BICYCLIC HETEROARYL COMPOUNDS AND THEIR USES

Abstract

This disclosure addresses SOS1 modulators and their use in the treatment of diseases. Pharmaceutical compositions comprising these modulators are also described.

Description

BICYCLIC HETEROARYL COMPOUNDS AND USES OF THESE CROSS REFERENCE WITH RELATED REQUESTS This application claims the benefit of the priority of US provisional application no. of being. 62 / 933,141, filed November 8, 2019, the description of which is incorporated herein by reference as if set forth in its entirety. This application claims the benefit of the priority of US provisional application no. of being. 63 / 031,318, filed May 28, 2020, the description of which is incorporated herein by reference as if set forth in its entirety. This application claims the benefit of the priority of US provisional application no. of being. 63 / 070,593, filed August 26, 2020, the description of which is incorporated by reference as if set forth in its entirety. DESCRIPTION FIELD The present description relates to SOS1 inhibitors useful in the treatment of diseases or disorders. Specifically, the present disclosure relates to compounds and compositions that inhibit SOS1, methods for treating diseases associated with SOS1, and methods for synthesizing these compounds. BACKGROUND OF THE DESCRIPTION RAS family proteins including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma virus oncogene) and any mutant of these are small GTPases that exist in cells in GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl), 2016, 94(3):253-8; Nimnual et al. ., Sci. STKE., 2002, 2002(145):pl36). RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rates (Hunter et al, Mol. Cancer Res., 2015, 13(9): 1325-35). Binding of GTPase-activating proteins (GAPs), such as NF1, increases the GTPase activity of RAS family proteins. Binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promotes GDP release from RAS family proteins, allowing GTP binding (Chardin et al., Science, 1993 , 260(5112):1338-43). When in the GTP-bound state, RAS family proteins are active and engage effector proteins including RAF and phosphoinositide 3-kinase (PI3K) to promote RAF / mitogen or extracellular signal-regulated kinases (MEK / ERK). Published data indicate a critical involvement of SOS1 in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depletion of SOS1 levels decreased the proliferation rate and survival of tumor lymphocytes carrying a KRAS mutation, while no effect was observed in KRAS wild-type cell lines. The effect of SOS1 loss could not be rescued by the introduction of a mutated SOS1 catalytic site, demonstrating the essential role of SOS1 GEF activity in KRAS mutant cancer cells. SOS1 is critically involved in the activation of RAS family protein signaling in cancer through mechanisms other than mutations in RAS family proteins. SOS1 interacts with the adapter protein Grb2 and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated tyrosine receptors (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL) (Pierre et al., Biochem. Pharmacol., 2011,82(9): 1049-56) . SOS1 is also recruited by other phosphorylated cell surface receptors, such as the T cell receptor (TCR), the B cell receptor (BCR), and the monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75). This localization of SOS1 on the plasma membrane, close to RAS family proteins, allows SOS1 to promote the activation of RAS family proteins. SOS1 activation of RAS family proteins may also be mediated by the interaction of SOS1 / Grb2 with the BCR-ABL oncoprotein commonly found in chronic myelogenous leukemia (Kardinal et al, 2001, Blood, 98:1773-81 ; Sini et alL, Nat. Cell BioL, 2004, 6(3):268-74). Furthermore, alterations in SOS1 have been implicated in cancer. SOS1 mutations are found in embryonal rhabdomyosarcomas, testicular Sertoli cell tumors, skin granular cell tumors (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3):242-52), and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature, 2014,511 (751 1):543-50). Meanwhile, overexpression of SOS1 has been described in bladder cancer (Watanabe et al., IUBMB Life, 2000, 49(4):317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol ., 2009; 35(4):751-60). In addition to cancer, inherited SOS1 mutations are implicated in the pathogenesis of RASopathies such as Noonan syndrome (NS), cardio-faciocutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et al. al., Biochem. Pharmacol., 2011,82(9):1049-56). SOS1 is also a GEF for the activation of the GTPases RAC1 (Ras-related botulinum toxin C3 substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1):125-36). RAC1, like RAS family proteins, is involved in the pathogenesis of a variety of human cancers and other diseases (Bid et al, Mol. Cancer Ther. 2013, 12(10):1925-34). Son of Sevenless 2 (SOS2), a homolog of SOS1 in mammalian cells, also acts as a GEF for the activation of RAS family proteins (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049 -56; Buday et al., Biochim. Biophys. Acta., 2008, 1786(2):178-87). Published data from gene knockout mouse models suggest a redundant role for SOS1 and SOS2 in homeostasis in adult mice. While germline knockout of SOS1 in mice is lethal during mid-embryonic gestation (Qian et al, EMBO J., 2000, 19(4):642-54), adult mice with gene knockouts for conditional systemic SOS1 They are viable (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). Selection of the SOS2 gene did not result in any overt phenotype in mice (Esteban et al., Mol. Cell. Biol., 2000, 20(17):6410-3). In contrast, double inactivation of SOS1 and SOS2 leads to rapid lethality in adult mice (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). These published data suggest that selective targeting of individual SOS isoforms (e.g., selective targeting of SOS1) may be adequately tolerated to achieve a therapeutic index among cancers driven by SOS1 / RAS family proteins (or other protein pathologies of the SOS1 / RAS family) and normal cells and tissues. Selective pharmacological inhibition of SOS1 catalytic site binding to RAS family proteins is expected to prevent SOS1-mediated activation of RAS family proteins to the GTP-bound form. Such SOS1-inhibiting compounds are expected to consequently inhibit signaling in cells downstream of RAS family proteins (e.g., ERK phosphorylation). In cancer cells associated with dependence on RAS family proteins (e.g., KRAS mutant cancer cell lines), SOS1-inhibiting compounds are expected to provide anticancer efficacy (e.g., inhibition of proliferation, survival , metastasis, etc.). High potency toward inhibition of SOS1:RAS family protein binding (IC50 values ​​at nanomolar level) and ERK phosphorylation in cells (IC50 values ​​at nanomolar level) are desirable characteristics for an SOS1 inhibitor compound. Furthermore, a desirable feature of an SOS1 inhibitory compound would be the selective inhibition of SOS1 over SOS2. This conclusion is based on the viable phenotype of SOS1 knockout mice and the lethality of SOS1 / SOS2 double knockout mice, as described above. These features have not been achieved in previously described SOS1 inhibitor compounds. In recent decades, the RAS family protein-SOS1 protein interaction has gained increasing recognition. Various efforts have been made to identify and optimize binders, which target the effector binding site of RAS or the catalytic binding site of SOS1 (for a selected review, see: Lu et al., ChemMedChem. 2016, 11(8):814 -21), have been carried out with limited success. Recently, small activating molecules have been identified that bind to a lipophilic pocket of SOS1 very close to the RAS binding site (Burns et al., Proc. Nati. Acad. Sci. 2014, 111 (9):3401-6) . However, binding of these molecules appears to lead to increased nucleotide exchange and thus activation of RAS rather than its deactivation. In an effort to stabilize the protein-protein interaction of RAS family proteins with SOS1 and prevent reloading of RAS family proteins with GTP, several different fragments were subsequently identified (Winter et al., J. Med. Chem. 2015, 58(5):2265-74). However, reversible binding of fragments to SOS1 did not translate into a measurable effect on nucleotide exchange and only a weak effect was observed for fragments covalently linked to RAS. Also recently, studies have been conducted to combine rational design and screening platforms to identify small molecule inhibitors of SOS1 (Evelyn et al., Chem. Biol. 2014, 21 (12): 1618-28; Evelyn et al. , J. BioL chemistry 2015,290(20):12879-98; Zheng et aL, WO 2016 / 077793), that is, compounds that bind to SOS1 and inhibit protein-protein interaction with RAS family proteins. Although compounds with a slight inhibitory effect on SOS1 have been identified, the effects on guanine nucleotide exchange and modulation of cellular signal transduction (e.g., ERK phosphorylation) are weak. BRIEF COMPENDIUM The present description refers to compounds capable of inhibiting the activity of SOS1. The present description further provides a process for the preparation of compounds, pharmaceutical preparations comprising said compounds and methods for using said compounds and compositions in the treatment of diseases or disorders associated with aberrant SOS1 activity. One aspect of the description refers to compounds of Formula (I): R3(i) a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein: Ri is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6 membered aryl and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, Ci-6 alkyl, halogen, -NHR2a, -OR2a, cyclopropyl and -CN; wherein C1-6 alkyl is optionally substituted with halogen, -NHR2a, -OR2a, or 5-6 membered heterocyclyl, and further wherein R2ase selects from the group consisting of H, C1-6 alkyl, 3-6 membered heterocyclyl and C1-6 haloalkyl; R3 is selected from the group consisting of H, C1-3 alkyl, -OR3a, cyclopropyl and 3-6 membered heterocyclyl, wherein each of C1-3 alkyl, cyclopropyl and 3-6 membered heterocyclyl is optionally substituted with R3a , and further R3ase is selected from the group consisting of Oí53 alkyl, halogen, -OH or -CN; L4 is selected from the group consisting of bond, -C(O)-, -C(O)O-, -C(O)NH(CH2)o- -NH-, -S- , -(CH2)P-, and -O-; where o is 0, 1 or 2; and in H, Ci-e alkyl, 3-14 membered cycloalkyl, 3-14 membered, 6-10 membered aryl v where p is a number from 1 to 6; and R4 is selected from the group consisting of 3-14 membered cycloalkenyl, 5-10 membered heteroaryl heterocyclyl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with Ci-6 alkyl , -R4a, -OR4a, alkyl O—Ci-6—R4a, =O, halogen, —C(O)R4a, —C(OO)R4a, —C(O)NR4bR4c, —NR4bC(O)R4c, — CN, =NR4a, — NR4bR4c, -SO2R4a, 3-6 membered cycloalkyl optionally substituted with R4a, 37-membered heterocyclyl optionally substituted with R4a, 6-10 membered aryl optionally substituted with R4a, or 5-10 membered heteroaryl optionally replaced with R4a; where R4a is H, C1-6 alkyl, Ci-e haloalkyl, -C(O)R4b, -C(O)NR4bR4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with -OR4b , -CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, -(CH2)rOCH3, or -(CH2)rOH, where r is 1.2, or 3; wherein each R4bes independently H, Ci-6 alkyl; and where each R4 is independently H or Ci-6 alkyl. Another aspect of the description refers to compounds of Formula (II): a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, U, and R4 are as defined in Formula (I); Rs, Re, R7, Rs and R9 are independently selected from the group consisting of H, D, Ci-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, heterocyclyl 3-14 members, -OH, halogen, -NO2, -CN, -NR11R12, -SR10, -S(O)2NRnRi2, -S(O )2Rio, -NRi0S(O)2NRiiRi2, -NRioS(0)2Rh , -S(O)NRhRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, NRioS(0)Rn, -C(0)Rio, -CO2R10, 6-10 membered aryl and 5-10 membered heteroaryl, wherein each Ci -6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with -OH, Ci-θ alkyl, halogen, -NO2, oxo , -CN, -Rio, -ORw, NRiiRi2, -SRio, -S(O)2NRhRi2, - S(O)2RW, -NRi0S(O)2NRhRi2, -NRi0S(O)2Rn, -S(O)NRhRi2, S(O)Rw, -NRioS(0)NRiiRi2, -NRi0S(O)Rh, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8 and R9 form an optionally substituted 3-14 membered fused ring; Rio, Rii and Ri2 each time they appear are independently selected from H, D, Cve alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OR13, -SR13, halogen, -NR13R14, -NO2, and -CN; and R13 and R14 whenever they appear are independently selected from H, D, Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl and 3-membered heterocyclyl. 14 membered, wherein each Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, - SH, -NH2, -NO2or -CN. Another aspect of the description refers to compounds of Formula (III): r3 (III) a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, U, and R4 are as defined in Formula (I); R5, Re, R7, Rs and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, heterocyclyl 3-14 members, -OH, halogen, -NO2, -CN, -NRhRi2, -SR10, -S(O)2NRnRi2, -S(O )2Rw, -NRioS(0)2NRiiRi2, -NRioS(0)2Rh , -S(O)NRhRi2, -S(0)Rio, -NRioS(0)NRiiRi2, NRioS(0)Rn, -C(O)Rw, -CO2Rw, 6-10 membered aryl and 5-10 heteroaryl members, wherein each C1-e alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 members is optionally substituted with -OH, Ci-6 alkyl, halogen, -NO2, oxo, -CN, -R10, -OR10, NRhRi2, -SR10, -S(O)2NRnRi2, - S(O)2Rw , -NRi0S(O)2NR11R12, -NRi0S(O)2Rh, -S(O)NRnRi2, S(O)Rw, -NRioS(0)NRnRi2, -NRi0S(O)Rn, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8 and R9 form an optionally substituted 3-14 membered fused ring; Rio, Rii and R12 are independently selected whenever they appear from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-membered heterocyclyl. 14 members, -OR13, -SR13, halogen, -NR13R14, -NO2, and -CN; and R13 and R14 whenever they appear are independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-membered heterocyclyl. 14 membered, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, - SH, -NH2, -NO2 or -CN. Another aspect of the description refers to compounds of the Formula (IV-a), (IV-b), or (IV-c), a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, U, and R4 are as defined in Formula (I); R5, Re, R7, Rs and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, heterocyclyl 3-14 members, -OH, halogen, -NO2, -CN, -NR11R12, -SR10, -S(O)2NRnRi2, -S(O )2Rio, -NRi0S(O)2NRh R12, -NRi0S(O) 2Rh, -S(O)NRnRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, NRioS(0)Rn, -C(0)Rio, -CO2R10, 6-10 membered aryl and 5-membered heteroaryl 10 members, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl and heteroaryl 5-10 membered is optionally substituted with -OH, Ci-6 alkyl, halogen, -NO2, oxo, -CN, -R10, -OR10, NR11R12,—SR10, —S(O)2NRi 1R12, — S(0 )2Rio, —NRioS(0)2NRnRi2, —NRioS(0)2Rh, —S(O)NRhRi2, — S(O)Rw, -NRioS(0)NRhRi2, -NRi0S(O)Rn, 3-8 cycloalkyl members, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8 and R9 form an optionally substituted 3-14 membered fused ring; R10, R11 and R12 are independently selected whenever they appear from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-membered heterocyclyl. 14 members, -OR13, -SR13, halogen, -NRi3Ri4, -NO2, and -CN; and Ri3 and Ru each time they occur are independently selected from H, D, Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl and 3-14 heterocyclyl. members, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, -SH ,-NH2,-NO2o -CN. One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject an SOS1 inhibitor of the present invention, or one of its pharmaceutically acceptable salts, solvates, hydrates, tautomers or isomers. . Another aspect of the present description refers to methods of treatment or prevention of a disease that is carried out by inhibiting the interaction of SOS1 and a protein of the RAS and / or RAC1 family in a subject that needs it, which comprise the administration to the subject of an effective amount of a compound of any of formulas (l)-(lV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof. Another aspect of the present description relates to methods of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any of formulas (l)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof. Another aspect of the present disclosure relates to methods of inhibiting SOS1. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (l)-(IV) and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers. Another aspect of the present description relates to pharmaceutical compositions comprising a compound of any of formulas (l)-(IV) and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent or surfactant. The pharmaceutical composition may be effective in treating or preventing a disease associated with SOS1 modulation in a subject in need thereof. The pharmaceutical composition may be effective in treating or preventing cancer in a subject in need thereof. Another aspect of the present description relates to a compound of any of the formulas (I)(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof, for use in the treatment or prevention of a disease associated with the modulation of SOS1. Another aspect of the present description relates to a compound of any of the formulas (l)-(IV), and to pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers thereof, for use in the treatment or prevention of a cancerous disease. Another aspect of the present description relates to the use of a compound of any of the formulas (l)-(lV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers of these, in the manufacture of a medicament for treat or prevent a disease associated with the modulation of SOS1. Another aspect of the present description relates to the use of a compound of any of the formulas (l)-(IV) and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers of these, in the manufacture of a medicament for treat or prevent cancer. The present disclosure also provides compounds useful for inhibiting SOS1. DETAILED DESCRIPTION OF THE DESCRIPTION The details of this description are set out in the description attached below. Although methods and materials similar or equivalent to those described herein may be used to practice or analyze the present invention, illustrative methods and materials are described below. Other features, objects and advantages of the invention will be apparent from the detailed description and claims. In the specification and the attached claims, singular forms also include the plural, unless the context clearly indicates otherwise. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning commonly understood by one skilled in the art to which the present invention pertains. All patents and publications cited herein are incorporated herein in their entirety by this reference. Terms The articles a and a are used in the present description to refer to one or more than one (that is, at least one) of the grammatical objects of the article. By way of example, an element means one element or more than one element. The term and / or is used in this description to indicate and or or, unless otherwise indicated. The use of the term or is used to mean and / or unless it is explicitly stated that they refer only to alternatives or that the alternatives are mutually exclusive, although the description supports a definition that refers only to alternatives and and / or. As used herein, the term approximately is used to indicate that a value includes the standard deviation of error for the device or method that is used to determine the value. In certain embodiments, the term approximately refers to a range of values ​​falling within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%. 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise indicated or is evident from the context (e.g., when such a number exceeds 100% of a possible value). nozrcn / zznz / q / υιλι By optionally or optionally it is meant that the event or circumstance described later may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, optionally substituted aryl encompasses both aryl and substituted aryl as defined herein. Those skilled in the art will understand that, with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution patterns that are spherically impractical, synthetically infeasible, and / or inherently unstable. The term optionally substituted, unless otherwise specified, means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1.2, 3, 4, or 5 or more, or any interval derivable from this) of the substituents listed for that group where said substituents may be the same or different. In one embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents. In another embodiment, an optionally substituted group has 3 substituents. In another embodiment, an optionally substituted group has 4 substituents. In another embodiment, an optionally substituted group has 5 substituents. For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may, at any point along the chain, be attached to a halogen atom, a hydroxyl group or any other substituent described herein. Therefore, the term optionally substituted means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any additional functional groups. As used herein, alkyl can mean a straight chain or a branched saturated chain having from 1 to 10 carbon atoms. Representative saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, nhexyl and the like, and longer alkyl groups, such as heptyl and octyl and the like. An alkyl group may be substituted or unsubstituted. Alkyl groups containing three or more carbon atoms can be linear or branched. As used herein, lower alkyl means an alkyl having 1 to 6 carbon atoms. As used herein, the term heteroalkyl refers to an alkyl group (as defined herein), wherein at least one carbon atom has been replaced by a heteroatom (e.g., an O, N or S atom). . The heteroatom can appear in the middle or at the end of the radical. The term alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched with about 2 to about 6 carbon atoms in the chain. Preferred alkenyl groups may have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkenyl chain. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl and i-butenyl. A C2-C6 alkenyl group is an alkenyl group with between 2 and 6 carbon atoms. The term alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched with about 2 to about 6 carbon atoms in the chain. Preferred alkynyl groups may have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a linear alkynyl chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl and n-pentynyl. A C2-C6 alkynyl group is an alkynyl group with between 2 and 6 carbon atoms. As used herein, the term halo or halogen means fluoro, chloro, bromo or iodine. The term oxo, as used herein, refers to an =O group. When an oxo group is attached to a carbon atom, it can also be abbreviated here as C(O) or as C=O. An oxo group can also be attached to a sulfur atom (e.g., S=O and S(O)2) or on the phosphorus atom (e.g., P=O, PO2, PO3, PO4, etc.). The term ¡mina as used in this document refers to a group =N. When a mine is bonded to a carbon atom, it can also be abbreviated here as C=N. Nitrogen can also have a double bond with sulfur, for example S=N, which is known as a thioimine. The term ring atoms used in conjunction with terms related to the ring systems described herein (e.g., cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl) refers to the total number of ring atoms present in the system. Therefore, ring atoms do not include atoms present on a substituent attached to the ring. Therefore, the number of ring atoms includes all the atoms present in a fused ring. For example, a 2-indolyl ring, , is considered a 5-membered heteroaryl, but it is also a heteroaryl containing 9 ring atoms. In another example, pyridine is considered a 6-membered heteroaryl and is a heteroaryl containing 6 ring atoms. Cycloalkyl refers to a single saturated carbon ring having 3 to 20 ring carbon atoms (i.e., C3-C20 cycloalkyl), for example 3 to 15 ring atoms, for example 3 to 12 ring atoms. In certain embodiments, the cycloalkyl group is monocyclic (monocyclic cycloalkyl) or contains a fused, bridged or spiro ring system, such as a bicyclic system (bicyclic cycloalkyl) and may be saturated. Cycloalkyl includes ring systems in which the cycloalkyl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkyl ring and, in In such cases, the number of carbon atoms listed still designates the number of carbons in the cycloalkyl ring containing the attachment point. Examples of cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl), 2-(2,3Oo+ Cc$o dihydro-1 H-indene) (-z) and 9-fluorenyl ( ). As noted above, cycloalkyl rings can be further characterized by the number of ring atoms. For example, a cyclohexyl ring is a Ce cycloalkyl ring with 6 ring atoms, while 2-(2,3dihydro-1H-indene) is a Cs cycloalkyl ring with 9 ring atoms. Furthermore, for example, 9fluorenyl is a Cs cycloalkyl with 13 ring atoms and 2-adamantyl is a Ce cycloalkyl with 10 ring atoms. As used herein, the term cycloalkenyl may refer to a partially saturated, monocyclic, fused or spiropolycyclic carbon ring, having 3 to 18 carbon atoms per ring and containing at least one double bond. Cycloalkenyl includes ring systems in which the cycloalkenyl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkenyl ring. and, in such cases, the number of carbon atoms listed still designates the number of carbons of the cycloalkenyl ring containing the attachment point. Cycloalkenyl rings can be further characterized by the number of ring atoms. Examples of cycloalkenyl include 1-cyclohex-1-enyl and cyclopent-1-enyl. The term aryl, as used herein, refers to a single fully carbon aromatic ring or a multiple fully carbon fused ring system where at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 5 to 20 ring carbon atoms, 5 to 14 ring carbon atoms, or 5 to 12 ring carbon atoms. Aryl also includes multiple fused ring systems (e.g., ring systems comprising 2, 3, or 4 rings) having about 9 to 20 carbon atoms where at least one ring is aromatic and where the other rings may be aromatic. or non-aromatic (i.e. cycloalkyl). Aryl includes ring systems in which the aryl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, and where the point of attachment is on a ring of aryl, and, in such cases, the number of carbon atoms listed still designates the number of carbon atoms in the aryl ring containing the attachment point. Examples of aryl groups include phenyl and 5-(2,3-dihydro-1H-indene): As noted above, rings can be further characterized by the number of ring atoms. For example, phenyl is a Ce aryl with 6 ring atoms, while 5-(2,3-dihydro-1H-indene) is a Ce aryl with 9 ring atoms. Heterocyclyl, as used herein, refers to a single saturated or partially unsaturated non-aromatic ring or a system of multiple non-aromatic rings (including fused polycyclic and spiro) having at least one heteroatom in the ring (at least a ring heteroatom selected from oxygen, nitrogen, phosphorus and sulfur). Unless otherwise specified, a heterocyclyl group has from 5 to about 20 ring atoms, for example from 5 to 15 ring atoms, for example from 5 to 10 ring atoms. Therefore, the term includes saturated or partially unsaturated single rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) having 1 to 6 ring carbon atoms and 1 to 3 ring heteroatoms selected from the group which consists of oxygen, nitrogen, phosphorus and sulfur in the ring. The term also includes saturated or partially unsaturated single rings (e.g., 5, 6, 7, 8, 9, or 10-membered rings) having about 4 to 9 ring carbon atoms and about 1 to 3 ring heteroatoms selected from group consisting of oxygen, nitrogen, phosphorus and sulfur in the ring. Heterocyclyl includes ring systems in which the heterocyclyl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a heterocyclic ring. , and, in such cases, the number of ring members listed still designates the number of ring atoms of the heterocyclic ring containing the attachment point. Heterocyclic rings can be further characterized by the number of ring atoms. Examples of heterocyclic groups include piperidinyl (6-membered heterocycle with 6 ring atoms), azepanyl (7-membered heterocycle with 7 ring atoms), and 3-chromanyl (6-membered heterocycle with 10 ring atoms) The term heteroaryl as used herein refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; The term also includes multiple fused ring systems having at least one such aromatic ring. Therefore, the term includes simple heteroaryl rings of about 1 to 10 ring carbon atoms and about 1-5 ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. Sulfur and nitrogen atoms can also be present in oxidized form as long as the ring is aromatic. Heteroaryl includes ring systems in which the heteroaryl ring, as defined above, is fused to one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a heteroaryl ring and, In such cases, the number of ring members still designates the number of ring members in the heteroaryl ring containing the attachment point. Heteroaryl rings can be further characterized by the number of ring atoms. For example, pyridine is a 6-membered heteroaryl that has 6 ring atoms. The description also includes pharmaceutical compositions comprising an effective amount of a described compound and a pharmaceutically acceptable carrier. Representative pharmaceutically acceptable salts include, e.g. e.g., water-soluble and non-water-soluble salts, such as acetate, amsonate (4,4-diaminoslbene-2,2-dísulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate , calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide , sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucato, napsylate, nitrate, ammonium salt of N-methylglucamine, 3-hydroxy-2-naphthoate, oleate, oxalate , palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate salts. The term tautomers refers to a set of compounds with the same number and type of atoms, but that differ in bond connectivity and are in equilibrium with each other. A tautomer is an individual member of this set of compounds. Generally, a single tautomer is represented, but it is understood that this simple structure is intended to represent all possible tautomers that could exist. Examples include enol-ketone tautomerism. When a ketone is drawn it is understood that both the enol and ketone forms are part of the present description. Unless otherwise noted, the structures depicted herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. Illustrative isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O ,17O,180,32P,33P,35S,18F,36CI,123l and125L Isotope-labeled compounds (e.g., those labeled with3H and14C) may be useful in tissue distribution assays of compounds or substrates. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes may be useful because of their ease of preparation and detection. Furthermore, substitution with heavier isotopes such as deuterium (i.e.,2H) may provide certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by 13C or 14C-enriched carbon. Positron-emitting isotopes such as 150,13N,11C, and 18F are useful for positron emission tomography (PET) studies to examine receptor occupancy of the substrate. Preparations of isotopically labeled compounds are known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared following procedures analogous to those described for the compounds of the present invention described herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The term prodrug, as used herein, means a compound that can be converted in vivo by metabolic means (e.g., by hydrolysis) to a described compound. Furthermore, as used herein, a prodrug is a drug that is inactive in the body, but is transformed in the body normally during absorption or after absorption from the gastrointestinal tract into the active compound. The conversion of the prodrug to the active compound in the body can be done chemically or biologically (i.e., using an enzyme). The term solvate refers to a complex of variable stoichiometry consisting of a solute and solvent. Such solvents, for the purposes of the present description, may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH and AcOH. Solvates where water is the solvent molecule are usually called hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. The term isomer refers to compounds with the same composition and the same molecular weight but that differ in physical and / or chemical properties. The structural difference may be in the constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds herein may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers. The term stereoisomers refers to the set of compounds with the same number and type of atoms and that share the same bond connectivity between these atoms, but differ in the three-dimensional structure. The term stereoisomer refers to any member of this group of compounds. For example, a stereoisomer may be an enantiomer or a diastereomer. The term enantiomers refers to a pair of stereoisomers that are mirror images that cannot be superimposed on each other. The term enantiomer refers to a single nozrcn / zznz / q / υιλι member of this pair of stereoisomers. The term racemic refers to a 1:1 mixture of a pair of enantiomers. The term diastereomers refers to the set of stereoisomers that cannot be overlapped by rotation approximately single bonds. For example, cis and trans double bonds, endo- and exosubstitution in bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations are considered diastereomers. The term diastereomer refers to any member of this group of compounds. In some examples presented, the synthetic route can produce a single diastereomer or a mixture of diastereomers. An effective amount, when used in connection with a compound, is an amount effective to treat or prevent a disease in a subject, as described herein. The term carrier, as used herein, encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a filler, diluent, excipient, solvent or liquid or solid encapsulating material involved in the transport or transfer of a pharmaceutical agent from one organ or part of the body to another organ or part of the body of a subject. The term treat, with respect to a subject, refers to the improvement of at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder. The term "prevent or impede" with respect to a subject refers to preventing a disease or disorder from affecting the subject. Prevention includes prophylactic treatment. For example, prevention may include administering to the subject a compound described herein before the subject suffers from a disease and the administration will prevent the subject from suffering from the disease. The terms inhibit and reduce, or any variation of these terms, include any measurable or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%. 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable from this, reduction in activity (e.g., binding activity to proteins of the SOS1 :Ras family) compared to normal. The term disorder is used herein to indicate a disease or condition and is used interchangeably with these terms, unless otherwise indicated. The term administer or administration, as used herein, refers to the direct administration of a described compound or a pharmaceutically acceptable salt of the described compound or a composition to a subject or the administration of a prodrug derivative or analog of the compound. or the pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the body of the subject. A patient or subject is a mammal, e.g. e.g., a human being, a mouse, a rat, a guinea pig, a dog, a cat, a horse, a cow, a pig or a non-human primate, such as a monkey, chimpanzee, baboon or rhesus. Compounds of described formulas In some embodiments, the present description relates to compounds of the following formula (A): Ri h3c'' nh h Λ A A 1X R2^N / ^N'X)R3 (A) a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein: Ri is selected from the group consisting of optionally substituted 3-6-membered cycloalkyl, optionally substituted 3-6-membered heterocycloalkyl, optionally substituted 6-membered aryl and optionally substituted 5-6-membered heteroaryl; R2 is selected from the group consisting of H, C1-6 alkyl, halogen, —NHR2a, -OR2a, cyclopropyl and -CN; wherein the C1-6 alkyl is optionally substituted with halogen, -NHR2a, -OR2a or 5-6 membered heterocycloalkyl, and further wherein R2ase selects from the group consisting of H, C1-6 alkyl, 3-6 membered heterocyclyl and Ci-e haloalkyl; R3 is selected from the group consisting of H, C1.3 alkyl, cyclopropyl and 3-6 membered heterocycloalkyl, wherein each of C1-3 alkyl, cyclopropyl and 3-6 membered heterocycloalkyl is optionally substituted with halogen, -OH , or -CN; L4 is selected from the group consisting of bond, -C(O)-, -C(O)O-, -C(O)NH(CH2)o-, -NH-, -S-, alcuiio C] r, i i , -8(0)2-,^^1, -(CH2)P-, and -O-; where p is a number from 1 to 6; and R4 is selected from the group consisting of H, Ci-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with Ci-6 alkyl , -OR4a, =0, halogen, -C(O)R4a, -C(OO)R4a, -C(O)NR4bR4c, -CN, -NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; where R4a is H, C1-6 alkyl, C1-6 haloalkyl, 3-7 membered heterocyclyl or -(CH2)rOCH3, where r is 1.2 or 3; where R4bes H or Ci-θ alkyl; and where R4ces H or C1-6 alkyl. In other embodiments, the present description refers to compounds of the following formula (B): FV N a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein: R2 is selected from the group consisting of H, C1-6 alkyl, halogen, -NHR2a, -OR2a, cyclopropyl and CN; wherein the C1-6 alkyl is optionally substituted with halogen, -NHR2a, -OR2a or 5-6 membered heterocycloalkyl, and further wherein R2ase selects from the group consisting of H, C1-6 alkyl, 3-6 membered heterocyclyl and Ci-θ haloalkyl; R3 is selected from the group consisting of H, Ci-3 alkyl, cyclopropyl and 3-6 membered heterocycloalkyl, wherein each of Ci-3 alkyl, cyclopropyl and 3-6 membered heterocycloalkyl is optionally substituted with halogen, -OH, or -CN; L4 is a link; and R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with C1-6 alkyl , -OR4a, =0, halogen, -C(O)R4a, -C(OO)R4a, -C(O)NR4bR4c, -CN, -NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; where R4a is H, C1-6 alkyl, C1-6 haloalkyl, 3-7 membered heterocyclyl or -(CH2)rOCH3, where r is 1.2 or 3; where R4bes H or Ci-6 alkyl; where R4ces H or Ci-6 alkyl; R5, Re, R?, R8 and Rg are independently selected from the group consisting of H, D, Cr C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, -OH, halogen , -NO2, CN, — NRnRi2, — SRw, —S(O)2NRnRi2, — S(O)2Riq, — NRioS(0)2NRhRi2, —NRiqS(O)2Rh, —S(O)NRnRi2, — S( 0)Rio, —NRioS(0)NRhRi2, —NRioS(0)Rn, —C(O)Rw, —C02Rio, aryl and heteroaryl, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with -OH, Ci-C alkyl Optionally substituted with -OH, NRnRi2, or heterocyclyl, halogen, —NO2, oxo, —CN, —Rio, —OR10, —NRhRi2, —SR10, —S(O)2NRnRi2, —S(0 )2Rio, — NRioS(0)2NRhRi2, -NRi0S(O)2Rh, -S(O)NRhRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, -NRi0S(O)Rn, heterocycle, aryl or heteroaryl ; Rio, Rn, and Ri2 are independent, each time they appear, H, D, Ci-C8 alkyl, Ο2-Ο8 alkenyl, C4-C8 cycloalkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-14 membered heterocyclyl, - OR13, SR13, halogen, -NR13Ri4, -NO2, or -CN; and R13 and Ri4 are independently, whenever they occur, H, D, Ci-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-14 membered heterocyclyl, where each alkyl , alkenyl, cycloalkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally substituted with -OH, -SH, -NH2, -NO2 or -CN. Additional compounds from described formulas In some embodiments, the present description relates to compounds having the structure of Formula (I), Ri h3c'' nh h Λ Λ KR411Ύ4r2^ n^o R3(I) a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein: Ri is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6 membered aryl and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, C1-6 alkyl, halogen, -NHR2a, -OR2a, cyclopropyl and CN; wherein Ci-8 alkyl is optionally substituted with halogen, -NHR2a, -OR2a, or 5-6 membered heterocyclyl, and further wherein R2ase is selected from the group consisting of H, Ci-8 alkyl, 36 membered heterocyclyl and Ci haloalkyl -8; R3 is selected from the group consisting of H, Ci-3 alkyl, -OR3a, cyclopropyl and 3-6 membered heterocyclyl, wherein each of C1-3 alkyl, cyclopropyl and 3-6 membered heterocyclyl is optionally substituted with R3a, and further R3ase selects from the group consisting of Ci3 alkyl, halogen, -OH or -CN; L4 is selected from the group consisting of bond, -C(O)-, -C(O)O-, -C(O)NH(CH2)o-, -NH-, -Salkyle ( , -S( O)2 - , ' -(CH2)P-, and -O-; where o is 0, 1 or 2; and where p is a number from 1 to 6; and R4 is selected from the group consisting of H, Ci-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; wherein each Ci 6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with Ci-e alkyl , -R4a, -OR4a, -O-alkyl Ci-6-R4a, =0, halogen, -C(O)R4a, -C(OO)R4a, -C(O)NR4bR4c, -NR4bC(O)R4c, -CN, =NR4a, NR4bR4c, -SO2R4a, 3-6 membered cycloalkyl optionally substituted with R4a, 37-membered heterocyclyl optionally substituted with R4a, 6-10 membered aryl optionally substituted with R4a, or 5-10 membered heteroaryl optionally substituted with R4a; where R4a is H, C1-6 alkyl, C1-6 haloalkyl, -C(O)R4b, -C(O)NR4bR4c, =0, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with -OR4b , -CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, -(CH2)rOCH3, or -(CH2)rOH, where r is 1.2, or 3; where each R4bes independently H, Ci-e alkyl; and where each R4 is independently H or C1-6 alkyl. In some embodiments of compounds of Formula (I), Ri is the optionally substituted 6-membered aryl. In some embodiments, the 6-membered aril has the following structure: where Rs, Re, Rz, Rs and Rg are as defined below in relation to the formula (Il)-(lV). In some embodiments of compounds of Formula (I), Ri is the optionally substituted 5-6 membered heteroaryl. In some embodiments, Ri is a 6-membered heteroaryl having any of the following structures: where Rs, Re, R?, Rs and R9 are as defined below in relation to the formula (Il)-(lV). In some embodiments of compounds of Formula (I), R1 is the optionally substituted 5-6 membered heteroaryl. In some embodiments, R1 is a 5-membered heteroaryl having the following structure: I where R5, Re and R7 are as defined below in relation to formula (ll)-(IV). In some embodiments, the present description relates to compounds having the structure of Formula (II), a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, U, and R4 are as defined in Formula (I); Rs, Re, R7, Rs, and R9 are independently selected from the group consisting of H, D, C16 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, heterocyclyl 3-14 members, -OH, halogen, -NO2, -CN, -NR11R12, -SR10, -S(O)2NRnRi2, S(O)2Rw, -NRioS(0)2NRnRi2, -NRi0S(O)2Rh, -S(O)NRhRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, NRioS(0)Rn, -C(0)Rio, -C02Rw, 6-10 membered aryl, and 5-10 membered heteroaryl members, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and heteroaryl 5-10 membered is optionally substituted with -OH, C1-6 alkyl optionally substituted with -Rw, halogen, NO2, oxo, —CN, -Rw, — OR10, —NR11R12, -SRw, — S(O)2NRnR12, — S(O)2Rw, —NRwS(O)2NRhRi2, — NRwS(O)2Rn, — S(O)NRnRi2, — S(0)Rio, —NRwS(O)NRnRi2, —NRwS(O)Rn, cycloalkyl 3-8 membered, 3-14 membered heterocyclyl optionally substituted with Rw, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 form an optionally fused ring replaced from 3-14 members; Rio, Rii and R12 are independently selected whenever they appear from H, D, Ci-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-membered heterocyclyl. 14 members, -OR13, -SR13, halogen, -NR13R14, -NO2, and -CN; and R13 and R14 whenever they appear are independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-membered heterocyclyl. 14 membered, wherein each C1-6 alkyl, C2-e alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, - SH,_NH2, -NO2o -CN. In some embodiments, the present description relates to compounds having the structure of Formula (III), r3 (III) a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, L4 and R4 are those defined in Formula (I); R5, Re, R?, Re, and R9 are independently selected from the group consisting of H, D, C16 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OH, halogen, -NO2, -CN, -NRuRi2, -SR10, -S(O)2NRnRi2, S(0)2Rio, -NRioS(0)2NRiiRi2, —NRi0S(O)2Rh , -S(O)NRhRi2, -S(O)RW, -NRi0S(O)NRnRi2, NRioS(0)Rn, -C(0)Rio, -C02Rw, 6-10 membered aryl, and 5-membered heteroaryl 10 members, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl optionally substituted with -OH, C1-6 alkyl optionally substituted with -R10, halogen, NO2, 0X0, —CN, -R10, —OR10, —NRiiRi2, —SR10, —S(O)2NRhRi2 , —S(0)2Rio, —NRioS(0)2NRhRi2, — NRioS(0)2Rh, — S(O)NRi 1 Ri2, — S(O)Rw, —NRiqS(O)NRhRi2, —NRioS(0) Rn, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rw, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 form a 3-14 membered optionally substituted fused ring; R10, R11 and R12 are independently selected whenever they appear from H, D, Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl, 3-membered heterocyclyl. 14 members, -OR13, -SR13, halogen, -NRi3Ri4, -NO2, and -CN; and Ri3 and Ri4 whenever they appear are independently selected from H, D, Ci-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl. , wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, -SH, -NH2, -NO2, or -CN. In some embodiments, the present description relates to compounds having the structure of Formula (IV-a), (IV-b), or (IV-c), a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, U, and R4 are as defined in Formula (I); Rs, Re, R7, Rs, and R9 are independently selected from the group consisting of H, D, C16 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, heterocyclyl 3-14 members, -OH, halogen, -NO2, -CN, -NRnRi2, -SR10, -S(O)2NRnRi2, S(0)2Rio, -NRioS(0)2NRiiRi2, -NRi0S(O)2Rh, -S(O)NRhRi2, -S(0)Rio, -NRi0S(O)NRhRi2, NRioS(0)Rn, -C(0)Rw,-C02Rio, 6-10 membered aryl, and 5-10 heteroaryl members, wherein each Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and heteroaryl 5-10 membered is optionally substituted with -OH, Ci-6 alkyl optionally substituted with -R10, halogen, NO2, oxo, —CN, —R10, — OR10, — NRiiRi2, —SR10, —S(O)2NRhRi2, — S(0)2Rio, —NRioS(0)2NRhRi2, — NRioS(0)2Rn, -S(O)NRiiRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, -NRi0S(O)Rh, cycloalkyl 3-8 membered, 3-14 membered heterocyclyl optionally substituted with Rw, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 form an optionally substituted fused ring from 3-14 members; R10, R11 and Ri2 are independently selected whenever they occur from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 heterocyclyl members, -OR13, -SR13, halogen, -NRi3Ri4, -NO2, and -CN; and R13 and Ri4 each time they appear are independently selected from H, D, C1.6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 heterocyclyl. members, wherein each Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, -SH , -NH2, -NO2or -CN. In some embodiments, the present description relates to compounds having the structure of Formula (IV-a) or Formula (IV-b). In some embodiments of compounds of formula (ll)-(IV), one to three of R5, Re, R7, King Rg is Cve alkyl, wherein the alkyl is optionally substituted with halogen. In some embodiments of the compounds of Formula (Il)-(lV), one to three of R5, Re, R?, Rs, and R9 is C1-6 alkyl, wherein the alkyl is optionally substituted with halogen or -OH . In some embodiments of compounds of formula (ll)-(IV), one to three of R5, Re, R7, Rs and R9 is C1-6 alkyl and one to three of Rs, Re, R7, Rs and R9 is Ci alkyl. -6 optionally substituted with halogen. In some embodiments of compounds of formula (ll)-(IV), one to three of R5, Re, R7, King Rg is halogen, and one to three of R5, Re, R7, Re, and R9 is Ci-alkyl. 6optionally substituted with halogen. In some embodiments of compounds of formula (ll)-(IV), one to three of R5, Re, R7, King R9 is NH2. In some embodiments of compounds of formula (ll)-(IV), one to three of Rs, Re, R7, Re and R9 is NH2; and one of Rs, Re, R7, Re, and R9 is C1-6 alkyl optionally substituted with halogen. In some embodiments of the compounds of formula (ll)-(IV), any two adjacent R5, R6, R7, R8 and R9 form a 3-14 membered fused ring. In some embodiments of the compounds of formula (ll)-(IV), any two adjacent R5, R6, R7, R8 and R9 form a 3-8 membered fused ring. In some embodiments of the compounds of formula (ll)-(IV), any two adjacent R5, R6, R7, R8 and R9 form a 4-8 membered fused ring. In some embodiments of the compounds of formula (Il)-(lV), any two adjacent R5, R6, R7, R8 and R9 form a 4-membered fused ring or a 5-membered fused ring. In some embodiments, the fused ring is a 3-8 membered heterocyclyl or a 3-8 membered cycloalkyl. In some embodiments, the fused ring is a 4-8 membered heterocyclyl or a 4-8 membered cycloalkyl. In some embodiments, the fused ring is a 4-membered heterocyclyl or a 5-membered heterocyclyl. In some embodiments, the fused ring is a 4-membered cycloalkyl or a 5-membered cycloalkyl. In some embodiments, the fused ring is optionally substituted with -OH, Ci-6 alkyl, halogen, -NO2, oxo, -CN, -R10, OR10, — NRhRi2, —SR10, — S(O)2NRi 1 Ri2, — S(0)2Rio, —NRiqS(O)2NRhRi2, —NRiqS(O)2Rh, —S(O) NRhRi2, -S(0)Rio, -NRi0S(O)NRhRi2, —NRi0S(O)Rh, cycloalkyl 3-8 membered, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, the fused ring is optionally substituted with halogen. In some embodiments of compounds of formula (ll)-(IV), one or more of R5, Re, R?, Re and R9 are selected from -CF3, -NH2, -F and -CF2CH2OH. In some embodiments of compounds of Formula (II), one of R5, R6, R7, Rs and R9 is -CF3 and one of R5, Re, R7, Rs and R9 is -NH2. In some embodiments of compounds of Formula (II), one of R5, Re, R7, Rs and R9 is -F and one of R5, Re, R7, Rs and R9 is CF2CH2OH. In some embodiments of compounds of Formula (I), R1 is selected from: In some embodiments of compounds of Formula (I), Ri is selected from: nh2y In some embodiments of compounds of Formula (I), Ri is selected from: In some embodiments of compounds of Formula (l)-(IV), R2 is H. In some embodiments of compounds of Formula (l)-(IV), R2 is Ci-6 alkyl. In some embodiments of compounds of Formula (l)-(lV), R2 is -CH3. In some embodiments of compounds of Formula (l)-(IV), R2 is Ci-6 alkyl substituted with 5-6 membered heterocycloalkyl. In some embodiments of compounds of Formula (l)-(lV), R2 In some embodiments of compounds of Formula (l)-(IV), R2 is C1-6 alkyl substituted with -NHR2a, where R2a is C1-6 alkyl or 3-6 membered heterocyclyl. In some embodiments of compounds of Formula (l)-(IV), R2 is selected from and -CH2NHCH3. In some embodiments of compounds of Formula (l)-(IV), R2 is Ci-6 alkyl substituted with -OR2a, where R2a is H or C1-6 alkyl. In some embodiments of compounds of Formula (l)-(lV), R2 is -CH2OH. In some embodiments of compounds of Formula (l)-(IV), R2 is -NHR2a, where R2a is C1-6 alkyl. In some embodiments of compounds of Formula (l)-(lV), R2 is -NHCH3. In some embodiments of compounds of Formula (l)-(IV), R2 is -OR2a; where R2a is Ci-6 alkyl. In some embodiments of compounds of Formula (l)-(IV), R2 is -OCH3. In some embodiments of compounds of Formula (l)-(IV), R3 is C1-3 alkyl. In some embodiments of compounds of Formula (l)-(IV), R3 is -CH3. In some embodiments of compounds of Formula (l)-(lV), R3 is -CD3. In some embodiments of compounds of Formula (l)-(IV), R3 is C1-3 alkyl substituted with -OH. In some embodiments of compounds of Formula (l)-(lV), R3 is -CH2CH2OH. In some embodiments of compounds of Formula (l)-(IV), R3 is H. In some embodiments of compounds of Formula (I)-(IV), R3 is -OR3a. In some embodiments of compounds of Formula (l)-(IV), R3 is -OCH3. In some embodiments of compounds of Formula (l)-(lV), R3 is cyclopropyl. In some embodiments of compounds of Formula (l)-(IV), R3 is 3-6 membered heterocyclyl. Yo JWW In some embodiments of compounds of Formula (l)-(lV), R3es0 In some embodiments of compounds of Formula (l)-(IV), L4 is selected from the group consisting of ° C^alkyl ...... . *\, (CH2)P-, and -O-; where o is 0, 1 or 2; and where p is a number from 1 to 6. In some embodiments of compounds of Formula (l)-(IV), L4 is a bond. In some embodiments of compounds of Formula (l)-(lV), L4 is -C(O)-. In some embodiments of compounds of Formula (l)-(IV), L4es -(CH2)p- In some embodiments of compounds of Formula (I), L4es -(CH2)-. In some embodiments of compounds of Formula (l)-(IV), R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with Ci-6 alkyl , R4a, -OR4a, -O-Ci.6alkyl-R4a, =0, halogen, -C(O)R4a, -C(OO)R4a, -C(O)NR4bR4c, -NR4bC(O)R4c, -CN , =NR4a, -NR4bR4c, -SO2R4a, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl. In some embodiments of the compounds of Formula (l)-(IV), R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl , 6-10 membered aryl and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 314 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with Ci-6 alkyl, - OR4a, =0, halogen, -C(O)R4a, -C(OO)R4a, -C(O)NR4bR4c, -CN, -NR4bR4c, 3-6-membered cycloalkyl, 3-7-membered heterocyclyl, aryl 6-10 membered or 5-10 membered heteroaryl; In some embodiments of compounds of Formula (l)-(lV), R4a is H, C1-6 alkyl, C1-6 haloalkyl, -C(O)R4b, -C(O)NR4bR4c, =0, 3-6 cycloalkyl members, 6-10 membered aryl optionally substituted with -OR4b, -CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, (CH2)rOCH3, or -(CH2)rOH, where r is 1, 2, or 3; where each R4bes independently H, alkyl Cve; and where each R4 is independently H or Ci-e alkyl. In some embodiments of compounds of Formula (l)-(IV), R4aes H, C1-6 alkyl, C1-6 haloalkyl, -C(O)R4b, -C(O)NR4bR4c, 3-6 membered cycloalkyl, aryl 6-10 membered optionally substituted with -OR4b, -CN, 3-7 membered heterocyclyl, -(CH2)rOCH3, or -(CH2)rOH, where r is 1, 2, or 3; wherein each R4b is independently H, Ci-e alkyl; and where each R4 is independently H or Ci-6 alkyl. In some embodiments of compounds of Formula (l)-(IV), R4 is a 3-14 membered heterocyclyl. In some embodiments of compounds of Formula (l)-(IV), R4 is 3-14 membered substituted heterocyclyl. In some embodiments of compounds of Formula (l)-(IV), R4 is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl. In some embodiments, the heterocyclyl substituent is oxetanyl. In some embodiments of compounds of Formula (l)-(IV), R4 is 3-14 membered heterocyclyl substituted with C1-6 alkyl. In some embodiments of compounds of Formula (l)-(IV), R4 is 3-14 membered heterocyclyl substituted with -CH3. In some embodiments of compounds of Formula (l)-(IV), R4 is a 3-14 membered heterocyclyl substituted with -CH2, that is, the substituent is a methylene bridge linking 2 carbon atoms in the heterocyclyl ring. In some embodiments of compounds of Formula (l)-(IV), R4 is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl. In some embodiments, the cycloalkyl substitute is cyclopropyl. In some embodiments of compounds of Formula (l)-(IV), R4 is 3-14 membered substituted heterocyclyl with =0. In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, the FU is a heterocyclyl selected from: In some embodiments, the FU is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, the FU is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, R4 is a heterocyclyl selected from: In some embodiments, R4 is selected from: ΗΟ In some embodiments, R4 is a 3-14 membered cycloalkyl. In some embodiments, R4 is 3-14 membered substituted cycloalkyl. In some embodiments, R4 is selected from: EITHER In some embodiments, R4 is a 6-10 membered aryl. In some embodiments, R4 is a 610-member aryl. In some embodiments, R4 is phenyl. In some embodiments, R4 is phenyl substituted with one or two groups selected from -OCH3 and -CN. In some embodiments, R4 is a 5-10 membered heteroaryl. In some embodiments, R4 is a 5-10 membered substituted heteroaryl. In some embodiments, R4 is selected from 1 H-pyrrole, thiazole, pyridine, pyridazine, pyrimidine, each of which is optionally substituted with a group selected from -F, -OCH3 and -OCH2CH2OH. In some embodiments, R4 is selected from: The present description provides a compound and its pharmaceutically acceptable salts, solvates, stereoisomers and tautomers, selected from the group consisting of the compounds of Table A: Table A. Example # Structure Example # Structure Example 1. n TI ω z=z 1--v / / Z \—z 3 -7 y / 1 - / \ x —Z # oz \--\ '—z z Example 32-29 . TI / =z\ z / >—z 3 v 7 / / I —z / / \ o— q / / \ >° Example 1-1. / =zx / / I —Z zz ° or T Example 32-30. F F^| = 0 ^'R> ; A NH I A J [i J I I Example 1-2. CF3^ / V M A w NH < NH ΐ^Α 1 Example 32-31. z—< I I l . (Ó?} ν' α / Z\ / ° —o \ / )—λ £“ 2-(7 z VA \ z= / Example 1-3. TI Z / >—z v' / / I —z q / # —\ ^z T Example 32-32. F ρΛΟ F^l ''' NH 1 .-----. / ^N^N^'O 1 nozrcn / zznz / q / υιλι Example 1-4. / =zx z / )—z '—' \\ I —Z \ Ό \--\ Example 32-33. o II O=W\ / ( Lo V / L P \ z~ z= / Example 1-5. Z / )—z ' ' \\ / / I —z \ Q \—\ Example 32-34. 1 m 1 Ζ^ ))— ζ7!- \\ # I “ΖΟ οχ ο ι 2 / \__ω=Ο II Ο 1___________________________________________________________________________________________________________________________________________________________________________________________1 CO Example 1-6. / =\ \\ / / I —z \ o \—\ \ ° Example 32-35. F FLn F^l I NH ¿ Λη η I I \ ) 1 0 Example 1-7. °θ / \ z— I Λ-Λ Z—V Ζ LL Example 32-36. Π Π \—Π / =^ ζ / >—ζ 5 ν_7 / / I —ζ / / \ ο— o λ° nozrcn / zznz / q / υιλι Example 1-8. CF3^^ Lr; '''' NH | N I Example 32-37. 1 g: o^z^ o —o \ z— z / 7^ 7—λ £· z—7 z vJ^\ z= / LL—¿ LL Example 1-9. Z / )—z v' / / I —z / 7 c> \—< ^z T Example 32-38. 1 o<^z / y 'V~7\ / ° —o \— \ z— 7—λ £ z—(z z z= / Example 1-10. z Λ, KW Z / >—z '--' Ύλ t —Z / 7 o \—y ^z Example 32-39. / =zv z / >—z 3 v_7 \\ / / T —z / 7 o— o y—κ Example 1-11. Z / )—z J \\ / / I —z o \—< h° Example 32-40. F ρΛΟ ''' NH 1 1 O«\(R) / <\ >-·Ν N N 0 0 1 nozrcn / zznz / q / υιλι Example 1-12. °z z^ '— / o i Λ—λ 2—(Z Z # yv \= / LL \= / > Example 32-41. F ρΛΟ F^T NH I i °<sy\ís\ / OCX N N 0 0 I Example 1-13. / =zx Z / )—z '-- / —z u Ό \--< 1° / z ΞΕ Example 32-42. F F^9 v NH \ N^T^ZZZ N N^O 1 Example 1-14. o '—\ / ° \ z— χ Λ-Λ 2-( / Z \ z= / Example 32-43. 1 1 । vy ° ° 1________________________________________________________________________________________________________________________________________________________________________________1 co Example 1-15. / )—Z '--- / \ \ / / I —z )> O \--V \ ° / Z T Example 32-44. F 'Z y ' NH Z \ N N^O 1 nozrcn / zznz / q / υιλι Example 1-16. F ρΛη F^y 0 NH I Example 32-45. o II _ ^cl-Z \ z— i 7 λ ñ> z—z z= / Example 1-17. / =zx Z ,)— Z v—y \\ # T —z \ Ό \-\ / / u o Example 32-46. 1 1 z Λ— z 3 v_y \\ # I —Z / 7 ° oVa II 1_______________________°_______________________1 co Example 1-18. Z—\ '—ξ o \ z— T r—λ z—7 z z= / ^>4 / 0 Example 32-47. °^ü θ —o )— \ z— f / £ 2—v z z= / u_ Example 1-19. \ A-H / =z ''r\) Z / >—z J \\ # T —Z / 7 oZ \—< λ° Example 32-48. °^ü o —oc \ z— i 7 λ Ó? η—ν Z vy \ z= / LL--( LL U- nozrcn / zznz / q / υιλι Example 1-20. z^ '— / o Λ—λ Z—(' ( yv \= / LL >=< ' Example 32-49. \ I g <z~z^\ o L / θ —o \ \ z— / / — \ θ' z^^z yYy A= / Example 1-21. Qf Z / )—z y \\ / / T —z \ o7 / / —\ Example 32-50. 'Z'-Z^X ° l / O —o'' \ \ Z— yYy z= / Example 1-22. Z / )—z vJ A / / T -ςΟ C) \--V Example 32-51. TI \--TI / =^ Z / >—Z 3 V 7 / / I —z —\ o— τΑ__ Example 1-23. / =z 'r\) ~Z. Λ—z J \\ / / I —z \ d \—\ λ° Example 32-52. / =zx Z / )—Z 5 V 7 \\ / / I —z \ o— O7 Y-Λ / / -2 Example 1-24. - >=< H Z / )—Z vy \\ # I —z o \—< Example 32-53. / =z\ Z / )—z 5 V_7 \\ / / I —z ^T \ θ— o z / co \Z λ° Example 1-25. KW Z / >— z y \\ / / I —z \ Ό \-\ / / u o Example 32-54. / =\ Z / )—Z 3 V 7 \\ # I —z )> / L cn'° / o Example 1-26. Z / >—z V—J / / T —Z / 7 CJ \--V b Example 32-55. T Z—\ z\ ° —o \_7 \ z— 1 7—λ £ 2—7 -Z. Example 1-27. Π \--TI / =z z / )—z ' ' V / / T —z )> C> \—k ^z > o ω Example 32-56. Z\ / ° —O \ \ Z— T / / Λ 7—λ £ z—7 z v= / \ z= / u_ Example 1-28. / =zx \\ X ΞΕ —Z <D \---y ^Z Example 32-57. n-w l 1 ° i Lo / ° \ / / λ £ zU z z= / LL--( LL Example 1-29. o^\ '—¿ o \ z— I / T~^ r—λ z—σ z Example 32-58. z ,)—z 3 v 7 \\ / / I —Z 2 y \ °— ° z V0 Example 1-30. / =\ 'rA) Z / )—Z '---' \\ X I —z / / O \--y Example 32-59. F ρΛπ F^''l 1 NH A .—. O 1 u\ / \ II A X >— s— n \__ / H H 1 1 ° 1 Example 1-31. ti 2—ti Z / )— z '--y / / I — Z A o \< ^z T Example 32-60. F oyH '' NH \ / l Λ X N N O 1 nozrcn / zznz / q / υιλι Example 1-32. f=\ z / )—z 3 v_y \\ / / I —z O \--V \ 3! / '—O-,, O Example 32-61. °^v6° \ z— z= / LL— / LL Example 1-33. í=\ z Λ— z 3 v_u \\ / / T —z \ C) / / —\ \ s / '— / / o Example 32-62. z / )—z 5 v_y \\ / / T —z \ —\ >o— O ·φ\ \— z V0 Example 2. O x—z o )= / % O T Example 32-63. Π \--TI / =\ z A—z 3 \ y / / T —z \ >o— O \—z θ σ^ο σ Example 2-1. hf2c^^ IJ F^Y ''e NH | ° X J ΧχΎ ^'N^N^O I Example 32-64. τι TI \—TI / =z\ z / )—z 3 'ύ__y \\ T —z / / D-° ^b nozrcn / zznz / q / υιλι Example 2-2. LL- / —7 O and Example 32-65. 1 1 O \__i \\ Z^i 1 n;W \ ,O ° yp \ — I f / —λ 5? z—V -z. / X i___________________________________________________________________________________________________________________________________________________________________________________________1 Example 2-3. hf2c^^ IJ F^Y .¼ ro NH χΥΎ ^N N^O I Example 32-66. 1 1 O \__I \\ Z^i 1 n;W \ ,O ° \ y o \ — 1 / / -^f / —λ ? 2-( / z LL—( U_ 1________í__________________________________1 co Example 2-4. F F^O F^y ,X O. '' NH y NH / N.J N ϊ 1 L N^O 1 Example 32-67. 1 1 / =z\ ζΧΓγ Z / >—z 3 V__'J / / I —H / 7 o A n O \ ω'° \ ° 1 1 1 Example 2-5. F Fbo f^Z X 0^^ / '' NH y N NXyyN ^ ^N N^O 1 Example 32-68. TI \—ΤΊ í=\ z Λ—z 5 v_7 Y / / i —z ZX o— oz yy o ΟΛ Example 3. I o s A-n —Z / 7 o \--\ c> Example 32-69. P —O V-7 \ z— T / / —£ z—\ ^05 κ Example 4. F. F H JlYY^ Example 32-70. / =z\ y=r-C~ / > z Λ—z 5 v 7 / / T —z \ o o \ / 4 r Example 5. O ω r— ~Z. \ á λ / VJ7 \ / I —H / 7 c> / 7—\ '—a Example 32-71. I I / =z\ z Λ— z 5 v_7 / / I —H / 7 oZ o \ / ¿ r Example 6. O TI ω Ξ / Φ x / < Ύλ - / \ I —Z / 7 oz \—< ' —z T Example 32-72. / =\ z / )—z 3 v 7 / 7 i —Z / 7 o o _ 1 M?o nozrcn / zznz / q / υιλι Example 7. q Z / )—z v—< / \ 1 —H / 7 M C> / / --\ Example 32-73. TI 2--TI / =zx / / I —z 2 u—(°-- ° — / II O Example 8. O TI co Z \—Z 3 V-y / \ T ιζ Λ O \--y '—z T Example 32-74 1 1 / =z\ Z / )—z 3 V 7 # I —z / / >7—\ ° ° ο=ω— / II 1____________°________________________________1 Example 8-1. F ρΛΟ F T 1 . w; 1 Example 32-75. / =z\ Z / )—z 5 V 7 / / I —z \ o \¿ o—^-o o o / ω 2 \—Z Ί^° Example 8-2. Z / )— z vJ \\ / / I —z \ Ό \\ '—z Example 32-76. Oj c' NH 1,—. or 1 nozecn / zznz / q / υιλι Example 8-3. Z—\ '—¿ o \ z τ / 7^ Λ—λ Z—(7 Z \ W z= / Example 32-77. Οχ zO —o \ z~ vJW z= / LL Example 8-4. t \ —τι / =z\ r\) Z / >—z ' 7 \\ / / I —z \ Ό \\ ^z Example 32-78. Π TI \—TI —Z / 7 7\ ^O-^. ° z O^ Example 8-5. / =zx r\ / ) Z / >—z J / / T —z \ Ό y--k / / o o Example 32-79. F F^l .¼ / NH 0 / y 1 Example 8-6. / =zx r\ / ) Z / )—Z '—7 \\ / / T —Z / 7 or \< >° Example 32-80. F FSn F^l ''' NH —0 nh ^N^N^O 1 nozecn / zznz / q / υιλι Example 8-7. Z / )—z '—7 \\ / / I —z o / —\ λ° Example 32-81. F f^A A I D D P A 7 Al I Example 8-8. \\ / / I —z \ Ό \\ b Example 32-82. z Q p op—O \- Q <7 \_ τ O / / £ z—(' z vaC z= / Example 8-9. F ρΛΟ F J 0 NH ΝΑγΑγΑ / A A X I Example 32-83. I I z^ / ) —zA-^^- A< 1 “ZO Λ—\ o ° -V O' / > z—<J 1________________________________________________________________________________________________________________________________________________________________________________1 Example 8-10. F ρΛπ F^y o A A / OH ν^ά^Α^^ A ί N N Π3 I Example 32-84. / =^ XA / ζ Λ—z 5 v_y \\ / 7 τ —z \ u—\ o— ° A\ o / x6 nozecn / zznz / q / υιλι Example 8-11. F JKF F jQ T 0 '' NH r S'ü H J I I Example 32-85. i m 1 \\ / 7 I / T \ o— ° i________________________________________________________________________________________________________________________________________________i Example 8-12. o Q-11 '--¿ O \ — r,—λ Z—(7 z O / . z=^ Example 32-86. / =\ z / )—z 3 \ y \\ / / I —z / / \ o— οζ V—\ II O Example 8-13. TI “Π 2—TI / =zx Z Λ—z '—7 \\ / / I -2O oz / —\ 4 TI Example 32-87. TI / =z\ z / )—z 5 v_y / / I —z \ \ o— O V-A ^Z o Example 8-14. Z / )—z vJ \\ / / I or S—. b Example 32-88. F f iD ' NH 1 ,—. o VyOí 1 nozrcn / zznz / q / υιλι Example 8-15. Z / )—z vJ \\ / / T —z \ d \—v xO o- \ Example 32-89. F F>XX X ''' NH 1 / —\ o dXd D Example 8-16. z Λ—z '--' \\ / / I —z \ o7 / —\ ^z > o Example 32-90. F fXO F'X| J / R? ZNH 1 / ---κ / 1 Example 8-17. Z A—Z '--' \\ / / T —z \ o / —\ '—z > o Π ω Example 32-91. either . \___¿ Z / )—Z 3 V_7 / T —z \ dx o— ^z^ Example 9. CF3.^.NH2 ΊίΎ '''' NH X NH nX^X^X JL X X H Example 32-92. F ρΛΟ 'Jw . Οχ\__ D NH ¿ A. i u J L 1 nozrcn / zznz / q / υιλι Example 10. CF3^^ '''' NH \ 0 A xn Jt J 11Ύ I Example 32-93. / x 7 í=\ z Λ—z 3 v y \\ / / ΞΕ —z \ / —\ p— ° \ 3 / Example 11. CF3^^, '''' NH | ° ,<\ / x A J tiX Λ Example 32-94. Ο^Ζ-Λ / CO / z\ P —O \_1 / \ z— Z= / ^zC / O Example 11-1. ΤΊ 2—Ή A PQ Z / )—z '—' \\ / / I ^Z va T ° \ ° Example 32-95. F ρΛπ F^l •X '''' NH -0 ϊι N Ή^Ν 73 o Example 11-2. F F^| o 'e‘ NH r^N^^ nA / X / X / h I I N^N^O N^^ Example 32-96. No / —z ° o \—7 10- / —λ £ 2— / z <ζ LL 1__________________________________________________________________________________________________________________________________________________________________________________________________________1 nozrcn / zznz / q / υιλι Example 11-3. / =zx z / )—z -2 v__y \\ / / T II ° or Example 32-97. 0^=7 z—\ X P —Q \ Z— i Q f / —λ ε- z—v -z. v= / \ z= / Example 11-4. Π 2--TI / =z\ o-xT# z Λ— z 3 v_y I [X~z 7 °rO / Example 32-98. F f7o NH ¿ r~n N \X H I I ^N^N^O I Example 12. CF3.^.NH2 and Me'' NH | ° n ηρ N^O I Example 32-99. z / )—z 5 v_y / / I —z )r \ P— °Z / 0 \—z 7^° Example 13. CF3-^^ M NH < 0 OCX ^N^N^O I Example 32-100. / ^z\ ΤτλΓ# z Λ—z 5 v_y \\ / / T —z \—C o— o zX,.·''' \ \—z 7^° Example 14. Z / )—z '— / \\ z I —z \ a Λ / ω=ο θ' Example 32-101. TI \—TI / =\ Z / )— Z 5 V 7 \\ / / I —z \ \—\ o— o7 / OL-· \—z y° Example 15. CF3.^. ,NH2 1 T f o X'^NH nA / Z / K / h 1 1 1 Example 32-102. , \=< >=\ zZZ Z / )—Z 5 V_7 \\ / / T —z 7—\ °'~- ° r\ Z''J Example 16. zQf Z / )—z '-- / / / I —Z / 7 o7 Example 32-103. / =z\ ztC# Z / )— Z 5 V_7 Z T —Z 7 7-\>O — O Example 17. o TI ω / =zx λΛ / —z.\ z O \--y z° Example 32-104 . / =Z\ Z h— Z 5 V_7 # I —z \ 7-\ P— O \ / Z~yO nozrcn / zznz / q / υιλι Example 18. m 2--Π Z / )—Z vJ \\ / / I z \ Ό \--y '—Z Example 32-105. I m I / =z —z P —\ a~ o yx, o \—v Xo Example 32-106. F ^<0 %x F γ 'X__Z-D L(R) I / n X ór\. ñ J I XN^N^O I J Example 20. TI \--TI TI TI 2—Ή f=\ ü Example 20-1. φ O Φ \___, or. ° \ / —\ P \ z~ τ r—λ Ζ—(7 ζ Oh ZX Example 32-108. TI 2—Ή / =z\ / τχχ zp\ 3 —z 2 —\ O-° / Ά '— z σ Example 20-2. / =z hj Z / )—z J \\ T / I —z \ Ό '--¿ \ Example 32-109. 1 or 1 Ο=ω— / r-í Qí o O \__[ / Or--λ K LL— / LL LL 1_________________________________________________________________________________________________________________________________________________________________________________1 Example 20-3. Π / =z Hj Z / )—z y \\ / {T —z \ Ό '--¿ \ Example 32-110. 1 t 1 Jl <=> W o op— O \—7 Q <7 K 7--2 / \= / 1___________t_____________________________________1 Example 20-4. f=\ —z o \ ω—' ' / \\ o o Example 32-111. I pee p W p Qp—O \—í / Q / r-λ K / --7 2 Z= / U-—( U- Example 21. F F^T ,N. '' NH f N 7 r h ú I I I Example 32-112. O \\ Ο=ω—» TA o —o \_n \ z— Γ—λ i? / --ς Z Vv^z= / nozrcn / zznz / q / υιλι Example 21-1. / =zx Z / 2—2 '--' \\ 7 I —z \ Example 32-113. F AF F JJ F^Y 0 l(R) , X X °X J H I I ^N^N^O I Example 21-2. 2 / )—2 '--7 a# 1 — Z \ U Z z= / Example 32-114. F tA °v 1 (R) I \ / / 1 °A> Ñ J 1 Ν N^O 1 Example 21-3. A Z / )—Z J \\ / / X —z \ o ¿ 2 v\ '> ^z Example 32-115. F v UR) I \ / / 1 °AA nAyaA·7 [1 J [ n n^o 1 Example 21-4. F f^ A '' NH f ΐ j 1 1 Example 33. 2 / )—Z '---7 A# X —Z # q / nozrcn / zznz / q / υιλι Example 21-5. F ρΛη A ,F '' NH < A A^n N H I I I Example 33-1. O '—¿ o \ z— τ AA Λ—λ z—7 z (aA z= / Example 21-6. aai Z / )—Z '--' \\ / / I —Z\ 7 Z λ—7 o o Va Example 33-2. / =\ 'r~\ / ) Z / >— Z J \\ / / I —Z / 7 o \ o Example 21-7. F fAo f^ A / 0. ,N. '' NH Al ΰ J L A^N^O 1 Example 33-3. Cp V-L -0 7' NH ( SC I I l'o N / Y / 'Y / \z η I I ^N^N^O I Example 21-8. F fAo F^A N-0 l A / N nh A y N^A^A^^ Ú J 1 ^N^N^O 1 Example 33-4. ~ A-n / ^Z\ Api / / I —Z / 7 O \\ oz o nozrcn / zznz / q / υιλι Example 21-9. F F^f .Λ XX '' nh yx ϊ X 1 ^'N^'N^O 1 Example 33-5. / 0 X <O '' NH f SC 1 1 Do η 1 1 1 Example 21-10. / =zx Z / )—Z '—' \\ / / I —z u o \ / ° Example 33-6. AF F jQ ek <O '' NH C SC 1 1 Do [i 1 1 ^N^N^O 1 Example 21-11. z Λ yy / ° T / ° / / \ a—' / z— T —z o ^z o ω( z xo Example 21-12. F fXd F^l N ^XYlí N jl X X o N N 0 1 Example 33-8. 1 1 TI / =z\ xy# Z / )—z 3 V_7 A / / I —z / / O \--y iro o 1________________________________________________________________________________________________________________________________________________________________________________________________1 nozrcn / zznz / q / υιλι Example 21-13. TI z / >—z 3 v_y A I —z A oz Example 33-9. I I o OJI \—l O \ z— 1 / T^ f / —λ í Z—Q z i_____________Lr____________________________________________________1 1 Example 21-14. F F^l NH Z^N X X j Ν^γ^Αγ^^ H I I ^N^N^O I Example 33-10. F ρΛπ f^x °J Ira s-o A NH r-N Ν^γ^Αγ^χΖ [i J I ^N^N^O I Example 21-15. z / )—z 5 v y \\ / / I —z \ \ z Example 33-11. F F^T xRj II Z- NH ΓΝ^ N'Y^^T^7 u X L N N^O I Example 22. / =z 'r\) Z Λ—z J \\ A I —z / / o \—\ \\ o Example 33-12. / =z\ z / >— z 3 v y A T —Z / / oz 2— '--Wk / / xn o ° nozrcn / zznz / q / υιλι Example 23. Z / >—z vJ # T —z \ Ό \--v 7^ω=ζ w I O Example 33-13. I I o o ω—\ '—( o I__________________________________________________________________________________________________________________________________________________________________________I co Example 23-1. F fAq F I NH NH < S^° Λ Λ Λ ^'N^'N^O I Example 33-14. F F^O F^y 0 •v ' ''' NH H γ-Ν N^Y^YfS^ / li I I ^N^N^O I Example 24. ti / =zx r~X / ) Z. Λ—z v—J \\ / / T —Z A o \— 7— m-z. w o Example 33-15. F F^Y 0 xC NH H r-N N^Y^Y^ / [i 1 1 ^N^N^O 1 Example 25. “Π \--TI / =zx r~\ / ) Z Λ—z J \\ / / I —z / 7 o \< w O Example 33-16. o o.ii Wi \ / ° \ Z— T / λ 6? z\ z YY„ LL-- / LL LL nozrcn / zznz / q / υιλι Example 26. F Λ Me 'NH N N iCl 0 I Example 33-17. / =z\ z / )—z 3 v y 0 / / I \ — Z \ # 0 / 7--\ z \= / ° / A ΙΓΟ o Example 26-1. F F^y ΉΗ 0 VU I Example 33-18. ^nh2 A'S 'e‘ NH I^A=O η I I I Example 26-2. 0 o=¿ o \ z~ I #0 Λ-λ Z—y \ Va z= / Example 33-19. nh2 J.ÍR) p ZNH i^^S=O H J I I Example 26-3. F ρΛΟ F^y 0 OH I Example 33-20. I I TI TI \--TI / =zx z Λ— z v y y # I —z / / O )---y O O I________________________________________________________________________________________________________________________________________________________________________________________________I nozrcn / zznz / q / υιλι Example 26-4. / =z wT? Z / )—z '—J \\ # T —Z / 7 o VzpYo Example 33-21. I I o o ω '—\ / ° Hy 2—z z=z LL—( LL I________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________I co Example 26-5. F f γ '''\h 0 Example 33-22. 7=z\ MA z Λ—z 3 V : 7 \\ / / I —Z / 7 o \< / -O Example 26-6. F F^f 'x'XNH 0 I Example 33-23. I I o x / / Q.—\ \—( p \ z — 7—λ £· Z—7 Z z= / LL—¿ LL I_________________________________________________________________________________________________________________________________________________________________________________________________I Example 26-7. / =z zA? Z / )—z vJ \\ / / T —z \ O A© ρ Example 33-24. F F^y NH2 A '''' NH A'S^O ° H I I I nozrcn / zznz / q / υιλι Example 26-8. F ''Ά 0 νλλ N N 0 0H Example 33-25. / A A< 1 —z 2 q / / —\ A Example 26-9. F ρΛΟ 0 J A A ​​I Example 33-26. / =zx aO Z Λ—Z 3 v 7 \\ / / T —z oz 2—\ Example 26-10. TI / =zx '^C) z / )—z v—y # I —z \ o / =0 —z \ z Example 33-27. 1 O 1 0^7 —( o \ z— f / ó? z—7 ~z. 2—% z— / LL—¿ LL 1_________í___________________________________1 Example 26-11. F ρΛΑ f^A Ah 0 AA I Example 33- 28. / =z\ A-C# \\ / / T —z \ q / / —\ ó / so Example 26-12. Π \--TI / =zx Z / )—Z J \\ / / T —Z / 7 oz 2=0 0 Example 33-29. I I TI τι 2—TI / =z\ z / >—z 3 v 7 2 1 —Z / 7 o 1_________HE?____________1 Example 26-13. F F^T '''XNH 0 Example 33-30. o o=w—, „ <\ P i \—7 \ z— r--λ y---Z z= / u_—ς u_ Example 26-14. F F^T Λ o. ''' NH 0 / / I Example 33-31. Or 0=7)—. — \ 3 / P τ \—7 \ z Λ 2 νΛ^^ζ= / u_—ς ir Example 26-15. F F^T X’^NH 0 Example 33-32. F pyo F y? v'-sk i τ Gil N N 1 1 nozecn / zznz / q / υιλι Example 26-16. F F^J ΉΗ 0 n r° Example 33-33. F F^Q F z®> Ί i Q X N N O I oo Example 26-17. F f^ ®‘^NH 0 ¥λνλοΗ·η Example 33-34. I I TI \—“Π Y?- o 2— / ^-( / )=0 \\ o I________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________I Example 26-18. F f y ®'^NH 0 I Example 33-35. TI ΊΊ \--TI / =z, h® / —Z # o \— / ^ω=ο \\ o Example 26-19. F F^O ÚX® I Example 33-36. I I o \\ ο=ω^ V\— / o \ z— Γ--Λ Q? / --7 Z # \= / I__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________I nozrcn / zznz / n / υιλι Example 26-20. F fX f^Z ZNH 0 n^XX / II X 1 1 N N^O 1 Example 33-37. / =a χΧΧ γχ* —z O \\ A ω=ο \\ o Example 26-21. boz p \ z— I ZZ r—λ z (χζ z= / Example 34. F X f^Z ^Z X X i X i 1 Example 36. F fX F^y o 'Xh [ NCJ J u J X ^N^N^O 1 nozrcn / zznz / q / υιλι Example 26-24. F FXn F T ' Z °x '' NH 0 \ CcZ I Example 36-1. ti ^n / =^ Xy# Z / )— z J # I — \ y 2 λ—Y o o xZ Oz o Example 26-25. / =\ ζχ / Z / )— z vJ \\ / / T —z / 7 ό i Cj..... Example 36-2. F FXn F^Y [(R) '' nh y | N [i I I ^N^N^O I Example 26-26. Z^z z-O oZ o \ z— i XX Λ-Λ 2—(Z Z (yx z= / U-—( LL Example 36-3. ΤΊ / =zx Z / >— Z 3 V 7 Y / / I — / Z o yl 'z 7^° Example 26-27. F F^y ''''^NH 0 coy Example 36-4. TI ΤΊ \—TI / =z\ yy i —zz o -O / / O nozrcn / zznz / q / υιλι Example 26-28. F f^Z ''''^NH 0 \ΛΝΛΟ N I Example 36-5. F ρΛΟ n Me NH r-N H I I ^N^N^O I Example 26-29. Z z '---' / / I —z \ O / =o Z \ z Example 36-6. / =z\ z / )—z 3 v y \\ / / I ~z^ # ^z o7 II O Example 26-30. / =\ z / )—z J \\ # I —z \ Ό )=O £p Example 36-7. Π / =z\ z / >—z -S v y / / T ~Z\ χζ o yC Z\ / O Example 26-31. / =z\ Z Λ—z v7 \\ / / T —z \ a ,—z zZ ) Example 36-8. / =^ z=r-C# z / )—z 5 v_y y I ~Z\y χζ O y—\ x I I o nozrcn / zznz / q / υιλι Example 26-32. F F^Y ''Άη 0 nAa / Aa [i A A i n n— N N OM / I Example 36-9. Π \—TI z / )—z 5 v_y \\ / / I — / Z O VA \^z 'x0 Example 26-33. F fA ''' ^NH 0 coA Example 36-10. F ρΛΑ FA N '' NH η A 1 nnA 1 Example 26-34. F '''Ah or Example 36-11. TI / =z\ z / >—z 3 v y T Μ Z Example 26-35. Π}—TI f=\ -ζ. Λ— z v—y y# 1 —Z / 7 o7 Ao A Example 36-12. 1 1 / ° τ AA ^z= / 1_________í______________________________________1 co Example 26-36. F f^ ''' ^NH 0 I Example 36-13. / =zx OhCA Z / )—Z 5 V_7 \\ / / I —Z \-7 / Z oz Example 26-37. F F I I ,Λ o. '' NH O X úcCó I Example 36-14. O II / —ω=ο p -zP / / —\ \ z~ x Lí / / —X £ z—7 z z= / Example 26-38. / =zx τχχ \\ / X —Z 2 Ό 2=0 o X' ​​o o Example 36-15. I I / =z\ LrO Z / )—z 3 V 7 / / F pLn n^n Λ HN λ nh o y-N OH I Example 36-16. ΤΊ Ti TI / =z\ 'hO \\ / / X —z \ a LOO Lo nozrcn / zznz / q / υιλι Example 26-40. F f^ ''''^NH O ΧΛ Y i Y 0 Example 37. F FXn F^Y F fY Ύη 0 'N^'N^O 0H 1 Example 38. F ÓQ II O F .-Y I '''' NH í^N^^ NAxY^ H J [ N n Y 1 Example 26-42. F f7o ''’^ΝΗ 0 ya Example 39. Xzx zrO z Λ—z 3 v_y Ύ< 1 —Z / / OZ \--y F Y F^^í ''' ^NH O νΧχΥνΧ N N O XX 1 Vo Example 40. z X -n z Xz 2 v y \\ / / I —Z # O \—< II υ O Example 26-44. / =zx z χζ v—7 \\ / / I —z 2 O <y ejemplo 41. z m í="\" ^a x>Z / >—z 5 V_7 \\ / / I —z β Ό \—\ ¿T° Example 26-45. F Fl >'ANH 0 óV’a NV / 0H I Example 41-1. z v / =zx Z Xz ¿2 V_7 Va 1 —z \ C» \—\ '— Example 26-46. F FVn f^ 0 0 ΝΑΖγΑΑΑ i X <n i ejemplo 26-47. f ρλπ f^="\" ''''^nh 0 a°\ ☆χδ 43. 1ί ή φζ f="\" ) hxa>< —Z ?7 \ / y_7 z 7 \ ° 2—L >° nozrcn / zznz / q / υιλι Example 26-50. Example 26-51. Example 26-52. / =zx zt / z A—z 5 v_y \\ / / I —Z 7 o i ,.z w o Example 48. F 1 1 NH F íJ o o Me''' NH y'N'^ nAzvAZ h 1 1 ^N ^N^O 1 Example 27. 0 Me NH N ^^N^N^O 1 Example 49. F f'Sz F^l NH ' ΪΗ nA / ^K7 Gil N N ^0 1 00 Example 28. o w Ο=ω ^ \ / X \—^0 / 0 \ z— z z= / Example 28-1. / =zx r\ / ) z 7— z vJ \\ Z I —z ° 07 \ 1 \ / '—z Example 51. 1 1 o ___ \ x_,^cn \ ^u. V_z\ / ° \ z— x / 71' 7—λ ? 2-( / Z LL-- / LL 1_________í_____________________________________1 nozrcn / zznz / q / υιλι Example 28-2. X—i YA P o \—7 x A \ \ — τ JA Λ—Λ 2—<7 Z Οχ A Example 51-1. F ρΛΟ and Άκ) 1 E ? ú \ 1 1 Example 28-3. / =\ OXA Z / >—z —7 \\ / / X or Y—, II O O Example 51-2. F F Ά I i Ότ ü J L N N^O 1 Example 28-4. F ρΛΟ θ H \ [ N N^O I Example 51-3. 1 1 —o \—κ o ζ=ω—χ Υχ O ry~ / r~\ S / —z z= / 1_____________A__________________________________________1 Example 28-5. / =zx HO Z / )—z y A / / X —z \ ° ογΧΑ T I M / Example 51-4. F F XQ j° F Ά ^¿° 1 F\l i H 1 1 N N^O 1 nozrcn / zznz / q / υιλι Example 28-6. TI Z / )—Z vJ \\ I —Z / 7 ° 07 \ I / ) / / u O Example 51-5. I I "Π \--TI O V—X ^ω=ζ o '— I I Example 28-7. TI 2—TI / =^ z / >—z 3 V 7 / / I o Y W;n II υ o Example 51 -6. TI 2—"Π / =^ —z 2 O / ^Λ ω=ζ \χ \ o '— Example 28-8. F F^| o Me'' NH ^xN^~'Me i H04 j H 1 1 N^N^O Me Example 52. / ^Z\ z / )—z 3 V 7 / / T —z 2 oz h -n \ ω ' \ \\ \ o Example 28-9. F F2o Y f^T v / NH 7 hoJ \ |l 1 1 1 Example 53. / =z\ z / pz 3 V_7 \\ y i / O-z 2 o \ Example 29. F F f ° '' NH r S'ü íVyV ^N^N^O I Example 54. .—z pA o \ z~ T #0 f / —λ £ z—V z z= / Example 29-1. / =z\ \\ / / I —z p a ^z Example 54-1. I I z / ° e z—z z= / l _______________________________________________________________________________________________________________________________________| co Example 29-2. TI 2—Ή / =zx ~Z. / )— z J 0 # T —z p >° Example 54-2. I I .o / ° \ #0 f / --0 Q? 2-(7 Z y 2-\ 2= / I_________í_____________________________________I co Example 29-3. TI / =z\ Z / >—z —y \\ / / I —Z / 7 '—z Example 54-3. F F^ l ' ' NH V7—\ A o N \__ / η J I ^N^N^O I nozrcn / zznz / q / υιλι Example 29-4. Z / )—z vJ \\ / / z —z β \—\ o VA '—z Example 54-4. 7=z\ A-Ο z / )—z 3 Y 7 Y / / T —z \ °7 ''z' Example 29-5. Z / >— z y Y 7 Z —Z / 7 θ -ny \ Example 55. F F mo N F^^ o λ Ar? A ΖΛ Me 'NH A^n^^ h I I ^N^N^O I Example 29-6. Ο=ω=θ z^ / \ / ° \ z~ z Ay / 7 λ Z—7 z / A= / LL·—¿ LL· Example 56. । . । \\ 7 i ~ Αλ o A—·'1 Ο=ω^ w Z^\7 1________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________1 Example 29-7. F f^A 0 r 1 1 r-s=0 Y' NH < T fJ \ ν^ΑΑΑγ^^ H J 1 N^N^O 1 Example 56-1. TI / =^ aO z / )—z 3 Y_7 \\ 7 z —z \ z—<Ί nozrcn / zznz / q / υιλι Example 29-8. o II Ο=γ γ / O i f,—λ ? zZ Example 56-2. I I TI / =χ zxx z / >—z 3 v_7 \\ / / ΞΓ —Z 7 z—<Ί I_______________________________________________________________________________________________________________________________________________________________________________________I Example 29-9. F ρΛχχ F^l NH F / --\ I Example 56-3. Λπ θγ A J ''<N F r \ z NH / \ N N 0 I co Example 29-10. I I vp .o / z\ ° ^xx I O LL I__________________________________________________________________________________________________________________________________________________________________________________________I Example 56-4. \\ 'ω=ο u—K o \ z~ ^^^z \=y^\ ^XX LL Example 29-11. F ρΛπ f^ líR) ' NH F N V s=0 H J I ii 0 I Example 56-5. fXx Ί XX z NH F n^^yvA'oA II S U ii N N^O N 1 V nozrcn / zznz / q / υιλι Example 29-12. o II / —ω=ο / ° z (xx 2= / LL I__________________________________________________________________________________________________________________________________________________________________________________________I Example 57. TI \—ΊΊ Z / >—z 5 V_7 \\ / / T — Z y O χ— -π z-^ 4 Example 29 -13. z Λ— z 3 v 7 \\ / / I —Z / 7 c> ^z^ Example 58. F ρΛχ F^l X N NH N ΧχΧχ U AL .k ii N N O O \ / I Example 29-14. F ρΛΟ Fzy c' NH F II X F F Π Χί °y Jl J ·>Ν F rs\ ,χ —X ''c NH / \ H J I \\ N N^O N I nozrcn / zznz / q / υιλι Example 30. F FV| f^Z Ah Occc I Example 58-3. 1 1 - O XL Example 31. A / Z / >—z vJ \\ / / T — Z Y ° zy \ T ( \ hJ \ / Example 58-4. F ρΛΰ Λ F r-s>0 | NC\ / / Z n H 1 1 1 Example 31-1. / =z\ zzTA Z / >—z J \\ # T —z p ° A \ T / \ re \ / ^ω=ο w O Example 59. 1 ? A ω- ζ o z^ \_ / / 7 γ— T Zv i________________________________________________________________________________________________________________________________________________________________________________________________1 co Example 31-2. z z—< p z \—7 17 z— T / A f / —λ £ 2—7 z Y / ~Z z= / Example 60 . / ^z\ z-O z / )—z 3 v_y \\ / / I —Z / 7 G> \---y '—ω=Ο z\ z^2 θ nozrcn / zznz / q / υιλι Example 31-3. / =zx zzb / 7 z Λ— z 5 v_7 \\ / / T / \ ^-z / )_ Φ Φ ΜΗ o y—v o Υω. iro o Example 61. TI \—TI / =z\ z Λ—z 3 v 7 / / I —z X z-^ c / oA—7 / O—7 Χ Example 31-4. o II O=W-^ / \ / ° Z \—7 ^ / / \ xy z— i M λ—λ £ z—<7 z ξ / ~A z= / Example 62. F F y .γ 7 NH I ,—. ApX kN^N^O I Example 31-5. F 0 ' T UR) —S = O nh f h2nJ \ νΗυμ^ H J I N N^O I Example 63. o. / ? ω— \ / O \ Z— r AA 7 ó? z Y7 z A / —Y z Example 31-6. Mzx / Ty# z / )—z 3 v 7 \\ z —z )z \ / Z y—\ z o V). cT° Example 64. I I TI \—-Ti / Y X ° b / / z O I__________________________________________________________________________________________________________________________________________________________________________________________________________I co nozrcn / zznz / q / υιλι Example 31-7. F F^Y ,γ θ NH r-S-° T h2nJ \ ΝΑγΥ / \ / |l I I I Example 64-1. / =\ ’My) z / )— z 3 X:__7 \\ 7 τ —z \ O )--\ ω=θ \\ z—<Ί Example 31-8. F pyo F^y \h r-s-o T h2nj \ nA / Wx7 η I I ^n^n^o I co Example 64-2. / =z\ z Λ—z 3 v_7 \\ / / I —z 2 ° Üx / / z o Example 31-9. ΤΊ \—TI í=\ z / )—Z 3 V_7 / / I —z Λτ λ—7 z Z zO ar / xo Example 64-3. o 'W—< —¿ o \ z / / —λ £ zXz z Z= / Example 31-10. F pyo r o NH KN^N^O I Example 65. I I z~ P~ ζΡΓ^—^~ \\ 7^ I "ZO c> Λ Ο=ω^ w Ζ--Χλ \ζ·Ο ι_____________r_______________ι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι Example 32-3. / A Aa / Z / )—z vJ / / I —z \ —\ o~- o / A '—z Example 68-2. I I O ^-«=Z Example 32-4. / =\ z / >—z v—y \\ / / z — Z 2 \—\ o— o VX ^ωχ ó''o Example 68-3. F f>A] a F^l N\T .A / I ° Λ~~α N -VAy J H I I I Example 32-5. 'r\) Z Λ—Z n^AVA— / 'o I co Example 32-6. ^7° C / 3 - o A / \ / ° —° va \ z— I / A n—λ ó? z—7 z ξ z= / Example 70. F ρΛΟ f^A^ I (R) H ] WNx[^ H I I I nozrcn / zznz / q / υιλι Example 32-7. F F Y' | 0 Me' NH I Λ || N ΥΓ ®Y V h J I I Example 71. F Fto F^Y 0 l (R) , K JL °jO H I I I Example 32-8. S Λ / Ή í=\ / A z> z Λ—z 3 v 7 \\ / / X —Z 2 ^r \o— o jy z I Example P-1. or LL—ζ LL / Example 32-9. Π \—TI / =\ z / )—z 3 V 7 y / / X —z / ) o \\ z^o Example P-2. F ρΛΟ ft Μθ7ΉΗ f^° 0 > N ®Y Y7 Ά. N N I Example 32-10. / =zx z Λ— z 5 v_7 y 7 x —z 2 2—7o— o yL Z .o ωζ / o Example P-3. F ΡΛχ F^l Me''' ΉΗ ι^Ό / L zN. J H ΪΙ M γ-γ N N 0 oJ | nozrcn / zznz / n / υιλι Example 32-11. Z / )—Z 3 V_7 y y i —z y X \o— or Example P-4. O ^Z O u-—ς 'j. Example 32-12. z^ / )—zy^X^\\ y z —z \ X \o— o yz '—z i cX Example Q5. F FXn F X / z Me' NH K N A J N W χχι Z^N^N^O 1 Example 32-13. F o X I A / CK X °X J n ZzZZ ú I I I Example P-6. F FXn Mec>' ΉΗ J n y y ho. X A A N N 0 1 Example 32-14. F fXc F^V 0 e'Z JL '' NH N i χΆ N ZZ H H 1 1 ^N^N^O 1 Example P-7. o '—Z O _y ' 2 7 LL—( LJ- IZ LL \ nozrcn / zznz / q / υιλι Example 32-15. Ξ Λ / Ή <0 / / =\ f=\ y Z / )—Z -5 V__7 \\ y I —z \ o— oz Y ^z x° Example P-8. F FZn Me'-<NH X° X / N. J A A ​​X ^^N^N^O H Example 32-16. o \ / / Ox z^\ o —° γχ X Z~ i zz f,—λ Ó? Z —x z \ y--Z= / LL— / LL Example P-9. D ^z o σ )—( Φ ' ll—ς 'j_ Example 32-17. F fZz X I NH I r- N Γ 0,,l \ Ν^χΧ / o )-----( x LL--ζ 'J- Example 32-18. Π λ--TI / =\ ζΧχ Z / >—z 3 V_7 \\ y I —Z # Z \o— C> i X z^ Xz Example P-11. 1 o „ P: LL--ζ 'J_ nozrcn / zznz / q / υιλι Example 32-19. F FZ V ''' NH I r—N 7 ) νΖ^ζζΖΖ / H I I ^N^N^O I Example P-12. z— \—Y O \ z— )----( L^ / Y z Example 32-20. F ρΛΖ f^Z 0 ZW' ^N^N^O I Example P-13. F ρΛΖ F^^Z Me 'zNH ΓζΖ7° ^nZ tiZ ^N^N^^O I Example 32-21. TI / =zx A} z λ— z 5 v_y z# z O V >° Example P-14. GEg.^^^NHs ΊΓΎ Me '' ^NH Z^NH N^ZZZr^^ Λ A 15. CF3^^ M '''^NH ZZh ^N^N^O I nozrcn / zznz / q / υιλι Example 32-23. / A ΑγΧ Z / )—Z 5 V__( / \\ / / I —z β \—\ P— o 3 / Π νζγ° Example P-16. cf3.^^nh2 |ΓΎ Mec'' ΉΗ A^NH N A A Z / )—z J Aτ —z z A Example 32-25. z^ P —o \—y \ z— τ O f / —λ ? 2—V 2 ξ / ~Az 2= / ll—ς ll Example P-18. Z—X '—V o \ z— τ Αχ Λ—λ Z AH Ll—ζ 'j_ 2 Example 32-26. z / )—z 5 v y \\ / / T —Z λ Λ—\ o z Example P-19. ^Z—< \—y O \ z^0° I Λ—λ 2 A Z A A LL—¿ LL LL nozecn / zznz / q / υιλι Example 32-27. / =zx Z / )—Z 3 Y_7 \\ / / X —z \ °~\l O w ° O Example P-20. Π 2—Ή tí Example 32-28. ζ—χ "-S' Ή \ 00 / o —Ó \ z X f,—X ? 2X7 Z L 2= / LL--( LL Example P-21. 2 / )—Z '--7 ^Z L \\ 1 0 H ^z nozrcn / zznz / q / υιλι Note: Any compound shown in parentheses in Table A above and elsewhere herein indicates that the compound is a diastereomer, and the absolute stereochemistry of that diastereomer may not be known. The present description provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers and tautomers thereof, selected from the group consisting of compounds of Compilation 1: Compilation 1: Certain Compounds of the Present Invention nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι The present description provides a compound, and pharmaceutically acceptable salts, solvates, submersions and tautomers thereof, selected from the group consisting of compounds of Compilation 2: Compilation 2: Certain Compounds of the Present Invention nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 102 nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 104 nozrcn / zznz / q / υιλι 105 106 107 nozrcn / zznz / q / υιλι 109 The present description provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers and tautomers thereof, selected from the group consisting of compounds of Compilation 3: 110 Compilation 3: Certain Compounds of the Present Invention nozrcn / zznz / q / υιλι 111 nozrcn / zznz / q / υιλι 112 nozrcn / zznz / q / υιλι 113 nozrcn / zznz / q / υιλι 114 nozrcn / zznz / q / υιλι 115 nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 117 nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 120 nozrcn / zznz / q / υιλι 121 nozrcn / zznz / q / υιλι 122 nozrcn / zznz / q / υιλι 123 nozrcn / zznz / q / υιλι 124 nozrcn / zznz / q / υιλι 125 nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 127 nozrcn / zznz / q / υιλι 129 nozrcn / zznz / q / υιλι 130 nozrcn / zznz / q / υιλι 131 nozrcn / zznz / q / υιλι 132 nozrcn / zznz / q / υιλι The present description provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers and tautomers thereof, selected from the group consisting of compounds of Compilation 4: Compilation 4: Certain Compounds of the Present Invention nozrcn / zznz / q / υιλι 134 nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 136 The present description provides a compound and its pharmaceutically acceptable salts, solvates, stereoisomers and tautomers, selected from the group consisting of compounds of compilation 5. One skilled in the art can prepare them using conventional methods, including adaptations of synthetic methods described herein . 137 Compilation 5: Certain Compounds of the Present Invention nozrcn / zznz / q / υιλι 138 Methods for synthesizing the described compounds The compounds of the present invention can be made by a variety of methods, including standard chemistry. Suitable synthetic routes are described in the schemes given below. 139 Compounds of any of the formulas described herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following schemes and synthetic examples. In the schemes described below, it is understood that protecting groups for sensitive or reactive groups are used when necessary according to chemistry or general principles. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, third edition, Wiley, New York 1999). These groups are removed at a convenient step in the synthesis of the compound using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and the order of their execution, must be consistent with the preparation of compounds of any formula described in this document. Those skilled in the art will recognize whether a stereocenter exists in any of the compounds of the present disclosure. Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds, but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereoisomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. The resolution of the final product, an intermediate product or a starting material can be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by EL Eliel, SH Wilen and LN Mander (Wiley-interscience, 1994). Preparation of the compounds The compounds described herein can be manufactured from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes. The compounds of the present invention can be prepared in various ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, appreciated by those skilled in the art. These methods include, but are not limited to, the methods described below. A general synthesis of substituted (4-aminoprído[2,3-d]pririmídin-7(8H)-one or analogous heterocycles is described in Scheme 1. 6-bromo-4-chloropyrid[2,3-d]pyrimidin-7(8H)-one (1-1) can undergo nucleophilic aromatic substitution with an appropriately substituted benzyl amine (G-1 ). The bromide substituent in the resulting intermediate I-2 can be used for cross-coupling reactions with appropriately substituted alcohols, amines, amides, alkyls, olefins, aromatics or heteroaromatics. 140 Scheme 1: A R a · R Cl NH,. G-1 NH N Br N Br R,. N N 0 SnAr R,. N N O R. R , 1-1 I-2 A—R NH A N R, N N O R . Yo Alternatively, the final compounds with a nitrogen substituent in the 6-position (bromo) can be prepared from 6-amino-4-chlorondo[2,3-d]pyrimidin-7. (8H)-one by alkylation or acylation to provide type I-5 intermediates, which can undergo nucleophilic aromatic substitution with an appropriately substituted benzylamine (G-1) to provide the final analogues I according to Scheme 2. Scheme 2: O a and a: c o a :iiac on Cl N N NH R, N N O R? N N R, R I 4 1-5 A ' R A • R R; NH. N G-1 NH R. R; ___________ N SnAr N R 0 R. N N C R. The building block G-1 can be prepared as described in Scheme 3. Appropriately substituted aryl or heteroaryl bromides G-2 can be transformed into the corresponding acetyl hetero)aryls G-3 by metal halogen exchange, followed by the addition of an acylating agent. The ketone functionality can be stereoselectively transformed to the chiral amine using the Ellman method. Scheme 3: G-2 G-3 G-4 G-5 G-1 Therapeutic use Due to their biological properties, the compounds of the present description, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and salts of all forms 141 mentioned above may be suitable for treating diseases characterized by excessive or abnormal cell proliferation, such as cancer. For example, the following cancers, tumors and other proliferative diseases can be treated with compounds of the present description, without being restricted thereto: cancers / tumors / carcinomas of the upper respiratory and digestive tracts: for example, tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gingiva, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pillar, palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); infraocular cancers (eg, uveal melanoma) and orbital and adnexal cancers; lung cancers / tumors / carcinomas: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), lung cancer small cell cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer); mediastinal neoplasms: for example neurogenic tumors (including neurofibroma, neurilemmoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma) thymic tumors (including thymoma, thymolipoma , thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma), astrocytoma (brain , cerebellar, diffuse, fibrillar, anaplastic, pilocytic, protoplasmic, gemistocyte), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomomas, ependymomas, ependimoblastomas, choroid plexus tumors, medulloblastomas, meningiome , hemangiopericitomas, neuromas, ganglioneuromas, neuroblastomas , retinoblastomas, neuromas (eg. e.g., acoustic), tumors of the vertebral axis; cancers / tumors / carcinomas of the gastrointestinal tract (Gl): for example, tumors / carcinomas / cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), for example, childhood HCC, Fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, tumor of Klatskin), the gallbladder, the extrahepatic bile ducts, the intestine 142 small intestine (including duodenum, jejunum, and ileum), large intestine (including cecum, colon, rectum, and anus; colorectal cancer and gastrointestinal stromal tumor (GIST)), genitourinary tract (including kidneys, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), hypernephroma, Grawitz tumor; ureter; urinary bladder, e.g. urachus cancer, urothelial cancer; urethra, e.g. example, distal, bulbomembranous, prosthetic; prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis); cancers / tumors / carcinomas of the testicle: for example, seminomas, non-seminomas; gynecological cancers / tumors / carcinomas: for example, tumors / carcinomas / cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); breast cancers / tumors / carcinomas: for example, breast carcinoma (infiltrating ductal, colloid, invasive lobular, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), HER2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast; Cancers / tumors / carcinomas of the endocrine system: for example tumors / carcinomas / cancers of the endocrine glands, thyroid gland (papillary, follicular, anaplastic, medullary thyroid carcinomas / tumors), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (carcinoma / adrenal cortical tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma , VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; soft tissue sarcomas: for example, fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of the tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, soft alveolar partial sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas of bone: for example, myeloma, reticular cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parostic, periosteal, high-grade surface, small cell, induced osteosarcoma 143 by radiation, Paget sarcoma), Ewing tumor, malignant giant cell tumor, adamantinoma, histiocytoma (fibrous), fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma ; mesothelioma: for example, pleural mesothelioma, peñtoneal mesothelioma; skin cancers: for example, basal lymphocyte carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma (including cutaneous, superficial extension, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer; neoplasms of the peripheral and central nervous system and the brain: for example astrocytoma (cerebral, cerebellar, diffuse, fibrillar, anaplastic, pilocytic, protoplasmic, gemistocytic), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas , meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g., acoustic), spinal axis tumors, neurogenic tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma , neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma , mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma); lymphomas and leukemias: for example, B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MOL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt lymphoma (BL), Burkitt leukemia, T cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), leukemia / lymphoma (ATLL), cutaneous lymphoma lymphocytic leukemia B-cell lymphoma (B-CLL), T-cell chronic lymphocytic leukemia (T-CLL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL) ), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte predominant HD (NLHDN), nodular sclerosis HD (NSHD), mixed cell HD (MCHD), classical lymphocyte-rich HD, lymphocyte-depleted HD ( LDHD), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous / myeloid leukemia (AML), acute lymphocytic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), 144 hairy cell leukemia, chronic myelogenous / myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), JMML (juvenile myelomonocytic leukemia), acute ambiguous lineage, myeloproliferative neoplasms, blastic plasmacytoid dendritic cells neoplasm, early T-cell precursor leukemia, early T-cell precursor leukemia, natural cytotoxic lymphocyte leukemia / lymphoma, myeloid / lymphoid neoplasms with eosinophilia, myeloid sarcoma, transient abnormal myelopoiesis; and cancers of unknown primary site (CUP). All of the above-mentioned cancers / tumors / carcinomas that are characterized by their specific location / origin in the body are understood to include both primary tumors and metastatic tumors derived from them. All of the cancers / tumors / carcinomas mentioned above can be further differentiated by their histopathological classification: epithelial cancers, for example, squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cells, ductal, small cells, signet ring cells, spindle cells, clear cells, oat cells, colloid, adenosquamous, mucoepidermoid, cystic adenoids), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, cell carcinoma small, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; and non-epithelial and mesenchymal cancers, for example, sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed neoplasms and undifferentiated carcinomas. The compounds of the present disclosure can be used in therapeutic regimens in the context of first line, second line or any additional line treatments. The compounds of the invention can be used for the prevention, short or long-term treatment of the diseases mentioned above, optionally also in combination with radiotherapy, and / or surgery and / or other compounds. Of course, the above also includes the use of the compounds of the present description in various methods of treating the above diseases by administering a therapeutically effective dose to a patient in need, as well as the use of these compounds for the manufacture of medications for the treatment of such diseases, as well as pharmaceutical compositions that include said compounds of the invention, as well as the 145 preparation and / or manufacturing of medications that include said compounds of the invention, and the like. Additional methods of use of the described compounds One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject an SOS1 inhibitor of the present invention, or one of its pharmaceutically acceptable salts, solvates, hydrates, tautomers or isomers. . Another aspect of the present description relates to a method for treating or preventing a disease that is affected or characterized by the modification of the interaction of SOS1 and a protein of the RAS and / or RAC1 family in a subject in need thereof. The method involves administering to a patient in need of treatment for diseases or disorders associated with SOS1 modulation an effective amount of a compound of any formula described herein, or one of its pharmaceutically acceptable salts, solvates, isomers, prodrugs or tautomers. . In certain embodiments, a method is provided for inhibiting the interaction of SOS1 and a RAS family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of any formula described in the herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier. In certain embodiments, a method of treating or preventing cancer in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of any formula described herein, or a salt, solvate, hydrate, tautomer or isomer of this. In certain embodiments, the disease may be, but is not limited to, cancer. In certain embodiments, the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, JMML (juvenile myelomonocytic leukemia), acute lymphoblastic leukemia / lymphoma, lymphomas, tumors of the central and peripheral nervous system, epithelial and non-epithelial tumors and mesenchymal tumor, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, cell carcinoma squamous cells of the upper respiratory and digestive tracts, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas. In some embodiments, the cancer is a colorectal cancer or a pancreatic cancer. In certain embodiments, the disease may be, but is not limited to, cancer. In certain embodiments, the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, 146 melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, ladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the respiratory and upper digestive tract, diffuse lymphocytic lymphoma large B, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcomas. In certain embodiments, the disease may be, but is not limited to, RASopathy. In certain embodiments, RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), arteriovenous malformation-capillary malformation syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome and Hereditary Gingival Fibromatosis. Another aspect of the disclosure relates to a method of inhibiting SOS1. The method involves administering to a patient in need thereof an effective amount of a compound of any formula described herein, or one of its pharmaceutically acceptable salts, solvates, isomers, prodrugs or tautomers. The present description relates to compositions capable of modulating the activity of (for example, inhibiting) SOS1. The present description also refers to the therapeutic uses of said compounds. The described compound can be administered in amounts effective to treat or prevent a disorder and / or prevent the development of a disorder in subjects. Another aspect of the present disclosure relates to a compound of any formula described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, for use in the treatment or prevention of a disease that It is affected by the modification of the interaction of SOS1 and a protein from the RAS and / or RAC1 family. Another aspect of the present disclosure relates to a compound of any formula described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, for use in the treatment or prevention of a disease that It is characterized by the inhibition of the interaction of SOS1 with a RAS family protein or the interaction of SOS1 with RAC1. Another aspect of the present disclosure relates to a compound of any formula described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, for use in the treatment or prevention of a disease. , where the treatment or prevention is effected or characterized by the inhibition of the interaction of SOS1 and a RAS family protein or by the inhibition of the interaction of SOS1 and RA. Another aspect of the present description relates to a compound of any formula described in 147 herein, or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers, for use in inhibiting the binding of hSOS1 to Η- or N- or K-RAS including its clinically known mutations that inhibit the reaction of nucleotide exchange catalyzed by hSOS1 in the presence of a concentration of 20 μΜ or less, but which are substantially inactive against EGFR kinase at concentrations of 20 μΜ or less for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder . Another aspect of the present disclosure relates to a compound of any formula described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, for the manufacture of a medicament for use that inhibits binding. of hSOS1 specifically to the K-RAS G12C protein or another Ras mutant, as described herein, and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 μΜ or less, but which are substantially inactive against EGFR-kinase at concentrations of 20 μΜ or less for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder. In another aspect, the present disclosure relates to the use of a compound of any formula described herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof, in the manufacture of a medicament for treating or prevent a disease. Administration of the described compounds can be achieved through any mode of therapeutic agent administration. These modes include systemic or local administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration. Likewise, they can also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously or intramuscularly, and all of them using forms well known to those skilled in the pharmaceutical art. Depending on the intended mode of administration, the compounds or pharmaceutical compositions described may be presented in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, extended-release capsules, elixirs, tinctures, emulsions. , syrups, powders, liquids, suspensions or the like, sometimes in unit doses and in accordance with conventional pharmaceutical practices. Illustrative pharmaceutical compositions are gelatin tablets and capsules comprising a compound of the description and a pharmaceutically acceptable carrier, such as a) a diluent, e.g. e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, 148 cellulose, sodium, saccharin, glucose and / or glycine, b) a lubricant, e.g. e.g., silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol, also for tablets, c ) a binder, e.g. e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or alginate sodium, waxes and / or polyvinylpyrrolidone, if desired, d) a disintegrant, e.g. e.g., starches, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt or effervescent mixtures, e) absorbent, colorant, flavoring and sweetener, f) an emulsifying or dispersing agent, such as Tween 80, Labrasol, HPMC , DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier and / or g) an agent that enhances the absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. Liquid compositions, particularly injectables, for example, can be prepared by dissolution, dispersion, etc. For example, the described compound is dissolved or mixed with a pharmaceutically acceptable solvent such as water, saline, aqueous dextrose, glycerol, ethanol and the like, to form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles or whey proteins may be used to solubilize the described compounds. The described compounds can also be formulated as a suppository that can be prepared from fatty emulsions or suspensions, using polyalkylene glycols, such as propylene glycol, as a carrier. The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids with cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of the drug to form a lipid layer that encapsulates the drug, as described, for example, in Pat. No. 5,262,564, the contents of which are incorporated by reference. The described compounds can also be delivered using monoclonal antibodies as individual carriers to which the described compounds are coupled. The described compounds can also be coupled with soluble polymers as target drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspanamidaphenol or polyethyleneoxidepolylysine substituted with palmitoyl residues. Likewise, the described compounds can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyepsilon 149 caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and antipathetic or cross-linked block copolymers of hydrogels. In one embodiment, the disclosed compounds are not covalently linked to a polymer, e.g. e.g., a polycarboxylic acid polymer or a polyacrylate. Injectable parenteral administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid before injection. Another aspect of the present description relates to a pharmaceutical composition comprising a compound of the present description and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, diluent or surfactant. The compositions may be prepared according to conventional mixing, granulation or coating methods, respectively, and the pharmaceutical compositions herein may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1%. to approximately 20% of the described compound by weight or volume. The dosage regimen using the described compound is selected according to a variety of factors including the type, species, age, weight, sex and medical condition of the patient, the severity of the condition to be treated, the route of administration, the kidney or liver function of the patient and the particular described compound that is used. A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the drug necessary to prevent, counteract or stop the progression of the condition. Effective dosage amounts of the described compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the described compound, as necessary to treat the condition. Compositions for use in vivo or in vitro may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the described compound or in a range from one amount to another amount on the dosage list. In one embodiment, the compositions are in the form of a tablet that may be marked. Combination therapy Methods of the invention may include a compound of the invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). Combination therapy may, for example, combine two therapies or may combine three therapies (e.g., a triple therapy of three therapeutic agents) or more. Doses of one or more of the additional therapies (e.g., nonpharmacologic treatments or therapeutic agents) may be reduced from standard doses when administered alone. For example, doses can 150 can be determined empirically from drug combinations and permutations or can be deduced through isobolographic analyzes (e.g., Black et al., Neurology 65:S3-S6 (2005)). A compound of the present invention may be administered before, after or at the same time as one or more of said additional therapies. When combined, doses of a compound of the invention and doses of one or more additional therapies (e.g., non-pharmacological treatment or therapeutic agent) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). . A compound of the present invention and an additional therapy, such as an anticancer agent, may be administered together, as in a unitary pharmaceutical composition, or separately and, when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time. In some embodiments, the additional therapy is the administration of side effect limiting agents (e.g., agents intended to decrease the occurrence or severity of side effects of treatment. For example, in some embodiments, the compounds of the present invention can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron and prochlorperazine, or their pharmaceutically acceptable salts. In some embodiments, the one or more additional therapies include a non-pharmacological treatment (e.g., surgery or radiation therapy). In some embodiments, one or more additional therapies include a therapeutic agent (e.g., a compound or biological product that is an antiangiogenic agent, a signal transduction inhibitor, an antiproliferative agent, a glycolysis inhibitor or an inhibitor). of autophagy). In some embodiments, the one or more additional therapies include a non-pharmacological treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an antiangiogenic agent, a signal transduction inhibitor, a antiproliferative agent, a glycolysis inhibitor or an autophagy inhibitor). In other embodiments, the one or more additional therapies include two therapeutic agents. In still other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents. Non-pharmacological therapies Examples of non-pharmacological treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and adoptive T cell transfer therapy (ACT). In some embodiments, the compounds of the invention can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the invention can be used as neoadjuvant therapy before surgery. 151 Radiotherapy can be used to inhibit abnormal cell growth or treat a hyperproliferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)). Techniques for administering radiotherapy are known in the art. Radiation therapy may be delivered through one of several methods or a combination of methods, including, but not limited to, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiation therapy, and Permanent or temporary interstitial brachial therapy. The term brachial therapy, as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other site of proliferative tissue disease. The term is intended, but not limited to, to include exposure to radioactive isotopes (e.g., At-211, 1-131, 1-125, Y-90, Re-186, Re188, Sm-153, Bi-212 , P -32, and radioactive isotopes of Lu). Radiation sources suitable for use as the cell conditioner of the present invention include both solids and liquids. By way of non-limiting example, the radiation source may be a radionuclide, such as 1-125, I131, Yb-169, lr-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles , gamma radiation or other therapeutic rays. The radioactive material may also be a fluid made from any solution of radionuclide(s), for example a solution of 1-125 or 1-131, or a radioactive fluid may be produced using a suspension of a suitable fluid containing small particles of solid, radionuclides, such as Au-198 or Y-90. Additionally, the radionuclide(s) can be incorporated into a gel or radioactive microspheres. In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiation treatment in order to destroy or inhibit the growth of said cells. Accordingly, this invention further relates to a method of sensitizing abnormal cells in a mammal to radiation treatment comprising administering to the mammal an amount of a compound of the present invention, which amount is effective to sensitize abnormal cells to radiation treatment. The amount of the compound in this method can be determined according to the means for determining effective amounts of such compounds described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy. In some embodiments, the non-pharmacological treatment is an adoptive T cell transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell can be modified to express a chimeric antigen receptor (CAR). CAR modified T cells (CAR-T) can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding CAR into a T cell. Prior to the expansion and genetic modification of T cells, a source of T cells is obtained from a subject. T lymphocytes can be obtained from several 152 sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, tissue of the spleen and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art can be used. In some embodiments, the T cell is an autologous T cell. Whether before or after genetic modification of T cells to express a desirable protein (e.g., a CAR), T cells can generally be activated and expanded using methods as described, for example, in U.S. Pat. . 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041. Therapeutic agents A therapeutic agent may be a compound used in the treatment of cancer or symptoms associated therewith. For example, a therapeutic agent may be a steroid. Accordingly, in some embodiments, the one or more additional therapies include a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoxymetasone, dexamethasone, diflorasone, diflucortolone , difuprednate, enoxolone, fluazacort, fiuchloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinon ida, halobetasolone propionate , hydrocortisonets, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednilidene, rimexolone, tixocortol, triamcinolone, acetonide triamcinolone, triamcinolone benetonide, triamcinolone hexacetonide and salts or derivatives thereof. Other examples of therapeutic agents that can be used in combination therapy with a compound of the present invention include compounds described in the following patents: US Patent Nos. International Patent Applications WO0 1 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871. A therapeutic agent may be a biological agent (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in the treatment of cancer or symptoms associated therewith. 153 In some embodiments, the biological agent is an immunoglobulin-based biological agent, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fe fusion protein, or a functional fragment thereof) that agonizes a target. to stimulate an anti-cancer response or antagonizes an important cancer antigen. Also included are antibody-drug conjugates. A therapeutic agent may be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, for example, an Fe receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a protein. from the checkpoint. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or a fusion). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of PDL-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fe fusion or a small molecule inhibitor) of PDL-2 (e.g., a PDL-2 / lg fusion protein). ). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049 family ligands, CHK 1, CHK2, A2aR, B-7 or a combination of these. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g. e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or a checkpoint inhibitor described in Preusser, M. et al. (2015) National. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F90, and KW-6 002. A therapeutic agent may be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, small non-peptide molecules, or other compound useful in the treatment of cancer or symptoms associated therewith, collectively , an anticancer agent). Anticancer agents may be, for example, chemotherapeutic or targeted therapy agents. 154 Anticancer agents include mitotic inhibitors, intercalated antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine and related inhibitors, vinca alkaloids, epipodopilotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted urea, methylhydrazine derivatives, adrenocortical suppressors, adrenocorticosteroids, progestogens, estrogens, antiestrogens , androgens, antiandrogens and gonadotropin-releasing hormone analogues. Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and doxetaxeL. In some embodiments, one or more additional therapies include two or more anticancer agents. The two or more anticancer agents can be used in a cocktail to be administered in combination or administered separately. Suitable dosage regimens of combined anticancer agents are known in the art and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al, Lancet 355(9209): 1041-1047 (2000). Other non-limiting examples of anticancer agents include Gleevec® (Imatinib Mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylololamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callistatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); crypto-offices (particularly crypto-office 1 and crypto-office 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodicta A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranimustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, such as calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed. Engl.33:183-186 (1994)); dynemycin as dynemycin A; bisphosphonates such as clodronate; aesperamycin; Chromophore of neoczinostatin and chromoproteins related chromophores antibiotics enedin, acclaimycin, actinomycin, autotramicine, azaserine, bleomycin, cottonomycin, caliqueamicin, carabicine, walk, carminomycin, carzinophiline, chromicines, dactinomycin, dactinomycin, daunorubicin Torrubicin, 6-Diazo-5Oxo-l-norleucin, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino155 doxorubicin, 2-pyrrolino-doxorubicin, deoxidoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, Puromycin, Chelamycin, Rhodorubicin, streptongrin, streptozocin, tubercidin, ubenimex, zinostatin, zorrubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glucoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defamina; demecolcine; diaziquone; elfomitin; elliptinium acetate; an epothilone such as epothilone B; ethoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; freak; pirarubicin; losoxantrone; podophylinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2-trichlorotriethilamine; trichothecenes such as T-2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobromán; gacitosin; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, for example, Taxol® (paclitaxel), Abraxane® (cremophor-free, albumin-manipulated nanoparticle formulation of paclitaxel) and Taxotere® (doxetaxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; 4(5)-midazoles that inhibit aromatase; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; gemcitabine Gemzar®; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; bandronato; irinotecan (eg, CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; Esperamycins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above. Additional non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17 -N-allylamino-17demethoxygeldanamycin, alfaradine, alvocidib, 3-aminoplrídina-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., non-cell cycle-specific antineoplastic agents and other antineoplastics described in this document), 156 antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostalicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozo lomida, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebecamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonin, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, ths(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 and zosuquidar. Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin ( actinomycin D), daunorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase that systematically metabolizes L-asparagine and deprives cells that do not have the ability to synthesize its own asparagine), antiplatelet agents, alkylating antiproliferative / antimitotic agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogues, melphalan and chlorambucil), ethyleneimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), inhibitors of CDK (e.g., a CDK 4 / 6 inhibitor such as ribociclib, abemaciclib, or palbociclib), seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P2700, AT-7519, RGB286638, and SCH727965), sodium sulfonates alkyl (p. busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites such as folio acid analogues, pyrimidine analogues (e.g. fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and coordination complexes platinum (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors (e.g., Array 520), binding agents to DNA (e.g. Zalypsis®), PI3K inhibitors such as PI3K delta inhibitor (e.g. e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multikinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin) , BAFF neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), nozrcn / zznz / zi / υιλι antibodies 157 cell surface monoclonals (e.g., anti-CD38 (HUMAX-CD38), anti-CSI (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K inhibitors / Akt (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTI (e.g., Zarnestra™), anti- CD138 (e.g. BT062), Torcl / 2 specific kinase inhibitors (e.g. INK128), ER / UPR targeting agents (e.g. MKC-3946), cFMS inhibitors (e.g. , ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists. In some embodiments, an anticancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib or any analogous or derivative variant thereof. In some embodiments, an anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005 and AP26113. Additional examples of ALK kinase inhibitors are described in examples 3-39 of WO05016894. In some embodiments, an anticancer agent is an inhibitor of a downstream member of a Receptor Tyrosine Kinase (RTK) / Growth Factor Receptor (e.g., an SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC- 4630, JAB-3068, RLY-1971), another SOS1 inhibitor (e.g., BI-1701963), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, a AKT inhibitor or an mTOR inhibitor (e.g., an mTORCI or mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312. In some embodiments, an anticancer agent is a Ras inhibitor (e.g., AMG 510, MRTX1257, LY349946, MRTX849, ARS-3248 (JNJ-74699157), MRTX1133 or ARS-1620), or a Ras vaccine, or other therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras. In some embodiments, the Ras protein is wild type. Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a RasWT (e.g., K-Rasm, H-RasWTo N-RasWT). In some embodiments, the Ras protein is an amplification of Ras (e.g., K-Rasamp). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Rasamp (K-Rasamp, HRasampo N-Rasamp). In some embodiments, the cancer comprises a Ras mutation (RasMUT). In some embodiments, a mutation is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations of these; 158 (b) the following Η-Ras mulants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T , G12a, A146V, G12N or G12R, and combinations of these; and (c) the following N-Ras mulants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations of these; a combination of any of the above (e.g., both K-Ras G12C and K-Ras G13C). In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, a cancer comprises an NF1LOF mutation. In some embodiments of the methods herein, the cancer comprises a RasMUT and a compound of the present invention is administered to, for example, a patient in need thereof, in combination with an additional therapeutic agent, for example, a MEK inhibitor, such as a MEK inhibitor described herein. In some embodiments of the methods herein, the cancer is colorectal cancer and a compound of the present invention is administered, for example, to a patient in need thereof, in combination with an additional therapeutic agent, such as a topoisomerase I inhibitor. (for example, irinotecan). In some embodiments of the methods herein, the cancer is a non-small cell lung cancer and a compound of the present invention is administered, for example, to a patient in need thereof, in combination with an additional therapeutic agent, by For example, a MEK inhibitor, such as a MEK inhibitor described herein (for example, trametinib). In some embodiments of the methods herein, the cancer is non-small cell lung cancer or colorectal cancer, and a compound of the present invention is administered, for example, to a patient in need thereof, in combination with an inhibitor of Ras, such as the Ras inhibitor described herein (e.g., MRTX849, MRTX1133 or AMG-510). In some embodiments, a therapeutic agent that can be combined with a compound of the present invention is a MAP kinase (MAPK) pathway inhibitor (or MAPK inhibitor). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the MAPK inhibitor can be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 2014 Nov. 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). 159 In some embodiments, an anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathways. The PI3K / AKT inhibitor may include, but is not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep; 7(3): 17581784. For example, the PI3K / AKT inhibitor can be selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458. In some embodiments, an anticancer agent is a PD-1 or PD-L1 antagonist. In some embodiments, additional therapeutic agents include EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors. , proteasome inhibitors and immune therapies. IGF-1R inhibitors include linsitinib or one of its pharmaceutically acceptable salts. EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et aL, Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res.1999, 59:1236-1243. The EGFR inhibitor may be the monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity of this. Small molecule EGFR antagonists include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; US Patents No. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; US Patent No. 5,789,427; 160 US Patent No. 5,650,415; US Patents No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, an EGFR inhibitor is osimertinib. MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from AE51-Q58; AF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N. PI3K inhibitors include, but are not limited to, wortmannin; the 17hydroxwortmannin analogues described in WO06 / 044453; 4-[2-(1H-lndazol-4-yl)-6-[[4(methylsulfonyl)p¡peraz¡n-1 -¡l]methyl¡l]thiene[3,2-d]p ¡ñm¡d¡n-4-yl]morphol¡ne (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]cinolin-1 -yl] phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06 / 122806); (S)-l-(4-((2-am¡nop¡r¡m¡dina-5-¡l)-7-methyl-4morpholy nothieno[3,2-d]pyrimidine-6-yl) methyl)pi perazin-1 -i l)-2-hydroxypropane-1 -one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyrane-4-one (available from Axon Medchem); Pl 103 hydrochloride (3-[4-(4-morpholinyl) ¡r¡do-[3',2':4,5]furo[3,2-d]p¡r¡m¡d¡n-2-¡l] phenol hydrochloride (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromo¡m¡dazo[1,2a]p¡ñdin-3-¡l)methylene]Tmethylh¡draz¡da-benzenesulfon¡co ) (available from Axon Medchem); PIK 90 (N-(7,8-dimethox¡-2,3-d¡hydro-¡m¡dazo[l,2-c]quinazolin-5- l)-nicotinamide (available from Axon Medchem); AS-252424 (5-[l-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-met-(Z)- ylidene]-thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1, 2-a]piñrnidine-4-one (available from Axon Medchem); XL-765; and XL-147.-il Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-113, PI-26 103, GNE-477, CUDC-907 and AEZS-136. AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, 385 (Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-im¡dazo[4,5-c]pyrid¡n¡l compounds (e.g. WO 05 / 011700); indole-3-carbinol and its derivatives (e.g., US Patent No. 6,656,963; Sarkar and LI J Nutr. 2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: nozrcn / zznz / q / υιλι 161 NSC 154020; Yang et al, Cancer Res. 2004, 64:4394-9). mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC2 inhibitors, e.g., PI-103, PP242, PP30; torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, for example, as described in WO98 / 02441 and WO01 / 14387, for example, AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi(tetrazolite)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynylox¡-32(S)dihydrorapanicin; derivatives described in WO05 / 005434; derivatives described in US Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02 136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (eg, WO05 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552. BRAF inhibitors that can be used in combination with the compounds of the invention include, for example, vemurafenib, dabrafenib and encorafenib. A BRAF may comprise a BRAF Class 3 mutation. In some embodiments, the BRAF Class 3 mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596RyA762E. MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key antiapoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. MCL-1 overexpression has been closely linked to tumor progression as well as resistance, not only to traditional chemotherapies but also to targeted therapies, including BCL-2 inhibitors such as ABT-263. In some embodiments, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive autoinhibited conformation stabilized by a binding network involving residues of the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors acting through receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site resulting in 162 the enzymatic activation of SHP2. SHP2 is involved in signaling through RAS mitogen-activated protein kinase (MAPK), the JAK-STAT pathway, or phosphoinositol 3-kinase-AKT. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental diseases, such as Noonan syndrome and Leopard syndrome, as well as in human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, leukemia acute myeloid and breast, lung and colon cancers. Some of these mutations destabilize the autoinhibited conformation of SHP2 and promote autoactivation or enhanced growth factor-driven activation of SHP2. SHP2, therefore, represents a very attractive target for the development of new therapies for the treatment of various diseases, including cancer. An SHP2 inhibitor (e.g., RMC-4550 or SHP099) in combination with a RAS pathway inhibitor (e.g., a MEK inhibitor) has been shown to inhibit the proliferation of multiple cancer cell lines in vitro (e.g., pancreatic, lung, ovarian, and breast cancer). Therefore, combination therapy involving an SHP2 inhibitor with a RAS pathway inhibitor could be a general strategy to prevent tumor resistance in a wide range of malignancies and may form the basis of a triple combination of inhibitor with an SOS1 inhibitor. Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al. Mol Pharmacol. 2006, 70, 562; Sarver etal., J. Med. Chem. 2017, 62,1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe ef al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2005094314; WO2007117699; WO2008124815; WO2009049098; WO2009135000; WO2010011666; WO2010121212; WO2011022440; WO2012041524; WO2014113584; WO2014176488; WO2015003094 WO2015107493; WO2015107494; WO2015107495; WO2016191328; WO2016196591; WO2016203404; WO2016203405; WO2016203406; WO2017078499; WO2017079723; WO2017100279; WO2017156397; WO2017210134; WO2017211303; WO2018013597; WO2018057884; WO2018081091; WO2018129402; WO2018130928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; WO2018218133; WO2019051469; WO2019051084; WO2019067843; WO2019152454; WO2019158019; WO2019165073; WO2019167000; WO2019182960; WO2019183364; WO2019183367; WO2019213318; WO2019233810; WO2020022323; WO2020033286; WO2020033828; WO2020061101; WO2020061103; WO2020063760; WO2020072656; WO2020073945; WO2020073949; WO2020081848; US20110281942; US20160030594 and US8637684, each of which is incorporated herein by reference. In some embodiments, an SHP2 inhibitor binds to the active site. In some embodiments, an SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, an SHP2 inhibitor binds to an allosteric site, for example, a non-covalent allosteric inhibitor. In some embodiments, an SHP2 inhibitor is a covalent inhibitor of SHP2, such as an inhibitor that is 163 targets the cysteine ​​residue (C333) that is located outside the active site of the phosphatase. In some embodiments, an SHP2 inhibitor is a reversible inhibitor. In some embodiments, an SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RCM-4630. In some embodiments, the SHP2 inhibitor is JAB-3068. Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib. Immune therapies include, but are not limited to, monoclonal antibodies, immunomodulatory drugs (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-inflammatory drugs. -PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40 agents). Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that adjust immune responses) that contain an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide and apremilast). Illustrative anti-PD-1 antibodies and methods for their use are described in Goldberg et al, Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1), as well as described elsewhere herein. GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as a GITR fusion protein described in US Pat. 6,111,090, US attack no. 8,586,023, WO2010 / 003118 and WO2011 / 090754; or a described anti-GITR antibody, e.g. e.g., in US Patent No. 7,025,962, EP 1947183, US Patent No. 7,812,135, US Patent No. 8,388,967, US Patent No. 8,591,886, US Patent No. 7,618,632, EP 1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO0 6 / 083289, WO05 / 115451, and WO2011 / 051726 . Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an antiangiogenic agent. Antiangiogenic agents include, but are not limited to, chemical compositions prepared synthetically in vitro, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An antiangiogenic agent may be an agonist, antagonist, allosteric modulator, toxin, or, more generally, may act to inhibit or stimulate its target (e.g., activation or inhibition of receptors or enzymes), and thereby promote cell death. or stop cell growth. In some embodiments, one or more additional therapies include an antiangiogenic agent. Antiangiogenic agents may be inhibitors of MMP-2 (matrix metalloproteinase 2), nozrcn / zznz / q / υιλι 164 MMP-9 (matrix metalloproteinase 9) inhibitors and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of antiangiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, and US Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. More preferred are those that selectively inhibit MMP-2 or AMP-9 relative to the other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7 , MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830. Other examples of antiangiogenic agents include KDR (kinase domain receptor) inhibitory agents (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind VEGF, or soluble VEGF receptors or a ligand-binding region thereof) such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that bind specifically to them), EGFR inhibitory agents (e.g., antibodies or antigen-binding regions that specifically bind to them) such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitor agents (e.g. ., antibodies or antigen-binding regions that specifically bind to them). Other antiangiogenic agents are Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), antiTWEAK agents (for example specific binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM distingrin domain to antagonize the binding of integrin to its ligands (US 2002 / 0042368), specific binding antibodies against the ef receptor or against ephrin or antigen binding regions (US Patents Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of the patent family thereof), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind), as well as antibodies or antigen-binding regions that specifically bind to PDGFBB ligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigen-binding regions that specifically bind thereto). Other antiangiogenic agents are: SD7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, 165 (Gilead Sciences, USA); alfastatin, (BioActa, United Kingdom); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US5892112); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); FTA ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); Mab alpha-D148 (Amgen, USA); CEP-7055 (Cephalon, USA) anti-Vn MAb (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Arlad, USA); YIGSR Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenic inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Sosei, Japan); 2methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lañe Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenic inhibitors (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, integrin alfa5beta3, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Cancer Research Institute, Italy); rBPI 21 and BPI-derived antiangiogenic (XOMA, USA); Pl 88 (Progen, Australia); cilengitide (Merck KGaA, Germany; Technical University of Munich, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474, (AstraZeneca, United Kingdom); ZD 6126, (Angiogene Pharmaceuticals, United Kingdom); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, United Kingdom); AZD 2171, (AstraZeneca, United Kingdom); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea); vaccine, based on the gene, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5. 2, (Supratek, Canada); SDX 103, (University of California San Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXIGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C, (University of British Columbia, Canada); CDP 791, (Celltech Group, United Kingdom); atiprimod (pINN), (GlaxoSmithKIine, United Kingdom); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); angiogenic vaccine, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF inhibitors 166 lalfa, (Xenova, United Kingdom); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKIine, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKIine, UK); KRN 633, (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol; anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor alpha inhibitors; SU 11248 (Pfizer, USA and SUGEN, USA); ABT 518, (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5 beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA) CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladin, (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine, (Genaera, USA); RPI 4610 (Sima, USA); heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin2 antagonists (ImClone Systems, USA); vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneren, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA). Other examples of therapeutic agents that can be used in combination with the compounds of the invention include agents (e.g., antibodies, antigen binding regions or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF, also known as Scatter Factor) antagonists and antibodies or antigen-binding regions that specifically bind to its receptor, cMet. Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazole 167 carboxamide riboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogues and drugs that increase cAMP levels such as adenosine, LY204002, N6-mercaptopuhna riboside and vinblastine. Additionally, antisense or siRNA can also be used that inhibits the expression of proteins including, but not limited to, ATG5 (which are involved in autophagy). In some embodiments, one or more additional therapies include an autophagy inhibitor. Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an antineoplastic agent. In some embodiments, the one or more additional therapies include an antineoplastic agent. Non-limiting examples of antineoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleucine, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, bromocriporubicinin, do xcriporubicinin , carmustine, cytarabine, fluorouracil, diclofenac HIT, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitfur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formes soo, fotemustine, gallium nitrate, gemcitabine, gemtuzumabzogamycin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibadronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa -2, interferon alfa-2a, interferon alfa2b, interferon alfa -NI, interferon alfa-n3, interferon alfacon-1, natural interferon alfa, interferon beta, interferon beta-la, interferon beta-Ib, interferon gamma, interferon gamma-la natural, interferon gamma-Ib, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LO 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte interferon alpha, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, double-stranded mismatch RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, new stimulant protein erythropoiesis, NSC 631570 octreotide, oprelvequin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit polyclonal antithymocyte antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene , raltitrexed, rasburiembodiment, rhenium Re 186 etidronate, Rll retinamide, rituximab, romurtide, samarlo (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermine, strontium-89 chloride, suramin, tasonermin, Tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab 168 iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifen , LDI200 (Milkhaus), leridistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fe MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM -1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, protein P 30, pegvisomant, pemetrexed, porfiromycin , prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, taliblastin, thrombopoietin, tin ethyl etiopurpurin, tirapazamine , cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), melanoma cell lysates vaccine viral (Royal Newcastle Hospital) or valspodar. Additional examples of therapeutic agents that can be used in combination with compounds of the invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonabCD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; amp 224; adalimumab (Humira®); adotrastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetñs®); canakinumab (llaris®); certolizumab pegol (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tositumomab; tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 169 951. In some embodiments, an additional compound used in combination therapy with a compound of the present invention is selected from the group consisting of a CDK4 / 6 inhibitor (e.g., abemaciclib, palbociclib or ribociclib), a KRAS:GDP inhibitor G12C (e.g., AMG 510, MRTX 1257) or another Ras:GDP mutant inhibitor, a KRAS:GTP inhibitor of G12C or another Ras:GTP mutant inhibitor, a MEK inhibitor (e.g., refametinib, selumetinib, trametinib or cobimetinib), a SHP2 inhibitor (e.g., TNO155, RMC-4630), an ERK inhibitor, and an RTK inhibitor (e.g., an EGFR inhibitor). In some embodiments, an SOS1 inhibitor may be used in combination with a Ras inhibitor, a SHP2 inhibitor, or a MEK inhibitor. In some embodiments, a combination therapy includes an SOS1 inhibitor, a RAS inhibitor, and a by MEK. In some embodiments, an additional compound used in combination therapy with a compound of the present invention is selected from the group consisting of ABT-737, AT-7519, carfilzomib, cobimetinib, danusertib, dasatinib, doxorubicin, GSK-343, JQ1, MLN -7243, NVPADW742, paclitaxel, palbociclib and volasertib. In some embodiments, an additional compound used in combination therapy with a compound of the present invention is selected from the group consisting of neratinib, acetinib and reversin. The compounds described herein may be used in combination with the agents described herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more compounds of the invention will be co-administered with other therapies as described herein. When used in combination therapy, the compounds described herein may be administered with the second agent simultaneously or separately. This combination administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the invention and any of the therapies described herein may be administered simultaneously, where both agents are present in separate formulations. In another alternative, a compound of the present description may be administered and followed with any of the therapies described herein, or vice versa. In some embodiments of the separate administration protocol, a compound of the invention and any of the therapies described herein are administered within a few minutes, a few hours, or a few days of each other. In some embodiments, a combination therapeutic regimen employs two therapeutic agents, a 170 compound of the present invention and a second selected from the therapeutic agents described herein. In some embodiments, a combination therapeutic regimen employs three therapeutic agents, a compound of the present invention and two selected from the therapeutic agents described herein. In some embodiments, a combination therapeutic regimen employs four or more therapeutic agents, one compound of the present invention and three selected from the therapeutic agents described herein. In some embodiments of any of the methods described herein, the first therapy (e.g., a compound of the invention) and one or more additional therapies are administered simultaneously or sequentially, in any order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours or up to 1 -7, 1 -14, 1 -21 or 1 -30 days before or after one or more additional therapies. The invention also features kits that include (a) a pharmaceutical composition that includes an agent (e.g., a compound of the invention) described herein, and (b) a package insert with instructions for performing any of the methods described in this document. In some embodiments, the kit includes (a) a pharmaceutical composition that includes an agent (e.g., a compound of the invention) described herein, (b) one or more additional therapies (e.g., treatment non-pharmacological or therapeutic agent), and (c) a package insert with instructions for performing any of the methods described herein. Since one aspect of the present invention contemplates the treatment of the disease or symptoms associated therewith with a combination of pharmaceutically active compounds that can be administered separately, the invention further relates to the combination of separate pharmaceutical compositions in kit form. . The kit may comprise two separate pharmaceutical compositions: a compound of the present invention and one or more additional therapies. The kit may comprise a container for containing the separate compositions, such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may comprise instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when the prescribing healthcare professional wishes to perform the titration of the individual components of the combination. In this Combination Therapy section, all references are incorporated by reference for the agents described, whether explicitly stated as such or not. 171 EXAMPLES The description is illustrated in more detail by the following examples and summary schemes, which should not be construed as limiting the scope or spirit of the present description to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the description in any way. It should also be understood that various other modalities, modifications and equivalents thereof that may be presented to those skilled in the art may be resorted to, without departing from the spirit of the present invention and / or the scope of the attached claims 10. The definitions used in the following examples and elsewhere herein are: BOP (benzotriazol-1-yl)tris(dimethylamino)phosphonate CH2CI2, dcm Methylene chloride, Dichloromethane ACN, CH3CN, Acetonitrile 15 MeCN DAST Diethylaminosulfur trifluoride DBU Diazabicycloundecene DCE 1,2-dichloroethane DDQ 2,3 -dichloro-5,6-dicyano-1,4-benzoquinone 20 DIEA Ν,Ν-diisopropylethylamine DIPEA Diisopropylethylamine DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine FME Dimethyl ether 25 DMF Ν,Ν-Dimethylformamide DMSO Dimethylsulfoxide EDCI 1-ethyl-3- (3-dimet¡lam¡noprop¡l)carbod¡mide EtOAc Ethyl acetate h Hour 30 HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramet¡luron ¡um hexafluorophosphate H2O Water HOBt Hydroxybenzotriazole HCI Hydrochloric acid 35 K3PO4 Potassium phosphate (tribasic) 172 LHMDS mCPBA MeOH Mscl Lithium bis(trimethylsilyl)amide meta-chloroperoxybenzoic acid Methanol Methanesulfonyl chloride 5 MTBE Methyl tert-butyl ether Na2SO4 Sodium sulfate NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methylpyrrolidone 10 rt Room temperature SMI2 samanum iodide (ll) TEA Tnethylamine TES Tnethylsilane TFA Trifluoroacetic acid 15 THF Tetrahydrofuran TMSCI Chlorotrimethylsilane XPhos 2-D¡cyclohex¡lphosphíno-2',4',6'-tr¡soprop¡lb¡phen¡l Example 1: Synthesis of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(1,2,3,620 tetrahydropyridin-4- il)pyrido[2,3-d]pyrimidin-7(8H)-one Stage 1 To a mixture of 4-[[(1 F?)-1-[3-amino-5-(tñfluoromethyl)phenyl]ethyl]amino]-6-bromo-8-methyl-pyrodium [2,3d]pyrimídin-7-one (50 mg, 113 pmol) in dioxane (1 ml) and H2O (0.2 ml) was added K2CO3 (47 mg, 339 pmol), tert-butyl 4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborlan-2-¡l)-3,6-d¡hydro-2H-pyr¡dine-1-carboxylate (38 mg, 124 pmol) and Pd(PPh3)4(Tetraks(triphenylphosphine)palladium(0), 13 mg, 11 pmol). The mixture was heated at 100 °C for 3 h in N2. After cooling to rt, the mixture was filtered and the solvent was removed under reduced pressure to give tere-butyl 4-[4-[[(1 phy)-1-[3-amino-5-(trifluoromethyl)phen! l]eth¡l]am¡no]-8-methyl-7oxo-p¡ñdo[2,3-d]pyrim¡din-6-¡l]-3,6-dih¡dro-2H-p ¡r¡dina-1 -carboxylate (50 mg, 81% yield). LCMS (ESI): m / z: [Μ +H] calculated for C27H32F3N6O3: 545.2; found 545.2. Stage 2 173 To a mixture of tere-butyl 4-[4-[[(1 / :?)-1-[3-amino-5-(trifluoromethyl)phen¡l]ethyl]amino]-8-methyl- 7-oxopyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2 / - / -pyridine-1-carboxylate (50 mg, 92 pmol) in MeOH (1 mi) HCl / MeOH (4 M, 23 μΙ) was added. The mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to provide 4-[[(1 fi)-1-[3-amino-5(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-6- (1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7-one (38 mg, 91% yield). LCMS (ESI): m / z: [Μ +H] calculated for C22H24F3N60:445.2; found 445.2;1H NMR (400MHz, methanol-d4) δ = 8.53 (s, 1H), 8.35 (s, 1H), 8.25 (s, 1H), 6.92 (s, 2H), 6.79 (s, 1H), 6.42 (s, 1H), 5.50 (q, J=6.8 Hz, 1H), 3.82 (d, J=2.6 Hz, 2H), 3.70 (s, 3H), 3.40 (t, J=6.0 Hz, 2H), 2.81 (s, 2H), 1.60 (d, J=7.1 Hz, 3H). The following examples 1-1 to 1-33 shown in Table 1 were synthesized in a similar manner to Example 1. Table 1. Examples 1-1 to 1-33 Example # Structure Mass found 1-1 / =z zX# 2 / >—2 ' \\ # I —z # 0 0 I 416.5 1-2 CF3^^ '''' NH Z NH ÓZZ^ Z^Z^o I 430.2 174 1-3 / =z\ ζΑΧ z Λ—z '—' \\ / / X —z Π d \—\ '—z I 430.5 1-4 z o / \ —Z / Z ll ZZ. τ \ λ Z—X z \ / Z z= / LL—( LL 431.5 nozrcn / zznz / q / υιλι 175 1-7 F F^ ''Άη γΆ nAzv^ Λ A A N^O I 431.6 1-8 CF3^^ M a NH A N ^N^N^O I 444.2 1-9 A aX Z / )—z vJ \\ 7 X —Z 7 O \—\ '—z nozrcn / zznz / q / υιλι 176 1-11 F 0 Ζ Λ—ζ ' ' 'λ / / τ —Η / 7 Ο \—< 1 ° / ζ ο CK 472.5 nozrcn / zznz / q / υιλι 177 1-15 F f^A A ΖΑ '' NH [ °j πΑγΑ / l / O \ z— Γ,—λ 2—7 Z # V z= / 479.0 1-18 F< F 0^^ 0 '''' NH r^A^A N Αγ / ZV H 1 1 N N A) 1 482.2 nozrcn / zznz / q / υιλι 178 1-19 Z / )—z J / / X —Z / 7 oz \--< 486.2 1-20 / =Α Z / )—z J \\ # 486.3 1-21 z—\ '— / o \ z— r,—λ z Ch y 486.5 1-22 Z / >—Z vJ / / X —Z / 7 o \—< A 486.5 nozrcn / zznz / q / υιλι 179 1-23 F cr γ o NH n ΑγγΑ ¡i J I N N A) 488.2 1-24 z^ '— / o \ z— I O Λ-λ 2—7 Ζ a 490.2 1-25 o O- Z / '— / o \ H— x nozecn / zznz / q / υιλι 180 1-27 co o < z^ \—\ / ° \ H— 1 JA Λ-Λ 2—(7 Z ( ;A z= / 512.6 1-28 ΤΊ \--TI / =H, ''J) Z Λ—z v7 a / 1 —Z / 7 O \--y '—Z z 432.4 1-29 z n—z J \\ # X —z / / o \, A° 433.5 1-30 °Λ —( o \ — x JA' Γ,—A 2—(7 Z \ / Z= / u_—ς ll 433.5 nozrcn / zznz / q / υιλι 181 1-31 Z / )—Z '---' / / —Z / 7 O \—< \ 3 / o 477.3 1-33 7=z\ 'τχ) z Λ—z 3 Y_7 \\ / / x —Z / 7 O \—< \ 3 / / / O 477.1 Example 2: Synthesis of ( / 7)-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-8-methyl-6morpholinopyrido[2,3 -d]pyrimidin-7(8H)-one Stage 1 To a solution of 6-bromo-4-hydroxyl-8-methyl-pyrido[2,3-d]pyrimidin-7-one (430 mg, 1.68 mmol) and 2-[3[(1 / 7)-1-aminoethyl]phenyl]-2,2-difluoro-ethanol (507 mg, 2.52 mmol) in DMF (10 ml) BOP was added 182 (1.11 g, 2.52 mmol) and DBU (760 μΙ, 5.04 mmol). The mixture was stirred at 25 °C for 16 h. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography to provide 6-bromo-4-[[(1 / ?)-1-[3-(1,1-difluoro-2-h¡ drox¡-ethyl)phen¡l]et¡l]amino]-8-methyl-pyr¡do[2,3d]piñm¡din-7-one (190 mg, 26% performance). LCMS (ESI): m / z: [Μ +H] calculated for Ci8Hi7BrF2N4O2: 439.1; found 439.2 Stage 2 A mixture of 6-bromo-4-[[(1 F?)-1 -[3-(1,1 -difluoro-2-hydroxy-ethyl)phenyl]ethyl]amino]-8-methyl-pine[ 2,3d]piñm¡din-7-one (200 mg, 455 pmol), morpholine (2.89 ml, 33 mmol) and DIEA (2.86 ml, 16.4 mmol) were stirred under nitrogen at 160 °C for 12 h. The solvent was removed under reduced pressure and the crude residue was purified by prep-HPLC to provide 4-[[(1 F?)-1 -[3-(1,1-difluoro-2-hydroxyethyl)phenyl ]eth¡l]am¡no]-8-methyl¡l-6-morphol¡no-p¡r¡do[2,3-d]p¡r¡m¡d¡n-7-one (16 mg , 8% performance). LCMS (ESI): m / z: [Μ +H] calculated for C22H26F2N5O3: 446.2; found 446.3;1H NMR (400 MHz, chloroform-d) δ ppm 8.25 (s, 1H) 7.59 (s, 1H) 7.54 (d, J = 8 Hz, 2H) 7.4 (m, 2H) 5.59 (m, 1H) 3.88 (m, 6H) 3.73 (s, 3H) 3.2 (d, J = 2.08Hz, 4H) 1.66 (d, J = 7.09 Hz, 3H). The following examples 2-1 to 2-5 shown in Table 2 were synthesized in a similar manner to Example 2. 183 2-2 F F^ l F nh y-Af χχΥ Λ Λ A ^N N^O I 454.2 2-3 HF2C^^ IJ .¼ ro NH γγ A XX ^N^ / γΤ ^^N^N^O I 460.2 2-4 F fXo F^l A o. / x '' NH Ύ NH Α / χΥ J A X Example 3: Synthesis of (fi)-4-(( 1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-6-(3,6-dihydro2H-pyran-4-yl )-2,8-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one Stage 1 To a solution of 6-bromo-4-hydroxy-2,8-dimethyl-piñdo[2,3-d]pyrimidin-7-one (1.1 g, 4.07 mmol) in DMF (10 ml) was added BOP (2.81 g, 6.35 mmol), 2-[3-[(1 / ?)-1-aminoethyl]phenyl]-2,2-difluoro-ethanol (1.64 g , 8.15 mmol) and DBU (1.84 mi, 12.22 mmol). The reaction was stirred at 20SC for 12 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography to provide 6-bromo-4-[[(1 fi)-1 -[3-(1,1 difluoro-2-hydroxy-ethyl)phenyl]et ¡l]amino]-2,8-dimet¡l-pyr¡do[2,3-d]p¡r¡m¡d¡n-7-one (1.4 g, 76% yield).1H NMR ( 400 MHz, methanol-d4) δ ppm 8.71 (s, 1 H) 7.61 (s, 1 H) 7.53 (d, J = 8 Hz, 1 H) 7.43 - 7.36 (m, 2 H) 5.60 - 5.55 (m, 1 H) 3.91 - 3.84 (m, 2 H) 3.68 (s, 3 H) 2.41 (s, 3 H) 1.62 (d, J = 8 Hz, 3H). Stage 2 To a solution of 6-bromo-4-[[(1fi)-1-[3-(1,1-difluoro-2-hydroxy-ethyl) phenyl]ethyl]amino]-2, 8-dimethylpyrido[2,3 -d]pyrimidin-7-one (0.2 g, 441 pmol) in DME (2 ml) 2-(3,6-dihydro-2H-pyran-4-¡l)4,4,5,5-tetramethyl was added -1,3, 2-dioxaborolane (139 mg, 662 pmol), H2O (0.4 ml), Na2CO3 (94 mg, 882 pmol) and Pd(PPh3)4 (Tetrak¡s(tr¡phenylphosphine)palladium(0), 51 mg, 44 pmol) in N2. The mixture was stirred at 90 °C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by prep-HPLC to provide 4-[[(1fi)-1-[3-(1,1difluoro-2-hydroxy¡-ethyl)phenyl]ethyl]amino]-6-(3,6- dihydro-2H-pyran-4-yl)-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7one (0.03 g, 15% yield). LCMS (ESI): m / z: [M+H] calculated for C24H27F2N4O3: 457.2; found 457.3;1H NMR (400 MHz, methanol-cQ δ ppm 8.16 (s, 1 H) 7.62 (s, 1 H) 7.54 (d, J= 8 Hz, 1 H) 7.43 - 7.37 (m, 2 H) 6.46 (s, 1 H) 5.68 - 5.62 (m, 1 H) 4.33 - 4.29 (m, 2 H) 3.94 - 3.83 (m, 4 H) 3.69 (s, 3 H) 2.59 - 2.53 (m, 2 H) 2.44 (s, 3 H) 1.63 (d, J = 4 Hz, 3 H). Example 4: Synthesis of ( / 7)-4-((1 -(3-(1,1 -difluoro-2-hydroxyethyl)phenyl)amino)-2,8-dimethyl-6-(1,2, 3,6tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 185 Stage 1 To a solution of 6-bromo-4-[(1 / ^)-1 [3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]amino]-2,8-dimethylpyrido[2,3-d ]pyrimídin-7-one (0.2 g, 441 pmol) in DME (2 ml) tere-butyl 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-íl) was added -3,6-dihydro-2H-pyridine-1-carboxylate (205 mg, 662 pmol), H2O (0.4 ml), Na2CO3 (94 mg, 882 pmol) and Pd(PPh3 )4(Tetrakis(triphenylphosphine)palladium(0), 51 mg, 44 pmol) at 25 °C in N2. The reaction mixture was stirred at 90 °C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2SO4, the solvent was removed under reduced pressure and the crude residue was purified by silica gel chromatography to provide tere-butyl 4-[4-[[(1 R)-1 -[3-(1, 1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]amino]-2,8-dimethyl-7oxo-pyrido[2,3-d]pyrimidin-6-yl]-3 ,6-dihydro-2H-pyridine-1 -carboxylate (0.2 g, 82% yield).1H NMR (400 MHz, methanol-á4) δ ppm 8.14 (s, 1 H) 7.62 (s, 1 H) 7.54 (d, J= 8 Hz, 2 H) 7.43-7.37 (m, 2 H) 6.27 (s, 1 H) 5.67 - 5.57 (m, 1 H) 4.08 (d, J= 8 Hz, 2 H) 3.93 - 3.80 (m, 2 H) 3.66 (s, 3 H) 3.64 - 3.58 (m, 2 H) 2.57 - 2.51 (m, 2 H) 2.43 (s, 3 H) 1.63 (d, J = 8 Hz, 3 H) 1.49 (s, 9 H). Tere-butyl 4-[4-[[(1 R)-1 -[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]amino]-2,8-dimethyl- was dissolved 7-oxopyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.1 g, 180 umol) in HCl / MeOH (5 ml) at 20° C and the reaction was stirred at 20 °C for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to provide 4-[(1R)-1-[3-(1,1-difluoro-2hydroxyethyl)phenyl]amino]-2,8- dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7-one (30 mg, 35% yield). LCMS (ESI): m / z: [M+H] calculated for C24H28F2N5O2: 456.2; found 456.2;1H NMR (400 MHz, methanol-d4) δ ppm 8.54 (s, 1 H) 8.21 (s, 1 H) 7.63 (s, 1 H) 7.55 (d, J= 8 Hz, 1 H) 7.47 - 7.36 (m, 2 H) 6.41 (s, 1 H) 5.72 - 5.60 (m, 1 H) 3.92 - 3.80 (m, 4 H) 3.70 (s, 3 H) 3.38 - 3.46 (m, 2 H) 2.77 - 2.87 (m, 2 H) 2.45 (s, 3 H) 1.64 (d, J= 4 Hz, 3 H). Example 5: Synthesis of ( / 7)-6-(3,6-dihydro-2H-pyrano-4-yl)-8-methyl-4-((1-(3(trifluoromethyl)phenyl)amino)pyrido[2 ,3-d]pyrimidine-7(8H)-one 186 Stage 1 To a solution of 6-bromo-4-hydroxyl-8-methyl-pyrido[2,3-d]pyrimidin-7-one (987 mg, 3.86 mmol), (1R)1 -[3-(trifluoromethyl)phenyl]ethanamine (663 mg, 3.50 mmol) in DMF (9.6 ml), DBU (2.11 ml, 14.02 mmol) and BOP (2.33 g, 5.26 mmol) were added. The mixture was stirred at 25 °C for 0.5 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over NNa2SÜ4, the solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide 6-bromo-8-methyl-4-[[(1 fi)-1- [3-(trifluoromet¡l)phen¡l]ethyl]amino]pyrido[2,3d]piñm¡din-7-one (107 mg, 7% yield).1H NMR (400 MHz , methanol-oít) δ = 8.82 (s, 1 H) 8.37 (s, 1 H) 7.63 - 7.73 (m, 2 H) 7.48 - 7.54 (m, 2 H) 5.58 (q, 1 H) 3.75 (s, 3 H) 1.64 (d, J= 4.00 Hz, 3 H). Stage 2 To a mixture of 6-bromo-8-methyl-4-[(1 R)-1-[3-(trifluoromethyl)phen¡l]amino] pyrido[2,3-d]pyr¡ midín-7-one (38 mg, 89 pmol) and 2-(3,6-dihydro-2H-pyrano-4-íl)-4,4,5,5-tetramethyl-1, 3,2-dioxaborolane (28 mg, 133 pmol) in DME (0.7 ml) and water (0.13 ml) added Pd(PPh3)4(Tetraks(triphenylphosphine)palladium(0), 21 mg, 17.79 pmol ), NapCOs (28 mg, 266 pmol). The mixture was stirred at 85 °C for 1 h. After cooling to rt, the reaction mixture was filtered and purified by preparative HPLC to provide 6-(3,6-dihydro2H-pyran-4-yl)-8-methyl-4-[[(1 F ?)-1-[3-(trifluoromethyl)phenyl]ethyl]amino]pyr¡do[2,3-d]pyrimidin-7-one (25.4 mg, 23% performance). LCMS (ESI): m / z: [Μ +H] calculated for C22H22F3N4O2: 431.2; found; 431.2;1H NMR (400 MHz, methanol-d4) δ = 8.32 (s, 1 H) 8.21 (s, 1 H) 7.65 - 7.72 (m, 2 H) 7.47 - 7.56 (m, 2 H) 6.52 (s, 1 H) 5.58 - 5.64 (m, 1 H) 4.32-4.34 (q, 2 H) 3.92-3.94 (t, J=8.00 Hz, 2 H) 3.71 (s, 3 H) 2.52-2.62 (dd, 2 H ) 1.65 (d, J=8.00 Hz, 3 H). nozrcn / zznz / n / υιλι Example 6: Synthesis of 4-[(1 / ?)-1-[3-amino-5-(trifluoromethyl)phenyl]amino]-2,8-dimethyl-6-(1,2,3, 6187 tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7-one OH Stage 1 To a mixture of 6-chloro-A / 2-dimethyl-pyrimidine-4-amine (6.0 g, 38 mmol) in DMF (60 mi) at room temperature was added NBS (8.13 g, 45.7 mmol) . The mixture was stirred at rt for 2 h, then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to provide 5-bromo-6-chloro- / V2-dimethyl-pyrimidin-4-amine (7 g, 78% performance).1H NMR (400 MHz, DMSO-ofe) δ ppm 7.44 (d, J= 4.0 Hz, 1H), 2.87 (d, J = 4.0 Hz, 3H), 2.34 (s, 3H). Stage 2 A mixture of 5-bromo-6-chloro-A / 2-dimethyl-pyrimidin-4-amine (4.0 g, 16.9 mmol), TEA (5.9 ml, 42.3 mmol), prop-2 -butyl enoate (24.1 ml, 169.1 mmol) and Pd(PPh3)4(tetraks(triphenylphosphine)palladium(0), 1.95 g, 1.69 mmol) were combined and heated to 140 °C for 36 hrs. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and filtered. The solvent was removed under reduced pressure and the residue was purified 188 by preparative HPLC to provide (E)-3-[4-chloro-2-methyl-6-(methylamino)pyrimidin-5-yl]prop-2enoate (0.35 g, 7 % performance). LCMS (ESI): m / z: [M+H] calculated for Ci3Hi9CIN3O2: 284.1; found 284.1;1H NMR (400 MHz, methanol-c / 4) δ ppm 7.58 (d, J= 16.0 Hz, 1H), 6.46 (d, J= 16.0 Hz, 1H), 4.21 (t, J= 12.0 Hz, 2H), 2.97 (s, 3H), 2.42 (s, 3H), 1.75- 1.63 (m, 2H), 1.53- 1.35 (m, 2H), 0.97 (t, J = 16.0 Hz, 3H). Stage 3 To a mixture of butyl (E)-3-[4-chloro-2-methyl-6-(methylamino)pyrimidin-5-¡l]prop-2-enoate (0.35 g , 1.23 mmol) in MeOH (5 ml) NaOMe (200 mg, 3.7 mmol) was added. The mixture was heated to 60°C and stirred for 2 hours. Aqueous NH4Cl was added, the solvent was removed under reduced pressure and the crude residue was purified by preparative TLC to provide 4-methoxy-2,8-dimethyl-p¡ñdo[2,3c(]pyr¡m¡ d¡n-7-one (0.15 g, 59% yield).1H NMR (400 MHz, DMSO-ofe) δ ppm 7.92 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 12.0 Hz, 1H), 4.05 (s, 3H), 3.59 (s, 3H), 2.59 (s, 3H). Stage 4 To a mixture of 4-methoxy-2,8-dimethyl-pyrido[2,3-a(]pyrimidin-7-one (0.15 g, 0.73 mmol) in DMF ( 1 ml) NBS (130 mg, 0.73 mmol) was added to rt. The mixture was heated to 50 °C and stirred for 2 h. The mixture was poured into cold H2O and stirred for 5 min, the emerging precipitate was filtered and the filter cake was dried under vacuum to provide 6-bromo-4-methoxy-2,8-dimet¡l-p¡ñdo[2,3-a(|p¡r¡m¡d¡n-7- one (0.12 g, 58% yield) LCMS (ESI): m / z: [M+H] calculated for CioHnBrN302: 284.0, found 284.0, Ή NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1H), 4.06 (s, 3H), 3.67 (s, 3H), 2.59 (s, 3H). Stage 5 To a mixture of 6-bromo-4-methox¡-2,8-dimet¡l-piñdo[2,3-c / |p¡r¡m¡d¡n-7-one (120 mg, 0.42 mmol) in DCM (1 ml) at 0 °C BBr3 (204 pl, 2.11 mmol) was added. The mixture was heated to rt and stirred for 12 h, then poured into cooled aqueous Na2CO3 (0 °C) and the emerging precipitate was filtered to give 6-bromo-4-hydroxy¡-2,8-dimethyl-p ¡hdo[2,3-G(]p¡ñm¡d¡n-7-one (0.14 g).1H NMR (400 MHz, methanol-di) δ ppm 8.41 (s, 1H), 3.77 (s, 3H ), 2.45 (s, 3H). Stage 6 A mixture of 6-bromo-4-hydroxy-2,8-dimethyl-pyrido[2,3-c / ]pyrimidin-7-one (0.2 g, 0.74 mmol) and Ph3P (583 mg, 2.22 mmol) in DCE ( 5 ml) was stirred until the mixture became clear, then CCL (285 μΙ, 2.96 mmol) was added. The mixture was heated to 70 °C and stirred for 2.5 h, then the solvent was concentrated under reduced pressure and the crude residue was purified by column chromatography to provide 6-bromo-4-chloro-2,8-dimethyl-p ¡rido[2,3-c / ]pyr¡m¡din-7-one (50 mg, 23% yield).1H NMR (400 MHz, methanol-c / 4) δ ppm 8.55 (s , 1H), 3.82 (s, 3H), 2.71 (s, 3H). Stage 7 To a mixture of 6-bromo-4-chloro-2,8-dimethyl-pindo[2,3-c(]pyrimidin-7-one (0.05 g, 0.17 mmol) in tBuOH (0.5 ml), DIPEA (302 μΙ, 1.73 mmol) and 3-[(1 / ?)-1-aminoethyl]-5-(trifluoromethyl)anline (43 mg, 0.21 mmol) were added. The mixture was heated to 100 °C in a crimped vial and stirred for 2 h, 189 then the solvent was concentrated under reduced pressure and the crude residue was purified by prepTLC to provide 4-[[(1 / ?)-1 ¿3-amino-5-(trifluoromethyl)phen¡l] ethyl]amino]-6-bromo-2-methyl-8H-pyr¡do[2,3d]pyrimidín-7-one (0.03 g, 39% yield).1H NMR (400 MHz, methanol-c / 4) δ ppm 8.77 (s, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 6.80 (s, 1H), 5.54 - 5.48 (m, 1H), 3.76 (s, 3H), 2.44 (s, 3H), 1.58 (d, J = 8.0 Hz, 3H). Stage 8 To a mixture of tere-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2 / - / -pyr¡ d¡n-1carboxylate (31 mg, 1.0 mmol) in DME (0.5 ml) under N2 atmosphere, 4-[[(1 R)-1 -[3-amino-5(trifluoromethyl)phenyl]et was added ¡l]am¡no]-6-bromo-2,8-dimethyl-pyr¡do[2,3-ó|p¡r¡m¡d¡n-7-one (0.03 g, 66 pmol), Na2CO3 (14 mg, 0.13 mmol), H2O (0.1 mi) and Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0), 7.6 mg, 6.6 pmol). The mixture was heated to 85 °C and stirred for 2 h, then the solvent was concentrated under reduced pressure and the residue was purified by prep-TLC to give tere-butyl. 4-[4-[[(1 F?)-1-[3-amino5-(trifluoromethyl)phen¡l]ethyl]amino]-2,8-dimethyl-7-oxo- p¡r¡do[2,3-ó]p¡r¡m¡d¡n-6-¡l]-3,6-d¡hídro-2 / - / -p¡r¡d¡na1 -carboxylate (40 mg).1H NMR (400 MHz, methanol-^) δ ppm 8.16 (s, 1H), 6.96 (s, 1H), 6.94 (s, 1H), 6.79 (s, 1H), 6.26 (s , 1H), 5.58 - 5.49 (m, 1H), 4.11 - 4.03 (m, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.55 (s, 2H), 2.44 (s, 3H) , 1.58 (d, J = 4.0 Hz, 3H), 1.49 (s, 9H). Stage 9 A mixture of tero-butyl 4-[4-[[(1 R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-2,8-dimethyl -7-οχοpyrido[2,3-cy]pyr¡m¡n-6-¡l]-3,6-d¡hídro-2 / 7-p¡r¡d¡n-1-carboxylate (30 mg, 54 pmol) in 4M HCl in MeOH (3 ml) was then degassed at rt for 15 min. the solvent was concentrated under reduced pressure and the residue was purified by prep-HPLC to provide 4-[[(1 R)-1-[3-amino-5(trifluoromethyl)phen¡l]ethyl]am¡ no]-2,8-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-c / ]pyrimidin-7-one as acid salt formic (8 mg, 30% yield). LCMS (ESI): m / z: [M+H] calculated for C23H26F3N6O: 459.2; found 459.2;1H NMR (400 MHz, methanol-d4) δ ppm 8.52 (s, 1H), 8.22 (s, 1H), 6.95 (s, 2H), 6.80 (s, 1H), 6.40 (s, 1H) , 5.59 - 5.53 (m, 1 H), 3.85 (s, 2H), 3.70 (s, 3H), 3.45- 3.42 (m, 2H) 2.83 (s, 2H), 2.45 (s, 3H), 1.60 (d , J=8.0 Hz, 3H). Example 7: Synthesis of ( / 3)-4-((1 -(3-amino-5-(trifluoromethyl)phenyl)amino)-6-(3,6-dihydro-2H190 pyrano-4-yl )-2,8-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one Ni 3 i .. NaC-V«rp.- ur । κCO N4'''N M 3DM S N C N N OC· HM o8’V's► NH NHO dp.c8C=» nuF g, ~ o 9:: c N N Os' Pji ΡΡη4Na Cü ·' ’·. N O N N O Stage 1 To a mixture of 6-methoxy¡-2-methyl-pyr¡mid¡n-4-amine (15 g, 108 mmol) in ACN (150 ml) was added NIS (24 g, 108 mmol). The reaction mixture was stirred at 50 °C for 2 h. After cooling to rt, an excess of aqueous Na2SOs was added and the mixture was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide 5-iodo-6-methoxy-2-methylpyrimidin-4-amine (22 g, 77% yield). LCMS (ESI): m / z: [Μ +H] calculated for C6H8IN3O: 265.0; found 266.2. Stage 2 To a mixture of 5-iodo-6-methoxy¡-2-methyl-pyrimidín-4-amine (20 g, 75 mmol) and butyl prop-2-enoate (21.5 ml, 151 mmol) In DMA (80 ml), tr / s-o-tolylphosphane (4.6 g, 15 mmol), TEA (42 ml, 302 mmol) and Pd(OAc)2 (3.4 g, 15 mmol) were added. The mixture was heated to 100 °C and stirred for 10 h in N2. After cooling to rt, the reaction was filtered through a pad of silica. The solvent was removed under reduced pressure. The residue was dissolved in EtOA and washed with 10% aqueous LiCl followed by water and brine. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide butyl (E)-3-(4-amino-6-methoxy-2-methyl-pyrimidin-5yl )prop-2- enoate (15 g, 75% yield). LCMS (ESI): m / z: [Μ +H] calculated for CnHigNsOs: 265.1; found 266.3. Stage 3 To a mixture of butyl (E)-3-(4-amino-6-methoxy-2-methyl-pyrimidin-5-l)prop-2-enoate (15 g, 57 mmol) in MeOH (20 ml) NaOMe (30.5 g, 170 mmol) was added. The mixture was heated to 90 °C for 191 h. After cooling to rt, aqueous NH4CI was added and the mixture was concentrated under reduced pressure to remove most of the solvent. The precipitate was collected by filtration, washed with EtOAc and dried under vacuum to provide 4-methoxy-2-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (9 g , 83% efficiency).1H NMR (400 MHz, DMSO-cfe) δ ppm 7.84 (d, J = 8 Hz, 1 H) 6.41 (d, J = 8 Hz, 1 H) 4.01 (s, 3 H) 2.50 (s, 3 H). Stage 4 To a mixture of 4-methoxy-2-methyl-8H-pyrid [2,3-d]pinmidin-7-one (9 g, 47 mmol) in DMF (80 ml) was added NBS (8.4 g , 47 mmol). The mixture was heated at 50 °C for 2 h. After cooling to rt, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography to provide 6-bromo-4-methoxy-2-methyl-8H-pyrido[2,3-d]pyrimidin-7one (9 g, 71% yield).1H NMR (400 MHz, DMSO-cfe) δ ppm 12.83 (s, 1 H) 8.28 (s, 1 H) 4.03 (s, 3 H) 2.52 (s, 3 H). Stage 5 To a mixture of 6-bromo-4-methoxy¡-2-methyl-8H-p¡r¡do[2,3-d]pyr¡m¡d¡n-7-one (1 g, 3.7 mmol) in DMF (10 ml) K2CO3 (1 g, 7.4 mmol) and CH3I (0.46 ml, 7.4 mmol) were added. The mixture was stirred at rt for 2 hours. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide 6-bromo-4-methoxy-2,8-dimethylpyrido[2,3-d]pyrimidin. -7-one (0.6 g, 57% yield).1H NMR (400 MHz, DMSO-cfe) δ ppm 8.32 (s, 1 H) 4.06 (s, 3 H) 3.65 (s, 3 H) 2.59 (s , 3H). Stage 6 A mixture of 6-bromo-4-methox¡-2,8-dimet¡l-p¡ñdo[2,3-d]pyrám¡din-7-one (0.6 g, 2.1 mmol) in HBr (6 ml, 33% in AcOH) was heated at 100 °C for 2 h. After cooling to rt, the mixture was concentrated under reduced pressure and the precipitate was collected by filtration. After recrystallization from EtOAc, 6-bromo-4-hydroxyl-2,8-dimethyl-pindo[2,3-d]pyrimidin-7-one (0.5 g, crude) was obtained. .1H NMR (400 MHz, DMSO-c / 6) δ ppm 12.80 (s, 1 H) 8.23 ​​(s, 1 H) 3.62 (s, 3 H) 2.39 (s, 3 H). Step 7 to a mixture of 6-bromo-4-hydroxyl-2,8-dimethyl-pyrido[2,3-d]pyrmidin-7-one (0.1 g, 0.37 mmol) and 3[(1 fi)-1-aminoethyl]-5-(trifluoromethyl)aníline (151 mg, 0.74 mmol) in DMF (1 ml) benzotñazole 1-íloxí-tns was added (dimethylamino)phosphono;hexafluorophosphate (255 mg, 0.58 mmol) and 2,3,4,6,7,8,9,10octahydropyrimide[1,2-a]azepine (167 μΙ , 1.1 mmol). The mixture was stirred at rt for 3 h. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. the solvent was removed under reduced pressure and the residue was purified by preparative TLC to provide 4-[[(1 R)-1 -[3-amino-5-(trifluoromethyl)phen¡l]ethyl] amino]-6-bromo-2,8-dimethylpyrido[2,3-d]pyrimidin-7-one (0.15 g, 89% yield). DMSO-cfe) δ ppm 8.91 192 (s, 1 H) 8.26 (d, J= 8 Hz, 1 H) 6.85 (s, 1 H) 6.81 (s, 1 H) 6.70 (s, 1 H) 5.54 (s, 2 H) 5.50 - 5.39 (m, 1 H) 3.60 (s, 3 H) 2.38 (s, 3 H) 1.50 (d, J= 8 Hz, 3 H). Stage 8 To a mixture of 2-(3,6-dihydro-2H-pyran-4-¡l)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (104 mg, 0.49 mmol) in DMA (1.5 ml) 4-[[(1 / =?)-1 -[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-6-bromo-2,8dimethyl-pyr was added ¡do[2,3-d]p¡r¡m¡din-7-one (0.15 g, 0.33 mmol), Na2CO3(69 mg, 0.66 mmol), H2O (0.3 mi) and Pd(PPh3)4(tetrak (triphenylphosphine)palladium(0), 38 mg, 33 umol). The mixture was stirred in N2a at 90 °C for 2 h. After cooling to rt, water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to provide 4-[[(1 phy)-1-[3-amino-5(trifluoromethyl)phenyl]ethyl]amino]-6-( 3,6-dihydro-2H-pyran-4-yl)-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (30 mg, 20% yield). LCMS (ESI): m / z: [Μ +H] calculated for C23H25F3N5O2: 460.2; found 460.2;1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (s, 1 H) 6.97 (s, 1 H) 6.94 (s, 1 H) 6.79 (s, 1 H) 6.46 (s, 1 H) 5.57 - 5.52 (m, 1 H) 4.34 - 4.29 (m, 2 H) 3.93 - 3.90 (m, 2 H) 3.69 (s, 3 H) 2.59 - 2.52 (m, 2 H) 2.44 (s, 3 H) 1.59 (d, J= 8 Hz, 3 H). Example 8: Synthesis of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)amino)-2-methyl-6-(piperidín-4yl)pyrido[2 ,3-d]pyrimidin-7(8H)-one HCl / MeOH I -------► NH / NH λ Λ Λ N N O H Stage 1 To a mixture of tere-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-¡l)-3,6-dihydro-2H-p¡ ñdina-1carboxylate (73 mg, 0.25 mmol) in DME (1 ml) 4-[(1 F?)-1-[3-amino-5(trifluoromethyl)phenyl]amino] was added -6-bromo-2-met¡l-8H-pyr¡do[2,3-d]pyr¡m¡din-7-one (0.07 g, 0.16 mmol), Na2CO3 (34 mg , 0.32 mmol), H2O (0.2 mi) and Pd(PPh3)4(Tetrakis(triphenylphosphine)palladium(0), 18 mg, 16 umol). The mixture was stirred in N2a at 90 °C for 2 h. After cooling to rt, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried with 193 Na2SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide tere-butyl 4-[4-[[(1 R)-1-[3-amino-5-(trifluoromethyl)pheníl ]ethyl]amino]-2-methyl-7oxo-8H-pyrido[2, 3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1 -carboxylate (30 mg 35% performance).1H NMR (400 MHz, methanol-í / 4) δ ppm 8.17 (s, 1 H) 6.96 (s, 1 H) 6.93 (s, 1 H) 6.80 (s, 1 H) 6.44 - 6.38 (m , 1 H) 5.56 - 5.51 (m, 1 H) 4.12 - 4.05 (m, 2 H) 3.64 - 3.59 (m, 2 H) 2.58 - 2.52 (m, 2 H) 2.39 (s, 3 H) 1.58 (d , J = 4 Hz, 3 H) 1.48 (d, J = 4 Hz, 9 H). Stage 2 To a mixture of tere-butyl 4-[4-[[(1 / z?)-1-[3-amino-5-(trifluoromethyl)phen¡l]ethyl]amino]-2- methyl-7-oxo-8Hpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (30 mg, 55 pmol) in MeOH ( 2 ml) Pd / C (0.01 g) was added. The mixture was stirred at rt for 1 h in H2 (15 psi). The reaction mixture was filtered and the solvent was removed under reduced pressure to give tere-butyl 4-[4-[[(1 R)-1-[3-amino-5(trifluoromethyl)phenyl]ethyl]amino] -2-methyl-7-oxo-8H-pyrido[2,3-d]pyrimidin-6-yl]piperidine-1 -carboxylate (20 mg, 66% yield). LCMS (ESI): m / z: [Μ +H] calculated for C27H34F3N6O3: 547.3; found 547.3. Stage 3 A mixture of tere-butyl 4-[4-[[(1F?)-1-[3-amino-5-(trifluoromethyl)phen¡l]ethyl]amino]-2-met l-7-oxo-8Hpyrido[2,3-d]pyrimidin-6-yl]piperidine-1-carboxylate (30 mg, 55 pmol) in HCl / MeOH (2 ml) was stirred at room temperature. for 20 min. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to provide 4-[[(1F?)-1-[3-am¡no-5-(tñfluoromet¡l)phen¡l]ethyl]am ¡no]-2methyl¡l-6-(4-p¡per¡d¡l)-8H-p¡ndo[2,3-d]p¡ñmid¡n-7-one (9 mg, 37% performance). LCMS (ESI): m / z: [Μ +H] calculated for C22H26F3N60:447.2; found 447.2;1H NMR (400 MHz, methanol-cQ δ ppm 8.51 (s, 1 H) 8.07 (s, 1 H) 6.97 - 6.95 (m, 2 H) 6.81 (s, 1 H) 5.60 - 5.54 (m, 1 H) 3.52 (d, J= 12 Hz, 2 H) 3.21 -3.12 (m, 2 H) 3.10-3.01 (m, 1 H) 2.40 (s, 3 H) 2.18 (d, J= 12 Hz, 2 H) 1.99- 1.84 (m, 2 H) 1.61 (d, J= 8 Hz, 3 H). The following examples 8-1 to 8-17 and 1-28 to 1-31 shown in Table 3 were synthesized in a similar manner to Example 8. Table 3. Examples 8-1 to 8-17 and 1-28 to 1-31 Example # Structure Mass found 194 8-1 F F I A / N. '' nh r > ^N^N^O I 448.4 8-2 A Z / )—Z vJ y / / X —Z / 7 O \< ^Z 460.6 8-3 / A Πγγ \\ # X —z # o 2 — nozecn / zznz / q / υιλι 195 8-5 Z Λ—z ' ' y / / 482.3 8-7 z—< '—( o \ z— 1 / 70 r,—λ z—7 z {Va z= / 484.3 8-8 ti \—ti 7=zx \\ / / z —H / 7 o \< b 488.5 nozrcn / zznz / q / υιλι 196 8-9 F ρΆι F y o NH ZA^A nZ / AZ A A 490.5 8-11 o w Ο=ω^ '—¿ O \ z— Γ,—2-7 z (Vz 495.1 8-12 F FX^] F¡ ° ''Άη nZ / AZ A A A ^A^n Ad 1 495.4 nozrcn / zznz / q / υιλι 197 8-13 F F^y x ΉΗ «vn1 f ¡i J l N N^O I 496.6 8-14 & z^ —¿ o \ z— X O r—λ Z—7 z 502.5 8-15 F fLo F Λ V '' NH K N mA / xH'X ú I I I 510.5 8-16 Π 2—Ή / =zx 'r~\¡) ~Z. / >—z —J X 7 2 —z 2 o 2— \ ) or T ω 514.5 nozrcn / zznz / q / υιλι 198 8-17 Η ζ Λ—ζ J # ζ —Ζ # ο 2—\ ζ > ο 00 528.5 1-28 F ρΛπ f^Z '''Ζη ι^ΝΗ ΝΖ^ / ^Ζ\Ζ Η I I Ζ^Ν ^Ζ I 432.4 1-29 Π Ζ Λ—ζ '—' \\ # Τ — Ζ y Ο \—, Xo 433.5 1-30 —1 ο \ — ι Λ—Λ 2-(7 Ζ / y^ / y = / 433.5 nozrcn / zznz / q / υιλι Example 9: Synthesis of ( / 7)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)amino)-2-methyl-6-(1,2,3, 6tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one Stage 1 A mixture of tere-butyl 4-[4-[[(1fi)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-2-methyl 7-oxo-8Hpyrido[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (0.15 g, 0.28 mmol) in HCl / MeOH (5 ml ) was stirred at rt for 0.5 h. The solvent was removed under reduced pressure and the crude residue was purified by prep-HPLC to provide 4-[(1phy)-1-[3-amino-5-(trifluoromethyl)phenyl]amino]-2 -methyl-6(1,2,3,6-tetrahydropyridine-4-!l)-8H-pyrido[2,3-d]pyrimidine-7-one (20 mg, 15% yield). LCMS (ESI): m / z: [Μ +H] calculated for C22H24F3N6O: 445.2; found 445.2;1H NMR (400 MHz, methanol-d4) δ ppm 8.53 (S, 1 H) 8.22 (s, 1 H) 6.94 (d, J= 4 Hz, 2 H) 6.80 (s, 1 H) 6.55 ( s, 1 H) 5.59 - 5.53 (m, 1 H) 3.83 (s, 2 H) 3.45 - 3.39 (m, 2 H) 2.86 - 2.78 (m, 2 H) 2.41 (s, 3 H) 1.60 (d, J = 8Hz, 3H). Example 10: Synthesis of 2,8-dimethyl-6-(morpolin-4-yl)-4-[[(1 / 7)-1-(3200 (trifluoromethyl)phenyl]ethyl]amino]-7H,8H-pyrido [2,3-d]pyrimidin-7-one Stage 1 To a stirred solution of 2-[(4-methoxyphenyl)methylidene]amino acetate (2.1 g, 10.35 mmol) and triethylamine (2.16 ml, 15.53 mmol) in methanol (43 ml), 4- chloro-2-methyl-6(methylamino)pyrimidine-5-carbaldehyde (1.9 g, 10.40 mmol) and the mixture was stirred for 48 h at room temperature. Acetic acid (2.96 ml, 51.80 mmol) was added and the mixture was stirred for 30 minutes at 50 °C. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EtOAc, extracted with water and dried with Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to provide 6-amino-4-chloro-2,8-dimethyl-7H,8H-pyrido[2,3-d] pyramidin-7-one (1.50 g, 65% yield). LCMS (ESI): m / z: [M+H] calculated for CgHioCIN40: 225.1; found 225.1. Stage 2 To a solution of 6-amino-4-chloro-2,8-dimethyl-7H,8H-pyrido[2,3-d]pyrimidin- 7-one (500 mg, 2.23 mmol) in NMP (15.0 ml), 2-bromoethyl ether (560 μΙ, 4.50 mmol) and DIPEA (1.94 ml, 11.13 mmol) were added. The reaction was stirred for 18 h at 150 °C in a sealed tube. After cooling to rt, brine was added and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography to provide 4-chloro-2,8-dimethyl-6-(morpholín-4-íl)-7H,8H-pyrido[2,3d]pyrim ¡din-7-one (285 mg, 43% yield).1H NMR (300 MHz, DMSO-de): δ 6.97 (s, 1H), 3.76 (m, 4H), 3.67 (s, 3H) , 3.25 (m, 4H), 2.64 (s, 3H). Stage 3 4-Chloro-2,8-dimet¡l-6-(morpholín-4-¡l)-7H,8H-p¡ñdo[2,3-d]p¡r¡m¡din was suspended -7-one (287 mg, 201 0.98 mmol) and (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride (220 mg, 0.98 mmol) in propan2-ol (11 ml). Triethylamine (408 pl, 2.90 mmol) was added and the mixture was heated at 100 °C for 16 h. After cooling to rt, the solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to provide 2,8-dimethyl-6-(morpholin-4-yl)-4-{[(1 R)1-[3-(tnfluoromethyl)phen¡l]ethyl] am¡no}-7H,8H-p¡ñdo[2,3-d]p¡ñmidin-7-one (150 mg, 34% yield). LCMS (ESI): m / z: [M+H] calculated for C22H25F3N5O: 448.2; found 447.9;1H NMR (300 MHz, DMSO-áe): δ 8.07 (d, J = 7.7 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.66 7.54 (m , 2H), 7.45 (s, 1H), 5.63 (q, J = 7.3 Hz, 1H), 3.77 (t, J = 4.6 Hz, 4H), 3.58 (s, 3H), 3.15 (t, J = 4.8 Hz , 4H), 2.35 (s, 3H), 1.61 (d, J= 7.1 Hz, 3H). Example 11: Synthesis of 8-cyclopropyl-6-(morpholino-4-yl)-4-{[(1 / ?)-1-[3(trifluoromethyl)phenyl]ethyl]amino}-7H,8H-pyrido[ 2,3-d]pyrimidin-7-one or Stage 1 To a solution of 4,6-dichloropyrimidine-5-carbaldehyde (3.0 g, 16.95 mmol) in DCM (170 ml) under argon atmosphere, cyclopropylamine (1.29 ml, 18.65 mmol) and triethylamine (3.54 ml, 25.40 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with DCM and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give 4-chloro-6-(cyclopropylamine)pyrimidina- 5-carbaldehyde (3.90 g, 100% yield), which was used in the next step without further purification. LCMS (ESI): m / z: [M+H] calculated for CsHgCINsO: 198.1; found 198.1. Stage 2 202 To a stirred solution of 2-[(Z)-[(4-methoxyphenyl)methylidene]amino]acetate (2.5 g, 12.06 mmol) and triethylamine (2.52 ml, 18.10 mmol) in MeOH (50.0 ml) was added 4 -chloro-6(cyclopropylamine)pyrimidine-5-carbaldehyde (2.4 g, 12.10 mmol). The mixture was stirred for 48 h at room temperature. Acetic acid (3.45 ml, 60.30 mmol) was added and the mixture was stirred for 30 minutes at 50 °C. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water, dried with Na2SO4 and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to provide 6-amino-4-chloro-8-cyclopropyl-7H,8H-pyrido[2,3-d]pyrimide. 7-one (1.44 g, 50% yield). LCMS (ESI): m / z: [M+H] calculated for C9H10CIN4O: 237.1; found 237.1. Stage 3 To a solution of 6-amino-4-chloro-8-cyclopropyl-7H,8H-pyrido[2,3-d]piñmidin-7-one (500 mg, 2.11 mmol) in NMP (15.0 ml) 2-bromoethyl ether (530 μΙ, 4.20 mmol) and DIPEA (1.84 ml, 10.56 mmol) were added. The reaction mixture was stirred for 18 h at 150 °C in a sealed tube. After cooling to rt, brine was added and the mixture was extracted with EtOAc. The organic phases were dried with Na2SO4 and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to provide 4-chloro-8-cyclopropyl-6-(morpholino-4-yl)-7H,8H-pyrid[2,3d] pinmine-7-one (157 mg, 24% yield). LCMS (ESI): m / z: [M+H] calculated for C14H16CIN4O2: 307.1; found 306.9. Stage 4 4-chloro-8-cyclopropyl-6-(morpholín-4-íl)-7H,8H-pyrÍdo[2,3-d]piñmidín-7-one (156) was dissolved mg, 0.51 mmol), (1 fi)-1 -[3-(trifluoromethyl)phenyl]ethan-1 -amine hydrochloride (115 mg, 0.51 mmol) and triethylamine (213 μΙ, 1.50 mmol) in propan-2- ol (5.8 mi). The mixture was heated at 100 °C for 48 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to provide 8-cyclopropyl-6-(morpholin-4-yl)-4-{[(1 Rj1 -[3-(trifluoromethyl)phenyl]ethyl]amino}-7H,8H-pyrido [2,3-d]pyrimidin-7-one (95 mg, 41% yield) LCMS (ESI): m / z: [M+H] calculated for C23H25F3N5O2:460.2, found 459.9;1H NMR (300 MHz , DMSO-d6): δ 8.25 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.73 - 7.68 (m, 1H), 7.66 - 7.54 (m, 2H) , 7.39 (s, 1H), 5.59 (q, J = 7.1 Hz, 1H), 3.78 (t, J = 4.5 Hz, 4H), 3.22 - 3.07 (m, 4H), 2.96 - 2.80 (m, 1H), 1.58 (d, 3H), 1.21-1.02 (m, 2H), 0.84 - 0.50 (m, 2H). The following examples 11-1 to 11-4 shown in Table 4 were synthesized similarly to Example 11. Table 4. Examples 11-1 to 11-4 Example # Structure Mass found 203 1-11 "Π X XX Z / >—z vJ \\ / / / —v. 2= / 498.8 1-13 / =\ XA# z / )—z 3 v_7 'λ # LL—( LL LL 530.1 Example 12: Synthesis of 4-{[(1 R)-1-[3-amino-5-(trifluoromethyl)phenyl]amino}-8-methyl-6-(morpholino204 4-yl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one Stage 1 Triethylamine (3.02 ml, 21.72 mmol), 2-[(Z)-[(4-methoxyphenyl)methylidene]amino]acetate (3.0 g, 14.48 mmol), and 4-chloro-6-(methylamine) were dissolved. no)pyr¡m¡d¡n-5-carbaldehyde (2.5 g, 14.50 mmol) in MeOH (60 ml). The mixture was stirred for 48 h at room temperature. Acetic acid (4.14 ml, 72.40 mmol) was added and the mixture was stirred for 30 min at 50 °C. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed with water and dried with Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to provide 6-amino-4-chloro-8-methyl-7H,8H-piñdo[2,3d]piñm¡din- 7-one (1.84 g, 60% yield).1H NMR (300 MHz, DMSO-ofe) δ 8.60 (s, 1H), 6.79 (s, 1H), 6.41 (s, 2H), 3.71 (s, 3H ). Stage 2 DIPEA (2.48 ml, 14.24 mmol), 2-bromoethyl ether (0.72 ml, 5.70 mmol), and 6-amino4-chloro-8-methyl-7H,8H-pyrido[2,3-d] were dissolved. prímídin-7-one (600 mg, 2.85 mmol) in NMP (18.0 ml). The mixture was stirred for 18 h at 150 °C in a sealed tube. After cooling to rt, brine was added and the mixture was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to provide 4-chloro-8-methyl-6-(morpholín-4-íl)-7H,8H-pyrido[2,3-d ]p¡r¡m¡din-7-one (356 mg, 45% yield).1H NMR (300 MHz, DMSO-cfc) δ 8.77 (s, 1H), 6.99 (s, 1H), 3.77 - 3.75 (m, 4H), 3.69 (s, 3H), 3.31 -3.20 (m, 4H). Stage 3 205 4-Chloro-8-met¡l-6-(morphol¡n-4-yl)-7H,8H-pyr¡do[2,3-d]pyr¡m¡d¡n- was dissolved 7-one (350 mg, 1.25 mmol), 3-[(1R)-1-am¡noethyl]-5-(trifluoromethyl)aníline hydrochloride (300 mg, 1.25 mmol) and triethylamine ( 521 μΙ, 3.74 mmol) in propan-2-ol (15 ml). The mixture was heated at 100 °C for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to provide 4-{[(1F?)-1-[3-amino-5(trifluoromethyl)phenyl]ethyl] am¡no}-8-methyl-6-(morphol¡n-4-¡l)-7H,8H-p¡r¡do[2,3-d]p¡r¡m¡d¡n-7- one (74 mg, 54% yield). LCMS (ESI): m / z: [M+H] calculated for C21H24F3N6O2: 449.2; found 449.1;1HNMR(300 MHz, DMSO-cfe): δ 8.27 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.48 (s, 1H), 6.83-6.78 (m, 2H), 6.72 - 6.67 (m, 1H), 5.60 - 5.52 (m, 2H), 5.46 (q, J = 7.1 Hz, 1H), 3.78 (t, J = 4.6 Hz, 4H), 3.61 (s, 3H), 3.22 - 3.12 (m, 4H), 1.54 (d, J = 7.1 Hz, 3H). Example 13: Synthesis of 8-methyl-6-(morpholino-4-yl)-4-{[(1 / ?)-1-[3-(tnfluoromethyl)phenyl]-ethyl]amino} 7H,8H-pyrido[2,3-d]pyrimidin-7-one nozrcn / zznz / q / υιλι Stage 1 4-Chloro-8-methyl-6-(morpholin-4-l)-7H,8H-pindo[2,3-d]pyrimidin-7-one (187) was suspended mg, 0.66 mmol), triethylamine (278 pl, 1.99 mmol) and (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride (150 mg, 0.66 mmol) in propan-2-ol (7.5 mi). The mixture was heated at 100 °C for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to provide 8-methyl-6-(morpholin-4-yl)-4-{[(1R)-1[3-(trifluoromethyl)phenyl]-et ¡l]am¡no}-7H,8H-p¡r¡do[2,3-d]pyr¡midín-7-one (46 mg, 16% yield). LCMS (ESI): m / z: [M+H] calculated for C2iH23F3N5O2: 434.2; found 433.7;1H NMR (300 MHz, DMSO-d6): δ 8.26 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.64-7.55 (m, 2H), 7.48 (s, 1H), 5.61 (q, J = 7.2 Hz, 1H), 3.78 (t, J = 4.6 Hz, 4H), 3.61 (s, 3H), 3.19 (t, J = 4.7 Hz, 4H), 1.61 (d, J =7.1 Hz, 3H). Example 14: Synthesis of 4-{[(1 R)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-6-(1206 methanesulfonyl-3-methylazetidin-3-yl) -8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one Stage 1 To a solution of tere-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (1 g, 4.14 mmol) and copper (I) iodide (78.8 mg, 414 pmol) in 5 ml of THF, in a N2 atmosphere, chlorotrimethylsilane (8.28 ml, 8.28 mmol) was added. After stirring for 10 min at rt, the mixture was cooled to -15eC, then a solution of methyl magnesium bromide (2.89 ml, 8.69 mmol) was added dropwise over 30 min. The resulting solution was stirred at room temperature for another 2 hours and then quenched with a saturated aqueous solution of NH4CL. The mixture was diluted with MTBE. The organic layer was separated and the aqueous layer was extracted with MTBE. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide tere-butyl 3-(2-ethoxy-2-oxoethyl)-3methylazetidine-1-carboxylate (782.3 mg, 73.7%). LCMS (ESI) m / z: [Μ + H] calculated for Ci3H23NO4: 257.2; found 257.4. Stage 2 Tere-butyl 3-(2-ethoxy-2-oxoethyl)-3-methylazethin-1-carboxylate (500 mg, 1.94 mmol), LHMDS (324 mg, 1.94 mmol) and mol 3A sieves were added. to THF and stirred for 10 min. 4Chloro-6-(methylamino)pyrimidine-5-carbaldehyde (221 mg, 1.29 mmol) was dissolved in a minimal amount of DMF and added dropwise. The reaction mixture was stirred at rt for 3 h. The reaction was quenched with NH4Cl and extracted with MTBE. The organic layers were combined and washed with water and brine and then dried in Na2SO4. the solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give tere-butyl 3-(4-chloro-8-methyl-7-oxo-7,8dihydropyrido[2,3-d]pyrimidin-6 -yl)-3-methylazetidine-1-carboxylate (76.8 mg, 16%). LCMS (ESI) m / z: [M 207 + H] calculated for C17H21CIN4O3: 364.1; found 364.4. Stage 3 (7 / 3)-1-[3-(difluoromethyl)-2-fluorophenyl]ethan-1-amine (59.5 mg, 315 pmol) and tert-butyl3-{4-chloro-8-methyl-7-oxo were suspended -7H,8H-pyrido[2,3-c / ]pyrim¡din-6-yl}-3-methylazetidine-1-carboxylate (76.8 mg, 210 pmol) in DMF (3 mL). DIPEA (109 pL, 630 pmol) was added. The reaction was stirred at rt overnight. The reaction mixture was diluted with H2O and washed with EtOAc. The organic layers were combined and washed with water and brine and the solvent was removed under reduced pressure. The crude material was purified by column chromatography to provide tere-butyl ( / 3)-3-(4-((1-(3(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7 -oxo-7,8-dihydropyrido[2,3-c / ]pyrimidin-6-yl)-3methylazetidine-1 -carboxylate (20.8 mg, 19%). LCMS (ESI) m / z: [M 4- H] calculated for C26H30F3N5O3: 518.2; found 518.6. Stage 4 Tere-butyl 3-(4-{[(1 / 3)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-methyl-7- was dissolved oxo-7H,8Hpyrido[2,3-o(]p¡r¡m¡d¡n-6-¡l)-3-met¡lazet¡naTcarbox¡late (20.8 mg,40.1 pmol) in DCM ( 3 ml) followed by the addition of TFA (15.3 pl, 200 pmol), the reaction was stirred overnight at rt. The solvent was removed under reduced pressure and the crude product was used without further purification. LCMS (ESI) m / z : [Μ + H] calculated for C2iH22F3N5O: 417.2; found 418.5. Stage 5 4-{[(1 / 3)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-methyl-6-(3-met ¡lazet¡din-3-yl)-7H,8H-p¡ñdo[2,3d]piñm¡din-7-one; Fluoroacetic acid (21.3 mg, 40.0 pmol) was dissolved in DCM (2 ml) followed by the addition of TEA (16.6 pL, 120 pmol) and mesyl chloride (3.70 pL, 48.0 pmol). The reaction mixture was stirred at rt for 4 hours. The mixture was washed with water and brine, then dried over Na2SO4 and the solvent was removed under reduced pressure. The crude residue was purified by prepHPLC to provide 4-{[( 1 F?)-1 -[3-(difluoromet¡ l)-2-f luorophen ¡l]ethyl]amino}-6-( 1 -methanesulfonyl-3met ¡lazet¡din-3-yl)-8-methyl-7H,8H-pyr¡do[2,3-d]pyr¡m¡d¡n-7-one (6.90 mg, 34.8 %). LCMS (ESI) m / z: [M + H] calculated for C22H24F3N5O3S: 496.2; found 496.5.1H NMR (500 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.55 (q, J= 6.9 Hz, 2H), 7.25 (t, J = 7.7 Hz, 1H), 5.78 (p, J = 7.0 Hz, 1H), 5.67 (t, J = 7.5 Hz, 1H), 4.32 (t, J= 7.7 Hz, 2H), 3.96 - 3.91 (m, 2H), 3.74 (s, 3H), 2.93 (s , 3H), 1.77 (s, 3H), 1.73 (d, J=6.9 Hz, 3H). Example 15: Synthesis of 6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[3-amino-2-fluoro-5(trifluoromethyl)phenyl]ethyl]amino] -8-methyl-pyrido[2,3-d]pyrimidin-7-one 208 H2SO4. 75°c ηνο3 Fe, NH4CI TEA, DCM, 0->25 °C N HCI HOBt, EDCI, TEA, DMF, 0->25 °C EtOH, H2O, 90 °C Stage 1 To a mixture of 2-fluoro-5-(trifluoromethyl) benzoic acid (2 g, 9.61 mmol) and HNO3 (10 mL) was added H2SO4 (2.5 mL) at 25 °C. The mixture was stirred at 75 °C for 1 h and then added to ice water and stirred for 10 min. EtOAc was added and the pH was adjusted to 2-3 by adding NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to provide 2fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2.3 g, 94.56% yield). ).1H NMR (DMSO-ofe,400 MHz) δ ppm 14.28 (s, 1 H), 8.71 (dd, J= 5.8, 2.2 Hz, 1 H), 8.46 (dd, J= 5.4, 2.2 Hz, 1 H ). Stage 2 To a solution of 2-fluoro-3-nitro-5-(tnfluoromethyl)benzoic acid (2 g, 7.90 mmol) in EtOH (9.6 mL) and H2O (4.8 mL) was added iron powder (1.32 g, 23.71 mmol ) and NH4Cl (211.34 mg, 3.95 mmol). The mixture was stirred at 90 °C for 1 h and then poured into ice water. After filtration, the filtrate was extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure to provide 3-amino-2-fluoro-5-(trifluoromethyl)ac. benzoic acid (2 g, crude). The material was used without further purification. LCMS (ESI): m / z: [Μ + H] calculated for C8H5F4NO2: 224.0; found 224.1. Stage 3 TEA (1.10 mL, 7.89 mmol) and acetyl acetate (2.59 ml, 27.61 mmol). The reaction mixture was heated to 25 °C and stirred for 3 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure to provide 3-acetamido-2-fluoro-5-(trifluoromethyl)acid. benzoic acid (2.2 g, crude). LCMS (ESI): m / z: [M + H] calculated for C10H7F4NO3: 266.0; found 266.1. Stage 4 209 To a solution of 3-acetamido-2-fluoro-5-(trifluoromethyl)benzoic acid (1.2 g, 4.53 mmol) in DMF (10 mL) at 0 °C was added N-methoxymethanamine hydrochloride (485.58 mg, 4.98 mmol ), HOBt (733.81 mg, 5.43 mmol), EDCI (1.04 g, 5.43 mmol), and TEA (1.89 mL, 13.58 mmol). The mixture was heated to 25SC and stirred for 2 h. The reaction mixture was diluted with ice water and filtered. The filtrate was extracted with EtOAc, dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography to provide 3-acetamido-2fluoro-N-methoxy¡-N-methyl-5-(trifluoromethyl)benzamide (785 mg, 56.28% yield).1H NMR ( methanol-dk, 400MHz) δ ppm = 8.55 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 3.6 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H), 2.21 (s , 3H). Stage 5 To a solution of 3-acetamido-2-fluoro-N-methoxy¡-N-methyl¡l-5-(trifluoromethyl)benzamide (785 mg, 2.55 mmol) in THF (8 mL) at 0 °C LHMDS (1 M in THF, 2.55 mL, 2.55 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min and then 3M MeMgBr in THF (2.55 mL, 7.65 mmol) was added. The reaction mixture was heated to 25 °C and stirred for 30 min. The reaction was quenched with H2O, extracted with EtOAc, washed with brine, dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography to provide N-[3-acetyl-2fluoro-5-(trifluoromethyl)phenyl]acetamide (510 mg, 76.09% yield). 1H NMR(methanol-d4, 400 MHz) δ ppm = 8.62 (dd, J = 6.4, 2.0 Hz, 1 H), 7.84 (dd, J = 6.0, 2.0 Hz, 1 H) ), 2.66 (d, J = 4.4 Hz, 3H), 2.23 (s, 3H). Stage 6 To a solution of N-[3-acetyl-2-fluoro-5-(trifluoromethyl)phenyl]acetamide (510 mg, 1.94 mmol) and (F?)-2methylpropane-2-sulfinamide (281.83 mg , 2.33 mmol) in THF (6 mL) Ti(0Et)4 (1.21 mL, 5.81 mmol) was added. The mixture was stirred at 90 °C for 3 h. The reaction was cooled to 0 °C, and then MeOH (78.42 pL, 1.94 mmol) and UBH4 (42.21 mg, 1.94 mmol) were added to the solution. The reaction was stirred at 0°C for 1 h and then diluted with ice water and filtered. The filtrate was extracted with EtOAc, dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography to provide N-[3-[(1 R)-1-[[(R)-tert-butylsulf¡n¡l]amino]ethyl]-2-fluoro- 5-(trifluoromethyl)phenyl]acetamide (150 mg, 20.17% yield). LCMS (ESI): m / z: [Μ + H] calculated for C15H21F4N2O2S: 369.1; found 369.1.1H NMR (methanol-c / 4, 400MHz) δ ppm = 8.29-8.38 (m, 1H), 7.62 (d, J = 4.4 Hz, 1H), 4.2 (m, 1H), 2.20 (s, 3H ), 1.53 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H). Stage 7 To a solution of N-[3-[(1 phy)-1-[[(phy)-tert-but¡lsulf¡n¡l]amino]ethyl]-2-fluoro-5-(tñfluoromethyl) ) phenyl]acetamide (150 mg, 407 pmol) in MeOH (2 mL) 4M HCl in MeOH (1.63 mL, 6.52 mmol) was added. The solution was stirred at 25 °C for 2 h. The pH was then adjusted to ~8 using a NaOH / MeOH solution and the mixture was filtered, the solvent was removed under reduced pressure and the residue was washed with DCM / MeOH (10:1), filtered and the solvent was removed. at reduced pressure to provide 3 210 [(1 / 7)-1-aminoethyl]-2-fluoro-5-(trifluoromethyl)aniline (110 mg, crude). LCMS (ESI): m / z: [Μ + H] calculated for C9H11F4N2: 223.1; found 223.0. Stage 8 To a solution of 3-[(1 / 7)-1-aminoethyl]-2-fluoro-5-(trifluoromethyl)aniline (110 mg, 495.09 pmol) in DMF (1.5 mL) was added 6-(1 - acetyl-4-piperidyl)-4-hydroxy-8-methyl-pine[2,3-d]pyrimidin-7-one (149.68 mg, 495.09 pmol), BOP (350.35 mg, 792.14 pmol) and DBU (223.87 pL, 1.49 mmol). Then, the mixture was stirred at 25 °C for 3 h. The reaction was diluted with sat. of NaHCO3, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to provide 6-(1-acetyl-4-piperidyl)-4-[[(1 / 7)-1[3-amino-2-fluoro-5-(trifluoromet ¡l)phenyl]ethyl]am¡no]-8-methyl-pyr¡do[2,3-d]pyr¡m¡d¡n-7-one (24.5 mg, 9.47% of performance). LCMS (ESI): m / z: [Μ + H] calculated for C24H27F4N6O2: 507.2; found 507.3.1H NMR (methanol-d4, 400MHz) δ ppm = 8.33 (s, 1H), 8.16 (s, 1H), 6.98 (dd, J= 7.6, 2.0 Hz, 1H), 6.90 (d, J= 5.6 Hz, 1H), 5.71-5.80 (m, 1H), 4.67-4.78 (m, 1H), 4.07 (d, J= 13.2 Hz, 1H), 3.72 (s, 3H), 3.13-3.28 (m, 2H) , 2.67-2.83 (m, 1H), 2.15 (s, 3H), 1.92-2.06 (m, 1 H), 1.90-1.96 (m, 1H), 1.60-1.70 (m, 5H). Example 16: Synthesis of 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2,8-dimethyl-6(oxetan-3-¡l)p¡ rido[2,3-d]pyrim¡din-7-one FF l. Yo .... Fγ.. F. ρθΓ V / i ' NHBrNH. ' ..-Bf. Ζ---·’'' N cocataizadcres lr / Νι LiOH γ ’ r W blue LEO light lamp N N O „ N N O । DME 25"C Stage 1 To a solution of (lr(dF(CF3)ppy)2(dtbbpy))PF6(1.27 mg, 1.13 pmol), 6-bromo-4-[[(1 / 7)-1-[3(difluoromethyl) -2-fluoro-phenyl]ethyl]amino]-2,8-dimethyl-pyr¡do[2,3-d]pyrimidin-7-one (50 mg, 113.32 pmol), 3-bromooxetane (23.28 mg, 169.97 pmol), 4-tert-but¡l-2-(4-tert-but¡l-2-pyrid¡l)pineapple (304.14 ug, 1.13 pmol) and bis(trimethylsil¡ lo)silyl-trimethyl-silane (34.96 pl, 113.32 pmol) in DME (2 mL) lithium hydroxide (5.43 mg, 226.63 pmol) and dichloronickel 1,2-dimethoxyethane (248.98 pg, 1.13 pmol) were added. . The solution was degassed by sparging with nitrogen for 10 min. The reaction was stirred and irradiated with a 34 W blue LED lamp for 16 h. The solvent was removed under reduced pressure, concentrated and purified by prep-HPLC to provide 4-[[(1 / 7)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]-2,8 -dimethyl-6-(oxetan-3-yl)pyrido[2,3-d]pyrimidin-7-one (2 mg, 4.08% yield). 211 LCMS (ESI): m / z: [Μ +H] calculated for C21H22F3N4O2: 419.16; found 419.2.1H NMR (400 MHz, methanol-d4) δ ppm 8.32 (s, 1 H) 7.59 (t, J= 8.0 Hz, 1 H) 7.47(t, J = 6.0 Hz, 1 H) 7.23 (t, J= 6.0 Hz, 1 H) 7.02 (t, J = 54 Hz, 1 H) 5.83 - 5.77 (m, 1 H) 5.08 - 5.04 (m, 2 H) 4.88 (d, J = 8 Hz, 2 H) 4.47 - 4.39 (m, 1 H) 3.68 (s, 3 H) 2.40 (s, 3 H) 1.66 (d, J = 8.0 Hz 3 H). Example 17: Synthesis of 6-(1-acetyl-4-pyridyl)-4-[[(1R)-1-[4-amino-6-(trifluoromethyl)-2pyridyl] ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one i .1 · NH MI ν' N ΝΊ N N N 'í► M-H H< i|1HtcN N ¡ Stage 1 To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (2 g, 6.51 mmol) and (4methoxyphenyl)methanamine (841.89 pL, 6.51 mmol) in toluene (10 mL ) CS2CO3 (4.24 g, 13.01 mmol) and Pd(dppf)Cl2.DCM (265.63mg, 325.27 pmol) were added. The mixture was stirred under nitrogen at 100 °C for 3 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried with Na2SÜ4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography to provide 2-chloro-N-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)pyridin-4amine (1.7 g, 82.51% yield). LCMS (ESI): m / z: [Μ +H] calculated for C14H13CIF3N2O: 317.1; found 317.1.1H NMR (400 MHz, methanol-c / 4) δ ppm 7.26 (d, J = 8.60 Hz, 2 H) 6.93 6.88 (m, 3 H) 6.65 (s, 1 H) 4.32 (s, 2 H ) 3.78 (s, 3 H). Stage 2 To a solution of 2-chloro-N-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)piñdin-4-amine (1.1 g, 3.47 mmol) and tributyl (1-ethoxyvinyl)stannane (5.28 mL, 15.63 mmol) in dioxane (10 mL) TEA (2.42 mL, 17.37 mmol) and Pd(PPh3)2CI2(487.58 mg, 694.65 pmol). The mixture was stirred under nitrogen at 100 °C for 18 h. The reaction was diluted with M HCl (10 mL) and stirred for 16 h. The mixture was filtered and the filtrate 212 was extracted with EtOAc. The combined organic layers were washed with aqueous KF solution and stirred for 20 min. The mixture was filtered. The organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to provide 1-[4-[(4-methoxyphenyl)methylamino]-6-(trifluoromethyl)-2pyridyl]ethanone (980 mg, 87.02% yield).1H NMR (400 MHz, methanol-á4) δ ppm 7.30 - 7.24 (m, 3 H) 7.02 (d, J= 0.88 Hz, 1 H) 6.91 - 6.87 (m, 2 H) 4.36 (d, J= 5.51 Hz, 2 H) 3.77 ( s, 3 H) 2.59 (s, 3 H). Stage 3 To a solution of 1-[4-[(4-methoxy¡phen¡l)methylamine]-6-(trifluoromethyl)-2-p¡hd¡l]ethanone (980 mg, 3.02 mmol), 2-methylpropane-2-sulfinamide (476.14 mg, 3.93 mmol) in THF (2 mL) tetraethoxytitanium (3.13 mL, 15.11 mmol) was added. The reaction mixture was stirred at 90 °C for 16 h. Then LIBH4 (78.98 mg, 3.63 mmol) and MeOH (122.28 pL, 3.02 mmol) were added to the mixture at 0 °C and the reaction was stirred at 0 °C for 30 min. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography providing (fi)-N-[(1 / 7)-1-[4[(4-methoxyphenyl)methylamine]-6-(trifluoromet) l)-2-p¡hd¡l]ethyl]-2-methyl-propane-2-sulf¡nam¡de (800 mg, 59.79% yield). LCMS (ESI): m / z: [Μ +H] calculated for C20H27F3N3O2S: 430.2; found 430.1; Ή NMR (400 MHz, methanol-d4) δ ppm 7.29 (d, J= 8.50 Hz, 2 H) 6.92 (d, J= 8.63 Hz, 2 H) 6.82 (d, J = 11.26 Hz, 2 H) 4.44 - 4.40 (m, 1 H) 4.37 (s, 2 H) 3.79 (s, 3 H) 1.46 (d, J = 6.88 Hz, 3 H) 1.24 (s, 9 H). Stage 4 To a solution of (fi)-N-[(1 / 7)-1-[4-[(4-methoxyphenyl)methylamine]-6-(thfluoromethyl)-2-p ¡r¡d¡l]ethyl]-2-methylpropane-2-sulfinamide (200 mg, 465.66 pmol) in DCM (5 mi) and H2O (0.25 mL) at 0 °C DDQ (158.56 mg) was added , 698.49 pmol). The mixture was heated to 25 °C and stirred for 3 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by prep-TLC to provide ( / 7)-N-[( 1 / 7)-1 -[4-amino-6-(trifluoromethyl)-2-p¡hdil]et ¡l]-2-methyl-propane-2-sulf¡nam¡de (60 mg, 41.65% yield). LCMS (ESI): m / z: [Μ +H] calculated for C12H19F3N3OS: 310.1; found 310.1. Stage 5 ( / 7)-N-[(1 / 7)-1 -[4-amino-6-(trifluoromethyl)-2-pyridyl]ethyl]-2-met was added l-propane-2-sulfinamide (60 mg, 193.95 pmol) to 4M HCl in MeOH and stirred for 1 h. The mixture was neutralized with aqueous NaOH solution. The solvent was removed under reduced pressure. The residue was dissolved in DCM, filtered and concentrated under reduced pressure to give 2-[(1 / 7)-1-aminoethyl]-6-(trifluoromethyl)pyridin-4amine (39 mg, crude). LCMS (ESI): m / z: [Μ +H] calculated for CsHnF3N3:206.1; found 206.1. Stage 6 213 To a solution of 2-[(1phyl)-1-aminoethyl]-6-(trifluoromethyl)pyridin-4-amine (39.8 mg, 193.98 pmol) and 6(1-acetyl) -4-p¡per¡dil)-4-hydroxy¡-8-methyl-pyr¡do[2,3-d]p¡ñmid¡n-7-one (64.51 mg, 213.37 pmol) in DMF (1 mL) was added BOP (137.27 mg, 310.36 pmol) and DBU (87.71 pL, 581.93 pmol). The mixture was stirred for 16 h. The mixture was diluted with sat. of NaHCO3, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to provide 6-(1-acetyl-4-piperidyl)-4-[[(1 phy)-1-[4-amino-6(trifluoromethyl)-2-pyridyl]ethyl]amino ]-8-methyl-pyrido[2,3-d]pyrimidin-7-one (20 mg, 20.85% yield). LCMS (ESI): m / z: [Μ +H] calculated for C23H27F3N7O2: 490.2; found 490.3.1H NMR (400 MHz, methanol-c / 4) δ ppm 8.32 (s, 1 H) 8.12 (d, J = 1.2 Hz, 1 H) 6.78 (s, 1 H) 6.69 (t, J = 2.21 Hz, 1 H) 5.39 - 5.36 (m, 1 H) 4.76 - 4.67 (m, 1 H) 4.10 - 4.03 (m, 1 H) 3.71 (s, 3 H) 3.29 - 3.26 (m, 1 H) 3.25- 3.14 (m, 1 H) 2.80 - 2.71 (m, 1 H) 2.14 (s, 3 H) 2.06 - 1.90 (m, 2 H) 1.68- 1.61 (m, 1 H) 1.59 (d, J = 7.06 Hz, 3H). Example 18: Synthesis of 4-[[(1 / ^-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(3-fluoro-1methyl-4-piperidyl)- 2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one NHN H||n H-i I··. '1' MIH ,ίΝ . 4 | t > . ।N N N ή N Stage 1 To a solution of 6-bromo-4-[[(1 phy,M-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2,8-di Methylpyrido[2,3-d]pyrimidin-7-one (1.8 g, 4.08 mmol) in dioxane (18 mL) 1-methyl-4-(4,4,5,5tetramethyl-1,3) was added ,2-dioxaborolan-2-¡l)-3,6-dihydro-2H-pyr¡dine (1.37 g, 6.12 mmol), Pd(dppf)CI2(298.49 mg, 407.94 pmol) , H2O (3.8 ml) and Na2CO3 (864.74 mg, 8.16 mmol). The mixture was stirred in nitrogen at 90 ° C for 2 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried with Anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography to provide 4-[[(1 / ?>1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino]- 2,8-dimethyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)pyrido[2,3-d]pyrimidin-7-one (1.9 g, crude).1H NMR (400 MHz, methanol-ofe) δ ppm 8.17 (s, 1 H) 7.59 - 7.55 (m, 1 H) 7.47 - 7.44 (m, 1 H) 214 7.23 - 7.20 (m, 1 Η) 7.00 (t, J= 54.8 Hz, 1 H) 6.42 (s, 1 H) 5.80 - 5.75 (m, 1 H) 3.65 (s, 3 H) 3.26 (s, 2 H) ) 2.84 - 2.81 (m, 2 H) 2.70 (s, 2 H) 2.48 (s, 3 H) 2.37 (s, 3 H) 1.64 (d, J = 8 Hz, 3 H) Stage 2 To a solution of 4-(((1 / ? / -1-[3-(difluoromethyl)-2-fluoro-phen¡l]ethyl¡l]amino]-2,8-dimethyl-6- (1-methyl-3,6dihydro-2H-pyridin-4-yl)pyrido[2,3-d]pyrimidin-7-one (1 g, 2.19 mmol) in THF (30 mL) in nitrogen at 0 °C, BH31Men THF (13.12 mL, 13.14 mmol) was added. The resulting mixture was stirred at 20 °C for 12 h. The reaction was cooled to 0 °C and a 2M aqueous NaOH solution (3.28 mL) was added. , 6.56 mmol), followed by 30% H2O2 (2.10 mL, 21.86 mmol), maintaining the internal temperature below 5 ° C. The reaction mixture was heated to 30 ° C and stirred for 1 h. reaction was poured into 10% aqueous Na2S2O3 solution and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered and the Solvent was removed under reduced pressure. The residue was purified by prep-HPLC to provide 4-(((1 / 7 / -1-(3(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6- (3-hydroxy¡-1 -methyl-4-piperidyl)-2,8-dimethyl-pyrido[2,3d]pyrimidín-7-one (100 mg, 9.62% yield). LCMS (ESI): m / z: [Μ +H] calculated for C24H29F3N5O2: 476.2; found 476.3. Stage 3 To a solution of 4-(((1 / 7 / -1-[3-(difluoromethyl)-2-fluoro-phen¡l]ethyl]amino]-6- (3-hydroxy¡-1 - methyl-4p¡pehd¡l)-2,8-dimethyl-p¡ndo[2,3-d]pyrim¡din-7-one (0.07 g, 147.21 pmol) in DCM (5 mL) a -60 °C N-ethyl-N-(trifluorosulfan¡l)ethanamine (38.90 pL, 294.42 pmol) was added. The reaction mixture was heated to 25 °C and stirred for 12 h. The reaction mixture was poured gradually in NaHCO3 and stirred for 15 min. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to provide 4-((1 / 7 / -1-[3-(difluoromethyl)-2-fluoro-phenyl]amino]-6-(3-fluoro-1- methyl-4-p¡perídil)-2,8-dimethyl-pyr¡do[2,3d]pyrimidín-7-one (8 mg, 10.47% yield). LCMS (ESI): m / z: [Μ +H] calculated for C24H28F4N5O: 478.2; found 478.1.1H NMR (400 MHz, methanol-c / 4) δ ppm 8.47 (s, 1 H) 7.58 (t, J= 8 Hz, 1 H) 7.47 (t, J= 8 Hz, 1 H) 7.22 (t, J= 8 Hz, 1 H) 6.99 (t, J= 54.8 Hz, 1 H) 5.83 - 5.77 (m, 1 H) ) 3.68 (s, 3 H) 3.15 - 2.81 (m, 5 H) 2.62 (s, 3 H) 2.39 (s, 3 H) 1.91 (t, J= 12 Hz, 2 H) 1.64 (d, J = 8 Hz, 3H). Example 19: Synthesis of 6-(1-acetyl-4-piperidyl)-4-[(1 R)-1-[5-amino-2-fluoro-3(trifluoromethyl)phenyl]amino]-8-met ¡l-pyrido[2,3-d]p¡nm¡d¡n-7-one nozrcn / zznz / n / υιλι 215 *1' I t.'. ί ?| < Stage 1 To a solution of 3-bromo-4-fluoro-5-(trifluoromethyl)anilline (1 g, 3.88 mmol) and tributyl(1ethoxyvinyl)tin (1.96 mL, 5.81 mmol) in dioxane (10 mL) TEA (1.35 mL, 9.69 mmol) and Pd(PPh3)2CI2 (272.04 mg, 387.58 pmol) were added. The mixture was stirred under nitrogen at 90 °C for 3 h. The reaction was adjusted to pH = 2 using 1M HCl and stirred for 16 h. The mixture was filtered and the filtrate was extracted with EtOAc. The organic layer was poured into aqueous KF solution and stirred for 20 min. The mixture was filtered, washed with brine, dried with anhydrous Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography to provide 1-[5amino-2-fluoro-3-(trifluoromethyl)phenyl]ethanone (440 mg, 51.33% yield).1H NMR (400 MHz, methanol-d4) δ ppm 7.25 (d, J = 4 Hz, 1 H) 7.11 (d, J = 4 Hz, 1 H) 2.58 (d, J = 4.63 Hz, 3 H). Stage 2 To a solution of 1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethanone (440 mg, 1.99 mmol) and 2-methylpropane-2-sulfinamide (313.48 mg, 2.59 mmol) in THF ( 5 mL) tetraethoxytitanium (1.24 mL, 5.97 mmol) was added. The reaction mixture was stirred at 90 °C for 3 h. Then, the reaction was cooled to 0 °C and LIBH4 (47.67 mg, 2.19 mmol) and MeOH (80.51 pL, 1.99 mmol) were added. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with water, filtered and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to provide N[(1 F?yi-[5-amino-2-fluoro-3-(trifluoromethyl)phen¡l]ethyl]-2-methyl -propane-2-sulf¡nam¡de (350 mg, 53.90 % yield) LCMS (ESI): m / z: [Μ +H] calculated for Ci3H19F4N2OS:327.1; found 327.05. Step 3 To a solution of N-[(1 R,)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-propane- 2sulfinamide (350 mg, 1.07 mmol) in MeOH (4 mL) was added 4 M HCl in MeOH (1.07 mL, 4.28 mmol). The mixture was stirred at 25 °C for 3 h. The mixture was adjusted to pH = 8 using aqueous NaOH solution and the solvent was removed under reduced pressure. The residue was dissolved in DCM / MeOH (10:1), filtered and the solvent was removed under reduced pressure to give 3-[(1 fi>1 -aminoethyl]-4-fluoro5-(trifluoromethyl)aniline (200 mg, crude.) LCMS (ESI): m / z: [Μ +H] calculated for CgHnF4N2:223.1; 216 found 223.1. Stage 4 To a solution of 3-[(1 R)-l -aminoethyl]-4-fluoro-5-(trifluoromethyl)aniline (100 mg, 450.08 pmol) and 6-(1 acetyl-4-piperídyl)-4- Hydroxy-8-methyl-pyrido[2,3-d]pyrimidin-7-one (136.07 mg, 450.08 pmol) in DMF (2 mL) BOP (318.50 mg, 720.13 pmol) and DBU (203.5 pL, 1.35 mmol). The mixture was stirred at 25 °C for 16 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The residue was purified by prep-HPLC to provide 6-(1-acetyl-4-piper¡d¡l)-4-[(1 R)-1-[5-amino-2-fluoro-3(trifluoromethyl)phenyl ]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one (20 mg, 8.60% yield). LCMS (ESI): m / z: [Μ +H] calculated for C24H27F4N6O2:507.2; found 507.2.1H NMR (400 MHz, methanol-d4) δ ppm 8.31 (s, 1 H) 8.19 (s, 1 H) 6.90 - 6.85 (m, 1 H) 6.80 - 6.76 (m, 1 H) 5.68 - 5.60 (m, 1 H) 4.74 - 4.67 (m, 1 H) 4.12 - 4.01 (m, 1 H) 3.71 (s, 3 H) 3.26 - 3.14 (m, 1 H) 2.79 - 2.72 (m, 1 H) 2.14 (d, J = 1.32 Hz, 3 H) 2.07 - 1.90 (m, 2 H) 1.70 - 1.62 (m, 2 H) 1.60 (d, J= 7.06 Hz, 3 H). Example 20: Synthesis of ( / ?)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2,3dimethoxybenzyl)-2-methylpyrido[2,3-d] pyrimidin-7(8H)-one nozrcn / zznz / q / υιλι Stage 1 To a solution of 6-bromo-4-{[(1 R)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-2,8-dimet ¡l-7H,8Hpyr¡do[2,3-d]pririm¡din-7-one (81.3 mg, 184 pmol) and Pd(PPh3)4(21.2 mg, 18.3 pmol) in THF (2.0 mL) a solution of 3,4-dimethoxybenzylzinc chloride (0.5 M in THF, 10 mL, 0.50 mmol) was added at 25 oC in N2. The mixture was heated to 60 °C and stirred for 30 min. The mixture was quenched with water, extracted with EtOAc, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to provide ( / ^-4-((1-(3-(difluoromethyl)-2fluorophen¡l)ethyl)amino)-6-(2,3-d¡ methoxy¡benz¡l)-2-met¡lp¡ñdo[2,3-d]p¡r¡m¡din-7(8H)-one (9.7 mg, 10% yield) LCMS (ESI ): m / z: [M+H] calculated for C21H28N5O3: 513.2; found: 513.5;1H NMR (500 MHz, METHANOL-c / 4) δ ppm 8.07 (s, 1 H), 7.55 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.1 Hz, 1H), 7.22 (t, J=7.7Hz, 1H), 7.15-6.88 (m, 3H), 6.81 (d, J=7.1 Hz, 1H) , 5.77 (q, J=7.1 Hz, 1H), 4.01 -3.92 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.70 (s, 3H), 2.39 (s, 3H), 1.61 (d, J= 7.1 Hz, 3H). 217 The following examples 20-1 to 20-4 shown in Table 5 were synthesized similarly to Example 20. Table 5. Examples 20-1 to 20-4 Example # Structure Mass found 20-1 F F'AfX OMe AJ A. / OMe I O ^NH Λ A X I 513.5 20-2 \\ 7 \ z— χ (XA 2= / x >=7 439.6 Example 21: Synthesis of (R)-4-((1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6(pyridazín-4-yl )p¡r¡do[2,3-d]p¡r¡m¡din-7(8H)-one II II ti I; II NH ‘ 'NllN.K;,A N N O or 'K.'.j ii! either Stage 1 A mixture of 6-bromo-4-{[(1 / ^T[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-methyl-7H,8Hpyrido[ 2,3-d]pyrimídin-7-one (43.6 mg, 102 pmol), pinacol ester of pyridazine-4-boronic acid (33.1 mg, 160 pmol) and KOAc (32.0 mg, 326 pmol) in dioxane ( 2.0 mL) and water (0.5 mL) with N2 for 10 min. To this mixture, dichloromethane complex Pd(dppf)2CI2 (8.3 mg, 10 pmol) was added at 25 °C in N2. The mixture was heated to 100 °C and stirred for 30 min. The mixture was quenched with water, extracted with EtOAc, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to provide (fi)-4- ((1-(3-(difluoromethyl)-2fluorophen¡l)ethyl)amino)-8-methyl-6-(pyridaz¡n-4-¡l)pyr¡do[2,3-d] p¡r¡m¡d¡n-7(8H)-one (16.5 mg, 38% yield) LCMS (ESI): m / z: [M+H] calculated for C2iHiaF3N6O: 427.1, found: 427.3; 1H NMR (500 MHz, MetanOL-d4) δ ppm 9.69 (dd, J = 2.4, 1.2 Hz, 1H), 9.25 (dd, J = 5.5, 1.3 Hz, 1H), 8.89 (s, 1H), 8.40 (s , 1H), 8.27 (dd, J = 5.5, 2.4 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.26 (t, J = 7.8 Hz , 1H), 7.02 (t, J = 54.9 Hz, 1H), 5.82 (q, J = 7.1 Hz, 1H), 3.77 (s, 3H), 1.69 (d, J= 7.0 Hz, 3H). The following examples 21-1 to 21-15 shown in Table 6 were synthesized similarly to Example 21. 219 Table 6. Examples 21-1 to 21-15 Example # Structure Mass found 21-1 TI / =H\ yO Z Λ—z J / / I —Z / 7 ° 414.5 21-2 Π 2--TI / Y yC# Z Λ— z J / / I —Z / 7 ° Y z=^ 427.5 21-3 z^ z' y O \ — Λ Λ Z—C Z YK LL—( LL 441.3 21-4 z Λ— z J \\ # z —H / 7 Z=^ 441.4 220 21-5 F F—f / N. ,F '' NH X Λ Λ N N^O I 445.4 21-6 ΤΊ \--TI / =z\ z F r—λ zX Z \ z= / 456.0 21-8 ti \—ti / =zx Z / >—z v7 \\ 7 X —H 7 O \=x x nozrcn / zznz / q / υιλι 221 21-9 F FT A XX '' nh y y n \ y i —Z y ZX qA 1 ° \ z 500.0 21-12 TI \—ΤΊ Xv / Aj Z / >—z J Y, / / I —Z / 7 O \=\ o y \ z—' I 500.0 nozrcn / zznz / q / υιλι 222 21-13 XX P \ Z— Z—y z \\ LL— / U- 426.07 21-15 F FX N '' NH < 'jl h I I N n X I 426.07 Example 22: Synthesis of 4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)amino)-6-(1-imino-1-oxide1,2,3,6-tetrahydro-1A6 -thiopyran-4-¡l)-8-methylpyrido[2,3-d]p¡r¡m¡din-7(8H)-one NH ·. Η”s l· ►► N, , . · - TO · !. N S · ' · ' % N ' · N N Stage 1 A mixture of 6-bromo-4-{[(1 / 3)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-methyl-7H,8Hpyr ¡do[2,3-d]pyrám¡din-7-one (1.52 g, 3.55 mmol), 3,6-dihydro-2h-t¡opyran-4nozrcn / zznz / q / υιλι pinacol ester 223 Boronic I (2.07 g, 9.15 mmol), Pd(PPh3)4 (627 mg, 542 pmol) and K2CO3 (1.52 g, 10.9 mmol) in dioxane (50 mL) and H2O (20 mL) were sprayed with N2 for 5 min. The mixture was heated to 100 °C and stirred in N2 for 2 h. The reaction was quenched with water, extracted with EtOAc, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to provide (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(3, 6-d¡hydro-2H-t¡op¡ran-4-¡l)-8methylp¡r¡do[2,3-d]pyr¡midín-7(8H)-one (1.41 g, 89% performance). LCMS (ESI): m / z: [M+H] calculated for C22H22F3N4OS: 447.2; found: 447.4. Stage 2 To a mixture of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(3,6-dihydro -2H-t¡op¡ran-4-¡l)8-methylpyr¡do[2,3-d]pyr¡midín-7(8H)-one (1.41 g, 3.15 mmol) in acetic acid (30 mL) an aqueous solution of hydrogen peroxide (30%, 416 pL, 4.05 mmol) was added. The mixture was stirred at 25 °C for 30 min. The reaction mixture was diluted in EtOAc (100 mL), quenched with water (200 mL), and neutralized with NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide 4-((( / 7)-1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)am ¡no)-8-methyl-6-(1 -oxide-3,6dihydro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one ( 1.43 g, 99% yield). LCMS (ESI): m / z: [M+H] calculated for C22H22F3N4O2S: 463.1; found: 463.4;1H NMR (500 MHz, Metanold4) δ 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (t, J= 7.5 Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H) , 7.24 (t, J= 7.8 Hz, 1H), 7.02 (t, J= 54.9 Hz, 1H), 6.12 - 6.06 (m, 1H), 5.83 - 5.74 (m, 1H), 3.77 (d, J= 17.7 Hz, 1H), 3.70 (S, 3H), 3.49 (dd, J = 17.9, 4.7 Hz, 1H), 3.30 - 3.21 (m, 1H), 3.16 - 3.06 (m, 1H), 3.05 - 2.89 (m, 2H), 1.66 (d, J = 7.0 Hz, 3H). Example 23: Synthesis of 4-(( / 7)-1-(3-(difluoromethyl)-2-fluorophenyl)amino)-6-(1-imino-1-oxido1,2,3,6- tetrahydro-1A6-thiopyran-4-l)-8-methylpyrido[2,3-d]pyrimidine-7(8H)-one Stage 1 nozrcn / zznz / q / υιλι To a mixture of magnesium oxide (407 mg, 10.1 mmol), Phl(OAc)2 (1.48 g, 4.59 mmol), trifluoroacetamide (516 mg, 4.56 mmol) and Rh2(OAc)4 (135 mg, 305 pmol) added a solution of 4-((( / 7)-1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxide-3,6-dih¡ dro-2Hthiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (711 mg, 1.53 mmol) in DCM (15 mL). The mixture was heated to 60 °C and stirred for 90 min. The reaction mixture was filtered through Celite® and 224 concentrated under reduced pressure. The crude residue was purified by column chromatography to provide / ^-(4-(4-((( / 7)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8 -methyl-7-oxo-7,8-dihydroxido[2,3d]pyrimidin-6-yl)-1 -oxido-3,6-dihydro-2H-1 Á6-thiopyran -1-ylidene)-2,2,2-trifluoroacetamide (741 mg, 72% yield). LCMS (ESI): m / z: [M+H] calculated for C24H22F6N5O3S: 574.1; found: 574.2. Stage 2 To a solution of A / -(4-(4-((( / 7)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-oxo-7,8dih¡ drop¡r¡do[2,3-d]p¡r¡m¡d¡n-6-¡l)-1 -oxide-3,6-dihydro-2H-1 A6-thiopyran-1-¡l¡ deno)-2,2,2trifluoroacetamide (213 mg, 371 pmol) in MeOH (6.0 mL) K2CO3 (102 mg, 738 pmol) was added. The mixture was stirred at 25 °C for 5 min. The reaction mixture was concentrated under reduced pressure, quenched with water, extracted with EtOAc, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to provide 4-((( / 7)-1 -(3-(difluoromethyl)2-fluorophenyl)ethyl)amino)-6-(1-imino- 1-oxide-1, 2,3,6-tetrahydro-1 A6-thiopyran-4-yl)-8-methylpyrido[2,3d]piñm¡din-7(8H)-one (26.7 mg, 16% performance). LCMS (ESI): m / z: [M+H] calculated for C22H23F3N5O2S: 478.1; found: 478.1.1H NMR (500 MHz, METHANOL-d4) δ ppm 8.32 (s, 1H), 8.29 (s, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 6.9 Hz , 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 54.9 Hz, 1H), 6.07-6.03 (m, 1H), 5.78 (q, J= 7.1 Hz, 1H), 4.01 - 3.89 (m, 2H), 3.70 (s, 3H), 3.48-3.35 (m, 2H), 3.21 - 3.05 (m, 2H), 1.66 (d, J = 7.1 Hz, 3H). The following example 23-1 shown in Table 7 was synthesized in a similar manner to Example 23. Example 24: Synthesis of 4-((( / 7)-1-(3-(difluoromethyl)-2-fluorophenyl)amino)-8-methyl-6-(1(methylamino)-1-oxide-1, 2,3,6-tetrah¡dro-1A6-thiopyran-4-¡l)p¡r¡do[2,3-d]p¡r¡m¡d¡n-7(8H)-one Stage 1 To a mixture of 4-(((í?)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-mino-1-oxido-1 ,2,3,6tetrah¡dro-1A6-t¡opyran-4-¡l)-8-met¡lp¡r¡do[2,3-d]p¡r¡m¡d¡n-7(8H )-one (85.6 mg, 179 pmol) in MeCN (4.0 mL) an aqueous solution of formaldehyde (37%, 53.2 pL, 712 pmol) and trifluoroacetic acid (54.4 pL, 710 pmol) was added. The solution was stirred at 25 °C for 30 min. Triethylsilane (114 pL, 712 pmol) was added and the mixture was stirred at 25 °C for 4 h. The mixture was concentrated under reduced pressure, partitioned between water and DCM and neutralized by the addition of NaHCO3. The aqueous layer was extracted with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to provide 4-(((F?)-1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1 -(methylimino) -l -oxide-1,2,3,6tetrahydro-1 A6-t¡op¡ran-4-¡l)p¡r¡do[2,3-d]piñm¡din-7(8H)- one (26.8 mg, 30% yield). LCMS (ESI): m / z: [M+H] calculated for C23H25F3N5O2S: 492.2; found: 492.4.1H NMR (500 MHz, METHANOL-d4) δ ppm 8.33 (s, 1H), 8.29 (s, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.1 Hz , 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 54.9 Hz, 1H), 6.08 - 6.01 (m, 1H), 5.78 (q, J = 7.1 Hz, 1H), 4.08 - 4.00 (m, 1H), 3.94 - 3.87 (m, 1H), 3.70 (s, 3H), 3.51 - 3.41 (m, 2H), 3.16 - 3.00 (m, 2H), 2.86 (s, 3H), 1.66 (d, J= 7.0 Hz, 3H). Example 25: Synthesis of (R)-4-((1-(difluoromethyl)-2-fluorophenyl)amino)-8-methyl-6-(1-oxidotetrahydro-2H-thiopyran-4-yl)pyrido[2 ,3-d]pyrimidine-7(8H)-one Stage 1 To a solution of (R)-4-((1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(3,6-dihydro -2H-t¡op¡ran-4-¡l)8-methylpyr¡do[2,3-d]pyr¡m¡din-7(8H)-one (450 mg; 1.00 mmol) in AcOH (5.0 mL) in N2, 10 wt% 226 Pd / C (462 mg, 0.434 mmol) was added. The mixture was placed under a hydrogen balloon (1 atm) and stirred at 25 °C for 2 h. The mixture was filtered through Celite® and concentrated under reduced pressure. The crude residue was purified by column chromatography to give ( / 3)-4-((1 -(3-(difluoromet¡I)2-fluorophen¡l)amino)-8-methyl-6-(tetrahi¡ dro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidine-7(8H)-one (247 mg, 55% yield) LCMS (ESI): m / z : [M+H] calculated for C22H24F3N4OS: 449.2; found: 449.2. Stage 2 To a solution of ( / 3)-4-((1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(tetrahydro-2Ht¡op¡ran-4-¡l )pyr¡do[2,3-d]p¡hm¡din-7(8H)-one (106 mg, 236 pmol) in AcOH (3.0 mL) an aqueous solution of hydrogen peroxide was added ( 30%, 48.0 pL, 467 pmol). The mixture was stirred at 25 °C for 30 min. The reaction was diluted with EtOAc and water, then treated with NaHCO3a pH = 7. The phases were separated and the aqueous solution was extracted with EtOAc. The combined organic extracts were concentrated and the crude residue was purified by prep-HPLC to provide ( / 3)-4-((1-(3(difluoromethyl)-2-fluorophen¡l)ethyl)amino )-8-met¡l-6-(1-oxy¡dotetrahydro-2H-t¡op¡ran-4-¡l)pyridium[2,3d]pyrimide-7(8H) -one (31.3 mg, 29% yield). LCMS (ESI): m / z: [M+H] calculated for C22H24F3N4O2S: 465.2; found: 465.3.1H NMR (500 MHz, METHANOL-d4) δ ppm 8.31-8.20 (m, 2H), 7.61-7.56 (m, 1H), 7.51-7.48 (m, 1H), 7.26-7.23 (m, 1H ), 7.13-6.91 (m, 1H), 5.82-5.76 (m, 1H), 3.72-3.70 (m, 3H), 3.61-3.14 (m, 2H), 2.98-2.90 (m, 1H), 2.50-2.28 (m, 1H), 2.06-1.96 (m, 1H), 1.69-1.66 (m, 3H). Example 26: Synthesis of 4-{[(1 / 3)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2,8-dimethyl-6(morpholine -4-carbonyl)-7H,8H-pyrido[2,3-d]pyrimidín-7-one 'y. Thousand i' i > ;i. 1 · !· ¿ 41·. Yo . |u + . > ' · :· . / '1 (। · ΊΑ ' !Λ· M Á Ll· Stage 1 To a solution of morpholine (169 pl, 1.93 mmol) and 4-methoxy-2,8-dimethyl-7-oxo-7H,8H pyrido[2,3-d]pyrimidine-6-carboxylic acid (400 mg, 1.61 mmol) in DMF (8 mL) DIPEA was added 227 (839 μΙ_, 4.82 mmol). After 5 min of stirring, HATU (749 mg, 2.09 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was diluted with EtOAc, washed with sat. ac. of NaHCO3, the solids were filtered and the layers separated. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was combined with the filtered solid and triturated with water to provide 4-methoxy-2,8-dimethyl-6-(morpholine4-carbonyl)-7H,8H-pyrido[2,3-d]pyrim ¡d¡n - 7 - one (356 mg, 71% yield). LCMS (ESI): m / z: [M+H] calculated for Ci5Hi9N4O4: 319.1; found 319.0.1H NMR (300 MHz, methanol-ck) δ ppm 7.30 (s, 1H), 3.32 (s, 3H), 2.95 (d, J = 1.4 Hz, 7H), 2.87 - 2.79 (m, 2H), 2.59 - 2.53 (m, 2H), 1.85 (s, 3H). Stage 2 Sodium iodide (1.02 g, 6.8 mmol) was added to a suspension of 4-methoxy-2,8-dimethyl-6-(morpholine-4-carbonyl)-7H,8H-pyrido[2,3-djpyrimidin- 7-one (360 mg, 1.13 mmol) in MeCN (14.4 mL). Chlorotrimethylsilane (861 pL, 6.79 mmol) was added and the mixture was heated in a sealed tube at 80 °C for 2 h and then cooled to rt. The solvent was removed under reduced pressure. The residue was suspended in water and a sat. solution was added. ac. of thiosulfate until the dark color faded. The solution was extracted with EtOAc and the solvent was removed under reduced pressure to give 4-hydroxy2,8-dimethyl-6-(morpholine-4-carbonyl)-7H,8H-pyhdo[2, 3 - d]pyrimidin - 7 - one (322 mg, 94% yield).1H NMR (300 MHz, DMSO-cfc) δ ppm 7.87 (s, 1H), 3.64 - 3.48 (m, 6H), 3.55 (s , 3H), 3.26 - 3.18 (m, 2H), 2.37 (s, 3H). Stage 3 TEA (900 pL, 4.73 mmol) was added to a suspension of 4-hydroxy-2,8-dimethyl-6-(morpholine-4carbonyl)-7H,8H-pyrido[2,3- d]pyrimidin-7-one (320 mg, 1.05 mmol) in DMF (11.2 mL). 2,4,6-Triisopropylbenzenesulfonyl chloride (637 mg, 2.1 mmol) and DMAP (13 mg, 0.11 mmol) were added and the reaction mixture was stirred for 1 h before adding (1 R)-1-[3- (difluoromethyl)-2fluorophenyl]ethan1-amine hydrochloride (320 mg, 1.42 mmol) and the reaction was stirred overnight at rt. The reaction mixture was diluted with diethyl ether, washed with water and brine, dried with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The crude product was purified by prep-HPLC to provide 4-{[(1 F?)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-2,8dimet ¡lo-6-(morpholine-4-carbonyl)-7H,8H-pyr¡do[2,3-d]pyrimidin-7-one (100 mg, 20% yield). LCMS (ESI): m / z: [M+H] calculated for C23H25F3N5O3: 476.2; found 476.0.1H NMR (300 MHz, methanol-dt) δ ppm 8.44 (s, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.49 (t, J= 7.1 Hz, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 54.9 Hz, 1H), 5.80 (q, J = 7.1 Hz, 1H), 3.78 (s, 4H), 3.71 (s, 3H), 3.71 -3.66 ( m, 2H), 3.41 (t, J = 4.8Hz, 2H), 2.43 (s, 3H), 1.64 (d, J=7.1 Hz, 3H). The following examples 26-1 to 26-52 shown in Table 8 were synthesized similarly to 228 Example 26. Table 8. Examples 26-1 to 26-52 Example # Structure Mass found 26-1 F fZz ^NH 0 XA a I 450.6 26-2 Z / >— Z V—J y / / i —z / / OZ ' ^NH O χνΛνΛο °h I 462.5 26-4 F f^A Anh n nAz / Aq η J I N nA) I 474.0 229 26-5 F F T Ύη 0 Ao 474.4 26-6 F 'Ύη o ύΧ I 474.4 26-7 F fY εΎ 'Ύη o nAxYnX Y / N. N N O I 475.0 26-8 TI \—TI / Y xO Z / )-Z —y Ύ 1 —z 2 c / )=O -Z O-A; T\476.5 nozrcn / zznz / q / υιλι 5 26-9 230 F F 'l 0 vLXo Q I 476.6 10 15 26-10 Z / >—Z vJ y 7 x —Z 7 oz )=o —z ¿ / Π ξ z 483.6 20 26-11 F fLo f^ X ^NH O CoM I 487.2 25 F F 30 26-12 Xzx ''r~\ z n—z ^\\ 7 x —H 7 oz L=o 488.4 nozrcn / zznz / q / υιλι 231 26-13 F F y ''' ^NH O 16 F fZo f^X ''ANH 0 xCX^nO-h N ΧΧ 488.5 nozrcn / zznz / q / υιλι 232 26-17 F '' NH 0 S® nAy^anan / y X 1 1 N N^O 1 489.3 nozrcn / zznz / q / υιλι 233 nozrcn / zznz / q / υιλι 2. 3. 4 26-25 F F l ,ANH 0 A N^O xvX° I 490.5 26-26 z·—' o4 o \ — Λ—λ Z—V ~Z. \ / X 495.2 26-27 F fXo f^ '''^NH O VA 495.4 26-28 F fXo F^l '''ANH o νΛΝΛο na 1 495.5 nozrcn / zznz / q / υιλι 235 26-29 F F T N N 0 I 495.6 26-30 Cr o \ 2— z # o7 )=o / —z z=\ / — 498.5 26-32 F ρΛΟ F^l ''' ^NH O JL X N N— N N OM J I 501.5 nozrcn / zznz / q / υιλι 5 26-33 236 F FAy F l '''' ΉΗ 0 Ά'ο 502.5 10 15 26-34 F f^ 'Άη 0 502.5 20 26-35 / =zx Z / )— z '--J 0 # X —z # C> / =O o—' 504.5 25 30 26-36 F fAo ''' ^NH O ÚXCF 1 504.5 nozrcn / zznz / q / υιλι nozrcn / zznz / q / υιλι 238 26-41 F F l ''Zh 0 oh I 516.4 26-42 F F^O ''''Ζη 0 vU Z 516.5 26-43 / =zx zzA Z / >— z vJ \\ / / z —H / 7 o i 0 ύ 517.0 26-44 TI \—"Π / =z\ —z \ o i 517.5 nozrcn / zznz / q / υιλι 239 26-45 F F y Ύ O ^ν^νλο Nl0H i Y 517.5 26-46 F fAY εΎ Ύη o 0 nAyAnAx Y / O N N ^O I 518.4 26-47 / Y χχ# Z / )—Z v—J 'λ / / I —H / / a i OQ 518.5 26-48 F fY F^y '''^NH O N Χγ / χΝΥ N N 0 0 I 519.5 nozrcn / zznz / q / υιλι 26-49 240 F fA^) F^T N N Y I 524.2 26-50 co __ LL 515.3 26-52 F 'Λπ 'A ''' NH 0 A^° Y^nAd I 522.14 Example 27: Synthesis of 4-{[(7R)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl¡l]am¡no}-2,8-dimethyl-6nozrcn / zznz / q / υιλι 241 [(morpholin-4-yl)meth-yl]-7H,8H-pyrido[2,3-d]pyrimidin-7-one Stage 1 A solution of 6-bromo-4-hydrox¡-2,8-dimethyl-7H,8H-pyrido[2,3-d]pyr¡m¡din-7-one was degassed ( 500 mg, 1,851 mmol) in aqueous ethanol (ethanol / water, 9:1.20 mL) and potassium (morpholin-4-yl)methyltinfluoroborate (498 mg, 2.41 mmol), palladium (II) acetate was added (12 mg, 0.056 mmol), XPhos (44 mg, 0.093 mmol) and cesium carbonate (1.51 g, 4.63 mmol). The mixture was stirred in an inert atmosphere at 80 °C for 18 h. The mixture was filtered through a pad of Celite®, the solvent was removed under reduced pressure and the residue was purified by column chromatography to provide 4hydroxy¡-2,8-dimethyl-6-[(morpholin- 4-¡l)methyl]-7H,8H-pyr¡do[2,3-d]pyr¡m¡din-7-one (196 mg, 37% yield). LCMS (ESI): m / z: [M+H] calculated for C14H19N4O3: 291.1; found 291.1. Stage 2 To a solution of 4-hydroxy-2,8-dimethyl-6-[(morpholin-4-yl)methyl]-7H,8H-pyrido[2,3-d]-pyrimidin-7-one (300 mg , 1.11 mmol) in DMF (9.0 mL) 2,4,6-triisopropylbenzenesulfonyl chloride (673 mg, 2.2 mmol), TEA (952 pL, 5.00 mmol) and 4-dimethylaminopyridine (53.2 mg, 0.44 mmol) were added. The reaction mixture was stirred at rt for 1 h. (1 fi)-1-[3-(Difluoromethyl)-2-fluorophenyl]ethan1-amine hydrochloride (330 mg, 1.50 mmol) was added and the mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product was purified by prep-HPLC to provide 4-{[(1R)1 -[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2,8-dimethyl- 6-[(morpholin-4-yl)meth-yl]-7H,8H-pyrid[2,3d]piñmidin-7-one (50 mg, 10% yield). LCMS (ESI): m / z: [Μ +H] calculated for C23H27F3N5O2: 462.1; found 462.0.1H NMR (300 MHz, methanol-d4) δ ppm 8.26 (s, 1H), 7.57 (t, J = 7.5 Hz, 2H), 7.45 (t, J= 7.1 Hz, 1H), 7.21 (t, J= 7.8 Hz, 1H), 7.00 (t, J= 54.9 Hz, 1H), 5.77 (q, J = 7.0 Hz, 1H), 3.71 (t, J= 4.6 Hz, 4H), 3.65 (s, 3H) , 3.49 (s, 2H), 2.55 (t, J = 4.7 Hz, 4H), 2.37 (s, 3H), 1.64 (d, J= 7.1 Hz, 3H). Example 28: Synthesis of 4-(4-{[(1 phy)-1-[3-(difluoromethyl)-2-fluorophenyl]-ethyl]amino}-8-methyl-7-oxo242 7H,8H-pyrido[2,3-d]pyrimidin-6-yl)-4-hydroxy-1A6-thiano-1,1-dione Stage 1 To a solution of 6-bromo-4-{[(1 / 7)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8H pyridide[2 ,3-d]pyrimidín-7-one (150 mg, 0.35 mmol) and tetrahydrothiopyran-4-one dioxide 1,1 (104 mg, 0.7 mmol) in THF (4.5 mL) at -78 °C a solution of 20.1 M Sml in THF (24.6 mL, 2.46 mmol) was added. After 4 h of stirring at −78 °C, additional 20.1 M Sml solution in THF (1.4 mL, 0.14 mmol) was added and the reaction mixture was stirred overnight at rt. The reaction was quenched with a sat. ac. of NH4Cl and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to provide 4-(4-{[(1 / =?)-1-[3-(difluoromethyl)-2-fluorophenyl]-ethyl]amino}-8-methyl-7-oxo -7H,8H-pyrido[2,3d]pyrimidin-6-yl)-4-hydroxy-1 A6-thiano-1,1-dione (80 mg, 46% yield). LCMS (ESI): m / z: [Μ +H] calculated for C22H24F3N4O4S: 497.1; found 497.0.1H NMR (300 MHz, DMSO-cfe) δ ppm 8.74 - 8.59 (m, 2H), 8.37 (s, 1 H), 7.71 - 7.59 (m, 1H), 7.52 (t, J = 7.1 Hz, 1 H), 7.31 (t, J = 7.7 Hz, 1H), 7.25 (t, J= 54.4 Hz, 1H), 5.97 (s, 1H), 5.77 (t, J=7.0 Hz, 1H), 3.60 (s , 3H), 3.43 (d, J= 13.1 Hz, 2H), 3.15-2.95 (m, 4H), 1.92 (d, J= 13.9 Hz, 2H), 1.59 (d, J = 7.0 Hz, 3H). The following examples 28-1 to 28-9 shown in Table 9 were synthesized in a similar manner to Example 28. 243 Table 9. Examples 28-1 to 28-9 Example # Structure Mass found 28-1 L—χ \—Xo o \ z— i 7-Λ Z—7 Z Fyp z= / LL 462.2 28-2 n 2—-° H'Hy \\ / / X —ζ Λ \ 7 x 7—\ ° O X-, '—z 476.2 28-3 ti \—ti Z / )—z ' 7 \\ y / \ P o Vx Z^z7-Λ ZX Z z= / LL 507.04 244 28-5 / \V I τ ¿Αχν o \ z— x O r-λ 7—V Z yjM z= / LL--¿ LL 523.3 28-6 o O - 11 ( A Vo o \ z— χ / / y Λ -Λ Z—V Z Πχ z= / LL--¿ LL 537.0 28-7 o O- 11 ω Δ P o \—% T\ z_ i PP / / —λ θ' z—V -z. CVa z= / LL—¿ LL 469.3 28-8 F ρΛπ F^| o A A Me'' NH Α^'Ν^'Μθ 7 hoJ j n Ñ 1 1 N N^O Me 490.1 nozrcn / zznz / q / υιλι 245 Example 29: Synthesis of 4-(4-{[(1 fi)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-methyl-7-oxo7H,8H -pyrido[2,3-d]-pyrimidin-6-l)-4-fluoro-1Ae-thiano-1,1-dione Stage 1 To a solution of 4-(4-{[(1 R)-1-[3-(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-methyl-7- oxo-7H,8Hpyrido[2,3-d]pyrimidin-6-yl)-4-hydroxy-1 A6-thiano-1,1-dione (150 mg, 0.3 mmol) in DCM (4.5 mL) at 0 °C in N2 DAST was added (60 pL, 0.45 mmol). The reaction mixture was stirred at rt for 2. Sat. ac. of NaHCO3 and the mixture was extracted with DCM. The organic layer was dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to provide 4-(4-{[(1 / 3)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl -7-oxo7H,8H-pyrido[2,3-d]-pyrimidin-6-¡l)-4-fluoro-1 Ae-thiano-1,1-dione (76 mg, 50% yield). LCMS (ESI): m / z: [Μ +H] calculated for C22H23F4N4O3S: 499.1; found 499.1.1H NMR (300 MHz, DMSO-de) δ ppm 8.71 (d, J = 7.2 Hz, 1H), 8.62 (s, 1 H), 8.39 (s, 1 H), 7.64 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.1 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 5.75 (p, J = 7.0 Hz, 1H), 3.59 (s, 3H), 3.49-3.36 (m, 3H), 3.27-3.07 (m, 3H), 2.24-2.12 (m, 2H), 1.58 (d, J = 7.0 Hz, 3H) . The following examples 29-1 to 29-15 shown in Table 10 were synthesized in a similar way 246 to Example 29. Table 10. Examples 29-1 to 29-15 Example # Structure Mass found 29-1 Π \—TI / =z\ 7 x —Z 7 o ® Z 436.1 29-2 / =zx ΑχΊ / \\ / / I —z 7 λ---ζ τι O VL > ° 464.1 29-3 / =zx r-\¡) Z / )—z ' ' 7 Z 478.2 nozrcn / zznz / n / υιλι 247 29-5 F F y o NH A^N^X γγγ z Λ— z '—y \\ / / z —z # o xa ω-Ο O 539.11 29-8 / =zx zxAA z Λ—z 3 v 7 \\ / / T —Z Y o yC ^Φ-Ο II O 511.08 nozrcn / zznz / q / υιλι 248 29-9 Π / =ζχ ζΧΧ Ζ / >—Ζ 2 V_7 Α / / I —ζ Η οΑ 497.2 29-10 I I Π λ—-Π / =\ ζΧΧ ζ Λ—ζ 3 ν_y Α / / I —ζ Α ο”γΑ ο'\ I________________________________________________________________________________________________________________________________________________________________________________________________________________I 497.4 29-11 Ο II χ—ω=ο yP Ρ \ ζ— ι ΡΡ 7 / λ 2 ζ—7 ζ ==7 485.1 29-12 I I -π \—τι ζ / >— ζ 3 ν_y A# ζ —Ζ 7 Ο=ω— / II 1____________°___________________________________1 485.2 nozrcn / zznz / q / υιλι 249 29-13 TI Π \—TI Z / )—z 3 V_7 / 7 T —Z / 7 \¿ TI oz ^Z^ 7 506.14 29-14 F f^Z ''' NH F A X xo N N O 1 498.1 29-15 1 1 T Pp / O \ z— f / —λ ? z—7 z z= / 1________________________________________________________________________________________________________________________________________________________________________________________________________________1 co 498.5 Example 30: Synthesis of 4-{[(1 / 7)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-6(phenylsulfanyl)-7H,8H- pyrido[2.3 - d]pyrimidin-7-one thiophenol F Pd(PPh3)4t-bu'.jodia oxide DMSO. 100cC Stage 1 250 A solution of 6-bromo-4-{[(1 / z?)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8Hpyrido[2, 3-d]pyrimidin-7-one (200 mg, 0.47 mmol) in DMSO (1.2 mL) was purged with argon for 15 min. Pd(PPh3)4(43 mg, 0.037 mmol) was added and the reaction was stirred at 100 °C for 1 h. Then, a solution of thiophenol (48 pL, 0.47 mmol) and sodium f-butoxide (90 mg, 0.94 mmol) in DMSO (5.0 mL) was added dropwise. The reaction mixture was stirred in N2 overnight at 100 °C. The mixture was filtered through a layer of Celite®, diluted with sat. ac. of NaHCO3, extracted with EtOAc, dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC to provide 4-{[(1 R)-1-[3(difluoromethyl)-2-fluorophen¡l]ethyl]amino}-8-met ¡lo-6-(phen¡lsulfan¡lo)-7H,8H-p¡ñdo[2,3 - d]pyrimidin-7one (64 mg, 30% yield). LCMS (ESI): m / z: [Μ +H] calculated for C23H2oF3N4OS: 457.1; found 457.1.1H NMR (300 MHz, DMSO-cfe) δ ppm 8.85 (s, 1H), 8.53 (d, J= 7.2 Hz, 1H), 8.38 (s, 1H), 7.61 (t, J= 7.4 Hz, 1H), 7.51 (t, J= 7.1 Hz, 1H), 7.39 - 7.17 (m, 6H), 7.24 (t, J= 54.5 Hz, 1 H), 5.79 - 5.62 (m, 1 H), 3.57 (s , 3H), 1.54 (d, J = 7.0 Hz, 3H). Example 31: Synthesis of 6-(4-aminooxan-4-yl)-4-{[(1F?)-1-[3-(difluoromethyl)-2fluorophen¡l]ethyl]amino}-8-methyl- 7H,8H-pyrido-[2,3-d]pyrimidin-7-one Stage 1 A solution of 6-bromo-4-{[(1 / 7)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7H,8H pyrido[2,3 - d] -pyrimidin - 7 - one (330 mg, 0.77 mmol) and tetrahydro-4H-pyran-4-one (140 pL, 1.54 mmol) in THF (10 mL) was cooled to -78 °C and then 0.1 M Sml2en was added THF (54 mL, 5.41 mmol). The reaction mixture was stirred at −78 °C for one hour, then warmed to rt and quenched with sat. ac. of NH4CI, extracted with EtOAc, dried with anhydrous Na2SO4, filtered and the solvent 251 was removed under reduced pressure. The crude product was purified by column chromatography to provide 4-{[(1 fi)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-6-(4-hydrox ¡oxan-4-¡l)-8-methyl-7H,8Hpyrido[2,3-d]pyrim¡din-7-one (254 mg, 73% yield). LCMS (ESI): m / z: [Μ +H] calculated for C22H24F3N4O3: 449.2; found 449.3.1H NMR (300 MHz, chloroform-d) δ ppm 8.46 (s, 1H), 7.64 - 7.41 (m, 3H), 7.22 (t, J = 7.7 Hz, 1H), 6.92 (t, J = 55.0 Hz, 1H), 5.98 (d, J = 7.4 Hz, 1 H), 5.76 (p, J = 7.1 Hz, 1H), 5.60 (s, 1H), 4.07 (tt, J= 11.3, 3.9 Hz, 2H) , 3.90 (d, J= 10.6 Hz, 2H), 3.76 (s, 2H), 2.20 - 1.95 (m, 4H), 1.71 (d, J = 7.0 Hz, 3H). Stage 2 Concentrated sulfuric acid (1.5 mL, 27.4 mmol) was added dropwise to a suspension of 4{[(1 / ?)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-6-(4 -hydroxyoxan-4-yl)-8-methyl-7H,8H-pyrido[2,3d]piñm¡din-7-one (225 mg, 0.5 mmol) in MeCN (4.3 mL) at 0 °C. The solution was stirred at rt overnight and then poured onto ice and the pH was adjusted to 8 with sat solution. ac. of NaHCO3. The solution was extracted with DCM, washed with brine, dried with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure to provide N-[4-(4-{[(1 / 7)-1 [3-( difluoromethyl)-2-fluorophenyl]ethyl]amino}-8methyl-7-oxo-7H,8H-pyr¡do[2,3-d]pyrim¡din-6-¡l)oxan -4-¡l]acetam¡de (220 mg, 98% yield). LCMS (ESI): m / z: [Μ +H] calculated for C24H27F3N5O3:490.2; found 490.1.1H NMR (300 MHz, DMSO-de) δ ppm 8.49 (d, J=7.2 Hz, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.63 ( t, J=7.5Hz, 1H), 7.52 (t, J = 7.1 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 5.79 (q , J = 7.0 Hz, 1H), 3.74 (d, J= 7.7 Hz, 4H), 3.55 (s, 3H), 2.72 (d, J= 13.1 Hz, 2H), 2.02 - 1.83 (m, 2H), 1.80 (s, 3H), 1.61 (d, J=7.1 Hz, 3H). Stage 3 A solution of N-[4-(4-{[( 1 R)-1 -[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7- oxo-7H,8Hpyrido[2,3-d]pyrimidin-6-yl)oxan-4-yl]acetamide (220 mg, 0.45 mmol) in 3.0 M aq solution. of HCl (3.7 mL, 11.24 mmol) was heated at 100 °C overnight. The solution was poured onto ice and neutralized with sat. ac. of NaHCOs. The aqueous layer was extracted with DCM, dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC to provide 6-(4-aminooxan-4-yl)-4-{[(1 R)-1-[3-(difluoromethyl)-2fluorophenyl]ethyl]amino}-8-met¡l-7H,8H-pyr¡do-[2,3-d]p¡r¡m¡d¡n-7-one (38 mg, 18% yield). LCMS (ESI): m / z: [Μ +H] calculated for C22H25F3N5O2: 448.2; found 448.1.1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (d, J = 7.3 Hz, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.24 (t, J = 54.4 Hz, 1H), 5.83 - 5.69 (m, 1 H)), 3.95 (t, J = 11.2 Hz, 2H), 3.71 -3.64 (m, 2H), 3.59 (s, 3H), 2.13 - 1.96 (m, 4H), 1.87- 1.73 (m, 2H), 1.60 (d, J = 7.1 Hz, 3H). The following examples 31-1 to 31-11 shown in Table 11 were synthesized similarly to Example 31. Table 11. Examples 31 -1 to 31 -11 252 Example # Structure Mass found 31-1 Z / >—z '—7 0# X —Z y x / z Λχ \ ZZ k> λ—y z oz V-A A 589.3 31-3 S Λ A Ή % / =\ / =zx ΑΛ z> z Λ—z 3 0_y 0 / / X S-Z Λ> φ φ \ / / 1 / M / ZA ° / \ ° iro o 538.18 31-4 / ^Z\ AA# z A—z 3 0_y 0 # X —Z Ai \ / / ro λ—( Z oz ^0=0 II o 508.14 nozrcn / zznz / q / υιλι 253 31-5 or O- υ-ω—। p Z \\ CN / / \ xe z f,—λ £ z—(7 z v / A z= / LL—¿ U_ 536.2 31-6 Π \—TI / =z\ ζχγ Z Λ—Z 3 V_7 # I — ζ Λζ λ--í Z O Y 4Z)X ó''0 468.2 31-7 o w / \ P Λ—\ CN / / \ X<7 Z— I ZZ f / —λ θ' Z—(7 ζ / / Ζ 'ζ= / 481.8 31-8 1 / ( Ρ Ζ. Λ—\ ζ— ϊ^Ζ^ζ Υ / Κ ζ= / 1_________ί__________________________________________1 CO 525.2 nozrcn / zznz / q / υιλι 254 31-9 oz-Va t / / ” w° \ 494.4 31-11 1 '-x 1 O'A\ cn / / i Az p \ τ 2a / / —λ ? Z—(' z vaX z= / LL—ζ LL 1________________________________________________________________________________________________________________________________________________________________________________________________1 494.4 Example 32: Synthesis of 4-(4-{[(1R)-1-[3-(difluoro-methyl)-2-fluorophenyl]ethyl]amino} 8-methyl-7-oxo-7H,8H-pyrido[2 ,3 - d]pyrimidin - 6 - I) - 4 - methoxy - 1λβ- thiano - 1,1 dione nozrcn / zznz / q / υιλι 255 NaOMe ACN. MeOH. water Stage 1 To a solution of 4 - (4 - {[(1F?) - 1 - [3 - (difluoromethyl) - 2 - fluorophenyl]ethyl]amino} - 8 - methyl - 7 oxo - 7H,8H - pyrido[2,3 - djpyrimidin - 6 - ¡I) - 4 - hydroxy - 1Λ6- thiano - 1,1 - dione (190 mg, 0.38 mmol) in a mixture of ACN (4.75 mL), MeOH (2.85 mL) and water (0.95 mL) Sodium methoxide (186 mg, 3.43 mmol) was added. The reaction was stirred overnight. The reaction mixture was quenched with a sat. ac. of NH4CI, extracted with EtOAc, dried with anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC to provide 4-(4-{[(1R)-1-[3-(difluoro-methyl)-2-fluorophenyl]ethyl]amino}-8-methyl-7- oxo 7H,8H-pyrido[2,3-djpyrimidin-6-yl)-4-methoxy-1λ6-thiano-1,1-dione (138 mg, 71% yield). LCMS (ESI): m / z: [Μ +H] calculated for C23H26F3N4O4S: 511.2; found 511.0.1H NMR (300 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.33 (s, 1H), 7.58 (t, J= 7.5 Hz, 1H), 7.48 (t, J= 7.1 Hz, 1H ), 7.23 (t, J=7.7 Hz, 1H), 7.00 (t, J=54.9 Hz, 1H), 5.79 (q, J=7.1 Hz, 1H), 3.69 (s, 3H), 3.53 - 3.38 (m , 2H), 3.21 (s, 3H), 3.07 - 2.77 (m, 4H), 2.77 - 2.58 (m, 2H), 1.66 (d, J = 7.1 Hz, 3H). The following examples 32-1 to 32-115 shown in Table 12 were synthesized in a manner 256 similar to Example 32. Table 12. Examples 32-1 to 32-115 Example # Structure Mass found 32-1 / =zx Ha 1 —z # o 504.2 32-2 z^ \ P o\_Λ \ — χ JA Γ,—λ 2—7 z (Αχ z= / 490.1 32-3 \ z^. AX ° O / —\ \ z— I Γ,—λ 2-(7 Z \ / z= / 476.2 32-4 η \—TI / ^z\ aCy Z / )—z J / / X — H / / X \ o— ° / λ cí^ 551.2 257 32-5 / =zx z Λ—z ' 7 z —Z / 7 7\ ° / S ^~·ω=θ II o 523.2 32-6 F ρΛΟ F U ''' NH I r—N T oY ) H I I ^N ^N^O I 526.2 32-7 F ρΛΟ F | 0 Me' NH I || n v H I I ^N^N^O I 476.2 32-8 ξ Λ / <Dz / =^ / =zx A z / )— z 5 v_7 \\ # T —z A \ o— o Y z I 448.2 nozrcn / zznz / q / υιλι 258 32-9 O^z—λ P —o yy \ z— f / —λ ε z—<z z y / Y / z= / LL—ζ LL 490.3 32-10 F fYx F Ύ Y . %° ''' NH 1 / ~-m-s\ i ox / ΝΛγ[ / ''ί ú 1 1 1 512.1 32-11 F F^| or θγΎ Η 1 1 1 530 32-12 Xo °γ z^. / \ P —° \—\ \ x O f / —λ ε z \z z y γζζ z= / LL--¿ LL 546.0 nozrcn / zznz / q / υιλι 259 32-13 F F | o A I '' NH I K N ^^ 1 °Z J NAAA ú 1 1 ZZA 1 534.2 32-14 F fZz F ΊΓ 0 / A Α-ζ A< T —z \ )r \ o— o Y ^z 516.1 32-16 F ρΛΟ F i V •A Zo '''' NH 1 r-N Ϊ oZ \ n ΑζγΑΑ A Λ ^N^N ^O 1 526.3 nozrcn / zznz / q / υιλι 260 32-17 Π 2—-Π / =ζχ ττΟ ζ Λ—ζ 3 ti_7 χ^γ^ ρ —ο \ ζ I 7Χ 7—X ζ—7 ζ yLz ζ= / 516.1 32-19 cAzX θ —° \F. \ ζ— 7—ti \ 2 / / Lz ζ= / 490.1 32-20 F fLo F^Y O ''' nh I A A H J I I 530.2 nozrcn / zznz / q / υιλι 261 32-21 F fA< f^ A o ® NH I A T °AAn^ Ν'γγνΧ d A A I 530.2 32-22 F fAa f ΊΓ 0 •X u T oJ νΑ / Υ / \Ω ú I I I 530.2 32-23 F fA< F < A 7 NH I r—N A °A ) Ν^γ^γίΑ7 ñ I I ^N^N^O I 490.1 32-24 ΤΊ 2—Π / =a aO z / Yz 5 v_7 VA 1 —Z / 7 7— \ O— ° / Ά Z\ <z>C / O 540.1 nozrcn / zznz / n / υιλι 262 32-25 ζ ζ 3 ν_y y / / ζ —ζ / / λ—\ Ο— O V-A λ° 516.1 32-26 Π \—Π >ζ ζ Λ— ζ 3 ν_y y / / ζ —Ζ / 7 Λ— ( ο— ο Υ ζ <7\ 530.1 32-27 / =\ V-O ζ / —ζ 3 ν_y \\ # Ζ —ζ / ο Αγ \\ Ο 537.17 32-28 °Ρ ζ^. "-Λ?' 7 - > Υ <ζ> / ΥΑ / ° —o va \ ζ— Λ—Λ £- Ζ—Ζ / Χχ ζ= / LL—¿ LL 518.1 nozrcn / zznz / q / υιλι 263 32-29 z^ y / o —° yy \ z— Λ—Λ £ Z—Z Z 532.1 32-30 °z 1111 · / C / ? —. > \ 00 / P —ο yy \ z— Λ—λ ¢- Z7 Z ξ Vy 2=7 518.1 32-31 °z Z^ IH(CO —, > V c / Z\ P —° yy \ z— Λ —Λ ¢- Z—7 Z c Vy 518.1 32-32 z / >—z 3 v_7 \\ / / I Z 7 o— o y¿ ^z^ 518.2 nozrcn / zznz / q / υιλι 264 32-33 o II θ=ω-\ / ( Lo / ° \ z— χ pp y—λ £ z—z ξ z= / 525.2 32-34 I I o II Ο=ω—κ / ( l / O P \ z — χ PP y—λ £ z—v z yx z=^ LL I________________________________________________________________________________________________________________________________________________________________________________________________________________I co 525.2 32-35 pp ° —° \—y \ z~ χ pp / / —λ ó? z— <z z yx zz 530.1 32-36 F f Ά , 0 NH I X A n V Z \^L í u ^N^N^O 516.1 nozrcn zznz q υιλι 265 32-37 Π \—-Π =α Αχ# ζ / > —ζ 3 ν_y \\ / / —ζ \ ο— o yA ί,ζ ,ο IS [ 504.1 32-39 F fX f __ =ζ\ ζ / >— ζ 3 ν_y 'λ / / X —ζ \ ^Γ~\ ο— c> \s °Χ'Ζ\ 504.1 nozrcn / zznz / q / υιλι 266 32-41 F f^A ''' NH I χΧΧο o I 504.1 32-42 Π \—TI / =zx zXX z Λ—z 3 V_7 / / I — Z y । A 530.1 32-43 I I °M i \a°o \ z— zr^x ? ζ—ςΧζ ξ Va LL—¿ LL LL I__________________________________________________________________________________________________________________________________________________________________________________________________________I co 530.1 32-44 V V 0' A Z^N ' NH < \ η I L ° ^N^N^O I 530 nozrcn / zznz / q / υιλι 267 32-45 o II _ __i-A \ — I #0 / i—λ £ z—y z / A 509.2 32-46 I I TI X--TI / =^ AA / > z / >—z 3 0_y y y T — Z y A—u'' II 1_________________________________°______________________1 co 509.1 32-47 F fA^ F^l 0 I / A AC>- ú I I N N^O I 504.1 32-48 o —o'' \ \ z— i / A f ,—0 ? -Z—(' z / yA LL— / LL 504.1 nozrcn / zznz / q / υιλι 268 32-49 Z / >—Z 3 Y_y Y / / X / — O < 1 ,O 504.1 32-50 / =z\ XXv z / )—z 3 Y_y Y / / f1 / 504.1 32-51 F fAo F A i A 'nh 1 iAFn^A ^N^N^O 1 518.1 32-52 ΤΊ 2—Π / =z\ XX# z Λ— z 5 Y_y Y # X —z # A \ o— O A y / 3 vz >° 532.1 nozrcn / zznz / q / υιλι 269 32-53 F F 0 J / R) \Z II Ah I ϊ j N |l I I I 532.1 32-54 TI \--TI f=\ Z Λ—Z 3 V_'J χ # X —Z 7 οοΑ J L C0' ° / o O 555.2 32-55 — χ JA 1 / —λ ? z Y 2 ( / A Ll_— / LL 463.1 nozrcn / zznz / q / υιλι 270 32-57 Π \—-Π / =ζ\ ζ Λ—ζ 3 ν_y A# τ —Ζ y C> Χχ -Ο ύ ° 553.17 32-58 Π \—Π )=ζ ζ Λ—ζ 3 ν y Α # I —ζ y \ ο— or ζ y° 504.1 32-59 F ρΛΧ F^l I NH Á .—. Ο ι Ά / \ 11 ν^ΧΧ / η Λ Λ 0 Ν Ν X 1 539.1 32-60 nozrcn / zznz / q / υιλι 271 32-61 Ζ 1 \ ζ— 1 ζζ ί / —λ £ ζ—ν ζ Ζ ^ / Ζ 520.2 32-62 οΑ ζ-ά —° yy \ ι ζζ Γ,—λ ? ζ Qa -α LL— / LL LL 504.1 32-63 ^Ζ Ζ-ΧΔ Ζ / >— Ζ 3 V_7 \\ / / Τ —ζ \ / )—< ρ— Ο \—ζ □Ί σ ο 493.1 32- 64 / =ζχ Zr-C / Ζ / )— Ζ 5 V_7 # Ζ —Ζ \ o JZ \ η Ο \ ω'° 1 '— / \χ ° 525.2 nozrcn / zznz / q / υιλι 272 32-65 I I o \__ i \ / O ° \ Ay o \ z— £ z—^~^z (V z= / I________________________________________________________________________________________________________________________________________________________________________________________________I 525.31 32-66 I I O \__ i n;W \ .O ° V A P \ z~ z ^\ e z^y ^z Ox z= / 1__________________________________________________________________________________________________________________________________________________________________________1 co 525.05 32-67 1 1 O \__ i \ o ° A / \ P \ z~ 1________í__________________________________1 1 525.32 32-68 F fV v Xz I X NH I < > Ϊ ° A J |l I I ^N^N^O I 504.1 nozrcn / zznz / q / υιλι 273 32-69 Π \—-Π 5=ζ Ζ / >—ζ 3 V 7 Y# # I —z \ o XA 4 y 516.2 32-71 I I f=\ z=AA Z ,)—Z 3 V 7 \\ / / / ° \ z— i 2a / —λ ? z C / V z= / 503.19 nozrcn / zznz / q / υιλι 274 32-73 Π 2—-Π / =ζ\ ζ Λ—ζ 5 ν 7 # —ζ 2 ° Ο-ω— / II ι_____________Ξ______________________________ι 497.2 32-75 θΑ\ ζ \ ο ο Q-^-° Ατ Q 7 ζ— χ 7—λ ? ζ ζ 493.1 32-76 ο<τ^ ζ Ρ —ο νγ \ ζ— χ yy ί / —λ θ' Ζ—<ζ ζ χ 2—ζ ζ= / ^Τχ / 0 514.1 nozrcn / zznz / q / υιλι 275 nozrcn / zznz / q / υιλι 276 32-81 F । d d I 507.1 32-82 z Q S< o Q^—O \-7 Q 7 I TV λ—V z—7 z / Y 507.2 32-83 F FÓO / V '' NH O Y \>x\ N \ Z\ S ii '—< U X. o N N 1 590.18 32-84 ° —° \—7 \ z— τ TV / Yz z=Z 537.4 nozrcn / zznz / q / υιλι 277 32-85 1 5 P 1 ω —° \—7 \ Z~ a= / LL—¿ U- LL 1_________________________________________________________________________________________________________________________________________________________________________________________________1 537.4 32-86 F fLq A । ? NH I < S=O 1 °4 J |i J 1 ^N^N^O 1 507.1 32-87 z / >—z 5 ti__7 \\ 7 x —2 7 \—\ o— O VA Xz O 500.1 32 -88 F fAjO f yD X nh 1 ,—. o VyCX ^N^N^O 1 505.2 nozrcn / zznz / q / υιλι 278 32-89 F F^T •Y Z NH 1 / —\ o nYXA D^D D 507.1 32-90 rx —o γγ \ z— f / —λ ε zx z y / Y z=Z 506.1 32-91 o . \___( Υγ X# z / )-z 3 v_y Ύ< 1 —Z / 7 γγ o— o ^z^ 505.1 32-92 o. -- γγ í=\ Ύγ z> z / >—z 3 v_7 'λ / / z —Z / 7 Λ—( O— ° X / 491.1 nozrcn / zznz / q / υιλι 279 32-93 z Λ—z 3 v_7 \\ / / T —Z ...

Claims

1. A compound having the structure of Formula (I), Ri h3c'' nh h AAA χΤΎ4 Rg^lM N'®) R3 (i) or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein: Ri is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6 membered aryl and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, C1-6 alkyl, halogen, -NHR2a, -OR2a, cyclopropyl and -CN; wherein the Ci-e alkyl is optionally substituted with halogen, -NHR2a, OR2ao 5-6 membered heterocyclyl, and further wherein R2a is selected from the group consisting of H, Ci-6 alkyl, 3-6 membered heterocyclyl and Ci-β haloalkyl;R3 is selected from the group consisting of H, Ci-3 alkyl, -OR3a, cyclopropyl, and 3-6 membered heterocyclyl, wherein each of the Ci-3 alkyl, cyclopropyl, and 3-6 membered heterocyclyl is optionally substituted with R3a, and furthermore R3a is selected from the group consisting of Ci-3 alkyl, halogen, -OH, or -CN; L4 is selected from the group consisting of bond, -C(O)-, -C(O)O-, -C(O)NH(CH2)o-, NH-, -S-, -S(O)2-, O, -(CH2)P-, and -O-; wherein O is 0, 1, or 2; and wherein p is a number from 1 to 6; and R4 is selected from the group consisting of H, Ci-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;wherein each Ci-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with Ci-6 alkyl, -R4a, -OR4a, -O-Ci-6-R4a alkyl, -O, halogen, -C(O)R4a, -C(OO)R4a, -C(O)NR4bR4c, -NR4bC(O)R4c, -CN, -NR4a, -NR4bR4c, -SO2R4a, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl substituted with R4a; wherein R4a is H, Ci-6 alkyl, Ci-6 haloalkyl, -C(O)R4b, -C(O)NR4bR4c, =0, 3- to 6-membered cycloalkyl, 6- to 10-membered aryl optionally substituted with -OR4b, -CN, =N-3-6-membered cycloalkyl, 3-7-membered heterocyclyl, -(CH2)rOCH3, or -(CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, Ci-θ alkyl;and where each R4c is independently H or C1-6 alkyl.; 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein Ri is an optionally substituted 6-membered aryl group.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein Ri is an optionally substituted 5-6 membered heteroaryl.

4. The compound of claim 1, having the structure of Formula (II), r3 (II) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, wherein R2, R3, L4, and R4 are as defined in claim 1; Rs, Re, R?, Rs, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OH, halogen, -NO2, -CN, -NR11R12, -SR10, S(O)2NRnRi2, -S(O)2Rio, -NRi0S(O)2NRiiRi2, -NRioS(O)2Ru, -S(O)NRhRi2, -S(O)Rw, NRioS(O)NRnRi2, -NRioS(O)Rh, -C(O)Rio, -CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl are optionally substituted with -OH,optionally substituted C1-6 alkyl with -R10, halogen, -NO2, oxo, -CN, -R10, -OR10, -NR11R12, -SRio, -S(O)2NRnRi2, -S(O)2Rio, -NRioS(O)2NRiiRi2, -NRioS(O)2Rh, -S(O)NRhRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, -NRi0S(O)Rh, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rw, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forming an optionally substituted fused 3-14 membered ring; Rio, Rii and R12 are independently selected each time they occur from among H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OR13, -SR13, halogen, -NR13R14, -NO2, and -CN; and R13 and R14 each time they occur are independently selected from among H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl,wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, -SH, -NH2, -NO2 or -CN.

5. The compound of claim 1, having the structure of Formula (III), or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2, R3, L4, and R4 are as defined in claim 1; Rs, Re, R7, Rs, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OH, halogen, -NO2, -CN, -NRhRi2, -SR10, S(O)2NRnRi2, -S(O)2Rio, -NRioS(O)2NRiiRi2, -NRi0S(O)2Rh, -S(O)NRhRi2, -S(O)Rw, NRioS(O)NRhRi2, -NRi0S(O)Rii, -C(O)Rio, -CO2Rw, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, alkenyl C2-6, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl optionally substituted with -OH, C1-6 alkyl optionally substituted with -R10,halogen, —NO2, oxo, —CN, — Rw, —OR10, — NR11R12, _SRio, —S(O)2NRhRi2, — S(O)2Rio, — NRioS(O)2NRiiRi2, -NRioS(O)2Rh, -S(O)NRhRi2, -S(O)Ri0, -NRioS(O)NRhRi2, -NRioS(O)Rn, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 form an optionally substituted fused 3-14 membered ring; R10, R11, and R12 are independently selected each time they occur from among H, D, C1-6 alkyl, C2-6 alkenyl, 4-8-membered cycloalkenyl, C2-6 alkynyl, 3-8-membered cycloalkyl, 3-14-membered heterocyclyl, -OR13, -SRi3, halogen, -NRi3Ri4, -NO2, and -CN; and Ri3 and Ri4 each time they occur are independently selected from among H, D, C1-6 alkyl, C2-6 alkenyl, 4-8-membered cycloalkenyl, C2-6 alkynyl, 3-8-membered cycloalkyl, and 3-14-membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl,4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, -SH, -NH2, -NO2 or -CN.

6. The compound of claim 1, having the structure of Formula (IV-a), (IV-b), or (IV- or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R2, R3, U, and R4 are as defined in claim 1; R5, Re, R?, Re, and Rg are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OH, halogen, -NO2, -CN, -NRhRi2, -SR10, S(O)2NRhRi2, -S(O)2Rio, -NRioS(O)2NRiiRi2, -NRi0S(O)2Rh, -S(O)NRhRi2, -S(O)Rio, NRiqS(O)NRiiRi2, -NRi0S(O)Rii, -C(O)Rio, -CO2Rw, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Ci-6 alkyl, C2.6 alkenyl, 4-8 membered cycloalkenyl, C2.6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with -OH,optionally substituted Ci-6 alkyl with -Rio, halogen, -NO2, oxo, -CN, -Rio, -OR10, -NRnRi2, -SR10, -S(O)2NRnRi2, -S(O)2Riq, -NRioS(O)2NRhRi2, -NRioS(O)2Rh, -S(O)NRhRi2, -S(O)Ri0, -NRi0S(O)NRhRi2, -NRi0S(O)Rn, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rw, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forming an optionally substituted fused 3-14 membered ring; Rio, Rii and R12 are independently selected each time they occur from among H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -ORi3, -SR13, halogen, -NRi3Ri4, -NO2, and -CN; and Ri3 and Ri4 each time they occur are independently selected from among H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl.wherein each C2-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl and 3-14 membered heterocyclyl are optionally independently substituted with -OH, -SH, -NH2, -NO2 or -CN.

7. The compound of any of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein one to three of Rs, R6, R?, Re, and Rg is a C1-6 halogen-substituted alkyl.

8. The compound of any of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein one to three of Rs, Re, R?, Rs and Rg is a C+e alkyl substituted with halogen and -OH.

9. The compound of any of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein one to three of Rs, R6, R?, Re, and Rg is a halogen, and one to three of Rs, Re, R?, Rs, and Rg is a halogen-substituted C1-6 alkyl.

10. The compound of any of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein one to three of Rs, Re, R?, Re, and Rg is —NH2.

11. The compound of any of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein one of Rs, Rs, R?, Rs, and Rg is -NH2; and one of Rs, Rs, R?, Rs, and Rg is a halogen-substituted C1-6 alkyl.

12. The compound of any of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein any two adjacent R5, R6, R7, R8 and R9 form a fused ring of 3-14 members, wherein the fused ring is substituted with a halogen.

13. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2 is H.

14. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2 is C1-6 alkyl.

15. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2 is a cis-substituted 5-6-membered heterocyclyl alkyl.

16. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2 is a Ci-6 alkyl substituted with -NHR2a, wherein R2a is a Ci-6 alkyl or 3-6 membered heterocyclyl.

17. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R2 is a C+e alkyl substituted with -OR2a, wherein R2a is a Ci-6 alkyl. 400 18. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2 is -NHR2a, wherein R2 a is Ci-6 alkyl.

19. The compound of any of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R2 is -OR2a, wherein R2a is Ci-6 alkyl.

20. The compound of any of claims 1-19, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R3 is Ci-3 alkyl.

21. The compound of any of claims 1-19, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R3 is a Ci.3 alkyl substituted with -OH.

22. The compound of any of claims 1-19, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R3 is H.

23. The compound of any of claims 1-19, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R3 is cyclopropyl.

24. The compound of any of claims 1-19, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R3 is a 3-6 membered heterocyclyl.

25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L4 is selected from the group consisting of alkyl linkages, -C(O)-, -C(O)O-, -C(O)NH(CH2)o-, -NH-, -S-, -S(O)2-, -(CH2)P-, and -O-; wherein o is 0, 1, or 2; and wherein p is a number of 26. The compound of any of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein L4 is a linkage.

27. The compound of any of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein L4 is-C(O)-.

28. The compound of any of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein L4 is -(CH2)P-, 29. The compound of any of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R4 is selected from the group consisting of H, C1-6 alkyl, 3-14-membered cycloalkyl, 3-14-membered cycloalkenyl, 3-14-membered heterocyclyl, 6-10-membered aryl, and 5-10-membered heteroaryl; 401 wherein each Ci-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl and 5-10 membered heteroaryl is optionally substituted with Ci-6 alkyl -OR4a, =0, halogen, -C(O)R4a, -C(OO)R4a, C(O)NR4bR4c, -CN, -NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl.

30. The compound of any of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R4 is a 3-14 membered heterocyclyl.

31. The compound of any of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R4 is a 3-14 membered heterocyclyl substituted with a 3-6 membered heterocyclyl.

32. The compound of any of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R4 is a Ci-6 alkyl-substituted 3-14 member heterocyclyl.

33. The compound of any of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R4 is a 3-14 membered heterocyclyl substituted with a 3-6 membered cycloalkyl.

34. The compound of any of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug or tautomer thereof, wherein R4 is a 3-14 membered heterocyclyl substituted with =0.

35. The compound of claim 1, or a salt, a solvate, or a pharmaceutically acceptable isomer thereof, selected from the compounds in compilation 1.

36. The compound of claim 1, or a salt, a solvate, or a pharmaceutically acceptable isomer thereof, selected from the compounds in compilation 2.

37. The compound of claim 1, or a salt, a solvate, or a pharmaceutically acceptable isomer thereof, selected from the compounds in compilation 3.

38. The compound of claim 1, or a salt, a solvate, or a pharmaceutically acceptable isomer thereof, selected from the compounds in compilation 4.

39. The compound of claim 1, or a salt, a solvate, or a pharmaceutically acceptable isomer thereof, selected from the compounds in compilation 5.

40. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or group consisting of a hydrate, a tautomer or group consisting of a hydrate, a tautomer or group consisting of a hydrate, a tautomer or group consisting of a hydrate, a tautomer or group consisting of a hydrate, a tautomer or group consisting of a hydrate, a tautomer or group or a pharmaceutically acceptable isomer thereof, selected from the group consisting of the compounds in Table A.

41. A pharmaceutical composition comprising a compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.

42. Use of a compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof, to prepare a medicament for inhibiting SOS1 in a subject.

43. An in vitro method for inhibiting the interaction of SOS1 and a RAS family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising contacting the cell with a compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof.

44. Use of a compound of any of claims 1-40, or one of its pharmaceutically acceptable salts, solvates, hydrates, tautomers or isomers, to prepare a medicament for treating or preventing a disease, wherein treating or preventing the disease is characterized by the inhibition of the interaction of SOS1 and a protein of the RAS family or by the inhibition of the interaction of SOS1 and RAC1.

45. Use of a compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof, to prepare a medicament for treating or preventing cancer in a subject in need.

46. ​​Use according to claim 44 or 45, wherein the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematologic cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the upper respiratory and digestive tracts, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcomas.

47. Use in accordance with claim 44, wherein the disease is a RASopathy.

48. Use according to claim 47, wherein RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Capillary Malformation-Arteriovenous Malformation (CM-AVM) syndrome, Costello syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFG), Legius syndrome, and hereditary gingival fibromatosis.

49. Use according to claim 45 or 46, wherein the cancer comprises a RasMUT or NF1LOF mutation. 403 50. A compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof for use in inhibiting SOS1 in a subject.

51. A compound of any of claims 1-40, or one of its salts, solvates, hydrates, tautomers or isomers pharmaceutically acceptable for use in treating or preventing a disease, wherein treating or preventing the disease is characterized by the inhibition of the interaction of SOS1 and a protein of the RAS family or by the inhibition of the interaction of SOS1 and RAC1.

52. A compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or isomer thereof for use in treating or preventing cancer in a subject in need.

53. The compound for use according to claim 51 or 52, wherein the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematologic cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the upper respiratory and digestive tracts, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcomas.

54. The compound for use in accordance with claim 51, wherein the disease is a RASopathy.

55. The compound for use according to claim 54, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Capillary Malformation-Arteriovenous Malformation (CM-AVM) syndrome, Costello syndrome (CS), Cardiofaciocutaneous syndrome (CFG), Legius syndrome, and hereditary gingival fibromatosis.

56. The compound for use according to claim 52 or 53, wherein the cancer comprises a RasMUT or NF1L0F mutation.