluoroazetidin-1-yl)-N-(5(4-(5-fluoropyridin-2-yl)-3- methylpiperazine-1-yl)pyrazine-2yl)nicotinamide 117 (R)-N-(5-(4-(5-fluoropyridine-2-yl)3-(methoxymethyl)piperazine-1yl)pyrazine-2-yl)-6-(1-methyl-1Hpyrazol-4-yl)nicotinamide 118 / / —λ / λ / λ \ —Λ z= _ ζ '#\ z—\ (S)-N-(2-(4-(5-fluoropyradine-2-yl)2-methylpiperazine-1-yl)pyrimidine-5yl)-6-(1-methyl-1H-pyrazol-4yl)nicotinamide 119 <C^v3 ~y~ \_y=w^ z^v1x (R)-N-(2-(3-((2-fluoroetoxi)metil)4-(pirimidin-2-il)piperazin-1il)pirimidin-5-il)-6-(1-metil-1Hpirazol-4-il)nicotinamida. Petition 870260070497, dated 07 / 16 / 2026, p. 41 / 214 / 205 Ex. no Structure Name 120 \ \_A '— '—' —' n—1 (R)-N-(2-(4-(6-fluoropyrimidine-4yl)-3-(methoxymethyl)piperazine-1yl)pyrimidine-5-yl)-6-(1-methyl-1Hpyrazol-nico1amidyl)yl (R)-N-(4-fluoro-2-(3- (methoxymethyl)-4-(pyrimidine-2yl)piperazine-1-yl)pyrimidine-5-yl)-6- (1-methyl-1H-pyrazol-4yl)nicotinamide 122 (S)-N-(5-(4-(5-fluoropyrimidine-2yl)-3-methylpiperazine-1-yl)pyrazine-2yl)-6-(pyrrolidin-1-yl)nicotinamide 123 Λ \ 0 Çi ó Φ (S)-6-(1-(2-fluoroethyl)-1H-pyrazol4-yl)-N-(2-(4-(5-fluoropyridine-2-yl)2-methylpiperazine-1-yl)pyrimidine-5yl)nicotinamide 124 0 r_z? (R)-N-(5-(3-((2-fluoroethoxy)methyl)4-(5-fluoropyridin-2-yl)piperazine-1yl)pyrazine-2-yl)-6-(1-methyl-1Hpyrazol-4-yl)nicotinamide 125 O (S)-2-(3,3-difluoroazetidine-1-yl)-N(5-(4-(6-fluoropyrimdin-4-yl)-2methylpiperazine-1-yl)pyrazine-2yl)pyrimidine-5-carboxamide 126 ′ O (S)-6-(3,3-difluoroazetidine-1-yl)-N(5-(4-(6-fluoropyridin-3-yl)-2methylpiperazine-1-yl)pyrazine-2yl)nicotinamide 127 / =\ ΗΚ' (S)-N-(2-(4-(6-fluoropyradine-3-yl)2-methylpiperazine-1-yl)pyrimidine-5yl)-6-(1-methyl-1H-pyrazol-4yl)nicotinamide 128 / y 0 T) / 5 (R)-N-(5-(4-(6-fluoropyperazine-3-yl)2-methylpiperazine-1-yl)pyrazine-2-yl)6-(1-methyl-1H-pyrazol-4yl)nicotinamide 129 (R)-N-(2-(4-(5-fluoropyrizine)2mi-methyl il)-6-(1-methyl-1H-pyrazol-4yl)nicotinamide, Petition 870260070497, dated 07 / 16 / 2026, p. 42 / 214 / 205 Ex. no Structure Name 130 0^ (S)-6-(3-(fluorometil)azetidin-1yl)-N-(2-(4-(5-fluoropiridin-2-yl)-2- metilpiperazin-1-yl)pirimidin-5yl)nicotinamida 131 33 33 3^ (R)-6-(3-(fluorometil)azetidin-1yl)-N-(2-(4-(5-fluoropiridin-2-yl)-3(methoxymetil)piperazin-1yl)pirimidin-5-yl)nicotinamida 132 : r ~33 3n (S)-6-(3-(fluorometil)azetidin-1yl)-N-(5-(4-(5-fluoropirimidin-2yl)-3-metilpiperazin-1-yl)pyrazin-2yl)nicotinamida 133 313· ^3 -33-v 33 0 \ (S)-6-(3-(fluoromethyl)azetidin-1yl)-N-(5-(4-(5-fluoropyridin-2-yl)-3methylpiperazin-1-yl)pyrazin-2yl)nicotinamide 134 y_ Γ 3733? (S)-6-(5,6-dihydro-4H-pyrrol[1,2b]pyrazol-3-yl)-2-fluoro-N-(2-(2methyl-4-(pyrimidin-2-yl)piperazin-1yl)pyrimidin-5-yl)nicotinamide 135 \ 3-- VV - (S)-6'-amino-6-fluoro-N-(2-(2methyl-4-(pyrimidin-2-yl)piperazin-1yl)pyrimidin-5-yl)-[2,3'-bipyridine]5-carboxamide 136 c / Φ (S)-6-(5,6-dihydro-4H-pyrrol[1,2b]pyrazol-3-yl)-2-fluoro-N-(2-(4-(5fluoropyrazin-2-yl)-2methylpiperazin-1-yl)pyrimidin-5yl)nicotinamide 137 V^\ 23 (S)-6-(5,6-dihydro-4H-pyrrol[1,2b]pyrazol-3-yl)-2-fluoro-N-(2-(4-(6fluo ropmmidin-4-yl)-2methylpiperazine-1-yl)pyrimidine-5yl)nicotinamide 138 CK —— (R)-6-(5,6-dihydro-4H-pyrrol[1,2b]pyrazol-3-yl)-2-fluoro-N-(2-(3(methoxymethyl)-4-(pyrimidine-2yl)piperazine- 1-yl)pyrimidine-5yl)nicotinamide ~ 139 nr3 (S)-6-(3-fluoroazetidin-1-yl)-N-(6(4-(6-fluoropyrimidine-4-yl)-2methylpiperazine-1-yl)pyridin-3-yl)nicotinamide, Petition 870260070497, dated 07 / 16 / 2026, p. 43 / 214 / 205 Former. no Structure Name 140 çx () TT (S)-6-(3,3-difluoroazetidine-1-yl)-N(5-(4-(6-fluoropyridin-2-yl)-2methylpiperazine-1-yl)pyrazine-2yl)nicotinamide 141 oKHÍrv y- x7 —y (S)-N-(5-(4-(5-fluoropyradine-2-yl)2-methylpiperazine-1-yl)pyrazine-2-yl)6-(1-methyl-1H-pyrazol-4-yl)nicotinamide 142 .......o '0 (S)-6-(3,3-difluoroazetidine-1-yl)-N(5-(4-(5-fluoropyridin-2-yl)-2methylpiperazine-1-yl)pyrazine-2yl)nicotinamide 143 (S)-N-(5-(4-(5-fluoropyrimidine-2yl)-2-methylpiperazine-1-yl)pyrazine-2yl)-6-(1-methyl-1H-pyrazol-4yl)nicotinamide 144 C 2…… (S)-6-(1-(2-fluoroethyl)-1H-pyrazol4-yl)-N-(5-(4-(5-fluoropyrimidine-2yl)-2-methylpiperazine-1-yl)pyrazine-2yl)nicotinamide or a pharmaceutically acceptable salt both.

[0033] The present invention is directed to a compound of Formula I for use as use as a contrast agent.

[0034] One embodiment of the invention comprises a compound selected from Ex. Nos. 1, 6, 9, 11, 12, 37, 39, 47, 51, 57, 58, 64, 72, 75, 78, 79, 80, 91, 96, 112, 113, 115, 116, 118, 134, 138 and 141, or a pharmaceutically acceptable salt thereof. A further embodiment of the invention comprises a compound selected from Ex. Nos. 39, 47, 51, 78, 79, 96, 112, 116 and 141, or a pharmaceutically acceptable salt thereof. Another embodiment of the invention comprises a compound selected from Ex. Nos. 96, 112, 113, 115, 116, 118, 134, 138 and 141, or a pharmaceutically acceptable salt thereof. A further embodiment of the invention comprises a compound selected from Ex. Nos. 96, 112, 116 and 141, or a pharmaceutically acceptable salt thereof.

[0035] Another aspect of the invention is directed to compounds of Formula I, or a pharmaceutically acceptable salt thereof, which are labeled with an isotope selected from 2H, 3H, 11C, 13C, 14C, 13N, 15N, Petition 870260070497, dated 07 / 16 / 2026, page 44 / 214 / 20515O,17O,18O,18F,35S,36CL,82Br,76Br,77Br,123I,124I or131I. In a further aspect of the invention, the compounds of Formula I are isotopically labeled with 3H, 11C or 18F. Examples of an isotopically labeled compound of Formula I, or pharmaceutically acceptable salts thereof, include, among others, 3H-1, 3H-24, 18F-39, 18F-47, 18F-51, 18F-78, 18F-79, 11C94, 18F-96, 11C-97, 18F-116, 11C-117, 11C-118, 18F-141, 11C-143 and the like. Additional examples of an isotopically labeled compound of Formula I, or pharmaceutically acceptable salts thereof, include, among others, 3H-1, 3H-24, 18F-39, 18F-47, 18F-51, 18F-78, 18F-79, 18F-96, 18F-116, 18F-141 and the like. Additional examples of an isotopically labeled compound of Formula I, or pharmaceutically acceptable salts thereof, include, among others, 11C-118, 11C-143 and the like.Additional examples of an isotopically labeled compound of Formula I, or pharmaceutically acceptable salts thereof, include, among others, 18F-96, 18F-116, 18F-141 and the like. Additional examples of an isotopically labeled compound of Formula I, or pharmaceutically acceptable salts thereof, include, among others, 18F78, 18F-79, 18F-96, 18F-116, 18F-141 and the like. Additional examples of an isotopically labeled compound of Formula I, or pharmaceutically acceptable salts thereof, include, among others, 18F-96, 18F-116, 18F-141 and the like.

[0036] Another aspect of the invention is directed to compounds of Formula I, or a pharmaceutically acceptable salt thereof, which are labeled with an isotope selected from among 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 76Br, 77Br, 123I, 124I or 131I, for use as a contrast agent.

[0037] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, for example, a compound of Formula I and at least one pharmaceutical excipient. Petition 870260070497, dated 07 / 16 / 2026, p. 45 / 214 / 205

[0038] Formula I compounds are inhibitors and / or binders of alpha-synuclein or aggregated tau protein. Formula I compounds, and isotopically labeled variants thereof, may be useful for the diagnosis and / or treatment of Parkinson's disease and / or Alzheimer's disease. Means for detecting markers are well known to those skilled in the art. For example, isotopic markers can be detected by imaging techniques, photographic film, or scintillation counters. In a preferred embodiment, the marker is detected in vivo in the individual's brain by imaging techniques, for example, positron emission tomography (PET).

[0039] Compounds of Formula (I) can also form a component of bifunctional compounds that are target protein degrading compounds that bind to aggregated alpha-synuclein proteins. Such alpha-synuclein-targeted protein degrading compounds contain a target protein-binding moiety, formed by a compound of Formula (I), and a ubiquitin ligase E3-binding moiety. Alpha-synuclein-targeted protein degrading compounds typically contain a linker group that joins the alpha-synuclein protein-binding moiety and the ubiquitin ligase E3-binding moiety. The ubiquitin ligase 3-binding moieties in the targeted protein degrading compounds may be, among others, binders for von HippelLindau E3 ligase protein, binders for cereblon E3 ligase protein, or binders for MDM2 protein.These compounds can be administered in pharmaceutical compositions to treat disease conditions, including, but not limited to, the conditions described herein.

[0040] In the following description, conventional structural representation is employed and conventional stereochemical notation is included for certain asymmetric carbon centers. Thus, the structural representation of compounds of the invention includes conventional stereochemical notation for Petition 870260070497, dated 07 / 16 / 2026, page 46 / 214 / 205, some asymmetric carbon centers shown in the example compounds. Thus, in such cases, solid black “wedge” bonds represent bonds projecting from the plane of the representation medium, hatched “wedge” bonds represent bonds descending into the plane of the representation medium, and a “wavy” line attached to a carbon carrying a double bond indicating both possible cis and trans orientations is included. As is conventional, simple solid lines represent all spatial configurations for the represented bond. Thus, when no stereochemical notation is provided, the representation encompasses all stereochemical and spatial orientations of the structural features.

[0041] As shown in the examples of the invention, and mentioned above, certain asymmetric carbon centers are structurally represented using the representation for “solid wedge” and “hatched wedge” bonds. For the most part, the absolute configuration has not been determined for the example compounds, but has been assigned by analogy to specific example compounds of known stereochemical configurations (determined by X-ray crystallography), prepared using identical or analogous reaction conditions and starting reagents and isolated under the same chromatographic conditions.Thus, the specific designation of the structural configurations represented here is intended to identify the specific compounds prepared in which a particular stereoisomer is present in excess and is not necessarily presented here as a statement of the absolute determination of the stereochemical structure of said compound, unless otherwise noted in the data presented.

[0042] It will be recognized that, when isomeric mixtures are obtained, the preparation of the individual stereoisomers in significant percentages of enantiomeric excess can be carried out, if desired, by separation of the Petition 870260070497, dated 07 / 16 / 2026, page 47 / 214 / 205 mixture using customary methods, for example, by chromatography or crystallization, or by using starting materials with stereochemical uniformity for the described synthesis or by stereoselective synthesis. Optionally, a derivatization can be performed before a separation of stereoisomers. The separation of a mixture of stereoisomers can be performed in an intermediate step during the synthesis of a compound of Formula I or can be carried out in a final racemic product.

[0043] When indicated herein, absolute stereochemistry is determined by X-ray crystallography of crystalline products or crystalline intermediates obtained by derivatization, if necessary, with a reagent containing a stereogenic center of known configuration. Unless a particular isomer, salt, solvate (including hydrates) or solvated salt of such racemate, enantiomer or diastereoisomer is indicated, the present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereoisomers and mixtures thereof.

[0044] When a wavy line terminates a conventional bond (as opposed to connecting two atoms within a structure), it indicates a point of attachment to a structure, for example: This indicates that the secondary butyl portion is linked, via the methyl group, through the bond ending with the wavy line. When an alphabetical notation is used to represent a substituent portion, a dash is employed to indicate the point of attachment to the indicated substrate, for example: -CH2-C(O)-CH2Cl indicates that the acetyl chloride portion is linked via the methylated portion of the substitution. Petition 870260070497, dated 07 / 16 / 2026, p. 48 / 214 / 205

[0045] When compounds of Formula I are capable of tautomerization, all individual tautomers as well as mixtures thereof are included within the scope of this invention.

[0046] When any variable (e.g., R, R1, n, heteroaryl, alkyl, etc.) occurs more than once in any constituent or in Formula I, its definition at each occurrence is independent of its definition at each other occurrence, unless otherwise specified at the point of definition. Any person skilled in the art will recognize that the choice of combinations of the various substituents defined in a structural representation, i.e., R1, R2, etc., must be chosen in accordance with the well-known principles of connectivity and stability of chemical structures, and combinations of substituents and / or variables are permitted only if such combinations result in stable compounds.

[0047] A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain, or can be made to remain, essentially unchanged for a period of time sufficient to permit the use of the compound for the purposes described herein (e.g., therapeutic administration to an individual). The compounds of the present invention are limited to stable compounds covered by Formula I.

[0048] When any variable or portion is expressed in the form of a range, for example, (-CH2-)i-4, both extremes of the specified range are included (i.e., 1 and 4 in the example), as well as all intermediate integer values ​​(i.e., 2 and 3 in the example).

[0049] It is understood that the reference to “Formula I” also includes compounds of Formula IA, Formula IB and Formula IC, unless otherwise indicated.

[0050] In this descriptive report, “alkyl” is intended to include straight, branched-chain saturated aliphatic hydrocarbon groups with the specified number of carbon atoms. Petition 870260070497, dated 07 / 16 / 2026, page 49 / 214 / 205

[0051] “Halogen” or “halo”, in this descriptive report, means fluorine, chlorine, bromine and iodine.

[0052] In this descriptive report, “cycloalkyl” is intended to include cyclic saturated aliphatic hydrocarbon groups with the specified number of carbon atoms. Preferably, the cycloalkyl is C3-C10 cycloalkyl. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0053] In this descriptive report, “aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenantryl, anthryl, or acenaphthyl. In one embodiment of the present invention, the aryl is phenyl or naphthyl. In a further embodiment, aryl is phenyl.

[0054] The term heterocycline, heterocycle, or heterocyclic, in this descriptive report, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring that is saturated or unsaturated and consists of carbon atoms and one to four heteroatoms selected from the group consisting of N, O, and S, and includes any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. The heterocyclic ring may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. The term heterocycline, heterocycle, or heterocyclic may include heteroaryl moieties when two rings are fused together. Examples of heterocyclic elements include, among others, azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, benzodioxolyl, cromanyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydro-pyrrolo[1,2-b]pyrazolyl, 1,3dioxolanyl, imidazolidinyl, indolinyl, isocromanyl, isoindolinyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptanyl, 2-oxopiperazinyl, 2. Petition 870260070497, de 16 / 07 / 2026, pág. 50 / 214 / 205 oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyrazolidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and thiamorpholinyl.

[0055] In one embodiment, the heterocycline is selected from azabicyclo[2.2.1]heptanile, azepanil, azetidinil, dihydropyrrole[1,2b]pyrazolyl, morpholinil, oxa-5-azabicyclo[2.2.1]heptanile, piperidyl, piperazinil, pyrazolidinil, pyrrolidinil, pyrrolyl and tetrahydrofuryl. In another embodiment, the heterocycline is selected from azabicyclo[2.2.1]heptanile, azepanil, azetidinil, dihydropyrrole[1,2b]pyrazolyl, oxa-5-azabicyclo[2.2.1]heptanile, piperazinil and pyrrolidinil.

[0056] “Heteroaryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, in which at least one ring is aromatic and in which one to four carbon atoms are substituted by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, among others, azepinyl, furanyl, furyl, imidazolyl, indolinyl, indolyl, isocromanyl, isoindolinyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, 5Hpyrrol[2,3-b]pyrazinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, thienofuryl, thienothienyl, thienyl, triazolyl and the like.In one embodiment, the heteroaryl is selected from furyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, 5H-pyrrol[2,3-b]pyrazinyl, tetrazolyl, thiazolyl, thienyl, triazolyl and the like.

[0057] For use in medicine, the salts of the compounds of Formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is Petition 870260070497, dated 07 / 16 / 2026, page 51 / 214 / 205 acid, the appropriate “pharmaceutically acceptable salts” refer to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and similar salts. Ammonium, calcium, magnesium, potassium and sodium salts are especially preferred.Pharmaceutically acceptable salts derived from non-toxic organic bases include salts of primary, secondary, and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, methylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0058] When the compound of the present invention is basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, tartaric, ptoluenesulfonic and the like acids. Citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids are especially preferred.

[0059] The preparation of the pharmaceutically acceptable salts described above and of other typical pharmaceutically acceptable salts is described more fully by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19. Petition 870260070497, dated 07 / 16 / 2026, page 52 / 214 / 205

[0060] If the compounds of Formula I contain both acidic and basic groups in the molecule, the invention also includes zwitterions, in addition to the salt forms described above.

[0061] The present invention also encompasses isotopically labeled compounds of the present invention that are structurally identical to those mentioned herein, except that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope generally found in nature, thus altering the natural abundance of that isotope present in a compound of the invention. Another aspect of the invention relates to the use of isotopically labeled compounds as radiotracers in neuroimaging examinations for in vivo visualization of alpha-synuclein aggregates in the brain, in the diagnosis, monitoring and / or treatment of Parkinson's disease (PD). Another aspect of the invention is the use of isotopically labeled compounds in PET, which is an in vivo analytical technique in the diagnosis, monitoring and / or treatment of PD.Compounds labeled with 3H, 11C, or 18F can be used in in vitro and in vivo methods for determining binding, receptor occupancy, and in metabolic studies, including covalent labeling.

[0062] Another aspect of the invention relates to the use of isotopically labeled compounds to screen for new chemical matter. In particular, several isotopically labeled compounds find utility in magnetic resonance imaging, autoradiography, and other similar analytical tools. The present invention aims to include all suitable isotopic variations of the compounds of Formula I. Examples of isotopes that may preferably be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, Petition 870260070497, dated 16 / 07 / 2026, p. 53 / 214 / 205 fluorine and chlorine, for example, among others: isotopically labeled compounds of Formula I that are substituted heterocyclic derivatives with 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 76Br, 77Br, 1231, 1241, 125I or 131I. It will be recognized that other isotopes may be incorporated by known means as well. In particular, the present invention is directed to isotopes of 11C, 13C, 14C, 18F, 15O, 13N, 35S, 2H and 3H of compounds of Formula I, compositions and methods of their preparation and use as radiotracers or PET tracers to diagnose and measure the effects of a compound in the treatment of PD. In a further embodiment, the present invention is directed to compounds of Formula I that are isotopically labeled with 3H, 11C or 18F, together with compositions and methods of their preparation and use as PET tracers to diagnose and measure the effects of a compound in the treatment of PD.The present invention also relates to non-toxic compounds that bind to the alpha-synuclein protein and that can rapidly cross the blood-brain barrier, exhibit low non-specific binding properties, and are rapidly cleared from the system. This and other aspects of the invention will become apparent upon review of the descriptive report in its entirety.

[0063] Isotopically enriched compounds within Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein, using isotopically enriched reagents and / or intermediates.

[0064] As indicated herein, the present invention includes isotopically labeled compounds of the invention. An “isotopically labeled”, “radiolabeled”, “tracer”, “radiotracer”, “labeled tracer” or “radioligand” compound is a compound in which one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., of Petition 870260070497, dated 07 / 16 / 2026, page 54 / 214 / 205 (natural occurrence). Suitable radionuclides (i.e., “detectable isotopes”) that can be incorporated into compounds of the present invention include, among others, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 76Br, 77Br, 123I, 124I and 131I. The isotopically labeled compounds of the invention need only be enriched with a detectable isotope to or above the degree that permits detection with a technique suitable for the particular application. The radionuclide that is incorporated into the present radiolabeled compounds will depend on the specific application of that radiolabeled compound. In another embodiment of the invention, the radionuclides are represented by 11C, 13C, 14C, 18F, 15O, 13N, 35S, 2H and 3H, preferably 11C, 3H and 18F.

[0065] The isotopically labeled compounds of this invention are prepared by incorporating a selected isotope into the substrate molecule. This is accomplished using reagents in which one or more of the contained atoms have become radioactive upon being placed in a source of radioactivity, such as a nuclear reactor, a cyclotron, and the like. Furthermore, many isotopically labeled reagents, such as 2H2O, 3H3Cl, 14C6H5Br, ClCH214COCl, and the like, are commercially available. The isotopically labeled reagents are then used in standard synthetic organic chemistry techniques to incorporate the atom, or atoms, of the isotope into a compound of Formula I as described below. The following Schemes illustrate how to prepare the compounds of Formula I.

[0066] This invention further relates to a pharmaceutical composition comprising an effective amount of at least one compound of Formula I and a pharmaceutically acceptable carrier. The composition may comprise, among others, one or more buffering agents, wetting agents, emulsifiers, suspending agents, lubricants, adsorbents, surfactants, preservatives and the like. The composition may be formulated as a solid, liquid, gel or suspension. Petition 870260070497, dated 07 / 16 / 2026, pp. 55 / 214 / 205 for oral administration (e.g., nutrient solution (drench), bolus, tablet, powder, capsule, oral spray, emulsion); parenteral administration (e.g., subcutaneous, intramuscular, intravenous, epidural injection); topical application (e.g., cream, ointment, controlled-release patch, spray); intravaginal, intrarectal, transdermal, ocular, or nasal administration. In a further embodiment, the pharmaceutical composition of the present invention may be formulated for parenteral administration, such as an intravenous formulation.

[0067] This invention provides radiolabeled compounds of Formula I, as alpha-synuclein contrast agents, synthetic precursor compounds from which the agents are prepared. The compounds of Formula I bind to aggregated alpha-synuclein to potentially track the progression of age-related diseases such as PD, as well as other synucleinopathies and neurodegenerative diseases such as multiple system atrophy (MSA), dementia with Lewy bodies (DLB), etc. The compounds of this invention can also be used in combination with a wide range of agents for cognitive enhancement.Thus, in another embodiment of this invention, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of Formula (I) is administered concomitantly, simultaneously, sequentially or separately from another pharmaceutically active compound or compounds used in therapies for AD / PD, including, for example, donepezil, memantine, tacrine, carvidopa, levodopa, MOA-B inhibitors, catechol O-methyltransferase (COMT) inhibitors, etc., and pharmaceutically active equivalents and isomer(s) and metabolite(s) thereof.

[0068] An object of the present invention is to provide a radiopharmaceutical agent, as an isotopically labeled compound of Formula I, which is useful for visualizing alpha-synuclein imaging and has high Petition 870260070497, dated 07 / 16 / 2026, page 56 / 214 / 205 specific radioactivity and high selectivity for the target tissue due to its high affinity for alpha-synuclein aggregates.

[0069] According to the present invention, a method for visualizing the image of alpha-synuclein deposits in a patient, wherein an isotopically labeled compound of Formula I is employed as the contrast agent, comprises the steps of: a) placing a human patient in a supine position in a PET camera; b) intravenously administering around 0.1 to around 10 mCi of an isotopically labeled compound of Formula I to the patient; and c) performing an emission scan of the brain region of the patient's head to identify alpha-synuclein aggregations in the patient's brain tissue. The technique for performing an emission scan of the head is well known to those skilled in the art. PET techniques are described in Freeman et al., Freeman and Johnson's Clinical Radionuclide Imaging, 3rd ed. Vol. 1 (1984); Grune & Stratton, New York; Ennis et Q. Vascular Radionuclide Imaging: A Clinical Atlas, John Wiley & Sons, New York (1983).

[0070] The term “labeled tracer” refers to any molecule that can be used to track or detect a defined activity in vivo, for example, a preferred tracer is one that accumulates in regions where alpha-synuclein aggregates can be found. Preferably, the labeled tracer is one that can be visualized in a live experimental animal, healthy human or patient (referred to as an individual), for example, by positron emission tomography (PET) scanning. Suitable markers include, among others, radioisotopes, fluorochromes, chemiluminescent compounds, dyes and proteins, including enzymes.

[0071] The present invention also provides methods for determining the in vivo activity of an enzyme or other molecule. In one embodiment, an isotopically labeled compound of Formula I is used as a tracer. Petition 870260070497, dated 07 / 16 / 2026, pp. 57 / 214 / 205 to track the binding activity of an aggregated alpha-synuclein protein in the brain and central nervous system.

[0072] Biomarkers of Parkinson's disease status, prognosis, and progression will all be useful for general diagnostic services as well as for clinical development plans for therapeutic agents for Parkinson's disease. The compounds of Formula I can be used to provide biomarker information for patients in clinical trials of novel symptomatic and disease-modifying treatments for Parkinson's disease and to aid in selection and assignment to patient cohorts. The present invention will serve as one of the disease status biomarkers, aiming to obtain the correct patients for the appropriate cohort of Phase IIb trials. Furthermore, the present invention can serve as a disease prognostic marker as an inclusion criterion for admission, in order to improve the likelihood that the disease will progress in the placebo treatment arm, an issue that continues to plague clinical trials for Parkinson's disease.Finally, the present invention can serve as a disease progression biomarker to monitor the clinical evolution of patients undergoing therapy and could provide a biomarker-independent measure of treatment response by a therapeutic drug. The tracer can be selected according to the chosen detection method. Before conducting the method of the present invention, a diagnostically effective amount of a labeled or unlabeled compound of the invention is administered to a living being, including a human.

[0073] The present invention also provides a method for measuring the clinical efficacy of therapeutic agents useful for the treatment of Parkinson's disease (PD), comprising the steps of a) administering an isotopically labeled compound of Formula I to a patient diagnosed with PD prior to treatment with said therapeutic agent, b) measuring the degree of alpha-synuclein aggregate formation in the patient's brain tissue, c) Petition 870260070497, dated 07 / 16 / 2026, page 58 / 214 / 205 administer an isotopically labeled compound of Formula I to the patient after treatment with said therapeutic agent, d) measure the degree of alpha-synuclein aggregate formation in the patient's brain tissue after treatment, and ee) analyze whether said therapeutic agent interrupted or reduced the progression of alpha-synuclein aggregate formation in the patient's brain tissue.

[0074] The diagnostically effective amount of the labeled or unlabeled compound of the invention, to be administered before conducting the in vivo method for the present invention, is in a range of 0.1 ng to 100 mg per kg of body weight, preferably in a range of 1 ng to 10 mg per kg of body weight.

[0075] The compounds of the present invention are useful in the diagnosis, monitoring and measurement of Parkinson's disease and other non-PD synucleinopathies such as multiple system atrophy (MSA), dementia with Lewy bodies (DLB).

[0076] In preferred embodiments, the compounds of the invention are useful in diagnosing, monitoring or measuring Parkinson's disease, synucleinopathies other than PD, neurodegenerative disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders.

[0077] The term “composition,” in this descriptive report, is intended to encompass a product comprising specified ingredients in predetermined quantities or proportions, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified quantities. In relation to pharmaceutical compositions, this term is intended to encompass a product comprising one or more active ingredients and an optional vehicle comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, complexation, or aggregation of any two or more of the... Petition 870260070497, dated 07 / 16 / 2026, page 59 / 214 / 205 ingredients, or the dissociation of one or more of the ingredients or other types of reactions or interactions of one or more of the ingredients.

[0078] In general, pharmaceutical compositions are prepared by bringing the active ingredient to uniform and intimate association with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active compound, which is a compound of Formula I, is included in a sufficient amount to produce the desired effect on the disease process or condition. Thus, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention and a pharmaceutically acceptable vehicle.

[0079] In this descriptive report, the term “patients” (alternatively, “individuals”) refers to an animal, preferably a mammal and, in particular, a human who requires evaluation by means of an imaging study. In this descriptive report, the term “administration” and variants thereof (e.g., “administering” a compound), in reference to a compound of Formula I, means providing the compound, or a pharmaceutically acceptable salt thereof, to an individual in need of treatment.

[0080] The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the invention.

[0081] The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and further exemplified by the following specific examples. Deuterated versions of the compounds of the invention can be prepared by replacing an isotopically unlabeled reagent with an appropriate isotopically labeled reagent. The compounds illustrated in Petition 870260070497, dated 16 / 07 / 2026, page 60 / 214 / 205. The examples, however, should be interpreted as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the preparatory procedures below can be used to prepare these compounds. The reagents and starting materials for preparing the intermediates and compounds of examples are commercially available unless otherwise indicated. All temperatures are in degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ionization mass spectrometry (ESI). Ή NMR spectra were recorded at 300-500 MHz. List of abbreviations

[0082] DA = Alzheimer's disease

[0083] (ipcADI)NiBr2 = N,N'-bis(lR,2R,3R,5S)-(-)- bromide isopinocampheyl-2,3-butanediimine nickel (II)

[0084] Anal. = analytical

[0085] calc. = calculated

[0086] BSA = bovine serum albumin

[0087] Cellulose SC = immobilized stationary phase of polysaccharides [cellulose tris(3,5-dichlorophenylcarbamate) selector]

[0088] CPME = cyclopentyl methyl ether

[0089] Crabtree catalyst = (1,5- hexafluorophosphate) cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(i)

[0090] CS2CO3 = cesium carbonate

[0091] CsF = cesium fluoride

[0092] DAST = diethylaminosulfur trifluoride

[0093] DCM = dichloromethane

[0094] DEA = diethylamine Petition 870260070497, dated 07 / 16 / 2026, page 61 / 214 / 205

[0095] DIPEA = A^V-diisopropylethylamine

[0096] DMF = dimethylformamide

[0097] DMSO = dimethyl sulfoxide

[0098] DMA = dimethylacetamide

[0099] DPBS = Dulbecco's phosphate-buffered saline solution

[00100] EDTA = ethylenediaminetetraacetic acid

[00101] EtOAc = ethyl acetate

[00102] EtOH = ethanol

[00103] h = hour(s)

[00104] HATU = 3-oxide of (1- hexafluorophosphate) [bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium

[00105] HPLC = high-performance liquid chromatography

[00106] IHC = immunohistochemistry

[00107] IPA = alpha-propyl alcohol

[00108] IP Ac = alpha-propyl acetate

[00109] K2CO3 = potassium carbonate

[00110] K3PO4 = tribasic potassium phosphate

[00111] LCMS = liquid chromatography coupled to spectrometry masses

[00112] mCi = millicurie

[00113] MeCN = acetonitrile

[00114] MeOH = methyl alcohol

[00115] MgSOd = magnesium sulfate

[00116] MS = mass spectrometry

[00117] NaHBEts = sodium triethylborohydride

[00118] NaHCCfi = sodium bicarbonate

[00119] NaiSCfi = sodium sulfate

[00120] NH4Cl = ammonium chloride

[00121] NH4OH = ammonium hydroxide Petition 870260070497, dated 07 / 16 / 2026, page 62 / 214 / 205

[00122] NMP = N-methylpyrrolidone

[00123] NMR = nuclear magnetic resonance spectroscopy

[00124] DP = Parkinson's disease

[00125] Pd / C = palladium in carbon 10% by weight

[00126] PdCh (dppf) = l,l'-Bis(diphenylphosphine)ferrocene] dichloropalladium (II)

[00127] PE or Pet ether = petroleum ether

[00128] PEI = polyethyleneimine

[00129] RuPhos Pd G2 = 2nd generation RuPhos precatalyst, Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[00130] rt = ambient temperature

[00131] SNAr = aromatic nucleophilic substitution reaction

[00132] TFA = trifluoroacetic acid

[00133] TLC = thin layer chromatography

[00134] tR = retention time

[00135] THF = tetrahydrofuran

[00136] % by weight = percentage by weight

[00137] XPhos Palladacycle-G2 = 2nd generation XPhos precatalyst, Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino1,1'-biphenyl)]palladium(II)

[00138] The compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures. In some cases, the final product may be further modified, for example, by manipulation of the substituents. These manipulations may include, among others, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are commonly known to those skilled in the art. In some cases, the order in which the preceding reaction schemes were carried out may be varied to facilitate the reaction or to Petition 870260070497, dated 07 / 16 / 2026, page 63 / 214 / 205 to avoid unwanted reaction products. The following schemes and examples are provided so that the invention may be more fully understood. These examples are for illustrative purposes only and should not be construed as limitations to the invention in any way. 1. Lack of protection SNAr or Pd CN Coupling Generic Scheme A SNAr or Pd CN Coupling

[00139] Substituted piperazines (A-1) can be transformed into aryl piperazines A-2 via CN coupling reactions mediated by SNAr or Pd. Deprotection followed by CN couplings mediated by SNAr or Pd with aryl halides yields the A-3 intermediates. If Y is nitro in A-3, reductions (such as hydrogenation) can yield aniline intermediates A-4 and subsequent amide couplings yield the A-5 target molecules. Pd, then unprotected Amide coupling

[00140] Alternatively, if Y is bromide (or Cl), A6 intermediates may result from Pd-mediated CN coupling with Boc-amine and subsequent amide couplings provide the A-7 target molecules. Generic Scheme B Petition 870260070497, dated 07 / 16 / 2026, page 64 / 214 / 205 SNAr or Pd CN Coupling 2. Lack of protection SNAr or Pd CN Coupling Reduction Amide coupling

[00141] Substituted piperazines (B-1) can be transformed into aryl piperazines B-2 via CN coupling reactions mediated by SNAr or Pd, followed by deprotection. B-2 can undergo CN couplings mediated by SNAr or Pd with aryl halides, yielding the intermediates B-3. B-3 can be involved in reduction reactions to yield the aniline intermediates B-4, and subsequent amide couplings yield the target molecules B-5. Generic Scheme C SNAr C-1Ra OX=XR X=X —(x / )— N Ar—NN—(\ / )—NH X-NRx—Xx-x C-2

[00142] C-1 intermediates can be involved in SNAR reactions with amines or NH-containing heterocycles to provide the C2 target compounds. Generic Scheme D

[00143] D-1 intermediates can be involved in Pd-mediated CC coupling reactions to provide D-2 target compounds. Petition 870260070497, dated 07 / 16 / 2026, pages 65 / 214 / 205 Generic Scheme E 1. Lack of protection SNAr or Pd CN Coupling 2. Ar-[F / Cl / Br] SNAr or Pd Coupling CN

[00144] Substituted piperazines (E-1) can be transformed into aryl piperazines E-2 via CN coupling reactions mediated by SNAr or Pd. Deprotection followed by SNAr or Pd-mediated CN couplings with aryl halides provides the intermediates E-3. The halide E-3 can undergo Pd-mediated CN coupling with pre-formed primary amides to provide the target molecules E-4. Intermediate Preparation Synthesis of Intermediate A: (S)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-amine Synthesis of 1-2: (S)-tert-butyl (3-methyl-4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate

[00145] To a solution of (S)-tert-butyl 3-methylpiperazine-1-carboxylate (1-1, 13.6 g, 67.9 mmol) in DMF (150 mL), K2CO3 (14.08 g, 102 mmol) and 2-chloro-5-nitropyrimidine (12.46 g, 78 mmol) were added. The mixture was stirred for 12 hours at 25°C under a N2 balloon. TLC showed that the starting material was completely consumed. Water (450 mL) was added and the mixture was stirred at 25°C (rt) for 30 minutes. The precipitated solid Petition 870260070497, dated 07 / 16 / 2026, p. 66 / 214 / 205 was collected by filtration, washed with water (100 mL x 3) and dried to provide 1-2 as a solid. 1H NMR (500 MHz, Chloroform-d): δ = 9.07 (s, 2H), 5.06 (br s, 1H), 4.67 (br s, 1H), 3.91~4.29 (m, 2H), 3.28~3.36 (m, 1H), 3.13 (br s, 1H), 2.83~3.01 (m, 1H), 1.45~1.52 (m, 9H), 1.26 (d, J = 6.5 Hz, 3H) Synthesis of 1-3: (S)-2-(2-methylpiperazin-1-yl)-5-nitropyrimidine

[00146] To a solution of 1-2 (21 g, 64.9 mmol) in DCM (160 mL), TFA (40 mL) was added at 0°C. The mixture was stirred for 2 hours at 25°C. TLC showed that most of the starting material was completely consumed. The mixture was concentrated under reduced pressure to give the crude product (S)-2-(2-methylpiperazin-1-yl)-5-nitropyrimidine (25 g, 78 mmol) as an oil. The product was diluted with DCM (200 mL) and H2O (160 mL). Then, NivCC) was added to the solution to adjust the pH to 7-8. The solution was extracted with DCM (200 mL*2). The organic layer was dried with Na2SO4, filtered, and concentrated to give 1-3 as a solid. 1H NMR (400 MHz, DMSO-d6): δ = 9.44 (s, 1H), 8.92~9.10 (m, 1H), 5.13~5.24 (m, 1H), 4.82 (d, J = 14.4 Hz, 1H), 3.31~3.49 (m, 3H), 3.26 (d, J = 7.2 Hz, 1H), 3.06 (d, J = 8.8 Hz, 1H), 1.52 (s, 1H), 1.33 (d, J = 7.2 Hz, 3H). MS (ESI) m / z: 224.0 [M+H]+. Synthesis of 1-4: (S)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)-5-nitropyrimidine

[00147] A solution of 1-3 (2.5 g, 11.20 mmol) in dioxane (50 mL), 2-bromopyridine (3.72 g, 23.52 mmol), Cs2CO3 (14.96 g, 45.9 mmol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'amino-1,1'-biphenyl)]palladium(II) (0.968 g, 1.344 mmol). The mixture was stirred for 12 hours at 110°C under a N2 flask. TLC showed that most of the starting material was completely consumed. The mixture was filtered and concentrated. The residue was extracted with EtOAc (3 x 50 mL) and H2O (60 mL). The combined organic extracts were washed with brine (100 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under pressure. Petition 870260070497, dated 07 / 16 / 2026, p. 67 / 214 / 205 reduced. The residue was purified with a silica gel column eluting with 15-30% EtOAc / PE to provide 1-4 as a solid. 1H NMR (400 MHz, Chloroform-d): δ = 9.10 (s, 2H), 8.17~8.24 (m, 1H), 7.47~7.59 (m, 1H), 6.62~6.71 (m, 2H), 5.11 (dt, J = 6.4; 3.2 Hz, 1H), 4.74 (dt, J = 13.6; 3.6 Hz, 1H), 4.24 (d, J = 12.8 Hz, 1H), 4.13 (d, J = 13.2 Hz, 1H), 3.53~3.63 (m, 1H), 3.37 (dd, J = 13.2; 4.0 H, 1H), 3.12 (td, J = 12.0; 3.6 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 301.0 [M+H]+. Synthesis of (S)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-5-amine (Int A)

[00148] To a solution of 1-4 (2.5 g, 8.32 mmol) in MeOH (40 mL), Pd / C (0.2 g, 1.879 mmol) was added. The mixture was stirred for 2 hours at 25°C under a flask of H2. TLC showed that most of the starting material was completely consumed. The mixture was filtered, and the filter cake was washed with MeOH (3 x 200 mL). The combined organic extracts were concentrated under reduced pressure to give Int A as an oil. 1H NMR (400 MHz, Chloroform-d): δ = 8.19 (dd, J = 4.8; 1.2 Hz, 1H), 8.01 (s, 2H), 7.45~7.50 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 6.8; 5.2 Hz, 1H), 4.76~4.85 (m, 1H), 4.32~4.40 (m, 1H), 4.19~4.26 (m, 1H), 4.10 (dt, J = 12.8; 2.0 H, 1H), 3.23~3.41 (m, 2H), 3.15 (s, 2H), 3.01~3.08 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 271.1 [M+H]+. Synthesis of Intermediate B: (R)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-amine

[00149] (R)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-5-amine (Int B) was isolated as an oil by a sequence analogous to the synthesis of Int A. Petition 870260070497, dated 07 / 16 / 2026, page 68 / 214 / 205 1H NMR (400 MHz, DMSO-d6): δ = 8.07 (dd, J = 4.8; 1.3 Hz, 1H), 7.90 (s, 2H), 7.48~7.54 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.59 (dd, J = 6.8; 5.2 Hz, 1H), 4.54~4.72 (m, 3H), 4.12~4.25 (m, 3H), 3.05~3.13 (m, 1H), 2.79~2.91 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 271.0 [M+H]+. Synthesis of Intermediate C: (R)-2-(3-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-amine Synthesis of 3-2: 3-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate of (R)-tert-butyl

[00150] A solution of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (3-1.2 g, 9.99 mmol) in dioxane (40 mL), 2-bromopyridine (3.31 g, 20.97 mmol), Cs2CO3 (13.34 g, 40.9 mmol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.864 g, 1.198 mmol) was prepared. The mixture was stirred for 12 hours at 110°C under a N2 flask. TLC showed that most of the starting material was completely consumed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column eluting with 15% EtOAc / PE to provide the 3-2 as an oil. 1H NMR (400 MHz, Chloroform-d): δ = 8.18 (dd, J = 4.8; 1.3 Hz, 1H), 7.42~7.52 (m, 1H), 6.54~6.64 (m, 2H), 4.46 (br s, 1H), 3.78~4.25 (m, 3H), 2.93~3.23 (m, 3H), 1.48 (s, 9H), 1.12 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 278.1 [M+H]+. Synthesis of 3-3: (R)-2-methyl-1-(pyridin-2-yl)piperazine Petition 870260070497, dated 07 / 16 / 2026, p. 69 / 214 / 205

[00151] To a solution of 3-2 (2 g, 7.21 mmol) in EtOAc (17 mL), EtOAc / HCl (34 mL) was added. The mixture was stirred for 5 hours at 25°C. TLC showed the starting material was completely consumed. The resulting solid was collected by filtration. The cake was washed with EtOAc (5 mL) and dried to give the 3-3 as an oil. 1H NMR (400 MHz, DMSO-d6): δ = 10.07 (br d, J = 7.2 Hz, 1H), 9.72 (br s, 1H), 8.02~ 8.12 (m, 2H), 7.40 (br d, J = 9.2 Hz, 1H), 7.03 (t, J = 6.4 Hz, 1H) Hz, 3H). Synthesis of 3-4: (R)-2-(3-methyl-4-(pyridin-2-yl)piperazin-1-yl)-5-nitropyrimidine

[00152] A solution of 3-3 (1.7 g, 9.59 mmol) in DMF (20 mL), 2-chloro-5-nitropyrimidine (1.836 g, 11.51 mmol) and K2CO3 (5.30 g, 38.4 mmol) was prepared. The mixture was stirred for 2 hours at 80°C under a N2 balloon. TLC showed that most of the starting material was completely consumed. Water (150 mL) was added and the mixture was stirred at 25°C (rt) for 30 minutes. The precipitated solid was collected by filtration, washed with water (100 mL x 3) and dried to give the 3-4 as an oil. 1H NMR (400 MHz, DMSO-d6): δ = 9.15 (d, J = 4.4 Hz, 2H), 8.14 (d, J = 3.6 Hz, 1H), 7.51~7.60 (m, 1H), 6.82 (s, 1H), 6.65 (dd, J = 6.8; 5.2 Hz, 1H), 4.62~4.76 (m, 3H), 4.13~4.24 (m, 1H), 3.53 (d, J = 4.0 H, 1H), 3.33~3.40 (m, 1H), 3.11~3.23 (m, 1H), 1.02 (d, J = 6.4 Hz, 3H). MS (ESI) m / z: 301.1 [M+H]+. Synthesis of (R)-2-(3-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-5-amine (Int C)

[00153] To a solution of 3-4 (1.8 g, 5.99 mmol) in MeOH (30 mL), Pd / C (0.2 g, 1.879 mmol) was added. The mixture was stirred for 2 hours at 25°C under a flask of H2. TLC showed that most of the starting material was completely consumed. The mixture was filtered, and the filtered cake was Petition 870260070497, dated 07 / 16 / 2026, p. 70 / 214 / 205 washed with MeOH (3*200 mL). The combined organic extracts were concentrated under reduced pressure to provide Int C as an oil. 1H NMR (400 MHz, DMSO-d6): δ = 8.12 (dd, J = 4.8; 1.2 Hz, 1H), 7.91 (s, 2H), 7.50~7.55 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 6.8; 5.2 Hz, 1H), 4.54~4.64 (m, 3H), 4.27~4.45 (m, 2H), 4.08 (s, 1H), 2.99~3.10 (m, 2H), 2.83~2.90 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H). MS (ESI) m / z: 271.0 [M+H]+. Synthesis of Intermediate D: (S)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-amine

[00154] (S)-2-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-5-amine was isolated as an oil in a synthetic sequence analogous to that of Int C above. NMR1H (400 MHz, DMSO-d6): δ = 8.09 (dd, J = 4.8; 1.2 Hz, 1H), 7.89 (s, 2H), 7.48~7.52 (m, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.58 (dd, J = 6.8; 5.2 Hz, 1H), 4.51~4.60 (m, 3H), 4.28~4.41 (m, 2H), 3.98~4.11 (m, 1H), 2.99~3.08 (m, 2H), 2.84 (td, J = 12.0; 3.6 Hz, 1H), 1.01 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 271.1 [M+H]+. Synthesis of Intermediate E: (S)-2-(4-(6-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-amine

[00155] (S)-2-(4-(6-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin5-amine was isolated as an oil in a synthetic sequence analogous to that described for Int A. Synthesis of Intermediate F: (S)-6-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyridin-3-amine Petition 870260070497, dated 07 / 16 / 2026, page 71 / 214 / 205 Synthesis of 6-2: 2-methyl-4-(pyridin-2-yl)piperazine-1-carboxylate of (S)-tert-butyl

[00156] A mixture of (S)-1-N-BOC-2-methylpiperazine (15 g, 74.9 mmol), 2-fluoropyridine (36.4 g, 374 mmol) was heated at 135°C for 48 hours. LCMS showed that starting material remained and that a new product had formed. LCMS (ESI) calculated for C15H23N3O2[M+H]+: 278.1; found: 278.2, tR = 0.684 min. The mixture was evaporated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluting with petroleum ether / EtOAc = 4:1 to give 6-2 as a colorless liquid. Synthesis of 6-3: (S)-3-methyl-1-(pyridin-2-yl)piperazine dihydrochloride

[00157] Hydrogen chloride in EtOAc (37.9 ml, 151 mmol) was added to 6-2 (7 g, 25.2 mmol) at room temperature and stirred at 20°C for 18 hours. LCMS (ESI) showed that the starting material was consumed and a new product formed. LCMS (ESI) calculated for C10H15N3-2ClH [M+H]+: 178.1; found: 178.1; tR = 0.170 min. The mixture was evaporated under reduced pressure. Then, EtOAc (25 ml *3) was added to the residue, which was evaporated under reduced pressure to give 6-3 as a solid. Synthesis of 6-4: (S)-2-methyl-1-(5-nitropyridin-2-yl)-4-(pyridin-2-yl)piperazine

[00158] 2-chloro-5-nitropyridin (0.697 g, 4.40 mmol) was added to a stirred mixture of 6-3 (1 g, 4.00 mmol) and K2CO3 (2.210 g, 15.99 mmol) in DMF (12 ml) and the mixture was stirred at 80°C for 15 hours. LCMS (ESI) showed that the starting material was consumed and a new product was formed. Petition 870260070497, dated 07 / 16 / 2026, p. 72 / 214 / 205 formed. LCMS (ESI) calculated for C15H17N5O2 [M+H]+: 300.1; found: 300.1; tR = 0.351 min. After being poured into 30 mL of ice water, the mixture was filtered and the filtered cake was washed with water (15 mL * 3), dried under vacuum and dried to provide 6-4 as a brown solid. Synthesis of (S)-6-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyridin-3-amine (Int F)

[00159] Iron (0.933 g, 16.70 mmol) was added to a stirred mixture of 6-4 (1.0 g, 3.34 mmol), ammonium chloride (1.787 g, 33.4 mmol) in EtOH (20 ml) and water (10 ml) at room temperature and the mixture was stirred at room temperature (Temp.: 40°C) under a N2 atmosphere. LCMS (ESI) showed that starting material was consumed and a new product was formed. LCMS (ESI) calculated for C15H19N5 [M+H]+: 270.1; found: 270.1; tR = 0.128 min. The mixture was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. Water (25 mL) was added, and the mixture was extracted with EtOAc (30 mL* 3). The combined organic fractions were dried (Na2SO4), filtered, the solvent was evaporated under reduced pressure, and they were dissolved in EtOAc (10 mL). 0.5 mL of HCl (4 M EtOAc solution) was added, and the solvent was evaporated under reduced pressure.The residue was purified by preparative HPLC (reversed-phase C-18 column), eluting with acetonitrile / water + 0.1% TFA, to give Int F as a brown solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.31 (d, J=6.26 Hz, 3 H) 3.61-3.76 (m, 2 H) 3.86 (dd, J=13.69; 3.91 Hz, 1 H) 4.01-4.16 (m, 3 H) 4.52 (br d, J=6.65 Hz, 1 H) 7.03 (t, J=6.65 Hz, 1 H) 7.10 (d, J=9.39 Hz, 1 H) 7.40 (d, J=9.39 Hz, 1 H) 7.64 (dd, J=9.39; 3.13 Hz, 1 H) 7.81 (s, 1 H) 7,978.11 (m, 2 LCMS (ESI) calculated for C15H19N5 [M+H]+: 270.1; found: 270.1. Synthesis of Intermediate G: (S)-5-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyridin-2-amine Petition 870260070497, dated 07 / 16 / 2026, pp. 73 / 214 / 205 Synthesis of 7-1: (S)-2-methyl-1-(6-nitropyridin-3-yl)-4-(pyridin-2-yl)piperazine

[00160] 5-fluoro-2-nitropyridine (1.2 g, 8.45 mmol) and 6-3 (2.42 g, 13.65 mmol) in DMA (20 mL) were added to K2CO3 (4.67 g, 33.8 mmol). The mixture was stirred at 100°C for 18 hours. TLC (Petroleum ether: ethyl acetate = 1:1) showed little starting material remaining. LCMS (ESI) calculated for C15H17N5O2[M+H]+: 300.1; found: 300.5; tR = 0.57 min. The mixture was cooled, diluted with ethyl acetate (20 mL) and water (20 mL), the organic layer was washed with aqueous Na2CO3 (saturated, 10 mL), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluting with petroleum ether / ethyl acetate = 1:1 to give 7-1 as a solid. 1H NMR (400 MHz, Chloroform-d) δ 8.36-8.58 (m, 1H) 8.178.28 (m, 2H) 8.12 (d, J = 3.1 Hz, 1H) 7.46-7.72 (m, 1H) 7.18 (dd, J=9.2; 2.9 Hz, 1H) 6.50-6.82 (m, 2H) 4.17-4.38 (m, 2H) 4.04-4.43 (m, 1H) 3.69-3.95 (m, 1H) 3.44-3.62 (m, 2H) 3.27-3.38 (m, 1H) 3.01 (s, 7H) 2.94 (s, 7H) 2.08 (s, 7H) 1.30 (d, J=6.7 Hz, 4H); LCMS (ESI) calculated for C15H17N5O2 [M+H]+: 300.1; found: 300.5. The synthesis of (S)-5-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyridin-2-amine (Int G)

[00161] 7-1 (1.1 g, 3.67 mmol) and Pd-C (300 g, 2819 mmol) in MeOH (20 mL) was treated with H2 (15 psi (0.1 MPa)) and the mixture was stirred at 20°C for 18 hours. TLC (DCM: MeOH = 10:1) showed that no starting material remained. The desired mass was detected, LCMS (ESI) calculated for Ci5Hi9N5[M+H]+: 270.2; found: 269.8; tR = 0.596 min. The solvent was filtered, the filtrate was concentrated, and the residue was purified. Petition 870260070497, dated 07 / 16 / 2026, p. 74 / 214 / 205 by flash chromatography on a silica gel column, eluting with ethyl acetate: EtOH = 10:1 to 20:1 to provide Int G as a solid. 1H NMR (500 MHz, Chloroform-d) δ 8.20 (dd, J = 4.9; 1.1 Hz, 1H) 7.86 (d, J = 2.4 Hz, 1H) 7.48 (ddd, J = 8.6; 7.1; 2.0 H, 1H) 7.26 (dt, J = 5.8; 2.8 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H) 6.58-6.63 (m, 1H) 6.50 (d, J=8.7 Hz, 1H) 4.30 (br s, 2H) 3.92 (m, 1H) 3.73-3.81 (m, 1H) 3.53 (m, 1H) 3.32 (m, 1H) 3.21 (dd, J=12.4; 7.4 Hz, 1H) 3.08-3.14 (m, 1H) 3.00-3.07 (m, 1H) 0.97 (d, J = 6.3 Hz, 3H); LCMS (ESI) calculated for C15H19N5 [M+H]+: 270.2; found: 269.8. Synthesis of Intermediate H: (S)-5-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrazin-2-amine N ,__B BBr^\ Br ' yN NH ___________N____NCsF, DMSO 6-3\N=\HCl-EtOAc p—NN—ά NHBoc NN 8-2 / \ ,N=\ BocNH2y- NN—4 fi— Br ------------->=N —N —N Pd(OAc)2, xantphos8-1' CS2CO3, dioxane / N=\ yN N—ά / )—NH2 NN Int H Synthesis of 8-1: (S)-2-bromo-5-(2-methyl-4-(pyridine-2-yl)piperazine-1-yl)pyrazine

[00162] In a clean, sealed tube, CsF (3.04 g, 19.99 mmol) was added to 2,5-dibromopyrazine (1.046 g, 4.40 mmol) and 6-3 (1 g, 4.00 mmol) in DMSO (10 mL), then the resulting mixture was stirred at 90°C for 18 hours. LCMS (ESI) showed that the starting material was consumed and a new product formed. The mixture was cooled to room temperature, filtered, and the filter cake was washed with DCM (10 mL * 3). The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on a silica gel column, eluting with petroleum ether / EtOAc = 4:1 to give (S)-2-bromo-5-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrazine as a gum. LCMS (ESI) calculated for C14H16BrN5 [M+H]+: 336.0; found: 335.9. Petition 870260070497, dated 07 / 16 / 2026, pp. 75 / 214 / 205 Synthesis of 8-2: (S)-tert-butyl(5-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2yl)carbamate

[00163] (9,9-dimethyl-9H-xanthene-4,5-di-yl)bis(diphenylphosphine) (0.519 g, 0.898 mmol) and diacetoxypalladium (0.101 g, 0.449 mmol) were added to a stirred mixture of 8-1 (1.5 g, 4.49 mmol), tert-butyl carbamate (1.052 g, 8.98 mmol) and cesium carbonate (4.39 g, 13.46 mmol) in dioxane (25 ml) at room temperature under a N2 atmosphere and the mixture was heated with stirring at (Temp.: 70°C) for 18 hours. LCMS (ESI) showed that the starting material was consumed and a new product formed. The residue was filtered, concentrated and purified by flash chromatography on silica gel (ISCORF150; Sepa flash column), eluting with petroleum ether / EtOAc = 3:1 to give 8-2 as a solid. RMN 1H (400 MHz, Clorofórmio-d) δ 8,72 (brs, 1H), 8,108,28 (m, 1H), 7,74 (s, 1H), 7,41-7,55 (m, 1H), 6,99 (brs, 1H), 6,51-6,74 (m, 2H), 4,47 (brdd, J = 3,06; 5,99 Hz, 1H), 4,22 (brd, J = 12,23 Hz, 1H), 4,10 (brdd, J = 1,47; 12,72 Hz, 1H), 3,97 (brdd, J = 2,69; 12,72 Hz, 1H), 3,26-3,42 (m, 2H), 3,05-3,20 (m, 1H), 1,51-1,58 (m, 9H), 1,19 (dd, J = 2,32; 6,48 Hz, 3H); LCMS (ESI) calculado para C18H24N6O2 [M+H]+: 357,2, encontrado: 357,2. Synthesis of (S)-5-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-amine (Int H)

[00164] HCl / EtOAc (0.675 mL, 2.70 mmol) was added to a stirred mixture of 8-2 (1.0 g, 2.70 mmol) in ethyl acetate (5 mL) at room temperature and the mixture was stirred at room temperature (Temp.: 20°C) for 48 hours. LCMS (ESI) showed that the starting material was consumed and a new product formed. After concentration, the residue was adjusted to pH 9 with saturated NebCO3, extracted with EtOAc (20 mL, 3 times), then washed with brine (20 mL), dried with Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel. Petition 870260070497, dated 07 / 16 / 2026, p. 76 / 214 / 205 (ISCORF150; Sepa flash column), eluting with petroleum ether / EtOAc = 1:1 to provide Int H as a solid. 1H NMR (500 MHz, Chloroform-d) δ 8.18-8.22 (m, 1H), 7.72 (d, J = 1.53 Hz, 1H), 7.67 (d, J = 1.22 Hz, 1H), 7.46-7.53 (m, 1H), 6.68 (d, J = 8.54 Hz, 1H), 6.63 (dd, J = 5.19; 7.02 Hz, 1H), 5.47-5.50 (m, 1H), 4.34 (td, J = 3.32; 6.48 Hz, 1H), 4.20 (brdd, J = 1.68; 12.05 Hz, 1H), 3.96-4.07 (m, 3H), 3.76 (td, J = 3.55; 12.13 Hz, 1H), 3.38 (dd, J = 3.81; 12.66 Hz, 1H), 3.27 (dt, J = 3.51; 11.52 Hz, 1H), 3.15-3.21 (m, 1H), 1.15 (d, J = 6.71Hz, 3H); LCMS (ESI) calculated for C14H18N6 [M+H]+: 271.2; found: 271.1. Preparation of Intermediate Compound I: (S)-2-(4-(4-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-amine Synthesis of I-2: (S)-4-(4-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate tert-butyl

[00165] A stirred solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (I-1, 5 g, 24.96 mmol) in toluene (200 mL) (purged with argon gas for 10 minutes), 2-bromo-4-fluoropyridine (4.39 g, 24.96 mmol), sodium tert-butoxide (2.399 g, 24.96 mmol) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (19.39 g, 24.96 mmol) at room temperature. The reaction mixture was purged again with argon for 10 minutes and stirred at 120°C for 12 hours. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried with concentrated Na2SO4e under reduced pressure to obtain the crude product. The crude product was purified using 100-200 mesh silica gel (300 cartridge). Petition 870260070497, dated 07 / 16 / 2026, p. 77 / 214 / 205 g) and eluted with 20% EtOAc / PET ether as a gradient. The pure fractions were concentrated under reduced pressure to give compound I-2 as a yellow liquid. M / Z (ESI): 296.37 [M+H]+. Synthesis of I-3: (S)-1-(4-fluoropyridin-2-yl)-3-methylpiperazine

[00166] To a stirred solution of compound I-2 (5 g, 16.93 mmol) in DCM (80 mL), TFA (6.52 mL, 85 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to give compound I-3 as a clear yellow liquid. M / Z (ESI): 196.23 [M+H]+. Synthesis of I-4: (S)-2-(4-(4-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)-5nitropyrimidine

[00167] To a stirred solution of compound I-3 (3.5 g, 17.93 mmol) in DMF (80 mL), 2-chloro-5-nitropyrimidine (3.43 g, 21.51 mmol) and K2CO3 (9.91 g, 71.7 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with ice-cold water (20 mL) and the resulting solid was filtered, washed with water (2 x 50 mL) and dried under reduced pressure to give compound I-4 as a light yellow solid. M / Z (ESI): 319.20 [M+H]+. Synthesis of Intermediate I: (S)-2-(4-(4-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-amine

[00168] To a solution of compound I-4 (3.5 g, 11 mmol) in EtOH (50 mL), 10% Pd-C (1.170 g, 5.50 mmol) was added at room temperature. The reaction mixture was degassed with nitrogen three times and stirred under pressure from a H2 gas flask for 16 hours at room temperature. The reaction mixture was filtered in a Buckner funnel through a layer of celite, washed with EtOAc (50 mL), and concentrated under reduced pressure to give compound Int I as a yellow liquid. M / Z (ESI): 289.17 [M+H]+. Petition 870260070497, dated 07 / 16 / 2026, p. 78 / 214 / 205 Preparation of the intermediate compound J: 6-(3,3-difluoroazetidin-1-yl)nicotinic acid Synthesis of J-2: methyl 6-(3,3-difluoroazetidin-1-yl)nicotinate

[00169] To a stirred solution of 3,3-difluoroazetidine hydrochloride (8.35 g, 64.5 mmol) in DMF (250 mL), K2CO3 (26.7 g, 193 mmol) was added at room temperature, followed by methyl 6-fluoronicotinate (J-1, 10 g, 64.5 mmol) added at room temperature. The reaction mixture was stirred at 90°C for 12 hours. The resulting reaction mixture was rapidly cooled with ice-cold water (200 mL), the separated solid was filtered in a Buchner funnel, washed with water (100 mL x 2), and dried under reduced pressure to give compound J-2 as a solid. M / Z (ESI): 229.04 [M+H]+. Synthesis of Intermediate J: 6-(3,3-difluoroazetidin-1-yl)nicotinic acid

[00170] A stirred solution of compound J-2 (10 g, 43.5 mmol) in THF (70 mL), water (140 mL) and LiOH (3.13 g, 131 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, acidified (pH = 5) with saturated KHSO4 solution, extracted with DCM (3 x 200 mL), dried with Na2SO4, filtered, concentrated, washed with pentane and dried under reduced pressure to give compound Int J as a whitish solid. M / Z (ESI): 215.04 [M+H]+. Preparation of the intermediate compound K: (S)-2-(4-(4-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-amine Petition 870260070497, dated 07 / 16 / 2026, p. 79 / 214 / 205 Synthesis of K-1: tert-butyl (S)-3-methyl-4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate

[00171] To a stirred solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (5 g, 24.96 mmol) in DMF (50 mL), potassium carbonate (6.90 g, 49.9 mmol) and 2-chloro-5-nitropyrimidine (4.78 g, 30.0 mmol) were added and stirred for 3 hours at 60°C under a N2 atmosphere. The reaction mixture was rapidly cooled with ice water (200 mL) and stirred at room temperature for 30 minutes. The resulting solid precipitate was filtered, washed with water (100 mL x 3) and dried under vacuum suction to give K-1 as a light yellow solid. 1H NMR (400MHz, Chloroform-d) δ: 9.08 (s, 2H), 4.97-5.14 (m, 1H), 4.61-4.76 (m, 1H), 3.87-4.32 (m, 2H), 3.26-3.43 (m, 1H), 3.14 (br d, J=11.8 Hz, 1H), 2.90-2.99 (m, 1H), 1.50 (s, 9H), 1.27 (d, J=6.8 Hz, 3H). Synthesis of K-2: tert-butyl (S)-4-(5-aminopyrimidin-2-yl)-3-methylpiperazine-1-carboxylate

[00172] To a solution of K-1 (3 g, 9.28 mmol) in THF / MeOH / ethyl acetate (1:1:1) (50 ml), sustained palladium was added. Petition 870260070497, dated 16 / 07 / 2026, page 80 / 214 / 205 in carbon (1.975 g, 18.56 mmol) and stirred for 15 hours at 25°C under a hydrogen balloon atmosphere. The reaction mixture was filtered, washed with MeOH / THF (3 x 50 mL) and the combined organic layer was concentrated under reduced pressure to give K-2 as a yellow solid. M / Z (ESI): 294.15 [M+H]+. Synthesis of K-3: tert-butyl (S)-4-(5-(6-fluoronicotinamido)pyrimidin-2-yl)-3methylpiperazine-1-carboxylate

[00173] To a stirred solution of K-2 (1.20 g, 4.09 mmol) and 6-fluoronicotinic acid (1.154 g, 8.18 mmol) in DMF (20 ml), a solution of 50% 1-propanephosphonic anhydride in EtOAc (5.21 g, 8.18 mmol) and TEA (1.710 ml, 12.27 mmol) at room temperature was added and stirred at room temperature for 15 hours. The reaction mixture was diluted with EtOAc (100 ml) and washed with brine (100 ml) saturated NaHCO3 solution (100 ml). The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure to give K-3 as a solid. M / Z (ESI): 417.42 [M+H]+. Synthesis of K-4: tert-butyl (S)-4-(5-(6-(3,3-difluoroazetidin-1-yl)nicotinamido)pyrimidin2-yl)-3-methylpiperazine-1-carboxylate

[00174] To a stirred solution of 3,3-difluoroazetidine hydrochloride (641 mg, 4.95 mmol) in DMF (10 ml), K2CO3 (912 mg, 6.60 mmol) and K-3 (700 mg, 1.649 mmol) were added at room temperature and stirred at 100°C overnight. The reaction mixture was rapidly cooled with ice water (30 ml), extracted with EtOAc (3 x 25 ml). The organic layer was washed with brine solution (2 x 25 ml), dried with NebSO4, filtered, and concentrated to give K-4 as a brown solid. M / Z (ESI): 490.45 [M+H]+. Synthesis of Intermediate K: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(2-(2methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, page 81 / 214 / 205

[00175] To a stirred solution of K-4 (700 mg, 1.158 mmol) in DCM (10 ml), TFA (0.268 ml, 3.47 mmol) was added at 0°C and stirred at 0°C for 5 hours. The reaction mixture was concentrated and co-distilled with toluene twice to give Int K as a yellow semisolid. M / Z (ESI): 390.18 [M+H]+. Preparation of the intermediate compound L: (S)-2-(4-(2-fluoropyridin-4-yl)-2-methylpiperazin-1-yl)pyrimidin-5-amine Synthesis of L-1: (S)-4-(2-fluoropyridin-4-yl)-2-methylpiperazine-1-carboxylate tert-butyl

[00176] To a stirred solution of 4-bromo-2-fluoropyridine (1.142 g, 6.49 mmol) in toluene (20 mL), chlorine(2-dicyclohexylphosphino2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (1.939 g, 2.496 mmol), tert-butyl (S)-2-methylpiperazine-1-carboxylate (1 g, 4.99 mmol), and sodium tert-butoxide (1.200 g, 12.48 mmol) was added at room temperature and stirred at 110°C for 18 hours. The reaction mixture was rapidly cooled with ice water (10 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with brine solution (2 x 30 mL), dried with sodium sulfate, filtered, concentrated under reduced pressure, and the crude compound was purified by flash chromatography on a Biotage silica gel 100-200 column, using 50% EtOAc / petroleum ether as eluent. The pure fractions were concentrated under reduced pressure to give compound L-1 as a sticky yellow solid. M / Z (ESI): 296.31 [M+H]+. Synthesis of L-2: (S)-1-(2-fluoropyridin-4-yl)-3-methylpiperazine Petition 870260070497, dated 07 / 16 / 2026, p. 82 / 214 / 205

[00177] To a stirred solution of compound L-1 (1.0 g, 3.39 mmol) in DCM (12 mL), TFA (0.777 mL, 10.16 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction mixture was rapidly cooled with NaHCO3 solution (10 mL), extracted with DCM (2 x 50 mL) and washed with water (2 x 30 mL). The combined organic layer was washed with brine solution (20 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to give compound L-2 as a yellow solid. M / Z (ESI): 196.07 [M+H]+. Synthesis of L-3: (S)-2-(4-(2-fluoropyridin-4-yl)-2-methylpiperazin-1-yl)-5nitropyrimidine

[00178] To a stirred solution of compound L-2 (700 mg, 3.59 mmol) in DMF (12 ml), potassium carbonate (1487 mg, 10.76 mmol) and 2-chloro-5-nitropyrimidine (858 mg, 5.38 mmol) were added at room temperature and stirred at 80°C for 3 hours. The reaction mixture was rapidly cooled with ice water (20 ml) and the precipitated solid was filtered and dried under vacuum to give compound L-3 as a whitish solid. M / Z (ESI): 319.24 [M+H]+. Synthesis of the L-Intermediate: (S)-2-(4-(2-fluoropyridin-4-yl)-2-methylpiperazin-1-yl)pyrimidin-5-amine

[00179] To a stirred solution of compound L-3 (600 mg, 1.885 mmol) in EtOH (15 ml), Pd-C (241 mg, 2.262 mmol) was added at room temperature and stirred for 12 hours at room temperature under a hydrogen flask. The reaction mixture was filtered in a Buckner funnel through a layer of celite, washed with EtOAc (2 x 50 ml) and concentrated under reduced pressure to give compound Int L as a sticky solid. M / Z (ESI): 289.25 [M+H]+. EXAMPLES Example 1: Synthesis of (S)-6-methoxy-N-(2-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, pages 83 / 214 / 205

[00180] To a solution of Int A (185 mg, 0.684 mmol) in DMF (3422 μL), 6-methoxynicotinic acid (131 mg, 0.855 mmol), DIEA (359 μL, 2.053 mmol) and HATU (325 mg, 0.855 mmol) were added. The mixture was stirred for 16 hours at 25°C. The mixture was then purified by preparative HPLC (C18 reversed-phase column), eluting with acetonitrile / water + 0.1% TFA, to give 1 as a solid. 1H NMR (500 MHz, Chloroform-d) δ 8.72 (d, J = 2.2 Hz, 1H), 8.57 (s, 2H), 8.22 (dd, J = 4.9; 1.2 Hz, 1H), 8.11 (dd, J = 8.7; 2.5 Hz, 1H), 7.52 (ddd, J=8.9; 11.3; 3.8 Hz, 1H), 3.34 (dd, J = 12.8; 3.9 Hz, 1H), 3.11 (td, J = 12.2; 3.8 Hz, 1H), 1.30 (d, J = 6.6 Hz, 3H). MS (ESI) m / z: 406.4 [M+H]+.

[00181] The compounds contained in Table 2 were synthesized by analogous methods from the synthetic sequences used to prepare the Intermediates, using the amide coupling reaction shown in Example 1. Commercially available reagents were substituted, where necessary, to produce the examples below. Table 2______________________________________________________________ In the example Structure Chemical name Observed mass (M+H) Exact mass 2 / =\ ' \= \ N-[2-[(3S)-3-ethyl-4(5-methyl-2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]-6-imidazol-1-ylpyridine-3-carboxamide 470.3 469.2 Petition 870260070497, dated 07 / 16 / 2026, pages 84 / 214 / 205 No exemplo Estrutura Nome químico Observed mass (M+H) Exact mass 3 N-[2-[(2S)-2-methyl- 4-(2- pyridyl)piperazin-1yl]pyrimidin-5-yl]-4- (3- pyridyl)benzamide 452,3 451,2 4 5-fluoro-N-[5[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrazin-2-yl]-1Hindol-2carboxamide 432,4 431,2 5 Ϊ Λ í V 6-imidazol-1-yl-N[2-[4-(5-methyl-2pyridyl)-3-(2,2,2trifluoroethyl)piperazin in-1-yl]pyrimidin-5yl]pyridine-3carboxamide 524,3 523,2 6 C '> V í 6-methoxy-N-[2[(2S)-2-methyl-4-(6methyl-2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 420.2 419.2 7 9 Λ 6-imidazol-1-yl-N[2-[(2S)-2-methyl-4(6-methyl-2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 456.3 455.2 8 6 6-methoxy-N-[2[(2S)-2-methyl-4-(5methyl-2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 420.2 419.2 9 X Λ ϊ 3 5-(2-fluoroethoxy)N-[2-[(2S)-2-methyl4-(6-methyl-2pyridyl)piperazin-1yl]pyrimidin-5yl]pyrazine-2carboxamide 453,3 452,2 10 0 1').0 in 6-methoxy-N-[2[(2S)-4-(5-methoxy2-pyridyl)-2-methylpiperazine-1yl]pyrimidine-5yl]pyridine-3carboxamide 436.3 435.2. Petition 870260070497, of 16 / 07 / 2026, p. 85 / 214 / 205 No exemplo Estrutura Nome químico Massa observada (M+H) Massa exata 11 4-(2-fluoroethoxi)N-[2-[(2S)-2-metil- 4-(6-metil-2pyridyl)piperazin-1yl]pyrimidin-5yl]benzamide 451.3 450.2 12 TA 6-methoxy-N-[2[(2S)-2-metil-4pyrazin-2-ylpiperazin-1yl]pyrimidin-5yl]pyridine-3carboxamida 407.2 406.2 13 Q o V N-[5-[(2S)-2-metil4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyrrol[2,3b]pyrazin-6carboxamide 416.4 415.2 14 ? :) V r 4-(2-fluoroethoxy)N-[2-[(2S)-2-methyl- 4-(2- pyridyl)piperazin-1yl]pyrimidin-5yl]benzamide 437.3 436.2 15 7 ò Y 6-methoxy-N-[2[(2S)-2-methyl-4pyrimidin-4-ylpiperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 407.4 406.2 16 0 : λ 7 r 6-(2-hydroxyethoxy)N-[2-[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 436.3 435.2 17 7 ò ò 6-methoxy-N-[2[(2S)-2-methyl-4-(4pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3-carboxamide 406.3 405.2 18 7' Al e 6-chloro-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3-carboxamide 410.10 409.1 Petition 870260070497, dated 07 / 16 / 2026, p. 86 / 214 / 205 No example Structure Chemical name Observed mass (M+H) Exacted mass 19 4-(1- cyanocyclopropyl)N-[5-[(2S)-2-methyl- 4-(2- pyridyl)piperazin-1yl]pyrazin-2yl]benzamida 440.4 439.2 20 0 C) c. 9 6-bromo-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamida 454.2 453.1 21 9 Λ Ó N-[2-[(2S)-2-methyl4-(2- pyridyl)piperazin-1yl]pyrimidin-5-yl]-5phenyl-pyrazine-2carboxamida 453.3 452.2 22 / w ΛΛ / 6-methoxy-N-[2- [(2R)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamida 406.3 405.2 23 6-(2-fluoroethoxy)N-[2-[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamida 438.2 437.2 24 2' ò 9· 2-methoxy-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-4carboxamida 406.3 405.2 25 9 Δ .....6 Λ 6-methoxy-N-[2[(2S)-2-methyl-4-(4methyl-2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamida 420.2 419.2 26 ò Ύ: i 4-(1- cyanocyclopropyl)N-[2-[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]benzamida 440.3 439.2 Petition 870260070497, dated 07 / 16 / 2026, p. 87 / 214 / 205 No exemplo Estrutura Nome químico Observed mass (M+H) Exact mass 27 -? :) V N-[2-[(2S)-4-(6fluoro-2-pyridyl)-2methyl-piperazin-1yl]pyrimidin-5-yl]-6methoxy-pyridine-3carboxamide 424.2 423.2 28 'r Λ 0 6-(difluoromethoxy)N-[2-[(2S)-2-methyl4-(2- pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 442.3 441.2 29 / 4-methoxy-N-[5[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrazin-2yl]pyridine-2carboxamide 406.4 405.2 30 t 1 í r 6-(2-fluoroethoxy)N-[6-[(2S)-2-methyl- 4-(2- pyridyl)piperazin-1-yl]-3- pyridyl]pyridine-3-carboxamide 437.4 436.2 31 C3 o 33 33 / 4-methoxy-N-[5[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]-2- pyridyl]pyridine-2-carboxamide 405 404.2 32 cc;.....Λ 2-(2-fluoroethoxy)N-[5-[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrazine-2yl]pyrimidine-5carboxamide 438.2 437.5 33 7 Λ / = \ / 6-methoxy-N-[2[(3R)-3-methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5yl]pyridine-3carboxamide 406.2 405.2 34 \ W / = \ / 6-methoxy-N-[2[(3C)-3-methyl-4-(2pyridyl)piperazin-1yl]pyrimidine-5yl]pyridine-3carboxamide 406.1 405.2. Petition 870260070497, of 16 / 07 / 2026, p. 88 / 214 / 205 No example Structure Chemical name Observed mass (M+H) Exact mass 35 A or N-[2-[(3S)-3-methyl4-(2pyridyl)piperazine-1yl1pyrimidine-5-yl15H-pyrrole[2,3b1pyrazine-6carboxamide 416.5 , 415 / 36 / \ = W 2-methoxy-N-[2[(3S)-3-methyl-4-(2pyridyl)piperazine-1yl1pyrimidine-5yl1pyrimidine-5carboxamide 407.4 406.2 Example 37: Synthesis of N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazine-1yl1pyrimidine-5-yl1-6-pyrazole-1-yl-pyridine-3-carboxamide Synthesis of 9-1: (S)-6-fluoro-N-(2-(2-methyl-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-yl)nicotinamide

[00182] A solution of Int A (200 mg, 0.740 mmol), 6-fluoronicotinic acid (157 mg, 1.110 mmol), HATU (422 mg, 1.110 mmol) and Hunig's base (517 µl, 2.96 mmol) was prepared in DMF (2466 µl) at 50°C. After 18 hours, the reaction was completed by LCMS. The reaction was diluted with EtOAc and washed with saturated NaHCO3, water and brine; the organic phase was dried with MgSO4, filtered and concentrated. The material was purified by normal phase column chromatography (EtOAc 0 to 100% in hexanes, 24 g ISCO column; 25 minute gradient) to give 9-1 as a solid. 1H NMR (500 MHz, DMSO-d) 7.60-7.47 (m, 1H), 7.39 (dd, J = 8.6; 2.4 Hz, 1H), 6.86 (d, J = 8.6 Hz, Petition 870260070497, dated 07 / 16 / 2026, pp. 89 / 214 / 205 1H), 6.64 (dd, J = 6.8; 5.1 Hz, 1H), 4.95–4.74 (m, 1H), 4.44 (d, J = 13.4 Hz, 1H), 4.24 (dd, J = 24.0; 12.8 Hz, H33–2H), 3.18 (dd, J = 12.9; 3.8 Hz, 1H), 2.95 (td, J = 12.1; 3.7 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H). LCMS (ESI) calculated for C20H20FN7O [M+H]+: 394.2; found: 394.3. Synthesis of N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazine-1-yl]pyrimidine-5-yl]-6pyrazol-1-yl-pyridine-3-carboxamide (37)

[00183] To a solution of 9-1 (25 mg, 0.064 mmol) and 1H-pyrazole (8.65 mg, 0.127 mmol) in DMF (635 μL) at room temperature, LiHMDS (63.5 μL, 0.095 mmol; 1.5M in THF) was added and the reaction was heated to 100°C. After 4 hours, the reaction was complete. The reaction was diluted with EtOAc and rapidly cooled with water and brine; the organic phase was dried with MgSO4, filtered, and concentrated. The material was purified by normal-phase column chromatography (0 to 100% EtOAc in hexanes, 12 g ISCO column; 20-minute gradient) to give 37 as a solid. 1H NMR (500 MHz, DMSO-d) 2H), 7.97-7.82 (m, 1H), 7.61-7.46 (m, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.696.56 (m, 2H), 4.94-4.77 (m, 1H), 4.52-4.36 (m, 1H), 4.24 (dd, J = 24.2; Hz, 2H), 3.29 (d, J = 3.7 Hz, 1H), 3.19 (dd, J = 13.0; 3.8 Hz, 1H), 2.96 (td, J = 12.2; 3.8 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H). LCMS (ESI) calculated for C23H23N9O [M+H]+: 442.2; found: 442.3.

[00184] The compounds listed in Table 3 were synthesized by methods analogous to those synthesized in Example 37. Commercially available reagents were substituted, where necessary, to produce the examples below. Table 3 Example in Structure Chemical Name Observed Mass (M+H) Exact Mass Petition 870260070497, dated 07 / 16 / 2026, pp. 90 / 214 / 205 Exemplo no Estrutura Nome químico Mass observed (M+H) Mass exact 38 9 9 6-(4methoxypyrazol1-yl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazi n-1yl]pyrimidin-5yl]pyridine-3carboxamide 472,2 471,2 39 0 o c. 6-(4fluoropyrazol1-yl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 460.2 459.2 40 9 ΐ- 6-(3methoxypyrazol1-yl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 472.2 471.2 41 ò .....ó ó N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]-6-(triazol-1yl)pyridine-3carboxamide 443.2 442.2 42 0 t) 0 í 6-(3methylpyrazol-1yl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 456.2 455.2 Petition 870260070497, de 16 / 07 / 2026, pág. 91 / 214 / 205 Example in Structure Chemical name Observed mass (M+H) Exact mass 43 9 Ò 6-(2methylimidazol1-yl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazine n-1yl1pyrimidine-5yl1pyridine-3carboxamide 45,29 45,2 (C)-N-(2-(2methyl-4(pyridin-2yl)piperazin-1yl)pyrimidine-5yl)-6-(2H-1,2,3triazol-2yl)nicotinamide 443.2 442.2 45 0 t > c. in 6-(3,5dimethylpyrazol1-yl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazine n-1yl1pyrimidine-5yl1pyridine-3carboxamide 470.2 469.2 Example 46: Synthesis of 6-(3,3-difluoroazetidin-1-yl)-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazine-1-yl1pyrimidine-5-yl1pyridine-3-carboxamide 9-1 HCl Honey Base, DMF

[00185] A solution of 9-1 (30 mg, 0.076 mmol) and Hunig's base (80 µl, 0.458 mmol) in DMF (763 µl) was added to 3,3-difluoroazetidine hydrochloride (29.6 mg, 0.229 mmol) and heated to 100°C. After 18 hours, the reaction was complete by LCMS. The reaction was cooled and diluted with EtOAc. The organic phase was washed with water / saturated NH4Cl, dried with MgSO4, and concentrated. The residue was purified by normal-phase column chromatography (100% EtOAc 20 in hexanes, 12 g ISCO column; 20-minute gradient) to give 46 as a solid. Petition 870260070497, dated 07 / 16 / 2026, pages 92 / 214 / 205 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.76 (d, J = 1.9 Hz, 1H), 8.67 (s, 2H), 8.25-8.03 (m, 2H), 7.60-7.47 (m, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.72-6.56 (m, 2H), 4.90-4.79 (m, 1H), 4.57-4.35 (m, 6H), 4.24 (dd, J = 24.8; 12.7 Hz, 2H), 3.31-3.24 (m, 1H), 3.22-3.11 (m, 1H), 2.95 (td, J = 12.1; 3.7 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H); LCMS (ESI) calculated for C23H24F2N8O [M+H]+: 467.2, found: 467.3.

[00186] The compounds listed in Table 4 were synthesized by methods analogous to those synthesized in Example 46. Commercially available reagents were substituted, where necessary, to produce the examples below. Table 4 Example no Structure Chemical name Observed mass (M+H) Exact mass 47 aa / =\ c VA -a J- 6-[(3R)-3fluoropyrrolidin-1yl]-N-[2-[(2S)-2methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5ylcarpiridine-46,27] 466.2 48 9 9 in 6-[rac-(4S)-2azabiciclo[2.2.1]hept an-2-yl]-N-[2-[rac(2S)-2-methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5yl]pyridine-3carboxamide 463, 462 > 492 6-[(3S)-3fluoropyrrolidine-1yl]-N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidine-5yl]pyridine-3carboxamide 471.3 470.3 50 0 t), G 6-(3,3- dimethylpyrrolidine-1yl)-N-[2-[(2S)-2methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5yl]pyridine-3carboxamide 463.3 462.2 Petition 870260070497, of 16 / 07 / 2026, p. 93 / 214 / 205 Example no Estrutura Nome químico Observed mass (M+H) Exact mass 51 ? V í 6-(3 -fluoroazetidin1-yl)-N-[2-[(2S)-2methyl-4-(6-methyl-2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 473.4 472.3 52 0 t > 0 í 6-(3 -methylazetidin1-yl)-N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 463.4 462.2 53 (r' ò ó 6-(azepan-1-yl)-N[2-[(2S)-2-methyl-4(2-pyridyl)piperazin1-yl]pyrimidin-5yl]pyridine-3carboxamide 445.4 444.2 54 Λ A: tt 6-(2-oxa-5azabicyclo[2.2.1]hept an-5-yl)-N-[2-[rac(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 473.4 472.3 55 ò 'Ó ó 6- [methyl(propyl)amino] -N-[2-[(2S)-2-methyl4-(2pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 447.5 446.3 56 Λ tt 6-(azetidin-1-yl)-N[2-[(2S)-2-methyl-4(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 431.3 430.2 57 (r ò A: ύ 6-(methylamino)-N[2-[(2S)-2-methyl-4(2-pyridyl)piperazin1-yl]pyrimidin-5yl]pyridine-3carboxamide 405.3 404.2 58 XA .....c: 0 6-(dimethylamino)-N[2-[(2S)-2-methyl-4(6-methyl-2pyridyl)piperazine-1yl]pyrimidine-5yl]pyridine-3carboxamide 433.3 432.2. Petition 870260070497, of 16 / 07 / 2026, p. 94 / 214 / 205 Example no Structure Chemical name Observed mass (M+H) Exact mass 59 τ' A 6 6-[ethyl(2hydroxyethyl)amino]N-[2-[(2S)-2-methyl4-(2- pyridyl)piperazine-1yl]pyrimidine-5yl]pyridine-36322,625 Λ tt 6-(3 -hydroxyazetidin1-yl)-N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidine-5yl]pyridine-3carboxamide 447.5 446.2 61 0 o 0 í r 6- [isobutyl(methyl)amine) o]-N-[2-[(2S)-2methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5yl]pyridine-3carboxamide 461.5 460.3 62 0 (). c. N-[2-[(2C)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]-6pyrrolidin-1-ylpyridine-3carboxamide 445.4 444.2 Example 63: Synthesis of 6-(3-fluorophenyl)-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide Petition 870260070497, of 16 / 07 / 2026, p. 95 / 214 / 205 Synthesis of 6-bromo-N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl1pyrimidin-5yl1pyridine-3-carboxamide (20)

[00187] A solution of Int A (200 mg, 0.740 mmol), 6-bromonicotinic acid (224 mg, 1.110 mmol), HATU (422 mg, 1.110 mmol) and Hunig's base (517 µl, 2.96 mmol) was prepared in DMF (2466 µl) and heated to 50°C. After 18 hours, the reaction was complete by LCMS. The reaction was diluted with EtOAc and washed with saturated NaHCO3, water and brine; the organic phase was dried with MgSO4, filtered and concentrated. The material was purified by normal phase column chromatography (100% EtOAc in hexanes, 24 g ISCO column; gradient 25 minutes) to give 20 as a solid. RMN 1H (500 MHz, DMSO-d6) δ 10,46 (s, 1H), 8,93 (d, J = 2,1 Hz, 1H), 8,69 (s, 2H), 8,24 (dd, J = 8,3; 2,5 Hz, 1H), 8,16-8,03 (m, 1H), 7,87 (d, J = 8,3 Hz, 1H), 7,60-7,45 (m, 1H), 6,86 (d, J = 8,6 Hz, 1H), 6,63 (dd, J = 6,8; 5,1 Hz, 1H), 4,84 (dd, J = 6,3; 3,2 Hz, 1H), 4,52-4,35 (m, 1H), 4,23 (dd, J = 23,9; 12,8 Hz, 2H), 3,32-3,25 (s, 1H), 3,18 (dd, J = 13,0; 4,1 Hz, 1H), 3,07-2,86 (m, 1H), 1,15 (d, J = 6,6 Hz, 3H). LCMS (ESI) calculado para C- [ 1,- BrVO [M+H]+: 454,1; encontrado: 454.2. Síntese de 6-(3-fluorofenil)-N-[2-[(2S)-2-metil-4-(2-piridil)piperazin-1il1pirimidin-5-il1piridina-3-carboxamida (63)

[00188] A solution of 20 (8.2 mg, 0.018 mmol), 3-fluorophenyl pinacolboronate (15.9 mg, 0.072 mmol), SPhos-Pd-G2 (2.6 mg, 0.033 mmol) and K3PO4 (23 µl of 1.5M solution in water, 0.036 mmol) was prepared in DMF (2466 µl) and heated to 80°C. After 18 hours, the reaction was complete by LCMS. The reaction was diluted with DMF (1.0 mL) and the mixture was purified by RP HPLC (reversed-phase column chromatography; MeCN in water, 0.1% NH4OH modifier, Fenomenex C18 Luna column, 100 x 21.2 mm, 5 micrometers) to give 63 as a solid after concentration. Petition 870260070497, dated 07 / 16 / 2026, pages 96 / 214 / 205 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.22 (s, 1H), 8.73 (s, 2H), 8.43 (dd, J = 8.4; 1.9 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 4.4 Hz, 1H), 8.04 (dd, J = 25.7; 9.0 H, 2H), 7.68-7.49 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.73-6.57 (m, 1H), 4.96-4.75 (m, 1H), 4.44 (d, J = 13.4 Hz, 1H), 4.25 (dd, J = 24.5; 12.8 Hz, 2H), 3.32-3.25 (m, 1H) 3.19 (dd, J = 12.8; 3.6 Hz, 1H), 2.96 (td, J = 12.0; 3.5 Hz, 1H), 1.16 (d, J = 6.6 Hz, 4H); LCMS (ESI) calculated for C26H24FN7O [M+H]+: 470.2; found: 470.2.

[00189] The compounds listed in Table 5 were synthesized by methods analogous to those synthesized in Example 63. Commercially available reagents were substituted, where necessary, to produce the examples below. Table 5 Example no Structure Chemical name Observed mass (M+H) Exact mass 64 9 O Ψ 0 6-(4-methyl-3furyl)-N-[2- [(2S)-2-methyl4-(2pyridyl)piperazi n-1yl]pyrimidin-5yl]pyridine-3carboxamide 456.2 455.2 65 9 cs 9 N-[2-[(2S)-2methyl-4-(2pyridyl)piperazi n-1yl]pyrimidin-5yl]-6-thiazol-5yl-pyridine-3carboxamide 459.2 458.2 66 0 Λ n-1yl]pyrimidin-5yl]-6-pyridazin4-yl-pyridine-3carboxamide 454.2 453.2 Petition 870260070497, dated 07 / 16 / 2026, pages 97 / 214 / 205 Example in Structure Chemical Name Observed Mass (M+H) Exact Mass 67 O 0 A ô N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]-6-(3-thienyl)pyridine-3-carboxamide 458.2 457.2 68 0 0 ò '13 6-(4-fluorophenyl)-N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 470.2 469.2 69 9 : 1, V 0 Aíi N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-5-yl]-6-(3-pyridyl)pyridine-3-carboxamide 453.2 452.2 70 9' : >. V 0 o N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]-6-(4pyridyl)pyridine3-carboxamide 453.2 452.2 71 9 o. V0 0 n-1yl]pyrimidin-5yl]pyridine-3carboxamide 442.2 441.2 Petition 870260070497, dated 07 / 16 / 2026, pages 98 / 214 / 205 Example Structure Chemical name Observed mass (M+H) Exact mass 73 9 o V 0 0 6-(4cyanophenyl)-N[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 477.2 476.2 74 9 <: V 0 V / \ 6-(5,6-dihydro4H-pyrrolo[1,2b]pyrazol-3-yl)N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 482.3 481.2 75 9 9 6-(2methylpyrazol-3yl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 456.2 455.2 76 HI 0 A 6 N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]-6-pyrimidin5-yl-pyridine-3carboxamide 454.2 453.2 77 0 AA 5 6-(2-methyl-4pyridyl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 467.3 466.2 78 9 t V 0 Ol 6-(5-fluoro-3pyridyl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 471.2 470.2 Petition 870260070497, de 16 / 07 / 2026, pág. 99 / 214 / 205 Example Structure Chemical name Observed mass (M+H) Exact mass 79 9 0 o 6-(3-fluoro-4pyridyl)-N-[2- [(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 471.2 470.2 80 0 ò .....ó 9 6-(6-fluoro-2pyridyl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 471.2 470.2 81 9 C) V 0 / A 6-(3,5-dimethylisoxazol-4-yl)N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 471.2 470.2 82 JU 0 ò c 6-(3 -methyl-4pyridyl)-N-[2[(2S)-2-methyl4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 467.3 466.2 83 ? O / =\ / =N 9 9 / N=\ N y— NN—(\ # NH VN 'iN \=NX—NN N-[2-[(2S)-2methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]-6-(2methylpyrimidin5-yl)pyridine-3carboxamide 468.2 467.2 84 0 ri 0 0 V / \ 6-(1methylpyrazol-4yl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5yl]pyridine-3carboxamide 456.3 455.2 Petition 870260070497, de 16 / 07 / 2026, pág. 100 / 214 / 205 Example no Structure Chemical name Observed mass (M+H) Exacted mass 85 / ΓΛ / =\ 1 6-(3-methylisoxazol-4-yl)N-[2-[(2S)-2methyl-4-(2pyridyl)piperazi n-1yl]pyrimidin-5yl]pyridine-3carboxamida 457.2 456.2 86 9 or V 0 0- 4-(3cyanophenyl)-N[2-[(2S)-2methyl-4-(2pyridyl)piperazi n-1yl]pyrimidin-5yl]benzamida 476.4 475.2 Example 87: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(2-(4-(4-fluoropyridin-2-yl)-2methylpiperazin- 1-yl)pyrimidin-5-yl)nicotinamide T3P, DIPEA, THF

[00190] To a stirred solution of Intermediate Compound I (500 mg, 1.734 mmol) in THF (10 mL), Intermediate Compound J (557 mg, 2.60 mmol), DIPEA (0.909 mL, 5.20 mmol) and 50% 1-propanephosphonic anhydride solution in EtOAc (1104 mg, 3.47 mmol) at room temperature were added. The reaction mixture was stirred at 50°C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried with concentrated Na2SO4e under reduced pressure to obtain the crude compound. The crude compound was subjected to purification by preparative HPLC (method: Mobile phase - 10mM ammonium bicarbonate in H2O:MeCN; Column - LUNA pack C18 (21.2X250) mm 5 Petition 870260070497, dated 07 / 16 / 2026, page 101 / 214 / 205; flow rate - 18ml / min, gradient method: 0 / 45, 12 / 70, 12.05 / 98, 14 / 98, 14.05 / 45, 17 / 45) to provide 87, as a light brown solid. M / Z (ESI): 485.30 [M+H]+. RMN 1H (DMSO-d6, 400 MHz): δ (ppm) 8,73 (t, J = 2 Hz, 1H), 8.65 (s, 2H), 8.09-8.15 (m, 2H), 6.65-6.71 (m, 2H), 6.51-6.55 (m, 1H), 4.81 (br s, 1H), 4.32-4.53 (m, 5H), 4.22 (t, J = 13.2 Hz, 2H), 3.21-3.32 (m, 2H), 2.95-3.2 (m, 1H), 1.12 (d, J = 2 Hz, 3H). Exemplo 88: (S)-6-(3,3-difluoroazetidin-1-il)-N-(2-(2-metil-4-(4-nitropiridin2-il)piperazin-1-il)pirimidin-5-il)nicotinamida Ruphos, PdG2 CS2CO3, dioxano Síntese de 88: (S)-6-(3,3-difluoroazetidin-1-il)-N-(2-(2-metil-4-(4nitropiridin-2-il)piperazin-1-il)pirimidin-5-il)nicotinamida

[00191] To a stirred solution of Int K (250 mg, 0.465 mmol) in dioxane (3 ml), Cs2COs (455 mg, 1.396 mmol) and 2-bromo-4-nitropyridine (123 mg, 0.605 mmol) were added at room temperature, degassed under nitrogen for 10 minutes, followed by chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (18.08 mg, 0.023 mmol) and stirred at 100°C for 16 hours. The reaction mixture was filtered through a celite layer and washed with ethyl acetate. The filtrate was dried with sodium sulfate, evaporated under reduced pressure, and the crude compound was purified by preparative HPLC (method: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - LUNA Omega C18 (21.2X250)). Petition 870260070497, dated 07 / 16 / 2026, page 102 / 214 / 205 mm 5 µm, flow rate -18 ml / min, gradient method - 0 / 50, 10.2 / 84, 10.25 / 100, 12 / 100, 12.05 / 50, 16 / 50) and lyophilized to provide 88 as a yellow solid. M / Z (ESI): 512.35 [M+H]+. 1H RMN (400MHz, DMSO-d6) δ: 10.07 (s, 1H), 8.76 (d, J=2.0 H, 1H), 8.68 (s, 2H), 8.41 (d, J=5.4 Hz, 1H), 8.84 (dd, Hz), J=14.8 (dd, Hz 7.49 (d, J=1.5 Hz, 1H), 7.26 (dd, J=5.5; 1.8 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 4.85 (dt, J=6.3; 3.3 Hz, 1H, 4.4-H3), 3.1-H3 (m, 2H), 3.11–3.20 (m, 1H), 1.14 (d, J=6.6 Hz, 3H). Example 89:(S)-N-(2-(4-(2-fluoropyradine-4-yl)-2-methylpiperazine-1yl)pyrimidine-5-yl)-6-(1H-pyrazol-1-yl)nicotinamide

[00192] To a stirred solution of compound Int L (150 mg, 0.520 mmol) in THF (3 ml), TEA (0.290 ml, 2.081 mmol), 50% 1-propanephosphonic anhydride solution in EtOAc (0.312 ml, 1.040 mmol), 6-(1H-pyrazol-1-yl)nicotinic acid (128 mg, 0.676 mmol) at 0°C was added and stirred for 12 hours at room temperature. The reaction mixture was rapidly cooled with NaHCO3 solution (10 ml), extracted with EtOAc (2 x 50 mL) and washed with water (2 x 10 ml). The combined organic layer was washed with brine solution (20 ml), dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by preparative HPLC (conditions: Mobile phase: 10 mM ammonium bicarbonate in H2O:MeCN, column: X-Select Phenyl Hexyl (19X250) mm 5 u, flow rate: 18 ml / min, gradient method: 0 / 35, 9.3 / 70, 9.4 / 99, 11 / 99, 11.05 / 35, 15 / 35). The pure fractions were concentrated. Petition 870260070497, 16 / 07 / 2026, pág. 103 / 214 / 205 and freeze-dried to supply 89 as solid peeled. M / Z (ESI): 460.15 [M+H]+. NMR 1H (400MHz, DMSO-d6) δ: 10.44 (s, 1H), 9.03 (d, J=2.2 Hz, 1H), 8.72 (s, 3H), 8.51 (dd, J=8.6; 2.2 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.87-7.96 (m, 1H), 7.81 (d, J=6.1 Hz, 1H), 6.81 (br d, J=6.1 Hz, 1H), 6.616.68 (m, 1H), 6.49 (s, 1H), 4.78 (dt, J=6.7; 3.1 Hz, 1H), 4.33-4.41 (m, 1H), 3.86-3.98 (m, 2H), 3.34-3.48 (m, 2H), 3.09-3.18 (m, 1H), 1.16 (d, J=6.6 Hz, 3H). Exemplo 90: (S)-N-(2-(2-methyl-4-(2-nitropyridin-4-yl)piperazin-1-yl)pyrimidin5-yl)-6-(1H-pyrazol-1-yl)nicotinamide Síntese de K-6: (S)-4-(5-(6-(1H-pirazol-1-il)nicotinamido)pirimidin-2-il)-3metilpiperasina-1-carboxylato de terc-butila

[00193] To a stirred solution of 1H-pyrazole (82 mg, 1.201 mmol), cesium carbonate (391 mg, 1.201 mmol) in DMF (5 mL), K-3 (250 mg, 0.600 mmol) was added at room temperature under a nitrogen atmosphere and stirred at 90°C for 3 hours. Reaction progress was monitored by LCMS and TLC. TLC showed that the reaction was complete. Then, the reaction mixture was diluted with ethyl acetate (100 mL) and water (60 mL). The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 x 40 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound K-6 as a light brown gummy solid. M / Z (ESI): 465.36 [M+H]+. Petition 870260070497, dated 07 / 16 / 2026, pages 104 / 214 / 205 Synthesis of K-7: (S)-N-(2-(2-methylpiperazin-1-yl)pyrimidin-5-yl)-6-(1H-pyrazol1-yl)nicotinamide

[00194] To a stirred solution of compound K-6 (190 mg, 0.409 mmol) in DCM (5.7 ml), TFA (1.565 ml, 20.45 mmol) was added at room temperature and stirred under a nitrogen atmosphere at room temperature for 2 hours. Reaction progress was monitored by TLC. TLC showed that the reaction was complete. Then, the reaction mixture was concentrated under reduced pressure and the crude residue was diluted with DCM (100 ml) and H2O (60 ml). Then, Na2CO3 was added to adjust the pH to 7-8 and extracted with DCM (100 ml x 3). The combined organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to give compound K-7 as a light brown solid. M / Z (ESI): 365.15 [M+H]+. Synthesis of 90: (S)-N-(2-(2-methyl-4-(2-nitropyridin-4-yl)piperazin-1yl)pyrimidin-5-yl)-6-(1H-pyrazol-1-yl)nicotinamide

[00195] To a stirred solution of compound K-7 (105 mg, 0.288 mmol), potassium carbonate (119 mg, 0.864 mmol) in DMF (5 mL), 4-chloro-2-nitropyridine (91 mg, 0.576 mmol) was added at room temperature under a nitrogen atmosphere and stirred at 50°C for 6 hours. Reaction progress was monitored by LCMS and TLC. TLC showed that the reaction was complete. Then, the reaction mixture was diluted with ethyl acetate (60 mL) and water (50 mL). The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 x 30 mL). The combined organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-BRIDGE C18 (19X250) mm 5 u, flow rate - 18 ml / min, gradient method - 0 / 30, 9 / 75, 9.05 / 100, 11 / 100, 11.05 / 30, 13.5 / 30). The obtained compound was further purified by the SFC method (conditions: Column Petition 870260070497, dated 07 / 16 / 2026, pages 105 / 214 / 205 Chiralpak IG (4.6*250 mm), 5 μ, Mobile phase- A: MeOH / DCM / DEA (50 / 50 / 0.2) Isocratic of A: 100%, Flow rate: 1.0 mL / min Diluent: EtOH). The pure fractions were concentrated and lyophilized to provide 90 as a yellow solid. M / Z (ESI): 487.12 [M+H]+. NMR1H (500MHz, DMSO-d6) δ: 10.45 (s, 1H), 9.00-9.05 (m, 1H), 8.69-8.76 (m, 3H), 8.52 (dd, J=8.5; 2.4 Hz, 1H), 8.18 (d, J=5.8 Hz, 1H), 8.05-8.10 (m, 1H), 7.89-7.94 (m, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.23 (dd, J=6.1; 2.4 Hz, 1H), 6.65 (dd, J=2.6; 1.7 Hz, 1H), 4.77-4.85 (m, 1H), 4.35-4.42 (m, 1H), 3.98-4.09 (m, 2H), 3.45-3.55 (m, 2H), 3.22-3.29 (m, 1H), 1.17 (d, J=6.4 Hz, 3H). Example 91: (S)-6-(1H-imidazol-1-yl)-N-(2-(2-methyl-4-(pyridin-2-yl)piperazin1-yl)pyrimidin-5-yl)nicotinamide

[00196] To a stirred solution of Intermediate A (150 mg, 0.555 mmol), 6-(1H-imidazol-1-yl)nicotinic acid (157 mg, 0.832 mmol) in THF (30 mL), TEA (0.193 mL, 1.387 mmol), 1-propanephosphonic anhydride (0.495 mL, 0.832 mmol) was added at 25°C and stirred for 16 hours at 25°C. The reaction mixture was rapidly cooled with ice water (10 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine solution (2 x 10 mL), dried with sodium sulfate, filtered, concentrated under reduced pressure, and the crude compound purified by preparative HPLC (Mobile phase - Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Select C18 (19X250) mm 5 u, flow rate - 18 mL / min). Petition 870260070497, dated 07 / 16 / 2026, p. 106 / 214 / 205 gradient method - 0 / 45, 6.9 / 76, 6.95 / 100, 9 / 100, 9.05 / 45, 12 / 45). The pure fractions were concentrated and lyophilized to provide 91 as a light yellow solid. M / Z (ESI): 442.14 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ: 10.43 (s, 1H), 9.04 (d, J=2.0 H, 1H), 8.71 (s, 2H), 8.66 (s, 1H), 8.52 (dd, J=8.7; 2.3 Hz, 1H), 8.12 (dd, J=4.9; 1.2 Hz, 1H), 8.06 (t, J=1.2 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.55 (ddd, J=8.6; 7.0; 2.2 Hz, 1H), 7.18 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.60-6.67 (m, 1H) 2.90-3.01 (m, 1H), 1.16 (d, J=6.6 Hz, 3H).

[00197] The compounds listed in Table 6 were synthesized by analogous methods from the synthetic sequences above. Commercially available reagents were substituted, where necessary, to produce the examples below. Table 6 Example in Structure Chemical name Observed mass (M+H) Exact mass 92 / / λ VV UD N-(2-((2S,6R)-2,6-dimethyl-4-(5methylpyridine-2 -yl)piperazine-1yl)pyrimidine-5-yl)-5'amide],35bicarboxy 499,2 498,23 93 o ΐ P N-(2-((S)-4-(5-fluoropyridin-2-yl)-2methylpiperazine-1-yl)pyrimidine-5-yl)-6((R)-3 -fluoropyrrolidin-1yl)nicotinamide 480,32 481 481 Petition 870260070497, dated 07 / 16 / 2026, p. 107 / 214 / 205 Example in Structure Chemical name Observed mass (M+H) Exact mass 94 / \ (R)-6-(1H-imidazol-1-yl)-N-(2-(2(methoxymethyl)-4-(pyridin-2yl)piperazine- 1-yl)pyrimidine-5- 7712,74 nicotinamide 1 ô (S)-N-(2-(4-(4-fluoropyradine-2-yl)-2methylpiperazine-1-yl)pyrimidm-5-yl)-6morpholinonicotinamide 479.4 478.22 96 7 C 1,. ¥ (S)-6-(3-fluoroazetidin-1-yl)-N-(2-(4(5-fluoropyridin-2-yl)-2-methylpiperazm1-yl)pyrimidine-5 -yl)nicotinamide 467.4 466.20 Petition 870260070497, dated 07 / 16 / 2026, p. 108 / 214 100 / 205 Example in Structure Chemical name Observed mass (M+H) Exact mass 97 9 9 / (S)-6-(3-methoxy-1H-pyrazol-1-yl)-N-(2(2-methyl-4-(pyridin-2-yl)piperazine-1yl)pyrimidine-5,5-da 7981)nicotine 9 % (S)-6-(3-fluoro-1H-pyrazol-1-yl)-N-(2(2-methyl-4-(pyridin-2-yl)piperazine-1yl)pyrimidine-5-yl)nicotinamide 460.3 459.19 99 _ ^2 CD ( S )-N-(2-(4-(6-fluoropyperazine-4-yl)-2methylpiperazine-1-yl)pyrimidine-5-yl)-6(4-methylpiperazine-1-yl)nicotinamide 493.3 492.25 Petition 870260070497, dated 07 / 16 / 2026, p. 109 / 214 101 / 205 Example no Structure Chemical name Observed mass (M+H) Exact mass 100 9 í λ,. [kl 0 ΓΪΙ (R)-6-(2-fluoropyrimidine-5-yl)-N-(5-(2(methoxymethyl)-4-(pyridin-2-yl)piperazine-1-yl)pyrazine-2yl)nicotinamide 502.4 501.20 o 10 (S)-N-(2-(2-methyl-4-(thiazol-2yl)piperazine-1-yl)pyrimidine-5-yl)-6-(1Hpyrazol-1-yl)nicotinamide 448.1 447.16 102 Y oc> 6-(dimethylamino)-N-(2-(5-(6fluoropyrimidine-4-yl)-2,5diazabicyclo[4.1.0]heptane-2yl)pyrimidine-5-yl)nicotinamide 436.4 435.19 103 SΛ / =\ / (S)-6-(dimethylamino)-N-(2-(4-(6fluoropyramidine-4-yl)-2-methylpiperazine1-yl)pyrimidine-5 -yl)nicotinamide 438,2 437,21 Petition 870260070497, dated 07 / 16 / 2026, p. 110 / 214 102 / 205 Example in Structure Chemical name Observed mass (M+H) Exact mass 104 \ V í) (S)-N-(2-(2-methyl-4-(1-methyl-1Hpyrazol-3-yl)piperazine-1-yl)pyrimidine-5yl)-6-(1H-damilyl)4nicotine-5 444,21 105 (S)-N-(2-(4-(3-fluoropyradine-4-yl)-2methylpiperazine-1-yl)pyrimidine-5-yl)-6morpholinonicotinamide 479,3 478,22 106 7 V 6-(3--dine -methylate 1-yl)-N-(2(5-(6-fluoropyrimidine-4-yl)-2,5- diazabicyclo[2.2.2]octan-2- il)pyrimidine-5-yl)nicotinamide 494.4 493.22 107 c λ V ' -dl / (S)-N-(2-(4-(6-fluoropyramidine-4-yl)-2methylpiperazine-1-yl)pyrimidine-5-yl)-3methyl-3H-imidazo[4,5-b]pyridine-6carboxamide 449,2 448,19 Petition 870260070497, dated 07 / 16 / 2026, p. 111 / 214 103 / 205 Example in Structure Chemical name Observed mass (M+H) Exact mass 108 Ã 71 V N-(2-((2S,5R)-2,5-dimethyl-4-(5methylpyridine-2 -yl)piperazine-1yl)pyrimidine-5-yl)-6-(1H3-1H-pyrazol)4 469,23 109 9 C 3..... Y 0 0 (S)-(2-(4-(5-fluoropyridin-2-yl)-2methylpiperazine-1-yl)pyrimidine-5-yl)-4- (pyridin-3-yl)benzamide 470.6 Y 119,20 6-(3,3-difluoroazetidine-1-yl)-N-(2((2R,3R)-4-(4-fluoropyperazine-2-yl)-2,3- dimethylpiperazine-1-yl)pyrimidine-5yl)nicotinamide 499.5 498.21 Petition 870260070497, dated 07 / 16 / 2026, p. 112 / 214 104 / 205 Example in Structure Chemical name Observed mass (M+H) Exact mass 111 Y í 3..... Y o (S)-N-(2-(4-(2-fluoropyperazine-3-yl)-2methylpiperazine-1-yl)pyrimidine-5-yl)-6morpholinonicotinamide,22 478 479 Example 112: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(5-(4-(6-fluoropyrimidine-4yl)-2-methylpiperazine-1-yl)pyrazine-2-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, p. 113 / 214 105 / 205 Synthesis of M-3: (S)-4-(6-fluoropyrimidin-4-yl)-2-methylpiperazine-1-tert-butylcarboxylate

[00198] To a stirred solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (M-1) (2.0 g, 9.99 mmol) in DMA (20 mL), N,N-diisopropylethylamine (5.2 mL, 30.0 mmol) was added at 0°C, followed by 4,6-difluoropyrimidine (M-2) (1.28 g, 11.0 mmol), and the mixture was stirred for 18 hours at 110°C. The reaction mixture was poured over ground ice, extracted with EtOAc, and the organic layer was washed with brine solution, dried with Na2SÜ4, and evaporated under reduced pressure to give compound M-3. M / Z (ESI): 297.12 [M+H+]. Synthesis of M-4: (S)-4-fluoro-6-(3-methylpiperazin-1-yl)pyrimidine

[00199] To a stirred solution of M-3 (2.2 g, 7.42 mmol) in DCM (10 ml), 4M HCl in 1,4-dioxane (9.25 g, 74.2 mmol) at 0°C was added and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, washed with saturated NaHCO3 solution and extracted with EtOAc. The organic phase was washed with brine solution, dried with Na2SO4 and concentrated under reduced pressure to give compound M-4. M / Z (ESI): 197.06 [M+H+]. Synthesis of M-6: (S)-4-(4-(5-bromopyrazin-2-yl)-3-methylpiperazin-1-yl)-6fluoropyrimidine

[00200] To a stirred solution of M-4 (1.9 g, 9.68 mmol) in DMSO (20 ml), cesium fluoride (2.94 g, 19.4 mmol) and 2,5-dibromopyrazine (M-5) (1.843 g, 7.75 mmol) at 0°C were added and stirred for 18 hours at 80°C. The reaction mixture was poured into ice water and extracted with EtOAc and the organic layer was washed with brine solution, dried with NibSO4, and evaporated under vacuum to give compound M-6. M / Z (ESI): 353.04 [M+H+]. Synthesis of M-7: tert-butyl (S)-(5-(4-(6-fluoropyrimidin-4-yl)-2-methylpiperazin-1yl)pyrazin-2-yl)carbamate Petition 870260070497, dated 07 / 16 / 2026, pp. 114 / 214 106 / 205

[00201] A stirred solution of M-6 (800 mg, 2.265 mmol) in toluene (10 mL), cesium carbonate (996 mg, 3.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (104 mg, 0.113 mmol), xanthos (131 mg, 0.227 mmol) and tert-butyl carbamate (292 mg, 2.492 mmol) at 0°C was stirred for 18 hours at 70°C. The reaction mixture was poured into ice-cold water (5 mL) and extracted with EtOAc (5 mL x 3), and the organic layer was washed with brine solution, dried with anhydrous Na2SO4, and evaporated under reduced pressure to give compound M-7. M / Z (ESI): 390.17 [M+H+]. Synthesis of M-8: (S)-5-(4-(6-fluoropyrimidin-4-yl)-2-methylpiperazin-1yl)pyrazin-2-amine

[00202] To a stirred solution of M-7 (600 mg, 1.541 mmol) in DCM (8 ml), TFA (0.590 ml, 7.70 mmol) at 0°C was added and stirred for 18 hours at room temperature. The reaction mixture was evaporated, rapidly cooled with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (10 ml x 3). The organic layer was washed with brine solution, dried with Na2SO4 and evaporated under reduced pressure to give M-8. M / Z (ESI): 290.21 [M+H+]. Synthesis of 112: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(5-(4-(6-fluoropyrimidin-4yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide:

[00203] To a stirred solution of int J (89 mg, 0.415 mmol) in DCM (5 mL), 1-methylimidazole (0.083 mL, 1.037 mmol) was added at 0°C, followed by methanesulfonyl chloride (0.035 mL, 0.456 mmol) at 0°C and stirred for 15 minutes, then M-8 (60 mg, 0.207 mmol) was added and stirred for 4 hours at 45°C. The reaction mixture was poured into ice-cold water (2 mL) and extracted with DCM (3 mL x 3). The organic layer was washed with brine solution, dried with anhydrous Na2SO4 and evaporated under reduced pressure, and the crude compound was purified by preparative HPLC (Mobile phase: 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Bridge C18 (19X250) mm 5 u, flow rate - 18 ml / min, gradient method - 0 / 30, 9.2 / 78, Petition 870260070497, dated 07 / 16 / 2026, pp. 115 / 214 107 / 205 9.25 / 99, 11.2 / 99, 11.25 / 30, 15.2 / 30) and lyophilized to provide 112, M / Z (ESI): 484.18 [M+H+]. RMN 1H (400MHz, DMSO-d6) δ: 10,57 (s, 1H), 8,82 (br dd, J=17,7; 1,6 Hz, 2H), 8,32 (br d, J=2,7 Hz, 1H), 8,20 (br dd, J=8,8; 2,4 Hz, 1H), 8,12 (br d, J=1,2 Hz, 1H), 6,58-6,65 (m, 2H), 4,60 (br dd, J=6,4; 2,7 Hz, 1H), 4,42-4,54 (m, 4H), 4,31-4,40 (m, 2H), 4,06-4,11 (m, 1H), 3,75-3,81 (m, 1H), 3,43 (br dd, J=13,7; 3,7 Hz, 1H), 3,24 (br dd, J=8,4; 4,5 Hz, 2H), 1,06 (d, J=6,4 Hz, 3H). Exemplo 113:(S)-6-(azetidin-1-il)-N-(2-(4-(5-fluoropiridin-2-il)-2metilpiperazin- 1-il)pirimidin-5-il)nicotinamida

[00204] To a stirred solution of N-1 (prepared analogously to M-8) (0.060 g, 0.208 mmol) and N-2 (prepared analogously to J) (0.074 g, 0.416 mmol) in DMF (2 mL), HATU (0.158 g, 0.416 mmol) and DIPEA (0.109 mL, 0.624 mmol) were added at 0°C and stirred at 100°C for 1 hour. The reaction mixture was rapidly cooled with ice-cold water (10 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution (2 x 20 mL), dried with sodium sulfate, filtered and concentrated under reduced pressure, and the crude compound was purified. Petition 870260070497, dated 07 / 16 / 2026, pp. 116 / 214 108 / 205 by preparative HPLC (conditions: Mobile phase - Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Bridge C18 (19X250) mm 5 u, flow rate - 18 ml / min Gradient method - 0 / 40, 8 / 73, 8.05 / 99, 10 / 99, 10.05 / 40, 13 / 40). The pure fractions were concentrated and lyophilized to provide 113, M / Z (ESI): 449.46 [M+H]+. 1H RMN (400MHz, DMSO-d6) δ: 9.94 (s, 1H), 8.61–8.75 (m, 3H), 8.10 (d, J=3.2 Hz, 1H), 8.03 (dd, J=8.9; 2.8, t = 7, 1H Hz, 1H), 6.92 (dd, J=9.4; 3.3 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 4.84 (br s, 1H), 4.42 (br d, J=13.4 Hz, 1H), 4.24 (t, 10-4 J=7.5 Hz, 4H), 3,233.30 (m, 1H), 3.13 (dd, J=13.0; 3.9 Hz, 1H), 2.91 (br d, J=3.7 Hz, 1H), 2,302.42 (m, 2H (3H), ,J=1.5). Example 114: (R)-6-(4-(fluoromethyl)-1H-pyrazol-1-yl)-N-(2-(2-(methoxymethyl)4-(pyridin-2-yl)piperazine-1-yl)pyrimidine-5-yl)nicotinamide Synthesis of O-3: (R)-2-(2-(methoxymethyl)-4-(pyridin-2-yl)piperazine-1-yl)-5nitropyrimidine

[00205] To a stirred solution of O-1 (prepared in a method analogous to that of Int 3-3) (300 mg, 1.231 mmol) in DMF (4 mL), K2CO3 (851 mg, 6.15 mmol) and 2-chloro-5-nitropyrimidine (O-2) (236 mg, 1.477 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere, rapidly cooled with H2O (25 mL), and extracted with EtOAc (2 x 50 mL). The organic layer Petition 870260070497, dated 07 / 16 / 2026, pages 117 / 214 109 / 205 combined was washed with brine (2 x 25 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide O-3. M / Z (ESI): 331.17 [M+H]+. Synthesis of O-4: (R)-2-(2-(methoxymethyl)-4-(pyridin-2-yl)piperazin-1yl)pyrimidin-5-amine

[00206] To a stirred solution of O-3 (50 mg, 0.151 mmol) in MeOH (5 mL), 10% Pd-C (16.11 mg, 0.015 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was diluted with EtOAc (15 mL), filtered through a layer of celite, and washed with EtOAc (2 x 15 mL). The filtrate was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give O-4. M / Z (ESI): 301.24 [M+H]+. Example 114: (R)-6-(4-(fluoromethyl)-1H-pyrazol-1-yl)-N-(2-(2-(methoxymethyl)4-(pyridin-2-yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00207] To a stirred solution of O-4 (40 mg, 0.133 mmol) in DMF (1 mL), HATU (50.6 mg, 0.133 mmol), O-5 (32.4 mg, 0.146 mmol) and DIPEA (0.070 mL, 0.4 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere, rapidly cooled with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (2 x 10 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Select C18 (19X250) mm 5 u, flow rate - 18 ml / min, gradient method - 0 / 45, 8 / 81, 8.05 / 99, 10 / 99, 10.05 / 45, 13 / 45). The pure fractions were combined, concentrated under reduced pressure and lyophilized to provide 114. M / Z (ESI): 504.32 [M+H]+. Petition 870260070497, dated 07 / 16 / 2026, pages 118 / 214 110 / 205 RMN ‘Η ​​(400 MHz, DMSO-d6) δ (ppm) = 10.46 (s, 1H), 9.05 (s, 1H), 8.90 (d, J= 3.2 Hz, 1H), 8.71 (s, 2H), 8.73, 81 (d, 4), J= Hz (m, 3H), 7.56 (t, J= 7.2 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 6.65 (t, J = 6.4 Hz, 1H), 5.32-5.55 (m, 2H), 4.84 (Hd), 4.84 (Hd, 4, 4 Hz, 1H), 4.37 (d, J= 13.2 Hz, 1H), 4.26 (d, J= 12.4 Hz, 1H), 3.49 (t, J= 9.0 Η, 1H), 3.38–3.45 (m, 1H, 3,41), 3,4H (s Hz, 3.6 Hz, 1H), 2.89–3.04 (m, 1H). Example 115: (S)-N-(5-(4-(6-fluoropyrimidine-4-yl)-3-methylpiperazm-lyl)pyrazine-2-yl)-6-( 1 -methyl- lH-pyrazol-4-yl)nicotinamide Br (1.2 eq) Na2CO3(3 eq), Pd(dppf)CI2(0.1 eq) 1,4- dioxane, H2O, 1Q0°C, 12 h NN / P-7 Synthesis of P-3: (S)-4-(6-fluoropyrimidine-4-yl)-3-methylpiperazine-l -tert -butyl carboxylate

[00208] To a stirred solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (P-1) (5 g, 24.96 mmol) in DMF (50 mL), DIPEA (13.08 mL, 74.9 mmol) and 4,6-difluoropyrimidine (P-2) (3.48 g, 30.0 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was rapidly cooled with ice-cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layer Petition 870260070497, dated 07 / 16 / 2026, pp. 119 / 214 111 / 205 combined was washed with brine (100 mL), dried with anhydrous Na2SÜ4, filtered and concentrated under reduced pressure. The crude compound was purified by Biotage with an 80 g silica gel cartridge (silica 230-400) and the compound eluted with 20% EtOAc in petroleum ether. The pure fractions were combined and concentrated under vacuum to provide P-3. M / Z (ESI): 297.16 [M+H]+. Synthesis of P-4: (S)-4-fluoro-6-(2-methylpiperazin-1-yl)pyrimidine

[00209] To a stirred solution of P-3 (2.3 g, 7.76 mmol) in DCM (30 mL), 4M HCl in 1,4-dioxane (9.70 mL, 38.8 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, concentrated, and dried under reduced pressure to give P-4. M / Z (ESI): 197.09 [M+H]+. Synthesis of P-6: (S)-4-(4-(5-bromopyrazin-2-yl)-2-methylpiperazin-1-yl)-6fluoropyrimidine

[00210] To a stirred solution of P-4 (500 mg, 2.149 mmol) in DMSO (8 mL), cesium fluoride (1958 mg, 12.89 mmol) and 2,5-dibromopyrazine (P-5) (613 mg, 2.58 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 6 hours under an argon atmosphere. The reaction mixture was rapidly cooled with ice-cold water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage with a silica gel cartridge and eluted with 25% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to give P-6. M / Z (ESI): 353.06 [M+H]+. Synthesis of P-7: 6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00211] To a solution of 6-bromonicotinamide (3 g, 14.92 mmol) in 1,4-dioxane (40 mL) and H2O (10 mL), 1-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.73 g, 17.91 mmol) and Na2CO3 were added. Petition 870260070497, dated 07 / 16 / 2026, pp. 120 / 214 112 / 205 (4.75 g, 44.8 mmol) at room temperature. The reaction mixture was degassed and purged with argon for 5 minutes. Then, PdCF (dppf) (1.092 g, 1.492 mmol) was added to this reaction mixture at room temperature. The reaction mixture was stirred at 100°C for 12 hours, rapidly cooled with water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage with an 80 g silica gel cartridge (mesh 230-400) and the compound eluted with 10-15% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure to provide P-7. M / Z (ESI): 203.02 [M+H]+. Example 115: (S)-N-(5-(4-(6-fluoropyrimidine-4-yl)-3-methylpiperazine-1yl)pyrazine-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00212] To a stirred solution of P-6 (100 mg, 0.283 mmol) in 1,4-dioxane (2 mL), P-7 (69 mg, 0.341 mmol), Cs2CO3 (277 mg, 0.849 mmol), copper(I) iodide (5 mg, 0.026 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (4 mg, 0.028 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 10 minutes. The reaction mixture was stirred in a microwave at 130°C for 30 minutes. The reaction mixture was rapidly cooled with water (30 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was macerated with diethyl ether (2 x 10 mL) and dried under reduced pressure.The obtained compound was purified again by preparative HPLC (conditions: Mobile phase - FA 0.1% in H2O:MeCN, column - X-Bridge C18 (19X250) mm, 5μ, flow rate - 15.0 ml / min, gradient method - 0 / 35, 2 / 35, 6 / 45, 10.5 / 48, 7.10, 55 / 100, 12.5 / 100, 12.55 / 35, 16 / 35). The pure compound was combined, concentrated under reduced pressure and lyophilized to provide 115, M / Z (ESI): 475.18 [M+H]+. Petition 870260070497, dated 07 / 16 / 2026, pp. 121 / 214 113 / 205 1H NMR (400 MHz, DMSO-do) δ (ppm) = 10.84 (s, 1H), 9.09 (dd, J = 2.4 Hz, 0.8 Hz, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.32-8.39 (m, 2H), 8.23 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 0.4 Hz, 1H), 7.78 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 6.58 (d, J = 1.2 Hz, 1H), 4.69 (br s, 1H), 4.15-4.39 (m, 3H), 3.91 (s, 3H), 3.35-3.48 (m, 2H), 3.08-3.20 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H). Example 116: (S)-6-(3-fluoroazetidin-1-yl)-N-(5-(4-(5-fluoropyridin-2-yl)-3methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide 4M HCl in dioxane (5.0 eq.) Toluene, 110°C, 16 h CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'dimethylcyclohexane-1,2-diamine (0.05 eq.), 1,4-dioxane, 150°C, MW, 2 h Synthesis of Q-3: (S)-4-(5-fluoropyridin-2-yl)-3-methylpiperazine-1-carboxylate tert-butyl

[00213] A stirred solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (Q-1) (1 g, 4.99 mmol) in toluene (20 mL), 2-chloro-5-fluoropyridine (Q-2) (0.995 mL, 9.99 mmol) and sodium tert-butoxide Petition 870260070497, dated 07 / 16 / 2026, pp. 122 / 214 114 / 205 (1.440 g, 14.98 mmol) at room temperature. The reaction mixture was degassed and purged with argon gas for 25 minutes. Then, RuPhos Pd G2 (0.388 g, 0.499 mmol) was added to this mixture at room temperature. The reaction mixture was stirred at 110°C for 16 hours under a nitrogen atmosphere in a sealed tube. The reaction mixture was rapidly cooled with water (50 mL) and extracted with EtOAc (2 x 85 mL). The combined organic layer was washed with brine (2 x 40 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using an 80 g silica cartridge (230-400 mesh) and the compound eluted with 15% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide Q-3. M / Z (ESI): 296.11 [M+H]+. Q-4 synthesis: (S)-1-(5-fluoropyridin-2-yl)-2-methylpiperazine

[00214] To a stirred solution of Q-3 (100 mg, 0.339 mmol) in DCM (2 mL), 4M HCl in 1,4-dioxane (0.423 mL, 1.693 mmol) at 0°C was added. The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The crude compound was macerated with 20% EtOAc in diethyl ether and dried under reduced pressure to give Q-4. M / Z (ESI): 196.12 [M+H]+. Synthesis of Q-6: (S)-2-bromo-5-(4-(5-fluoropyridin-2-yl)-3-methylpiperazin-1-yl)pyrazine

[00215] To a stirred solution of Q-4 (80 mg, 0.345 mmol) in DMSO (2 mL), CsF (157 mg, 1.036 mmol) and 2,5-dibromopyrazine (Q-5) (164 mg, 0.691 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere in a sealed tube. The reaction mixture was rapidly cooled with water (20 mL) and extracted with EtOAc (2 x 35 mL). The combined organic layer was washed with brine (2 x 20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified. Petition 870260070497, dated 07 / 16 / 2026, pages 123 / 214 115 / 205 by Biotage using an 80 g silica cartridge (230-400 mesh) and the compound was eluted with 25% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide Q-6. M / Z (ESI): 352.97 [M+H]+. Example 116: (S)-6-(3-fluoroazetidin-1-yl)-N-(5-(4-(5-fluoropyridin-2-yl)-3methylpiperazin- 1-yl)pyrazin-2-yl)nicotinamide

[00216] To a stirred solution of Q-6 (60 mg, 0.170 mmol) in 1,4-dioxane (1.5 mL), Cs2CO3 (167 mg, 0.511 mmol), copper(I) iodide (3.24 mg, 0.017 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (1.212 mg, 8.52 pmol) and (Q-7) (prepared analogously to X-5) (61.4 mg, 0.170 mmol) were added at room temperature. The reaction mixture was stirred in a microwave at 150°C for 2 hours under a nitrogen atmosphere. The reaction mixture was rapidly cooled with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layer was washed with brine (2 x 40 mL), dried with anhydrous NebSO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a 40 g silica cartridge (230-400 mesh) and eluted with 3% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure.The compound obtained was further purified by preparative achiral purification [Cellulose SC (250Χ30Χ5μ), MeCN:MeOH (90:10)]. The pure fractions were combined, concentrated under reduced pressure and lyophilized to provide 116. M / Z (ESI): 467.28 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.50 (s, 1H), 8.83 (d, J = 1.6 Hz, 1H), 8.76-8.82 (m, 1H), 8.10-8.26 (m, 3H), 7.49-7.59 (m, 1H), 6.87 (dd, J = 9.4 Hz, 3.4 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.40-5.72 (m, 1H), 4.50-4.63 (m, 1H), 4.32-4.49 (m, 2H), 3.98-4.32 (m, 5H), 3.16-3.30 (m, 2H), 3.00-3.12 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H). Petition 870260070497, dated 07 / 16 / 2026, pages 124 / 214 116 / 205 Example 117: (R)-N-(5-(4-(5-fluoropyridin-2-yl)-3-(methoxymethyl)piperazin-1yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide RuphosPdG3 (0.1 eq.), t-BuONa (3 eq.), 1,4-dioxane, 110°C, 16 h P-7 (1 eq.) CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'dimethylcyclo-hexane-1,2-diamine (0.05 eq.), 1,4-dioxane, 150°C, MW, 2 h Synthesis of R-3: (R)-4-(5-fluoropyridin-2-yl)-3-(methoxymethyl)piperazine-1benzyl carboxylate

[00217] A stirred solution of R-1 (2 g, 7.57 mmol) in 1,4-dioxane (30 mL), sodium tert-butoxide (2.182 g, 22.70 mmol) and 2-chloro-5-fluoropyridine (R-2) (1.194 g, 9.08 mmol) was added at room temperature. The reaction mixture was degassed and purged with argon gas for 5 minutes. Then, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.633 g, 0.757 mmol) was added to this reaction mixture at room temperature. The reaction mixture was stirred at 110°C for 16 hours in a sealed tube. The reaction mixture was rapidly cooled with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column spectroscopy and eluted with 20% EtOAc in petroleum ether. The pure fractions were... Petition 870260070497, dated 07 / 16 / 2026, pages 125 / 214 117 / 205 combined and concentrated under reduced pressure to provide R-3. M / Z (ESI): 360.07 [M+H]+· Synthesis of R-4: (R)-1-(5-fluoropyridin-2-yl)-2-(methoxymethyl)piperazine

[00218] To a stirred solution of R-3 (800 mg, 2.226 mmol) in MeOH (10 mL), 10% Pd / C (237 mg, 0.223 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere, filtered through a layer of celite, and the filtrate was concentrated and dried under reduced pressure to give R-4. M / Z (ESI): 226.00 [M+H]+ Synthesis of R-6:(R)-2-bromo-5-(4-(5-fluoropyridin-2-yl)-3(methoxymethyl)piperazin-1-yl)pyrazine

[00219] To a stirred solution of R-4 (600 mg, 2.66 mmol) in DMSO (10 mL), CsF (1214 mg, 7.99 mmol) and 2,5-dibromopyrazine (R-5) (1267 mg, 5.33 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere in a sealed tube. The reaction mixture was rapidly cooled with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with 20% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide R-6. M / Z (ESI): 382.17 [M+H]+ Example 117: (R)-N-(5-(4-(5-fluoropyridin-2-yl)-3-(methoxymethyl)piperazin-1yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00220] A stirred solution of R-6 (70 mg, 0.183 mmol) and P-7 (37.0 mg, 0.183 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (179 mg, 0.549 mmol), copper(I) iodide (3.49 mg, 0.018 mmol), and transN,N'-dimethylcyclohexane-1,2-diamine (1.302 mg, 9.16 pmol) at room temperature. The reaction mixture was degassed and purged with argon gas. Petition 870260070497, dated 07 / 16 / 2026, pp. 126 / 214 118 / 205 for 10 minutes. The reaction mixture was stirred in a microwave at 150°C for 2 hours, rapidly cooled with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (5 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Bridge, C18 (25X250) mm, 5μ, flow rate - 15.0 mL / min, gradient method 0 / 35, 1 / 35, 10.3 / 70, 10.35 / 98, 13.5 / 98, 13.55 / 35, 16 / 35). The pure fractions were combined, concentrated under reduced pressure, and lyophilized to provide 117. M / Z (ESI): 504.15 [M+H]+ RMN 1H (400 MHz, DMSO-d6) δ (ppm) = 10,84 (s, 1H), 9,09 (dd, J = 2,4 Hz, 0,8 Hz, 1H), 8,88 (d, J = 1,6 Hz, 1H), 8,41 (s, 1H), 8,34 (dd, J = 8,4 Hz, 2,4 Hz, 1H), 8,17 (d, J = 1,6 Hz, 1H), 8,08-8,15 (m, 2H), 7,78 (dd, J = 8,4 Hz, 0,8 Hz, 1H), 7,49-7,59 (m, 1H), 6,88 (dd, J = 9,4 Hz, 3,4 Hz, 1H), 4,54-4,63 (m, 1H), 4,38 (d, J = 13,2 Hz, 1H), 4,23 (d, J = 12,8 Hz, 1H), 3,994,13 (m, 1H), 3,91 (s, 3H), 3,46 (t, J = 9,2 Hz, 1H), 3,33-3,39 (m, 1H), 3,203,29 (m, 5H), 3,11-3,20 (m, 1H). Petição 870260070497, de 16 / 07 / 2026, pág. 127 / 214 119 / 205 Exemplo 118:(S)-N-(2-(4-(5-fluoropiridin-2-il)-2-metilpiperazin-1il)pirimidin-5-il)-6-(1-metil-1H-pirazol-4-il)nicotinamida RuphosPdG3 (0,1 eq.), tBuONa (3 eq.), 1,4-dioxano, 110°C, 16 h HCl 4M em 1,4dioxano (4 eq.), DCM, 0°C-rt, 2 h CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'dimethylcyclohexane-1,2-diamine (0.05 eq.), 1,4dioxane, 150°C, 2 h, MW Synthesis of S-2: tert-butyl (S)-4-(5-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate

[00221] To a stirred solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (S-1) (2 g, 9.99 mmol) and 2-bromo-5-fluoropyridine (2.109 g, 11.98 mmol) in toluene (50 mL), sodium tert-butoxide (2.88 g, 30.0 mmol) was added at room temperature, followed by degassing with argon for 5 minutes. Then, RuPhos Pd G2 (0.776 g, 0.999 mmol) was added to the reaction mixture at room temperature and degassing with argon was again performed for 1 minute. The reaction mixture was stirred at 110°C for 16 hours, diluted with water (50 mL) and extracted with EtOAc (50 mL). The combined organic layer was dried with sodium sulfate. Petition 870260070497, dated 07 / 16 / 2026, pp. 128 / 214 120 / 205 anhydrous, filtered and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel cartridge 24 geo-compound eluted with 50% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide S-2. M / Z (ESI): 296.11 [M+H]+. Synthesis of S-3: (S)-1-(5-fluoropyridin-2-yl)-3-methylpiperazine

[00222] To a stirred solution of S-2 (1.5 g, 5.08 mmol) in DCM (20 mL), 4M HCl in 1,4-dioxane (5.08 mL, 20.31 mmol) at 0°C was added. The reaction mixture was stirred at 25°C for 2 hours and concentrated under reduced pressure to give S-3. M / Z (ESI): 196.01 [M+H]+. Synthesis of S-4: (S)-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)-5iodopyrimidine

[00223] To a stirred solution of S-3 (1.2 g, 5.18 mmol) in DMF (20 mL) under argon, 2-chloro-5-iodopyrimidine (1.494 g, 6.21 mmol) and DIPEA (2.71 mL, 15.54 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours, rapidly cooled with water (50 mL), and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica column and eluted with 10% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to give S4. M / Z (ESI): 400.19 [M+H]+. Example 118: (S)-N-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00224] A stirred solution of S-4 (50 mg, 0.125 mmol) and P-7 (25.3 mg, 0.125 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (122 mg, 0.376 mmol), copper(I) iodide (2.385 mg, 0.013 mmol) and transN,N'-dimethylcyclohexane-1,2-diamine (0.891 mg, 6.26 pmol) at room temperature, followed by degassing with argon for 10 minutes. A Petition 870260070497, dated 07 / 16 / 2026, pp. 129 / 214 The reaction mixture was stirred at 150°C for 2 hours under microwave irradiation. The reaction mixture was rapidly cooled with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (5 mL), dried with NebSO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - 10 mM ammonium bicarbonate in H₂O:MeCN, column - XBridge, C₁₈ (19X250) mm, 5μ, flow rate - 12.0 mL / min, gradient method: 0 / 50, 2 / 50, 8.66 / 60, 8.7 / 100, 12 / 100, 12.05 / 50, 16 / 50). The pure fractions were combined, concentrated under reduced pressure, and lyophilized to provide 118. M / Z (ESI): 474.21 [M+H]+. 8,078.15 (m, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.49-7.58 (m, 1H), 6.92 (dd, J = 9.4 Hz, 3.4 Hz, 1H), 4.80-4.90 (m, 1H), 4.10-4.50 (m, 3H), 3.91 (s, 3H), 3,253,30 (m, 1H), 3.15 (dd, J = 12.8 Hz, 4.0 H, 1H), 2.92 (td, J = 12.0 H, 3.6 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H). Exemplo 119: (R)-N-(2-(3-((2-fluoroetoxi)metil)-4-(pirimidin-2-il)piperazin1-il)pirimidin-5-il)-6-(1-metil-1H-pirazol-4-il)nicotinamida Petition: 870260070497, on 07 / 16 / 2026, page. 130 / 214 122 / 205

[00225] To the solution of T-1 (prepared analogously to that of R-6) (100 mg, 0.225 mmol) in 1,4-dioxane (2 mL), P-7 (54.6 mg, 0.270 mmol), CS2CO3 (220 mg, 0.675 mmol), copper(I) iodide (4.29 mg, 0.023 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (3.20 mg, 0.023 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon for 10 minutes. Then, this reaction mixture was stirred in a microwave at 150°C for 2 hours.

[00226] The reaction mixture was rapidly cooled with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was macerated with diethyl ether (2 x 5 mL) and concentrated under reduced pressure. The obtained compound was purified by preparative HPLC (conditions: Instrument ID ANLMCL5-PREP-020, column name: Betasil Phenyl Hexyl (21.2X250) mm, 5 μm, column no. 250*19, Mobile phase A - 10 mM ammonium bicarbonate in water, Mobile phase B - acetonitrile; gradient program (T / %B) 0 / 35, 2 / 35, 10 / 55, 11.63 / 55, 11.65 / 100, 15 / 100, 15.01 / 35, 18 / 35). The pure fractions were Petition 870260070497, dated 07 / 16 / 2026, pp. 131 / 214 123 / 205 combined and concentrated under reduced pressure to provide 119. M / Z (ESI): 519.31 [M+H]+. Example 120: (R)-N-(2-(4-(6-fluoropyrimidin-4-yl)-3-(methoxymethyl)piperazin1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.1 eq.),1,4-dioxane, 150°C, MW, 2 h

[00227] To the solution of P-7 (100 mg, 0.232 mmol) in 1,4-dioxane (2 mL), U-1 (prepared analogously to Q-6) (56.4 mg, 0.279 mmol), Cs2CÜ3 (227 mg, 0.697 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (3.31 mg, 0.023 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon for 10 minutes. The reaction mixture was stirred in a microwave at 150°C for 2 hours. The reaction mixture was rapidly cooled with water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous Na2SÜ4, filtered, and concentrated under reduced pressure. The crude compound was macerated with diethyl ether (2 x 10 mL) and concentrated under reduced pressure. The resulting compound was purified by preparative HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate). Petition 870260070497, dated 07 / 16 / 2026, pp. 132 / 214 124 / 205 in H2U:MeCN, column - X-Bridge, C18 (19X250) mm, 5μ, flow rate -14.0 ml / min, gradient method: -0 / 35, 2 / 35, 8.60 / 45, 8.65 / 100, 11.65 / 100, 11.70 / 35, 15.0 / 35). The pure fractions were combined, concentrated under reduced pressure and lyophilized to provide 120, M / Z (ESI): 505.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.33 (s, 1H), 9.05 (d, J = 2.0 H, 1H), 8.71 (s, 2H), 8.41 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 8.10 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 6.58 (s, 1H), 4.57 - 4.96 (m, 2H), 4.11 - 4.56 (m, 2H), 3.91 (s, 3H), 3.43 - 3.50 (m, 2H), 3.11 - 3.29 (m, 6H). Example 121: (R)-N-(4-fluoro-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide 4M HCl in 1,4-dioxane (4 eq.), DCM, 0°C-rt, 12 h CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'dimethylcyclohexane-1,2-diamine (0.05 eq.), 1,4-dioxane, rt, 48 h Synthesis of V-2: (R)-2-(2-(methoxymethyl)piperazin-1-yl)pyrimidine

[00228] To a stirred solution of V-1 (prepared analogously to that of 3-2) (2 g, 6.49 mmol) in DCM (40 mL), HCl in 1,4-dioxane (3.08 mL, 25.9 mmol) at 0°C was added. The reaction mixture was stirred to Petition 870260070497, dated 07 / 16 / 2026, pages 133 / 214 125 / 205 ambient temperature for 12 hours. The reaction mixture was concentrated and dried under reduced pressure to provide V-2. M / Z (ESI): 209.18 [M+H]+. Synthesis of V-3: (R)-4-chloro-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1yl)-5-(trimethylsilyl)pyrimidine

[00229] To a stirred solution of V-2 (1.5 g, 6.13 mmol) in DMF (30 mL), 2,4-dichloro-5-(trimethylsilyl)pyrimidine (1.627 g, 7.36 mmol) and DIPEA (3.21 mL, 18.39 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was rapidly cooled with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified using a 100 g silica gel cartridge (60-120 mesh) and eluted with 20% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to give V-3. M / Z (ESI): 393.21 [M+H]+. Synthesis of V-4: (R)-4-chloro-5-iodo-2-(3-(methoxymethyl)-4-(pyrimidin-2yl)piperazin-1-yl)pyrimidine

[00230] To a stirred solution of V-3 (1.2 g, 3.05 mmol) in MeCN (10 mL) and DCM (5 mL), ICl (0.230 mL, 4.58 mmol) was added at -10°C. The reaction mixture was stirred at -10°C for 3 hours. The reaction mixture was rapidly cooled with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried with anhydrous NibSO4, filtered, and concentrated under reduced pressure. The crude compound was purified using a 100 g silica gel cartridge (100-200 mesh) and eluted with 25% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to give V-4. M / Z (ESI): 446.92 [M+H]+. Synthesis of V-5: (R)-4-fluoro-5-iodo-2-(3-(methoxymethyl)-4-(pyrimidin-2yl)piperazin-1-yl)pyrimidine Petition 870260070497, dated 07 / 16 / 2026, pp. 134 / 214 126 / 205

[00231] To a stirred solution of V-4 (500 mg, 1.119 mmol) in DMSO (10 mL), potassium fluoride (325 mg, 5.60 mmol) was added at room temperature. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was rapidly cooled with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a 100 g silica gel column (100-200 mesh) and eluted with 20% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to give V-5. M / Z (ESI): 431.00 [M+H]+. Example 121: (R)-N-(4-fluoro-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00232] To a stirred solution of V-5 (50 mg, 0.116 mmol) and P-7 (28.2 mg, 0.139 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (114 mg, 0.349 mmol), copper(I) iodide (2.213 mg, 0.012 mmol), and transN,N'-dimethylcyclohexane-1,2-diamine (0.827 mg, 5.81 gmol) were added at room temperature. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was rapidly cooled with water (30 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Bridge C18 (10X250mm), 5μ, flow rate -7 ml / min, gradient method 0 / 52, 2 / 52, 7.5 / 55.5, 10 / 55.5, 10.05 / 100, 12 / 100, 12.05 / 52, 16 / 52). The pure fractions were combined, concentrated under reduced pressure and lyophilized to provide 121. M / Z (ESI): 505.32 [M+H]+. RMN 1H (400 MHz, DMSO-d6) δ (ppm) = 10,15 (s, 1H), 9,05 (d, J = 1,6 Hz, 1H), 8,54 (d, J = 13,2 Hz, 1H), 8,38-8,45 (m, 3H), 8,28 (dd, J = 8,4 Hz, 2,4 Hz, 1H), 8,10 (s, 1H), 7,81 (d, J = 8,4 Hz, 1H), 6,68 (t, J = 4,6 Petição 870260070497, de 16 / 07 / 2026, pág. 135 / 214 127 / 205 Hz, 1H), 4,87-4,49 (m, 1H), 4,66 (d, J = 13,2 Hz, 1H), 4,49-4,58 (m, 1H), 4,43 (d, J = 11,2 Hz, 1H), 3,91 (s, 3H), 3,39-3,48 (m, 3H), 3,27 (d, J = 2,4 Hz, 1H), 3,24 (s, 3H), 3,15-3,21 (m, 1H). Exemplo 122: (S)-N-(5-(4-(5-fluoropirimidm-2-il)-3-metilpiperazm-1il)pirazin-2-il)-6-(pirrolidin- 1-il)nicotinamida RuphosPdG2 (0,1 eq.), NaOtBu (3 eq.), tolueno, 110°C, 16 h HCl 4M em 1,4-dioxano (4 eq.), DCM, 0°C-rt, 4 h CS2CO3 (3 eq.), CuI (0,1 eq.), trans-N,N'-dimetilciclohexano-1,2-diamina (0,1 eq.),1,4-dioxano, 100°C, 16 h Petition 870260070497, dated 07 / 16 / 2026, pp. 136 / 214 128 / 205 Synthesis of X-2: (S)-4-(5-fluoropyrimidin-2-yl)-3-methylpiperazine-1-carboxylate tert-butyl

[00233] A stirred solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (X-1) (1 g, 4.99 mmol) in toluene (20 mL) was purged with argon gas for 10 minutes. Then, 2-chloro-5-fluoropyrimidine (0.993 g, 7.49 mmol), sodium tert-butoxide (1.440 g, 14.98 mmol) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.388 g, 0.499 mmol) were added to the reaction mixture at room temperature and purged again with argon for another 10 minutes. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was rapidly cooled with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried with N2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel cartridge 25 geo-compound eluted with 30% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide X-2.M / Z (ESI): 297.27 [M+H]+. Synthesis of X-3: (S)-5-fluoro-2-(2-methylpiperazin-1-yl)pyrimidine hydrochloride

[00234] To a stirred solution of X-2 (1.1 g, 3.71 mmol) in DCM (20 mL), 4M HCl in 1,4-dioxane (3.71 mL, 14.85 mmol) at 0°C was added. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure to give X-3. M / Z (ESI): 197.02 [M+H]+. Synthesis of X-4: (S)-2-(4-(5-bromopyrazin-2-yl)-2-methylpiperazin-1-yl)-5fluoropyrimidine

[00235] To a stirred solution of X-3 (800 mg, 3.44 mmol) in DMSO (20 mL), CsF (1567 mg, 10.31 mmol) and 2,5-dibromopyrazine (981 mg, 4.13 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was then cooled. Petition 870260070497, dated 07 / 16 / 2026, pp. 137 / 214 129 / 205 rapidly with water (120 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel cartridge 25 geo. The compound was eluted with 30% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide X-4. M / Z (ESI): 353.09 [M+H]+. Synthesis of X-5: 6-(pyrrolidin-1-yl)nicotinamide

[00236] To a stirred solution of 6-chloronicotinamide (1 g, 6.39 mmol) in DMF (30 mL), pyrrolidine (0.681 g, 9.58 mmol) and K2CO3 (2.65 g, 19.16 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was rapidly cooled with water (80 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was dried with filtered Na2SO4 and concentrated under reduced pressure. The crude compound was washed with diethyl ether (2 x 30 mL) and concentrated under reduced pressure to give X-5. M / Z (ESI): 192.00 [M+H]+. Example 122: (S)-N-(5-(4-(5-fluoropyrimidin-2-yl)-3-methylpiperazin-1yl)pyrazin-2-yl)-6-(pyrrolidin-1-yl)nicotinamide

[00237] To a stirred solution of X-4 (60 mg, 0.170 mmol) and X-5 (40 mg, 0.204 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (166 mg, 0.510 mmol), copper(I) iodide (3.24 mg, 0.017 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (2.416 mg, 0.017 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was rapidly cooled with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried with filtered Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Bridge C18 (10X250mm), 5μm, flow rate -7 ml / min, gradient method -0 / 52, 2 / 52, 7.5 / 55, 5.10 / 55.5, 10.05 / 100, 12 / 100, Petition 870260070497, dated 07 / 16 / 2026, pp. 138 / 214 130 / 205 12.05 / 52, 16 / 52). As pure fractions combined, concentrated under reduced pressure and freeze-dried to bake 122. M / Z (ESI): 464.28 [M+H]+. NMR 1H (400 MHz, DMSO-dô) δ = 10.38 (s, 1H), 8.83 (d, J = 1.2 Hz, 1H), 8.77 (d, J = 2.0 H, 1H), 8.50 (d, J = 0.8 Hz, 2H), 8.18 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 6.49 (d, J = 8.8 Hz, 1H), 4.78-4.87 (m, 1H), 4.38-4.48 (m, 1H), 4.17-4.30 (m, 2H), 3.46 (s, 4H), 3.36-3.40 (m, 1H), 3.22 (dd, J = 12.8 Hz, 4.0 H, 1H), 3.02 (td, J = 11.8 Hz, 4.0 H, 1H), 1.96 (t, J = 6.6 Hz, 4H), 1.16 (d, J = 6.8 Hz, 3H). Example 123:(S)-6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-N-(2-(4-(5fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00238] To a stirred solution of S-4 (50 mg, 0.125 mmol) and Y-1 (prepared analogously to P-7) (29.3 mg, 0.125 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (122 mg, 0.376 mmol), copper(I) iodide (2.385 mg, 0.013 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.891 mg, 6.26 pmol) were added at room temperature, followed by degassing with argon for 10 minutes. The reaction mixture was stirred at 150°C for 2 hours under microwave irradiation. The reaction mixture was rapidly cooled with water (10 mL) and extracted with EtOAc (2 x 20 mL). Petition 870260070497, dated 07 / 16 / 2026, pp. 139 / 214 131 / 205 The combined organic layer was washed with brine (5 mL), dried with Na2SÜ4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - 2.5 mM ammonium bicarbonate in H2O:MeCN, column - X-Bridge, C18 (19X250) mm, 5μ, flow rate - 15.0 mL / min, gradient method - 0 / 45, 2 / 45, 10.5 / 62, 10.55 / 100, 13 / 100, 13.05 / 45, 17 / 45 ANL-MCL-PREP-023). The pure fractions were combined, concentrated under reduced pressure, and lyophilized to provide 123, M / Z (ESI): 506.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 9.07 (d, J = 1.6 Hz, 1H), 8.70 (s, 2H), 8.49 (s, 1H), 8.30 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.53 (td, J = 8.6 Hz, 2.9 Hz, 1H), 6.92 (dd, J = 9.4 Hz, 3.4 Hz, 1H), 4.40-4.91 (m, 6H), 4.10 4.25 (m, 2H), 3.24-3.30 (m, 1H), 3.15 (dd, J = 12.8 Hz, 4.0 H, 1H), 2.93 (td, J = 11.8 Hz, 3.4 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H). Example 124: (R)-N-(5-(3-((2-fluoroethoxy)methyl)-4-(5-fluoropyridin-2yl)piperazin-1-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'dimethylcyclohexane-1,2-diamine (0.05 eq.), 1,4-dioxane, 150°C, MW, 2 h Synthesis of Z-1: (R)-(4-(5-bromopyrazin-2-yl)-1-(5-fluoropyridin-2-yl)piperazin2-yl)methanol

[00239] To a stirred solution of R-6 (200 mg, 0.523 mmol) in DCM (2 mL), BBr3 (1.570 mL, 1.570 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, rapidly cooled with ice-cold water (10 mL), and extracted. Petition 870260070497, dated 07 / 16 / 2026, pp. 140 / 214 132 / 205 with EtOAc (2 x 10 mL). The combined organic layer was washed with saturated aqueous NaHCO3 (20 mL) and brine (2 x 20 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a 40 g silica cartridge (100-200 mesh) and the compound eluted with 10% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide Z-1. M / Z (ESI): 369.12 [M+H]+. Synthesis of Z-2: (R)-2-bromo-5-(3-((2-fluoroethoxy)methyl)-4-(5-fluoropyridin-2yl)piperazin-1-yl)pyrazine

[00240] To a stirred solution of Z-1 (120 mg, 326 μmol) in DMF (3 mL), NaH (39.1 mg, 1.63 mmol) was added at 0°C for 10 minutes. Then, 1-fluoro-2-iodoethane (567 mg, 3.26 mmol) was added to this mixture at 0°C. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was rapidly cooled with ice-cold water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with brine (25 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a 40 g silica cartridge (100-200 mesh) and the compound eluted with 20% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide Z-2. M / Z (ESI): 415.15 [M+H]+. Example 124: (R)-N-(5-(3-((2-fluoroethoxy)methyl)-4-(5-fluoropyridin-2yl)piperazin-1-yl)pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00241] To a stirred solution of Z-2 (80.0 mg, 193 μmol) and P-7 (43.0 mg, 212 μmol) in 1,4-dioxane (2 mL), cesium carbonate (189 mg, 579 μmol) at room temperature was added. The reaction mixture was degassed and purged with nitrogen gas for 10 minutes. Then, copper(I) iodide (3.68 mg, 19.3 μmol) and trans-(1r,2r)-N,N'-bismethyl-1,2-cyclohexanediamine (305 mL, 0.966 μmol) were added to this reaction mixture. The reaction mixture was stirred in a microwave at 150°C for 2 Petition 870260070497, dated 07 / 16 / 2026, pp. 141 / 214 133 / 205 hours. The reaction mixture was filtered through a celite layer and concentrated under reduced pressure. The residue was rapidly cooled with water (2 mL) and extracted with 10% MeOH in DCM (2 x 2 mL). The combined organic layer was washed with brine (2 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Select, C18 (10X150) mm, 5μ, flow rate - 6.0 mL / min, gradient method - 0 / 40, 14 / 40, 14.1 / 100, 17.9 / 100, 18 / 40, 22 / 40). The pure fractions were combined, concentrated under reduced pressure and lyophilized to provide 124, M / Z (ESI): 536.31 [M+H]+. RMN 1H (400 MHz, DMSO-d6) δ (ppm) = 10,84 (s, 1H), 9,09 (d, J = 1,6 Hz, 1H), 8,88 (d, J = 1,6 Hz, 1H), 8,41 (s, 1H), 8,34 (dd, J = 8,4 Hz, 2,4 Hz, 1H), 8,07-8,21 (m, 3H), 7,78 (d, J = 8,4 Hz, 1H), 7,54 (td, J = 8,8 Hz, 3,2 Hz, 1H), 6,89 (dd, J = 9,2 Hz, 3,2 Hz, 1H), 4,55-4,65 (m, 1H), 4,384,55 (m, 3H), 4,25 (d, J = 12,4 Hz, 1H), 3,99-4,10 (m, 1H), 3,91 (s, 3H), 3,45 3,71 (m, 5H), 3,24-3,28 (m, 1H), 3,12-3,20 (m, 1H). Exemplo 125: (S)-2-(3,3-difluoroazetidin-1-il)-N-(5-(4-(6-fluoropirimidin-4il)-2-metilpiperazin-1-il)pirazin-2-il)pirimidina-5-carboxamida CS2CO3 (3 eq.), CuI (0,1 eq.), trans-N,N’-dimetilciclohexano-1,2-diamina (0,05 eq.),1,4-dioxano, 150°C, MW, 2 h Petição 870260070497, de 16 / 07 / 2026, pág. 142 / 214 134 / 205

[00242] To a stirred solution of M-6 (200 mg, 566 μmol) in 1,4-dioxane (3 mL), CS2CO3 (553 mg, 1.70 mmol), CuI (10.8 mg, 56.6 μmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (4.03 mg, 28.3 μmol) and AA-1 (prepared analogously to X-5) (182 mg, 849 μmol) were added at room temperature. The reaction mixture was stirred in a microwave at 150°C for 2 hours under a nitrogen atmosphere. The reaction mixture was rapidly cooled with (20 mL) and extracted with 10% MeOH in DCM (2 x 45 mL). The combined organic layer was washed with brine (2 x 20 mL), dried with anhydrous N2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase: Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Bridge C18 (19X250) mm, 5μ, flow rate - 15.0 mL / min, gradient method - 0 / 40, 3 / 40, 10.5 / 65, 10.55 / 100, 13 / 100, 13.05 / 40, 17 / 40). The pure fractions were combined and concentrated under reduced pressure and lyophilized to provide 125.M / Z (ESI): 487.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.77 (br s, 1H), 9.00 (s, 2H), 8.87 (s, 1H), 8.33 (d, J = 2.4 Hz, s 1H), 8.15 (H6, (H6), 6.64 (s, 1H), 4.58 (t, J = 12.4 Hz, 4H), 4.04–4.52 (m, 3H), 3.44 (dd, J = 13.4 Hz, 3.4 Hz, 1H), 3.20–3.28 (J, 1, = 2H). Petition 870260070497, dated 07 / 16 / 2026, p. 143 / 214 135 / 205 Example 126: (S)-6-(3,3-difluoroazetidin-l-yl)-N-(5-(4-(6-fluoropyridin-3-yl)2-methylpiperazine-1 -i 1 jpyrazi n-2-yl )ni cotinamide BB-2 (1 eq) Pd2(dba)3(0.05), Xantphos (0.1 eq) tBuONa (3eq.), 1,4-dioxane, 110°C, 2 h BB-1 HCI 4M in 1,4-dioxane (1 eq.), DCM, O°C-rt, 1 h BB-3 BB-4 (1 eq) CsF (3 eq), DMSO.80 °C, 16 h Cs2CO3 (3 eq.), Cul (0.1 eq), trans-N,N'dimethylcyclohexane-1,2-diamine (0.05 eq), 1,4dioxane, 110°C, 4 h 126 Synthesis of BB-3: tert-butyl(S)-4-(6-fluoropyridin-3-yl)-2-methylpiperazine-1-carboxylate

[00243] To a stirred solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (5 g, 25 mmol) in 1,4-dioxane (100 mL), sodium 2-methylpropan-2-olate (8.03 mL, 74.9 mmol) and 5-bromo-2-fluoropyridine (4.39 g, 25 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Then, tris(dibezilideneacetone)dipalladium (1.14 g, 1.25 mmol) and 4,5bis(diphenylphosphamo)-9,9-dimethylxanthene (1.44 g, 2.5 mmol) were added to this reaction mixture at room temperature. The reaction mixture was stirred at 110°C for 12 hours under a nitrogen atmosphere in a test tube. Petition 870260070497, dated 07 / 16 / 2026, pp. 144 / 214 136 / 205 sealed. The reaction mixture was rapidly cooled with water (50 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layer was washed with brine (2 x 30 mL), dried with anhydrous NebSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using an 80 g silica cartridge (230-400 mesh) and eluted with 20% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide BB-3. M / Z (ESI): 296.28 [M+H]+. BB-4 synthesis: (S)-1-(6-fluoropyridin-3-yl)-3-methylpiperazine

[00244] To a stirred solution of BB-3 (2.5 g, 8.46 mmol) in DCM (30 mL), 4M HCl in 1,4-dioxane (309 mg, 8.46 mmol) at 0°C was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried under reduced pressure to give BB-4. M / Z (ESI): 196.24 [M+H]+. Synthesis of BB-5: (S)-2-bromo-5-(4-(6-fluoropyridin-3-yl)-2-methylpiperazin-1yl)pyrazine

[00245] To a stirred solution of BB-4 (500 mg, 2.16 mmol) in DMSO (10 mL), CsF (983 mg, 6.47 mmol) and 2,5-dibromopyrazine (513 mg, 2.16 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours in a sealed tube. The reaction mixture was rapidly cooled with water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with brine (2 x 20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a 12 g silica cartridge (230-400 mesh) and eluted with 30% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide BB-5. M / Z (ESI): 352.23 [M+H]+. Example 126: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(5-(4-(6-fluoropyridin-3-yl)2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, pp. 145 / 214 137 / 205

[00246] To a stirred solution of BB-5 (150 mg, 426 μmol) and BB-6 (prepared analogously to X-5) (90.8 mg, 426 μmol) in 1,4-dioxane (2 mL), CuI (8.11 mg, 42.6 μmol), trans-N,N'-bismethyl-1,2-cyclohexanediamine (6.72 pL, 21.3 μmol) and Cs2CO3 (416 mg, 1.28 mmol) were added at room temperature. The reaction mixture was stirred at 110°C for 40 hours in a sealed tube. The reaction mixture was rapidly cooled with water (5 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Column: XBridge C18 (4.6x150) mm, 3.5 pm, mobile phase - A: 10 mM ammonium bicarbonate in water, mobile phase - B: 100% acetonitrile, gradient (T / % B): 0 / 10, 12 / 98, 16 / 98, 16.1 / 10, 20 / 10, flow rate: 1.0 mL / min, column oven temperature: ambient, diluent: MeCN:water (90:10) V / V).The pure fractions were combined and concentrated under reduced pressure and lyophilized to provide 126. M / Z (ESI): 485.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.58 (s, 1H), 8.86 (d, J = 1.2 Hz, 1H), 8.80-8.85 (m, 1H), 8.22 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.87-7.94 (m, 1H), 7.63-7.72 (m, 1H), 7.06 (dd, J = 8.8 Hz, 3.4 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 4.60-4.69 (m, 1H), 4.50 (t, J = 12.4 Hz, 4H), 4.12 (d, J = 10.0H, 1H), 3.73 (d, J = 12.0H, 1H), 3.63 (d, J = 12.0H, 1H), 3.24-3.30 (m, 1H), 3.02 (dd, J = 12.4Hz, 3.6Hz, 1H), 2.84 (td, J = 12.0H, 3.6Hz, 1H), 1.23 (d, J = 6.4Hz, 3H). Petition 870260070497, dated 07 / 16 / 2026, pp. 146 / 214 138 / 205 Example 127: (S)-N-(2-(4-(6-fluoropyridin-3-yl)-2-methylpiperazin-1yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide CS2CO3 (3 eq.), CuI (0,1 eq.), trans-N,N’-dimetilciclohexano-1,2-diamina (0,05 eq.),1,4-dioxano, 110°C, 40 h

[00247] To a stirred solution of CC-1 (prepared analogously to BB-5) (150 mg, 376 μmol) and P-7 (76 mg, 376 μmol) in 1,4-dioxane (2 mL), cesium carbonate (367.0 mg, 1128 μmol), CuI (7.16 mg, 37.6 μmol), and trans-N,N'-bismethyl-1,2-cyclohexanediamine (5.93 μL, 18.8 pmol) were added at room temperature. The reaction mixture was stirred at 110°C for 40 hours in a sealed tube. The reaction mixture was rapidly cooled with water (5 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Column: X Bridge amide (4.6x150) mm, 3.5 pm, mobile phase - A: 20 mM ammonium bicarbonate in water, mobile phase - B: 50:50 MeCN : MEOH, gradient (T / % B): 0 / 5, 1 / 5, 12 / 60, 15 / 70, 20 / 100, 22.1 / 5, 24 / 5, flow rate: 1.0 mL / min, column oven temperature: ambient, diluent: MeCN:H2O).The pure fractions were combined and concentrated under reduced pressure and lyophilized to provide 127. M / Z (ESI): 474.19 [M+H]+. Petition 870260070497, dated 07 / 16 / 2026, pp. 147 / 214 139 / 205 1H NMR (400 MHz, DMSO-dô) δ (ppm) = 10.32 (s, 1H), 9.05 (d, J = 1.6 Hz, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.28 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 8.10 (s, 1H), 7.85-7.91 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62-7.69 (m, 1H), 7.06 (dd, J = 9.2 Hz, 3.4 Hz, 1H), 4.85-4.95 (m, 1H), 4.48 (d, J = 10.4 Hz, 1H), 3.91 (s, 3H), 3.71 (d, J = 12.0 H, 1H), 3.61 (d, J = 12.0 H, 1H), 3.33 3.39 (m, 1H), 2.97 (dd, J = 12.0 H, 4.0 H, 2H), 2.77 (td, J = 11.6 Hz, 3.6 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H). Example 128: (R)-N-(5-(4-(6-fluoropyridin-3-yl)-2-methylpiperazin-1-yl)pyrazin2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 eq.), 1,4-dioxane, 110°C, 16 h

[00248] To a stirred solution of DD-1 (prepared analogously to BB-5) (100 mg, 284 μmol) in 1,4-dioxane (1.5 mL), Cs2CO3 (278 mg, 852 μmol), CuI (5.41 mg, 28.4 μmol), P-7 (68.9 mg, 341 μmol) and trans-N,N'-bismethyl-1,2-cyclohexanediamine (4.48 μE, 14.2 pmol) were added at room temperature. The reaction mixture was stirred at 110°C for 16 hours under a nitrogen atmosphere in a sealed tube. The reaction mixture was rapidly cooled with water (45 mL) and extracted with EtOAc (2 x 85 mL). The combined organic layer was washed with brine (2 x 45 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase Petition 870260070497, dated 07 / 16 / 2026, pp. 148 / 214 140 / 205 Ammonium bicarbonate 10 mM in H2O:MeCN, column - Princeton Spher ULTIMA C18 (21.2X250) mm, 5μ, flow rate - 15.0 ml / min, gradient method - 0 / 48, 3 / 48, 14 / 59, 14.05 / 98, 17 / 98, 17.05 / 48, 2 1.0 / 48). The pure fractions were combined and concentrated under reduced pressure and lyophilized to provide 128. M / Z (ESI): 474.36 [M+H]+. 1H NMR (400 MHz, DMSO-do) δ (ppm) = 10.83 (s, 1H), 9.09 (dd, J = 2.2 Hz, 0.6 Hz, 1H), 8.90 (d, J = 1.2 Hz, 1H), 8.41 (s, 1H), 8.34 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 7.87-7.94 (m, 1H), 7.78 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 7.62-7.71 (m, 1H), 7.06 (dd, J = 8.8 Hz, 3.4Hz, 1H), 4.58-4.75 (m, 1H), 4.14 (d, J = 10.0H, 1H), 3.91 (s, 3H), 3.74 (d, J = 12.0 H, 1H), 3.63 (d, J = 12.0 H, 1H), 3.27 (dd, J = 12.8 Hz, 3.6 Hz, 1H), 3.03 (dd, J = 12.0H, 3.6Hz, 1H), 2.84 (td, J = 12.0H, 3.6Hz, 1H), 1.24 (d, J = 6.4 Hz, 3H). Example 129: (R)-N-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide CS2CO3 (3 eq.), CuI (0.1 eq.), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 eq.), 1,4-dioxane, 120°C, 16 h

[00249] To a stirred solution of EE-1 (prepared analogously to S-4) (100 mg, 250 μmol) and P-7 (60.8 mg, 301 μmol) in 1,4-dioxane (2 mL), trans-N,N'-bismethyl-1,2-cyclohexanediamine (3.95 μL, 12.5 μmol), Cs2CO2 (245 mg, 751 μmol) and CuI were added. Petition 870260070497, dated 07 / 16 / 2026, pp. 149 / 214 141 / 205 (4.77 mg, 25.0 μmol) at room temperature. The reaction mixture was stirred at 120°C for 16 hours under a nitrogen atmosphere. The reaction mixture was rapidly cooled with saturated aqueous Na2CO3 (20 mL) and extracted with 10% MeOH in DCM (2 x 35 mL). The combined organic layer was washed with brine (2 x 20 mL), dried with anhydrous NebSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - YMC-Actus (20X100) mm, 3μ, flow rate - 12 ml / min, gradient method - 0 / 43, 3 / 43, 9.0 / 62, 9.05 / 100, 12 / 100, 12.05 / 43, 15 / 43). The pure fractions were combined and concentrated under reduced pressure and lyophilized to provide 129. M / Z (ESI): 474.26 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.31 (s, 1H), 9.05 (d, J = 2.0 H, 1H), 8.70 (s, 2H), 8.41 (s, 1H), 8.28 (dd, J = 2.2 Hz, 1H), 8.08-8.15 (m, 2H), 7.81 (dd, J = 8.4 Hz, 0.4 Hz, 1H), 7.49-7.59 (m, 1H), 6.92 (dd, J = 9.4 Hz, 3.4 Hz, 1H), 4.80-4.9 (d, J = 4.4 Hz, t 13.2 Hz, 3.2 Hz, 1H), 4.16 (dd, J = 21.4 Hz, 12.6 Hz, 2H), 3.91 (s, 3H), 3.27 (d, J = 3.6 Hz, 1H), 3.15 (dd, J = 3.8 Hz, 12.1H), (td, J = 12.2 Hz, 3.6 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H). Petition 870260070497, of 16 / 07 / 2026, p. 150 / 214 142 / 205 Example 130: (S)-6-(3-(fluoromethyl)azetidin-1-yl)-N-(2-(4-(5-fluoropyridin-2yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide Synthesis of FF-2: (S)-N-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1yl)pyrimidin-5-yl)-6-(3-(hydroxymethyl)azetidin-1-yl)nicotinamide

[00250] To a stirred solution of S-4 (215 mg, 0.501 mmol) and FF-1 (prepared analogously to X-5) (104 mg, 0.501 mmol) in 1,4-dioxane (3 mL), Cs2CO3 (490 mg, 1.503 mmol), copper(I) iodide (9.54 mg, 0.050 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (3.56 mg, 0.025 mmol) were added at room temperature, followed by degassing with argon for 10 minutes. The reaction mixture was stirred at 150°C for 2 hours under microwave irradiation. The reaction mixture was rapidly cooled with water (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica column and eluted with 10% MeOH in DCM. Petition 870260070497, dated 07 / 16 / 2026, pages 151 / 214 143 / 205 The pure fractions were combined and concentrated under reduced pressure to provide FF-2. M / Z (ESI): 477.07 [MH]-. Example 130: (S)-6-(3-(fluoromethyl)azetidin-1-yl)-N-(2-(4-(5-fluoropyridin-2yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00251] To a stirred solution of FF-2 (70 mg, 0.146 mmol) in DCM (1 mL), DAST (0.039 mL, 0.293 mmol) at 0°C was added. The reaction mixture was stirred under an argon atmosphere at 0°C for 30 minutes. The reaction mixture was rapidly cooled with water (5 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (5 mL), dried with NebSO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Bridge, C18 (19X250) mm, 5μ, flow rate - 12.0 ml / min, gradient method - 0 / 50, 2 / 50, 10.5 / 66.5, 10.6 / 100, 13 / 100, 13.1 / 50, 16 / 50). The pure fractions were combined and concentrated under reduced pressure and lyophilized to provide 130. M / Z (ESI): 481.14 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 9.99 (s, 1H), 8.69 (d, J = 2.0 H, 1H), 8.66 (s, 2H), 8.10 (d, J = 2.8 Hz, 1H), 8.05 (dd, J = 8.8 Hz, 2.0 H, 1H), 7.48-7.57 (m, 1H), 6.92 (dd, J = 9.4 Hz, 3.4 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 4.80-4.89 (m, 1H), 4.54-4.75 (m, 2H), 4.38-4.48 (m, 1H), 4.09-4.25 (m, 4H), 3.80-3.90 (m, 2H), 3.23-3.30 (m, 1H), 3.04-3.20 (m, 2H), 2.91 (td, J = 12.0 H, 3.6 Hz, 1H), 1.15 (d, J = 6.4 Hz, 3H).

[00252] The compounds contained in Table 7 were synthesized by analogous methods from the synthetic sequences above. Commercially available reagents were substituted, where necessary, to produce the examples below. Petition 870260070497, dated 07 / 16 / 2026, pp. 152 / 214 144 / 205 Table 7 Ex. No Structure Chemical name Observed mass (M+H) Exacted mass 131 \ (R)-6-(3- (fluoromethyl)azetidin-1yl)-N-(2-(4-(5fluoropyridm-2-yl)-3(methoximethyl)piperazin1-yl)pyrimidin-5yl)nicotinamide 511.30 510.5 132 A cYr ψι (S)-6-(3- (fluoromethyl)azetidin-1yl)-N-(5-(4-(5fluoropyrimidm-2-yl)-3methylpiperazin-1yl)pyrazin-2yl)nicotinamide 482.40 481.5 133 0 cr y (S)-6-(3- (fluoromethyl)azetidin-1yl)-N-(5-(4-(5fluoropyridin-2-yl)-3methylpiperazin-1yl)pyrazin-2yl)nicotinamide 481.30 480.5 Petition 870260070497, 16 / 07 / 2026, pág. 153 / 214 145 / 205 Example 134: 6-(5,6-dihydro-4H-pyrrol[1,2-b1pyrazol-3-yl)-2-fluoro-N-(2-(4(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide 1,4-dioxane Synthesis of GG-2: (S)-2-methyl-4-(pyrimidin-2-yl)piperazine-1-carboxylate of terc-butyl

[00253] To a solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (GG-1, 1.2 g, 1 eq., 5.99 mmol) in DMF (24 mL), potassium carbonate (2.484 g, 3 eq., 17.97 mmol) was added, followed by 2-chloropyrimidine (1.029 g, 1.5 eq., 8.99 mmol). The mixture was stirred for 3 hours at 22°C. Water (100 mL) was added to the mixture, stirred for 30 minutes at 22°C, and extracted with EtOAc (100 mL x 3). The organic layer was dried with MgSO4, filtered through a fine filter, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (3 mL) and purified by normal-phase chromatography (ISCO 80 g RediSep Gold High Performance Silica, hexane 0-100%, EtOAc, gradient 26 minutes). Petition 870260070497, dated 07 / 16 / 2026, pages 154 / 214 146 / 205 fractions containing the desired product were combined and concentrated under vacuum to produce GG-2. MS (ESI) m / z: 279.3 [M+H]+ Synthesis of GG-3: (S)-2-(3-methylpiperazin-1-yl)pyrimidine hydrochloride

[00254] To a solution of (S)-2-methyl-4-(pyrimidin-2-yl)piperazine-1-carboxylate tert-butyl (GG-2, 1.20 g, 1 eq., 4.31 mmol) in 1,4-dioxane (12.0 mL), 4M hydrogen chloride (2.16 mL, 4.00 molar, 2 eq., 8.62 mmol) in 1,4-dioxane was added. The mixture was stirred for 18 hours at 22°C and concentrated under reduced pressure to yield GG-3. MS (ESI) m / z: 179.4 [M+H]+ Synthesis of GG-4: (S)-2-(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)-5nitropyrimidine

[00255] To a solution of (S)-2-(3-methylpiperazin-1-yl)pyrimidine hydrochloride (GG-3, 1.00 g, 1 eq., 3.98 mmol) in DMF (18.0 mL), potassium carbonate (2.20 g, 4 eq., 15.9 mmol) and 2-chloro-5-nitropyrimidine (762 mg, 1.2 eq., 4.78 mmol) were added. The mixture was stirred for 18 hours at 60°C. Water was added to the mixture and it was stirred for 30 minutes at 22°C. The resulting precipitated solid was collected by filtration through a filter, washed with water (100 mL x 3) and dried to give GG-4. MS (ESI) m / z: 302.5 [M+H]+ Synthesis of GG-5: (S)-2-(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5amine

[00256] A solution of (S)-2-(2-methyl-4-(pyrimidin-2-yl)piperazin-1yl)-5-nitropyrimidine (GG-4, 1.00 g, 1 eq., 3.32 mmol) in THF (8.00 mL) and MeOH (8.00 mL) was degassed and purged with N2 (x 3), then palladium was added at 10% carbon (177 mg, 0.5 eq., 1.66 mmol), followed by degassing and purging with H2 (x 3). The mixture was stirred for 18 hours at 22°C under a flask filled with H2. The mixture was filtered through a filter paper, washed with MeOH (5 mL x 3) and concentrated under vacuum to yield GG-5. MS (ESI) m / z: 272.4 [M+H]+ Petition 870260070497, dated 07 / 16 / 2026, pp. 155 / 214 147 / 205 Synthesis of GG-6: (S)-6-bromo-2-fluoro-N-(2-(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00257] To a solution of (S)-2-(2-methyl-4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-amine (GG-5, 250.0 mg, 1 eq., 921.4 μmol) in DCM (6.0 mL), diisopropylethylamine (595.4 mg, 793 μL, 5 eq., 4.607 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (700.7 mg, 2 eq., 1.843 mmol) and 6-bromo-2-fluoronicotinic acid (243.2 mg, 1.2 eq., 1.106 mmol) were added. The mixture was stirred for 30 minutes at 22°C. The crude mixture was purified by basic reversed-phase chromatography (Waters XBridge Prep C18 5 mm - 30x250 mm column, aqueous solution of NH₄₂|HCO₃ 5 mM 10-100%:acetonitrile, gradient 30 minutes). The fractions containing the product were combined and extracted with water (100 mL) and DCM (100 mL x 3). The collected organic layer was dried with MgSO₄, then concentrated under vacuum to produce GG-6. MS (ESI) m / z: 473.5 [M+H]+ Synthesis of Example 134: 6-(5,6-dihydro-4H-pyrrol[1,2-b]pyrazol-3-yl)-2fluoro-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00258] In a solution of (S)-6-bromo-2-fluoro-N-(2-(2-methyl-4(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide (GG-6, 60.0 mg, 1 eq., 127 pmol) in 1,4-dioxane (0.50 mL) was added 1M potassium phosphate, tribasic (31.5 pL, 3 eq., 380 pmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrol[1,2-b]pyrazole (44.5 mg, 1.5 eq., 190 pmol). The mixture was purged with N2 for 5 minutes, then XPhos Palladaciclo-G2 (9.97 mg, 0.1 eq., 12.7 pmol) was added. The mixture was stirred for 3 hours at 80°C, concentrated, and purified by normal-phase chromatography (ISCO 12 g RediSep Gold High Performance Silica, hexane 10-100%, EtOAc, gradient 18 minutes). The fractions containing the desired product were combined and concentrated under reduced pressure.LCMS showed a significant byproduct and was therefore dissolved again in DCM (1 mL). Petition 870260070497, dated 07 / 16 / 2026, pages 156 / 214 148 / 205 and placed in a TLC chromatography chamber (hexane 1:4, EtOAc). The desired product was collected from the TLC plate, stirred in EtOAc and filtered through a filter to yield 134. MS (ESI) m / z: 501.6 [M+H]+ 1H NMR (500 MHz, CDCfi): δ 8.60 (s, 2H), 8.58-8.52 (m, 1H), 8.33 (d, J = 4.7 Hz, 2H), 8.22 (d, J = 15.6 Hz, 1H), 8.07 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 6.51 (t, J = 4.7 Hz, 1H), 4.98 (s, 1H), 4.69 (d, J = 12.7 Hz, 1H), 4.63 (d, J = 13.2 Hz, 1H), 4.55 (d, J = 13.3 Hz, 1H), 4.22 (t, J = 7.3 Hz, 2H), 3.42-3.28 (m, 2H), 3.24 (t, J = 7.3 Hz, 2H), 3.16 (td, J = 12.2; 3.5 Hz, 1H), 2.74 (p, J = 7.3 Hz, 2H), 1.23 (d, J = 6.8 Hz, 3H). Example 135: 6-(4-aminophenyl)-2-fluoro-N-(2-(4-(pyrimidin-2-yl)piperazin-1yl)pyrimidin-5-yl)nicotinamide 1,4-dioxane

[00259] To a solution of (S)-6-bromo-2-fluoro-N-(2-(2-methyl-4(pyrimidin-2-yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide (GG-6, 15.1 mg, 1 eq., 0.032 mmol) in 1,4-dioxane (0.50 mL), potassium phosphate was added, 1M tribasic (0.064 mL, 1.00 molar, 2 eq., 0.064 mmol) and 5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (10.5 mg, 1.15 eq., 0.048 mmol). The mixture was purged with N2 for 1 minute, then XPhos Palladaciclo-G2 (2.52 mg, 0.1 eq., 0.003 mmol) was added. The mixture was stirred for 3 hours at 80°C. The mixture was filtered through a filter paper, concentrated, and purified by reverse-phase HPLC (XBridge Prep OBD C18 column, 40-100% water with 0.01% NH4OH, acetonitrile). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 135, MS (ESI) m / z: 487.5 [M+H]+ 1H NMR (500 MHz, DMSO): δ 8.73 (d, J = 2.3 Hz, 1H), 8.67 (s, 2H), 8.38 (d, J = 4.7 Hz, 2H), 8.24 (dd, J = 9.8; 8.0 H, 1H), 8.10 (dd, J = Petition 870260070497, of 16 / 07 / 2026, p. 157 / 214 149 / 205 8.8; 2.5 Hz, 1H), 7.91 (dd, J = 8.0; 1.9 Hz, 1H), 6.65 (t, J = 4.7 Hz, 1H), 6.56 (d, J = 10.6 Hz, 3H), 4.87 (d, J = 10.6 Hz, 3H), Hz, 1H), 4.56 (d, J = 13.0 H, 1H), 4.47-4.40 (m, 1H), 3.24 (ddd, J = 17.1; 11.3; 3.8 Hz, 2H), 3.07 (td, J = 12.5; 3.0 Hz, J = 19.0). 6.6 Hz, 3H). Synthesis of Intermediate HH-1: 6-(5,6-dihydro-4H-pyrrole[1,2-b]pyrazol3-yl)-2-fluoronicotinic acid Synthesis of HH-1: 6-(5,6-dihydro-4 H-pyrrole[1,2-b ]pyrazol-3-yl)-2fluoronicotinic acid

[00260] A mixture of 6-bromo-2-fluoronicotinic acid (1.90 g, 8.64 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4-Hpyrrol[1,2-b]pyrazole (3.03 g, 12.9 mmol) and 1M aqueous K3PO4 (25.9 mL, 25.9 mmol) in dioxane (57 mL) was purged with nitrogen for 10 minutes. XPhos-Pd-G2 (680 mg, 864 μmol) was added and the mixture was stirred for 2.5 hours at 100°C. The mixture was cooled, poured over water (100 mL) and extracted with EtOAc (3 x 30 mL) and DCM (3 x 20 mL). The aqueous layer was acidified with 1M HCl and the resulting precipitated solid was collected by filtration, washed with water (10 mL x 2) and dried to yield HH-1. MS (ESI) m / z: 248.2 [M+H]+ Petition 870260070497, dated 07 / 16 / 2026, pp. 158 / 214 150 / 205 Synthesis of Example 136: (S)-6-(5,6-dihydro-4H-pyrrol[1,2-b1pyrazol-3-yl)-2fluoro-N-(2-(4-(5-fluoropyrazin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5yl)nicotinamide Synthesis of HH-2: tert-butyl (5)-4-(5-aminopyrimidin-2-yl)-3-methylpiperazine-1carboxylate

[00261] To a solution of 1-2 (8.88 g, 27.5 mmol) in methanol (137 mL), 10% Pd / C (2.00 g, 1.88 mmol) was added. The mixture was stirred for 16 hours at 25°C under a hydrogen flask. Ice-cold water (300 mL) was added and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, washed with water (20 mL x 2) and dried to give HH-2. MS (ESI) m / z: 294.3 [M+H]+. Synthesis of HH-3: (S)-4-(5-(6-(5,6-dihydro-4H-pyrrolo[1,2-b 1pyrazol-3-yl)-2fluoronicotinamido)pyrimidin-2-yl)-3-methylpiperazine-1-tertbutylcarboxylate

[00262] A solution of HH-2 (2.14 g, 7.30 mmol), HH-1 (1.80 g, 7.30 mmol), HATU (3.33 g, 8.75 mmol) and DIPEA (6.35 mL, 36.5 mmol) in DCM (73 mL) was stirred at 25°C for 2 hours. The reaction was concentrated and purified by normal-phase column chromatography [EtOAc 0 to Petition 870260070497, dated 07 / 16 / 2026, pp. 159 / 214 151 / 205 100% / EtOH (3:1 mixture) in hexanes] to provide HH-3. MS (ESI) m / z: 523.5 [M+H]+. Synthesis of HH-4: (S)-6-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-2-fluoro-N(2-(2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00263] To a stirred solution of compound HH-3 (822 mg, 1.57 mmol) in DCM (3.2 mL), 4M HCl in dioxane (3.93 mL, 15.7 mmol) was added at 25°C. The mixture was stirred at room temperature for 2 hours, then poured into saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to give HH-4. M / Z (ESI): 423.4 [M+H]+. Synthesis of 136: (S)-6-(5,6-dihydro-4 H-pyrrol[1,2-b ]pyrazol-3-yl)-2-fluoro- N-(2(4-(5-fluoropyrazin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00264] To a solution of HH-4 (10.0 mg, 0.024 mmol) in DMF (0.4 mL), 2,5-difluoropyrazine (4.1 mg, 0.036 mmol) and DIPEA (1.0 mL, 0.12 mmol) were added. The mixture was stirred for 16 hours at 80°C. The reaction mixture was purified by reversed-phase HPLC (MeCN 40 at 100% / H2O with a 0.1% NH4OH gradient on an XBridge Prep OBD C18 column). The desired fractions were concentrated to yield 136, MS (ESI) m / z: 519.2 [M+H]+. Example 137: (S)-6-(5,6-dihydro-4H-pyrrol[1,2-b]pyrazol-3-yl)-2-fluoro-N-(2(4-(6-fluoropyrimidin-4-yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide Synthesis of 137: (S)-6-(5,6-dihydro-4H-pyrrol[1,2-b]pyrazol-3-yl)-2-fluoro-N-(2(4-(6-fluoropyrimidin-4-yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00265] To a solution of HH-4 (20.0 mg, 0.0473 mmol) in DMF (0.473 mL), 4,6-difluoropyrimidine (8.24 g, 0.0710 mmol) and DIPEA (0.0412 mL, 0.237 mmol) were added. The mixture was stirred for 2 hours at 22°C. Petition 870260070497, dated 07 / 16 / 2026, pages 160 / 214 152 / 205 The reaction mixture was purified by reversed-phase HPLC (MeCN 40 a 100% / H2U with a 0.1% NH4OH gradient on a Gemini-NX column). The desired fractions were concentrated to yield 137. MS (ESI) m / z: 519.4 [M+H]+. 1H NMR (500 MHz, CDCfe) δ 8.62 (s, 2H), 8.55 (dd, J = 10.3; 8.0 H, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.23 ​​(d, J = 10, 17, 7), Hz 7.42 (dd, J = 8.0; 2.7 Hz, 1H), 6.02 (s, 1H), 4.99–4.94 (m, 1H), 4.56 (dt, J = 13.7 (3.6 Hz, 1H), 4.33–4.06 (m, 4.4), 4.33–4.06 (m, 1H). 3.30–3.21 (m, 3H), 2.74 (p, J = 7.4 Hz, 2H), 1.23 (d, J = 6.6 Hz, 3H). Example 138: (R)-6-(5,6-dihydro-4H-pyrrol[1,2-b]pyrazol-3-yl)-2-fluoro-N-(2(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidineamidin-5-dyl)yl HN K2CO3 DMF \ O NH HCl II-1 II-2 II-3 NO2 K2CO3 DMF HCl 1,4-dioxane NH2 1,44-dioxane 138 Synthesis of II-2: (R)-3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazine-1 tert-butyl carboxylate Petition 870260070497, dated 07 / 16 / 2026, pp. 161 / 214 153 / 205

[00266] To a solution of tert-butyl (II-1, 1.0 g, 1 eq., 4.34 mmol) (R)-3-(methoxymethyl)piperazine-1-carboxylate (II-1, 1.0 g, 1 eq., 4.34 mmol) in DMF (15 mL), diisopropylethylamine (1.68 g, 2.24 mL, 3 eq., 13.0 mmol) was added, followed by 2-chloropyrimidine (746 mg, 1.5 eq., 6.51 mmol). The mixture was stirred for 18 hours at 130°C. Water (50 mL) was added to the mixture, which was stirred for 30 minutes at 22°C and then extracted with EtOAc (60 mL x 3). The organic layer was dried with MgSO4, filtered through a fine filter, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (3 mL) and purified by normal-phase chromatography (ISCO 80 g RediSep Gold High Performance Silica, hexane 0-100%, EtOAc, gradient 28 min). The fractions containing the desired product were combined and concentrated under vacuum to produce II-2. MS (ESI) m / z: 309.5 [M+H]+ Synthesis of II-3: (R)-2-(2-(methoxymethyl)piperazin-1-yl)pyrimidine hydrochloride

[00267] To a solution of tert-butyl (R)-3-(methoxymethyl)-4-(pyrimidin-2yl)piperazine-1-carboxylate (II-2, 870 mg, 1 eq., 2.82 mmol) in 1,4-dioxane (12.0 mL), 4M hydrogen chloride (1.41 mL, 2 eq., 5.64 mmol) in 1,4-dioxane was added. The mixture was stirred for 2 hours at 22°C. More 4M hydrogen chloride (4 mL) in 1,4-dioxane was added to the mixture and stirred for 1 hour. The mixture was concentrated under reduced pressure to produce II-3. MS (ESI) m / z: 209.4 [M+H]+ Synthesis of II-4: (R)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1-yl)-5nitropyrimidine

[00268] To a solution of (R)-2-(2(methoxymethyl)piperazin-1-yl)pyrimidine hydrochloride (II-3, 790 mg, 1 eq., 2.81 mmol) in DMF (15.0 mL), potassium carbonate (1.55 g, 4 eq., 11.2 mmol) and 2-chloro-5-nitropyrimidine (538 mg, 1.2 eq., 3.37 mmol) were added. The mixture was stirred for 18 hours at 60°C. Water was added to the mixture and it was stirred for 30 minutes at 22°C. The resulting precipitated solid was collected by filtration. Petition 870260070497, dated 07 / 16 / 2026, pages 162 / 214 154 / 205 through a filter, washed with water (100 mL x 3) and dried to provide II-4. MS (ESI) m / z: 332.4 [M+H]+ Synthesis of II-5: (R)-2-(3-(methoxymethyl)-4-(pyrimidin-2-yl)piperazin-1yl)pyrimidin-5-amine

[00269] A solution of (R)-2-(3-(methoxymethyl)-4-(pyrimidin-2yl)piperazin-1-yl)-5-nitropyrimidine (II-4, 820 mg, 1 eq., 2.47 mmol) in THF (8.00 mL) and MeOH (8.00 mL) was degassed and purged with N2 (x 3), then 10% palladium on carbon (132 mg, 0.5 eq., 1.24 mmol) was added, followed by degassing and purging with H2 (x 3). The mixture was stirred for 18 hours at 22°C under a flask filled with H2. The mixture was filtered through a filter paper, washed with MeOH (5 mL x 3) and concentrated under vacuum to yield II-5. MS (ESI) m / z: 302.5 [M+H]+ Synthesis of II-6: (R)-6-bromo-2-fluoro-N-(2-(3-(methoxymethyl)-4-(pyrimidin-2yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00270] To a solution of (R)-2-(3-(methoxymethyl)-4-(pyrimidin-2yl)piperazin-1-yl)pyrimidin-5-amine (II-5, 100.0 mg, 1 eq., 331.8 μmol) in DCM (2.0 mL), diisopropylethylamine (286 pL, 5 eq., 1.659 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (252.4 mg, 2 eq., 663.7 pmol) and 6-bromo-2-fluoronicotinic acid (87.61 mg, 1.2 eq., 398.2 pmol) were added. The mixture was stirred for 1 hour at 22°C. The crude mixture was purified by basic reversed-phase chromatography (Waters XBridge Prep C18 5 mm - 30x250 mm column, 5 mM aqueous NH4HCO3 solution 10-100%:acetonitrile, gradient 26 minutes). The fractions containing the product were combined and extracted with water (80 mL) and DCM (80 mL x 3). The collected organic layer was dried with MgSO4 and then concentrated under vacuum to produce II-6. MS (ESI) m / z: 503.5 [M+H]+ Example 138: (R)-6-(5,6-dihydro-4H-pyrrol[1,2-b]pyrazol-3-yl)-2-fluoro-N-(2(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidineamidin-5-dyl)yl Petition 870260070497, dated 07 / 16 / 2026, p. 163 / 214 155 / 205

[00271] A solution of (R)-6-bromo-2-fluoro-N-(2-(3 (methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine-5-yl)nicotinamide (II 6, 20.0 mg, 1 eq., 39.7 μmol) in 1,4-dioxane (0.50 mL), 1M tribasic potassium phosphate (9.87 pL, 3 eq., 119 μmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrol[1,2-b]pyrazole (14.0 mg, 1.5 eq., 59.6 pmol) were added. The mixture was purged with N2 for 5 minutes, then XPhos Palladaciclo-G2 (3.13 mg, 0.1 eq., 3.97 pmol) was added. The mixture was stirred for 2 hours at 80°C. The mixture was filtered through a filter, concentrated, and purified by reverse-phase HPLC (XBridge Prep OBD C18 column, 40-100% water with 0.1% NH4OH, acetonitrile). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 138. MS (ESI) m / z: 531.6 [M+H]+ RMN 1H (500 MHz, CDCfi): δ 8.61 (s, 2H), 8.58–8.52 (m, 1H), 8.35 (d, J = 4.7 Hz, 2H), 8.21 (d, J = 15.5 Hz, 1H), J = , 8.07 7.8 Hz, 1H), 6.53 (t, J = 4.7 Hz, 1H), 5.06 (s, 1H), 4.88 (d, J = 13.4 Hz, 1H), 4.62 (t, J = 13.1 Hz, 2H), 4.3 Hz = 2,1 (H = 15.6; 6.5 Hz, 3H), 3.33 (s, 3H), 3.29 (dd, J = 13.6; 3.9 Hz, 1H), 3.26–3.16 (m, 3H), 2.78–2.69 (m, 2H). Example 139: (S)-6-(3-fluoroazetidin-1-yl)-N-(6-(4-(6-fluoropyrimidine-4-yl)-2methylpiperazine- 1-yl)pyridin-3-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, p. 164 / 214 156 / 205 Synthesis of JJ-2: (S)-6-bromo-N-(6-(4-(6-fluoropyrimidine-4-yl)-2methylpiperazine- 1-yl)pyridin-3-yl)nicotinamide

[00272] To a stirred solution of JJ-1 (500 mg, 1.734 mmol) in DMF (20 mL), 6-bromonicotinic acid (525 mg, 2.60 mmol), HATU (1319 mg, 3.47 mmol) and DIPEA (0.909 mL, 5.20 mmol) was added at room temperature and stirred for 16 hours at 60°C. Then, the reaction mixture was cooled, diluted with ethyl acetate (20 mL), washed with cooled brine, dried with Na2SÜ4, filtered, concentrated under reduced pressure, and the crude product was purified using preparative HPLC. (Preparative HPLC conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Select C18 (19X250) mm 5u, flow rate - 18 ml / min, gradient method - 0 / 20, 9 / 78, 9.05 / 99, 11 / 99, 11.02 / 20, 14 / 20. The obtained compound was further purified by the SFC method (conditions: Column: Chiralpak IG (4.6*250 mm), 5μ, Mobile phase - A: MeOH / DCM / DEA (50 / 50 / 0.2) Isocratic of A: 100% Flow rate: 1.0 mL / min Diluent: EtOH.) The pure fractions were concentrated and lyophilized to provide JJ-2. M / Z (ESI): 472.14 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ: 10.37 (s, 1H), 8.91 (d, J=2.0 H, 1H), 8.46 (d, J=2.7 Hz, 1H), 8.32 (d, J=2.4 Hz, 1H), 8.23 ​​(dd, J=8.3; 2.4 Hz, 1H) 4.06 (br dd, J=9.5; 3.2 Hz, 1H), 3.41 (br dd, J=13.4; 3.4 Hz, 1H), 3.15-3.25 (m, 2H), 1.03 (d, J=6.4 Hz, 3H). Example 139: (S)-6-(3-fluoroazetidin-1-yl)-N-(6-(4-(6-fluoropyrimidin-4-yl)-2methylpiperazin-1-yl)pyridin-3-yl)nicotinamide

[00273] To a stirred solution of JJ-2 (90 mg, 0.210 mmol) in toluene (3 ml), 3-fluoroazetidine hydrochloride (25.8 mg, 0.231 mmol), Cs2CO3 (93 mg, 0.284 mmol), 4,5-bis(diphenylphosphine)-9,9- was added. Petition 870260070497, dated 16 / 07 / 2026, p. 165 / 214 157 / 205 dimethylxanthene (12.17 mg, 0.021 mmol) was added at room temperature and purged with argon for 10 minutes, followed by the addition of Pd2(dba)3 (9.63 mg, 10.52 pmol) at room temperature and again purged with argon for another 10 minutes and stirred for 16 hours at 110°C. The reaction mixture was then filtered through a celite layer and washed with EtOAc. The filtrate was washed with cooled brine, dried with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by preparative HPLC. (Conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Select C18 (19X250) mm 5u, flow rate - 18 ml / min, gradient method - 0 / 60, 8 / 80, 8.02 / 100, 10 / 100, 10.08 / 60, 14 / 60. The obtained compound was additionally purified by the SFC method (conditions: Column: Chiralpak IE (4.6*250 mm), 5μ, Mobile phase - A: MeOH / DCM / DEA (50 / 50 / 0.2) Isocratic of A: 100%, flow rate: 0.70 mL / m³ in diluent: EtOH. The pure fractions were concentrated under reduced pressure and lyophilized to provide 139. M / Z (ESI): 467.18 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ: 9.95 (s, 1H), 8.70 (br d, J=2.0 H, 1H), 8.45 (br d, J=2.4 Hz, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.09 (br dd, J=8.8; 2.2 Hz, 1H), 7.87-7.94 (m, 1H), 6.88 (br d, J=8.1 Hz, 1H), 6.61 (s, 1H), 6.53 (br d, J=8.6 Hz, 1H), 5.42-5.63 (m, 1H), 4.50-4.56 (m, 1H), 4.43 (br d, J=4.4 Hz, 8H), 3.16-3.24 (m, 2H), 2.54 (s, 1H), 1.03 (br d, J=6.4 Hz, 3H). Example 140: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(5-(4-(6-fluoropyridin-2-yl)2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, pages 166 / 214 158 / 205

[00274] To a stirred solution of NN-4 (70 mg, 164 μmol) in DMF (1 mL), DIPEA (0.18 mL, 1 mmol) and 2,6-difluoropyridine (23 mg, 200 μmol) were added at room temperature. The reaction mixture was stirred at 100°C for 16 hours under an argon atmosphere. The reaction mixture was rapidly cooled with ice water (5 mL) and the precipitated solid was filtered and dried under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O:MeCN, column - X-Bridge C18 (19X250) mm, 5μ, flow rate - 15.0 ml / min, gradient method 0 / 55, 2 / 55, 10 / 67, 10.05 / 100, 12 / 100, 12.05 / 55, 15 / 55). The pure fractions were combined and concentrated under reduced pressure to provide 140. M / Z (ESI): 485.29 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.58 (s, 1H), 8.86 (d, J = 1.2 Hz, 1H), 8.82 (d, J = 2.0 H, 1H), 8.22 (dd, J = 8.8 Hz, 13 Hz, 1H), (d, J = 1.2 Hz, 1H), 7.69 (q, J = 8.0 H, 1H), 6.75 (dd, J = 8.0 H, 2.4 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.27 (dd, J = 7.8 Hz, 1H), 4.57-4.65 (m, 1H), 4.50 (t, J = 12.4 Hz, 4H), 4.02-4.18 (m, 3H), 3.26 (dd, J = 14.4 Hz, 3.2 Hz, 2H), 3.09 (td, J = 1.0, 3H), 1.11 (d, J = 6.4 Hz, 3H). Example 141: (S)-N-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrazine2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide Petition 870260070497, of 16 / 07 / 2026, p. 167 / 214 159 / 205 1,4-dioxane Toluene XPhos, 1,4-dioxane Synthesis of KK-2: (S)-4-(5-fluoropyridin-2-yl)-2-methylpiperazine-1-tert-butyl carboxylate

[00275] To a solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (KK-1, 1.00 g, 1 eq., 4.99 mmol) in toluene (30.0 mL), sodium 2-methylpropan-2-olate (1.44 g, 1.61 mL, 3 eq., 15.0 mmol) and tert-butyl (S)-2-methylpiperazine-1-carboxylate (1.00 g, 1 eq., 4.99 mmol) were added. The mixture was purged with N2 for 5 minutes, then chlorine(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2yl)palladium(II) (194 mg, 0.05 eq., 250 μmol) was added. The mixture was stirred for 48 hours at 110°C. Water (50 mL) was added to the mixture, which was extracted with EtOAc (100 mL x 3). The organic layer was dried with MgSO4, filtered through a fine filter, and concentrated under reduced pressure. The resulting residue was dissolved in DCM (3 mL) and purified by normal-phase chromatography (ISCO 80 g RediSep Gold High Performance Silica, hexane 0-100%, EtOAc, gradient 26 minutes). The fractions containing the desired product were... Petition 870260070497, dated 07 / 16 / 2026, pages 168 / 214 160 / 205 combined and concentrated under vacuum to produce KK-2. MS (ESI) m / z: 296.4 [M+H]+ Synthesis of KK-3: (S)-1-(5-fluoropyridin-2-yl)-3-methylpiperazine hydrochloride

[00276] To a solution of tert-butyl (S)-4-(5-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxylate (KK-2, 1.00 g, 1 eq., 3.39 mmol) in 1,4-dioxane (14.0 mL), 4M hydrogen chloride (3.39 mL, 4 eq., 13.5 mmol) in 1,4-dioxane was added. The mixture was stirred for 18 hours at 22°C and concentrated under reduced pressure to yield KK-3. MS (ESI) m / z: 196.3 [M+H]+ Synthesis of KK-4: (S)-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)-5nitropyrazine

[00277] A solution of (S)-1-(5-fluoropyridin-2-yl)-3-methylpiperazine hydrochloride (KK-3, 900 mg, 1 eq., 3.36 mmol) in DMF (15.0 mL), potassium carbonate (1.86 g, 4 eq., 13.4 mmol) and 2-chloro-5-nitropyrazine (642 mg, 1.2 eq., 4.03 mmol) was prepared. The mixture was stirred for 18 hours at 60°C. Water was added to the mixture and stirred for 30 minutes at 22°C. The resulting precipitated solid was collected by filtration through a filter, washed with water (100 mL x 3) and dried to provide KK-4. MS (ESI) m / z: 319.3 [M+H]+ Synthesis of KK-5: (S)-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)-5nitropyrazine

[00278] A solution of (S)-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)-5-nitropyrazine (KK-4, 579 mg, 1 eq., 1.82 mmol) in THF (5.00 mL) and MeOH (5.00 mL) was degassed and purged with N2 (x 3), then added 10% palladium on carbon (96.8 mg, 0.5 eq., 909 μmol), followed by degassing and purging with H2 (x 3). The mixture was stirred for 18 hours at 22°C under a flask filled with H2. The mixture was filtered through a filter paper, washed with MeOH (5 mL x 3) and concentrated under vacuum to produce KK-5. MS (ESI) m / z: 289.3 [M+H]+ Petition 870260070497, dated 07 / 16 / 2026, pp. 169 / 214 161 / 205 Synthesis of KK-6: (S)-6-chloro-N-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin1-yl)pyrazin-2-yl)nicotinamide

[00279] To a solution of (S)-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)-5-nitropyrazine (KK-5, 520.00 mg, 1 eq., 1.8035 mmol) in DMF (8.0 mL), diisopropylethylamine (1.165 g, 1.57 mL, 5 eq., 9.0174 mmol), 2,4,6-trioxide of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatirphosphinan (1.1477 g, 1.22 mL, 50% by weight, 1 eq., 1.8035 mmol) and 6-chloronicotinic acid (340.97 mg, 1.2 eq., 2.1642 mmol) was added. The mixture was stirred for 1.5 hours at 22°C. The crude mixture was purified by basic reversed-phase chromatography (Waters XBridge Prep C18 5 mm column - 50x250 mm, 10-100% aqueous NH4HCO3 solution:acetonitrile, gradient 33 minutes). The fractions containing the product were combined and extracted with water (100 mL) and DCM (100 mL x 3). The collected organic layer was dried with MgSO4, then concentrated under vacuum to produce KK-6. MS (ESI) m / z: 428.4 [M+H]+ Example 141: (S)-N-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrazin2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00280] To a solution of (S)-6-chloro-N-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide (KK-6, 20.00 mg, 1 eq., 46.74 μmol) in 1,4-dioxane (0.30 mL), 1M tribasic potassium phosphate (140.2 pL, 1.00 molar, 3 eq., 140.2 μmol) and 1-methyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.67 mg, 1.2 eq., 56.09 pmol) was added. The mixture was purged with N2 for 5 minutes, then XPhos Palladaciclo-G2 (3.678 mg, 0.1 eq., 4.674 pmol) was added. The mixture was stirred for 2 hours at 80°C. After the reaction time, LCMS showed high conversion of the desired product. The mixture was then filtered through a filter paper, concentrated, and purified by reverse-phase HPLC (XBridge Prep OBD C18 column, 40-100% water with 0.1% NH4OH, acetonitrile). The fractions Petition 870260070497, dated 07 / 16 / 2026, pages 170 / 214 162 / 205 containing the desired product were combined and concentrated under reduced pressure to produce 141. MS (ESI) m / z: 474.5 [M+H]+ 1H NMR (500 MHz, DMSO): δ 10.84 (s, 1H), 9.09 (s, 1H), 8.89 (s, 1H), 8.41 (s, 1H), 8.34 (dd, J = 8.3; 2.1 Hz, 1H), 8.16 (s, 1H), 8.12 (d, J = 3.0H, 1H), 8.10 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.54 (td, J = 8.7; 3.1 Hz, 1H), 6.95 (dd, J = 9.3; 3.3 Hz, 1H), 4.62 (s, 1H), 4.25-4.09 (m, 3H), 3.91 (s, 3H), 3.30-3.23 (m, 1H), 3.20 (dd, J = 12.8; 3.5 Hz, 1H), 2.99 (td, J = 12.0; 3.7 Hz, 1H), 1.14 (d, J = 6.5 Hz, 3H). Example 142: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(5-(4-(5-fluoropyridin-2-yl)2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide

[00281] To a solution of (S)-6-chloro-N-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide (KK-6, 20.00 mg, 1 eq., 46.74 μmol) in DMF (0.50 mL), potassium carbonate (19.38 mg, 3 eq., 140.2 μmol), potassium fluoride (8.147 mg, 3.284 pL, 3 eq., 140.2 μmol) and 3,3-difluoroazetidine (6.526 mg, 1.5 eq., 70.11 pmol) was added. The mixture was concentrated under vacuum, then dissolved again in DCM (1 mL), and purified by normal-phase chromatography (ISCO 80 g RediSep Gold High Performance Silica, hexane 0-100%, EtOAc, gradient 26 minutes). The fractions containing the desired product were combined and concentrated under vacuum to yield 142. MS (ESI) m / z: 485.4 [M+H]+ 1H NMR (500 MHz, CDCfe): δ 9.17 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 5.7 Hz, 3H), 7.82 (s, 1H), 7.32-7.28 (d, 1H), J = 6.6, 9.2; 3.2 Hz, 1H), 6.42 (d, J = 8.7 Hz, 1H), 4.55 (s, 1H), 4.46 (t, J = 11.8 Hz, 4H), 4.15 (d, J = 12.1 Hz, 1H), 4.0 (dd, J = 13.6 Hz; 2H), 3.40 (td, J = 12.1; 3.6 Hz, 1H), 3.34 (dd, J = 12.7; 3.7 Hz, 1H), 3.13 (qd, J = 12.2; 4.4 Hz, 1H), 1.26 (d, J = 6.5 Hz, 3H). Petition 870260070497, of 16 / 07 / 2026, p. 171 / 214 163 / 205 Example 143: (S)-N-(5-(4-(5-fluoropyrimidin-2-yl)-2-methylpiperazin-1yl)pyrazine-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide 1,4-dioxane XPhos, 1,4-dioxane Synthesis of LL-2: (S)-4-(5-fluoropyrimidin-2-yl)-2-methylpiperazine-1tert-butyl carboxylate

[00282] To a solution of tert-butyl (S)-2-methylpiperazine-1-carboxylate (LL-1, 5.43 g, 1.00 eq., 27.1 mmol) in DMF (67.8 mL), diisopropylethylamine (17.5 g, 23.6 mL, 5.00 eq., 136 mmol) and 2-chloro-5-fluoropyrimidine (5.39 g, 3.75 mL, 1.50 eq., 40.7 mmol) were added. The mixture was stirred for 16 hours at 80°C. Water (300 mL) was added to the mixture, which was extracted with ether (100 mL x 3). The organic layer was dried with Na2SÜ4, filtered through a filter paper, and concentrated under reduced pressure. The resulting residue was purified using normal phase chromatography (ISCO 330 g RediSep Gold High Performance Silica, hexane 0-25%, EtOAc). The fractions containing the desired product were combined and concentrated under vacuum to produce LL-2. MS (ESI) m / z: 297.1 [M+H]+ Petition 870260070497, dated 07 / 16 / 2026, pages 172 / 214 164 / 205 Synthesis of LL-3: (S)-5-fluoro-2-(3-methylpiperazin-1-yl)pyrimidine hydrochloride

[00283] To a solution of tert-butyl (S)-4-(5-fluoropyrimidin-2-yl)-2-methylpiperazine-1-carboxylate (LL-2, 7.35 g, 1 eq., 24.8 mmol) in DCM (124 mL), 4M hydrogen chloride (62.0 mL, 4.00 molar, 10 eq., 248 mmol) in DCM was added. The mixture was stirred for 2 hours at 22°C and concentrated under reduced pressure to yield LL-3. MS (ESI) m / z: 320.2 [M+H]+ Synthesis of LL-4: (S)-5-fluoro-2-(3-methyl-4-(5-nitropyrazin-2-yl)piperazin-1yl)pyrimidine

[00284] To a solution of (S)-5-fluoro-2-(3-methylpiperazin-1-yl)pyrimidine hydrochloride (LL-3, 1.00 g, 1 eq., 5.10 mmol) in DMF (25.5 mL), potassium carbonate (2.82 g, 4.00 eq., 20.4 mmol) and 2-chloro-5-nitropyrazine (976 mg, 1.20 eq., 6.12 mmol) were added. The mixture was stirred for 16 hours at 60°C. Ice-cold water was added to the mixture and the resulting precipitated solid was collected through a filter, washed with water (5 mL x 3) and dried to provide LL-4. MS (ESI) m / z: 290.2 [M+H]+LL-5 Synthesis: (S)-5-(4-(5-fluoropyrimidin-2-yl)-2-methylpiperazin-1yl)pyrazin-2-amine

[00285] A solution of (S)-5-fluoro-2-(3-methyl-4-(5-nitropyrazim-2-yl)piperazin-1-yl)pyrimidine (LL-4, 1.20 g, 1 eq., 3.76 mmol) in DCM (9.40 mL) and MeOH (9.40 mL) was degassed and purged with N2 (x 3), then 10% palladium on carbon (200.0 mg, 0.500 eq., 1.879 mmol) was added, followed by degassing and purging with H2 (x 3). The mixture was stirred for 6 hours at 22°C under a flask filled with H2. The mixture was filtered through a filter paper and concentrated under vacuum to yield LL-5. MS (ESI) m / z: 290.2 [M+H]+ Synthesis of LL-6: (S)-6-chloro-N-(5-(4-(5-fluoropyrimidin-2-yl)-2methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide Petition 870260070497, dated 07 / 16 / 2026, pp. 173 / 214 165 / 205

[00286] To a solution of (S)-5-(4-(5-fluoropyrimidin-2-yl)-2-methylpiperazin-1-yl)pyrazin-2-amine (LL-5, 520.00 mg, 1 eq., 1.8035 mmol) in DMF (8.0 mL), diisopropylethylamine (670.11 mg, 903 pL, 5 eq., 5.1846 mmol), 2,4,6-trioxide of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatirphosphinan (659.85 mg, 699 pL, 50% by weight, 1 eq., 1.0369 mmol), and 6-chloronicotinic acid (196.04 mg, 1.2 eq., 1.2443 mmol) were added. The mixture was stirred for 3 hours at 22°C. The crude mixture was purified by basic reversed-phase chromatography (Waters XBridge Prep C18 5 mm column - 50x250 mm, 5 mM aqueous NH4HCO3 solution 10-100%:acetonitrile, gradient 33 minutes). The fractions containing the product were combined and extracted with water (100 mL) and DCM (150 mL x 3). The collected organic layer was dried with MgSO4, then concentrated under vacuum to produce LL-6. MS (ESI) m / z: 429.3 [M+H]+ Example 143: (S)-N-(5-(4-(5-fluoropyrimidine-2-yl)-2-methylpiperazine-1yl)pyrazine-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)nicotinamide

[00287] To a solution of (S)-6-chloro-N-(5-(4-(5-fluoropyrimidin-2yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide (LL-6, 20.00 mg, 1 eq., 46.64 pmol) in 1,4-dioxane (0.50 mL), 1M tribasic potassium phosphate (139.9 pL, 1.00 molar, 3 eq., 139.9 pmol) and 1-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (11.64 mg, 1.2 eq., 55.96 pmol) was added. The mixture was purged with N2 for 5 minutes, then XPhos Palladaciclo-G2 (3.669 mg, 0.1 eq., 4.664 pmol) was added. The mixture was stirred for 2 hours at 80°C. The mixture was concentrated and purified by normal-phase chromatography (ISCO 12 g RediSep Gold High Performance Silica, hexane 10-100%, EtOAc, gradient 18 minutes). The fractions containing the desired product were combined and concentrated under reduced pressure.LCMS showed a significant byproduct and therefore was dissolved again in DMSO (1 mL) and purified again by basic reversed-phase chromatography (Gilson Waters XBridge Prep OBD C18 5 pm, 10-100% NH4OH). Petition 870260070497, dated 07 / 16 / 2026, pages 174 / 214 166 / 205 0.1% in water: acetonitrile, gradient 10 minutes). The fractions containing the product were combined and concentrated to produce 143, MS (ESI) m / z: 475.4 [M+H]+ 1H NMR (500 MHz, CDCl3): δ 9.20 (s, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.29-8.16 (m, 4H), 8.02 (s, 2H), 7.83 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 4.63 (d, J = 13.2 Hz, 1H), 4.56 (d, J = 13.0 H, 2H), 4.06 (d, J = 12.7 Hz, 1H), 3.99 (s, 3H), 3.42-3.29 (m, 2H), 3.23 (td, J = 12.3; 3.6 Hz, 1H), 1.20 (d, J = 6.5 Hz, 3H). Example 144: (S)-6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-N-(5-(4-(5fluoropyrimidin-2-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide LL-6 K3PO4, XPhos F 1,4-dioxane Λ N takes %nn N F 144

[00288] To a solution of (S)-6-chloro-N-(5-(4-(5-fluoropyrimidin-2yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)nicotinamide (LL-6, 20.00 mg, 1 eq., 46.64 μmol) in 1,4-dioxane (0.50 mL), 1M tribasic potassium phosphate (139.9 μE, 1.00 molar, 3 eq., 139.9 μmol) and 1-(2-fluoroethyl)-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (13.44 mg, 1.2 eq., 55.96 μmol) was added. The mixture was purged with N2 for 5 minutes, then XPhos Palladaciclo-G2 (3.669 mg, 0.1 eq., 4.664 μmol) was added. The mixture was stirred for 2 hours at 80°C. The mixture was concentrated using a concentrator, dissolved in DCM (1 mL), and purified by normal-phase chromatography (ISCO 12 g RediSep Gold High Performance Silica, hexane 10-100%, EtOAc, gradient 18 minutes). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 144. MS (ESI) m / z: 507.4 [M+H]+ 1H NMR (500 MHz, CDCl3): δ 9.20 (s, 1H), 9.07 (d, J = 1.9 Hz, 1H), 8.25 (s, 1H), 8.23 ​​(s, 2H), 8.20 (dd, J = 8.3; Petition 870260070497, of 16 / 07 / 2026, p. 175 / 214 167 / 205 8.09 (s, 1H), 7.82 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 4.87 (t, J = 4.7 Hz, 1H), 4.78 (t, J = 4.7 Hz, 1H), J = 13.0 H, 2H), 4.49 (dt, J = 26.7; 4.8 Hz, 3H), 4.06 (d, J = 12.7 Hz, 1H), 3.41-3.30 (m, 2H), 3.23 (td, J = 12.3; 6.5 Hz, 3H). Synthesis of radiolabeling intermediates: Synthesis of Intermediate NN-5: (S)-N-(5-(4-(6-chloropyrimidin-4-yl)-2methylpiperazin- 1-yl)pyrazine-2-yl)-6-(3,3-difluoroazetidin- 1-yl)nicotinamide CS2CO3 (3 equiv), CuI (0.1 equiv), trans-N,N'-dimethylcyclo-hexano1,2-diamine (0.05 equiv),1,4dioxano, 150°C, 2 h, MW 4M HCl in 1,4-dioxane (5 eq.), DCM, 0°c-rt, 4 h Synthesis of NN-1: tert-butyl (S)-4-(5-bromopyrazin-2-yl)-3-methylpiperazine-1-carboxylate

[00289] To a stirred solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (5 g, 24.96 mmol) in DMSO (100 mL), CsF (11.38 g, 74.9 mmol) and 2,5-dibromopyrazine (7.13 g, 30.0 mmol) were added to Petition 870260070497, dated 07 / 16 / 2026, pp. 176 / 214 168 / 205 room temperature. The reaction mixture was stirred under an argon atmosphere at 80°C for 6 hours. The reaction mixture was rapidly cooled with cold water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica column (230-400 mesh) and eluted with 15% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide NN-1. M / Z (ESI): 357.15 [M+H]+. Synthesis of NN-3: tert-butyl (S)-4-(5-(6-(3,3-difluoroazetidin-1-yl)nicotinamido)pyrazin2-yl)-3-methylpiperazine-1-carboxylate

[00290] A stirred solution of NN-1 (1.50 g, 4.20 mmol) in 1,4-dioxane (30 mL), NN-2 (985 mg, 4.62 mmol), Cs2COs (4.10 g, 12.6 mmol), Cul (80.0 mg, 420 μmol) and trans-(1r,2r)-N,N'-bismethyl-1,2-cyclohexanediamine (66.2 pL, 210 μmol) at room temperature, followed by degassing with argon for 10 minutes. The reaction mixture was stirred at 150°C for 2 hours under microwave irradiation. The reaction mixture was rapidly cooled with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried with filtered NibSCL, and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica column (230-400 mesh) and eluted with 5% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure to provide NN-3. M / Z (ESI): 490.77 [M+H]+. Synthesis of NN-4: (S)-6-(3,3-difluoroazetidin-1-yl)-N-(5-(2-methylpiperazin-1yl)pyrazin-2-yl)nicotinamide

[00291] To a stirred solution of NN-3 (900 mg, 1.84 mmol) in DCM (10 mL), 4M HCl in 1,4-dioxane (2.30 mL, 9.19 mmol) at 0°C was added. The reaction mixture was stirred under an argon atmosphere at 25°C for 4 Petition 870260070497, dated 07 / 16 / 2026, pages 177 / 214 169 / 205 hours. The reaction mixture was concentrated under reduced pressure to provide NN-4. M / Z (ESI): 390.23 [M+H]+. Synthesis of NN-5: (S)-N-(5-(4-(6-chloropyrimidin-4-yl)-2-methylpiperazin-1yl)pyrazin-2-yl)-6-(3,3-difluoroazetidin-1-yl)nicotinamide

[00292] To a stirred solution of NN-4 (150 mg, 352 μmol) in DMF (2 mL), DIPEA (0.38 mL, 2.2 mmol) and 4,6-dichloropyrimidine (63.0 mg, 423 μmol) were added at room temperature. The reaction mixture was stirred under an argon atmosphere at 25°C for 6 hours and rapidly cooled with cold water (10 mL). The precipitated solution was stirred for 10 minutes, filtered, and dried under reduced pressure. The crude compound was macerated with diethyl ether (10 mL) to give NN-5. M / Z (ESI): 502.21 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 10.59 (s, 1H), 8.76-8.94 (m, 2H), 8.37 (s, 1H), 8.22 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.13 (s, 1H), 7.06 (s, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.21-4.70 (m, 7H), 4.01-4.17 (m, 1H), 3.42 (dd, J = 13.2 Hz, 3.6 Hz, 1H), 3.20-3.29 (m, 2H), 1.07 (d, J = 6.4 Hz, 3H). Synthesis of OO-7A: (S)-6-(azetidine-1-yl)-N-(2-(2-methyl-4-(5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)piperazine-1-yl)OpyrimidineOmidane-5ylanidine) (S)-(6-(4-(5-(6-(azetidin-1yl)nicotinamide)pyrimidine-2-yl)-3-methylpiperazine-1-yl)pyridin-3-yl)boronic Petition 870260070497, dated 07 / 16 / 2026, p. 178 / 214 170 / 205 4M HCl in 1,4-dioxane (5 eq.), DCM, 0°C-rt, 16 h (3 eq.), 1,4-dioxane, 100 °C, 16 h Synthesis of OO-1: (S)-3-methyl-4-(5-nitropyrimidine-2-yl)piperazine-1carboxylate tert-butyl

[00293] To a stirred solution of tert-butyl (S)-3-methylpiperazine-1-carboxylate (10 g, 49.9 mmol) in DMF (100 mL), 2-chloro-5-nitropyrimidine (9.56 g, 59.9 mmol) and cesium carbonate (16.3 g, 49.9 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at 80°C for 8 hours. The reaction mixture was rapidly cooled with ground ice and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel cartridge 120 geo and eluted with 70% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide OO-1. M / Z (ESI): 324.23 [M+H]+. Synthesis of OO-2: tert-butyl (S)-4-(5-aminopyrimidin-2-yl)-3-methylpiperazine-1carboxylate Petition 870260070497, dated 07 / 16 / 2026, pp. 179 / 214 171 / 205

[00294] To a stirred solution of OO-1 (15 g, 46.4 mmol) in EtOH (100 mL) and THF (100 mL), 10% Pd / C (4.94 g, 46.4 mmol) was added at room temperature. The reaction mixture was degassed and purged with nitrogen gas. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated and dried under reduced pressure. The crude compound was macerated with n-pentane and dried under reduced pressure to give OO-2. M / Z (ESI): 294.22 [M+H]+. Synthesis of OO-3: tert-butyl (S)-4-(5-(6-fluoronicotinamido)pyrimidin-2-yl)-3methylpiperazine-1-carboxylate

[00295] To a stirred solution of OO-2 (1 g, 3.41 mmol) and 6-fluoronicotinic acid (577 mg, 4.09 mmol) in THF (20 mL), DIPEA (1.78 mL, 10.2 mmol) and HATU (1.94 g, 5.11 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was rapidly cooled with water (20 mL) and extracted with EtOAc (20 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel cartridge and eluted with 40% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide OO-3. M / Z (ESI): 417.29 [M+H]+. Synthesis of OO-4: tert-butyl (S)-4-(5-(6-(azetidin-1-yl)nicotinamido)pyrimidin-2-yl)-3methylpiperazine-1-carboxylate

[00296] To a stirred solution of OO-3 (800 mg, 1.92 mmol) in DMSO (5 mL), azetidine hydrochloride (270 mg, 2.88 mmol) and K2CO3 (796 mg, 5.76 mmol) were added at room temperature under an argon atmosphere. The reaction mixture was stirred at 120°C for 24 hours. The reaction mixture was rapidly cooled with crushed ice and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine, dried with Petition 870260070497, dated 07 / 16 / 2026, pages 180 / 214 172 / 205 Anhydrous NaiSOd was filtered and concentrated under reduced pressure. The crude compound was purified by Biotage using a silica gel cartridge. The compound was eluted with 80% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to provide OO-4. M / Z (ESI): 454.33 [M+H]+. Synthesis of OO-5: (S)-6-(azetidin-1-yl)-N-(2-(2-methylpiperazin-1-yl)pyrimidin5-yl)nicotinamide

[00297] To a stirred solution of OO-4 (3 g, 6.61 mmol) in DCM (50 mL), 4M HCl in 1,4-dioxane (6.61 mL, 26.5 mmol) at 0°C under an argon atmosphere was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and dried under reduced pressure to give OO-5. M / Z (ESI): 354.33 [M+H]+. Synthesis of OO-6: (S)-6-(azetidin-1-yl)-N-(2-(4-(5bromopyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide

[00298] To a stirred solution of OO-5 (2 g, 5.13 mmol) and 5-bromo-2-fluoropyridine (1.08 g, 6.16 mmol) in DMSO (10 mL), potassium carbonate (2.13 g, 15.4 mmol) was added at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was rapidly cooled with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous NibSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography and eluted with 80% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to give OO-6. M / Z (ESI): 509.23 [M+H]+ . RMN 1H (400 MHz, DMSO-d6) δ (ppm) = 9.94 (s, 1H), 8,648.72 (m, 3H), 8.17 (d, J = 2.4 Hz, 1H), 8.03 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.69 (dd, J = 9.0 H, 2.6 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H), 4.77-4.90 (m, 1H), 4.36-4.48 (m, 1H), 4.13-4.29 (m, 2H), 4.04 (t, J = 7.4 Hz, Petition: 870260070497, on 07 / 16 / 2026, page. 181 / 214 173 / 205 4H), 3.21-3.30 (m, 2H), 2.96-3.06 (m, 1H), 2.32-2.43 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H). Síntese of OO-7A (S)-6-(azetidin-1-il)-N-(2-(2-metil-4-(5-(4,4,5,5-tetrametil1,3,2-dioxaborolan-2-il)piridin-2-il)piperazin-1-il)pirimidin-5-il)nicotinamide and OO-7B (S)-(6-(4-(5-(6-(azetidin-1-il)nicotinamido)pirimidin-2-il)-3metilpiperazin-1-il)piridin-3-il)borônico

[00299] To a stirred solution of OO-6 (300 mg, 588.9 μmol) in 1,4-dioxane (5 mL), potassium acetate (173.4 mg, 1.767 mmol) and bis(pinacolate)diboron (179.5 mg, 706.7 μmol) were added at room temperature under an argon atmosphere. The reaction mixture was degassed and purged with argon gas for 2 minutes. Then, the adduct PdCl2(dppf)-CH2Cl2 (48.09 mg, 58.89 μmol) was added to this reaction mixture at room temperature. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered through a layer of celite and the filtrate was concentrated under reduced pressure. The crude compound was purified by preparative HPLC (conditions: Mobile phase - Ammonium bicarbonate 10 mM in H2O:MeCN, column - X-Bridge C18 (19X250) mm, 5 μ, flow rate - 15.0 ml / min, gradient method: 0 / 40, 2 / 40, 15 / 75, 13 / 75, 13.05 / 100, 15 / 100, 15.05 / 40, 18 / 40 prep-020).The pure fractions were combined, concentrated under reduced pressure, and lyophilized separately to provide OO-7A and OO-7B. OO-7A: M / Z (ESI): 557.44 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 8.60-8.73 (m, 3H), 8.34 (d, J = 1.2 Hz, 1H), 8.03 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.71 (dd, J = 8.8 Hz, 2.0H, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 4.75-4.85 (m, 1H), 4.25-4.46 (m, 3H), 4.04 (t, J = 7.6 Hz, 4H), 3.27 (d, J = 3.2Hz, 2H), 3.05 (td, J = 11.8 Hz, 3.6 Hz, 1H), 2.34-2.40 (m, 2H), 1.27 (s, 12H), 1.10 (d, J = 6.8 Hz, 3H). OO-7B: M / Z (ESI): 473.32 [MH]-. Petition 870260070497, dated 07 / 16 / 2026, pp. 182 / 214 174 / 205 1H NMR (400 MHz, DMSO-do) δ = 9.94 (s, 1H), 8.63–8.72 (m, 3H), 8.47 (d, J = 1.2 Hz, 1H), 8.03 (dd, J = 8.8 Hz, 7, 12H-4), 3H), 6.80 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1H), 4.76–4.89 (m, 1H), 4.22–4.47 (m, 3H), 4.24 (t, J = 20, 3H), 4.3 Hz 2.99 (td, J = 12.0 H, 3.6 Hz, 1H), 2.34–2.41 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H). Synthesis of PP-3: 4-methylbenzenesulfonate from (S)-1-(5-((5-(4-(5 fluoropyperazine-2-yl)-3-methylpiperazine-1-yl)pyrazine-2-yl)carbamoyl)pyridin-2yl)azetidine-3-yl CS2CO3 (3 eq.), CuI (0.1 eq.), transN,N'-dimethylcyclo-hexane-1,2diamine (0.05 eq.), 1,4-dioxane, 150°C, 2 h, MW Synthesis of PP-1: 6-(3-hydroxyazetidine-1-yl)nicotinamide

[00300] To a stirred solution of 6-chloronicotinamide (1 g, 6.39 mmol) in DMF (40 mL), K2CO3 (2.65 g, 19.16 mmol) and 3-hydroxyazetidine hydrochloride (0.840 g, 7.66 mmol) at 0°C were added. The reaction mixture was stirred under a nitrogen atmosphere at 100°C for 16 hours. The reaction mixture was diluted with EtOAc (50 mL), filtered through a celite layer, and washed with EtOAc (2 x 50 mL). The filtrate was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using a 40 g silica cartridge (230-400 mesh) and eluted with 12% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure to provide PP-1. M / Z (ESI): 194.06 [M+H]+. Petition 870260070497, dated 07 / 16 / 2026, pages 183 / 214 175 / 205 Synthesis of PP-2: (S)-N-(5-(4-(5-fluoropyridin-2-yl)-3-methylpiperazin-1yl)pyrazin-2-yl)-6-(3-hydroxyazetidin-1-yl)nicotinamide

[00301] To a stirred solution of Q-6 (300 mg, 0.852 mmol) in 1,4-dioxane (3 mL), CS2CO3 (833 mg, 2.56 mmol), copper(I) iodide (16.22 mg, 0.085 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (6.66 pL, 0.043 mmol) and PP-1 (181 mg, 0.937 mmol) were added at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 150°C for 2 hours under microwave irradiation. The reaction mixture was rapidly cooled with water (80 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with brine (2 x 80 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by Biotage using an 80 g silica cartridge (230-400 mesh) and eluted with 3% MeOH in DCM. Pure fractions were combined and concentrated under reduced pressure to provide PP-2. M / Z (ESI): 465.34 [M+H]+. Synthesis of PP-3: (S)-1-(5-((5-(4-(5fluoropyridin-2-yl)-3-methylpiperazin-1-yl)pyrazin-2-yl)carbamoyl)pyridin-2yl)azetidin-3-yl 4-methylbenzenesulfonate

[00302] To a stirred solution of PP-2 (200 mg, 0.431 mmol) in DCM (4 mL), TEA (0.180 mL, 1.292 mmol), 4-dimethylaminopyridine (26.3 mg, 0.215 mmol) and tosyl-Cl (246 mg, 1.292 mmol) were added at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 3 hours. The reaction mixture was rapidly cooled with water (50 mL) and extracted with EtOAc (2 x 85 mL). The combined organic layer was washed with brine (2 x 40 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by Biotage using an 80 g silica cartridge (230-400 mesh) and eluted with 70% EtOAc in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. The resulting compound was macerated with 10% diethyl ether. Petition 870260070497, of 16 / 07 / 2026, p. 184 / 214 176 / 205 in pentane and dried under reduced pressure to provide PP-3. M / Z (ESI): 619.33 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 10.49 (s, 1H), 8.82 (d, J = 1.2 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.06-8.25 (m, 3H, 7H, 7, 8.8 Hz), J 2H), 7.47-7.60 (m, 3H), 6.87 (dd, J = 9.4 Hz, 3.4 Hz, 1H), 6.45 (d, J = 8.8 Hz, 1H), 5.27-5.36 (m, 1H), 4.50-4.60 (m, 4.6 H), 4H), 4.03 (d, J = 12.8 Hz, 1H), 3.95 (dd, J = 10.0 H, 2.8 Hz, 2H), 3.16-3.29 (m, 2H), 3.04 (td, J = 11.8 Hz, 3.4 Hz, 2H), (d, J = 6.4 Hz, 3H). Radiosynthesis procedures Synthesis of [3H]-1: [3H]-(S)-6-methoxy-N-(2-(2-methyl-4-(pyridin-2-yl)piperazineCrabtree Catalyst 1-yl)pyrimidine-5-yl)nicotinamide

[00303] Crabtree catalyst (0.15 mg) was added to a tritium reaction vessel, followed by a solution of Compound 1 (0.5 mg) in CH2Cl2 (0.2 mL). The vessel was connected to the tritium line and pressurized to 0.5 atm with tritium gas at -200°C. The solution was stirred for 17 hours, cooled to -200°C, and excess gas removed. A reaction flask was rinsed with 4 x 1 mL of CH3OH, transferring each to a 100 mL recovery flask. The combined CH3OH was removed under vacuum. Gross yield: 90 mCi. The material was purified by HPLC. The mobile phase was removed under vacuum, and the product was re-dissolved in absolute ethanol. Yield: 20.6 mCi, purity >99%. The specific activity determined was 81.04 Ci / mmol by mass spectrometry; molecular weight for C21H20T3N7O2 [M+H]+: 411.5, found: 412.4. Conditions for separation by preparatory HPLC

[00304] Method: 0-70%8 in 20 minutes

[00305] Column: Fenomenex Luna 5flm C18 100 x 21.2 mm Petition 870260070497, dated 07 / 16 / 2026, pp. 185 / 214 177 / 205

[00306] Flow rate: 4 mL / min

[00307] Injection volume: 0.5 mL

[00308] Detection: UV at 254 nm

[00309] Mobile phase A: TFA 0.05% in H2O

[00310] Mobile phase B: CH3CN

[00311] Product elution time: 16.7 minutes Synthesis of [3H]-24: [3H]-2-methoxy-N-[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine-4-carboxamide Crabtree Catalyst

[00312] Crabtree catalyst (0.3 mg) was added to a tritium reaction vessel, followed by a solution of Compound 24 (0.4 mg) in CH2Cl2 (0.2 mL). The vessel was connected to the tritium line and pressurized to 0.5 atm with tritium gas at -200°C. The solution was stirred for 17 hours, cooled to -200°C, and excess gas removed. A reaction flask was rinsed with 4 x 1 mL of CH3OH, transferring each to a 100 mL recovery flask. The combined CH3OH was removed under vacuum. Gross yield: 125 mCi. The material was purified by HPLC. The mobile phase was removed under vacuum, and the product was re-dissolved in absolute ethanol. Yield: 26 mCi, purity >99%. The specific activity determined was 150.01 Ci / mmol by mass spectrometry; molecular weight for C21H20T5N7O2 [M+H]+: 415.5, found: 416.3.

[00313] HPLC Prep

[00314] Method: 10%8 for 5 minutes; 10-90%8 in 20 minutes

[00315] Column: Fenomenex Luna Sum C18 100 x 21.2 mm

[00316] Flow rate: 4 mL / min

[00317] Injection volume: 0.5 mL

[00318] Detection: UV at 254 nm Petition 870260070497, dated 07 / 16 / 2026, pages 186 / 214 178 / 205

[00319] Mobile phase A: TFA 0.05% in H2O

[00320] Mobile phase B: CH3CN

[00321] Product elution time: 18.1 minutes Synthesis of [3H]-89: [3H]-(5)-N-(2-(4-(2-fluoropyridin-4-yl)-2-methylpiperazin1-yl)pyrimidin-5-yl)-6-(1H-pyrazol-1-yl)nicotinamide

[00322] Compound 89 in CH2Q2 was washed with 0.5 M aqueous Na2CÜ3 solution, then the organic layer was dried with N2SO4 and the filtrate was evaporated to dryness. The resulting residue (4 mg) was dissolved in CPME (75 pL) and NMP (50 pL). In a glove box, the nickel precatalyst (ipcADI)NiBr2 (6.65 mg) was dissolved in CPME (670 pL) and treated with NaHBEt3 in toluene (1 M, 23 pL) then stirred for 5 minutes. The substrate solution (100 pL) was added to the active catalyst solution (100 pL) in a tritiating vessel and secured with a Swagelok® portable valve. The valve was connected to the Trisorber and subjected to two freeze-pump-thaw cycles before 155 mmHg tritium gas was introduced. The reaction was thawed, then placed in an oil bath at 45°C and stirred overnight. After capturing the spent tritium in the waste bed, the reaction was transferred to a flask containing 10 mL of saturated aqueous sodium bicarbonate.The mixture was extracted three times with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated. The residue was dissolved in EtOH for LSC and radio-HPLC analysis. Gross yield: 247.2 mCi; RCP: 90%. The material was purified by HPLC. The collected fractions were diluted with an equal volume of water, concentrated in a pair of C18 cartridges, and eluted with EtOH. Yield: approximately 20 mL of ethanol solution at 4.22 mCi / mL. Petition 870260070497, dated 07 / 16 / 2026, pages 187 / 214 179 / 205 The specific activity determined was 55.52 Ci / mmol by mass spectrometry; MW for C23H19T4FN9O [M+H]+: 468.2, found: 468.3.

[00323] Conditions for analytical HPLC

[00324] Method: 10-95%B in 15 minutes, 6 minutes re-equilibration

[00325] Column: Gemini NX C18, 4.6 x 50 mm, 3.5 mm at 40°C

[00326] Flow rate: 1 mL / min

[00327] Injection volume: 1 µL

[00328] Detection: UV at 298 nm

[00329] Mobile phase A: TEAA 0.05 M, pH 10, in H2O

[00330] Mobile phase B: CH3CN

[00331] Time to elution of the product: 7.08 minutes

[00332] Conditions for preparatory HPLC separation

[00333] Column: Gemini NX C18, 10 x 250 mm at 40°C

[00334] Flow rate: 5 mL / min

[00335] Injection volume: 0.4 mL

[00336] Detection: UV at 298 nm

[00337] Mobile phase A: TEAA 0.05 M, pH 10, in H2O

[00338] Mobile phase B: CH3CN Synthesis of [3H]-87: [3H]-(5)-6-(3,3-difluoroazetidin-1-yl)-N-(2-(4-(4fluoropyridin-2-yl)-2-methylpiperazin-1-yl)pyrimidin-5-yl)nicotinamide Crabtree Catalyst

[00339] Compound 87 (0.50 mg, 1.03 µmol) was weighed into a tritiation vessel. Crabtree catalyst (1.12 mg, 0.51 µmol) was prepared as a solution in CH2Cl2 (1.4 mL). The catalyst solution (500 µL) was added to the tritiation vessel, which was connected to the Ultra torr port on the Trisorber and subjected to two freeze-thaw cycles. Petition 870260070497, dated 07 / 16 / 2026, pp. 188 / 214 180 / 205 pump-thaw cycle before 84 mmHg tritium gas was introduced. The reaction was thawed to room temperature after being stirred for 4 hours. After capturing the spent tritium in the waste bed, the reaction was transferred to a flask with 10 mL of saturated aqueous sodium bicarbonate. The mixture was extracted three times with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated. The residue was dissolved in EtOH for LSC and analysis by radioHPLC. Gross yield: 204.4 mCi; RCP: 89%. The material was purified by HPLC. The collected fractions were diluted with an equal volume of water, concentrated in a pair of C18 cartridges, and eluted with EtOH. A portion of the purified batch was dispensed and diluted to 20.0 mL. Yield: 20.0 mL of ethanol solution at 2.45 mCi / mL. Specific Activity determined was 131.4 Ci / mmol by mass spectrometry; MW for C23H19T5F3N8O [M+H]+: 495.2; found: 495.3. Conditions for analytical HPLC

[00340]

[00341]

[00342]

[00343]

[00344]

[00345]

[00346]

[00347]

[00348]

[00349]

[00350]

[00351]

[00352]

[00353] Method: 10-95%B in 15 minutes, 6 minutes re-equilibration Column: Gemini NX C18, 4.6 x 50 mm, 3.5 mm at 40°C Flow rate: 1 mL / min Injection volume: 1.5-2.0 µL Detection: UV at 304 nm Mobile phase A: TEAA 0.05 M, pH 10, in H2O Mobile phase B: CH3CN Time to elution of the product: 7.63 minutes Conditions for preparatory HPLC separation Method: Isocratic (A:B = 55:45) Column: Gemini NX C18, 10 x 250 mm at 40°C Flow rate: 5 mL / min Injection volume: 0.5 mL Detection: UV at 304 nm Petition 870260070497, dated 07 / 16 / 2026, pages 189 / 214 181 / 205

[00354] Mobile phase A: TEAA 0.05 M, pH 10, in H2O

[00355] Mobile phase B: CH3CN Synthesis of [3H]-91: [3H]-(S)-6-(1H-imidazol-1-yl)-N-(2-(2-methyl-4-(pyridin-2yl)piperazin-1-yl)pyrimidin-5-yl)nicotinamide CPME / NMP / toluene

[00356] In a glove box, Compound 91 (1.33 mg, 3.0 µmol) was dissolved in CPME (75 pL) and NMP (25 pL). The nickel precatalyst (ipcADI)NiBr2 (6.73 mg) was dissolved in CPME (670 pL) and treated with NaHBEts in toluene (1 M, 25 pL) then stirred for 5 minutes. The substrate solution (100 pL) was combined with the active catalyst solution (200 pL, 3.5 µmol) in a tritiating vessel and secured with a Swagelok® portable valve. The valve was connected to the Trisorber and subjected to two freeze-pump-thaw cycles before 102 mM tritium gas was introduced. The reaction was thawed, then placed in an oil bath at 45°C and stirred overnight. After capturing the spent tritium in the waste bed, the reaction was transferred to a flask containing 10 mL of saturated aqueous sodium bicarbonate. The mixture was extracted three times with dichloromethane. The combined organic layers were dried with sodium sulfate and evaporated.The residue was dissolved in EtOH for LSC and radio-HPLC analysis. Gross yield: 120 mCi; RCP: 67%. The material was purified by HPLC. The collected fractions were diluted with an equal volume of water, concentrated in a pair of C18 cartridges, and eluted with EtOH. Yield: approximately 20 mL of ethanol solution at 3.18 mCi / mL. The specific activity determined was 44.9 Ci / mmol by mass spectrometry; MW for C23H17T7N9O [M+H]+: 456.3, found: 456.0. Conditions for analytical HPLC Petition 870260070497, dated 07 / 16 / 2026, pages 190 / 214 182 / 205

[00357] Method: 10-95%B in 12 minutes, 3-minute wait, 6 minutes of rebalancing

[00358] Column: Gemini NX C18, 4.6 x 50 mm, 3.5 mm at 40°C

[00359] Flow rate: 1 mL / min

[00360] Injection volume: 1.0 uL

[00361] Detection: UV at 294 nm

[00362] Mobile phase A: TEAA 0.05 M, pH 10, in H2O

[00363] Mobile phase B: CH3CN

[00364] Product elution time: 6.32 minutes

[00365] Conditions for separation by preparatory HPLC

[00366] Method: Isocratic (A:B = 65:35)

[00367] Column: Gemini NX C18, 10 x 250 mm at 40°C

[00368] Flow rate: 5 mL / min

[00369] Injection volume: 0.5 mL

[00370] Detection: UV at 295 nm

[00371] Mobile phase A: TEAA 0.05 M, pH 10, in H2O

[00372] Mobile phase B: CH3CN

[00373] Test protocols Acquisition of post-mortem human tissue samples for in vitro ligation assays.

[00374] Frozen human brain tissues from patients with Parkinson's disease (PD) were acquired from Analytic Biological Services Inc. The samples were post-mortem tissue from donors with a clinical diagnosis of late-stage PD. Alpha-synuclein, tau, and amyloid loads were determined using a combination of immunohistochemistry on frozen thin coronal sections, as well as alpha-LISA-based quantification of protein levels in a detergent-insoluble protein fraction. In one tissue sample from the temporal cortex of one donor, moderate to high alpha-synuclein load, low amyloid, and minimal amyloid load were identified. Petition 870260070497, dated 07 / 16 / 2026, pages 191 / 214 183 / 205 no pathology associated with tau protein. The detergent-insoluble fraction of the temporal cortex of this patient was used as support for homogenate binding studies. Preparation of the detergent-insoluble fraction of human brain tissue for in vitro binding studies.

[00375] Gray matter was dissected from the temporal cortex tissue with a dissecting blade and minced with fine dissecting scissors. To prepare the insoluble fractions, the minced tissue was homogenized in chilled TBS-TX buffer (50 mM Tris + 150 mM NaCl + 1% Triton X100 + 1 mM EDTA + 1 tablet / 10 mL of complete protease inhibitor + 1 tablet / 10 mL of PHOSSTOP phosphatase inhibitor tablet) using a Dounce glass tissue macerator. The homogenates were centrifuged at 100,000 xg for 45 minutes. The pellet was resuspended in TBS-TX buffer using a Polytron at the highest setting for 30 seconds at 4°C. The homogenates were centrifuged at 100,000 xg for 45 minutes and the pellet was resuspended in TBS-TX buffer. A BCA protein assay was performed on the final homogenate to determine the protein concentration. The homogenates were divided into 0.5 ml / tube aliquots and stored at 70°C until use. Procedures for alpha-Synuclein binding assays in tissue homogenate (Assay 1)

[00376] For the hot saturation binding assay, various radioligand concentrations were prepared in Assay Buffer (DPBS plus 0.1% BSA) for final radioligand concentrations ranging from 0.84 to 50 nM [3H]-1. 25 µl of radioligand were added to 200 µl of insoluble fractions of DP brain homogenates, diluted to 50 pg / ml in Assay Buffer (incubation, filtration, and determination of the amount of radioligand used in the assay are described below). Self-blocking was used. Petition 870260070497, dated 07 / 16 / 2026, pages 192 / 214 184 / 205 with unlabeled compound to determine non-specific bonding. Saturation data were analyzed using GraphPad / Prism software.

[00377] Figure 2 depicts a saturation binding experiment using [3H]-1 and a Triton-insoluble fraction of temporal cortex tissue with DP enriched with aggregated alpha-synuclein. These data support the use of this ligand in radioligand binding assays to optimize potency for binding to pathological alpha-synuclein. Figure 2 shows an example of hot saturation binding of [3H]-1, where the radioligand shows high affinity for alpha-synuclein in DP brain homogenates with a measured dissociation constant of 25 nM.

[00378] For the alpha-synuclein displacement binding assay, unlabeled test compounds were dissolved in 10 mM DMSO. Dilutions of the test compounds to various concentrations were made in 100% DMSO at 1000x the final assay concentration, and 0.225 µL aliquots were dispensed onto assay plates. Insoluble fractions of DP brain homogenates were diluted to 50 pg / ml from the original volume of 10 mg / ml in Assay Buffer, and 200 µL were added to the assay plate for a final concentration of 10 pg per well. [3H]-1 was prepared at 10x the final concentration in Assay Buffer, and 25 µL were added to the assay plate for a final assay concentration of 2.0 nM. 200 µL of homogenates and 25 µL of radioligand were added to the assay plates, dispensed with titrated compounds. The plates were incubated at room temperature for 90 minutes.Unbound and bound ligands were separated by filtration of bound particles onto GF / C filter plates (pre-treated for 60 minutes with 0.2% PEI at 4°C), using a Perkin Elmer FilterMate Harvester Unifilter-96, and removing the unbound particles by washing with 1 ml of chilled DPBS three times. Filter plates were dried (1 hour at 47°C under vacuum in an oven or overnight at room temperature). 50 µl per well of Microscint-20 (Perkin Elmer) were added to the plates and the plates were... Petition 870260070497, dated 07 / 16 / 2026, pages 193 / 214 185 / 205 counted, 1 minute per well, on the Perkin Elmer TopCount. The data were analyzed with IDBS Activity Base to determine the Ki values ​​shown in Data Table 1 (Kd value 25 nM, ligand concentration 2.0 nM; Figure 2). Competitive binding of radioligand to pathological beta-amyloid aggregate in DA tissue (Test 2):

[00379] Frozen human brain samples from Alzheimer's disease (AD) patients were acquired from Analytic Biological Services Inc. The samples were post-mortem tissue from donors with a clinical diagnosis of AD, and much of the white matter was removed by dissection of the frontal cortex in order to enrich the tissue preparations with gray matter. Brain homogenates, enriched with gray matter from the frontal cortex, were prepared by homogenizing the tissue in ice-cold phosphate-buffered saline (PBS), pH 7.4, at 80 mg of tissue wet weight per 1 ml, for 45 seconds at 4°C on setting 16 of the Polytron. The homogenate was further diluted with ice-cold PBS to 30 mg of tissue wet weight per 1 ml and homogenized for one more minute as described above. The homogenates were divided into 5 ml / tube aliquots and stored at -70°C until use.

[00380] Radioligand [3H]-105, prepared as described in ACS Med. Chem. Lett., Vol. 2, pages 498-502, was used in this assay.

[00381] For the hot saturation binding assay, various concentrations of the radioligand, [3H]-105, were prepared in Assay Buffer (PBS plus 0.1% BSA) plus 20% DMSO, ranging from 3.9 to 500 nM. 25 µl of radioligand were added to 200 µl of crude brain homogenates (diluted to 0.5 mg / ml in Assay Buffer) for concentration Petition 870260070497, dated 07 / 16 / 2026, pages 194 / 214 186 / 205 final radioligand concentrations ranging from 0.39 to 50 nM and final crude brain homogenates of 100 µg wet weight / assay well (incubation, filtration, and determination of the amount of radioligand used in the assay are described below). Self-blocking with unlabeled compound was used to determine non-specific binding. Saturation data were analyzed using Graphpad / Prism software.

[00382] Figure 1 depicts the high-affinity saturation binding of [3H]-105 to DA cortical tissue homogenate enriched with pathologically aggregated beta-amyloid. The figure shows an example of hot saturation binding of [3H]-105, where the radioligand shows high affinity for aggregated beta-amyloid (abeta) in DA brain homogenates with a measured dissociation constant of 11 nM. These data support the use of this ligand in radioligand binding assays to track binding to aggregated beta-amyloid.

[00383] For Assay 2, unlabeled test compounds were dissolved in 10 mM DMSO. Dilutions of test compounds to various concentrations were made in 100% DMSO up to 1000x the final assay concentration, and 0.225 µl aliquots were dispensed into assay plates. Brain homogenates were diluted to 0.5 mg / ml from the original volume of 30 mg / ml in Assay Buffer, and 200 µl were added to the assay plate for a final concentration of 100 µg wet weight / assay well. [3H]-105 was prepared at 10x the final concentration in Assay Buffer plus 20% DMSO, and 25 µl were added to the assay plate for a final assay concentration of 3.0 nM. The plates were incubated at 37°C for 90 minutes. Unbound and bound ligands were separated by filtration of bound ligands on GF / B filter plates (pre-treated for 30 minutes with 0.1% PEI), using a Packard Filtermate, and unbound ligands were removed by washing with 2.5 ml of ice-cold 5 mM Tris at pH 7.4.The filter plates were dried for 1 hour at 57°C and 50 µl of Microscint were added to each well of the plate. Petition 870260070497, dated 07 / 16 / 2026, pages 195 / 214 187 / 205 The plates were counted for 3H cpm for 1 minute per well, using the PerkinElmer TopCount. The data were analyzed with IDBS Activity Base to determine the Ki values ​​shown below in Data Table 1 (Kd value 11.0 nM, ligand concentration 3.5 nM). Table 8 - Data on radioligand binding to alpha-synuclein extracted with Triton in DP tissue (Assay 1) and AP-rich DA tissue (Assay 2) Data Table 1 (ND = Not determined) Example in α-synuclein Tissue Ki (Assay 1, nM) AP Tissue Ki (Assay 2, nM) Selectivity Ratio (Assay 2 / Assay 1) 1 60 633 11 2 9 10810 1172 3 10 5850 576 4 14 10810 792 5 15 10810 720 6 22 2162 99 7 24 4545 187 8 26 2162 83 9 28 3085 110 10 30 3619 121 11 31 5996 193 12 36 1225 34 13 43 10810 249 14 52 4699 90 15 62 10810 175 16 66 10810 163 17 79 10810 137 18 85 3937 47 19 86 1538 18 20 93 3603 39 21 94 4595 49 22 97 2397 25 23 18 582 32 24 29 590 20 25 34 723 22 26 67 890 13 27 71 552 8 Petition 870260070497, dated 07 / 16 / 2026, pages 196 / 214 188 / 205 Example in α-synuclein Tissue Ki (Assay 1, nM) αβ Tissue K, (Assay 2, nM) Selectivity ratio (Assay 2 / Assay 1) 28 82 526 6 29 93 799 9 30 137 10810 79 31 113 2579 23 32 157 2862 18 33 185 3747 34 34 132 4526 34 35 158 10810 68 36 175 10810 62 37 2 10810 4680 38 3 10810 3615 39 3 10810 3593 40 6 10810 1869 41 7 10810 1510 42 9 2773 323 43 25 5762 231 44 40 10810 268 45 43 10810 249 46 54 10810 201 47 9 1388 155 48 14 10810 771 49 15 2383 155 50 21 10810 517 51 26 10810 421 52 28 5318 187 53 36 10810 299 54 43 5521 130 55 54 1459 27 56 55 4291 78 57 60 3700 61 58 64 3449 54 59 70 5152 73 60 71 4121 58 61 78 10810 139 62 30 576 19 63 5 10810 2208 64 3 10810 4182 65 3 2453 801 Petition 870260070497, dated 07 / 16 / 2026, pages 197 / 214 189 / 205 Example in α-synuclein Tissue Ki (Assay 1, nM) αβ Tissue K, (Assay 2, nM) Selectivity ratio (Assay 2 / Assay 1) 66 5 3429 752 67 5 3603 696 68 6 10810 1842 69 8 10810 1313 70 9 10810 1217 71 9 3603 400 72 9 10810 1141 73 11 10810 952 74 13 10810 839 75 13 1710 132 76 21 3062 145 77 21 4219 199 78 22 2762 125 79 23 2007 88 80 35 10810 313 81 41 10810 263 82 44 10810 246 83 55 10810 195 84 73 10810 148 85 6 942 147 86 14 691 51 87 3.8 12000 3158 88 2.8 12000 4286 89 5.1 10 2 90 30 ND ND 91 5.9 55 9 92 1.0 12000 12000 93 2.0 12000 6000 94 2.1 12000 5714 95 2.4 310 129 96 2.8 12000 4286 97 2.8 2620 936 98 4.4 10000 2273 99 4.8 330 69 100 5.3 12000 2264 101 6.4 20 3 102 6.5 12000 1846 103 7.0 4000 571 Petition 870260070497, dated 07 / 16 / 2026, pages 198 / 214 190 / 205 Example in α-synuclein Tissue Ki (Assay 1, nM) αβ Tissue K, (Assay 2, nM) Selectivity ratio (Assay 2 / Assay 1) 104 8.3 220 27 105 9.4 12000 1277 106 11 12000 1091 107 14 12000 857 108 14 12000 857 109 15 30 2 110 20 12000 600 111 30 12000 400 112 5.3 12000 2264 113 2.0 12000 6000 114 9.0 12000 1333 115 3.9 ND ND 116 2.7 ND ND 117 1.8 ND ND 118 0.4 ND ND 119 1.8 ND ND 120 1.0 ND ND 121 13 ND ND 122 1.3 ND ND 123 0.6 ND ND 124 2.0 ND ND 125 36 ND ND 126 9.2 ND ND 127 7.6 ND ND 128 1.7 ND ND 129 1.3 ND ND 130 1.6 ND ND 131 1.9 ND ND 132 4.5 ND ND 133 3.7 ND ND 134 3.7 ND ND 135 2.9 ND ND 136 3.0 ND ND 137 3.0 ND ND 138 2.3 ND ND 139 4.9 ND ND 140 8.7 ND ND 141 1.2 ND ND Petition 870260070497, dated 07 / 16 / 2026, pp. 199 / 214 191 / 205 Example in α-synuclein Tissue Ki (Assay 1, nM) Λβ Tissue Ki (Assay 2, nM) Selectivity ratio (Assay 2 / Assay 1) 142 3.1 ND ND 143 3.3 ND ND 144 1.5 ND ND

[00384] Procedure for saturation binding data in human cortical tissue homogenate of DP, enriched with aggregated alpha-synuclein, human cortical tissue homogenate of DA, enriched with pathological aggregate Ae: Banner Parkinson's disease (PD; Braak Stage 5 / 6) brain homogenates were obtained through the Michael J. Fox Foundation (MJFF) tissue consortium. The characterization of such brain tissue, as well as the preparation of the tissue for linkage studies, was as described in US 2019 / 0256492, paragraphs 0242-0244. Banner PD brain homogenates, which are post-mortem brain tissue from donors diagnosed with PD, were prepared using cingulate cortex collected from multiple PD brains that were rich in alpha-synuclein pathology but free of amyloid pathology and tauopathy by neuropathological validation. The final concentration of Banner PD brain homogenates was 333 mg of wet tissue per 1 mL of buffer. The homogenates were divided into 1 mL / tube aliquots and stored at -70°C before use.

[00385] Frozen human brain samples from Alzheimer's disease (AD) patients were acquired from Analytic Biological Services Inc. They constitute post-mortem tissue from donors with a clinical diagnosis of AD and validated by IHC for amyloid pathology. Brain homogenates of the frontal cortex were prepared by homogenizing the frontal cortex in chilled phosphate-buffered saline (PBS), pH 7.4, for 30 seconds at 4°C in setting 6 of the Polytron. The final concentration of the brain homogenates was 10 mg of wet tissue per 1 mL of buffer. The homogenates Petition 870260070497, dated 07 / 16 / 2026, pages 200 / 214 192 / 205 were divided into 1mL / tube aliquots and stored at -70°C before use.

[00386] [3H]-1 was synthesized as described in the procedures outlined above. The specific activity of [3H]-1 is 196.6 Ci / mmol in a volume of 3.9 mCi / mL.

[00387] Hot saturation binding assays, used to evaluate radioligand binding to DP Banner brain homogenates and ABS DA brain homogenates, were performed separately at nine concentrations from 60.0 nM to 0.6 nM. Brain homogenates were diluted to 2.0 mg / mL (ABS DA) or 2.8 mg / mL (DP Banner) from the original volume of 30 mg / mL with PBS buffer. Total binding was defined in the absence of competing compound, and non-displaceable binding was determined in the presence of unlabeled 1 μM self-blocking. The assay buffer was 30 nM Tris, pH 7.5, containing 0.1% BSA. The test tubes were pre-incubated at room temperature for 30 minutes, then dilutions of the radioligand (10X) were added to the test tube (10 μL each / per tube, separately) up to a final volume of 100 μL per tube.Incubation was performed at 37°C for 120 minutes, and assay samples were filtered through GF / C filters using a 12-well Skatron collector and washed in a 5-5-5 configuration (~3 x 2 mL) with ice-cold buffer (30 nM Tris, pH 7.5). GF / C filter papers for the Skatron collector were pre-soaked in 0.1% BSA for 1 hour at room temperature before use. The filters were punched into scintillation tubes and counted in 2 mL of Ultima Gold in a Perkin Elmer Tri-Carb 2900TR for 1 minute. Data analysis was performed using Prism software. All assays were performed in triplicate in the laboratory designated for human tissue studies.

[00388] The tests on [3H]-24 were carried out in a manner analogous to that of [3H]-1. Petition 870260070497, dated 07 / 16 / 2026, pages 201 / 214 193 / 205

[00389] Data for these saturation binding assays, using [3H]-1 and [3H]-24, are illustrated in Figures 3-6. Specifically, Figure 3 depicts a saturation binding experiment using [3H]-1 and cingulate cortex tissue homogenate with DP enriched with aggregated alpha-synuclein. These data demonstrate potent binding to pathological alpha-synuclein in tissue homogenate. Figure 4 depicts a saturation binding experiment using [3H]-1 and DA tissue homogenate enriched with aggregated beta-amyloid pathology. (ND = Not determined due to incomplete saturation of the binding signal). These data demonstrate weak binding to pathological beta-amyloid in tissue homogenate. Figure 5 depicts a saturation binding experiment using [3H]-24 and cingulate cortex tissue homogenate with DP enriched with aggregated alpha-synuclein. These data demonstrate a strong link to pathological alpha-synuclein in tissue homogenate.Figure 6 depicts a saturation binding experiment using [3H]-24 and DA tissue homogenate enriched with aggregated beta-amyloid pathology. (ND = Not determined due to incomplete saturation of the binding signal). These data demonstrate weak binding to pathological beta-amyloid in tissue homogenate. In vitro binding of alpha synuclein tracers in human brain tissue homogenates with PD

[00390] Frozen samples of human brain tissue from Parkinson's disease (PD) patients were provided by Banner Sun Health Institute (USA) through a collaboration with the Michael J. Fox Foundation (MJFF). These are post-mortem tissues from donors with a clinical diagnosis of PD and neuropathological validation of PD pathology. Cerebral cortex homogenates were prepared by homogenizing the cortex in chilled phosphate-buffered saline (PBS), pH 7.4, for 30 seconds at 4°C using Polytron setting 6. The final concentration of brain homogenates... Petition 870260070497, dated 07 / 16 / 2026, pages 202 / 214 194 / 205 was 30 mg of wet tissue per 1 mL of buffer. The homogenates were divided into 1 mL aliquots / tube and stored at -70°C before use.

[00391] [3H]-87 was synthesized and the specific activities of [3H]-87 are 131.5 Ci / mmol. For the hot saturation binding assay, 9 radioligand concentrations were used, ranging from 50 nM to 0.5 nM and from 10 nM to 0.1 nM. Brain homogenates were diluted from the original volume of 30 mg / mL to a final concentration of 2.8 mg / mL with assay buffer (Tris, pH 7.5, BSA 0.1%), and 250 μL per test tube were used in the assay. Unlabeled test compounds were dissolved in 1 mM DMSO. Dilution of the test compound to various concentrations was performed with assay buffer containing 2% DMSO. Total binding was defined in the absence of competing compound, and non-displaceable binding was determined in the presence of unlabeled self-locking 1 μM.Dilutions of the compound (10X) were added to test tubes (25 pL each / per tube, separately) containing 200 μL of brain homogenate dilution, and the tubes were pre-incubated at room temperature for 30 minutes. Then, dilutions of the radioligand (10X) were added to the test tubes (25 pL each / per tube, separately) to a final volume of 250 pL per tube. Incubation was performed at 37°C for 120 minutes, and then the assay samples were filtered through GF / C filters using a 12-well Skatron collector, washing in a 5-5-5 configuration (~3 x 2 ml) with ice-cold buffer (Tris, pH 7.5). The GF / C filter papers for the Skatron collector were pre-immersed in 0.1% BSA for 1 hour at room temperature before use. The filters were perforated into scintillation tubes. Liquid scintillation fluid (2mL Ultima Gold) was added to each vial, allowed to be absorbed by the filters for 4 hours, and counted on the Perkin Elmer Tri-Carb 2900TR for 1 minute.Data analysis was performed using Prism software. All tests were conducted in duplicate or triplicate. Petition 870260070497, dated 07 / 16 / 2026, pages 203 / 214 195 / 205 depending on the assay configuration, in the laboratory designated for studies with human tissues. Table 9 - Data Table 2 - In vitro binding data for [3H]87 in Human tissue homogenates with Parkinson's disease [3H]-87 Cortex with PD Bmax (nM) 5.0 Kd(nM) 0.2 Bmax / Kd 25

[00392] [3H]-89 was synthesized and the specific activities of [3H]-89 are 55.5 Ci / mmol. For the hot saturation binding assay, nine radioligand concentrations were used, ranging from 50 nM to 0.5 nM. Brain homogenates were diluted from the original volume of 30 mg / mL to a final concentration of 2.8 mg / mL with assay buffer (Tris, pH 7.5, BSA 0.1%), and 250 μL per test tube were used in the assay. Unlabeled test compounds were dissolved in 1 mM DMSO. Dilution of the test compound to various concentrations was performed with assay buffer containing 2% DMSO. Total binding was defined in the absence of competing compounds, and non-displaceable binding was determined in the presence of 1 μM unlabeled self-blocking.Dilutions of the compound (10X) were added to the test tube (25 μL each / per tube, separately) containing 200 μL of brain homogenate dilution, and the tubes were pre-incubated at room temperature for 30 minutes. Then, dilutions of the radioligand (10X) were added to the test tube (25 μL each / per tube, separately) to a final volume of 250 μL per tube. Incubation was performed at 37°C for 120 minutes, and then the assay samples were filtered through GF / C filters using the Skatron 12-well collector, washing in a 5-5-5 configuration (~3 x 2 ml) with ice-cold buffer (Tris, pH 7.5). The GF / C filter papers for the Skatron collector were pre-immersed in 0.1% BSA for 1 hour at room temperature before use. The filters were perforated into scintillation tubes. The liquid scintillation fluid (2mL Ultima. Petition 870260070497, dated 07 / 16 / 2026, pages 204 / 214 196 / 205 Gold) was added to each vial, allowed to be absorbed by the filters for 4 hours, and counted in the Perkin Elmer Tri-Carb 2900TR for 1 minute. Data analysis was performed using Prism software. All assays were performed in duplicate or triplicate, depending on the assay configuration, in the laboratory designated for studies with human tissues. Table 10 - Data table 3 - In vitro binding data for [3H]89 in Human tissue homogenates with Parkinson's disease [3H]-89 Cortex with PD Bmax (nM) 134 Kd(nM) 2.9 Bmax / Kd 46 Radiochemical synthesis of [18F]-ligands General methods

[00393] [18F] Fluoride was concentrated in an anion exchange resin and eluted prior to use. Unless specifically stated, the anion exchange resin containing the [18F] fluoride was eluted with Kryptofix 222 (7 mg, 19 pmol) and K2CO3 (2.1 mg, 15 pmol) in acetonitrile / water (80 / 20, 0.7 ml) and transferred to a 1 ml V-shaped vented flask in a microwave cavity. The fluoride was dried under an argon stream and microwave heating (35 W / 90°C). Additional aliquots of acetonitrile (3 x 0.5 ml) were added for azeotropic drying at 35 W / 90°C. Synthesis of [18F]-87

[00394] A solution of 88 (0.5 mg, 1.0 pmol) in DMSO (0.3 mL) was added to the microwave flask containing the dry [18F]fluoride, the vent line was removed, and the reaction mixture was heated to 170°C (60 W) for 3 minutes. After cooling to < 50°C, the reaction was diluted with H2O (0.8 Petition 870260070497, dated 07 / 16 / 2026, pages 205 / 214 The solution was prepared using a 197 / 205 mL solution, mixed, and injected into a semi-preparative HPLC column. The product was purified using a Gemini, C6-Phenyl, 110A, 150X10 mm, at a flow rate of 5 mL / min. The mobile phase was acetonitrile / trifluoroacetic acid 0.1% from 50 to 95%. The radioactive fraction that eluted between 12.5 and 13.5 minutes was collected, diluted with 20 mL of water for injection, and loaded into a Waters Sep-Pak Classic C18 cartridge (Waters, Milford, MA, USA). The Sep-Pak was rinsed with 10 mL of water and then eluted with ethanol (0.5 mL) into a sterile 10 mL vial and diluted to the desired formulation. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent), employing an ONYX Monolithic, 5μ, C18, 50X3 mm (Fenomenex) at a flow rate of 1 mL / min. The mobile phase was a mixture consisting of 0.1% acetonitrile / trifluoroacetic acid in water, condensed from 10 to 90% over 10 minutes. The concentration of [18F]-87 was determined using an ultraviolet detector (254 nm).The product's identity was confirmed by co-injection of a sample of compound 87, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [18F]-87 was 6.3 min. Synthesis of [18F]-89

[00395] A solution of 90 (0.5 mg, 1.0 μmol) in DMSO (0.3 mL) was added to the microwaveable flask containing the dry [18F]fluoride, the vent line was removed, and the reaction mixture was heated to 170°C (60 W) for 3 minutes. After cooling to < 50°C, the reaction was diluted with H2O (0.8 mL), mixed, and injected into the semi-preparative HPLC column. The product was Petition 870260070497, dated 07 / 16 / 2026, pages 206 / 214 198 / 205 purified with Gemini, C6-Phenyl, 110A, 150x10 mm, at a flow rate of 5 mL / min. The mobile phase was acetonitrile / trifluoroacetic acid 0.1%: 65 / 35. The radioactive fraction that eluted between 7.5 and 8.5 minutes was collected, diluted with 20 mL of water for injection, and loaded into a Waters Sep-Pak Classic C18 cartridge (Waters, Milford, MA, USA). The Sep-Pak was rinsed with 10 mL of water and then eluted with ethanol (0.5 mL) into a sterile 10 mL vial and diluted to the desired formulation. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) with an ONYX Monolithic, 5μ, C18, 50X3 mm column (Fenomenex) at a flow rate of 1 mL / min. The mobile phase was a mixture consisting of 0.1% acetonitrile / trifluoroacetic acid in water, diluted to 90% over 10 minutes. The concentration of [18F]-89 was determined using an ultraviolet detector (254 nm).The product's identity was confirmed by co-injection of a sample of compound 89, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [18F]-89 was 5.1 min. Synthesis of [18F]-112

[00396] A solution of NN-5 (1.4 mg, 2.40 μmol) in DMF (0.3 mL) was added to the microwaveable flask containing the dry [18F]fluoride, the vent line was removed, and the reaction mixture was heated to 120°C (110 W) for 3 minutes. After cooling to < 50°C, the reaction was diluted with H2O (0.8 mL), mixed, and injected into the semi-preparative HPLC column. The product was purified using a Zorbax Eclipse XDB-C18 HPLC column (Agilent), 5 μ, 9.4 x 250 mm, at a flow rate of 5 mL / min. The mobile phase was Petition 870260070497, dated 07 / 16 / 2026, pages 207 / 214 199 / 205 acetonitrile / Na2HPU4 (10 mM) was diluted from 30 to 70% over 15 minutes. The radioactive fraction that eluted between 14 and 15 minutes was collected in a flask containing a 30% β-cyclodextrin solution (1 mL), evaporated under negative pressure, diluted with saline solution, and transferred to a sterile container. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) with an ONYX Monolithic, 5μ, C18, 50X3 mm column (Fenomenex) at a flow rate of 1.5 mL / min. The mobile phase was a mixture consisting of 0.1% acetonitrile / formic acid in water diluted from 5 to 50% over 7 minutes. The concentration of [18F]-112 was determined using an ultraviolet detector (254 nm). The product's identity was confirmed by co-injection of a sample of compound 112, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [18F]-112 was 6.0 min. Synthesis of [18F]-113

[00397] [18F] Fluoride was concentrated in an anion exchange resin that was pretreated by washing with jets of EtOH (10 mL) followed by KOTf 0.5M in H2O (10 mL) and H2O (10 mL) before use.

[00398] The anion exchange resin containing [18F]fluoride was eluted with tetrabutylammonium triflate (7.5 mg, 19 mmol) and cesium carbonate (0.1 mg, 0.3 mmol) in H2O (0.5 mL), followed by CH3CN (1.0 mL) into a 2.5 mL V-shaped vented flask and dried under an argon jet using conventional heating at 100°C. Additional aliquots of CH3CN (2 x 0.5 mL) were added for azeotropic drying. The V-flask was purged with air from a syringe (10 mL) and heated to 120°C. Petition 870260070497, dated 07 / 16 / 2026, pages 208 / 214 200 / 205 after that, a solution of OO-7B (2.0 mg, 4.2 mmol), tetrakis(pyridine)copper(II) triflate (11.3 mg, 17 mmol) and pyridine (32 mL, 40 mmol) in 1,3-dimethyl-2-imidazolidinone (DMI; 0.5 mL) was added. The reaction mixture was heated to 120°C for 20 minutes, followed by transfer to a vial containing 10% CH3CN / 10 mM Na2HPO4 in H2O, pH 7.4 (1.0 mL), at room temperature for dilution, mixing and injection into a semi-preparative HPLC column. The product was purified using a Gemini C18 HPLC column, 5 mm, 110A, 150x10 mm (Fenomonex) with a flow rate of 5 mL / min and a mobile phase of CH3CN / Na2HPO4 10 mM, pH 7.4, with a gradient of 30-50%. The radioactive fraction that eluted between 16.3 and 16.4 minutes was collected in a round-bottom flask containing 10% captisol in H2O (0.5 mL), evaporated under negative pressure, and transferred to a sterile 10 mL vial.The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) with a Poroshell 120, 4 mm EC-C18 100x4.6 mm HPLC column (Agilent) at a flow rate of 1.5 ml / min and a 10 mM Cl I3CN / Ni I.iOAc mobile phase, pH 8.1, with a gradient of 35-45%. The concentration of [18F]-113 was determined using an ultraviolet detector (254 nm). Product identity confirmation was determined by co-injection of a sample of compound 113, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [18F]-113 was 6.8 min. Synthesis of [18F]-115 by isotope exchange

[00399] The anion exchange resin containing [18F]fluoride was eluted with tetraethylammonium bicarbonate (4.2 mg, 22 mmol) in CH3CN / H2O 1:1 Petition 870260070497, dated 07 / 16 / 2026, pages 209 / 214 201 / 205 (1.0 mL), followed by CH3CN (0.5 mL) into a 2.5 mL V-shaped vented flask, and dried under an argon jet using conventional heating at 100°C. Additional aliquots of CH3CN (2 x 0.5 mL) were added for azeotropic drying. The flask containing dried [18F]Et4NF was heated to 130°C, and then a solution of 115 (0.3 mg, 0.6 mmol) in DMSO (0.5 mL) was added. The reaction mixture was heated to 130°C for 10 minutes, followed by transfer to a flask containing H2O (0.8 mL) at room temperature for dilution, mixing, and injection into a semi-preparative HPLC column. The product was purified using a Zorbax XDB-C18 HPLC column, 5 mm, 150x9.4 mm (Agilent) with a flow rate of 5 ml / min and a mobile phase of 30% CH3CN / 10 mM Na2HPO4, pH 7.4.The radioactive fraction that eluted between 14.3 and 14.7 minutes was collected in a round-bottom flask containing 10% captisol in H2O (0.5 mL), evaporated under negative pressure to remove CH3CN, and transferred to a sterile 10 mL vial. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) with a Poroshell 120, 4 mm EC-C18 100x4.6 mm HPLC column (Agilent) at a flow rate of 1.5 mL / min and a 10 mM CH3CN / NH4OAc mobile phase, pH 8.0, with a gradient of 30-40%. The concentration of [18F]-115 was determined using an ultraviolet detector (254 nm). The product's identity was confirmed by co-injection of a sample of compound 115, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for compound [18F]-115 was 4.5 min. Synthesis of [18F]-116 Petition 870260070497, dated 07 / 16 / 2026, pages 210 / 214 202 / 205

[00400] [18F] Fluoride was concentrated in an anion exchange resin that was pretreated by washing with jets of EtOH (10 mL), followed by 0.5M K3PO4 in H2O (10 mL) and H2O (10 mL) before use.

[00401] The anion exchange resin containing [18F]fluoride was eluted with tetrabutylammonium mesylate (6.8 mg, 20 mmol) in 1:1 CH3CN / H2O (1.0 mL), followed by 0.5 mL of CH3CN into a 2.5 mL V-shaped vented flask and dried under an argon jet using conventional heating at 100°C. Additional aliquots of CH3CN (2 x 0.5 mL) were added for azeotropic drying. The flask containing dried [18F]Bu4NF was heated to 120°C, and then a PP-3 solution (0.9 mg, 1.5 mmol) in 1:1 DMSO / isoamyl alcohol (0.5 mL) was added. The reaction mixture was heated to 120°C for 10 minutes, followed by transfer to a flask containing H2O (1.0 mL) at room temperature for dilution, mixing, and injection into a semi-preparative HPLC column. The product was purified using a Zorbax XDB-C18, 5 mm, 150x9.4 mm HPLC column (Agilent) with a flow rate of 5 mL / min and a mobile phase of 30%...

Claims

1. Compound, characterized by being represented by Formula I: or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 alkyl, ORc or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, ORc or halo; Ra is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 groups of R; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or -O(CH2)nhalo; Rc is independently selected from H or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, ORd or halo; Rd is independently selected from H or C1-6 alkyl;R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, ORc, NO2, halo or C1-6 alkyl; Petition 870250071752, dated 14 / 08 / 2025, p. 215 / 259 2 / 41 Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups;Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, imidazopyridinyl, 3,4-dihydro-2Hpyrido[3,2,b][1,4]oxazine or phenyl; Ring B is selected from a) \----- / , b) c) or m is selected from 1, 2 or 3; n is selected independently from 0, 1, 2, 3 or 4; p is selected from 0, 1, 2 or 3; eq is selected from 1, 2 or 3.

2. Compound according to claim 1, characterized in that it has the structure of Formula IA: Petition 870250071752, dated 08 / 14 / 2025, page 216 / 259 3 / 41 IA or a pharmaceutically acceptable salt thereof, wherein; R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, ORc or halo; Ra is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or -O(CH2)nhalo; Rc is selected independently from H or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three C1-6 alkyl, ORd or halo groups; Rd is selected independently from H or C1-6 alkyl;R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, -NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, cycloalkyl, phenyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, ORc, halo or -C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Petition 870250071752, dated 14 / 08 / 2025, p. 217 / 259 4 / 41 Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups;Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 1, 2 or 3; n is selected independently from 0, 1, 2, 3 or 4; ep is selected from 0, 1, 2 or 3.

3. Compound according to claim 1 characterized in that: Ring A1 is selected from pyridyl, pyrazinyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl or pyridyl, wherein said pyrimidinyl, phenyl or pyridyl is optionally substituted with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl or phenyl; m is selected from 1 or 2; ep is selected from 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

4. Compound according to claim 1, characterized in that it has the structure of Formula IB: IB or a pharmaceutically acceptable salt thereof, wherein; Petition 870250071752, dated 08 / 14 / 2025, page 218 / 259 5 / 41 R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, ORc or halo; Ra is unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -NRc2, -(CH2)nhalogen or -O(CH2)nhalo; Rc is independently selected from H or C1-6 alkyl;R1 is selected from -(CH2)nORc, -(CH2)nO(CH2)nR, (CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, ORc, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl or pyrazinyl is optionally substituted with 1 to 3 R groups; Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, pyrrolpyrazinyl, oxadiazolyl, 3,4-dihydro-2Hpyrido[3,2,b][1,4]oxazine or phenyl;n is selected independently from 0, 1, 2, 3, or 4; ep is selected from 1 or 2.

5. Compound according to claim 1, characterized in that it has the structure of Formula IC: Petition 870250071752, dated 08 / 14 / 2025, page 219 / 259 6 / 41 or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, ORc or halo; Ra is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -(CH2)nhalogen or -O(CH2)nhalo; Rc is independently selected from H or C1-6 alkyl;R1 is independently selected from -(CH2)nORc, (CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, NR2, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocyclyl, wherein said alkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, ORc, halo or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, thiazolyl, pyrazolyl, oxazolyl or pyrimidinyl; Ring A2 is selected from pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl, wherein said pyrimidinyl, phenyl, pyridyl, pyrazinyl or pyridazinyl is optionally replaced with 1 to 3 R groups;Petition 870250071752, dated 08 / 14 / 2025, page 220 / 259 7 / 41 Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, indolyl, imidazolyl, pyrrolpyrazinyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; n is selected independently from 0, 1, 2, 3 or 4; ep is selected from 0, 1, 2 or 3.; 6. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ring A2 is selected from pyrimidinyl, pyridyl or pyrazinyl, wherein said pyrimidinyl, pyridyl or pyrazinyl is optionally substituted with 1 to 3 R groups.

7. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ring A2 is pyrimidinyl, wherein said pyrimidinyl is optionally substituted with 1 to 3 R groups.

8. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ring A3 is selected from pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl or phenyl.

9. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ring A3 is selected from pyridyl, pyrazinyl or phenyl.

10. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ring A1 is selected from pyridyl, pyrazinyl, pyrazolyl or pyrimidinyl.

11. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ring A1 is selected from pyridyl or pyrazinyl.

12. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 is Petition 870250071752, dated 08 / 14 / 2025, page.221 / 259 8 / 41 selecionado dentre -(CH2)nORc, -(CH2)nO(CH2)nR, -(CH2)nO(CH2)nORc, halo, -NR2, alkila C1-6 não substituído ou substituído, ciclopropila, imidazolila, piridila, indolila, pirazolila, triazolila, azetidinila, fenila, azepanila, pirrolpirazinila, pirrolidinila, azabiciclo-heptanila, furila, tiazolila, pyrimidinila, oxa-azabiciclo-heptanila, piridazinila, tienila, isoxazolila, oxazolila, dihidropirrolilpirazolila, morpholinila, tetrazolila ou piperazinila, em que o dito alquila, ciclopropila, imidazolila, piridila, indolila, pirazolila, triazolila, azetidinila, fenila, azepanila, pirrolpirazinila, pirrolidinila, azabicicloheptanila, furila, tiazolila, pyrimidinila, oxa-azabiciclo-heptanila, piridazinila, tienila, isoxazolila, oxazolila, dihidropirrolilpirazolila, morpholinila, tetrazolila ou piperazinila pode ser substituído com um a três grupos de Rb.

13. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R1 is selected from -(CH2)nORc, -(CH2)nO(CH2)nR, -NR2, pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl or furyl, wherein said pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl or furyl may be substituted with one to three Rb groups.

14. Compound according to claim 4, characterized in that: R is independently selected from H, C1-6 alkyl or halo, wherein said alkyl is optionally substituted with one to three groups from C1-6 alkyl, ORc or halo; Ra is independently selected from unsubstituted or substituted C1-6 alkyl, said alkyl optionally substituted with 1 to 3 R groups; Rb is independently selected from C1-6 alkyl, halo, -(CH2)nORc, -CN, -(CH2)nhalogen or -O(CH2)nhalo; Rc is independently selected from H or C1-6 alkyl; R1 is selected from -(CH2)nORc, -(CH2)nO(CH2)nR, -NR2, pyridyl, pyrazolyl, azetidinyl, pyrrolidinyl or furyl, wherein said pyridyl, Petition 870250071752, dated 08 / 14 / 2025, page.222 / 259 9 / 41 pyrazolyl, azetidinyl, pyrrolidinyl, or furyl may be substituted with one to three Rb groups; R2 is selected from hydrogen, Orc, halo, or C1-6 alkyl; Ring A1 is selected from pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, or pyrazolyl; Ring A2 is selected from pyridyl, pyrazinyl, or phenyl, wherein said pyridyl, pyrazinyl, or phenyl is optionally substituted with 1 to 3 R groups; Ring A3 is selected from pyrimidinyl, pyridyl, or pyrazinyl; n is independently selected from 0, 1, 2, 3, or 4; ep is selected from 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

15. Compound, characterized by fate to be selected within: Ex. no Structure Name 1 (S)-6-methoxy-N-(2-(2-methyl4-(pyridin-2-yl)piperazin-1il)pyrimidin-5il)nicotinamida 2 \ —C — / - / —(\ N-[2-[(3S)-3-ethyl-4-(5- methyl-2-pyridyl)piperazin-1yl]pyrimidin-5-yl]-6imidazol-1-yl-pyridine-3carboxamida 3 N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-4-(3 pyridyl)benzamida Request 870250071752, de 08 / 14 / 2025, pág. 223 / 259 10 / 41 Ex. no Structure Name 4 Cp C 1... 5-fluoro-N-[5-[(2S)-2methyl-4-(2-pyridyl)piperazin1-yl]pyrazin-2-yl]-1H-indol2-carboxamida 5 6-imidazol-1-yl-N-[2-[4-(5methyl-2-pyridyl)-3-(2,2,2trifluoroethyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 6 [y Λ X} 6-methoxy-N-[2-[(2S)-2methyl-4-(6-methyl-2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 7 c Λ / 6-imidazol-1-yl-N-[2-[(2S)2-methyl-4-(6-methyl-2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 8 íI.YT 6-metoxi-N-[2-[(2S)-2metil-4-(5-metil-2piridil)piperazin-1il]pirimidin-5-il]piridina-3carboxamida 9 Zp c i.„ Y 5-(2-fluoroetoxy)-N-[2[(2S)-2-metil-4-(6-metil-2piridil)piperazin-1- Petitção 870250071752, de 14 / 08 / 2025, pág 224 / 259 11 / 41 Ex il]pirimidin-5-il]pirazina-2carboxamida 10 6-metoxi-N-[2-[(2S)-4-(5metoxi-2-piridil)-2-metilpiperazin-1-il]pirimidin-5il]piridina-3-carboxamida 11 4-(2-fluoroetoxi)-N- [2[(2S)-2-metil-4-(6-metil-2piridil)piperazin-1il]pirimidin-5-il]benzamida 12 o.. / — / —\\ — / / N-[5-[(2S)-2-metil-4-(2piridil)piperazin-1il]pirazin-2-il]-5Hpirrol[2,3-b]pirazina-6carboxamida 14 zz ~y~ 4-(2-fluoroetoxi)-N- [2[(2S)-2-metil-4-(2piridil)piperazin-1il]pirimidin-5-il]benzamida Petição 870250071752, dated 08 / 14 / 2025, page. 225 / 259 12 / 41 Ex.no Structure Name 15 α, τ 6-methoxy-N-[2-[(2S)-2methyl-4-pyrimidin-4-ylpiperazin-1-yl]pyrimidin-5yl]pyridine-3-carboxamide 16 6-(2-hydroxyethoxy)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrimidin-5-yl]pyridine-3-carboxamide 17 9 C1. VT 6-methoxy-N-[2-[(2S)-2methyl-4-(4-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine3-carboxamide 18 o,. VT 6-chloro-N- [2-[(2S)-2-methyl4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 19 Cp C x.„ Xjj Λ7 4-(1-cyanocyclopropyl)-N[5-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrazin-2-yl]benzamide 20 α T 6-bromo-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin-1-yl]pyrimidin-3-carboxamide Petition 870250071752, de 14 / 08 / 2025, pág. 226 / 259 Ex. no Estrutura Nome 21 0 '6 ò N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-5-phenylpyrazine-2-carboxamide 22 6-methoxy-N-[2-[(2R)-2methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine3-carboxamide 23 Cp a.Y 6-(2-fluoroethoxy)-N- [2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3-carboxamide 24 Λ k: pp 2-methoxy-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine4-carboxamide 25 9 T 6-methoxy-N-[2-[(2S)-2methyl-4-(4-methyl-2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3-carboxamide 26 9 9' Λ7 4-(1-cyanocyclopropyl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]benzamide Petition 870250071752, of 14 / 08 / 2025, p. 227 / 259 14 / 41 Ex. no Structure Name 27 Λ Ó N-[2-[(2S)-4-(6-fluoro-2pyridyl)-2-methyl-piperazin-1yl]pyrimidin-5-yl]-6-methoxypyridine-3 -carboxamide 28 Λ '6 6-(difluoromethoxy)-N- [2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 29 Cp c I. 4-methoxy-N-[5-[(2S)-2methyl-4-(2-pyridyl)piperazin1-yl]pyrazin-2-yl]pyridine-2carboxamide 30 D .....C1 ò 6-(2-fluoroethoxy)-N- [6[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]-3pyridyl]pyridine-3carboxamide 31 / \ / --\ 4-methoxy-N-[5-[(2S)-2methyl-4-(2-pyridyl)piperazin1-yl]-2-pyridyl]pyridine-2carboxamide 32 Cp CX, 2-(2-fluoroethoxy)-N-[5[(2S)-2-methyl-4-(2pyridyl)piperazin-1-yl]pyrazin-2-yl]pyrimidine-5carboxamide Petition 870250071752, dated 14 / 08 / 2025, pág. 228 / 259 15 / 41 Ex.no Structure Name 33 o 6-methoxy-N-[2-[(3R)-3methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine3-carboxamide 34 6-methoxy-N-[2-[(3S)-3methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine3-carboxamide 35 o Al (5 N-[2-[(3S)-3-methyl-4-(2pyridyl)piperazin1-yl]pyrimidin-5-yl]-5Hpyrrole[2,3-b]pyrazine-6carboxamide 36 f / ——\ / =\ 3 2-methoxy-N-[2-[(3S)-3methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5yl]pyrimidin-5carboxamide 37 Λ ô N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-6-pyrazol1 -yl-pyridine-3 -carboxamide 38 0 r') 6 p \ 6-(4-methoxypyrazol-1-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide Petition 870250071752, dated 14 / 08 / 2025, pág. 229 / 259 16 / 41 Ex.no Structure Name 39 ò '6 6-(4-fluoropyrazol-1-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 40 c λ, VY, / 6-(3-methoxipyrazol-1-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 41 Cp C λ, Y r dl N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]-6-(triazol1 -yl)pyridine-3 -carboxamida 42 Y 6-(3-methylpyrazol-1-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 43 YYX ] Ipjj 6-(2-methylimidazol-1-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamida 44 YY) (S)-N-(2-(2-methyl-4(pyridin-2-yl)piperazin-1yl)pyrimidin- 5-yl)-6-(2H- Petition 870250071752, dated 14 / 08 / 2025, pág. 230 / 259 17 / 41 Ex. no Structure Name 1,2,3-triazol-2yl)nicotinamide 45 Cp C 1.6-(3,5-dimethylpyrazol-1-yl)N-[2-[(2S)-2-metil-4-(2pyridyl)piperazin-1il]pyrimidin-5-il]pyridina-3carboxamida 46 Cp c X, Y 6-(3,3-difluoroazetidin-1yl)-N-[2-[(2S)-2-metil-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridina-3carboxamide 47 6-[(3R)-3-fluoropyrrolidin1-il]-N-[2-[(2S)-2-metil-4(2-pyridil)piperazin-1il]pyrimidin-5-il]pyridina-3carboxamida 48 OQVyHVS / 6-[rac-(4S)-2- azabiciclo[2.2.1]heptan-2il]-N-[2-[rac-(2S)-2-metil4-(2-pyridil)piperazin-1il]pyrimidin-5-il]pyridina-3carboxamida Petição 870250071752, de 14 / 08 / 2025, pág. 231 / 259 18 / 41 Ex.no Structure Name 49 'Z— Λ X 9 ^Z„ 6-[(3S)-3-fluoropyrrolidin1-yl]-N-[2-[(2S)-2-methyl-4(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 50 — \_ / ~y~ y—cZ- 6-(3,3-dimethylpyrrolidin-1yl)-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 51 — Ή^- (A 6-(3-fluoroazetidin-1 -yl)-N [2-[(2S)-2-methyl-4-(6-methyl2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 52 — Ο 0^ 6-(3-methylazetidin-1-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 53 — 0 —CZ^- CZZ 6-(azepan-1-yl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide Petição 870250071752, de 14 / 08 / 2025, pág. 232 / 259 19 / 41 Ex. no Estrutura Nome 54 Cp c λ, Y 6-(2-oxa-5-azabiciclo[2.2.1]heptan-5yl)-N-[2-[rac-(2S)-2-methyl4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 55 Cp CX, 6-[methyl(propyl)amino] -N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 56 c Ó ipjj 6-(azetidin-1-yl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 57 Δ O 6-(methylamino)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 58 [Λ] .....o 6-(dimethylamino)-N- [2[(2S)-2-methyl-4-(6-methyl-2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide Petição 870250071752, de 14 / 08 / 2025, pág. 233 / 259 20 / 41 Ex. no Estrutura Nome 59 Z-\ —C \ ' / ~\\ '—\ 6-[ethyl(2-hydroxyethyl)amino] N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 60 Cp c X.6-(3-hydroxyazetidin-1-yl)N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 61 Λ 6 ipjj 6-[isobutyl(methyl)amino]-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 62 N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]-6pyrrolidin-1-yl-pyridine-3carboxamide 63 Ό Q Λ X) [pjl 6-(3-fluorophenyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide Petition 870250071752, de 14 / 08 / 2025, p. 234 / 259 21 / 41 Ex. no Structure Name 64 AA S—\ —C v—\Y z- / \\ 6-(4-methyl-3-furyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 65 / =\ \= N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-6-thiazol-5yl-pyridine-3-carboxamide 66 O 0 A N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]-6pyridazin-4-yl-pyridine-3carboxamide 67 Cp C1..... V 0 o N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-6-(3thienyl)pyridine-3carboxamide 68 Cp c X.0 0 6-(4-fluorophenyl)-N- [2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 69 Cp c λ Y 0 O1 N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]-6-(3-Petição 870250071752, de 14 / 08 / 2025, pág. 235 / 259 Ex. no Estrutura Nome pyridin-3carboxamide 70 Cp ( λ V 0 Cl N-[2-[(2S)-2-methyl-4-(2pyridyl)pyrimidine- 5-yl]-6-(4pyridyl)pyridine-3carboxamide 71 CA CD ZA N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-6-phenylpyridine-3-carboxamide 72 / =\ Ç_ z- __ / —\\ 6-(3-furyl)-N-[2-[(2S)-2methyl-4-(2-pyridyl)piperazin1-yl]pyrimidin-5-yl]pyridine3-carboxamide 73 6-(4-cyanophenyl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine3-carboxamide 74 \___ / Λ 0 AX) Cp 6-(5,6-dihydro-4Hpyrrolo[1,2-b]pyrazol-3 -yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine3-carboxamide Petition 870250071752, de 14 / 08 / 2025, pág. 236 / 259 23 / 41 Ex.no Structure Name 75 / \ 0 AA) 6-(2-methylpyrazol-3-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 76 N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]-6pyrimidin-5-yl-pyridine-3carboxamide 77 0 AAD 6-(2-methyl-4-pyridyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 78 0 AA) 6-(5-fluoro-3-pyridyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 79 0 AA) ^9 6-(3-fluoro-4-pyridyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide Petição 870250071752, de 14 / 08 / 2025, pág. 237 / 259 24 / 41 Ex.no Structure Name 80 σ 0 Δ Ó 6-(6-fluoro-2-pyridyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 81 0 ifS τ 6-(3,5-dimethyl-isoxazol-4yl)-N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 82 0 Λ X) 6-(3-methyl-4-pyridyl)-N-[2[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3carboxamide 83 \= y N-[2-[(2S)-2-methyl-4-(2pyridyl)piperazin-1yl]pyrimidin- 5-yl]-6-(2-methylpyrimidin-5-yl)pyridine-3-carboxamide 84 / Λ 0 Δ '6 6-(1-methylpyrazol-4-yl)-N[2-[(2S)-2-methyl-4-(2-pyridyl)piperazin-1yl]pyrimidin-5-yl]pyridine-3-carboxamide Petition 870250071752, dated 14 / 08 / 2025, pág. 238 / 259 25 / 41 Ex.no Structure Name 85 / A 1 \= / \__ / 6-(3-methyl-isoxazol-4-yl)-N[2-[(2S)-2-methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5-yl]pyridine-3carboxamide A—\— / Av— / ~\ / 4-(3-cyanophenyl)-N-[2-[(2S)2-methyl-4-(2pyridyl)piperazine-1yl]pyrimidine-5-yl]benzamide 87 ^ΖΥ· C3 =jx~ (S)-6-(3,3-difluoroazetidine1-yl)-N-(2-(4-(4fluoropyridin-2-yl)-2methylpiperazine-1yl)pyrimidine-5yl)nicotinamide 88 Aa>kv> ( S )-6-(3,3-difluoroazetidine1-yl)-N-(2-(2-methyl-4-(4nitropyridine-2-yl)piperazine1-yl)pyrimidine-5yl)nicotinamide 89 V CI V (S)-N-(2-(4-(2fluoropyrizine)pylpyridin-2-1-4 5-yl)-6-(1Hpirazol-1 -yl)nicotinamide Petition 870250071752, dated 14 / 08 / 2025, p. 239 / 259 26 / 41 Ex. no Structure Name 90 ( λ V or (S)-N-(2-(2-methyl-4-(2nitropyridine-4-yl)piperazine1-yl)pyrimidine-5-yl)-6-(1Hpyrazol-1 -yl)nicotinamide 91 9 V o (S)-6-(1H-imidazol-1-yl)-N(2-(2-methyl-4-(pyridine-2yl)piperazine-1 -yl)pyrimidine5 -yl)nicotinamide 92 A 3….Y N-(2-((2S,6R)-2,6-dimethyl4-(5-methylpyridine-2yl)piperazine-1 -yl)pyrimidine5-yl)-5′-fluoro-[2,3′bipyridine]-5-carboxamide 93 C k„ YP N-(2-((S)-4-(5fluoropyrazine-2-yl)-2methylpiperazine-1yl)pyrimidine-5-yl)-6-((R)-3fluoropyrrolidin-1yl)nicotinamide Petition 870250071752, de 2025 / 24 / 08 41 Ex. no Structure Name 94 / \ __ (R)-6-(1H-imidazol-1-yl)-N(2-(2-(methoxymethyl)-4(pyridin-2-yl)piperazine-1yl)pyrimidine-5yl)nicotinamide 95 9 t Y c. (S)-N-(2-(4-(4fluoropyradine-2-yl)-2methylpiperazine-1yl)pyrimidine- 5-yl)-6morpholinonicotinamide 96 9 t X. Y í (S)-6-(3-fluoroazetidin-1yl)-N-(2-(4-(5-fluoropyradine2-yl)-2-methylpiperazine-1yl)pyrimidine-5yl)nicotinamide Petition 870250071752, de 14 / 29,241 / 202 Ex. no Structure Name 97 r 7 0 / (S)-6-(3-methoxy-1H-pyrazol1-yl)-N-(2-(2-methyl-4(pyridin-2-yl)piperazine-1yl)pyrimidine-5yl)nicotinamide 98 : J, V 0 (S)-6-(3-fluoro-1H-pyrazol1-yl)-N-(2-(2-methyl-4(pyridin-2-yl)piperazine-1yl)pyrimidine-5yl)nicotinamide 99 líY í X.VA 1 (S)-N-(2-(4-(6fluoropyrimidine-4-yl)-2methylpiperazine-1yl)pyrimidine- 5-yl)-6-(4methylpiperazine-1yl)nicotinamide Petition 870250071752, of 14 / 08 / 2025, p. 242 / 259 29 / 41 Ex. and Structure Name 100 / \ V r~ ~A\ J- (R)-6-(2-fluoropyrimidine-5yl)-N-(5-(2-(methoxymethyl)-4(pyridin-2-yl)piperazine-1yl)pyrazine-2 -yl)nicotinamide 101 N^S Λ HN^N^NO (S)-N-(2-(2-methyl-4-(thiazol2-yl)piperazin-1yl)pyrimidin- 5-yl)-6-(1Hpyrazol-1-yl)nicotinamide 102 qj o V í 6-(dimethylamino)-N-(2-(5(6-fluoropyrimidin-4-yl)-2,5diazabicyclo[4.1.0]heptan-2yl)pyrimidin-5yl)nicotinamide 103 \A / =\ / (S)-6-(dimethylamino)-N-(2(4-(6-fluoropyrimidin-4-yl)2-methylpiperazin-1yl)pyrimidin-5yl)nicotinamide Petition 870250071752, of 14 / 08 / 2025, pp. 243 / 259 30 / 41 Ex. and Name Structure 104 \ in X.Y (S)-N-(2-(2-methyl-4-(1methyl-1H-pyrazol-3yl)piperazin-1 -yl)pyrimidin5-yl)-6-(1H-pyrazol-1yl)nicotinamide 105 Q í 5-yl)-6morpholinonicotinamida 106 çf V 6-(3-fluoro-3-methylazetidin1-yl)-N-(2-(5-(6fluoropyrimidin-4 -yl)-2,5diazabiciclo[2.2.2]octan-2yl)pyrimidin-5yl)nicotinamida Petição 870250071752, de 08 / 14 / 2025, pág. 244 / 259 31 / 41 Ex. no Estrutura Nome 107 ZjJ o. Y 9 / (S)-N-(2-(4-(6fluoropirimidin-4-yl)-2metilpiperazin-1yl)pirimidin- 5-yl)-3-metil3H-imidazo[4,5-b]piridina6-carboxamida 108 ? V í N-(2-((2S,5R)-2,5-dimetil4-(5-metilpiridin-2yl)piperazin-1 -yl)pirimidin5-yl)-6-(1H-pirazol-1yl)nicotinamida 109 9 c λ. y 0 0 (S)-N-(2-(4-(5fluoropyridin-2-yl)-2methylpiperazin-1yl)pyrimidin-5-yl)-4-(pyridin3-yl)benzamida 110 xo 6-(3,3-difluoroazetidin-1yl)-N-(2-((2R,3R)-4-(4fluoropyridin-2-yl)-2,3dimethylpiperazin-1yl)pyrimidin-5yl)nicotinamida Petição 870250071752, de 14 / 08 / 2025, pág. 245 / 259 32 / 41 Ex.no Structure Name 111 í λ Y í (S)-N-(2-(4-(2fluoropyradine- 3-yl)-2methylpiperazine-1yl)pyrimidine- 5-yl)-6morpholinonicotinamide 112 í λ (S)-6-(3,3-difluoroazetidine1-yl)-N-(5-(4-(6fluoropyrimidine-4-yl)-2methylpiperazine-1-yl)pyrazine2-yl)nicotinamide 113 c> (S)-6-(azetidine-1-yl)-N-(2(4-(5-fluoropyradine-2-yl)-2methylpiperazine-1yl)pyrimidine-5yl)nicotinamide 114 c:…. (R)-6-(4-(fluoromethyl)-1Hpyrazol-1-yl)-N-(2-(2(methoxymethyl)-4-(pyridin-2yl)piperazine-1 -yl)pyrimdin5 -yl)nicotinamide 115 (S)-N-(5-(4-(6fluoropyrimidine-4-yl)-3methylpiperazine-1-yl)pyrazin2-yl)-6-(1-methyl-1H-pyrazol4-yl)nicotinamide Petition 870250071752, pá 202 / 08 246 / 259 33 / 41 Ex.no Structure Name 116 9 cr V (S)-6-(3-fluoroazetidine-1yl)-N-(5-(4-(5-fluoropyrazine2-yl)-3-methylpiperazine-1yl)pyrazine-2-yl)nicotinamide 117 VA vΧ,' xγ (R)-N-(5-(4-(5fluoropyridine-2-yl)-3(methoxymethyl)piperazine-1yl)pyrazine-2-yl)-6-(1-methyl1H-pyrazol-4yl)nicotinamide 118 (S)-N-(2-(4--(methyl-2-methyl-fluoropyrizidine) 5-yl)-6-(1methyl-1H-pyrazol-4yl)nicotinamide 119 0 Λ XX rd (R)-N-(2-(3-((2fluoroethoxy)methyl)-4(pyrimidine-2-yl)piperazine-1yl)pyrimidine-1-H4-1pyrazol-4yl)-6 120 rj Λ j^2 (R)-N-(2-(4-(6fluoropyrimidine-4-yl)-3(methoxymethyl)piperazine-1yl)pyrimidine-5 -yl)-6-(1- Petition 870250071752, de 14 / 20 / 23 / 08 41 Ex.no Structure Name methyl-1H-pyrazol-4yl)nicotinamide 121 _ / |l J Ar A 0 (R)-N-(4-fluoro-2-(3(methoxymethyl)-4-(pyrimidine2-yl)piperazine-1yl)pyrimidine- 5-ylcomethyl)l)-6-4-(pyrimidin- 122 \\_\ — / \_ (S)-N-(5-(4-(5fluoropyrimidine-2-yl)-3methylpiperazine-1-yl)pyrazine2-yl)-6-(pyrrolidin-1yl)nicotinamide 123 Ha- 23 a Ã^1 A^Av. (S)-6-(1-(2-fluoroethyl)-1Hpyrazol-4-yl)-N-(2-(4-(5fluoropyridin-2-yl)-2methylpiperazine-1yl)pyrimidine-5yl)nicotinamide 124 A cr 0 AA (R)-oro-N-4()(5-methyl)(3 fluoropyridine-2-yl)piperazine1-yl)pyrazine-2-yl)-6-(1-methyl1H-pyrazol-4yl)nicotinamide Petition 870250071752, dated 14 / 08 / 2025, p. 248 / 259 35 / 41 Ex.no Structure Name 125 Çjf Cj Λ (S)-2-(3,3-difluoroazetidine1-yl)-N-(5-(4-(6fluoropyrimidine-4-yl)-2methylpiperazine-1-yl)pyrazine2-yl)pyrimidine-526 carboxamide 126 (S)-6-(3,3-difluoroazetidine1-yl)-N-(5-(4-(6fluoropyridin- 3-yl)-2methylpiperazine-1-yl)pyrazine2-yl)nicotinamide 127 / =\ (S)-N-(2-(4--(6fluoropyridine 3-yl)-2methylpiperazine-1yl)pyrimidine- 5-yl)-6-(1methyl-1H-pyrazol-4yl)nicotinamide 128 ϕ α 0 Ό (R)-N-(5-(4-(6fluoropyridin- 3-yl)-2methylpiperazine-1-yl)pyrazine2-yl)-6-(1-methyl-1H-pyrazol4-yl)nicotinamide 129 Ο Υ a Φ (R)-N-(2-(4-(4-(5-(4-(5-fluoropyridine-2-yl))-6-15-methylpiperazine) Petition 870250071752, dated 14 / 08 / 2025, pp. 249 / 259 36 / 41 Ex.no Structure Name methyl-1H-pyrazol-4yl)nicotinamide 130 (S)-6-(3- (fluoromethyl)azetidin-1-yl)N-(2-(4-(5-fluoropyridin-2yl)-2-methylpiperazin-1yl)pyrimidin-5yl)nicotinamide 131 Λ (R)-6-(3- (fluoromethyl)azetidin-1-yl)N-(2-(4-(5-fluoropyridin-2yl)-3-(methoxymethyl)piperazin-1yl)pyrimidin-5yl)nicotinamide 132 (S)-6-(3- (fluoromethyl)azetidin-1-yl)N-(5-(4-(5-fluoropyrimidin2-yl)-3-methylpiperazin-1yl)pyrazin-2-yl)nicotinamide 133 333^3^33^ / =^ / % laugh \ / r (S)-6-(3-(fluoromethyl)azetidin-1-yl)N-(5-(4-(5-fluoropyridin-2yl)-3-methylpiperazin-1yl)pyrazin-2-yl)nicotinamide Petition 870250071752, dated 08 / 14 / 2025, page 250 / 259 37 / 41 Ex.no Structure Name 134 a Λ (S)-6-(5,6-dihydro-4Hpirrol[1,2-b]pyrazol-3 -yl)-2fluoro-N-(2-(2-methyl-4(pyrimidin-2-yl)piperazin-1yl)pyrimidin-5yl)nicotinamide 135 (S)-6'-amino-6-fluoro-N(2-(2-methyl-4-(pyrimidin-2yl)piperazin-1 -yl)pyrimidin5-yl)-[2,3'-bipyridine]-5carboxamida 136 / / Χμ_ —( / A— VX / \= / ej xx kx1 (S)-6-(5,6-dihydro-4Hpirrol[1,2-b]pyrazol-3 -yl)-2fluoro-N-(2-(4-(5fluoropyrazin-2-yl)-2methylpiperazin-1yl)pyrimidin-5yl)nicotinamide 137 (S)-6-(5,6-dihydro-4Hpirrol[1,2-b]pyrazol-3 -yl)-2fluoro-N-(2-(4-(6fluoropyrimidin-4-yl)-2methylpiperazin-1yl)pyrimidin-5yl)nicotinamida Petição 870250071752, de 14 / 08 / 2025, pág. 251 / 259 38 / 41 Ex. no Structure Name 138 tb-abA (R)-6-(5,6-dihidro-4Hpirrol[1,2-b]pyrazol-3 -yl)-2fluoro-N-(2-(3- (methoxymethyl)-4-(pyrimidin2-yl)piperazin-1yl)pyrimidin-5yl)nicotinamide 139 ςΤ C 9.9 ν' Ϋ (S)-6-(3-fluoroazetidin-1yl)-N-(6-(4-(6fluoropyrimidine-4-yl)-2methylpiperazine-1-yl)pyridine3 -yl)nicotinamide 140 bd O (S)-6-(3,3-difluoroazetidine1-yl)-N-(5-(4-(6fluoropyridin-2-yl)-2methylpiperazine-1-yl)pyrazine2-yl)nicotinamide 141 o rd J= v bbY€1..... \= / J (S)-N-(5-(4-(5fluoropyradine-2-yl)-2methylpiperazine-1-yl)pyrazine2-yl)-6-(1-methyl-1H-pyrazol4-yl)nicotinamide 142 (S)-6-(3,3-difluoroazetidine1-yl)-N-(5-(4-(5fluoropyridin-2-yl)-2methylpiperazine-1-yl)pyrazine2-yl)nicotinamide Petition 870250071752, dated 14 / 2020 252 / 259 39 / 41 Ex. no Structure Name 143 x / X 1 - (S)-N-(5-(4-(5fluoropyrimidine-2-yl)-2methylpiperazine-1-yl)pyrazine2-yl)-6-(1-methyl-1H-pyrazol4-yl)nicotinamide 144 (S)-6-(1-(2-fluoroethyl)-1Hpyrazol-4-yl)-N-(5-(4-(5fluoropyrimdin-2-yl)-2methylpiperazine-1-yl)pyrazine2-yl)nicotinamide or a pharmaceutically acceptable salt of the same.

16. Compound according to claim 15, characterized in that it is selected from Examples Nos. 1, 6, 9, 11, 12, 37, 39, 47, 51, 57, 58, 64, 72, 75, 78, 79, 80, 91, 96, 112, 113, 115, 116, 118, 134, 138 and 141, or a pharmaceutically acceptable salt thereof.

17. Compound according to claim 15, characterized in that it is selected from Examples Nos. 39, 47, 51, 78, 79, 96, 112, 116 and 141, or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 1 or 15, or a pharmaceutically acceptable salt thereof, characterized in that it is labeled with an isotope selected from 2H, 3H, nC, 13C, 14C, 13N, 15N, 150, 170, 18O, 18F, 35S, 36Cl, 82Br, 76Br, 77Br, 1231, 124I or 131I.

19. Compound according to claim 15, or a pharmaceutically acceptable salt thereof, characterized in that it is isotopically labeled with 3H, nC or 18F.

20. Pharmaceutical composition, characterized in that it comprises a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

21. Method for visualizing alpha-synuclein deposits in a human patient, characterized in that it uses the compound as defined in claim 18, or a pharmaceutically acceptable salt thereof, as the contrast agent, wherein the method comprises the following steps: a) placing a human patient in a supine position in the PET camera; b) administering around 0.1 to around 10 mCi of a compound as defined in claim 17 to the patient; and c) performing an emission scan of the brain region of the patient's head to identify alpha-synuclein aggregates in the patient's brain tissue.

22. Method for measuring the clinical efficacy of therapeutic agents for Parkinson's disease, characterized in that it comprises the steps of: a) administering an isotopically labeled compound of Formula I, as defined in claim 18, to a patient diagnosed with PD before treatment with said therapeutic agent, b) measuring the degree of alpha-synuclein aggregate formation in the patient's brain tissue, c) administering an isotopically labeled compound of Formula I, as defined in claim 18, to the patient after treatment with said therapeutic agent, d) measuring the degree of alpha-synuclein aggregate formation in the patient's brain tissue after treatment and e) analyzing whether said therapeutic agent interrupted or reduced the progression of alpha-synuclein aggregate formation in the patient's brain tissue.

23. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is for use as a contrast agent.

24. Compound according to claim 18, or a pharmaceutically acceptable salt thereof, characterized in that it is for use as a contrast agent.

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