Bicyclic heteroaryl compounds and uses thereof

Abstract

The present disclosure is directed to modulators of SOS1 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.

Description

BICYCLIC HETEROARYL COMPOUNDS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of priority to U.S. provisional Application Ser. No. 62 / 933,141, filed November 8, 2019, the disclosure of which is hereby incorporated by reference as if set forth in its entirety. This application claims the benefit of priority to U.S. provisional Application Ser. No. 63 / 031,318, filed May 28, 2020, the disclosure of which is hereby incorporated by reference as if set forth in its entirety. This application claims the benefit of priority to U.S. provisional Application Ser. No. 63 / 070,593 filed August 26, 2020, the disclosure of which is hereby incorporated by reference as if set forth in its entirety. FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to inhibitors of SOS1 useful in the treatment of diseases or disorders. Specifically, the present disclosure is concerned with compounds and compositions inhibiting SOS1, methods of treating diseases associated with SOS1, and methods of synthesizing these compounds. BACKGROUND OF THE DISCLOSURE

[0003] 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 mutants thereof are small GTPases that exist in cells in either 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):p136). The RAS- family proteins have a 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 NF increases the GTPase activity of RAS-family proteins. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promote release of GDP from RAS-family proteins, enabling 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 the 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). Depleting SOS1 levels decreased the proliferation rate and survival of tumor cells carrying a KRAS mutation whereas no effect was observed in KRAS wild type cell lines. The effect of loss of SOS1 could not be rescued by introduction of a catalytic site mutated SOS1, demonstrating the essential role of SOS1 GEF activity in KRAS mutant cancer cells.

[0004] SOS is critically involved in the activation of RAS-family protein signaling in cancer via mechanisms other than mutations in RAS-family proteins. SOS1 interacts with the adaptor protein Grb2 and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated Receptor Tyrosine Kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, ¢-MET, VEGFR1 / 2 / 3, AXL) (Pierre et al., Biochem, Pharmacol., 2011, 82(9): 1049-56). SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR), B cell Receptor (BCR) and monocyte colony-stimulating factor receptor (Salojin et al, J. Biol. Chem. 2000, 275(8):5966-75). This localization of SOS1 to the plasma membrane, proximal to RAS-family proteins, enables SOS1 to promote RAS-family protein activation. SOS1 -activation of RAS-family proteins can 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 al., Nat. Cell Biol., 2004, 6(3):268-74). Furthermore, alterations in SOS1 have been implicated in cancer. SOS1 mutations are found in embryonal rhabdomyosarcomas, Sertoli cell testis tumors, granular cell tumors of the skin (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 over-expression 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, hereditary SOS1 mutations are implicated in the pathogenesis of RASopathies like e.g., Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56).

[0005] SOS1 is also a GEF for the activation of the GTPases RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1):125-36). RAC], like RAS-family proteins, is implicated in the pathogenesis of a variety of human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12(10):1925-34).

[0006] 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 mouse knockout models suggests a redundant role for SOS1 and SOS2 in homeostasis in the adult mouse. Whilst germline knockout of SOS1 in mice results in lethality during mid-embryonic gestation (Qian et al., EMBO J., 2000, 19(4):642-54), systemic conditional SOS1 knockout adult mice are viable (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). SOS2 gene targeting did not result in any overt phenotype in mice (Esteban et al., Mol. Cell. Biol., 2000, 20(17):6410-3). In contrast, double SOS1 and SOS2 knockout 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 SOS1 targeting) may be adequately tolerated to achieve a therapeutic index between SOS1 / RAS-family protein driven cancers (or other SOS1 / RAS- family protein pathologies) and normal cells and tissues.

[0007] Selective pharmacological inhibition of the binding of the catalytic site of SOS1 to RAS-family proteins is expected to prevent SOS 1-mediated activation of RAS-family proteins to the GTP-bound form. Such SOS1 inhibitor compounds are be 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 inhibitor compounds are be expected to deliver anti- cancer efficacy (e.g., inhibition of proliferation, survival, metastasis, etc.). High potency towards inhibition of SOS1:RAS-family protein binding (nanomolar level ICs, values) and ERK phosphorylation in cells (nanomolar level ICs values) are desirable characteristics for a SOS inhibitor compound. Furthermore, a desirable characteristic of a SOS1 inhibitor compound would be the selective inhibition of SOS1 over SOS2. This conclusion is based on the viable phenotype of SOS1 knockout mice and lethality of SOS1 / SOS2 double knockout mice, as described above.

[0008] These characteristics have not been achieved in previously described SOS1 inhibitor compounds. In the last decades, the RAS family proteins-SOS1 protein interaction has gained increasing recognition. Several efforts to identify and optimize binders, which target either 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 made with limited success.

[0009] Recently, small activating molecules have been identified, which bind to a lipophilic pocket of SOS1 in close proximity to the RAS binding site (Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). However, binding of these molecules seems to lead to increased nucleotide exchange and thereby activation of RAS instead of deactivation.

[0010] In an effort to stabilize the protein-protein-interaction of RAS-family proteins with SOS1 and to 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 the nucleotide exchange and only a weak effect was observed for fragments covalently bound to RAS.

[0011] 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. Chem. 2015, 290(20):12879-98; Zheng etal, WO 2016 / 077793), i.e. compounds which 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 cellular signal transduction modulation (e.g., ERK phosphorylation) are weak. BRIEF SUMMARY

[0012] The present disclosure relates to compounds capable of inhibiting the activity of SOS1. The present disclosure further provides a process for the preparation of compounds, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SOS1.

[0013] One aspect of the present disclosure relates to compounds of Formula (I): {I Ry wie Sn H <) Re NP A RZNTONT0 Rs or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein: R; 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; R; is selected from the group consisting of H, C, alkyl, halogen, -NHR34, ~ORa, cyclopropyl, and —CN; wherein Cy. alkyl is optionally substituted with halogen, -NHR,, — ORyg, or 5-6 membered heterocyclyl, and further wherein Ry, is selected from the group consisting of H, C4 alkyl, 3-6 membered heterocyclyl, and C1 haloalkyl; R; is selected from the group consisting of H, Cy.; alkyl, —OR3,, cyclopropyl, and 3- 6 membered heterocyclyl, wherein each of Cy; alkyl, cyclopropyl, and 3-6 membered heterocyclyl is optionally substituted with Rs,, and further wherein Rs, is selected from the group consisting of Cy.3 alkyl, halogen, “OH, or -CN; Ly is selected from the group consisting of bond, —C(Q)-, -C(0)0—, — C.¢ alkyl 0 C,.¢ alkyl C(O)NH(CH,),—, -NH-, Vy 1), -NH pity, 2 S I ne (CH,),—, and —O—; wherein 0 is 0, 1, or 2; and wherein p is a number from 1 to 6; and R, is selected from the group consisting of H, Cy alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cs 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 Cy. alkyl, ~Rsa, ~OR4a, ~O—Ci.¢ alkyl-Rya, =O, halogen, —C(O)R4a, ~C(OO)R4a, ~C(O)NR4sR4c, “NR4sC(O)R4c, ~CN, =NRyz, ~NR4pRc, — SO;Ry,, 3-6 membered cycloalkyl optionally substituted with Rss, 3-7 membered heterocyclyl optionally substituted with R4s, 6-10 membered aryl optionally substituted with Ry, or 5-10 membered heteroaryl optionally substituted with Rss; wherein Ry, is H, Cy alkyl, Ci¢haloalkyl, -C(O)R4p, —C(O)NR4R4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with -ORgp, — CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, —-(CH;);OCH; or — (CH,),OH whereinris 1, 2, or 3; wherein each Ry is independently H, C6 alkyl; and wherein each Ry. is independently H or C4 alkyl.

[0014] Another aspect of the present disclosure relates to compounds of Formula (II): H Ry Ry R 5: . I Rs . Hs Rs NEN Zz SJ RZ” NTN” 0 Rs a) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Rs, R;, Ly, and Ry are as defined in Formula (I); Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cs alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, —-CN, -NR11R 1», -SRyo, — S(0)2NR11R 12, =8(0)2R10, -NR108(0)2NR11R12, ~NR16S(0)2R11, ~=S(O)NR11R12, ~=S(O)R10. ~NR10S(0)NR11R12, -NR10S(O)R11, ~C(O)R10, -CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Cy. alkyl, C,. alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with ~OH, C; alkyl, halogen, — NO, 0x0, CN, —Ryp, “OR 1p, -NR1R12, =SR19, =S(0)2NR11R 12, =S(0)2R 10, — NR10S(0)2NR11R 12, -NR10S(0)2R11, ~S(O)NR11R12, ~S(O)R10, -NR10S(O)NR11R12, — NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R%, R% R’, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Rui, and Ry; are at each occurrence independently selected from H, D, C16 alkyl, Cy. alkenyl, 4-8 membered cycloalkenyl, C».¢ alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -ORj3, —SR 3, halogen, -NR3R 14, -NO,, and CN; and Ry; and Ry; are at each occurrence independently selected from H, D, Cy alkyl, Cs. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Ci. alkyl, Cs. alkenyl, 4-8 membered cycloalkenyl, Ca alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —-SH, —-NH,, -NO,, or CN.

[0015] Another aspect of the present disclosure relates to compounds of Formula (III), Rg (IID) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R,, Rs, Ls, and Ry are as defined in Formula (I); Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cis alkyl, C26 alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, -CN, -NR11R12, =SRyo, — S(0):NR11R12, —=8(0)2R10, -NR10S(0)2NR11R 12, ~NR18(0)2R11, ~=S(O)NR;1R 12, ~S(O)R10, —NR10S(O)NR11R 12, -NR10S(0)R 11, ~C(O)R 10, -CO2R 10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Cy. alkyl, C,. alkenyl, 4-8 membered cycloalkenyl, Ca alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —~OH, Ci alkyl, halogen, — NO, 0x0, -CN, —Rio, “OR1p, -NR11R12, =SRio, -S(0):NR11R 12, ~S(0)2R10, — NR0S(0):NR11R12, -NR108(0)zR11, =8(O)NR11R12, =S(0)R10, -NR10S(O)NR1R12, ~ NR1S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R%, RR, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Ri1, and Ry; are at each occurrence independently selected from H, D, Ci alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C2. alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR13, —=SR 3, halogen, -NR3R 14, -NO,, and -CN; and Ru: and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Co. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Cy alkyl, C,.¢ alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —-OH, —SH, —-NH,, -NO,, or -CN.

[0016] Another aspect of the present disclosure relates to compounds of Formula (IV- a), (IV-b), or (IV-c), 1 od 1 a: 1 R7 R7 Rs ON Rg Rs rs Rg NX Re | N A ZF FZ Re Ry Rg Rs Rg HC" NH H HC SNH H HC" NH H : Re ° Re : Re NZ No NZ Ne NZ XN 8 rn No RS No a No o£ Co Lo bo Rs (IV-b) Rs (IV-a) Rs (IV-c) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Rs, R;, Ly, and Ry are as defined in Formula (I); Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cis alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, -CN, -NR1R 12, —=SRyo, — S(0)2NR11R12, =8(0)2R10, -NR108(0)2NR11R12, ~NR10S(0)2R11, ~=S(O)NR11R 12, ~=S(O)R10, ~NR10S(O)NR11R12, “NR10S(O)R11, ~C(O)R10, ~CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Cy. alkyl, C,.c alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with ~OH, C1 alkyl, halogen, — NO, 0x0, -CN, —Ryp, “OR 1p, -NR1R1, =SR19, =S(0)2NR11R 12, ~S(0)2R 10, — NRi0S(0):NR11R12, -NR108(0)zR11, =8(O)NR11R12, =S(0)R10, -NR10S(O)NR11R12, — NR;S(0)R1y, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R%, R% R’, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Rui, and Ry; are at each occurrence independently selected from H, D, C16 alkyl, Cy. alkenyl, 4-8 membered cycloalkenyl, C».¢ alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR13, —=SR 3, halogen, -NR3R 14, -NO,, and —-CN; and Rus and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Ca. salkenyl, 4-8 membered cycloalkenyl, Cas alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Ci alkyl, Cs. alkenyl, 4-8 membered cycloalkenyl, Ca alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —SH, -NH,, -NO,, or CN,

[0017] One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject a SOS1 inhibitor of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof.

[0018] Another aspect of the present disclosure relates to methods of treating or preventing a disease that is effected by inhibition of the interaction of SOS1 and a RAS- family protein and / or RACI in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof

[0019] Another aspect of the present disclosure 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 one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.

[0020] 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 any one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof.

[0021] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of any one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, diluent, or surfactant. The pharmaceutical composition can be effective for treating or preventing a disease associated with SOS1 modulation in a subject in need thereof. The pharmaceutical composition can be effective for treating or preventing a cancer in a subject in need thereof,

[0022] Another aspect of the present disclosure relates to a compound of any one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, for use in treating or preventing a disease associated with SOS1 modulation. Another aspect of the present disclosure relates to a compound of any one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, for use in treating or preventing a disease cancer.

[0023] Another aspect of the present disclosure relates to the use of a compound of any one of Formula (I)-(IV), and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in the manufacture of a medicament for treating or preventing a disease associated with SOS1 modulation. Another aspect of the present disclosure relates to the use of a compound of any one of Formula (I)-(IV) and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, in the manufacture of a medicament for treating or preventing cancer.

[0024] The present disclosure also provides compounds that are useful in inhibiting SOS1. DETAILED DESCRIPTION OF THE DISCLOSURE

[0025] The details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Terms

[0026] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0027] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. The use of the term "or" is used to mean "and / or" unless explicitly indicated to refer to altematives only or the altemative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or."

[0028] As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall 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 stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).

[0029] By "optional" or "optionally," it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined herein. It will be understood by those ordinarily skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non- feasible, and / or inherently unstable.

[0030] 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 range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an 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 instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.

[0031] As used herein, “alkyl” may mean a straight chain or 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, 3-methyl-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, n-hexyl and the like, and longer alkyl groups, such as heptyl, and octyl and the like. An alkyl group can be unsubstituted or substituted. Alkyl groups containing three or more carbon atoms may be straight or branched. As used herein, “lower alkyl” means an alkyl having from 1 to 6 carbon atoms.

[0032] As used herein, the term “heteroalkyl” refers to an “alkyl” group (as defined herein), in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the end of the radical.

[0033] The term "alkenyl" means an aliphatic hydrocarbon group containing a carbon— carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl groups 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. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. A C,-Cs alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.

[0034] The term "alkynyl" means an aliphatic hydrocarbon group containing a carbon— carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups 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. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C,-C¢ alkynyl group is an alkynyl group containing between 2 and 6 carbon atoms.

[0035] As used herein, the term "halo" or "halogen" means a fluoro, chloro, bromo, or iodo group.

[0036] The term “oxo” as used herein refers to an “=O” group. When an oxo group is bonded to a carbon atom, it can also be abbreviated herein as C(O) or as C=0. An oxo group can also be bonded to a sulfur atom (e.g., S=0 and S(0),) or at phosphorous atom (e.g., P=0, PO,, POs, PO, etc).

[0037] The term “imine” as used herein refers to an “=N” group. When an imine is bonded to a carbon atom, it can also be abbreviated herein as C=N. Nitrogen can also be double bonded to sulfur, e.g., S=N, which is referred to as a thioimine,

[0038] The term “annular atoms” used in conjunction with terms relating to ring systems described herein (e.g., cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl) refers to the total number of ring atoms present in the system. “Annular atoms” therefore does not include the atoms present in a substituent attached to the ring. Thus, the number of “annular atoms” includes all atoms present in a fused ring. For example, a 2-indolyl C+ ring, B H , is considered a 5-membered heteroaryl, but is also a heteroaryl containing 9 annular atoms. In another example, pyridine is considered a 6-membered heteroaryl, and is a heteroaryl containing 6 annular atoms.

[0039] "Cycloalkyl" refers to a single saturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-Cyo cycloalkyl), for example from 3 to 15 annular atoms, for example, from 3 to 12 annular atoms. In certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or contains a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic cycloalkyl") and can be saturated. "Cycloalkyl" includes ring systems where the cycloalkyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkyl ring containing the point of attachment. Examples of cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl x ), 2-(2,3-dihydro-1H-indene) Co, and 9-fluorenyl A Ch, As noted above, cycloalkyl rings can be further characterized by the number of annular atoms. For example, a cyclohexyl ring is a Cg cycloalkyl ring with 6 annular atoms, while 2-(2,3-dihydro-1H-indene) is a Cs cycloalkyl ring with 9 annular atoms. Also, for example, 9-fluorenyl is a Cs cycloalkyl ring with 13 annular atoms and 2- adamantyl is a Cs cycloalkyl with 10 annular atoms.

[0040] As used herein, the term “cycloalkenyl” may refer to a partially saturated, monocyclic, fused or spiro polycyclic, all carbon ring having from 3 to 18 carbon atoms per ring and contains at least one double bond. "Cycloalkenyl" includes ring systems where the cycloalkenyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkenyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkenyl ring containing the point of attachment. Cycloalkenyl rings can be further characterized by the number of annular atoms. Examples of cycloalkenyl include 1-cyclohex-1-enyl and cyclopent-1-enyl.

[0041] The term "aryl" as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 5 to 20 annular carbon atoms, 5 to 14 annular carbon atoms, or 5 to 12 annular carbon atoms. Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e, cycloalkyl). "Aryl" includes ring systems where the aryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, and wherein the point of attachment is on an aryl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbon atoms in the aryl ring containing the point of attachment. Examples of aryl groups include phenyl and 5-(2,3-dihydro-1H-indene): x : As noted above, aryl rings can be further characterized by the number of annular atoms. For example, phenyl is a Cs can be further characterized by the number of annular atoms. For example, phenyl is a Cs aryl with 6 annular atoms, while 5-(2,3-dihydro-1H-indene) is a Cg aryl with 9 annular atoms.

[0042] "Heterocyclyl" as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system (including fused and spiro polycyclic) that has at least one heteroatom in the ring (at least one annular heteroatom selected from oxygen, nitrogen, phosphorus, and sulfur). Unless otherwise specified, a heterocyclyl group has from 5 to about 20 annular atoms, for example from 5 to 15 annular atoms, for example from 5 to 10 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus, and sulfur in the ring. The term also includes single saturated or partially unsaturated rings (e.g., 5, 6, 7, 8, 9, or 10-membered rings) having from about 4 to 9 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus, and sulfur in the ring. “Heterocyclyl" includes ring systems where the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a heterocyclic ring, and, in such instances, the number of ring members recited continues to designate the number of annular atoms in the heterocyclic ring containing the point of attachment. Heterocyclic rings can be further characterized by the number of annular atoms. Examples of heterocyclic groups include piperidinyl (6-membered heterocycle with 6 annular atoms), azepany! (7-membered heterocycle with 7 annular atoms), and 3-chromany] (6-membered heterocycle with 10 0. y CC, annular atoms)

[0043] The term "heteroaryl" as used herein refers to a single aromatic ring that has 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 condensed ring systems that have at least one such aromatic ring. Thus, the term includes single heteroaryl rings of from about 1 to 10 annular carbon atoms and about 1-5 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. "Heteroaryl" includes ring systems where the heteroaryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a heteroaryl ring, and, in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring containing the point of attachment. Heteroaryl rings can be further characterized by the number of annular atoms. For example, pyridine is a 6-membered heteroaryl having 6 annular atoms.

[0044] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water- insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methyInitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 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, teoclate, tosylate, triethiodide, and valerate salts.

[0045] The term “tautomers” refers to a set of compounds that have the same number and type of atoms, but differ in bond connectivity and are in equilibrium with one another. A “tautomer” is a single member of this set of compounds. Typically a single tautomer is drawn but it is understood that this single structure is meant to represent all possible tautomers that might 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 disclosure.

[0046] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as *H, *H, IC, *C, “C, PN, ®N, ¥0, V0, ®¥0, *?p, ¥*p, ¥*s, °F, 3¢l, 1 and "I Isotopically-labeled compounds (e.g., those labeled with *H and *C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., *H) and carbon-14 (i.e., “C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ’H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g, increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by *H or *H, or one or more carbon atoms are replaced by C- or 1*C- enriched carbon. Positron emitting isotopes such as 150, BN, 1c, and '®F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0047] The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. Furthermore, as used herein a prodrug is a drug which is inactive in the body, but is transformed in the body typically either during absorption or after absorption from the gastrointestinal tract into the active compound. The conversion of the prodrug into the active compound in the body may be done chemically or biologically (i.e., using an enzyme).

[0048] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the present disclosure 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 wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0049] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds herein may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0050] The term "stereoisomers" refers to the set of compounds which have the same number and type of atoms and share the same bond connectivity between those atoms, but differ in three dimensional structure. The term "stereoisomer" refers to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer.

[0051] The term "enantiomers" refers to a pair of stereoisomers which are non- superimposable mirror images of one another. The term "enantiomer refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers.

[0052] The term "diastereomers" refers to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo-substitution on bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations are considered to be diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers.

[0053] An “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0054] The term “carrier”, as used in this disclosure, encompasses excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0055] The term “treating” with regard to a subject, refers to improving at least one symptom of the subject’s disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0056] The term “prevent” or “preventing” with regard to a subject refers to keeping a disease or disorder from afflicting the subject. Preventing includes prophylactic treatment. For instance, preventing can include administering to the subject a compound disclosed herein before a subject is afflicted with a disease and the administration will keep the subject from being afflicted with the disease.

[0057] The terms “inhibiting” and “reducing,” or any variation of these terms, includes 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%, 10%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity (e.g., SOS1:Ras-family protein binding activity) compared to normal.

[0058] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0059] The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.

[0060] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. Compounds of Disclosed Formulae

[0061] In some embodiments, the present disclosure relates to compounds of the following formula (A): R4 ey H HaC! ° Re NZ XN -4 Aud RS” ON ONTYo Rs (A) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein: R; 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; R; is selected from the group consisting of H, Cy. alkyl, halogen, -NHR3,, —ORy,, cyclopropyl, and —CN; wherein Cy. alkyl is optionally substituted with halogen, -NHR,, — ORyg, or 5-6 membered heterocycloalkyl, and further wherein Ry, is selected from the group consisting of H, C1 alkyl, 3-6 membered heterocyclyl, and Cc haloalkyl; R; is selected from the group consisting of H, C.; alkyl, cyclopropyl, and 3-6 membered heterocycloalkyl, wherein each of C.; alkyl, cyclopropyl, and 3-6 membered heterocycloalkyl is optionally substituted with halogen, -OH, or —-CN; Ly is selected from the group consisting of bond, —C(O)-, -C(0)0-, — 0 C,.¢ alkyl mete C(O)NH(CHj)o—, -NH-, -8-,-8(0)—, 7 + 5 ~ 7% > ~ (CH), and -O—; wherein p is a number from 1 to 6; and R, is selected from the group consisting of H, Cy alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cs 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 C,. alkyl, ~ORy4a, =O, halogen, —C(O)Rua, — C(OO)Ry4s, ~C(O)NRypR4c, —CN, -NRypRy, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein Ry, is H, C1. alkyl, Ci.chaloalkyl, 3-7 membered heterocyclyl, or — (CH,),0CH; whereinris 1, 2, or 3; wherein Ry, is H or Cy alkyl; and wherein Ry is H or Cy alkyl.

[0062] In other embodiments, the present disclosure relates to compounds of the following formula (B): H Ry Re Rs : F Rg cn Ha Re NZ Nn 4 Js Ry” N”°N"O Rs B) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein: R; is selected from the group consisting of H, Cy. alkyl, halogen, -NHR3,, —OR24, cyclopropyl, and —CN; wherein Cs alkyl is optionally substituted with halogen, -NHR,, — ORy,, or 5-6 membered heterocycloalkyl, and further wherein Ry, is selected from the group consisting of H, Cy.¢ alkyl, 3-6 membered heterocyclyl, and C,.¢ haloalkyl; R; is selected from the group consisting of H, C.; alkyl, cyclopropyl, and 3-6 membered heterocycloalkyl, wherein each of C,.; alkyl, cyclopropyl, and 3-6 membered heterocycloalkyl is optionally substituted with halogen, OH, or —-CN; Ls is a bond; and R, is selected from the group consisting of H, Cy alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cs 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 Cy. alkyl, —ORs,, =O, halogen, —C(O)Rya, — C(O0)Ryz, —C(O)NR4pR4c, -CN, -NRypRsc, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein Ry, is H, C16 alkyl, Cy.chaloalkyl, 3-7 membered heterocyclyl, or — (CH,),0CH; whereinris 1, 2, or 3; wherein Ry is H or Cy alkyl; wherein Ry. is H or Cy alkyl; Rs, Rg, Ry, Rg, and Ry are independently selected from the group consisting of H, D, C1-Calkyl, C,-Cs alkenyl, C4-Cs cycloalkenyl, C-Cs alkynyl, C5-Cs cycloalkyl, ~OH, halogen, -NO,, -CN, -NRi1R12, —SRi, -S(0):NR11R12, -8(0):R10, “NR 108(0):NR11R1, — NR10S(0):R11, —S(O)NRyiR12, —S(0)Ri0, -NR10S(O)NR11R 12, -NR10S(0)R11, ~C(O)R10, COR 10, aryl, and heteroaryl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, and aryl is optionally substituted with-OH, C,-Cs alkyl optionally substituted with -OH, NRy1R12, or heterocyclyl, halogen, -NO,, 0x0, -CN, —Rig, “OR1o, “NR11R12, =SRig, =S(0):NR1 R13, — S(0)2R10, “NR 108(0)2NR11R12, -NR10S(0)2R11, =S(O)NR11R12, =S(O)R1o, — NR;,S(O)NR11R 13, -NR10S(O)R 13, heterocycle, aryl, or heteroaryl; Rio, Ri, and Ry» are independently, at each occurrence, H, D, C1-Cs alkyl, C>-Cs alkenyl, C4-Cscycloalkenyl, C,-Cs alkynyl, Cs-Cgcycloalkyl, 3-14 membered heterocyclyl, —OR13, —=SRy3, halogen, -NR3R14, -NO», or -CN; and Ry; and Ry4 are independently, at each occurrence, H, D, C1-Cs alkyl, C-Cs alkenyl, C4-Cg cycloalkenyl, C,-Cs alkynyl, C3-Cg cycloalkyl, 3-14 membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with—-OH, —-SH, -NH,, -NO,, or -CN. Additional Compounds of Disclosed Formulae

[0063] In some embodiments, the present disclosure relates to compounds having the structure of Formula (I), 0) Ry ole HC NH H ° Re N? XN 17 ot Ry” NTTNTT0 Rs or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein: R; 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; R, is selected from the group consisting of H, C1 alkyl, halogen, -NHR2s, “OR 2, cyclopropyl, and —CN; wherein Cy alkyl is optionally substituted with halogen, -NHR,, — ORyg, or 5-6 membered heterocyclyl, and further wherein Ry, is selected from the group consisting of H, Cy alkyl, 3-6 membered heterocyclyl, and Cy. haloalkyl; R; is selected from the group consisting of H, C1.; alkyl, —OR3,, cyclopropyl, and 3- 6 membered heterocyclyl, wherein each of Cy; alkyl, cyclopropyl, and 3-6 membered heterocyclyl is optionally substituted with Rs,, and further wherein Ry, is selected from the group consisting of Cy.; alkyl, halogen, -OH, or -CN; L, is selected from the group consisting of bond, —C(O)-, -C(0)0-, — C6 alkyl 0 C,.¢ alkyl TS q 2 - ll wl C(O)NH(CH,),—, -NH-, -S—, -S(0)>—, s ~ 4 oO Yr = (CH,)y—, and —O—; wherein o is 0, 1, or 2; and wherein p is a number from 1 to 6; and R, is selected from the group consisting of H, Cy alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cs 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 C,. alkyl, —R4a, “OR4a, ~O—C 1.6 alkyl-Rya, =O, halogen, —C(O)Rsa, ~C(OO)R4s, ~C(O)NRspR4c, “NR4pC(O)R4c, CN, =NRy,, -NRupRsc, — SO;Ry,, 3-6 membered cycloalkyl optionally substituted with Rss, 3-7 membered heterocyclyl optionally substituted with R4,, 6-10 membered aryl optionally substituted with Ra, or 5-10 membered heteroaryl optionally substituted with Rya; wherein Ry, is H, C1 alkyl, C1.¢ haloalkyl, -C(O)R4p, —C(O)NRpRy., =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with —-ORgp, — CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, —(CH,);OCH; or — (CH,),OH whereinris 1, 2, or 3; wherein each Ry is independently H, C6 alkyl; and ‘wherein each Ry. is independently H or Cj alkyl.

[0064] In some embodiments of compounds of Formula (I), R; is the optionally substituted 6-membered aryl. In some embodiments, the 6-membered aryl has the following structure: Ry fe " . - Re JL wherein Rs, Re, Rs, Rg, and Ry are as defined below in connection with Formula (II)-(IV).

[0065] In some embodiments of compounds of Formula (I), R; is the optionally substituted 5-6 membered heteroaryl. In some embodiments, R; is a 6-membered heteroaryl having any of the following structures: Res N X f Ry wherein Rs, Re, Rs, Rg, and Ry are as defined below in connection with Formula (I)-(IV).

[0066] In some embodiments of compounds of Formula (I), R; is the optionally substituted 5-6 membered heteroaryl. In some embodiments, R; is a 5-membered heteroaryl having the following structure: Rg wherein Rs, Rg, and R; are as defined below in connection with Formula (I)-(IV).

[0067] In some embodiments, the present disclosure relates to compounds having the structure of Formula (II), H Ry Ry R 6: . I Rs o . Hs Rs NEN Zz SJ RZ” NTN” 0 Rs a) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Rs, R;, Ly, and Ry are as defined in Formula (I); Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cis alkyl, C26 alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, -CN, -NR11R12, =SRyo, — S(0):NR11R12, —=S(0)2R10, -NR10S(0)2NR11R12, -NR18(0)2R11, ~=S(O)NR11R 15, ~S(O)R 10, —NR0S(O)NR11R 12, -NR10S(0)R 11, ~C(O)R 0, -CO2R 10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1. alkyl, Cas alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with ~OH, C1. alkyl optionally substituted with -Rio, halogen, -NO,, oxo, ~CN, —Rjg, “OR 10, -NR11R12, =SRyp, — S(0)2NR11R 12, =8(0)2R10, -NR108(0)2NR11R12, ~NR16S(0)2R11, ~=S(O)NR11R 12, ~=S(O)R10. —NR0S(O)NR11R 12, -NR10S(0)R 11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rio, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R% R% R, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Rui, and Ry; are at each occurrence independently selected from H, D, C16 alkyl, Cy. alkenyl, 4-8 membered cycloalkenyl, C».¢ alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR13, —=SR 3, halogen, -NR3R 14, -NO,, and -CN; and Ry; and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Ca. s alkenyl, 4-8 membered cycloalkenyl, Ca.s alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Ci. alkyl, Cs. alkenyl, 4-8 membered cycloalkenyl, Ca alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —-SH, -NH,, -NO,, or CN.

[0068] In some embodiments, the present disclosure relates to compounds having the structure of Formula (III), Rg (IID) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Ry, Rj, Ly, and Ry, are as defined Formula (I); Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cis alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, —-CN, -NR11R 1», -SRyo, — S(0)2NR11R 12, =8(0)2R10, -NR108(0)2NR11R12, ~NR16S(0)2R11, ~=S(O)NR11R12, ~=S(O)R10. -NR10S(O)NR R12, -NR19S(O)R11, —~C(O)R 10, -CO:R 10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Ci. alkyl, C,.c alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with ~OH, C,. alkyl optionally substituted with -Ryo, halogen, -NO,, oxo, ~CN, —Rjg, -OR 10, -NR11R12, =SRyo, — S(0)2NR11R12, =8(0)2R10, -NR10S(0)2NR11R 12, ~NR10S(0)2R11, ~=S(O)NR11R 12, ~=S(O)R10, —NR0S(O)NR11R 12, NR 0S(O)R 11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rio, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R*, R®, R”, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Ri1, and Ry; are at each occurrence independently selected from H, D, Ci alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C2. alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR13, —=SR 3, halogen, -NR3R 14, -NO,, and -CN; and Ru: and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Co. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Cy alkyl, C,.¢ alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —-OH, —SH, —-NH,, -NO,, or -CN.

[0069] In some embodiments, the present disclosure relates to compounds having the structure of Formula (IV-a), (IV-b), or (IV-c), 1 od 1 a: 1 R7 R7 Rs ON Rg Rs rs Rg NX Re | N A ZF FZ Re Ry Rg Rs Rg HC" NH H HC SNH H HC" NH H : Re ° Re : Re NZ No NZ Ne NZ XN 8 rn No RS No a No o£ Co Lo bo Rs (IV-b) Rs (IV-a) Rs (IV-c) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Rs, R;, Ly, and Ry are as defined Formula (I); Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cis alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, -CN, -NR1R 12, —=SRyo, — S(0)2NR11R12, =8(0)2R10, -NR108(0)2NR11R12, ~NR10S(0)2R11, ~=S(O)NR11R 12, ~=S(O)R10, ~NR10S(O)NR11R12, “NR10S(O)R11, ~C(O)R10, ~CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Cy. alkyl, C,.c alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —~OH, C1 alkyl optionally substituted with -Rio, halogen, -NO,, oxo, ~CN, —Rjg, -OR10, -NR11R12, =SRyo, — S(0):NR11R12, =8(0)2R10, -NR10S(0):NR11R12, -NR108(0)2R11, =S(O)NRi1R12, ~S(0)R10, —NR10S(0O)NR;1R 1, -NR;0S(O)R 11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rio, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R*, R®, R”, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Ri, and Ry; are at each occurrence independently selected from H, D, C16 alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,. alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -ORy3, —SR 3, halogen, -NR3R 14, -NO,, and CN; and Ris and Rug are at each occurrence independently selected from H, D, Cis alkyl, Ca. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Cy alkyl, C,.¢ alkenyl, 4-8 membered cycloalkenyl, Cy alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with -OH, —SH, —-NH,, -NO,, or -CN.

[0070] In some embodiments, the present disclosure relates to compounds having the structure of Formula (IV-a) or Formula (IV-b).

[0071] In some embodiments of compounds of Formula (I)-(IV), one to three of Rs, Rg, R7, Rg, and Ry is Cy alkyl, wherein the alkyl is optionally substituted with halogen.

[0072] In some embodiments of compounds of Formula (II)-(IV), one to three of Rs, Rg, R7, Rs, and Ry is Ci alkyl, wherein the alkyl is optionally substituted with halogen or — OH.

[0073] In some embodiments of compounds of Formula (I)-(IV), one to three of Rs, Rs, R7, Rg, and Ry is Cy alkyl, and one to three of Rs, Rs, Rs, Rs, and Ry is Cy alkyl optionally substituted with halogen.

[0074] In some embodiments of compounds of Formula (II)-(IV), one to three of Rs, Re, Rs, Rg, and Ry is halogen, and one to three of Rs, Rg, Rs, Rs, and Ro is Cis alkyl optionally substituted with halogen.

[0075] In some embodiments of compounds of Formula (I)-(IV), one to three of Rs, Rs, R7, Rs, and Rg is -NH,.

[0076] In some embodiments of compounds of Formula (II)-(IV), one of Rs, Re, Rv, Rs, and Ry is -NH,; and one of Rs, Rg, Ry, Rg, and Ry is Ci.¢ alkyl optionally substituted with halogen.

[0077] In some embodiments of compounds of Formula (I)-(IV), any two adjacent R®, RR’, R®, and R® forms a 3-14 membered fused ring. In some embodiments of compounds of Formula (II)-(IV), any two adjacent R®, R®, R’, R®, and R® forms a 3-8 membered fused ring. In some embodiments of compounds of Formula (I)-(IV), any two adjacent R%, RR, R®, and R’ forms a 4-8 membered fused ring. In some embodiments of compounds of Formula (I)-(IV), any two adjacent R% R® R, R®, and R’ forms 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, C1 alkyl, halogen, -NO,, 0x0, —CN, —R1g, OR, “NR R12, “SR 0, =S(0):NR11R 2, — S(0)2R10, “NR 108(0)2NR11R12, -NR10S(0)2R11, =S(O)NR11R12, =S(O)R1p, — NR; pS(O)NR11R5, -NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, the fused ring is optionally substituted with halogen.

[0078] In some embodiments of compounds of Formula (IT)-(IV), one or more of Rs, Rg, R7, Rs, and Ry is selected from among —CF3, -NH,, -F, and -CF,CH,0H. In some embodiments of compounds of Formula (II), one of Rs, Rs, R7, Rg, and Re is—CF; and one of Rs, Rg, R7, Rs, and Rg is -NH,. In some embodiments of compounds of Formula (II), one of Rs, Rg, R57, Rg, and Ry is—F and one of Rs, Rs, R47, Rg, and Rg is —-CF>,CH,0H.

[0079] In some embodiments of compounds of Formula (I), R; is selected from among: F F F 1_F a 0 CFs NH ~~ CF, 0 F T 0, wan aw wan ww ww LQ ROY CF. CF. ~~ ye F i FF Ton oN 7 F F or COCO 0 . SL oy iL hl 3 ¥ 1 1 T T 1 | E F F F FE = ? ? . p ¥ . NH NC. F. ww LoL aw F F E AO SNE A “- “NH, 2 nd A Lr HN < : F “NH Mo

[0080] In some embodiments of compounds of Formula (I), R; is selected from among: N, F. NH. he gl NEY REE 2 ZN F ZN F HF Ny i wi “MV and Y ~, and

[0081] In some embodiments of compounds of Formula (I), R; is selected from among: § 5 § \ NH, we Np

[0082] In some embodiments of compounds of Formula (I), R; is selected from among: F F F F CFs NH, HO. NH, CF; CFs NH, EN or OC Ah wan nA a ’ “0 “Pr 0 —- ,and

[0083] In some embodiments of compounds of Formula (I)-(IV), R, is H.

[0084] In some embodiments of compounds of Formula (I)-(IV), R, is Cis alkyl. In some embodiments of compounds of Formula (I)-(IV), R; is —CHs.

[0085] In some embodiments of compounds of Formula (I)-(IV), R, is Cys alkyl substituted with 5-6 membered heterocycloalkyl. In some embodiments of compounds of oS NY Formula (D)-(IV), Ry is

[0086] In some embodiments of compounds of Formula (I)-(IV), R; is Cys alkyl substituted with -NHR,,, wherein Ry, is C1. alkyl or 3-6 membered heterocyclyl. In some Rx embodiments of compounds of Formula (I)-(IV), R, is selected from among J and ~CH,NHCH;.

[0087] In some embodiments of compounds of Formula (I)-(IV), Rz is C1. alkyl substituted with -OR,, wherein Ry, is H or Ci alkyl. In some embodiments of compounds of Formula (I)-(IV), R; is -CH,OH.

[0088] In some embodiments of compounds of Formula (I)-(IV), R; is -NHR3,, wherein Ry, is C1 alkyl. In some embodiments of compounds of Formula (I)-(IV), R; is — NHCH;.

[0089] In some embodiments of compounds of Formula (I)-(IV), R; is OR; wherein Rais Cig alkyl. In some embodiments of compounds of Formula (I)-(IV), R; is -OCHj.

[0090] In some embodiments of compounds of Formula (I)-(IV), Rs is C1.; alkyl. In some embodiments of compounds of Formula (I)-(IV), R3 is -CHs. In some embodiments of compounds of Formula (I)-(IV), R3 is =CDs.

[0091] In some embodiments of compounds of Formula (I)-(IV), Rs is C13 alkyl substituted with -OH. In some embodiments of compounds of Formula (I)-(IV), Rs is — CH,CH,0H.

[0092] In some embodiments of compounds of Formula (I)-(IV), Rs is H.

[0093] In some embodiments of compounds of Formula (I)-(IV), R3 is -OR3,. In some embodiments of compounds of Formula (I)-(IV), R; is -OCH3.

[0094] In some embodiments of compounds of Formula (I)-(IV), Rs is cyclopropyl.

[0095] In some embodiments of compounds of Formula (I)-(IV), Rs is 3-6 membered N\ heterocyclyl. In some embodiments of compounds of Formula (I)-(IV), Rs is o”

[0096] In some embodiments of compounds of Formula (I)-(IV), Ls is selected from the group consisting of bond, —C(0)-, -C(0)0O-, —-C(O)NH(CH,),—,—NH-, -S—, —S(0),—, 0 Ce Cg alkyl TE Bee TES SS , (CHa)y—, and —O—; wherein ois 0, 1, or 2; and wherein p is a number from 1 to 6.

[0097] In some embodiments of compounds of Formula (I)-(IV), Ly is a bond.

[0098] In some embodiments of compounds of Formula (I)-(IV), L4 is -C(O)-.

[0099] In some embodiments of compounds of Formula (I)-(IV), Ls is (CHz)y—. In some embodiments of compounds of Formula (I), Ly is (CH;)-.

[00100] In some embodiments of compounds of Formula (I)-(IV), Ry is selected from the group consisting of H, C1 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cy. 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 Cy. alkyl, ~R4s, ~OR4a, ~O—C1.6 alkyl-Rya, =O, halogen, —C(O)R4a, ~C(OO)R4a, ~C(O)NR4sR4c, “NR4sC(O)R4c, ~CN, =NRyz, ~NR4pRc, — SOR, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5- 10 membered heteroaryl.

[00101] In some embodiments of compounds of Formula (I)-(IV), Rs is selected from the group consisting of H, C1. 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. 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 Cy. alkyl ~ORu,, =O, halogen, —C(O)Rss, — C(O0)Ryq, —C(O)NR4pR4c, -CN, -NRypR4c,3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.

[00102] In some embodiments of compounds of Formula (I)-(IV), Rya is H, Cys alkyl, C1 haloalkyl, ~-C(O)Rup, ~C(O)NRyyRy, =0, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with —ORg, -CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, —(CH,);OCH3, or —(CH,);OH, wherein is 1, 2, or 3;wherein each Ryp is independently H, Ci. alkyl; and wherein each Ry, is independently H or Cy. alkyl.

[00103] In some embodiments of compounds of Formula (I)-(IV), Ry, is H, Cys alkyl, C1 haloalkyl, -C(O)Rap, —C(O)NRypR4, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with -OR4p, —CN, 3-7 membered heterocyclyl, -(CH;);OCH; or — (CH,);OH wherein ris 1, 2, or 3;wherein each Ry is independently H, Ci alkyl; and wherein each Ry. is independently H or Cy alkyl.

[00104] In some embodiments of compounds of Formula (I)-(IV), Rs is 3-14 membered heterocyclyl. In some embodiments of compounds of Formula (I)-(IV), Ry is substituted 3- 14 membered heterocyclyl.

[00105] In some embodiments of compounds of Formula (I)-(IV), Rs is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl. In some embodiments, the heterocyclyl substituent is oxetanyl.

[00106] In some embodiments of compounds of Formula (I)-(IV), Rs is 3-14 membered heterocyclyl substituted with Ci alkyl. In some embodiments of compounds of Formula (D-(IV), Ry is 3-14 membered heterocyclyl substituted with -CH;. In some embodiments of compounds of Formula (I)-(IV), Ry is 3-14 membered heterocyclyl substituted with — CH», i.e., the substituent is a methylene bridge bridging 2 carbon atoms in the heterocyclyl ring.

[00107] In some embodiments of compounds of Formula (I)-(IV), Rs is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl. In some embodiments, the cvcloalkyl substituent is cyclopropyl.

[00108] In some embodiments of compounds of Formula (I)-(IV), Rs is 3-14 membered heterocyclyl substituted with =O.

[00109] In some embodiments, the Ry is a heterocyclyl selected from among: . | RB 70 PAN No IT CREST 9% ad wN aN Po Po BN mN I, “oN No ~~" No No y T NN abd A si, abe, YT hy 2A

[00110] In some embodiments, the Ry is a heterocyclyl selected from among: iN 3 RNS BNC ad and

[00111] In some embodiments, the Ry is a heterocyclyl selected from among: 0 “NH “Oo Qi ve of NT | | | | | sh ad 3 3 3 Pr Nw 2h ANTeE, NSF SNF NT OT OT OT 0 {NT N— NT NT ND LC J Lo BS l A | ES r J Oo dS x d Ag 1 d i I J CO C0 CO A od A JOEL COVA eC mC IO 0 0 0 0 D 4 Or YT plo 8 Or Os x LIN Es Ea Q 5 SN \ ~ N"% or g 0 WS ak 0O or 0, Q Ys” 5 NR N7 0 | O HN | © = 2 CF; Joon | 1 aN > Ly 0, WC ow FT

[00112] In some embodiments, the Ry is a heterocyclyl selected from among: aN 0 A A 0. — ~~ 0, [e} CN OS WT NOY A ~~ ay

[00113] In some embodiments, the Ry is a heterocyclyl selected from among: \ o / Bay N aN LOD aos TLS we Yop No N af oN oneN oN oN No ONY A Wh AON. NG N SC hss 0, D 0, D Y& 3% YY AY ~ ¥ Tie DC / DC J or "Re wy uc D Oo, iN N»— Db A NS wil Ny 3 "\™ MS ary . / 0 \ IAS \ Wed TN , and

[00114] In some embodiments, the Ry is a heterocyclyl selected from among: O / } On a bi RN" rm ov 5 | ro i 23 2 oN LO M0 TAO L070 NFAY Le > "a 5 F iT NG oO J R Be NC, A g A RTO LOTT OT ROT ROT rv F OH OH OH AT TT Te 5 nd wT OH F ~ ELAN 7 N. snd ]

[00115] In some embodiments, the Ry is a heterocyclyl selected from among; 2h No I 0} [relma x Pre he QO 20 20 x 2 . & Q, 20 hr 0 ran 5% myst 2 0 0 0 NH oN Ne [5% Ek 5 sey sg RG AHA aA nrg Vv CN Pe el se ) se se NT a 3A RA I 1 1 zN NH <NH NH zN zN [Pp by 2 | » 2 | > 0 or y Vv ZN <N 2N 2N 2N Ok nse Qi =) (r 2 2 E BAT Vv V IN 2A Q.0 yr i; 1 | ~~ ZN oe 3 % Q o Q o a > and

[00116] In some embodiments, the Ry is a heterocyclyl selected from among; the hg no H wf 4k vo Cfo 2d SA = “a EE and ANT ANS ARNT AN ANS and AN

[00117] In some embodiments, the Ry is a heterocyclyl selected from among: H PLN So 0 AN a 0 NH NT NTC, AON NPN s AN sN aN NS 3 3 sds Tt q j } NSN X | CN gO a2 to J © © NE N20 AN ~—0 x NH SN oN NN Ne? Ned EY 0 Nl Q ANH NN SN aN L ANT ART RT ART ARR AY AY and NH Ne

[00118] In some embodiments, the Ry is a heterocyclyl selected from among: Q NY wh CNTY aN AO y Oo o. 3 0 py / J RL To 255 2 2% ~~ aN aN of | HS NAO aN ; Oo AN To A A ) Q Q \ 1.0 We ,and

[00119] In some embodiments, the Ry is a heterocyclyl selected from among: o o o Os & oN di EN FOR Q” QQ aN KN) LW 2 aN aN ng ~ © N— + +) TWEE pT Te AVN Ne a gs TE H Lor Land” a heterocvelvl selecte

[00120] In some embodiments, the Ry is a heterocyclyl selected from among; \ a LY UN.» =N Ny UY dS AEX NGF HE Ho— Ho gd od Sof A ANG NS 0 1 and

[00121] In some embodiments, the Ry is a heterocyclyl selected from among: aN NT NN ON | | N | aN PY; a Res

[00122] In some embodiments, the Ry is a heterocyclyl selected from among; N-Q INT N HN Non oO :

[00123] Insome

[00123] In some embodiments, the Ry is a heterocyclyl selected from among: d o NC, 5 - d 0 HQ Og) I~ b f | A N / AN / xh = .

[00124] In some embodiments, R; is selected from among: Vv Mo NE To Ne sf 5% dS aN ATR / Yo NH To Ne se Oi ~~ WM NS BN A STR ana

[00125] In some embodiments, Ry is 3-14 membered cycloalkyl. In some embodiments, R, is substituted 3-14 membered cycloalkyl.

[00126] In some embodiments, Ry is selected from among; [e7} 52° wh $20 HO, Xe 0 ) hs ro x 2 Oy SL o NGS 9 ’ 0 0 0 0 sg Ss s% $5 JO OF (OFF oO = = = bY, sO A J sO A SOA sO A oO JOH OF NC, = = x = Q wl — s / s 0 0 oo 0 0 / Fo / jo] o 0 o Q N [o] i a H AN; N 's=0 S=0 2 '3=0 SC COCO OO 00 0 "Gg 0 ap / 0 x x wil x x ps . % 1 Cr 2 N Q / ~-N oO Zo Lo LT 7 SOI SCF sy =r So Ly Ay oO 0 Do 0 I ’= 7 Eh I oF 5 x xe x x HN 2 NG 72 HO 53 o, s<0 q, SON RTT STL LG : = ~ SA "FV > CL x and 0” , and

[00127] In some embodiments, R4 is 6-10 membered aryl. In some embodiments, Ry is substituted 6-10 membered aryl. In some embodiments, Ry is phenyl. In some embodiments, Ry is phenyl substituted with one or two group selected from among OCH; and —- CN.

[00128] In some embodiments, Ry is 5-10 membered heteroaryl. In some embodiments, R; is substituted 5-10 membered heteroaryl. In some embodiments, Ry is selected from among 1H-pyrrole, thiazole, pyridine, pyridazine, pyrimidine, each of which is optionally substituted with a group selected from among -F, -OCH3, and -OCH,CH,OH.

[00129] In some embodiments, R, is selected from among: x N, OHO .0.0.0.0 30.0.0. m0 ANT ANT AN ANT ANSTEY ANY ANF and re Ns WJ

[00130] The present disclosure provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers thereof, selected from the group consisting of compounds of Table A: Example Example | EE Structure a Structure 2 # FE Example | 17. Al oO ANU 32-29. | Example | LE I F FZ F oh F o Example | WSNH NH Example | = J 1. y SY 32-29. NH N NTR Le NT So 0. | NN So a — F F Example | F | Exampl | F q xample | xample I» : 1.1 EN ~NH 29.20) NH 1 A J SNH NH NX [= N N 0 = NHL NEN Ou )¢s) NTR LJ NN So CF. ww WSNH Example | 1-3 1 1 | 32-31. R 8 NH | NN J N“NTSo \ i 0 sme Go [pmme | Jo Ne Sw No \ No Fo F 3 0 7 A® Example | F abe ~~ | Example | TNH | Example | / 1-3. ail —~ i WUNH NH 2 wooo ee NJ AN ~ Su SX AE eS NH NIX LJ NN o FF NF > F F 9 Example | “X i Example | le Lg 1-4. WOONH CN 32-33. “OONH \ a0 H eS NN (C0 Lv No FE I F F { FY o = Exampl PY Exampl wi ~~ $0 ample | (Example NH 1-5. wWOUNH CB 32-34. wa “So NIX L NSN o | oo| Example | Example | FY IN :Xamp cE .] No 1-6. SNH AON 32-35. Fr oo wm a) CL Lv No J CNTONTTo TN Wo DS . F ae |# 2 7 F Example | ws 0 Example | «0 9 1.7, “NH x 32-36. t «Su Q NY A 7 N N 0 -— 0 F | F 7 ample ww & 9 -36. ow o | OCT Ly No CF3 ® Example | WSNH SN Example | 1-8. 32-37. NYS 5 | N N 0 F 0 F Example | ~~ (Example | Example i! Example 19. |! oS NH 32-38. | NX A 7 N N 0 F 0 F Example | A ec Example | ~Aainpic I, LAapic 7 / N ri Me SNH ANT 32.39 RAVINE Ww “NH i Lv O; NTR lJ N N 0 ye Me SNH NT Te | A No Fo 0 Example | 1 {Example | 1 Shy ON NX J NON F F 1 Iv 8 0 F’ Example | REN ~A Example | Cxample a Example RB 1-12. WUONH ON 32-41, UONH 2 | NTNTTo (7 N FF r I Example aN Example xample | © ( _Q>wy Example | <Aaiiiy™ WN ~._. NH ACP wr i 113 | WISNH “No | 32.42. | oN / N oO— L WN Shi So NIX 0. NN So NF Q } F 3 AF oy ~~ ~ am F Example “NH \ p! 1 x Example | A A Examp AN 1-14. ' “NH rN 32-43. eof a 1 SH NN I Le No Example | [= _e~y, Example | <AGiiiy®™ WN NH TEE oN | 1.15. |! WISH ~<o 32.44. | “Nu / N I REN ANH NX 0 2 NSN So FE ee F F 1 E: ample | SL A Examp Example | 1-16. ' wWOUNH rr NTN 32-45, oO AN / ~k=0 Oo o 1 wa ON NIX (> NTONTSo FY “AR dogs Example | ( _® | Example || * Li / ~keo| 1-17. 7 wo OUNH rr "S=An = 32-46. 1 oO wm gag NYY 0 J No Jeo FF RF N\ 0 Example | TX AA mee T° C: 1 J E; 1 wmple | (0 | Enampte | Je * 9 ] Exampl SS | ue | I Le No Example | ef C0 Slee Ja 3 sample | {A | Example | oT ad 0 Sau rods OL Le No Example | FY 0 i E: )! LR) ample | (a J | Brame | po AF 2 wh dls | Emme | Soa WW No CF CE | 0 oh Bample | © Lf |Exampe| 0, ba mel i AP ZF Zxample | F O bq | Example | 1-21. “SNH ON 32.50. A No | FF 0 FN 0| Example | To A Example | «Say J 4 | 32-51. LE NTR xn NTR I ~ Le No N + 7 A Srl o Example | © Tf | Exampe| Jo Nef To T | “XO F Example | x. bq | Example | F (R) J 1-23. WO NH ON 32-52, “NH ode COL 00 NZ No Le No Br 3S | F 0 F P 0 F ° Example | (J | Example | 2 Ne | Example | 1-24. wv NH rN 1 32.53, 5 o 1 oS ON NX 0 2 NONSo + F FE | f le ® , NH 1 ro Ou f(s) NTR 0 J NTN o Example | | Example | 1-25. WOUNH 7 "S=A = 32-54. \ o ww Sny Esq NX A 7 NN NNTSNNTRA > No SN N \ q | E F F F °c F Example w\® Bampe | © LSP emp] © Jo F ~ AF o pape | © (P| mae | A No — "0 Pome] vy un] Ege] o 1 Example | «SH Nor Example | 1-27. 32-56. NYY L N N 0 F pe E Example | A | Example | | Example | 1-28. ' wWOUNH rr NH 32-57. Shi NH NTR 0 NN o FF Example| ~~ [Example | 1-29. WISNH IN 32-58. - } SN Ww SNNH Qo NTR A 7 N N 0 e F le | ? 0 ple RG 8. “NH 4 oo NTR Az N"NTSo —_- 1 1 rT Example | A Example | 1-30. ' wWOUNH rr 0 32-59, “NH A — OO “So I jy —s— 0 I wn “0 NTR 0 oz NTN ; | | | QO, umne| © roe] “0 Xxample E Xample = (R) PETE - AONE 32-60. wNy OS Xr CO 2 N" "N" "0 eS NH NTR A 7 NONTSo ) | Oyo LAF A ig 1 w f Example | o & EN Example | <ONH Pag 32-61. FF Example | 1-33. ~ NH r«P=o = 32-62. F F F F # 0 F AR 1 | Example | - R Egg SNH Pso | 32-62. NH Ir. 1-33. © ~ NTN X79) N Nr X 3 0 Lp No NN “RF F | 0 | F - - 0 bp w - L Example ww iL be Example | Me™ “NH AN of xample | LX 1 rT R F F | 0 | F FE oD A c ample | Me™ SNH ~o| Example | “NH \ Mo 2. N_J| wes. AS D LW No Lv No F ur 1 — HF,C. | i ¢ (R F Example | 84 oo | Eampe| 0 lw 2-1. 1 dT 32-64. FY NF (R) F 2.0 Example | WW SNH No | Example | o * ~X 21. i] 32-64. NH y NZ NN NO Xr PN ! No TL 2 o- 1 NNO F F F F 9.0 Example | “ F 5 | Example | | RG SC _ | Example | 33 |! wWOUNH ~3F 32-65. ; ~N rr fl F ad NN A 7 NN So J FNP 1. 0 ; AE 0 | Example NSH r N— xample | NH ~ 32-66. \ < oJ 2.3. Ri HFC. F ® ple | WSNH ~~ . NE AN N N 0 F 4 F F Example | dL Co X. 2 0 am ® ~ A Example “NH Ny = pl | «SH ON NH 32.67. wo) 2-4. N y A «SH Ow NN A Z NTN" | ~ | FY “YoY ample | {on | Exempte | oA L 0. ~ -- Oy 100 Ave No Example | E | F ple | F “RB S 9. “NH 0, N NY RXR) Az NON 0 DT RF | “0 ww ample | Me™ SNH ~o Example | 3. 32-69. NZ NS A N o Example | RF ; | HO. 1 F ® F ju mple | WOSNH | Example | he R ~N 0 4, 32-70. NH NZ NS ee POL NTN So (7 Wo ~J [MF al CFs f F Example | AZ ’ i WSNH No | Example B® Jo X T 32-71, “ww ON NZ NN CJ CCC NNT So LW No s— — — a 0 ww F Example | EN SNH Example | ® 6 1 . | 29.77 woe QT ® le | “SNH -' NX A Me’ N N OQ CF. NH, Ww WSNH CF, NH, f - Ww F Example | 8, ~~ |Example| = lw | Example | 5 1 rT 32-73. iE NYY PP NN So Example | ss 4 RE 0 32-74. NH 1 ih oO CF NH, ww WSN oN NX A 7 NZ SN Xo H oT Example | A. Example | ANN Fo Fo © F » D a. N Example | ® B.p 3 WONH CN 32-75. NH 5 N | Lebo ho Lehoko = F : | ef ’ Example | . ai” I Example | 8-2. Ww UNH rr NT 32-76. Example B® SNH NT 32-76. CON \ NX NT HN MN Z 0 Z NN So NN So 1 Example | ; L I Xa ry Example | ok 8-3. wOUNH NTN 32.77. “NF 0 why ~~ (CC Lv No I nr % ple | WR 7: Woy NSIS ( NON Example | — — |e |* F F Rati | wt AF] Tsangle | - & 4 : NX ’ NX ~ Le No Le \ NN So 7 F 0 I 2 EF F F ® Exampe| ~~ (9 |Esampe| «©, | Example | 8-5 wWOUNH rr “Szn 32-79. 1 0 oS aS NTR 0 2 NN So F | F F ample | AE ! “UNH 2-79. Q 30 NTR / (p> NTNTSo FF LE 85. vo NA © 9x0 32-79. JX N N N 0 I FL F ; oc . pe Example | [J |Exampe| = [lo 8-6. WOUNH NTN 32-80. 0 A 1 ht Example SB om ~N | 32-80. | ki —0 0” (Lee (7 Wo Lr Wo _— Ke | Example | 8-7. WOUNH NTN 32.81. TTY 0 A® DD Example Example Ww! L Br | Sp AN | 32-81. | Woy LJ sXe NRT ni 3 11 Jn J | Example aw . NH ON 32-81. | Wb NX NTR AN J Lv NWS NSNSo Example | Nn ~~ Ja 0 wl ~~ | Example Sd N 32-82. | NTR 0 ZZ N J 0 Example | 89 WOUNH NTN 32-83. Xr » » LL 00 NSN So Lo. | NTN So F F F QR g xample SONH w Sr ~~ 32-83. Sree Y NX LAA 5 A 7 k NTONTSo Example | ¥ F "0 2 FE F o *® 1 oN Hon] Example & | ) e | NH ON vai. NH 4 0 NS Nr 2 x” POISE i NTN To F_ [se Tl 7 FF 7 Example | WL Q | Example & & 4 8-11. wT SNH 820 | 338s, 20 J NYY ST NR IP 0 LJ NSN So N“No | 1 o «Sn AE NTR 0 2 NTN Example | | Example | 8-12. wWOUNH rr "S=~ = 32-86. 1 o «SNH a NTR) A 7 No + F le | © 0 ; NH (8=0 NTR 0 Zz NN So F F F F 0 Cr F Example | Ny, oF] Example | [w 1 “No ~~ F| Example w N Nd YY 32-87. | i Ry” Le No E | F ple | 2 Jo 7. NH o o NTR I \ No - x EE = v “0 EK F Example | «Sn rode? | Example | ’ & 0 AN Js 0 w ~~ | Example mq N 32-88. | NX A 7 N N 0 F | F A D ol LL Le No _ | FE Ee F F Example | ~LAdinpic WN SS” manu | 4 A gis. | ewe OWS) ae, | 1 Oy 4 Q “~~ | Example NR | 32-89. | I deb ™ Sa AN NX Lo. NTNTo Example | 1 id wh elie I “Nh 8-16. ooo J | 32-90. NH 0 1 LY er Example | | 32-90. NX Lo. N N 0 NX" Xy” Cs N- IL 2) ¥ NT — D NTNo NN 0 D F F YS r FB F Example | Ny o~Syor, | Example | Jw \ 1 AN ASNT | Example . F pl NH N° CFs) Tan01, | NTR A 7 NTN ? I W N © oN? LJ 0 BF NH, F F ® F Q in JR) Example | \Q _~,, | Example | © SN | Example | 9, RE Cr 32-92, NH 1.0! | Example | R Example | wy No 10. i . «fh 1 R Example | Qu 7 Q Example | 11. CA AN. 32-94. F Example | SNH - ©N Example | 11-1. TT. | 32-95, o 1 wp ON NX A 7 NTN OH r ge F ple | © 5. SUNK gq S30, NT N 0 0 IT « TT OH F EF F F F 0 F AR Rr Example | SNH ~ Example <" “NH — 11-2. | 32-96. NY NT N L~ C2 dg N N 0 N WN 0 0 zz E 1 SW Ig E 1! xample | «Ny o~dLo Example | 11-3. 1 1 32-97. I er Example | & & iia Example | i F F F 0 : \g be: q AR Example Ww ¢ \ p . Rng wo 32-98. | SNH oo 11-4. Oofs NTR b NX I ~ Le X 0 (7 Wo A _ CFs NH, Rr ® Q Example | Qu Ng Example | (@ 1 F \ Q le rR 3 | SNH = Of NTR L N LJ 0 FF ¥ rR xample | «8 No Example 13. Tr a ¥ 32-100. & Example Example | «Cn (0 32-100. | 13. Aan J F F E Q le (R) - J. “s I =(S) 0. | NH b N NTR L N i 0 TF 1 F F F F F ° F Example | (Example | io ol Q Example xample RN SNE nT 14. | SNH NS 32-1 NX | Le No Je 0 = J NH | ORIN NTR LJ NTNo CFs. NH; XC Example | oO AN 15. T= rr 32-102. Example 32-102. a5 Shu ON (C0 Le No Example | 16. “UNH ~A 32-103. \ Example 32-103. o I «SNH o NTR A 7 N"NTSo CFs NH2 | 10f Example | 17. ¢ i il tT 32-104. Example 32-104. ~ 0 wShH ~~ (C0 Ls No ul A: UNH 5, N NTN XR 0 2 NTN So F NF : NF [e} pe] © 0 kame] | "lw ge F SP 18. | “UNH NT 32-105. Example 32-108. “Sw ow I Av No ¢ lo > | " oy... NX (R) | | Le No CFs NH, J ! ZF D 0 1 F (a 3 o Example | Ny, ~~ Example LN D 19. re rT 32-106. le 4] - | N 0, ap I Le No N° 0 oS ~~ (C0 Lv No F i F E A OMe A o. P Example | PY Ct Example | “Yo ; >< o | D \ OMe A 0, xample | FY Example Yo 5 ap EE - OMe 32-107. w AL —N Example 32-107. Nl r [ rr “J | Example AQ J 5 ug A ome 32-107. w S i A (R) NTR = Ae NSN So N"NTo \ =" = oO Example | 20-1. Ww UNH ~~ 32-108. Example 32-108. A | Sy NTR A 7 N WN 0 Yo, AX NX “Po = Example | 20-2. WwW ONH YY 32-109, Oo L ! «Sm No 0X LA, 0 Ea ZZ ww 7 aio ) Q 3) T N Xr (R) Le No F AN | Example | 20-3. WwW ONH YY "32-110. Oo d J v DID > | le J | Example IQ , | Su ¥ | 32-110. | | ” Y N si CX COC I Le No Le No —+ — Ss Example | 20-4. WON b32-111. | Example 32-111. I <0 Ly No ~5% | —+ — Example | a, WOUNH ” N ' 32-112. FF - 4 FZ ~~ # 9, 1 F N | Example . (R) , Ol ie | «Shy z WN 32-112, # Q = X Nr or C LW No NN So wr gee gr F FN F™ YY 0 Example | TT eae] Tl} LF F F Jw 21-1. WOUNH HN 32-113. Cd Example wr oS HN | 32-113. oN CoC CL Le No Le N ou AO 0. | ore Le No F I F FP | NF Q YY Emp | | © Xe yp | Example | ~~ ( , Exampl 31-3, ! WOUNH 7 32-114. Example 32-114. «San NN NNN LL N"NSo TN he Jo vy w N o™ or Le No F i F E Example | 21-3. wOUNH Mn °N 32-115. Example 32-115. ol Ng w SNH SN NTR Z A 7“ NNT CON MR Jo hg ® of NTR | Ly No ER FY ixample 1 Example il P P! «K N EN $50 21-4. WUNH Z 3 33. * NH NN NY Ak z 0 z N i 0 N ¥ 0 r 1 0 TL Example | A Zo Example oh NF ¥ WONH > 21-5, | NH Zr 33-1. \ EE rN NTR LL N N 0 1 “Sw 2 NNN 0 N N 0 go. | phy ZZ F Q Example | F w NC. Example | a” AT 21-6. fi be 3:2 I EI Ns. LPR a NTR Sy Ne NTR p> N"NTSo I oS ~ NY 0 AZ NTN FF \ {0 : Example | ; x 0. N > I oh yo MIN NN Example ma 31.7, WONH TNE TY 33-3. yy OL _N Example 1 WISN NZ ] 33-3, Shi sP NX Ly { pi { Xr N No NZ No N-O N—W fF W 7 Example | ~~ | [_N Example | 21-8. “UNH © Y 33-4. Sm ile i 0 NTR SOO NN No WINE { NTR L. NN © 1 Example | Example | ak AON Pra 21-9. WONH NYE YN 33-5, L Example i! _0 why AO a 33-5, Syn 5 NN Coy | A No 7 No LA Example | (Example | wh, 0. Example i WISNH ~ 33s. «SH eP 0 Co Or 2 NN So NN 0 OH Example | 21-11. WONH TY YY 33-7. — “F XQ L : | Example | F (R) [eNpe} «San oO ~ oy NH SN fies of NZ No L No aT = Example | F 0 F ample | «Shy N | EF 1-12. Ld dye AA © I B Example | 21-13. TNA © 11 °° 33-9, E X ell Se Ao pa 0 4 FY ZZ Exampl ® Hanmi r do xample | GO | Exampe | le | Example | 21-14. YY NR ~ N° 33-10. NX Example | ~~ A® nN Example | 21-15. > NRA | 33-11. Le 0 w <TONH ON I Lv No Example | * 1 Example | po wl AO eH ay “UNH © 5 33-12. o 1 «SN A NX Lo. NSN So + ; 7 I | F le Ww 0 3 <ONH AL I Lv No -T ] 1 Example | 33. “UNH rr Sev 33-13. x w WSNH g=0 NX 0 2 N“INSo NN Te | L ) Jeo I T F F F F Q Example | ~~ | Ni Example | = |® BS 23-1. wWOUNH rr SEY 33.14. x w WINE g=0 NX A 7 NN o l Z 0 ® A SNH NC) (9 NSN So Z BE xample | X N Example 24. “SNH g=0 33-15. NX Lo. N N 0 3 | F F o le | AR No . NH HN NYY TR) L N N oO 3 1 ol Example | Example | San 20 3316, 25. > Nn i009 I Sw NR LJ N iN O F “NH, A: F E S 0. ES GE TN 26. Me” “NH NT 33-17. Wiz by “<0 Me” NH SN NZX" 0 SJ N“ No J ) F | oY rm NH, ENP NS Example | Example | [4 . 26-1. wOUNH 0 33-18. oF 1 =0 Su 0 NN Cre Lr No F J Y \ NH, Tl Example | Example | 26-2. WONH 0 33-19. o = A I oS o COLC “vv No 0 Example | Sy 26-3. wWOUNH oO 33-20. SNH o NSN F | F F A» ~ °NH N20 NTR 0 L N N 0 fe TF ror Example | SL 216-4 “NH 26-4. wo OUNH N° 33-21. al £ E FE wR le NH M0 | NX 0 LJ NTN o oo Sor [L oof E F F F 1 ? Example | PF Rr 0 Example J o 5 oy | «SH 0 33.22. WOSNH PL oo Ia 0 NTR 0 N i 0 3 «Sn o NOY SYN LW No B 4 rx Example | 26-6. “UNH 0 33-23. CF 3 F AR / ~"ONH Pro NX 0 NN o 3 w Shu 0 I Lebho <0 FI Example | XK, Example | YL - ot Sau ~ a 2.7. | “UNH 0 33-24. + | F F Nr ® N ple | NH ~ 4. o NTR 0 = NTN wy o PONE “ No Kons Example | = [ Example | 26-8. | WOUNH [e] 33-25. ° 1 SNH 0 NTR N UD 0 NONTSo on F F Fo 7 1 F p | oH ~~ o | LW No Foo FT Example | L Example | ~~ AN ~~ yy ~~ 26-9. WOSNH Q 33-26. bo 1 Shy 0 COC | Lehoho Lg + E F le | Rr X 0 3 SNH S20 NTR (> N N 0 Example | | L _N_ a Example | ~ ( 26-10. WW OUNH QO ZN 33-27. eS o N Seas Lr No E | F E ple | | A» Xe | 7. ~ NH So (00 Ly No — 1 Example | x A Example | ~ [= 26-11. “UNH 0 33-28. = dq Shi 0 I Lhe ns F F le | F ple »® 3, NH SP “o NTR 2 NTN [r 1 Example | 26-12. WUNH 0 33-29, oo 1 oS o NNR OLY Lv N oP E \ E F rR le NH 2 ¥ : ~0 NYY 0 = N 0 Example | L A Example | = [ 26-13. wOUNH 0 33-30. 4 SNH o Nd N Le No Sy l = 0 1,0 To RS” H., NX (S) | Ly No La Example | ~~ ( o Example | 26-14. wWOUNH QL 7 33-31. A O. whi o L OLS I Le No | FZ 0 pe pio | H NX (S) I Lv No r Example | L Ye 12 WOSNH 26-15. “UNH 0 33.33. le AR 2.0 SE | COL Lo / | “SNH 0 NSN LLL, On N iN d ONT NTR ; 1 Ne Nd IL 1 F F "0 Exampl F Exampl ’ A Lo xample | xample WN NN 26-16. Ww NH oO 33-33. NF zo ~~Lo | Le No | = A | «Su 0 NTR N {J H NN "So I HY Example | Fr IT F Ca % oN Example UR) 0 NH 2 33-34, * YY NYS NN NY Sv N ° A Lo } Yo \ LE | ’ Example 3 Example » o 26-18. | w “nu 0 33-35, - Ne 1 1 NX LJ N™ "N" "0 Example | | " 26-18. UNH o NYY ON Lp Q N o E 0 F Example | WL 26-19. WSNH [e} 33-36. l = I Ly No v 1 «Su 0 NY COL) Z NTNTo F F F Example | L Example | ww 26.90 WOSNH oO Ss 22.37 aw Q 4:0 n | ", a 26-20. WW SNH 0 S™\ 33-37. J: NZ LJ N™ "N" 70 oN WSNH os A Sol Le No I E F CF Ei F x | 0 i ? Example | Example | am ° I ° 1 Rk Example i oS 0 34, oS FON QOCCr oa Le No Lo Le No FF } od F F Example | o £, no 1 | “Sn o Eamie | oS 4 CLG Le No F F 0 0 Example| © | |Exampe| © «Sn fo} LOC Le No (0 7 ho Example | ih | Example | ii bq 26-23. “UNH o 36. WINE N Cre NS Le No ° Le No F F F | . . Example | B k. 4. | Example | F k. 76.94 WOSNH oOo °\ 26.1 WOSNH = 0 i A yd oS 0 | Bg | «Syn NC 5 OLD he N N 0 N Li 0 F F | 0 - Example | F A in | Example | F AR Ne: oie | Example | 26-25. wWOUNH 0 36-2. Sn fo) COT NNT wo Example | | Example | 26-26. Ww NH QO = 36-3. wn 0 = | Cs “v No + pe 0 le \R | Sn NN = | LW No F Fr aly Q / Example | (. | Example | lo Fo F F w ~ NH I Ce A flares diner Sobol oN yl 26-27. Ny Q "364, | SHON N Cr Sn NSN So 0, I Ny | NINSo 7 Q ER TE F Ay ’ L | Example | “ 'N J SNH Q 36-4. <n NON xX COLT 0 oz 2 NTO al NTN =N Example | «Nyy \ Br Example oS Example 26-28. | oA 2 | 36-5. iP - NON N TF Fo | XO F Example] © (| Exampe| | [m 26-29. wOUNH 0 =N_ 36-6. F F Ir ‘ F F 0 Example Example wr n KN o N $=0 26-29. WSNH 0 EN 366. Se Ny Cone Co NZ No Le No 7 —- F F F F Example | (= | Example | ~ [@ Qp@ 26-30. v NR oO bo 36-7. F FT F pe oq Immele R 1 C7 | NT NTSo FF Example | | Example | 26-31. “NH Oo 36-8. F F | F F F 20 al | Example | RG Ww $= NH 0 36-8. SUONH ON COL Co 2 N 0 N" No No 7 3 N (0 | NSN So 3 F Example | | Example | ey 26-32. wWOUNH 0 bo 36-9, A N— | oS o NY NT COO Le N ol) F FF F E Q le | ey j- SNH TN | NR (p> N“NTo F 0 . F Example | Ny | Example | “\ ln 0 «SNH o COLO i“ I te TLE He wo Ba Be »N\ / 26-33. bd 1 "36-10, “ne N N NT CoCo Lt NTNTSo 0 | N° So FF Es F F Example | 26-34. MY NH 0 36-11. 3 Example Rr » Sh a | 36-11. | « hs NN COC Ce Lo ~~ Leo / o / I Example | Sy 26-35. wWOUNH 0 36-12. SNH o CLEC Le N oT Jeo F 0 . F Example | «Nyy 26-36. To mn ~A | 36-13. xX oS Example Ni 9 ol 3613. | Cr Le No Lo To AR N SNH NN i N R 0 J ° N“NTo FE Example | | Example | 26-37. “OUNH oN bo 36-14. oO «Sn 0° COL LW No Lo oO = 0d E om a Ne 2 N 0 NE | E f F | ¥ 2 F oN Example | ie | Example <ONH ON 26-38. UNH 0 36-15. SE i NS " 7-0 % MY Lo © L / (_sz0 N N N 0 So 3 " / ToT wl) | Example | Se —N Example | «SNH o WN !' 3616. ON 26-39. A) N OQ Foy N= x HN. Bi | Example | “NH 9 36-16. NSN OC N"NTo I Sr i F ® i | Example | Ar “SNH 0 am Example | +" | Example | E E F le | \® 0 <ONH S20 NTR LL N N 0 TF r 1 — | F F Example | SNH 0 | Examp 26-40. NAAN 37. Le No Bn, Y 0 F | ag F F | 0 : E Example | F JL | Example | F J» 26-41. WOONH 0 38. SNH ~ ample | [| lo 9 oS 9 iv |r RN AN NX 0 2 N N o Y ] Example Shi 9 | 38. | NTR” N\ cF, one: LW No OH | — TF ’ wi | Example | Ew J iH ? Puy 39. ST NH ON o Hr” ™H N NX Le No {J | , N“N"So —, Example | -5 | F A xmple | - o | Es -43. CLO Sr yy + ENN w HF | | F se] ly oem] dng 26-43. NA NN , PY LL LA C N \ © | NZ N 0 FE RF | F 2 FE F Example | JN | Example | I | Example | 26-44. RE mn to 41. 1 «Shu 0 | OL LW No rs Su? mF RF Lid F mple A(R) 0 1. NH [-S | NX 0 NNSo FF EN Example | | Example | ’ So” or 0” —_— F ZZ | |e ; F © 0 vig | w SNH ° | Brave | NH [5 | =n. GCL Z N = NTN o (lok | NTN F F e RE Example | 1 Apis Te 26-46. | I CY 42. 5 «SH ° ad coco Le No Lo RF | HN F mie | 12. =O NX LJ No Example | | Example | 26-47. wo OUNH oO / 43. «Sm o & oy 1 Lr No Ko CFax Hz ZN w ~ NH ” CFa~ NF; | "XO © F ® mple | Example & : 48. | “SNH 0 | ”, NH oN COLD Cre LW No Sto | Le No | ; I : | i EN 1 | “Se oY | Le No (ns Example | 26-50. i i 1 Lo 46. i F £ | F~ 0 ) F Example F Example AB 26-49. AN 45 TNH J - WISNH 0 . ra J =N NY NN LJ 3 POR yrs NTN ~ F F 0 ; F F o R N Example | EE - o | Example NH Ji 26-50. 46. NXT g=N NSN J) X LL CFs NNSo © NT NSo OH ! 4 «| 1 Sa o | I NSS ON p N N 0 OH FF ) NF ( N FY, Q F I E 1 oo E: 1 oO xample | J® )— Example | 9 E | F F Q ample | ~® » 6-51. NH oN CLE Lp No F foie id r= 11 A wie INET LF NTR ly NX 2 CS N" “NO NTONTSo F Foo= NH | F F F o Example | \® Q Exampe| = [m i F | F 7 w 0 ample | “UNH qo _%=0 5-52. NY or 0 7 NN So AON Example | 27. Me” “NH "N7 49, Me NH hg NEY A NN So £ g # ® NH : SONH Ss 8 0 NX (2 NSN o Jeol rE CF is F E cor o Example | A 8, Example | Sa 28. wOUNH z gg 50. NT POLE > N N 0 F ; Pe F le | » NH SNH sso NTR LJ NN So F I | Sf | = FN XG Noo | AR Example| [| Example | Jo 8 | Example | hl | F F \® ~ NH 28-1. wWOUNH NT &1. FE «SH NT NS OG 2 N" No Xr CO 2 N N 0 F 1 F F Example | 28-2. “Ww ONH uA NT 81-1. oS ~ TON po ON NTR A 7 NTONSo ZZ ~ R 1 NTR LJ N Ny 0 Example | 28-3. WwW ONH CY 81-2, XL &o . C “UNH Ho. \ NTR 0 Z N N 0 FY N FN RP | Example | “Te 4.0 Example | - ¢=0 iy . 28-3. Ho. a NY L, LAL N N 0 1 1 F | fF ~ i ~ F N ¥ 2 Example a (R) ~Lo Example | (FP | Exam 1 WO ow 28-4. WONH Oo ~Jd 77Y | 81-3. NF ~ \R N w 420 F | NTR 0. N N o NEY N No SN N N 2 2 0 UL 17 | Exampl F $=0 ple & Ho 51-3. » NTR (2 CX NN nN XO 2 A i 7 F QU No Example on "TI Ay | Exa Example | | | Example | 28-5. wWOUNH ( S= ' 51-4. OH IT «Sn $e Xr LT OH z NTN = Joo 3 NX Sy 0 = Example | 1 2 7 0 5 i F ~Fo | Example . 51-5. * 0 v J B* T iV F NF A Example | «SNH AT Example «RB No 28-6. 51-5. * rl § NTR Nr COO i$ NTNTTO NNO + 5 = |¥ F F F ~ Example | w® a | Example | RQ PR | Example | 28.7. + » NH 5 81-6. Z Io N° ot &20 R I NY Lo. N i 0 oO Example | Nr peed 2 N N 0 + J F F | F F F o / RG JL F "eo mple | Me™ “NH Ho N we | Example | Sw ~ 8, J 52. "NH " NX L NX N"N"So L 5 Me N ¥ F Example | ) oo a Example | F F ge V- ge 0, F F 0 w o Example | - 8 I Example | NH a 28-9. NH ho A 53. " Xr T > Lo N"No I o F F F F F F Example | ~~ (0 Example| = [@ Aciiiyit " nm AAI L 29. | w SNH E=0 54. [eo] RE 0 San NE NTR Coe 2 NSN o Example | 209.1. ! WIOSNH Ley” 54-1. || 1 OV \ Jed L "os WISNH ENT NTR LJ N W 0 Example | 29-2. “UNH NN 54-2. [1 Aa X Cl RN NRX r | ST 0 «Shu A oN ocr Le No oof Example | ~~ [Example | 29.3, WOUNH ~~ "NT 54-3. % 7 EN NT NY CO N N 0 ol Example Example | (Example | 20.4, ' “Ww ONH 7 NT 84-4, — oO J oN - i NTR A 7 N“No 1 E: ample | TU J Exam Example | 29.5, “UNH rr NT a5, F “ 0 wh ~S NTR Ly No = 3 = — lo NTF 0 R) ple | A Me” “NH AN de (C0 Lv No a F oN Example | L g Example | « SNH F y | 29.6. WISNH OL ees 56. keri i 1 ht i Nu eds oO NTR) LJ N N o Example | F | “ 2, w ~~ | Example “UNH F. 56-1. | Ny" 0 2 N W 0 1 Ty ¢ Y Ls 3 F F ¥ Example | o\® 2 | Example o£ 8 L i g WON ~ [TS=0 ia Y 29.8. ~ NH ~~ J | 56-2. FE E | F | F \® 2, | Example A Na 56-2. NTR (p> N"NTSo i 1 | - Y F Qn F § - t Example | wR | Example < NH mnt Ld NON PIE 1 a 29.9, © NH oe — 56-3. od “NH RN 0 = NN So F Vv ! F | F £ 7 wi Example | NH Ry 56-4. N NY Xo Le No L F | F. F F F Yo R AR Example = Example | SNH E 29-10. NHR 56-4. NX Xo NY N L. Le ; NNO N" N"To o 0 F Ni F % w Example | F o 8 | Example NH ¥ o 29-11. R 56-5. Cry NN So © Example | | 29-12. FE F | E F || E “ONE R Coc Ake E NTN + i IL i Fo | Example | ge 57. F Ww ~ONH EF Ne 5=0 1 reas E [ENS oO grt . |¥ |v F F Example | ww = Example | & & \ 29-13. F \ —o 58. soak COC G7 No L No o hd sr | eA F 7 | 5 Z F F Q Y —\® r WN Example | Fi A | Example | Rr L ~l A cut Pr = a Nd Rp TI oe NTR NOON oN FF | E —\® mple | NH f Example | N N ° 0 29-15. || N.C Ea {5} E F F A e NH | N Ny” “0 [p> NTN So eo e F F F © ’ = Example | | Example wR 4:0 30. NH 58-3. NC, NTR NS id 2 J NN"So NN o y ood EY NTR S. [p> N“NTo | Example | or Example | iN 21 WOSNH 31. wWOUNH rr 0 58-4, “So 0 co fet CT Nr OO Z N N 0 Jw Yo ¥ NC os \ No cl 0 «Sn AE RS XN OCT NONSo F F F F F . F «0 2 \ o Example 1 le ce Ieee) TR : = N N 0 N, Nr \ OO | Cl Js FF Example | | Example | "at WING AN gy | EN Ai=N 31-2. NH rN 60. NH Ns F F le F ® I |e BS HoN | NTR 0 NON (] | Example | Example | “\® Me O 11 Me" © ~¢", 31-3 ME NH | 7 7S=0 ' 61. Me E E | F ple RG Mesp© 0 Me" c NHL §=0 NTR 0 = N" No Me 0 Example | 31-4. ' YH oo md PTT 6d. F F | F FS F ° FN le | B® io | Example | Ww “NH ~ 62. SNH HoN 0. \ NX NT NM L~ L~ © N" No N77 No F F AN AA I ae A = I 1 a : A | F F g (R) F o ’ | $=0 | Example | R ’ 8 andy Example | ® we a oor — / Fo : Li EN o oO F §= | le LR) 5 nple | AR $ 0 Exaip | a, AL Ww . Xr y Ls Loh o N N 0 N Example | 31-6. MNH O90 ed. E 0 F \ ~B 2 e NH Ss Sead Le So eof FF Example | | Example | 31-7. | “MONH ~SEY 64-1. CF E F le | “\® Q o Ww =A NH HoN 7 rT LW No aT FY | | y E 1 o Su Yeo | | Example | F ® L xample 2 x I. 31.8. CL NY 64-2. «NH ANE E E E A® Q o “NH 5 | le HN NS / NTTNTTo eo oo E F ¢ < le | ® N ONH Esq NAS (p> NTNTSo br + + | F F ple | F - ® XP Example | F eg ® ~& 3 Leeld 64-3. UNH Ss LW No LW No F Example | 31-10. ' “UNH ZN 65. NH, Example wR Xo xample <ONH <0 Saaln | | YY NH TR 66. he ma - L ' Jeo CNN | E ] F ® ’ > | 1G] Nr F o Example NH eso Example | ~~ ( _Q Exam 33 “UNH rr SEV 67. ! ’ F F F 7 F } 5 E ® NH «Sm IL-0 a SNH s=0 | I * ; NR NRX LJ oH {J So No _ co F I 7 <A FANN fF F Example | 32-1. “UNH or N° 68. NN 0 «Sm 4 WS o NV LW No F = F F ® 4 / e SNH VY =N NTN 3 Lo. e} NN So Example | | Example | 33.3 1 “YW OSNH oo ff 68-1. EN d 2 NN N 0, NSN So rn | F \R NX =N | SS (LL aT i oN | ~N v NH 0. WN NTR 0 N N 0 E F F F 0 A Example | L _ | Example RG , 0 32-3. ONE dN 68-2. Q | NYY NTR 0 2 L. NTN NN F Is | J oR Example | AF - L «SH , S30 Example | 0. 68-3. NTR 2 N N 0 G A LR 1.0 ww d S’ NTR | Le No F FE 0 pe. F 0 F Example ] 0_ | Example ~ 32.5. | ww 50 | TW 0 NY oY N Xr IL 2 LW No Moye , rT ® Lb de FF " le Osg / . Example | & IFO . Example | AE Example rR 8s Example UR H 32.6. #2 , —N © 70. I WN —. x L Nr o Le No F o lo 3% “T Example | o. Tle , Exa Example | [® + | * - AB + ar F | F NS | F Example | 2 Ce bq ple AR xample . . Me" NH 2 71. v é N 0. NR N NTR GP (gp N W 0 N 0 - —-— de ASL NA CA Example - Rr Example 32-8. P-1. Mo o 1 Me SNH 0 OC | Sy N 0 oN 16” NH 1 [¢) op NS 0 Zz N"NTTo Example | - @ 3 Example | TL 29.0 ENE 4 nd Py ig P-2. To om RE EE CLC SAA 0 F P-3. H LA | Example Ww Q.0 Example A 32-10. | oC S NON P-3. Me" NH 0 N rr CL LW N70 7 N NT SNSo 1 oO | F F F le | ® 0 i ~ NH s NON NTR LJ No F £ k XO F o F T Example | & Cn " No Example | Me" “NH ¢ 32-11. 6 | P-4. 00d NTR | 0. Ae No NSNo | OH F = J _OH r F - 0 ; E 1 AF L E I F xample | 0 ~ | Example | CT 1 WW rT Rr 1 Example | 2, } 0 Example | eS ~~ JAN 32-12. 6 5 ps. i$ (Ly OY ~ | we fe Av No 1 F | F F o nple | & & Example | ~ NH | N 12. o 5| Ps. NX / N N 0 F PE i 0 I F | ¥ F 2 ® 9 E Example | 0 ~ Ao | Example | © [ CUNT NTN HASEET " SCN ~N Te Me™ “NH No 32-13. ooh Me SNH Yo or I Ho A 2 So —-— | F F o ® nple & Ae Example 13, | RE P-6. | N NTR Le N 0 — I | Example | a 0 — r= ; 0 Example | F R 8 | Example | F 32.14 8 nga J | Era waa To =e 11 lS NS 0X H | NA N 0 A N. N 0 = FF E ple | F ® 8 | Examp o R i «wy HE ws |p Zu ® NTR H 2 N N 0° Example | «OA Example | 32-15. P-8. To ror Me SNH Yo NX N~ Az N" No H TF | F F 0 mpl | “ NTR LW No F 1 E F r Bar ” Example | @ Yo Example | Me™ NH a 0 32-16. SNH ~N P-9. oo NS Ny Q / S=0 Fe TN Example | @ so Example | " L 39-17. = SNH 1 peeN P-10 Me™ “NH AB S=0 Example STH N P-10. Me SH Q Soi rd NZ No A NSO FF P-11. H F 7 NF Example | “Ys H Example | FY AP | 32-18. NH 4 {8 o PL Me" “NH oN ra ore Lr No H Av No F Q F Example | wr — | Example | ii 32-19. WONH 1 ~N P-12. Me” “Nt P-12. \ Me” NH “SN NZ N J NTN So “XO r F | F EN F ; Example | & 2 Example | ? -Xamp) SNH J | Lxamp ~ Example NN 1m | Example ., ow ML aah lw’ NH Ov - B Example i d., | P-13. | Me” NH ? A N NZ N ‘N“Y0 ! Se No F | E hes 2 Example oO o sample | OQ Example | oN 32-21. i CFs NH, | F 1 " F o 1 | © x Example | en AN ple » An) NTR xX | _ 5 Le No Oy F PA ! ~~ H 1 OC . F 0 Example | low [Example| oN 32-22. NH 1.0! I EN Ah | Le No TF F ple | F Ww J | Exampl 2. « Lol P-15. NTR Le No E go 89 mn Example | | Example | 32-23. P-16. Fo hd 1 Example | lo — | Example | Me SNH NH 32-23. NH 4 N P-16. | » NN { Xr RXR M 2 NZ N 0 MeO N Wy 0 F CF; TO * 0.0 Example | Ww NY | Example | «NH No 32-24. SONH A ONS P-17. | FF F F ple | w P | Exampl 4. SNH 4 NTIS P-17. | NW (qp” N N 0° E 1 FF Le 1 Example | To P | Example | «SNH “So 32-24. NH \ NT P-17. | jo! | NNN AN NTS NT IL {J NNT So NTNTo ) + — F F F 0 F Example | ® | Example | J BTR WON 1 mend Te AE wwe aie aS 32-25, | Me” NH SN NZ A A LE 7 0 Te J | Exampl STONES N P-18. NTR 0 ZZ N N o FF + EF F F . - 0 F F A Example | & & . Example | WSNH ON 32-26. je! P-19. NX NX N Py © Av No re S _o F ge A F E Example | | Example | 32-27. P-20. EN NN Or Ave No F F E le | Rr Y 2 J ~ =0 . v NH o. $ NS LL N Wy 0 — Example | | Example | 32-28. P-21. Sm Sy NYY A 7? NN o = Jo 2 NHR NN Ou)es) NTR 0 Z N“SNo OH Note: any compound shown in brackets in Table A above and anywhere herein indicates that the compound is a diastereomer, and the absolute stereochemistry of such diastereomer may not be known.

[00131] The present disclosure provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers thereof, selected from the group consisting of compounds of Collection 1: Collection 1: Certain Compounds of the Present Invention SNH oo! “0 No wo &: He Rea R) WISN - NIX A» Me” NTN CFs. NH, ww WOSNH So 0 CF. NH, ww WISN “TN NX A 7 NZ SIN Yo wy AR WSNH “So Ww Nw SH aS ZZ ZZ NT ONT So A N 0 Mo Pa 8 CON TN To CF3. NH; Jw ow NH ON NX MN NZ NT Xo H w® y Ww Con No HF,C. Xe A(R 0 ~o SNH ~ ; N Nd NZ ] Nx 0 ) A N Mo ,and CFs. Ww 0 a" NH “NH Ne NSN J > N N 0 CFan ; ad ® ” WUSNH “ON NENTS J N J 0

[00132] The present disclosure provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers thereof, selected from the group consisting of compounds of Collection 2: Collection 2: Certain Compounds of the Present Invention F F F v i 0 "0 F™ wo FY H Say A H 1! CL oS NS wh NH WISNH NT I I I LW No Le No Ae No «Sy NCE, oS NH | | Le No Le No 0 AN L SN oS <0 wo NX Lo. NN o 1 SNH ON NX 0 J NTN 1 oS ASO NX 0 P2 NN «Shy “No NX 0 PZ NNSo bo 1 «Sh So NTR [> N 0 EF I E F [o} YY ANS Shy “NH NX 0, NN So a 1 «Sn NN | Lr No or 0 I | - A | N wn A wn - wn vv I I I Le No Lv No Le No F F F I: 7 F Saw AON w Shy Q Sai o Or LO | | J A No A No Lo I I I Le No Av No Ave N REN ON I \ NX A NNN OH - Nw NX NO A 7 N N 0 - 1 Sw a NRT A 7 N N 0 F F F I 1 n XO Oo 0 F { a F . F WOSNH Ao Sw + oS Ow Av No Av No Av No oO 1 mn on 1 o oS I TR 8x I | Av No Ave No 3 x | 1 - NH SH 7 SH FON nm I I I Aye No Ae No Le N"So OMe } OMe ! | aod aod ew Pow Sw Mt eww I I I Ave No Av No Av No EF F F F F7Y ~o C7 TN 0 OY 0 ou rgd WS eS or XC Av No Lv No oO 1 mm oS AN CL Ly No hd 9 SH ls OL Lv No RF N\ TO NF 0 0 0 wu AON Sn ANON CL Xr Le No Ly No ES Q NE Ye A 7 N"N"So ° 1 Sn SORE Av N"So Lo I EF F 2 br F F F F eT FY o oS “NH wn ON Av No Av No NN FY 0 oS 2 wp AEN to od Ave No Le No NN 0 WN eS GOL LW No ON oN 5 x ax] No Ae No RE N- A NTS Non l NA Np © T o oS Sg NX 0 NTNo F OH Tr F F + 1 1 Sn 0. A «SNH Ho N NX NX | | A No Av No 4 = 1 = od «Sn Oo Noy un \ wy Ne NY od NYS NX | | | Le No Le No Ly No «SH AN NTR A Z N N 0 "YT 0 DOS LC Ave No T FT A ~~ A ? WISNH ON CFs WUSNH 8sg I I Le No Le No F F i I F F F F Sa SN er «Sn An SO CCC | | A No LW No N-Q INT 1 0 3 "yf 3 . [NN . Shy 2 why 7 Shy ic NX SN NX NX SN | | | Le No Le No Lr No ZZ ZF ZF F F A, 9 hs MH As S WSNH 8 WSN 520 WSNH N | | | Le No Av No Le N"So wn AON San Su Q CLO Le No A 1 Sy © ail NIX Lo. No F F LH 5 F F F F FY FY o wa 0 wi oh (XL0, XX “v No “hy Sv No A W WSNH 520 NIX (= NN o oS 0 CLC Le No Ko 0 0 { Z «Say WOSNH 0 | . NX ON NN N xX D N L Z Lone Le No NN So \ F F 4h V F F F F JE | CL 1 3 ; N Shy 0 “SNH NS I I Le No Ne Le No F EN AN Sam «Sa AN NY NYS NY 0 2 OH I 2 0 z E N“SNSo NN o NSN So F I F F «Sw 0 == NTR 2 L NTN oo 0 oS NE NTR Co 2 NSN So Sn SN San Rid Nan 1 «SH a's I Av N oF N° FY o «Shu 5 «Say AS CO CO N J 0 N i 0 CF3. NH, CFs. NH; ot TCC NN 0 OF o oS ps oS ~~ Lp No LW No : F XO 0 NN F o Sr E20 Shi ~Fo NX NX CoC OO NN So NN So o 1 Shi ~ Wy CO NONTSo «Sn NSF NY Lo N N 0 ae 0 roo 4 EE - N§e0 Su No NTR NTR NTN NN So F F pe 0 ’ IN 2 ’ IN wT SNH po WT SNH A NX oe | | Le No Le No F F LH v F F F F NN FY q _ uN F o\ 8 WSNH YY WSNH AN > I I Le No Le No boo Ni oS A NTR) 0 ZZ NTN oO CFa A NH2 | or Ee I nm SNH ON C0 Le No bo 1 Sw NTR Lo N N 0 1 ov 1 - Ao oN oY 0 ¥ NTR NTR Cr CO N N 0 N 0 F F t 1 0 0 F f o P oo x "oh Lo A &o i % o” Z WUSNH $5 SONH oS I I Le No Le No 7 E 1 1 F F F F oS 0 wm 0 Socodiivoqes L\~ No Lo Le N 0 NO F TC F F wl Je 0 S\ UNH o 1 1 SNH 0 0 «Shy 0 oe TOLD = i“ N Noo NSN So ~ 2 «SNH 0 £3 Le No Lo 1 wn o XCF Ne No Lo | "~ ik oS oo eS oo COC COC W Ne ~Y Swe ig N- , I oS 0 =N, Le No a al oS 0 oS 0 NTR N NTR [(q> 0 {2 NTN NTNSo 4 i EY 0 Shu 0 NX A NX ON NTN 0 wh 0 NT No SH oN oS 0 COC Org COC oO 2 N ° bd (7 N ° E F F v 5 F F F F v4 wf oS o oS o NI NY NX a Lv No 0 Le N op » oq + 4 oN Sam 0 WISNH 0 N (O00, O00: 2 “ 0 OH NSN So «SNH 0 NTR N L Q NT ON Xo TY 0 «Sm g EN ory LW No x SN WISNH ENT NTR LL N N 0 be 0 TN 0 ~IS eSe ~S 1 Wi 1 REN OS “Sw ocr oo 4 No Ne No F FE F I E F \ & NF 2 FN £. RE - d N «Sn . NY NX I I Le No Le No F F 0 XO F ( 0 F r 2 or S=0 o ANT SONH WISNH | | Le No Le No CL 7 CL o $=0 o ~~ SON WSN LL oe | | Le No Le No F F oS 0 HN NSS NN SC 0 No Ls ~ N WSNH EN Soe Le No oS o @N oS 0 NTR AJ NTR { CCT) NN Ny old) F F LH % F F F F wa 0° CLG “v No Ko * 4 «Sn 2 NTR N CCL Se Te So oo! L Sn 0 0 WNH o x oC OLR fo Wy 0 NN So J F F k ov F F F F FY "Tr REN 0 WOSNH 0 COS OOO Le N o> NTN rs ! 7 - o N | = JA LE SNH fo} Shi o NYY ON NSN { H L N"N"So NNO) | H © 1 oO REN 1 a0 oS 0 SH o COC ori Lo ~~ LA eo N i o / | «San 0 Sw 0 (TLC O00 (7 N 0 Kh Le N o Lo F7 NY Cl “X “Sw g Ni N NSN | Yn COC en Lv No Nr NTNTSo OH ! I oS o wn o CLES 00 | } | lo \ N od Le No J EF I E F i SA . 0. . WS o a Syn o NY N NYY ON (; LLL NT N"To NNT Lo = I - 41 «Sm 0 Sm 0 NY N o. NTR N LL. > 0. NTN NNT oH ah ES FY 0 NH 0 Sa Aon CoG NS 2 N L, No LS 0. NZ NNER F 1 E F FF \ (0 oS lie 0° NTR L~ NN A 2 WUONH NI NX (> NTONSo Ln oS ad wn AL ww ge | “0 “0 NTR NTR NTR | | | Le No Le No LW No «Sm eP 0 NTR Or NTN" No TN 0 "a 5% "UNH ’ o NTR [(Qp” N N 0 F F 4h v F oF © I nd 0 FY 9 «SNH NC WS EE - d S=0 NTR N Xr | Le No Le No FE XC J RE - 52° Sa d o NC. o Hn NTR NTR 1 CC OCC N” "N” "0 N™ °"N” “0 I and I Land

[00133] The present disclosure provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers thereof, selected from the group consisting of compounds of Collection 3: Collection 3: Certain Compounds of the Present Invention NY 7 ®! SNH 0 N NE or lL. NNT Io 0 “NH 0 _%§0 NS or 0. NN So F F + F o <4 ye Jy, 5) le Mowe N NR 0 oz NN Me = \ —o J TN “UNH NZ No © Rr ot \ aw NX B.S | Ny R | \ (7 0 UC XN AS) I NZ No E F E ; F E RG] “UNH F | S 0 LW No E oh ae Y F ro Ed Rr Cor z N N o = w n_ “NH / R wy $=0 | F. NX VS COG (§P NTN" So | NNSo NH, E : F F S$ \® XP \ “NH NON / HoN | NTR 2 0 = N"No F E F F F Q AR WN w $20 NH NS | NX 0 N"ONSo ec F q F | F A» Q 5 Ww S= NHN 3? NTR Le No eco | F E ’ F F 2 ® §=0 oO Ww A ™ han 0 NX Lo. NNo F E F ; E F F ° F A» Tl “® Me _O oO WN S=0 Me™ “NH ¥ 4 HN HN $=0 N Nx Uo XN oz Le No N" "N" 70 | Me F F M4 INF 0. NTR Lo. N N 0 Jo Te \® Arm DPD Joo Te od HN | \ NTR NTR A L ~ (p> NN NNSo CN Va WN Ro id “ONH 3 X “7 ONH 3 I I LW No Ly No rg rg \ \ o o \® A® aw Ww! Woe YY NSN NET / { ~ (~ NNT NTN - oO NSN 0 NY S\N / { (> NTNTSo N"NTSo 7 F a F F D 0 ® (R) D. D "wt J on Y oo NH 4 S) NT Co Le NN 0 Nye m0, Hebd EN - Xr NSN o 0 N“SNSo E F F EF F | F F Jo ofr “NH / N AR “NH / NTR o. | NS WA or \ 2 NON F | F al F ) oe 0 gree - No ~J F F 1 1 F F O. F F Q A® \ R Y aw ” NH 0, N NH oY NY XR NTR pW L. NT NTSo NTN F F | FZ Q % 0 “ 2 s% ® Ny Nw Nod qa | FE - { z Q.0 F Q.0 8 \® fe ba WUONH ba ~ J N < J XR COCs z N N o F F q Ek F F Q D o (R (R) or Yo o jp - NH 4 e 5 VONH SN NN So Ae No Nor PANS OH IN w® NC o It —s— 0 <n S I Wo 0 CL \® Q “NH 5 oe NTR Az N"NTo F F F Et NTR) CoC N LJ 0 \u x So 1 F F ; F F F 0 F 0 IR IR NH | i NH | i Owl Oul® NTR NTR | | Le No LW No F F F - oO Q Y- iN E F F 0 IR NH | Ans SN NTR L. NTNTSo F 1 NF NF O, F Q, F Q, ~ 1 ~ TT y —N NH 1 N NH 1 —N F F E “\® NI ~k =0 | / ~k=o ant rl “SNH ZR Nr N ou NTR Lr a) LL Oy | ; NZ ON Yo Jog FE JN SN ji NO - | are JN SN, \ s TN > E ; F F “RB o w Mb PN NTR Lo N LJ 0 E 1 co 2 ~ > s=0 i ~§=0 Jeo \ h ins F F F F 0 IR : NH (19 hh ~ Odl® NG 0 UL N"NTo F E F F F 0 F 0 L(R) z L(R) NH 79 NS NH | NS Of(s) o. | NTR NTR | | AW No LW No F F F F F 0 F ® \» Y o NH 1 (BR wis NH §=0 Ou) O. 1 NTR Ny | | Le No Le N"So F F F F F F 0 ® ® SONH OG STONE 4 Ne Nf NTS A 2 © L NN o NIN o F F ; " FN NY F F : \ F F F F Q » A = » & | ON 5 N oy Woo NTR NX XR) { ~ (~ NNT NT NTTo F F F : F F F o F Ww J 1G o SNH N SNH ON y Xr " Xr Le No Le No F F JEN JUN ® o Aw > SN She N N Nr N XR 71s) Le No Le No Q / S=0 ie \ Oo NA H Q A S=o NX E | F \ / F 0 RN 3 \ Me" NH 8 N NTR Lo N W 0 F 3 \ ZF . ZF R 2 F R q & i 3 e WN & NH , NANO “un ® © J NTR H NTR | | Le No Le No F F F F F 0 F 0 AR rR La NH N NH N oJ 5 oJ NTR NTR | | LW No Ly No F F F P F F F F o. ® AL AG — SUNH NSS SON NX NI | | Le No LW No E ; E F i , Q A N— © wi Vv Na Lo N"N"So E | Os —N © g oO oO Tb Naf oN NX" XY TR) Le No Jeo | E ; E ), F o — wo j « N NH NN { ’ NX Lo N N 0 F (A ° - 0 F oy $ ey AP STONE STUNH ON NSS CC or | | Le No Le No F F F F F F Q 0 wy Io oy 3 STONH OTN Me" NH "\ N CC Cr I I Le No Le No F F 1 1 Qs S=o x F : Q ) F 2 oO Sxo ® E o N 3 SUONH NUN z NX 0 oz N N 0 ® 3 3 NY wood Y =N NTR N hh 3 (q” Lo 70 N N o | E . . ® rd Y TN = Cros N N o] F ok PF le ¥ A® / i) ~bo | SNH Feo | P00 OC 2 Wo NZ No F F F Ww ~ NH ~F Pe fet Sh NY XY — = | . TX Nr oor WR NNT So : I eo. F . F \® 2 | “ 0% | ~~ NR 0. No leo q Y 7 D X / ={ “NH, E | J \ 7 \ F — - = = NH F \ 2 lo I NH; NS NH © | (R) ~E Ww» ~~ < 2 2 EN 0 NH §20 "NH =o Eh oer” oe ! Le No Le No AN Ee Ee NH, Eg: 2 $0 E ; ge F Q FE o£ $=0 Ney N NY YR 0. N"NSo | 7 0 \® A SNH NTN 1s) 0 NSN So N NU I eo F F : F F F F F o AR 0 wr SON AE UNH EN I I Lv No Le No do | ALo | ‘ Jy ON, A > N NH N NTR gp” N 0 Ao | E \ | F E To NH NN / NTR 0 P= N" No ba ~N N F Neo Ra 16 4 mh ENE, NX NX sod SOQ NONTSo NNTSo N —_—t | +f N YI! * : Q Rr en “NH F Nr COC _ 7 . N' N 0 N, V| N F F- Id oO Jeo ; | F F » | NH Lp Plo oN Lr No 0 I F % I — Oo Nn F : 7 ¥ \® 0 | «NH F N” ey” Shy OCC NoNSo N Jeo i 7 FE E * F E » N «SNH W\ NT T 3 PP JI} NTNTTo o hve E F Vv oO > el Vv 0 E | F F » Y | TW by en NN N So Lo. N i 0 le L Vo | a >. \ \ Mt / F™ No | To NH Ia S NH ~$=0 ! F + INE CT NTR 0 N N o Les Ll NEN o 1 3 oO | F S| F F i F F | @ NH SNH S50 NTR L NTN eo RF Nd F ® NH = 0 & “ i 7 SNH Ss NH sho NY NX (7 (7 NN NN o F F RF F NZ F F F & 2 w 2 NH eg < NH S50 CoC LoL NSN So NSNSo F F F F NS LR 2 NH 2 NYY 0 J NNSo RF * oo INE C0 NTR (qp> N N 0 1 1 RF RF 0. NZ 7 “NE ° he LWE AL NH ~s=0 Me™ “Ny ON or xg Le No Le No F Co oo 1 o fr E F . 0 fC o Fo Ak KX ' NX 0. NN So I A Sz F : F F F \ F & N NH so F . Uo = NH 8s NTN So NX Lv No leo | Jao lien F F r |= F F ® o A Nn 7 STUNH N sso | mn | NX NTR \ =N (; Le 3 7 NSN So N” N70 0 i I \ _. E N a “% | iN lo <ONH 2 | o NYY Lo. NT NTSo @ Van ) lw & 0 ! = NH 5% SNH 4 oo CYC ’ 3 I Nf NZ ON “oA A “So 07 NTN So F F | F | F F F SR X PL AR X PL ill $=0 = UNH S50 l | L wo - Ro F F F F ; F 3 XL 3 XL F F 0 Q IR J ® 2 J. NH NH LS Led a NTR NTR | | Le No LW No F F ; F F ® Q ® Q SNH = STONE = Olm Onl NY NX | | Le No Le No F H ~~ NS Lo. N N o # | | F w ] | YUONH Ap NSIS I 0 LP 0 Y I nF Noa F F , F NH; — ® N— { <ONH hg 0 ) NRX 0 2 NN So F F 1 1 fo] N—~ \ AY F F F F F F D A Je Xo ~ NH ! 0 ~ NH | N 0. N— 0, | NN” / NTRS | | Le No Lv No FE E Bh 0 NH o $=0 NTR J N 0 E | F EF F ie ® F i. SUONH « 2 20 TNH NR S< 20 L Z © Uo = “0 LE NZ No F 1 3 —N, \ Land E | F © SSH 4 NR 2 | NTN 0 nd L

[00134] The present disclosure provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers thereof, selected from the group consisting of compounds of Collection 4: Collection 4: Certain Compounds of the Present Invention F F F F F 0, F oR est WB | > | 0 FN To 5° pe go H,, * PRL OS ® NYE NN So Ly No F | £ ; F - ® NZ YY Sl lw H Jo a | Ww N h 0, ce Yoo Le Wo NZ No NZ EF - 0 wo & wR 4 oN | SCO COL <0 L\ No ~5% Le No F pa NT I SR AB No aw! F. $* ert Ly No C2 ~ RE Yo AN F. S NX 0 ZZ N bi 0 1 © wy Rr = Io * rR § Ry Yo NS 8 F S 2 NX NN LJ No 3 ~ bm] ~ | AZ Aw 0. D yo —N D ) F vel” oe A D | “7 iB n J% “Je a NTR R) 2 py L N Xr (R) NNR LW No r FE F ’ AQ [ A a oe ® L oy 5° or w (SF NA | mA | N Na il rr (R) (2 No NZ No F I AR LJ FY 7 2 l Dp _Q WR Yo F" Yr DID | e fH LB Y > 0G CC N N 0 (7 N 0 a Ly. YY, F Z D _0Q To 0 DUD w 8-0 RCE Se 3 ope RT NX (R) 2 | N N 0 Lek ) R 2 Cw 9 w iG he = ww ls EL CC CL Lr No Le No oe pa J o ~Eeo | 4 NTR (qp” N™ "N" 70 1 J NR 0. N” 'N" "0 pr J } Nv L. N" "NO I o NG §2° e RF N Nr (S) LW No NF NF oF 0 lo Vo Yeo 2 wt A wt / rR % of N Nr NX | Le No WW No F F F ® F G oo " IQ Lo iP d < " Xr Le No > 1G 1,0 ww d S$ N Xr Le No TONG had NZ 0, F Aa Te yy 0, \ w 0 N NTR i» ie NNR Wo F r F ® 1 and G A LR 21.0 » NC, ? NS Le No J. and w Yo w NC, 7 " XT Le No

[00135] The present disclosure provides a compound, and pharmaceutically acceptable salts, solvates, stereoisomers, and tautomers thereof, selected from the group consisting of compounds of Collection 5. A person of skill in the art may prepare these using conventional methods, including adaptations of synthetic methods disclosed herein. So - I Me SNH Yo IX” on Az NT Yo 1 Collection 5: Certain Compounds of the Present Invention £ E Lo F F Me SNH Yo Me SNH Yo seadel eens Ned No SoA No (To H rT Me SNH 0 NT N_~ A 7 NNo OH o 1 Me SNH 0 (00 INP No ng I So FT un re NX NO A 7 N N 0 = T Me SNH Yo 00 Ho A 2 Wo Me SNH Yo Yo on IT re I A 2 No oA LE Me SNH To Me™ SNH o LIL 0G NA N 0 Az N 0 F F LY r F F F F FF" YY 0 eS ~H 0 Av No Me SNH L NN A 7 NN So F F h 00 Me” NH ASN me ~~ KJ KJ NNT NN So 0 1 1 “N Me™ NH Phy N A or C H NH ON 2 Co Z NTN ’ No NN So or Me SH “NH NX XY A 7 Meo” “NTN S0 I “Sw NaN NT x 7 A FE I F F REN ASNT a oS CL Me” “NH SN NTN NN “= ) x tJ xX x N™ "N” “O NTS xr NA XD NTN So S Ay N"So wSnu NT NX A 7 NN So and OH Methods of Synthesizing the Disclosed Compounds

[00136] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below.

[00137] The compounds of any of the formulae described herein may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes and examples. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. 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 stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of any formula disclosed herein.

[00138] Those skilled in the art will recognize if 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 the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994). Preparation of Compounds

[00139] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzy matic processes.

[00140] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods include but are not limited to those ‘methods described below.

[00141] A general synthesis of substituted (4-aminopyrido[2,3-d]pyrimidin-7(8H)-one or analogous heterocycles is outlined in Scheme 1.

[00142] 6-bromo-4-chloropyrido[2,3-d]pyrimidin-7(8H)-one (I-1) can undergo a 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. Scheme 1° ON SNH, G1 A _Br Cross coupling R R Ge | “SNH “1 R cl . “NH c i NASA 2 r G1 2 Br ross coupling | NTS NY eo A BY IEC RW RNTNTT0 RNIN No &s Rs Rs 1-1 1-2

[00143] Alternatively final compounds with a nitrogen substituent in position 6 (bromo) can be prepared from 6-amino-4-chloropyrido[2,3-d]pyrimidin-7(8H)-one by alkylation or acylation to give intermediates if type I-5, which can undergo nucleophilic aromatic substitution with an appropriately substituted benzyl amine (G-1) to furnish final analogs I according to Scheme 2. Scheme 2 Oh WSNH, alkylation or SNA | -1 acylation SAAN G SnAr Cl Re Nig VR, PN RZNTNS0 Rs Cl NN A RST So Rs LE R To gl alkylation or ol Re WTNH, oo i Ye” acylation OE G-1 . R | SnAr NZ NY Rs Kk BUG G— fe Rs Ry RyNTNT0 1-4 1-5 Re

[00144] Building block G-1 can be prepared as outlined in scheme 3. Appropriately substituted aryl or heteroaryl bromides G-2 can be transformed into the correspond acetyl hetero)aryls G-3 by metal halogen exchange, followed by addition of an acylating agent. The ketone functionality can be stereoselectively transformed into the chiral amine using Ellman’s method. Scheme 3: {5 Br ATR of R J (RR SF. Gr 0 Ss Ss, NS > 0 “NH, R : Rr ¢ N — ji ro x ~o G-2 G-3 G4 G-5 G-1 Therapeutic Use

[00145] Due to their biological properties the compounds of the present disclosure, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms may be suitable for treating diseases characterized by excessive or abnormal cell proliferation such as cancer.

[00146] For example, the following cancers, tumors and other proliferative diseases may be treated with compounds of the present disclosure, without being restricted thereto:

[00147] cancers / tumors / carcinomas of the head and neck: e.g., tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); intraocular cancers (e.g., uveal melanoma), and orbital and adnexal cancers;

[00148] cancers / tumors / carcinomas of the lung: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer);

[00149] neoplasms of the mediastinum: e.g., 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, thabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma), astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependy momas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g., acoustic), spinal axis tumors;

[00150] cancers / tumors / carcinomas of the gastrointestinal (GI) tract: e.g., tumors / carcinomas / cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g., 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, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms tumor), hy pernephroma, Grawitz tumor; ureter; urinary bladder, e.g., urachal cancer, urothelial cancer; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis);

[00151] cancers / tumors / carcinomas of the testis: e.g., seminomas, non-seminomas;

[00152] gynecologic cancers / tumors / carcinomas: e.g., tumors / carcinomas / cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[00153] cancers / tumors / carcinomas of the breast: e.g., mammary carcinoma (infiltrating ductal, colloid, lobular invasive, 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;

[00154] cancers / tumors / carcinomas of the endocrine system: e.g., tumors / carcinomas / cancers of the endocrine glands, thyroid gland (thyroid carcinomas / tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma / tumor), adrenal cortex (adrenal cortical carcinoma / 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;

[00155] sarcomas of the soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of 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 Ewings sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor;

[00156] sarcomas of the bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[00157] mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma;

[00158] cancers of the skin: e.g., basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer;

[00159] neoplasms of the peripheral and central nervous system and brain: e.g., astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), 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, thy molipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma);

[00160] lymphomas and leukemias: e.g., B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), Burkitt leukemia, T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell 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 predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous / myeloid leukemia (AML), acute lymphatic / lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), 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 leukemia of ambiguous lineage, myeloproliferative neoplasms, blastic plasmacytoid dendritic cell neoplasm, early T-cell precursor leukemia, natural killer cell leukemia / lymphoma, myeloid / lymphoid neoplasms with eosinophilia, myeloid sarcoma, transient abnormal myelopoiesis; and

[00161] cancers of unknown primary site (CUP).

[00162] All cancers / tumors / carcinomas mentioned above which are characterized by their specific location / origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom.

[00163] All cancers / tumors / carcinomas mentioned above may be further differentiated by their histopathological classification:

[00164] epithelial cancers, e.g., squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet-ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; and

[00165] nonepithilial and mesenchymal cancers, e.g., sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[00166] The compounds of the present disclosure may be used in therapeutic regimens in the context of first line, second line, or any further line treatments.

[00167] The compounds of the invention may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy and / or surgery and / or other compounds.

[00168] Of course, the above also includes the use of the compounds of the present disclosure in various methods of treating the above diseases by administering a therapeutically effective dose to a patient in need thereof, as well as the use of these compounds for the manufacture of medicaments for the treatment of such diseases, as well as pharmaceutical compositions including such compounds of the invention, as well as the preparation and / or manufacture of medicaments including such compounds of the invention, and the like. Additional Methods of Using the Disclosed Compounds

[00169] One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject a SOS1 inhibitor of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof.

[00170] Another aspect of the present disclosure relates to a method of treating or preventing a disease that is effected or characterized by modification of the interaction of SOS1 and a RAS-family protein and / or RACI 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof.

[00171] In certain embodiments, a method is provided of 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, and a pharmaceutically acceptable carrier.

[00172] In certain embodiments, a method is provided of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof.

[00173] In certain embodiments, the disease can 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 nonepithelial tumors and mesenchymal tumor, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, 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 colorectal cancer or pancreatic cancer.

[00174] In certain embodiments, the disease can 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, ladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas.

[00175] In certain embodiments, the disease can be, but is not limited to, a RASopathy. In certain embodiments, 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 Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, and Hereditary gingival fibromatosis.

[00176] Another aspect of the present disclosure is directed 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof.

[00177] The present disclosure relates to compositions capable of modulating the activity of (e.g., inhibiting) SOS1. The present disclosure also relates to the therapeutic use of such compounds.

[00178] The disclosed compound can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects.

[00179] Another aspect of the present disclosure relates to a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease that is affected by modification of the interaction of SOS1 and a RAS-family protein and / or RAC1. Another aspect of the present disclosure relates to a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease that is characterized by inhibition of the interaction of SOS1 with a RAS-family protein or the interaction of SOS1 with RAC1.

[00180] Another aspect of the present disclosure relates to a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in treating or preventing a disease, wherein the treating or preventing is effected or characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RA.

[00181] Another aspect of the present disclosure relates to a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use inhibiting the binding of hSOS1 to H- or N- or K-RAS including their clinically known mutations and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 uM or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 uM or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder.

[00182] Another aspect of the present disclosure relates to a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for the manufacture of a medicament for use inhibiting the binding of hSOSI1 specifically to 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 uM or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 uM or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder.

[00183] In another aspect, the present disclosure relates to the use of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating or preventing a disease.

[00184] Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[00185] Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.

[00186] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com 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, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; ¢) a binder, 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 sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier 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 absorption of the compound such as cyclodextrin, hydroxypropyl- cyclodextrin, PEG400, PEG200.

[00187] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[00188] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[00189] 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, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described for instance in U.S. Pat. No. 5,262,564, the contents of which are hereby incorporated by reference.

[00190] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy propylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoy! residues. Furthermore, the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

[00191] Parental injectable 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 prior to injection.

[00192] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant.

[00193] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[00194] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[00195] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5,20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. Combination Therapy

[00196] The 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-drug 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. The dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:53-S6 (2005)).

[00197] A compound of the present invention may be administered before, after, or concurrently with one or more of such additional therapies. When combined, dosages of a compound of the invention and dosages of the one or more additional therapies (e.g., non- drug 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 anti-cancer agent, may be administered together, such 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.

[00198] In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen 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 pharmaceutically acceptable salts thereof.

[00199] In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies includes a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor). In other embodiments, the one or more additional therapies includes two therapeutic agents. In still other embodiments, the one or more additional therapies includes three therapeutic agents. In some embodiments, the one or more additional therapies includes four or more therapeutic agents. Non-drug therapies

[00200] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[00201] In some embodiments, the compounds of the invention may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the invention may be used as a neo-adjuvant therapy prior to surgery.

[00202] Radiation therapy may be used for inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachy therapy. The term "brachy 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 proliferative tissue disease site. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, or Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres.

[00203] In some embodiments, the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention, which amount is effective to sensitize abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. In some embodiments, the compounds of the present invention may be used as an adjuvant therapy after radiation therapy or as a neo-adjuvant therapy prior to radiation therapy.

[00204] In some embodiments, the non-drug treatment is a T cell adoptive transfer (ACT) therapy. In some embodiments, the T cell is an activated T cell. The T cell may be modified to express a chimeric antigen receptor (CAR). CAR modified T (CAR-T) cells can be generated by any method known in the art. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 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

[00205] A therapeutic agent may be a compound used in the treatment of cancer or symptoms associated therewith.

[00206] For example, a therapeutic agent may be a steroid. Accordingly, in some embodiments, the one or more additional therapies includes a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof

[00207] Further examples of therapeutic agents that may be used in combination therapy with a compound of the present invention include compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and Intemational Patent Applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, W002 / 55501, W004 / 05279, W004 / 07481, WO04 / 07458, WO04 / 09784, W002 / 59110, W099 / 45009, WO000 / 59509, W099 / 61422, WO00 / 12089, and WO00 / 02871.

[00208] A therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in treatment of cancer or symptoms associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Also included are antibody-drug conjugates.

[00209] 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, e.g., humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. 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 small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PDL-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL-2 (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDRO01 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, INJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[00210] A therapeutic agent may be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, non-peptide small molecules, or other compound useful in the treatment of cancer or symptoms associated therewith, collectively, an “anti-cancer agent”). Anti-cancer agents can be, e.g., chemotherapeutics or targeted therapy agents.

[00211] Anti-cancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Further anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies includes two or more anti-cancer agents. The two or more anti-cancer agents can be used in a cocktail to be administered in combination or administered separately. Suitable dosing regimens of combination anti- cancer agents are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[00212] Other non-limiting examples of anti-cancer agents include Gleevec® (Imatinib Mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, such as calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicin such as dynemicin A; bisphosphonates such as clodronate; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomy cin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo- 5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti- metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes such as T- 2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., Taxol® (paclitaxel), Abraxane® (cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; aromatase inhibiting 4(5)-imidazoles; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 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; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[00213] Additional non-limiting examples of anti-cancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2- carboxaldehy de thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell-cycle nonspecific antineoplastic agents, and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur- uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[00214] Further non-limiting examples of anti-cancer 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, bleomy cins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., a CDK 4 / 6 inhibitor such as ribociclib, abemaciclib, or palbociclib), seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes- dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogs, pyrimidine analogs (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 platinum coordination complexes (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), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors such as PI3K delta inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), copanlisib, alpelisib and idelalisib; multi-kinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as leutinizing 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., CNTO0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti- CSI (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (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.

[00215] In some embodiments, an anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analog or derivative variant of the foregoing.

[00216] In some embodiments, an anti-cancer 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; 4SC-203; 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.

[00217] In some embodiments, an anti-cancer agent is an inhibitor of a member downstream of a Receptor Tyrosine Kinase (RTK) / Growth Factor Receptor (e.g., a 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, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC]1 inhibitor or mTORC?2 inhibitor). In some embodiments, the anti-cancer agent is JAB-3312. In some embodiments, an anti-cancer agent is a Ras inhibitor (e.g., AMG 510, MRTX1257, LY 349946, MRTX849, ARS-3248 (JNJ-74699157), MRTX1133 or ARS-1620), or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras.

[00218] 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 Ras" (e.g., K-Ras"", H-Ras"" or N-Ras""). In some embodiments, the Ras protein is Ras amplification (e.g., K-Ras*™). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Ras®™ (K-Ras*"®, H-Ras*™® or N-Ras*™?). In some embodiments, the cancer comprises a Ras mutation (Ras™VT). 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 thereof: (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, DI119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G128, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or AS9T, and combinations thereof: or a combination of any of the foregoing (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, G128, 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, G128, G13S, G12V and G13V.

[00219] In some embodiments, a cancer comprises an NF1-°F mutation. In some embodiments of methods herein, the cancer comprises a Ras™™” and a compound of the present invention is administered to, e.g., a patient in need thereof, in combination with an additional therapeutic agent, e.g., a MEK inhibitor, such as a MEK inhibitor described herein. In some embodiments of methods herein, the cancer is colorectal cancer and a compound of the present invention is administered to, e.g., a patient in need thereof, in combination with an additional therapeutic agent, such as a topoisomerase I inhibitor (e.g., irinotecan). In some embodiments of methods herein, the cancer is non-small cell lung cancer and a compound of the present invention is administered to, e.g., a patient in need thereof, in combination with an additional therapeutic agent, e.g., a MEK inhibitor, such as a MEK inhibitor described herein (e.g., trametinib). In some embodiments of methods herein, the cancer is non-small cell lung cancer or colorectal cancer, and a compound of the present invention is administered to, e.g., a patient in need thereof, in combination with a Ras inhibitor, such as a Ras inhibitor described herein (e.g., MRTX849, MRTX1133 or AMG-510).

[00220] In some embodiments, a therapeutic agent that may be combined with a compound of the present invention is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK inhibitor”). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the MAPK inhibitor may 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 (ARRY- 424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 2014 Nov 25:9(11)); and GSK 1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989- 1000).

[00221] In some embodiments, an anti-cancer agent is a disrupter 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 inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226;, XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[00222] In some embodiments, an anti-cancer agent is a PD-1 or PD-L1 antagonist.

[00223] 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.

[00224] IGF-IR inhibitors include linsitinib, or a pharmaceutically acceptable salt thereof

[00225] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti- EGFR antibody or antibody fragment that can partially or completely block EGFR activation 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 can be 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 thereof.

[00226] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, e.g., 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. Further 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, W096 / 33980; U.S. Pat. No. 5,747,498, WO096 / 30347; EP 0787772; W097 / 30034; W097 / 30044; WO097 / 38994; W097 / 49688; EP 837063; W098 / 02434; W097 / 38983; W095 / 19774; W095 / 19970; WO97 / 13771; W098 / 02437, W098 / 02438; W097 / 32881; DE 19629652; W098 / 33798, W097 / 32880; W097 / 32880; EP 682027; W097 / 02266;, W097 / 27199; W098 / 07726; W097 / 34895, WO096 / 31510; WO98 / 14449; W098 / 14450; W098 / 14451; W095 / 09847, WO97 / 19065; W098 / 17662; U.S. Pat. No. 5,789,427; U.S. Pat. No. 5,650,415; U.S. Pat. No. 5,656,643; W099 / 35146; W099 / 35132; W099 / 07701; and W092 / 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.

[00227] 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 MEK 1 mutation selected from D67N; P124L; P1248; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from AE51-Q58; AF53-Q58; E203K; L177M; C1218; F53L; K57E; Q56P; and K57N.

[00228] PI3K inhibitors include, but are not limited to, wortmannin; 17- hydroxy wortmannin analogs described in W006 / 044453; 4-[2-(1H-Indazol-4-y1)-6-[[4- (methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-ylJmorpholine (also known as pictilisib or GDC-0941 and described in W009 / 036082 and WO09 / 055730); 2- methyl-2-[4-[3-methyl-2-0x0-8-(quinolin-3-y1)-2,3-dihy droimidazo[4,5-c]quinolin-1- yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO006 / 122806); (S)-1-(4-((2-(2-aminopyrimidin-5-y1)-7-methyl-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO008 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyrido- [3',2":4,5]furo[3,2-d]pyrimidin-2-yl] phenol hydrochloride (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]- 1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-y1)- nicotinamide (available from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy- phenyl)-furan-2-y1]-meth-(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]pyrimidin-4-one (available from Axon Medchem); XL-765; and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL 147, XL765, Palomid 529, GSK 1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS- 136.

[00229] 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-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05 / 011700); indole-3- carbinol and derivatives thereof (e.g., U.S. Pat. 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: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[00230] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1 / mTORC?2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; ‘W094 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in W098 / 02441 and WO01 / 14387, e.g., AP23464 and AP23841; 40-(2- hydroxyethyl)rapamycin; 40-[3-hydroxy (hy droxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolyt)-rapamycin (also called ABT578); 32- deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin; derivatives disclosed in WO005 / 005434; derivatives disclosed in U.S. 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 W(094 / 090101, WO92 / 05179, WO093 / 111130, W0O94 / 02136, W094 / 02485, W095 / 14023, W094 / 02136, W095 / 16691, WO096 / 41807, W096 / 41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., W005 / 016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g, W02018204416, W02019212990 and W02019212991), such as RMC-5552.

[00231] BRAF inhibitors that may be used in combination with compounds of the invention include, for example, vemurafenib, dabrafenib, and encorafenib. A BRAF may comprise a Class 3 BRAF mutation. In some embodiments, the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; GA66E; G466A; S46TL; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E.

[00232] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and $63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT- 263.

[00233] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor 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, self-inhibited conformation stabilized by a binding network involving residues from both 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 enzymatic activation of SHP2.

[00234] SHP2 is involved in signaling through the RAS-mitogen-activated protein kinase (MAPK), the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways. 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 human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. Some of these mutations destabilize the auto-inhibited conformation of SHP2 and promote autoactivation or enhanced growth factor driven activation of SHP2. SHP2, therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases including cancer. A SHP2 inhibitor (e.g., RMC-4550 or SHP099) in combination with a RAS pathway inhibitor (e.g., a MEK inhibitor) have been shown to inhibit the proliferation of multiple cancer cell lines in vitro (e.g., pancreas, lung, ovarian and breast cancer). Thus, combination therapy involving a SHP2 inhibitor with a RAS pathway inhibitor could be a general strategy for preventing tumor resistance in a wide range of malignancies, and may form the basis of a triple combination inhibitor with a SOS1 inhibitor.

[00235] Non-limiting examples of such SHP2 inhibitors that are known in the art, include: Chen et al. Mol Pharmacol. 2006, 70, 562, Sarver et al., 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: W02005094314; W02007117699; W02008124815; ‘W02009049098; W02009135000; W02010011666; W02010121212; W02011022440; ‘W02012041524; W02014113584; W02014176488; W02015003094 W02015107493; ‘W02015107494; W02015107495; W02016191328; W02016196591; W02016203404; ‘W02016203405; W02016203406, W02017078499; W02017079723; W02017100279; ‘WO02017156397, W02017210134; W02017211303; W02018013597; WO2018057884; ‘W02018081091; W02018129402; W0O2018130928; W02018136264; W02018136265; ‘W02018160731; WO2018172984; W02018218133; W02019051469; W02019051084; ‘W02019067843; W02019152454; W02019158019; W02019165073; W02019167000; ‘W02019182960, W02019183364; W02019183367; W02019213318; W02019233810; ‘W02020022323; W02020033286; W02020033828; W02020061101; W02020061103; W02020063760; W02020072656; W02020073945, W02020073949; W02020081848; US20110281942; US20160030594 and US8637684, each of which is incorporated herein by reference.

[00236] In some embodiments, a SHP2 inhibitor binds in the active site. In some embodiments, a SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, a SHP2 inhibitor binds an allosteric site e.g., a non-covalent allosteric inhibitor. In some embodiments, a SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets the cysteine residue (C333) that lies outside the phosphatase’s active site. In some embodiments a SHP2 inhibitor is a reversible inhibitor. In some embodiments, a SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP?2 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.

[00237] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[00238] Immune therapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T-cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGI, and anti-OX40 agents).

[00239] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[00240] Exemplary anti-PD-1 antibodies and methods for their use are described by Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 Al), as well as described elsewhere herein.

[00241] 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 U.S. Pat. No. 6,111,090, U.S. Pat. No. 8,586,023, W02010 / 003118 and ‘W02011 / 090754; or an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962, EP 1947183, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, U.S. Pat. No. 7,618,632, EP 1866339, and W02011 / 028683, W02013 / 039954, W005 / 007190, ‘W007 / 133822, WO05 / 055808, W099 / 40196, W001 / 03720, W099 / 20758, WO006 / 083289, W0O05 / 115451, and WO02011 / 051726.

[00242] Another example of a therapeutic agent that may be used in combination with the compounds of the invention is an anti-angiogenic agent. Anti-angiogenic agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An anti-angiogenic agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth. In some embodiments, the one or more additional therapies include an anti-angiogenic agent.

[00243] Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RADO01), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in W096 / 33172, WO096 / 27583, W098 / 07697, W098 / 03516, W098 / 34918, W(098 / 34915, W098 / 33768, WO098 / 30566, W090 / 05719, W099 / 52910, W099 / 52889, W099 / 29667, W099007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, and U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. 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.

[00244] Further exemplary anti-angiogenic 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 specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 2002 / 0042368), specifically binding anti-eph receptor or anti-ephrin antibodies or antigen binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members thereof), and anti-PDGF-BB antagonists (e.g, specifically binding antibodies or antigen binding regions) as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US5892112); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab (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 (Ariad, 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); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER- 68203-00 (IV AX, USA); BeneFin (Lane 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, alphaSbeta3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived antiangiogenic (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, German; Munich Technical University, 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, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); 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, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at 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, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine, angiogenic, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-lalfa inhibitors, (Xenova, UK); 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, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSL, USA); CP 547632, (Pfizer, USA), 786034, (GlaxoSmithKline, 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); irsogladine, (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-cadherin-2 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 (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[00245] Further examples of therapeutic agents that may be used in combination with 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 antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor, c-Met.

[00246] Another example of a therapeutic agent that may be used in combination with compounds of the invention is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin Al, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor.

[00247] Another example of a therapeutic agent that may be used in combination with compounds of the invention is an anti-neoplastic agent. In some embodiments, the one or more additional therapies include an anti-neoplastic agent. Non-limiting examples of anti- neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-la, interferon beta-1b, interferon gamma, natural interferon gamma- la, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-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, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAD (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, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, 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), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar.

[00248] Additional examples of therapeutic agents that may 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; AMGS57; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti- 0X40 (Providence Health Services); huMAbOX40L; atacicept, CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); 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 951.

[00249] 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 G12C inhibitor (e.g., AMG 510, MRTX 1257) or other mutant Ras: GDP inhibitor, a KRAS:GTP G12C inhibitor or other mutant Ras: GTP 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, a 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 a SOS1 inhibitor, a RAS inhibitor and a MEK inhibitor.

[00250] 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, JQI1, MLN-7243, NVP-ADW742, 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 reversine.

[00251] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of the disclosure 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 administration in combination can 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 can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered and followed by 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 a few minutes apart, or a few hours apart, or a few days apart.

[00252] In some embodiments, a combination therapeutic regimen employs two therapeutic agents, one 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, one 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.

[00253] 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 either 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 hours 16, up to 17 hours, up 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 the one or more additional therapies.

[00254] The invention also features kits including (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent), and (c) a package insert with instructions to perform any of the methods described herein.

[00255] As one aspect of the present invention contemplates the treatment of the disease or symptoms associated therewith with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining 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 directions for the 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), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

[00256] In this Combination Therapy section, all references are incorporated by reference for the agents described, whether explicitly stated as such or not. EXAMPLES

[00257] The disclosure is further illustrated by the following examples and synthesis examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[00258] Definitions used in the following examples and elsewhere herein are: BOP (benzotriazole-1-y)tris(dimethylamino)phosphonium CH,Cl,, DCM Methylene chloride, Dichloromethane ACN, CH;CN, Acetonitrile MeCN DAST Diethylaminosulfur trifluoride DBU Diazabicycloundecene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DIEA N,N-diisopropylethylamine DIPEA Diisopropylethylamine DMA Dimethylacetamide DMAP 4-Dimethylaminopyridine DME Dimethylether DMF N,N-Dimethylformamide DMSO Dimethyl Sulfoxide EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc Ethyl acetate h Hour HATU 0-(7-Azabenzotriazol-1-y1)-N,N,N’ N'-tetramethyluronium hexafluorophosphate H,0 Water HOBt Hydroxybenzotriazole HCI Hydrochloric acid KsPO4 Potassium phosphate (tribasic) LHMDS Lithium bis(trimethylsilyl)amide mCPBA meta-Chloroperoxybenzoic acid MeOH Methanol MsCl Methanesulfonyl chloride MTBE Methyl tert-butyl ether Na,SO4 Sodium sulfate NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methyl pyrrolidone It Room temperature SmI, Samarium(ID)iodide TEA Triethylamine TES Triethylsilane TFA Trifluroacetic acid THF Tetrahydrofuran TMSCI Chlorotrimethylsilane XPhos 2-Dicyclohexylphosphino-2'.4',6'-triisopropylbiphenyl

[00259] Example 1: Synthesis of (R)-4-((1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-8-methyl-6-(1,2,3,6-tetrahydropyridin-4- yDpyrido[2,3-d]pyrimidin-7(8H)-one HCIMeOH 0, oOo 3 Pd(PPha)s, Na,CO3 H,0, DME, 80°C TEE CFs. NH, CF oc ol HCIMeOH — SNH NBoe ———— = 3 y NNN LJ Ne

[00260] Step 1

[00261] To a mixture of 4-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-6- bromo-8-methyl-pyrido[2,3-d]pyrimidin-7-one (50 mg, 113 umol) in dioxane (1 ml) and H,0 (0.2 ml) was added K>CO; (47 mg, 339 pmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihy dro-2H-pyridine-1-carboxylate (38 mg, 124 pmol) and Pd(PPhs), (Tetrakis(triphenylphosphine)palladium(0), 13 mg, 11 pmol). The mixture was heated at 100 °C for 3 h under N,. After cooling to rt the mixture was filtered and the solvent was removed reduced pressure to give tert-butyl 4-[4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-8-methyl-7-oxo-pyrido[2,3-d] py rimidin-6-y1]-3,6- dihydro-2H-pyridine-1-carboxylate (50 mg, 81% yield). LCMS (ESI): m / z: [M +H] calculated for C,7H3:F3N¢O3: 545.2; found 545.2.

[00262] Step 2

[00263] To a mixture of tert-butyl 4-[4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-8-methyl-7-oxo-pyrido[2,3-d] py rimidin-6-y1]-3,6- dihydro-2H-pyridine-1-carboxylate (50 mg, 92 umol,) in MeOH (1 ml) was added HCI / MeOH (4 M, 23 ul). The mixture was stirred at rt for 1 h. The solvent removed under reduced pressure and the residue was purified by prep-HPLC to give 4-[[(1R)-1-[3-amino- 5-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-6-(1,2,3,6-tetrahy dropyridin-4- yl)pyrido[2,3-d]pyrimidin-7-one (38 mg, 91% yield). LCMS (ESI): m / z: [M +H] calculated for C;HyF3NeO: 445.2; found 445.2; 'H NMR (400MHz, methanol-d) 8 = 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).

[00264] The following examples 1-1 to 1-33 shown in Table 1 were synthesized in the ‘manner similar to Example 1. Table 1. Examples 1-1 to 1-33 Example # Structure Mass Found FE B= F F SNH _NH 416.5 1=1 "NH NH NYY 0 2 N i 0 CFs Ww WSNH “NH 430.2 NYS J NONTSo EE - SNH 430.5 NX 0 z NN 1 \ My 430.7 NNO S HX SMW NZ - 0 431.4 NIX LJ NN"So F F 4315 San AON NX L N""N"70 Sa o 431.6 NX A “ NN o CFs rR WSNH “NT A447 A ~ wSNH ON 444.2 ee Ng N N 0 i F F o 1 EE - SNH 444.4 NYY A 7? NN So o Me SNH NT 458.2 NX A 7 NSN" So 468.2 NF 0 oS ~~ OL Lv No 468.2 hd 9 Syn pL Hag Lv No 472.4 1 AWN REN So AH Wo NX J NTONTSo 0 Y ANS aod 1 «Sm AN 4725 | Lv No WSNH ~<o \H 472.5 NX 0 Z N"NTSo 0 ; SH EN 472.5 NYY Lo. NTN To WINE ASNT 472.5 NYY LJ N WN 0 0 «Sn Ee 479.0 NYY 0 Z N“N"So RF N\ LO = 1 tl. wm AEN 4822 NX 0 NN WISH ASNT 486.2 NX 0 2 NN F » 0 SNH AON 486.3 NX 0 J N“NSo WISH NTN 486.3 NX 2 N J 0 F 0 : Ny AEN 486.5 NX A 7 NSN So oe YY 0 486.5 aw OL Le No FE FE Cl WOSNH ASNT 488.2 NX 0 J N N 0 TF F F 0 * o£ mn Sy PNP 4902 NIX LJ NN So T F E 493 5 1 0 wh Eso NX A 7 NN o oe 500.3 "NT 0 SH OWE 5 OL Ave No «Sa NT CEs 512.6 NX 0 Zz NTNSo «SNH AN 432.4 NTR Lo, N N 0 433.5 - 1] Sw NST A ? N H 0 0 So 433.5 oo 1 Sup No NTR L N ji 0 EE - NH 446.7 NTR A # N"NTSo 477.3 477.1

[00265] Example 2: Synthesis of (R)-4-((1-(3-(1,1-difluoro-2- hydroxyethyl)phenyl)ethyl)amino)-8-methyl-6-morpholinopyrido[2,3-d] pyrimidin- 7(8H)-one RF Q Me'' “NH, BOP. DBU DMF, 25°C OH NNN EY A NN So RF HO. Ho ) : , me NH Me" NH aS — _— BU ore DIEA, 160°C, 12h 5°C Le No

[00266] Step 1

[00267] To a solution of 6-bromo-4-hydroxy-8-methyl-pyrido[2,3-d]pyrimidin-7-one (430 mg, 1.68 mmol) and 2-[3-[(1R)-1-aminoethyl]phenyl]-2,2-difluoro-ethanol (507 mg, 2.52 mmol) in DMF (10 ml) were added BOP (1.11 g, 2.52 mmol) and DBU (760 pl, 5.04 mmol). The mixture was stirred at 25 °C for 16 h. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na,SO;. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 6-bromo-4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy- ethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one (190 mg, 26% yield). LCMS (ESI): m / z; [M +H] calculated for C1gH;7BrF;N4O,: 439.1; found 439.2.

[00268] Step 2

[00269] A mixture of 6-bromo-4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy- ethyl)phenyl]ethyl]amino] -8-methyl-pyrido[2,3-d]pyrimidin-7-one (200 mg, 455 pmol), morpholine (2.89 ml, 33 mmol) and DIEA (2.86 ml, 16.4 mmol) was 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 give 4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy- ethyl)phenyl]ethyl]Jamino]-8-methyl-6-morpholino-pyrido[2,3-d]pyrimidin-7-one (16 mg, 8% yield). LCMS (ESI): m / z: [M +H] calculated for C;;HysF2NsO3: 446.2; found 446.3; 'H NMR (400 MHz, chloroform-d) & 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).

[00270] The following examples 2-1 to 2-5 shown in Table 2 were synthesized in the manner similar to Example 2. Table 2. Examples 2-1 to 2-5 Example # Structure Mass Found 2.1 WSNH “So 448.0 o r 2.2 WSN NF 4542 L F Sd NSN A 7 N"N"So 2.3 WW ONH ~~ 460.2 HFC : (rR 2 = NY XN A N N 0 2.4 J © Na 461.0 SNH Nw NYY N_~ A 7 NSN So 2.5 os 475.0 Sam Ny NX XN A 7 N 0

[00271] Example 3: Synthesis of (R)-4-((1-(3-(1,1-difluoro-2- hydroxyethyl)phenyl)ethyl)amino)-6-(3,6-dihydro-2H-pyran-4-yl)-2,8- dimethylpyrido[2,3-d]pyrimidin-7(8H)-one RF 0 Me™ “NH; 1-0 BOP, DBU, DMF or Re wy Pd(PPha)s, Na,COa H,0, DME " Br N Pw oy

[00272] Step 1

[00273] To a solution of 6-bromo-4-hydroxy-2,8-dimethyl-pyrido[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-[(1R)-1- aminoethyl]phenyl]-2,2-difluoro-ethanol (1.64 g, 8.15 mmol) and DBU (1.84 ml, 12.22 mmol). The reaction was stirred at 20°C for 12h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na,SO, and the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography to give 6-bromo-4-[[(1R)-1-[3-(1,1- difluoro-2-hydroxy-ethyl)phenyl]ethyl]amino]-2,8-dimethyl-pyrido[2, 3-d]pyrimidin-7-one (1.4 g, 76 % yield). 'H NMR (400 MHz, methanol-d,) & 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, 3H) 2.41 (s, 3H) 1.62 (d, J=8 Hz, 3 H).

[00274] Step 2

[00275] To a solution of 6-bromo-4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl) phenyl]ethyl]amino]-2, 8-dimethyl-pyrido[2,3-d] pyrimidin-7-one (0.2 g, 441 pmol) in DME (2 ml) was added 2-(3,6-dihydro-2H-pyran-4-y1)-4,4,5,5-tetramethyl-1,3, 2- dioxaborolane (139 mg, 662 pmol), H,0 (0.4 ml), Na,COs (94 mg, 882 pmol) and Pd(PPhs), (Tetrakis(triphenylphosphinejpalladiur(0), 51 mg, 44 pmol) under N,. The mixture was stirred at 90°C for 2h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried with anhydrous Na,SO; and the solvent was removed under reduced pressure. The crude residue was purified by prep-HPLC to give 4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy- ethyl)phenyl]ethyl]amino]-6-(3,6-dihy dro-2H-pyran-4-y1)-2,8-dimethyl-pyrido[2,3- d]pyrimidin-7-one (0.03 g, 15% yield). LCMS (ESI): m / z: [M+H] calculated for C14H27F,N403: 457.2; found 457.3;'H NMR (400 MHz, methanol-ds) 6 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, 3H) 1.63 (d, J=4 Hz, 3 H).

[00276] Example 4: Synthesis of (R)-4-((1-(3-(1,1-difluoro-2- hydroxyethyl)phenyl)ethyl)amino)-2,8-dimethyl-6-(1,2,3,6-tetrahydropyridin-4- yDpyrido[2,3-d]pyrimidin-7(8H)-one Tose H,0. DME, 80°C Pd(PPhy)s, NagCOs RF vo. vo goo HCMOOH WTNH N’ © 7 A N” “No I

[00277] Step 1

[00278] To a solution of 6-bromo-4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy- ethyl)phenyl]ethyl]amino]-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.2 g, 441 umol) in DME (2 ml) was added rert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-3,6- dihydro-2H-pyridine-1-carboxylate (205 mg, 662 pmol), HO (0.4 ml), Na,COs (94 mg, 882 pmol) and Pd(PPh;)s (Tetrakis(iriphenyiphosphine)palladium(0), 51 mg, 44 pmol) at 25 °C under N,. The reaction was stirred at 90 °C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried with anhydrous Na;SO4. The solvent was removed under reduced pressure and the crude residue was purified by silica gel chromatography to give tert-butyl 4-[4- [[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]amino]-2,8-dimethy1-7-0xo0- pyrido[2,3-d]pyrimidin-6-y1]-3, 6-dihydro-2H-pyridine-1-carboxylate (0.2 g, 82% yield). 'H NMR (400 MHz, methanol-ds) 8 ppm 8.14 (s, 1 H) 7.62 (s, 1 H) 7.54 (d, / = 8 Hz, 2H) 743-737 (m, 2H) 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,2H)3.66(s,3H)3.64-3.58(m,2H)2.57-251(m 2H)2.43(s,3H) 1.63(d,J=8 Hz, 3H) 1.49 (s, 9H).

[00279] Step 2 5 vo. h re «Sy . 7] A ¥ EE a

[00280] fert-Butyl 4-[4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]amino]- 2,8-dimethyl-7-o0x0-pyrido[2,3-d]pyrimidin-6-y1]-3,6-dihy dro-2H-pyridine-1-carboxylate (0.1 g, 180 umol) was dissolved in HCI / MeOH (5 ml) at 20°C and 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 give 4-[[(1R)-1-[3-(1,1-difluoro-2-hydroxy- ethyl)phenyl]ethyl]amino]-2,8-dimethyl-6-(1,2,3,6-tetrahy dropyridin-4-yl)pyrido[2,3- d]pyrimidin-7-one (30 mg, 35% yield). LCMS (ESI): m / z: [M+H] calculated for C,4HsF>NsO;: 456.2; found 456.2; 'H NMR (400 MHz, methanol-ds) § ppm 8.54 (s, 1 H) 8.21(s,1H)7.63(s,1H)7.55(d,J=8Hz, 1H) 747-736 (m,2H)6.41(s, 1H) 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, 2H) 2.45 (s, 3H) 1.64 (d, J=4 Hz, 3 H).

[00281] Example 5: Synthesis of (R)-6-(3,6-dihydro-2H-pyran-4-yl)-8-methyl-4-((1- (3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one CF. oe ie) © . wr ow 0 ez i SE Si. Jo Ses DBU, BOP, DMF N= NY Pd{(PPhs)s, Na;COs DME, H,0 OH NNN J %

[00282] Step 1

[00283] To a solution of 6-bromo-4-hydroxy-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) was added DBU (2.11 ml, 14.02 mmol) and BOP (2.33 g, 5.26 mmol). The mixture was stirred at 25 °C for 0.5 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried with Na,SOs. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give 6-bromo-8-methyl-4-[[(1R)-1-[3- (trifluoromethy1)phenyl]ethyl]amino] pyrido[2,3-d]pyrimidin-7-one (107 mg, 7% yield). 'H NMR (400 MHz, methanol-d) § = 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).

[00284] Step 2

[00285] To a mixture of 6-bromo-8-methyl-4-[[(1R)-1-[3- (trifluoromethyl)phenyl]ethyl]amino] pyrido[2,3-d]pyrimidin-7-one (38 mg, 89 umol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (28 mg, 133 pmol) in DME (0.7 ml) and water (0.13 ml) was added Pd(PPh;)s (Tetrakis(tripbeny)phosphine)palladiuro(0), 21 mg, 17.79 pmol), Na,COs (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 prep-HPLC to give 6-(3,6-dihydro-2H-pyran-4-yl)-8-methyl-4- [[(1R)-1-[3-(trifluoromethy])phenyl]ethyl]amino] pyrido[2,3-d]pyrimidin-7-one (25.4 mg, 23% yield). LCMS (ESI): m / z: [M +H] calculated for C»H;,F3N;0;: 431.2; found; 431.2; 'H NMR (400 MHz, methanol-d;) 8 = 8.32 (s, 1 H) 8.21 (s, 1 H) 7.65 - 7.72 (m, 2H) 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, 2H) 3.71 (s, 3 H) 2.52-2.62 ( dd, 2 H)1.65 (d, J=8.00 Hz, 3 H).

[00286] Example 6: Synthesis of 4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2,8-dimethyl-6-(1,2,3,6-tetrahydropyridin-4- yDpyrido[2,3-d]pyrimidin-7-one 1 Or i 1 NBS, MeCN Bi nesween (Ae ~~ AAS owe ! of Pd(PPha)s, EsN A ZA MeOH, 60 °C 140 °C cl o AS pe v Me’ N’ ye cl cl NBS, MeCN Br 0, = vr Ww wi WH BBry ad NRX NBS oo” oo” OH Br Nes, 2 DMF, 1-50°C | DCM 7 wey N 0 wy 0 Me” TN N 0 LJ T x f x J Ose PPhsCCly Aono FE bi er WTNH OE: DCE ALAA... [-BuOH, DIPEA UOH, DIPEA NESS Pd(PPh3)y, Na;CO3 100 °C 1 ie i aa H,0, DME, , 85 °C al NNN EE " ald ve” NN hey WSK . A NE MN Z Me’ N N 0 HCI, MeQH CFs ay NH2 7 o _Boc » NH N NYY AA ve” NTN So hey A a WTONH NH So pe No

[00287] Step 1

[00288] To a mixture of 6-chloro-N2-dimethyl-pyrimidin-4-amine (6.0 g, 38 mmol) in DMEF (60 ml) at rt was added NBS (8.13 g, 45.7 mmol). The mixture was stirred at rt for 2 h, then diluted with H,O and extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na,SO,, and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 5- bromo-6-chloro-N2-dimethyl-pyrimidin-4-amine (7 g, 78% yield). 'H NMR (400 MHz, DMSO-d) § ppm 7.44 (d, J = 4.0 Hz, 1H), 2.87 (d, J = 4.0 Hz, 3H), 2.34 (s, 3H).

[00289] Step 2

[00290] A mixture of 5-bromo-6-chloro-N2-dimethyl-pyrimidin-4-amine (4.0 g, 16.9 mmol), TEA (5.9 ml, 42.3 mmol), butyl prop-2-enoate (24.1 ml, 169.1 mmol) and Pd(PPh;) (Tetrakis(iriphenylphosphine)palladium{0), 1.95 g, 1.69 mmol) were combined and heated to 140 °C for 36 h. H,O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na,SO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give (E)-3-[4-chloro-2-methyl-6-(methylamino)pyrimidin-5-y1]prop-2- enoate (0.35 g, 7% yield). LCMS (ESI): m / z: [M+H] calculated for C 3H sCIN3O,: 284.1; found 284.1; 'H NMR (400 MHz, methanol-ds) 3 ppm 7.58 (d, J= 16.0 Hz, 1H), 6.46 (d, J =16.0 Hz, 1H), 4.21 (1, 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).

[00291] Step 3

[00292] To a mixture of butyl (E)-3-[4-chloro-2-methyl-6-(methylamino)pyrimidin-5- yl]prop-2-enoate (0.35 g, 1.23 mmol) in MeOH (5 ml) was added NaOMe (200 mg, 3.7 mmol). The mixture was heated to 60 °C and stirred for 2 h. Aqueous NH4Cl was added, the solvent was removed under reduced pressure and the crude residue was purified by prep-TLC to give 4-methoxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.15 g, 59% yield). '"H NMR (400 MHz, DMSO-de) & 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).

[00293] Step 4

[00294] To a mixture of 4-methoxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.15 g, 0.73 mmol) in DMF (1 ml) at rt was added NBS (130 mg, 0.73 mmol). The mixture was heated to 50 °C for and stirred for 2 h. The mixture was poured into cold H,O and stirred for 5 min, the emerging precipitate was filtered and the filter cake was dried under vacuum to give 6-bromo-4-methoxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.12 g, 58% yield). LCMS (ESI): m / z: [M+H] calculated for CoH;;BrN;0,: 284.0; found 284.0; 'H NMR (400 MHz, DMSO-de) § ppm 8.43 (s, 1H), 4.06 (s, 3H), 3.67 (s, 3H), 2.59 (s, 3H).

[00295] Step 5

[00296] To a mixture of 6-bromo-4-methoxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7- one (120 mg, 0.42 mmol) in DCM (1 ml) at 0 °C was added BBr; (204 pl, 2.11 mmol). The mixture was warmed to rt and stirred for 12 h, then poured into aqueous cooled (0 °C) Na,CO; and the emerging precipitate filtered to give 6-bromo-4-hydroxy-2,8-dimethyl- pyrido[2,3-d]pyrimidin-7-one (0.14 g). 'H NMR (400 MHz, methanol-ds) § ppm 8.41 (s, 1H), 3.77 (s, 3H), 2.45 (s, 3H).

[00297] Step 6

[00298] A mixture of 6-bromo-4-hydroxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.2 g, 0.74 mmol) and PhsP (583 mg, 2.22 mmol) in DCE (5 ml) was stirred until the mixture became clear, then CCl, (285 pl, 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 give 6-bromo-4-chloro- 2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (50 mg, 23% yield). 'H NMR (400 MHz, methanol-d;) 8 ppm 8.55 (s, 1H), 3.82 (s, 3H), 2.71 (s, 3H).

[00299] Step 7

[00300] To a mixture of 6-bromo-4-chloro-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.05 g, 0.17 mmol) in +-BuOH (0.5 ml) was added DIPEA (302 pl, 1.73 mmol) and 3- [(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline (43 mg, 0.21 mmol). The mixture was heated to 100 °C in a crimped vial and stirred for 2 h, then the solvent was concentrated under reduced pressure and the crude residue was purified by prep-TLC to give 4-[[(1R)-1- [3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-6-bromo-2-methyl-8H-pyrido[2,3- d]pyrimidin-7-one (0.03 g, 39% yield). "HNMR (400 MHz, methanol-ds) & 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).

[00301] Step 8

[00302] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-3,6- dihydro-2H- pyridine-1-carboxylate (31 mg, 1.0 mmol) in DME (0.5 ml) under an atmosphere of N, was added 4-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]- 6-bromo-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.03 g, 66 pmol), Na,COs (14 mg, 0.13 mmol), H,O (0.1 ml) and Pd(PPh;)s (Tetrakis(triphenyiphosphine)paliadiumn(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 fert- butyl 4-[4-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-2,8-dimethyl-7-0xo0- pyrido[2,3-d]pyrimidin-6-y1]-3,6-dihydro-2H-pyridine-1-carboxylate (40 mg). 'H NMR (400 MHz, methanol-d) 8 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).

[00303] Step 9

[00304] A mixture of tert-butyl 4-[4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2,8- dimethyl-7-oxo-pyrido[2,3-d]pyrimidin-6-y1]- 3,6-dihydro-2H-pyridine-1-carboxylate (30 mg, 54 pmol) in 4M HCI in MeOH (3 ml) was degassed, then at rt for 15 min. The solvent was concentrated under reduced pressure and the residue was purified by prep-HPLC to give 4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2,8-dimethyl-6-(1,2,3,6-tetrahy dropyridin-4- y1)pyrido[2,3-d]pyrimidin-7-one as a formic acid salt (8 mg, 30% yield). LCMS (ESI): m / z: [M+H] calculated for C3HaeFsN4O: 459.2; found 459.2; "H NMR (400 MHz, methanol-dy) 6 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, 1H), 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).

[00305] Example 7: Synthesis of (R)-4-((1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-6-(3,6-dihydro-2H-pyran-4-yl)-2,8- dimethylpyrido[2,3-d]pyrimidin-7(8H)-one NIS ar 0 A ve NaOMe AYO o or o” AOA o” o NN NIS AN o NNSA NSN NaOMe Py Dp ACN, 50°C py J PA(PPho)s, EN A Pp MeOH, 60°C on 5 NZ NH, NT NH, a NZ NH, NBS A A Br CH, K,CO5 eI HBr o” o” o” GHal, K,CO: COL = O00 (0 DMF. 50°C DMF A N 0 Ay 0 Ay \ 0 XO er SNH DBU,BOP, DMF A Br HO DMA 80°C Pd(PPhs)s, Na,COs OH N B Ae No er WUSNH 0 NTN > | A No

[00306] Step 1

[00307] To a mixture of 6-methoxy-2-methyl-pyrimidin-4-amine (15 g, 108 mmol) in ACN (150 ml) was added NIS (24 g, 108 mmol). The mixture was stirred at 50 °C for 2 h. After cooling to rt excess aqueous Na,SO; was added and the mixture was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na,SO;. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give 5-i0do-6-methoxy-2-methyl-pyrimidin-4-amine (22 g, 77% yield). LCMS (ESI): m / z: [M +H] calculated for C¢HgIN3O: 265.0; found 266.2.

[00308] Step 2

[00309] To a mixture of 5-iodo-6-methoxy-2-methyl-pyrimidin-4-amine (20 g, 75 mmol) and butyl prop-2-enoate (21.5 ml, 151 mmol) in DMA (80 ml) was added tris-o- tolylphosphane (4.6 g, 15 mmol), TEA (42 ml, 302 mmol) and Pd(OAc), (3.4 g, 15 mmol). The mixture was heated to 100 °C and stirred for 10 h under N,. After cooling to rt the reaction was filtered through a plug 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 Na,SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give butyl (£)-3-(4-amino-6-methoxy-2-methyl-pyrimidin-5-y1)prop-2- enoate (15 g, 75% yield). LCMS (ESI): m / z: [M +H] calculated for C13H1sN303: 265.1; found 266.3.

[00310] Step 3

[00311] To a mixture of butyl (£)-3-(4-amino-6-methoxy-2-methyl-pyrimidin-5-y1) prop-2-enoate (15 g, 57 mmol) in MeOH (20 ml) was added NaOMe (30.5 g, 170 mmol). The mixture was heated to 90 °C for 1 h. After cooling to rt aqueous NH4Cl 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 give 4-methoxy-2-methyl-8H-pyrido [2, 3-d] pyrimidin-7-one (9 g, 83% yield). *H NMR (400 MHz, DMSO-ds) 3 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, 3H).

[00312] Step 4

[00313] To a mixture of 4-methoxy-2-methyl-8H-pyrido [2,3-d]pyrimidin-7-one (9 g, 47 mmol) in DMF (80 ml) was added NBS (8.4 g, 47 mmol). The mixture was heated to 50 °C for 2 h. After cooling to rt H,O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na;SO4 and the solvent was removed under reduced pressure. The crude residue was purified by column chromatography to give 6-bromo-4-methoxy-2-methyl-8H-pyrido [2, 3-d] pyrimidin-7-one (9g 71%yield). 'H NMR (400 MHz, DMSO-d) & ppm 12.83 (s, 1 H) 8.28 (s, 1 H) 4.03 (s, 3H) 2.52 (s, 3H).

[00314] Step 5

[00315] To a mixture of 6-bromo-4-methoxy-2-methyl-8H-pyrido[2,3-d]pyrimidin-7- one (1 g, 3.7 mmol) in DMF (10 ml) was added K>COs (1 g, 7.4 mmol) and CH;I (0.46 ml, 7.4 mmol). The mixture was stirred at rt for 2 h. H,O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried with Na,SO4. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give 6-bromo-4-methoxy-2,8-dimethyl-pyrido[2,3- d]pyrimidin-7-one (0.6 g, 57% yield). HNMR (400 MHz, DMSO-dg) § ppm 8.32 (s, 1 H) 4.06 (s, 3 H) 3.65 (s, 3 H) 2.59 (s, 3 H).

[00316] Step 6

[00317] A mixture of 6-bromo-4-methoxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.6 g, 2.1 mmol) in HBr (6 ml, 33% in AcOH) was heated to 100 °C for 2h. 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-hydroxy-2,8- dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.5 g, crude) was obtained. ‘HNMR (400 MHz, DMSO-ds) 8 ppm 12.80 (s, 1 H) 8.23 (s, 1 H) 3.62 (s, 3 H) 2.39 (s, 3 H).

[00318] Step 7

[00319] To a mixture of 6-bromo-4-hydroxy-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.1 g, 0.37 mmol) and 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline (151 mg, 0.74 mmol) in DMF (1 ml) was added benzotriazol-1-yloxy- tris(dimethylamino)phosphonium;hexafluorophosphate (255 mg, 0.58 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (167 pl, 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 Na,SOs. The solvent was removed under reduce pressure and the residue was purified by prep-TLC to give 4-[[(1R)- 1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-6-bromo-2,8-dimethyl-pyrido[2,3- d]pyrimidin-7-one (0.15 g, 89% yield). 'H NMR (400 MHz, DMSO-d¢) & ppm 8.91 (s, 1 H) 8.26 (d,J=8Hz, 1 H) 6.85 (s, 1 H) 6.81 (s, 1 H) 6.70 (s, 1 H) 5.54 (s, 2H) 5.50 - 5.39 (m, 1 H) 3.60 (s, 3 H) 2.38 (s, 3H) 1.50 (d, J= 8 Hz, 3 H).

[00320] Step 8

[00321] To a mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (104 mg, 0.49 mmol) in DMA (1.5 ml) was added 4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]Jamino]-6-bromo-2,8-dimethyl-pyrido[2,3-d] py rimidin-7-one (0.15 g, 0.33 mmol), Na,CO; (69 mg, 0.66 mmol), H,0 (0.3 ml) and Pd(PPhs), (Tetrakis(tripheny Iphosphine)palladium(0), 38 mg, 33 umol). The mixture was stirred under N; 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 with Na;SO4. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give 4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-6-(3,6-dihy dro-2H-pyran-4-y1)-2,8-dimethyl- pyrido[2,3-d] pyrimidin-7-one (30 mg, 20% yield). LCMS (ESI): m / z: [M +H] calculated for C,3HasF3Ns0,: 460.2; found 460.2; "HNMR (400 MHz, methanol-ds) 8 ppm 8.15 (s, 1 H) 6.97 (s, 1H) 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, 2H) 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, 3H).

[00322] Example 8: Synthesis of (R)-4-((1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(piperidin-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one ooo Pd / C, Hy(15psi) HO, DME, 90°C Tr .. ~~ J MeOH Pd(PPhs)s, Na;CO3 CFs. NH, CF. NH; ~Boc : Boe _ PIC. Ha(15psi) “Sw J F Bee 2, = TW y MeOH J A xX , NIN Aq No N HCIMeOH er WSN NH N foo NN So HB

[00323] Step 1

[00324] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-3,6- dihydro-2H-pyridine-1-carboxylate (73 mg, 0.25 mmol) in DME (1 ml) was added 4- [[(1R)-1-[3-amino-5-(triflucromethyl)phenyl]ethyl]amino]-6-bromo-2-methyl-8H- pyrido[2,3-d]pyrimidin-7-one (0.07 g, 0.16 mmol), Na,COj3 (34 mg, 0.32 mmol), HO (0.2 ml) and Pd(PPhs), (Tetrakis(triphenylphosphine)palladium(0). 18 mg, 16 pmol). The mixture was stirred under N; at 90 °C for 2 h. After cooling to rt H,O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried with Na,SOs. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give fert-butyl 4-[4-[ [(1R)-1-[3-amino- 5-(trifluoromethy1)phenyl]ethyl]amino]-2-methyl-7-oxo-8H-pyrido[ 2, 3-d] pyrimidin-6- y1]-3,6-dihydro-2H-pyridine-1-carboxylate (30 mg 35% yield). 'H NMR (400 MHz, methanol-ds) 8 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,3H) 1.58 (d,J=4 Hz, 3H) 1.48 (d,J=4 Hz, 9 H).

[00325] Step 2

[00326] To a mixture of tert-butyl 4-[4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2-methyl-7-oxo-8H-pyrido[2,3-d]pyrimidin-6-y1]- 3,6-dihydro-2H-pyridine-1-carboxylate (30 mg, 55 pmol) in MeOH (2 ml) was added Pd / C (0.01 g). The mixture was stirred at rt for 1 h under H, (15psi). The reaction mixture was filtered and the solvent was removed under reduced pressure to give tert-butyl 4-[4-[[(1R)- 1-[3-amino-5-(trifluoromethyl)phenyl]ethylJamino]-2-methyl-7-oxo-8H-pyrido[2,3- d]pyrimidin-6-y1]piperidine-1-carboxylate (20 mg, 66% yield). LCMS (ESI): m / z: [M +H] calculated for C,7H34F3NgO3: 547.3; found 547.3.

[00327] Step3

[00328] A mixture of tert-butyl 4-[4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2-methyl-7-oxo-8H-pyrido[2,3-d] py rimidin-6- yl]piperidine-1-carboxylate (30 mg, 55 pmol) in HCI / MeOH (2 ml) was stirred at rt for 20 min. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give 4-[[(LR)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]amino]-2-methyl- 6-(4-piperidyl)-8H-pyrido[2,3-d]pyrimidin-7-one (9 mg, 37% yield). LCMS (ESI): m / z: [M +H] calculated for C,H,6F3NgO: 447.2; found 447.2; '"H NMR (400 MHz, methanol- ds) 8 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=12Hz, 2H) 3.21 - 3.12 (m, 2 H) 3.10 - 3.01 (m, 1 H) 2.40 (s, 3H) 2.18 (d, / = 12 Hz, 2H) 1.99 - 1.84 (m, 2 H) 1.61 (d, J=8 Hz, 3 H).

[00329] The following examples 8-1 to 8-17 and 1-28 to 1-31 shown in Table 3 were synthesized in the manner similar to Example 8. Table 3. Examples 8-1 to 8-17 and 1-28 to 1- Example # Structure Mass Found F A F F A N 448.4 8-1 REN. NS DE £2 NSS No Lo. NSN So F F @ 8.2 Nu ~~ 460.6 «Sh AN NTR A 7 N N 0 FY 0 83 Po AN 474.5 Le No 8-4 RCN. ASF 478.4 «Sm NF | LA No WINE deo 481.4 NTR 0. N 0 ~F ” 0 Sy AN 4823 NTR 0 Z NN So WSNH NN 482.3 NTR 0 2 N"NTSo JF C Q RE —- ~N 484.3 NTR Lo. N N 0 WOSNNH NOS 484.3 LW No «Sun ~~ 488.5 NX F XO F o rL- AN +L 11 ! 488.5 Sy ON NTR A 7 N N 0 0 . EN Ay 490.5 NTR 0 Z N N 0 4951 o do 495 4 SE o a - = NTR Lo NTN E " 0 os ? WISNH Ssq NRX A NT N"o F 4 F E 496.6 bv 1 oS Ay NTR J N iy 0 502.5 ne Lp Sn ON NR 510.5 = ~~ Q_ WSNH AN 1 O NTR Lo N iN 0 «Sn Nr 514.5 NT 0 Z N~ "N° SO F i F P 5285 ASNT NT CFs, o I Sm Ay NTR A Z N N 0 E &:- F F 432.4 o 1 oS “NH NX L NN So A 4335 Sw ro NTR A 7 NSN So 433.5 o 1 eS “0 NTR 0 _ NNT F x F E 1-31 Sm NH 446.7 o 1 Sai ON NTR A ? NTNSo

[00330] Example 9: Synthesis of (R)-4-((1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4- yDpyrido[2,3-d]pyrimidin-7(8H)-one ot or HCI / MeOH al _Boc HCIMeOH WSN SN _ «San NH Lr LCC ZZ NTN Ay 0

[00331] Step 1

[00332] A mixture of fert-butyl 4-[4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2-methyl-7-oxo-8H-pyrido[2,3-d]pyrimidin-6-y1]- 3,6-dihydro-2H-pyridine-1-carboxylate (0.15 g, 0.28 mmol) in HCI / 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 give 4-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino]-2-methyl-6-(1,2,3,6-tetrahy dropyridin-4-y1)-8H- pyrido[2, 3-d]pyrimidin-7-one (20 mg, 15% yield). LCMS (ESI): m / z: [M +H] calculated for CoHy4F3N6O: 445.2; found 445.2; 'H NMR (400 MHz, methanol-d;) § ppm 8.53 (S, 1 H)8.22(s, 1H) 6.94 (d,J=4Hz, 2H) 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 = 8 Hz, 3 H).

[00333] Example 10: Synthesis of 2,8-dimethyl-6-(morpolin-4-yl)-4-[[(1R)-1-[3- (trifluoromethyl)phenyl]ethyl]amino]-7H,8H-pyrido[2,3-d]pyrimidin-7-one TEA. MeOH. rt JET ee eo DIPEA, NMP, 150 °C Cl NASH A N N 0 CFs. ; Hl WI NHy TEA, i-PrOH, 100 °C 9 NSN Sd N Li 0

[00334] Step 1

[00335] 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) was added 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 Na,SOQ4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to give 6-amino-4-chloro-2,8-dimethyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (1.50 g, 65% yield). LCMS (ESI): m / z: [M+H] calculated for CoH1oCIN,O: 225.1; found 225.1.

[00336] Step 2

[00337] 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) was added 2-bromoethy! ether (560 ul, 4.50 mmol) and DIPEA (1.94 ml, 11.13 mmol). 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 Na,SO4 and the solvent was removed under reduced pressure. The resulting residue was purified by flash column chromatography to give 4-chloro-2,8-dimethyl-6-(morpholin-4-y1)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (285 mg, 43% yield). 'H NMR (300 MHz, DMSO-de): 8 6.97 (s, 1H), 3.76 (m, 4H), 3.67 (s, 3H), 3.25 (m, 4H), 2.64 (s, 3H).

[00338] Step 3

[00339] 4-chloro-2,8-dimethyl-6-(morpholin-4-yl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (287 mg, 0.98 mmol) and (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride (220 mg, 0.98 mmol) were suspended in propan-2-ol (11 ml). Triethylamine (408 pl, 2.90 mmol) was added and the mixture was heated to 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 Na,SO4 and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give 2,8-dimethyl-6- (morpholin-4-y1)-4-{[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]amino}-7H,8H-pyrido[2,3- d]pyrimidin-7-one (150 mg, 34% yield). LCMS (ESI): m / z: [M+H] calculated for C,HysF3N:O: 448.2; found 447.9; 'H NMR (300 MHz, DMSO-ds): § 8.07 (d, / =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=17.1 Hz, 3H).

[00340] Example 11: Synthesis of 8-cyclopropyl-6-(morpholin-4-yl)-4-{[(1R)-1-[3- (trifluoromethyl)phenyl]ethyl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one D>—NH, TEA, DCM, rt Iago TEA, MeOH, rt cl NEN NH J N A° CFs : HOI WSNH, BNO DIPEA, NMP, 150 °C RN TEA, i-PrOH, 100 °C § 9 SOG SN A 0

[00341] Step 1

[00342] 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) were added. 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 Na,SO4 and solvent was removed under reduced pressure to give 4- chloro-6-(cyclopropylamino)pyrimidine-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 CgHoCIN;O: 198.1; found 198.1.

[00343] Step 2

[00344] 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-(cyclopropylamino)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 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 Na,SO4 and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to give 6-amino- 4-chloro-8-cyclopropyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (1.44 g, 50% yield). LCMS (ESI): m / z; [M+H] calculated for CoH1gCIN4O: 237.1; found 237.1.

[00345] Step 3

[00346] To a solution of 6-amino-4-chloro-8-cyclopropyl-7H,8H-pyrido[2,3- d]pyrimidin-7-one (500 mg, 2.11 mmol) in NMP (15.0 ml) was added 2-bromoethy! ether (530 pl, 4.20 mmol) and DIPEA (1.84 ml, 10.56 mmol). 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 Na,SO; and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to give 4-chloro-8-cyclopropyl-6-(morpholin-4-y1)-7H,8H-pyrido[2,3- d]pyrimidin-7-one (157 mg, 24% yield). LCMS (ESI): m / z: [M+H] calculated for C14H16CIN4O5; 307.1; found 306.9.

[00347] Step 4

[00348] 4-chloro-8-cyclopropyl-6-(morpholin-4-y1)-7H,8H-pyrido[2,3-d]pyrimidin-7- one (156 mg, 0.51 mmol), (1R)-1-[3-(trifluoromethyl)phenyl]ethan-1-amine hydrochloride (115 mg, 0.51 mmol) and triethylamine (213 pl, 1.50 mmol) were dissolved in propan-2-ol (5.8 ml). The mixture was heated to 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 Na,SOs, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to give 8- cyclopropyl-6-(morpholin-4-y1)-4-{[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]amino}- 7TH,8H-pyrido[2,3-d]pyrimidin-7-one (95 mg, 41% yield). LCMS (ESI): m / z: [M+H] calculated for C23H,sF3NsO,: 460.2; found 459.9; "HNMR (300 MHz, DMSO-d): § 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).

[00349] The following examples 11-1 to 11-4 shown in Table 4 were synthesized in the ‘manner similar to Example 11. Table 4. Examples 11-1 to 11-4 Example # Structure Mass Found 8 0. SNH 3 475.0 11-1 N rr o 1 Su ON NX A 7 NN So Su 11-2 ~ "NH ONT 498.8 11-3 NH s=0 504 5 Rr N, 11-4 & ® oN 530.1

[00350] Example 12: Synthesis of 4-{[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]amino}-8-methyl-6-(morpholin-4-yl)-7H,8H-pyrido[2,3- d]pyrimidin-7-one Mo TEA, MeOH, rt TN Cl o & ? oe BO g IY ~ = 3 a m Sy NXg DIPEA NMP. 150°C NN" 0 DIPEA, NMP, 150 °C NT oN H CFs. NH, Ww WSNH Mo CFa. NH, > "HO! WSNH, TEA, i-PrOH, 100 °C 1 | x SON , N 0

[00351] Step 1

[00352] Triethylamine (3.02 ml, 21.72 mmol), 2-[(Z)-[(4- methoxyphenyl)methylidene]amino]acetate (3.0 g, 14.48 mmol) and 4-chloro-6- (methylamino)pyrimidine-5-carbaldehyde (2.5 g, 14.50 mmol)were dissolved 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 Na,SOs. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography to give 6-amino-4-chloro-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (1.84 g, 60% yield). 'H NMR (300 MHz, DMSO-ds) § 8.60 (s, 1H), 6.79 (s, 1H), 6.41 (s, 2H), 3.71 (s, 3H).

[00353] Step 2

[00354] DIPEA (2.48 ml, 14.24 mmol), 2-bromoethyl ether (0.72 ml, 5.70 mmol) and 6- amino-4-chloro-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (600 mg, 2.85 mmol) were dissolved 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 Na,SOj4 and the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography to give 4-chloro-8-methyl-6-(morpholin-4-y1)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (356 mg, 45% yield). "HNMR (300 MHz, DMSO-ds) 8.77 (s, 1H), 6.99 (s, 1H), 3.77 — 3.75 (m, 4H), 3.69 (s, 3H), 3.31 — 3.20 (m, 4H).

[00355] Step 3

[00356] 4-Chloro-8-methyl-6-(morpholin-4-yl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (350 mg, 1.25 mmol), 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline hydrochloride (300 mg, 1.25 mmol) and triethylamine (521 pl, 3.74 mmol) were dissolved in propan-2-ol (15 ml). The mixture was heated to 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 Na;SOs. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC to give 4-{[(1R)-1-[3- amino-5-(trifluoromethyl)phenyl]ethyl]amino} -8-methyl-6-(morpholin-4-y1)-7H,8H- pyrido[2,3-d]pyrimidin-7-one (74 mg, 54% yield). LCMS (ESI): m / z: [M+H] calculated for CHa F3NgOy: 449.2; found 449.1; 'H NMR (300 MHz, DMSO-ds): 8.27 (s, 1H), 8.09 (d, J=17.7Hz, 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 (1, J = 4.6 Hz, 4H), 3.61 (s, 3H), 3.22 — 3.12 (m, 4H), 1.54 (d, J=7.1 Hz, 3H).

[00357] Example 13: Synthesis of 8-methyl-6-(morpholin-4-yl)-4-{[(1R)-1-[3- (trifluoromethyl)phenyl]-ethyl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one CFs ; HCI WSNH, TEA, i-PrOH, 100 °C $Y 0 5 N 0

[00358] Step 1

[00359] 4-Chloro-8-methyl-6-(morpholin-4-y1)-7H,8H-pyrido[2,3-d] pyrimidin-7-one (187 mg, 0.66 mmol), triethylamine (278 ul, 1.99 mmol) and (1R)-1-[3- (trifluoromethyl)phenyl]ethan-1-amine hydrochloride (150 mg, 0.66 mmol) were suspended in propan-2-ol (7.5 ml). The mixture was heated to 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 Na,SO; and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC to give 8-methyl-6-(morpholin-4-y1)-4-{[(1R)-1-[3-(trifluoromethyl)phenyl]- ethyl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one (46 mg, 16% yield). LCMS (ESI): m / z: [M+H] calculated for C,1H3F3NsO,: 434.2; found 433.7; "H NMR (300 MHz, DMSO-de): 58.26 (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, ] =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).

[00360] Example 14: Synthesis of 4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-6-(1-methanesulfonyl-3-methylazetidin-3-yl)-8-methyl- TH,8H-pyrido[2,3-d]pyrimidin-7-one TMSCI, Cul cl o Xr LA H MeMgBr RES DIPEA THF, -15 °C mw LHMDS, 3A MS THF, it LE i DMF, rt oA. cl NNN NBoc 0 NN 1. TFA, DCM, rt 2. MsCl, TEA DCM, rt F F F M, it SNH 9 2 NN o

[00361] Step 1

[00362] To a solution of tert-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 THF, under an atmosphere of N,, was added chlorotrimethylsilane (8.28 mL, 8.28 mmol). After stirring for 10 min at rt, the mixture was cooled to —15 °C, 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 rt for another 2 h and then quenched with saturated aqueous NH4Cl solution. The mixture was diluted with MTBE. The organic layer was separated, and the aqueous layer was extracted with MTBE. The combined organic layers were washed with brine and dried over anhydrous Na;SO;. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give tert-butyl 3-(2- ethoxy-2-oxoethyl)-3-methylazetidine- 1-carboxylate (782.3 mg, 73.7%). LCMS (ESI) m / z: [M + H] caled for C13H23NOy: 257.2; found 257.4.

[00363] Step 2

[00364] tert-Butyl 3-(2-ethoxy-2-oxoethyl)-3-methylazetidine-1-carboxylate (500 mg, 1.94 mmol), LHMDS (324 mg, 1.94 mmol) and 3A mol sieves were added to THF and stirred for 10 min. 4-chloro-6-(methylamino)pyrimidine-5-carbaldehyde (221 mg, 1.29 mmol) was dissolved in a minimal amount of DMF and added dropwise. The reaction was stirred at rt for 3 h. The reaction was quenched with NH,Cl and extracted with MTBE. The organic layers were combined and washed with water and brine and then dried over Na,SO;. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give tert-butyl 3-(4-chloro-8-methyl-7-0x0-7,8- dihydropyrido[2,3-d]pyrimidin-6-y1)-3-methylazetidine-1-carboxylate (76.8 mg, 16%). LCMS (ESI) m / z; [M + H] calcd for C17H»1CIN4Os: 364.1; found 364.4.

[00365] Step 3

[00366] (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethan-1-amine (59.5 mg, 315 pmol) and tert-butyl 3-{4-chloro-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-y1}-3- methylazetidine-1-carboxylate (76.8 mg, 210 pmol) were suspended in DMF (3 mL). DIPEA (109 pL, 630 pmol) was added. The reaction was stirred at rt overnight. The reaction mixture was diluted with H,O 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 give tert-butyl (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-0x0-7,8- dihydropyrido[2,3-d] py rimidin-6-y1)-3-methylazetidine-1-carboxylate (20.8 mg, 19%). LCMS (ESI) m / z: [M + H] calcd for CaH3oF3Ns03: 518.2; found 518.6.

[00367] Step 4

[00368] fert-Butyl 3-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8- methyl-7-oxo-7H,8H-pyrido[2,3-d]pyrimidin-6-y1)-3-methylazetidine-1-carboxylate (20.8 mg, 40.1 pmol) was dissolved in DCM (3 mL) followed by the addition of TFA (15.3 UL, 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; [M + H] calcd for C,;H,,F3NsO: 417.2; found 418.5.

[00369] Step 5

[00370] 4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-8-methyl-6-(3- methylazetidin-3-y1)-7H,8H-pyrido[2,3-d] pyrimidin-7-one; trifluoroacetic 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 nmol). The reaction was stirred at rt for 4 h. The mixture was washed with water and brine, then dried over Na,SO; and the solvent was removed under reduced pressure. The crude residue was purified by prep-HPLC to give 4-{[(1R)-1-[3-(difluoromethy1)-2-fluorophenyl]ethyl]amino} -6-(1-methanesulfonyl-3- methylazetidin-3-y1)-8-methyl-7H,8H-pyrido[2,3-d] py rimidin-7-one (6.90 mg, 34.8%). LCMS (ESI) m / z: [M + H] calcd for C2,Hz4F3NsOsS: 496.2; found 496.5. 'H NMR (500 MHz, Chloroform-d) & 8.47 (s, 1H), 7.55 (q, J = 6.9 Hz, 2H), 7.25 (1, J = 7.7 Hz, 1H), 5.78 (p.J=7.0Hz, 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).

[00371] Example 15: Synthesis of 6-(1-acetyl-4- piperidyl)-4-[[(LR)-1-[3-amino-2- fluoro-5-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl- pyrido[2,3-d]pyrimidin-7- one i =F SEES 80, 75°C J fF EH HOC J fF TEADCM J HOB, EDCI. TEA. 1 Fs I F. 7 F r H Os, ~ " iL : wor NAN wi AL Ay fie Fo H80, 78% F EIOH, H,0,90°C TEA, DCM, ? Hot EDC. TEA. HO" HO" 0->25°C HO” Xo DMF, 0-325 °C ‘MaMgBr 1 TI{OEY), THF. 02°C Ng 25°C->80°C a) Ca) Hoo oC Ca oF, 0-25 °C : . 0 F N. F : BAA oli 8 Xr SO Tee F T ri 0 we oA, LHMDS, THE 1 TORY, THF. NH MeOH - w wh ° wesw i NH, Fa I R PY F . = NH, — “SNH, 2. MeOH, LiBH,, 0 °C Fe 7 H - - "© WSN y KK o on WN © Vv . E Soom - — AN Se L, ¥

[00372] Step 1

[00373] To a mixture of 2-fluoro-5-(trifluoromethyl) benzoic acid (2 g, 9.61 mmol) and HNO; (10 mL) was added H,SO4 (2.5mL) 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 NaHCOs. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na;SO, and the solvent was removed under reduced pressure to give 2-fluoro-3-nitro-5- (trifluoromethyl)benzoic acid (2.3 g, 94.56% yield). 'H NMR (DMSO-ds, 400 MHz) 8 ppm 14.28 (s, 1 H), 8.71 (dd, J=5.8, 2.2 Hz, 1 H), 8.46 (dd, J=5.4, 22 Hz, 1 H).

[00374] Step 2

[00375] To a solution of 2-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (2 g, 7.90 mmol) in EtOH (9.6 mL) and HO (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 Na;SOs, and the solvent was removed under reduced pressure to give 3-amino-2-fluoro-5- (trifluoromethyl)benzoic acid (2 g, crude). The material was used without further purification. LCMS (ESI): m / z: [M + H] calculated for CgHsFsNO;: 224.0; found 224.1.

[00376] Step 3

[00377] To a solution of 3-amino-2-fluoro-5-(trifluoromethyl)benzoic acid (1.76 g, 7.89 mmol) in DCM (20 mL) at 0 °C was added TEA (1.10mL, 7.89 mmol) and acetyl acetate (2.59 mL, 27.61 mmol). The reaction mixture was warmed to 25 °C and stirred for 3 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na,SO4, and the solvent was removed under reduced pressure to give 3- acetamido-2-fluoro-5-(trifluoromethyl)benzoic acid (2.2 g, crude). LCMS (ESI): m / z: [M + H] calculated for C10H7F4NOs: 266.0; found 266.1.

[00378] Step 4

[00379] 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 were 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 warmed to 25 °C and stirred for 2h. The reaction mixture was diluted with ice water and filtered. The filtrate was extracted with EtOAc, dried with anhydrous Na,;SO;,, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give 3-acetamido-2- fluoro-N-methoxy-N-methyl-5- (trifluoromethyl)benzamide (785 mg, 56.28% yield). 'H NMR (methanol-ds, 400MHz) 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).

[00380] Step 5

[00381] To a solution of 3-acetamido-2-fluoro-N-methoxy-N-methyl-5- (trifluoromethyl)benzamide (785 mg, 2.55 mmol) in THF (8 mL) at 0 °C was added LHMDS (1M in THF, 2.55 mL, 2.55 mmol). 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 warmed to 25 °C and stirred for 30 min. The reaction was quenched with HO, extracted with EtOAc, washed with brine, dried over Na,SOy, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give N-[3-acetyl-2-fluoro-5-(trifluoromethyl)phenyl]acetamide (510 mg, 76.09% yield). 'H NMR (methanol-ds, 400MHz) § ppm = 8.62 (dd, J = 6.4, 2.0 Hz, 1H), 7.84 (dd, J = 6.0, 2.0Hz, 1H), 2.66 (d, J =4.4 Hz, 3H), 2.23 (s, 3H).

[00382] Step 6

[00383] To a solution of N-[3-acetyl-2-fluoro-5-(trifluoromethyl)phenyl]acetamide (510 mg, 1.94 mmol) and (R)-2-methylpropane-2-sulfinamide (281.83 mg, 2.33 mmol) in THF (6 mL) was added Ti(OEt) (1.21 mL, 5.81 mmol). 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 LiBHs (42.21 mg, 1.94 mmol) were added to the solution. The reaction stirred at 0°C for 1 h and then diluted with ice water and filtered. The filtrate was extracted with EtOAc, dried over Na,SO; and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give N-[3-[(LR)-1-[[(R)-fert-butylsulfinyl]amino]ethyl]-2- fluoro-5-(trifluoromethyl) phenyl] acetamide (150 mg, 20.17% yield). LCMS (ESI): m / z: [M + H] calculated for C;sH21F4N,0,S: 369.1; found 369.1. "HNMR (methanol-dj, 400MHz) & 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).

[00384] Step 7

[00385] To a solution of N-[3-[(1R)-1-[[(R)-tert-butylsulfinyl]amino]ethyl]-2-fluoro-5- (trifluoromethyl) phenyl]acetamide (150 mg, 407 pmol) in MeOH (2 mL) was added 4M HCl in MeOH (1.63 mL, 6.52 mmol). The solution was stirred at 25 °C for 2h. 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 under reduced pressure to give 3-[(1R)-1-aminoethyl]-2-fluoro-5- (trifluoromethyl)aniline (110 mg, crude). LCMS (ESI): m / z: [M + H] calculated for CoH 1F4N»: 223.1; found 223.0.

[00386] Step 8

[00387] To a solution of 3-[(1R)-1-aminoethyl]-2-fluoro-5-(trifluoromethyl)aniline (110 mg, 495.09 umol) in DMF (1.5 mL) was added 6-(1-acetyl-4-piperidyl)-4-hydroxy-8- methyl- pyrido[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. NaHCOj, extracted with EtOAc, washed with brine, dried over anhydrous Na,SOy, filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 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 (24.5 mg, 9.47% yield). LCMS (ESI): m / z: [M + H] calculated for C24H27F4N60;3: 507.2; found 507.3. 'H NMR (methanol-ds, 400MHz) § 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, 1H), 1.90-1.96 (m, 1H), 1.60-1.70 (m, SH).

[00388] Example 16: Synthesis of 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]amino]-2,8-dimethyl-6-(oxetan-3-yl)pyrido[2,3-d] pyrimidin-7-one F F “O OC F re F f o wi — Ir / Ni cocatalysts, LIOH 1 ! - I LT Br EN O Br -- Or 1¢ / Ni cocatalysts, LIOH or A 7 No 34 W blue LED lamp A7 No | DME, 25°C I

[00389] Step 1

[00390] To a solution of (Ir(dF(CF3)ppy):(dtbbpy))PFe (1.27 mg, 1.13 pmol), 6-bromo- 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2,8-dimethyl-pyrido[2,3- d]pyrimidin-7-one (50 mg, 113.32 pmol), 3-bromooxetane (23.28 mg, 169.97 umol), 4- tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (304.14 ug, 1.13 pmol) and Dbis(trimethylsilyl)silyl-trimethyl-silane (34.96 pL, 113.32 pmol) in DME (2 mL) was added lithium hydroxide (5.43 mg, 226.63 pmol) and dichloronickel 1,2-dimethoxyethane (248.98 ug, 1.13 pmol). 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 give 4- [[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2,8-dimethyl-6-(oxetan-3- yl)pyrido[2,3-d]pyrimidin-7-one (2 mg, 4.08% yield). LCMS (ESI): m / z: [M +H] calculated for CyHaoF3N4O,: 419.16; found 419.2. 'H NMR (400 MHz, methanol-d4) § ppm 8.32 (s, 1 H) 7.59 (1, 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).

[00391] Example 17: Synthesis of 6-(1-acetyl-4-piperidyl)-4-[[(1LR)-1-[4-amino-6- (trifluoromethyl)-2-pyridyl]ethyl]amino]-8-methyl-pyrido[2,3-d]pyrimidin-7-one *C, Pd(dppfiCl.CH5Cly 1 Ea Darel A 1) TI(OEY)s, THF, 80 °C CFs. ~~! | 194 Cl we 4 TEA PAPPIYCL NO LBM, MeOH.0%C Cs,C0Os dioxane ) LiBH,, , Ay H ~N RN OST CRan AN, PMB CFa. AN Nepus YT 0) - NA — a TEA, PA(PPhg),Cly 0 dioxane toluene, 100°C DDQ NFA HCl DCM / H,0,0°C I. MeOH CFa NH2 | © WSNH, Cha ANH | © WSNH g o* “< H CFs NN pus IJ SNH 1 FH K o OH NN Le y a DBU, BOP, DMF

[00392] Step 1

[00393] To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (2 g, 6.51 mmol) and (4-methoxyphenyl)methanamine (841.89 uL, 6.51 mmol) in toluene (10 mL) was added Cs,CO3 (4.24 g, 13.01 mmol) and Pd(dppf)Cl,. DCM (265.63 mg, 325.27 pmol). 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 Na,SQy4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give 2-chloro-N-[(4-methoxyphenyl)methyl]-6- (trifluoromethyl)pyridin-4-amine (1.7 g, 82.51% yield). LCMS (ESI): m / z: [M +H] calculated for C14H;3CIF;N,0: 317.1; found 317.1. "HNMR (400 MHz, methanol-dy) & 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, 2H) 3.78 (s, 3H).

[00394] Step 2

[00395] To a solution of 2-chloro-N-[(4-methoxyphenyl)methyl]-6- (trifluoromethyl)pyridin-4-amine (1.1 g, 3.47 mmol) and tributyl(1-ethoxyvinyl)stannane (5.28 mL, 15.63 mmol) in dioxane (10 mL) was added TEA (2.42 mL, 17.37 mmol) and Pd(PPhs),Cl; (487.58 mg, 694.65 pmol). The mixture was stirred under nitrogen at 100 °C for 18 h. The reaction was diluted with 1 M HCI (10 mL) and stirred for 16 h. The mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layers were washed with aq. KF and stirred for 20 min. The mixture was filtered. The organic layer was washed with brine, dried with anhydrous Na,SOs, filtered, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give 1-[4-[(4-methoxyphenyl) methylamino] -6-(trifluoromethyl)-2- pyridyl] ethanone (980 mg, 87.02% yield). 'H NMR (400 MHz, methanol-dy) & 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, 3H) 2.59 (s, 3 H).

[00396] Step 3

[00397] To a solution of 1-[4-[(4-methoxyphenyl)methylamino]-6-(trifluoromethyl)-2- pyridyl]ethanone (980 mg, 3.02 mmol), 2-methylpropane-2-sulfinamide (476.14 mg, 3.93 mmol) in THF (2 mL) was added tetraethoxytitanium (3.13 mL, 15.11 mmol). The reaction mixture was stirred at 90°C for 16 h. Then LiBH, (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 Na,SOy, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography give (R)-N-[(1R)-1-[4-[(4-methoxyphenyl)methylamino]-6-(trifluoromethyl)-2- pyridyl]ethyl]-2-methyl-propane-2-sulfinamide (800 mg, 59.79% yield). LCMS (ESI): m / z: [M +H] calculated for CyoH,7F3N30,S: 430.2; found 430.1; 'H NMR (400 MHz, methanol-ds) 8 ppm 7.29 (d, J=8.50 Hz, 2H) 6.92 (d, J=8.63 Hz, 2H) 6.82 (d,J= 11.26 Hz, 2 H) 4.44 - 4.40 (m, 1 H) 4.37 (5,2 H) 3.79 (s, 3H) 1.46 (d, J= 6.88 Hz, 3H) 1.24 (s, 9H).

[00398] Step 4

[00399] To a solution of (R)-N-[(1R)-1-[4-[(4-methoxy phenyl)methylamino]-6- (trifluoromethy1)-2- pyridyl]ethyl] -2-methyl-propane-2-sulfinamide (200 mg, 465.66 pmol) in DCM (5 mL) and H,O (0.25 mL) at 0 °C was added DDQ (158.56 mg, 698.49 umol). The mixture was warmed to 25°C and stirred for 3 h. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na,S0s, and the solvent was removed under reduced pressure. The residue was purified by prep-TLC to give (R)-N-[(1R)-1-[4-amino-6-(trifluoromethyl) -2-pyridyl]ethyl]-2-methyl- propane-2-sulfinamide (60 mg, 41.65% yield). LCMS (ESI): m / z: [M +H] calculated for CoH 19F3N308: 310.1; found 310.1.

[00400] Step 5

[00401] (R)-N-[(1R)-1-[4-amino-6-(trifluoromethyl)-2-pyridyl]ethyl]-2-methyl-propane- 2-sulfinamide (60 mg, 193.95 umol) was added to 4M HCl in MeOH and stirred for 1 h. The mixture was neutralized with aq. NaOH. The solvent was removed under reduced pressure. The residue was dissolved in DCM, filtered and concentrated under reduced pressure to give 2-[(1R)-1-aminoethyl]-6-(trifluoromethyl) pyridin-4-amine (39 mg, crude). LCMS (ESI): m / z: [M +H] calculated for CsH11F3N3:206.1; found 206.1.

[00402] Step 6

[00403] To a solution of 2-[(1R)-1-aminoethyl]-6-(trifluoromethyl)pyridin-4-amine (39.8 mg, 193.98 pmol) and 6-(1-acetyl-4-piperidyl)-4-hydroxy-8-methyl-pyrido[2,3- d]pyrimidin-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. NaHCO; and water, extracted with EtOAc, washed with brine, dried with anhydrous Na,SOs, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 6-(1-acetyl-4-piperidyl)-4-[[(1R)-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: [M +H] calculated for C3H»7F3N-0,: 490.2; found 490.3. *H NMR (400 MHz, methanol-ds) & 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, 3H) 3.29 - 3.26 (m, 1 H) 3.25 - 3.14 (m, 1 H) 2.80 - 2.71 (m, 1 H) 2.14 (s, 3H) 2.06 -1.90 (m, 2H) 1.68 - 1.61 (m, 1 H) 1.59 (d, J= 7.06 Hz, 3 H).

[00404] Example 18: Synthesis of 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]amino]-6-(3-fluoro-1-methyl-4-piperidyl)-2,8-dimethyl-pyrido[2,3- d]pyrimidin-7-one Hl) “ 3 Pd(dppCl NH NT d(dppCly 1 rn 1)BH, THF, THF, 0°C dioxane / H,0, 90°C a LL 2)NaOH, H;0,, 0°C DAST DCM £0 -> 25°C

[00405] Step 1

[00406] To a solution of 6-bromo-4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]amino]-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (1.8 g, 4.08 mmol) in dioxane (18 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)-3,6- dihydro-2H-pyridine (1.37 g, 6.12 mmol), Pd(dppf)Cl, (298.49 mg, 407.94 pmol), H,0 (3.8 mL) and Na,CO; (864.74 mg, 8.16 mmol). The mixture was stirred under nitrogen at 90 °C for 2 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na,;SO filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give 4-[[(LR)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-2,8-dimethyl-6-(1-methyl-3,6-dihy dro-2H- pyridin-4-y1)pyrido[2,3-d]pyrimidin-7-one (1.9 g, crude). 'H NMR (400 MHz, methanol- ds) 5 ppm 8.17 (s, 1 H) 7.59 - 7.55 (m, 1 H) 7.47 - 7.44 (m, 1 H) 7.23 - 7.20 (m, 1 H) 7.00 (t,J=54.8Hz, 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)

[00407] Step 2

[00408] To a solution of 4-[[(1R)-1-[3-(difluoromethy1)-2-fluoro-phenyl]ethyl]amino]- 2,8-dimethyl-6-(1-methyl-3,6-dihy dro-2H-pyridin-4-yl)pyrido[2,3-d]pyrimidin-7-one (1 g, 2.19 mmol) in THF (30 mL) under nitrogen at 0 °C was added 1M BH; in THF (13.12 mL, 13.14mmol). The mixture was stirred at 20 °C for 12 h. The reaction was cooled to 0°C and aq. 2M NaOH (3.28 mL, 6.56mmol) was added, followed by 30% H,0, (2.10 mL, 21.86 mmol), keeping the internal temperature below 5 °C. The reaction mixture was warmed to 30 °C and stirred for 1 h. The reaction mixture was poured into 10% aq. Na,$,0; 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 Na,SOy filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]amino]-6-(3-hydroxy- 1-methyl-4-piperidyl1)-2,8-dimethyl-pyrido[2,3- d]pyrimidin-7-one (100 mg, 9.62% yield). LCMS (ESI): m / z: [M +H] calculated for C14H20F3N50;: 476.2; found 476.3.

[00409] Step 3

[00410] To a solution of 4-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6- (3-hydroxy-1-methyl-4-piperidyl)-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (0.07 g, 147.21 pmol) in DCM (5 mL) at -60 °C was added N-ethyl-N-(trifluoro- sulfanyl)ethanamine (38.90 uL, 294.42 pmol). The mixture was warmed to 25°C and stirred for 12 h. The reaction mixture was gradually poured into NaHCO; 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 Na,SOs, filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 4-[[(LR)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]amino]-6-(3- fluoro-1-methyl-4-piperidyl)-2,8-dimethyl-pyrido[2,3-d]pyrimidin-7-one (8 mg, 10.47% yield). LCMS (ESI): m / z: [M +H] calculated for C»4HasFsNsO: 478.2; found 478.1. 'H NMR (400 MHz, methanol-d;) & ppm 8.47 (s, 1 H) 7.58 (1, J=8 Hz, 1 H) 7.47 (1, J=8 Hz, 1H) 7.22 (t, J=8 Hz, 1 H) 6.99 (t, / =54.8 Hz, 1 H) 5.83 - 5.77 (m, 1 H) 3.68 (s, 3 H) 3.15-2.81 (m, 5H) 2.62 (s, 3H) 2.39 (s, 3H) 1.91 (t, J = 12 Hz, 2H) 1.64 (d, J=8 Hz, 3 H).

[00411] Example 19: Synthesis of 6-(1-acetyl-4-piperidyl)-4-[[(1R)-1-[5-amino-2- fluoro-3-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3-d |pyrimidin-7- one HCI Pd(PPh3),Cl,, TEA 2 T 1) T(OEt), THF. 80°¢ 8. MeOH dioxane, 90 °C Ng 2)LiBHs MeOH, 0°C S— ¥ AN i CFa. NH; 2 NH, ~opPY CFa. NH, ES jut F -— = F 0 F PA(PPhy)Cl, TEA TIE, THE. 80°C Br dioxane, 90 °C 0 2) LiBHg, MeOH, 0°C La K< 0 OH WN Sol Ly Ld "0 Ra BOP, DBU, DMF - ; NH ’ WSN, CF. NH, F 0 od PN NTR LJ Ll

[00412] Step 1

[00413] To a solution of 3-bromo-4-fluoro-5-(trifluoromethyl)aniline (1 g, 3.88 mmol) and tributyl(1-ethoxyvinyl)stannane (1.96 mL, 5.81 mmol) in dioxane (10 mL) was added TEA (1.35 mL, 9.69 mmol) and Pd(PPh;),Cl; (272.04 mg, 387.58 pmol). The mixture was stirred under nitrogen at 90 °C for 3 h. The reaction was adjusted to pH = 2 using 1M HCI and stirred for 16 h, The mixture was filtered, and the filtrate was extracted with EtOAc. The organic layer was poured into aq. KF and stirred for 20 min. The mixture was filtered, washed with brine, dried with anhydrous Na,SO,, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give 1-[5- amino-2-fluoro-3- (trifluoromethyl)phenyl]ethanone (440 mg, 51.33% yield). 'H NMR (400 MHz, methanol-d4) 8 ppm 7.25 (d,J=4Hz, 1 H) 7.11 (d,J=4Hz, 1H) 2.58 (d,J = 4.63 Hz, 3H).

[00414] Step 2

[00415] 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) was added tetraethoxytitanium (1.24 mL, 5.97 mmol). The reaction mixture was stirred at 90°C for 3 h. Then the reaction was cooled to 0 °C and LiBH; (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 give N-[(1R)- 1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (350 mg, 53.90% yield). LCMS (ESI): m / z: [M +H] calculated for C13H;oF4N,08:327.1; found 327.05.

[00416] Step 3

[00417] To a solution of N-[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]- 2-methy! -propane-2-sulfinamide (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 aq. NaOH 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-[(1LR)-1-aminoethyl]-4-fluoro-5- (trifluoromethyl) aniline (200 mg, crude). LCMS (ESI): m / z: [M +H] calculated for CoH11FsN»:223.1; found 223.1.

[00418] Step 4

[00419] To a solution of 3-[(1R)-1-aminoethyl]-4-fluoro-5-(trifluoromethyl)aniline (100 mg, 450.08 umol) and 6-(1-acetyl-4-piperidyl)-4-hydroxy-8-methyl-pyrido[2,3- d]pyrimidin-7-one (136.07 mg, 450.08 pmol) in DMF (2 mL) was added 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 mixture was diluted with water, extracted with EtOAc, washed with brine, dried with anhydrous Na,SO; filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 6-(1-acetyl-4-piperidyl)-4- [[(1R)-1-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]ethyl]amino]-8-methyl-pyrido[2,3- d]pyrimidin-7-one (20 mg, 8.60% yield). LCMS (ESI): m / z: [M +H] calculated for C24H27F4N40,:507.2; found 507.2. HNMR (400 MHz, methanol-d4) & 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, 1H) 3.71 (s,3H) 3.26 - 3.14 (m, 1 H) 2.79 - 2.72 (m, 1 H) 2.14 (d, J = 1.32Hz,3H)2.07-190(m,2H) 1.70 - 1.62 (m, 2H) 1.60 (d, J= 7.06 Hz, 3 H).

[00420] Example 20: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-6-(2,3-dimethoxybenzyl)-2-methylpyrido[2,3-d|pyrimidin- 7(8H)-one OMe my Pd(PPha)s, THF, 60 °C F F F NS AR Li WENH OMe — OMe A NN o

[00421] Step 1

[00422] To a solution of 6-bromo-4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-2,8-dimethyl-7H,8H-pyrido[2,3-d] pyrimidin-7-one (81.3 mg, 184 pmol) and Pd(PPhs)s (21.2 mg, 18.3 pmol) in THF (2.0 mL) was added a solution of 3,4-dimethoxybenzylzinc chloride (0.5 M in THF, 1.0 mL, 0.50 mmol) at 25 °C under N,. The mixture was warmed to 60 °C and stirred for 30 min. The mixture was quenched with water, extracted with EtOAc, dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give (R)-4-((1-(3- (difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2,3-dimethoxybenzyl)-2- methylpyrido[2,3-d]pyrimidin-7(8H)-one (9.7 mg, 10% yield). LCMS (ESI): nvz: [M+H] calculated for C2 HsNsO3: 513.2; found: 513.5; "HNMR (500 MHz, METHANOL-4;) 8 ppm 8.07 (s, 1H), 7.55 (1, J=7.5 Hz, 1H), 7.47 (t, J =7.1 Hz, 1H), 7.22 (1, J = 7.7 Hz, 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).

[00423] The following examples 20-1 to 20-4 shown in Table 5 were synthesized in the manner similar to Example 20. Table 5. Examples 20-1 to 20-4 Example # Structure Mass Found 20-1 Wo LJ 513.5 Sy vo NR T N” Sy” Ae N W 0 20-2 Go LY 439.4 Co I Sau 0X | LW No \ 20-3 WNL NF 439.6 Oo I | = «SNH 2 NSW” LL N W o 20-4 WR) 495.1 NTR ( sg N N 0 *Q

[00424] Example 21: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-8-methyl-6-(pyridazin-4-yl)pyrido[2,3-d] pyrimidin-7(8H)- one 4 Pd{dppf),Cl, KOAC dioxane / H,0Q, 100 °C

[00425] Step 1

[00426] A mixture of 6-bromo-4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (43.6 mg, 102 pmol), pyridazine-4-boronic acid pinacol ester (33.1 mg, 160 pmol) and KOAc (32.0 mg, 326 pmol) in dioxane (2.0 mL) and water (0.5 mL) was sparged with N; for 10 min. To this mixture was added Pd(dppf),Cl, dichloromethane complex (8.3 mg, 10 pmol) at 25 °C under N,. The mixture was warmed to 100 °C and stirred for 30 min. The mixture was quenched with water, extracted with EtOAc, dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(pyridazin-4- yDpyrido[2,3-d]pyrimidin-7(8H)-one (16.5 mg, 38% yield). LCMS (ESI): m / z: [M+H] calculated for C;H;sF3NgO: 427.1; found: 427.3; "HNMR (500 MHz, METHANOL-d}) 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=7.0Hz, 3H).

[00427] The following examples 21-1 to 21-15 shown in Table 6 were synthesized in the manner similar to Example 21. Table 6. Examples 21-1 to 21-15 Example # Structure Mass Found 21-1 Go 414.5 3 oS HN) NX 0 NTN 21-2 GL No 427.5 Sam a) NS oN Lr No A Ng, 21-3 Sy Ney 4413 ood o Ng, Sw NR 7 A 7? N N o «SH MN 441.4 NNN A 7 N J 0 oA F ? - LT Mr 445.4 NNN 0 z= N"SNo x! 450.4 oS Ne NTR Lo. NN Sy © a 456.0 NX LL N~ "N° SO 467.5 NN N-Q [N oS 7 NTR L N N 0 Sy © a 470.1 NX A 7 NN EN 0 485.4 NT 0” (2 NSN So OH 500.0 J 1 Sy © a NX A 7 NN So F 0 Sa 5 500.0 NYS Non I Ay No © 425 4 “Ny + NH NTS 0 N N 0 426.07 Y NH mn NX lL N 0 E 426.07

[00428] Example 22: Synthesis of 4-(((R)-1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-6-(1-imino-1-oxido-1,2,3,6-tetrahydro-1)’-thiopyran-d-yl)- 8-methylpyrido[2,3-d]pyrimidin-7(8H)-one Ha04 x AAPOR ent 0 Pd(PPha)s, KoCO3 NY YY AcOH, 25°C dioxane / H,0, 100 °C F F F oho 0 — % NX [2 No F F 5 J F WSNH S NNT coy iP ie No

[00429] Step 1

[00430] A mixture of 6-bromo-4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (1.52 g, 3.55 mmol), 3,6-dihydro-2h-thiopyran-4-y1 boronic acid pinacol ester (2.07 g, 9.15 mmol), Pd(PPh;)s (627 mg, 542 pmol), and K,COs (1.52 g, 10.9 mmol) in dioxane (50 mL) and H,0 (20 mL) was sparged with N; for 5 min. The mixture was heated to 100 °C and stirred under N; for 2 h. The reaction was quenched with water, extracted with EtOAc, dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give (R)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-6-(3,6-dihy dro-2H-thiopyran-4-y1)-8-methylpyrido[2,3- d]pyrimidin-7(8H)-one (1.41 g, 89% yield). LCMS (ESI): m / z: [M+H] calculated for CH» F3N4OS: 447.2; found: 447.4.

[00431] Step 2

[00432] To a mixture of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6- (3,6-dihy dro-2H-thiopyran-4-y1)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (1.41 g, 3.15 mmol) in acetic acid (30 mL) was added an aqueous solution of hydrogen peroxide (30%, 416 pL, 4.05 mmol). 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 NaHCO;. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSOy, filtered, and concentrated under reduced pressure to give 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1- oxido-3,6-dihy dro-2H-thiopyran-4-yl)pyrido[2,3-d] py rimidin-7(8H)-one (1.43 g, 99% yield). LCMS (ESI): m / z: [M+H] calculated for C5,H»F3N40,S: 463.1; found: 463.4; 'H NMR (500 MHz, Methanol-ds) 6 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (t, J= 7.5 Hz, 1H), 7.49 (t,J=17.3Hz 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).

[00433] Example 23: Synthesis of 4-(((R)-1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-6-(1-imino-1-oxido-1,2,3,6-tetrahydro-1A°-thiopyran-4-yl)- 8-methylpyrido[2,3-d]pyrimidin-7(8H)-one 9 ann 1 F F "X0 ] F 3g F «Cn row lo it lo MH Sol wm Gd El \ Ny No F F ° F Y arty = Ee y

[00434] Step 1

[00435] To a mixture of magnesium oxide (407 mg, 10.1 mmol), PhI(OAc); (1.48 g, 4.59 mmol), trifluoroacetamide (516 mg, 4.56 mmol), and Rhy(OAc), (135 mg, 305 umol) was added a solution of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 8-methyl-6-(1-oxido-3,6-dihydro-2H-thiopyran-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 concentrated under reduced pressure. The crude residue was purified by column chromatography to give N-(4- (4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-7-oxo0-7,8- dihydropyrido[2,3-d]pyrimidin-6-yl)-1-oxido-3,6-dihydro-2H- 1A5-thiopyran-1-ylidene)- 2,2 2-trifluoroacetamide (741 mg, 72 % yield). LCMS (ESI): m / z: [M+H] calculated for C4H2:F6NsOsS: 574.1; found: 574.2.

[00436] Step 2

[00437] To a solution of N-(4-(4-(((R)-1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-8-methyl-7-ox0-7,8-dihydropyrido[2,3-d] pyrimidin-6-y1)-1- oxido-3,6-dihydro-2H-1 2°-thiopyran-1-ylidene)-2,2,2-trifluoroacetamide (213 mg, 371 nmol) in MeOH (6.0 mL) was added K,COs (102 mg, 738 umol). 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 MgSO, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give 4-(((R)-1-(3- (difluoromethy1)-2-fluorophenyl)ethyl)amino)-6-(1-imino-1-oxido-1,2,3,6-tetrahydro-125- thiopyran-4-y1)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (26.7 mg, 16% yield). LCMS (ESI): m / z: [M+H] calculated for C;H,3F3N50,S: 478.1; found: 478.1, "H NMR (500 MHz, METHANOL-d,) 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=17.7 Hz, 1H), 7.02 (t, J = 54.9 Hz, 1H), 6.07 — 6.03 (m, 1H), 5.78 (q,J="7.1Hz, 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=17.1 Hz, 3H).

[00438] The following example 23-1 shown in Table 7 was synthesized in the manner similar to Example 23. Table 7. Example 23-1 Example # Structure Mass Found Example 23-1 Suu Ao 4923 NH 4=0 | 1 NF «Su 4 NX A i“ NNT

[00439] Example 24: Synthesis of 4-(((R)-1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-8-methyl-6-(1-(methylimino)-1-oxido-1,2,3,6-tetrahydro- 1 25-thiopyran-4-yl)pyrido| [2,3-d]pyrimidin-7(8H)-one CH,0, TFA, TES 7 F F F F F o Jw NH CH,0, TFA, TES ® N WU ENH S=0 MeCN, 25 °C «SH Lew 0 NYS ¥ NN 2 p> Woo LLL

[00440] Step 1

[00441] To a mixture of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6- (1-imino-1-oxido-1,2,3,6-tetrahydro-13°-thiopyran-4-y1)-8-methylpyrido[2,3-d]pyrimidin- 7(8H)-one (85.6 mg, 179 pmol) in MeCN (4.0 mL) were added an aqueous solution of formaldehyde (37%, 53.2 pL, 712 pmol) and trifluoroacetic acid (54.4 pL, 710 pmol). 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 NaHCO. The aqueous layer was extracted with DCM and the combined organic layers were dried over MgSOy, filtered, and concentrated under reduced pressure. The crude residue was purified by prep-HPLC to give 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 8-methyl-6-(1-(methylimino)-1-oxido-1,2,3,6-tetrahydro-1A°-thiopyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (26.8 mg, 30% yield). LCMS (ESI): m / z: [M+H] calculated for Cy3H,sF3N0,S: 492.2; found: 492.4. 'H NMR (500 MHz, METHANOL-d,) § 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).

[00442] Example 25: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxidotetrahydro-2H-thiopyran-4- yl)pyrido[2,3-d]pyrimidin-7(8H)-one H,, 10% Pd / C H,0,, AcOH, 25°C AcOH, 25 °C F F F 8 20 _ “TNH § 25°C NX L No F i F F” F i @ SNH s _ 9 x oa H;0; ACOH, 26 °C. ig Vo

[00443] Step 1

[00444] To a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6- (3,6-dihydro-2H-thiopyran-4-yl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (450 mg; 1.00 mmol) in AcOH (5.0 mL) under N», 10% wt. 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 (R)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-8-methyl-6-(tetrahy dro-2H-thiopyran-4-yl)pyrido[2,3- d]pyrimidin-7(8H)-one (247 mg, 55% yield). LCMS (ESI): m / z: [M+H] calculated for CoH4F3N40S: 449.2: found: 449.2.

[00445] Step 2

[00446] To a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8- methyl-6-(tetrahy dro-2H-thiopyran-4-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (106 mg, 236 pmol) in AcOH (3.0 mL) was added was added an aqueous solution of hydrogen peroxide (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 was treated with NaHCO; to 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 give (R)-4- ((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-methyl-6-(1-oxidotetrahydro-2H- thiopyran-4-y1)pyrido[2,3-d]pyrimidin-7(8H)-one (31.3 mg, 29% yield). LCMS (ESI): m / z: [M+H] calculated for C,,H,4F3N40,S: 465.2; found: 465.3. 'H NMR (500 MHz, METHANOL-dy) § 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).

[00447] Example 26: Synthesis of 4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-2,8-dimethyl-6-(morpholine-4-carbonyl)-7H,8H- pyrido[2,3-d]pyrimidin-7-one Nal, TMSCI Q DIPEA, HATU ANI, NO ACN, 80°C xa So o LL Sods AA, pr I DMF 2.4 8-triisopropylben- zenesulfonyl chloride TEA. DMAP DMF

[00448] Step 1

[00449] To a solution of morpholine (169 pl, 1.93 mmol) and 4-methoxy-2,8-dimethyl- 7-ox0-7H,8H-pyrido[2,3-d]pyrimidine-6-carboxylic acid (400 mg, 1.61 mmol) in DMF (8 mL) was added DIPEA (839 pL, 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. aq. NaHCOs, the solids were filtered off, and the layers were separated. The organic layer was washed with brine, dried with Na,SO4, filtered, and the solvent was removed under reduced pressure. The residue was combined with the filtered solid and triturated with water to give 4-methoxy-2,8-dimethyl-6- (morpholine-4-carbonyl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (356 mg, 71% yield). LCMS (ESI): m / z: [M+H] calculated for C1sH1sN4O4: 319.1; found 319.0. "HNMR (300 MHz, methanol-dy) 8 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).

[00450] Step 2

[00451] 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-d]pyrimidin-7-one (360 mg, 1.13 mmol) in MeCN (14.4 mL). Chlorotrimethylsilane (861 uL, 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 sat. aq. sodium thiosulphate was added until the dark color faded. The solution was extracted with EtOAc, and the solvent was removed under reduced pressure to give 4-hydroxy-2,8- dimethyl-6-(morpholine-4-carbonyl)-7H,8H-pyrido[2,3-d]pyrimidin-7-one (322 mg, 94% vield). 'H NMR (300 MHz, DMSO-ds) 3 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).

[00452] Step 3

[00453] TEA (900 pL, 4.73 mmol) was added to a suspension of 4-hydroxy-2,8- dimethyl-6-(morpholine-4-carbonyl)-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 (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethan-1-amine hydrochloride (320 mg, 1.42 mmol) was added and the reaction was stirred overnight at rt. The reaction mixture was diluted with diethyl ether, washed with water and brine, dried with anhydrous Na;SO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC to give 4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-2,8-dimethyl-6-(morpholine-4-carbonyl)-7H,8H-pyrido[2,3- d]pyrimidin-7-one (100mg, 20% yield). LCMS (ESI): m / z: [M+H] calculated for C,3H2sF3N505: 476.2; found 476.0. 'H NMR (300 MHz, methanol-d;) 8 ppm 8.44 (s, 1H), 7.59 (t,J=17.5 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 (1, J =4.8 Hz, 2H), 2.43 (s, 3H), 1.64 (d, J="7.1 Hz, 3H).

[00454] The following examples 26-1 to 26-52 shown in Table 8 were synthesized in the manner similar to Example 26. Table 8. Examples 26-1 to 26-52 Example # Structure Mass Found 26-1 LG RN 450.6 RE, SH 0 NYS Sg Le No F 26-2 WS NY 0 462.4 «Shy 9 CLC Lv No Lo 26-3 Sy 3 462.5 A Shi 0 NTR N oC BG, N"NSo 474.0 > a3 - 474.4 Ww SH 0 NX N i» 2 Ne [D0 br L; on o 474.4 LAL SNH 0 475.0 CD LN NN Lk a - 5 476.5 NN Lo 0 NNT by - fs F F * Ad ne 476.6 w SH oO OC I Le 0 yg «SH o 9 483.6 NNN LJ | N N 0 RE - o 4872 LA ne 4 «SH 8 488.4 NYY 0 J N © N 0 - Tr F F Co a 488.5 Ww Shu Q NTR N OL Sey N i 0 A 0. RE - ° & 488.5 NSN UL No N N 0 oS © 488.5 NIN 0 Sn NN So 3 488.5 = 4 wSwu fo} NTR N LJ H NT N"So | Ho F i F F San 4885 Sa 0 todny Le No H Y 2d 488.5 = wSwu [o} NTR N (2 Q NTONSo 488.6 v4 oS o Xr CCD oz NTN 4893 oN “UNH Qo § A err Le No FE ¥: F F 489.8 Sy oS [o} NT NY COC LW No (0 F i F E Sn ° 490.4 SNH o NX NY CC Le No Lo 490.5 «SNH o CLO Le N"To Lo * Lb | un oN 490.5 NSS NA lL Lv N Wy 0 7 fies F F * dq J 490.5 Shi 0 COT ) Le N 0 wh 0 1 «Sa Wo 495.2 LW No Fr «Shy 0 495.4 Coon =N = 1 «SNH o 495.5 P - NTN N F =r F F it 495.6 Shy o =N Aa 5 lL NNSo 498 3 Spi o OLD # N, NON NS N 498.5 «Si 0 Cor # N. 501.5 Saw [o} NY XM COS) G7 N ol3 ” &:- F F 502.5 Shi 0 NN NONTo (Ub SE | «Sn 5 502.5 OO Z NSN So cy ~~ «Sn o 504.5 NX NTN Wa N= "N” “Oo. = 4 «SH a 504.5 0 COLCH LW No Lo . fs F F A : 506.5 oS 0° COLO Lp No Lo ° 1 «SH o 510.5 (XO <0 7 N 0 ig N= HN ZN EAS gl HNN EE - o MN 514.5 NSN L~ (7 N° N° SO +d oS 0 515.4 NTRS N Le No Be! 1 Jy 0 E fies F F dd hi 516.4 oS o NTR” ONT CF, CO oe NTONTSo bn I «SNH 0 516.5 NSS NY Lo. N W o o «SNH 0 517.0 Co Z N. oy So ey 517.5 Ct «San 0 LCL Ly No rs ” No” F fs F F I. ni 517.5 Lk SH o NTR N OO lt «SH & 2 5184 OCC Le No Ko «Sam o £3 518.5 COS N's No Lo 519.5 - J Shu [o} (CLO (7 N 0 KN =r 524.2 Shy a AN COCO | Lh oi REN ° 544.4 SNH 0 NY COC en 2 NTN OH WN / W Lh ad N 515.3 NY or LJ N N 0 26-52 WN wN Y_po 522.14 F 2 # Aw» Q “NH o $0 NY or 0. NN So

[00455] Example 27: Synthesis of 4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-2,8-dimethyl-6-[ (morpholin-4-yl)meth-yl]-7H,8H- pyrido[2,3-d]pyrimidin-7-one E ED K* F ¢ & NH, Pd(OAc), 2.4 8-triisopropylben- XPhos,Cs;,CO; | zenesulfonyl chloride on bobbing ant Atal sinh k TEA PAAAD MEAS E1OHMWater, 80°C. TEA, DMAP, DMF

[00456] Step 1

[00457] A solution of 6-bromo-4-hydroxy-2,8-dimethyl-7H,8H-pyrido[2,3-d]pyrimidin- 7-one (500 mg, 1.851 mmol) in aqueous ethanol (ethanol / water, 9:1, 20 mL) was degassed and potassium (morpholin-4-yl)methyltrifluoroborate (498 mg, 2.41 mmol), palladium(II) acetate (12 mg, 0.056 mmol), XPhos (44 mg, 0.093 mmol) and cesium carbonate (1.51 g, 4.63 mmol) were added. The mixture was stirred under 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 give 4-hydroxy-2,8- dimethyl-6-[(morpholin-4-yl)methyl]-7H,8H-pyrido[2,3-d]pyrimidin-7-one (196 mg, 37% yield). LCMS (ESI): m / z: [M+H] calculated for C14H;sN4Os: 291.1; found 291.1.

[00458] Step 2

[00459] 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. (1R)-1-[3-(Difluoromethyl)-2-fluorophenyl]ethan-1-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 give 4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]amino}-2,8- dimethyl-6-[(morpholin-4-yl)meth-y1]-7H,8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 10% yield). LCMS (ESI): m / z: [M +H] calculated for C13H,7F3NsO,: 462.1; found 462.0. H NMR (300 MHz, methanol-ds) & ppm 8.26 (s, 1H), 7.57 (t, J = 7.5 Hz, 2H), 7.45 (1, 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=17.1Hz, 3H).

[00460] Example 28: Synthesis of 4-(4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]-ethyl] amino }-8-methyl-7-oxo-7H,8H-pyrido[2,3-d|pyrimidin-6-yl)-4- hydroxy-1°-thiane-1,1-dione Sml, THF, -78°C E y F i © * 5 } Si <5 — HO. 0 { NY °C 2 N N 0

[00461] Step 1

[00462] To a solution of 6-bromo-4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-8-methyl-7H,8H-pyrido[2,3-d]pyrimidin-7-one (150 mg, 0.35 mmol) and tetrahydrothiopyran-4-one 1,1-dioxide (104 mg, 0.7 mmol) in THF (4.5 mL) at -78 °C was added a 0.1 M Sml, solution in THF (24.6 mL, 2.46 mmol). After 4 h stirring at -78 °C additional 0.1 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 sat. aq. NH4Cl and extracted with EtOAc. The organic layer was dried with Na;SOy filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 4-(4-{[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]-ethyl]amino} -8-methyl-7-oxo- 7H,8H-pyrido[2,3-d]pyrimidin-6-y)-4-hydroxy-13°-thiane-1,1-dione (80 mg, 46% yield). LCMS (ESI): m / z: [M +H] calculated for C2,H,4F3N404S: 497.1; found 497.0. 'H NMR (300 MHz, DMSO-ds) 5 ppm 8.74 — 8.59 (m, 2H), 8.37 (s, 1H), 7.71 — 7.59 (m, 1H), 7.52 (t,J=7.1Hz, 1H), 7.31 (t, J= 7.7 Hz, 1H), 7.25 (t, J = 54.4 Hz, 1H), 5.97 (s, 1H), 5.77 (, J=17.0 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).

[00463] The following examples 28-1 to 28-9 shown in Table 9 were synthesized in the manner similar to Example 28. Table 9. Examples 28-1 to 28-9 Example # Structure Mass Found 28-1 ol a i 462.2 «Sh NY Xr CO Z N 3 0 28.2 WSN a Nd 476.2 oS - ON po” NY NX A ? NTONSo WN S=0 483.1 NH Ho. \ NTR 0 J N ji 0 A 1 507.04 SNH Lo NTR 0 z NN o Xx 5233 «Sa Lz - XT 90 2 NONSo 537.0 Oo Sco OF oo I Sw AN Xr C0 ZZ N y o 4693 F F F o \® pe Ve Me 490.1 NH HO. N N77 0 = N N 0 Me FE 534.1 Ny

[00464] Example 29: Synthesis of 4-(4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]-pyrimidin-6-yl)-4- fluoro-12%-thiane-1,1-dione F F 0 $=0 DAST DCM, 0°C I oly 2 o 0 NM we $C NTR 0 ZZ NT SNTNo F 7 E F AB 2 o r WTNH §=0 c NX (= NTNSo

[00465] Step 1

[00466] To a solution of 4-(4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-8-methyl-7-oxo0-7H,8H-pyrido[2,3-d] py rimidin-6-y1)-4- hydroxy-135-thiane-1,1-dione (150 mg, 0.3 mmol) in DCM (4.5 mL) at 0 °C under N, DAST (60 pL, 0.45 mmol) was added. The reaction mixture was stirred for 2 h at rt. Sat. aq. NaHCO; was added and the mixture was extracted with DCM. The organic layer was dried with Na,SO; filtered, and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC to give 4-(4-{[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]amino}-8-methyl-7-oxo-7H,8H-pyrido[2,3-d]-pyrimidin-6-y1)-4-fluoro- 135-thiane-1,1-dione (76 mg, 50% yield). LCMS (ESI): m / z: [M +H] calculated for CasHpFsN403S: 499.1; found 499.1. 'H NMR (300 MHz, DMSO-ds) § ppm 8.71 (d, J= 7.2 Hz, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 7.64 (1, J = 7.6 Hz, 1H), 7.52 (t, J = 7.1 Hz, 1H), 7.31 (t,J= 1.7 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).

[00467] The following examples 29-1 to 29-15 shown in Table 10 were synthesized in the manner similar to Example 29. Table 10. Examples 29-1 to 29-15 Example # Structure Mass Found 29-1 oS 436.1 a “SNH ENT NTR 0 N N 0 464.1 20.2 oT o Sm E ON or LW No 29.3 WOSN...

Claims

We Claim 1. A compound having the structure of Formula (I), IO Ry wy H 13 Re NE A RZNTNT0 Rs or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein: R; 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; R; is selected from the group consisting of H, C, alkyl, halogen, -NHR3, ~ORa, cyclopropyl, and —CN; wherein Cy. alkyl is optionally substituted with halogen, -NHR,, — ORyg, or 5-6 membered heterocyclyl, and further wherein Ry, is selected from the group consisting of H, Cy alkyl, 3-6 membered heterocyclyl, and C1 haloalkyl; R; is selected from the group consisting of H, Cy.; alkyl, —OR3,, cyclopropyl, and 3- 6 membered heterocyclyl, wherein each of Cy; alkyl, cyclopropyl, and 3-6 membered heterocyclyl is optionally substituted with Rss, and further wherein Rs, is selected from the group consisting of Cy.3 alkyl, halogen, -OH, or -CN; Ly is selected from the group consisting of bond, —C(OQ)-, -C(0)0—, — C.¢ alkyl 0 C,.¢ alkyl C(O)NH(CHy)o, -NH-, -$ 2H NH-, S-, S(O), “2% $0 ng 3 ! ~N (CH,),—, and —O—; wherein 0 is 0, 1, or 2; and wherein p is a number from 1 to 6; and R, is selected from the group consisting of H, Cy. alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cs 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 C,. alkyl, —R4a, “OR4q, ~O—C 1.6 alkyl-Rya, =O, halogen, —C(O)R4z, ~C(OO)R4a, ~C(O)NRupR4c, “NR4pC(O)R4c, ~CN, =NRyz, ~NRypR4, — SO;Ry,, 3-6 membered cycloalkyl optionally substituted with Ry,, 3-7 membered heterocyclyl optionally substituted with Rss, 6-10 membered aryl optionally substituted with Rya,, or 5-10 membered heteroaryl optionally substituted with Ry,,; wherein Ry, is H, C6 alkyl, C1. haloalkyl, —C(O)Rsp, —C(O)NR4Ryc, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with —-ORyp, — CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, —(CH,);OCH; or — (CH,),OH whereinris 1, 2, or 3; wherein each Ry is independently H, C6 alkyl; and wherein each Ry. is independently H or C14 alkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is optionally substituted 6-membered aryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R is optionally substituted 5-6 membered heteroaryl. 4, The compound of claim 1, having the structure of Formula (II), Ry In or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Ry, Rs, L4, and Ry are as defined in claim 1; Rs, Rg, Ry, Rg, and Ry are independently selected from the group consisting of H, D, Cs alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, ~OH, halogen, -NO,, —-CN, -NR;R 1», ~SRyq, — S(0):NR11R12, =8(0)2R10, -NR10S(0)2NR11R12, -NR108(0)2R11, =S(O)NRi1R12, ~S(O)R1o, -NR1S(O)NR R12, -NR1pS(O)R11, —~C(O)R 10, -CO1R 19, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1. alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, Ca alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —~OH, Ci. alkyl optionally substituted with -Ryo, halogen, -NO,, oxo, -CN, —Rjo, -OR10, -NR11R12, —SRyo, — S(0):NR11R12, —=8(0)2R10, -NR10S(0)2NR11R12, -NR108(0)2R11, —-S(O)NR11R 15, ~S(O)R 10, —NR0S(O)NR11R 12, -NR0S(O)R 11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rio, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent RS R% R, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Ruo, Rui, and Ry; are at each occurrence independently selected from H, D, C16 alkyl, Cy. alkenyl, 4-8 membered cycloalkenyl, C2. alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR13, —SR3, halogen, -NR3R 14, -NO,, and -CN; and Ry; and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Ca. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Cy alkyl, C,.¢ alkenyl, 4-8 membered cycloalkenyl, Cz alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —SH, —-NH,, -NO,, or —-CN.

5. The compound of claim 1, having the structure of Formula (III), H Rr f S Rs oF EH Hal L NEN Pay Ry” N7 NTO Re (IIT) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Ry, Rs, Ly, and Ry are as defined in claim 1; Rs, Rg, Ry, Rg, and Ry are independently selected from the group consisting of H, D, Cs alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, -CN, -NR11R12, =SRuo, — S(0):NR11R13, =8(0)2R10, -NR10S(0)2NR11R12, -NR108(0)2R11, —=S(O)NR11R 15, ~S(O)R 10, —NR0S(O)NR11R 12, -NR19S(0)R 11, ~C(O)R 0, -CO2R 10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1. alkyl, C,. alkenyl, 4-8 membered cycloalkenyl, C6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —~OH, Ci. alkyl optionally substituted with -Ryo, halogen, -NO,, oxo, -CN, —Rjg, -OR10, -NR11R12, —SRyp, — S(0):NR11R12, =8(0):R10, -NR10S(0)2NR11R 12, “NR 108(0)2R11, =S(O)NR11R 12, =S(O)R 10, —NR10S(O)NR;1R12, ~NR;0S(O)R 11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Ryo, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R% R% R, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Ryo, Rui, and Ry; are at each occurrence independently selected from H, D, C16 alkyl, Cy. alkenyl, 4-8 membered cycloalkenyl, C2. alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR;3, —SR3, halogen, -NR;3R 14, -NO», and -CN; and Ry; and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Ca. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C.¢ alkyl, C,.¢ alkenyl, 4-8 membered cycloalkenyl, Cys alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —-SH, -NH,, -NO,, or —-CN.

6. The compound of claim 1, having the structure of Formula (IV-a), (IV-b), or (IV-c), Re rs Rg Rg 7 Re le HsC" "NH hk 0] Ra a AM Ry ONT ONTO R7 R7 Res ON Rg Rs BD Rg NX Re | N A ZF ZF Rg Rs Ro Rs Rg HC" NH H HC SNH H HC" NH H ¢ Re ° Rs ¢ Re IN ~ NZ Ne NZ Ne RN No RN No RN No Lo 4 Co Lo ob re = Ap Ve Ry Rs (Toa) Rs (TVR) Rs (IV-a) Ra (IV-b) (IV-c) or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R,, Rs, Ly, and Ry are as defined in claim 1; Rs, Rg, Ry, Rs, and Ry are independently selected from the group consisting of H, D, Cs alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, OH, halogen, -NO,, -CN, -NR1;R 1», —SRyo, — S(0):NR11R12, =8(0)2R10, -NR10S(0)2NR11R12, -NR108(0)2R11, =S(O)NRi1R12, ~S(O)R1o, —NR10S(O)NR11R 12, -NR10S(0)R11, ~C(O)R10, -CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each Cy. alkyl, C,. alkenyl, 4-8 membered cycloalkenyl, C6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with —OH, Cy. alkyl optionally substituted with -Ryo, halogen, -NO,, oxo, -CN, —Rjo, “OR10, -NR11R12, —SRy0, — S(0):NR11R12, —=8(0)2R10, -NR10S(0)2NR11R12, -NR108(0)2R11, ~=S(O)NR11R 12, ~S(O)R10, —NR10S(O)NR11R 12, “NR 0S(O)R 11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with Rio, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R% R% R, R®, and R’ forms an optionally substituted 3-14 membered fused ring; Rio, Rui, and Ry; are at each occurrence independently selected from H, D, Ci. alkyl, Ca. alkenyl, 4-8 membered cycloalkenyl, C26 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, -OR13, —=SR 3, halogen, -NR3R 14, -NO,, and -CN; and Ry; and Ry, are at each occurrence independently selected from H, D, Cy alkyl, Ca. s alkenyl, 4-8 membered cycloalkenyl, C,.¢ alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each Cy alkyl, C,.¢ alkenyl, 4-8 membered cycloalkenyl, Cys alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with —OH, —-SH, -NH,, -NO,, or —-CN.

7. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of Rs, Rs, R7, Rs, and Ry is C1. alkyl substituted with halogen.

8. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of Rs, Rs, Rs, Rs, and Ry is C1. alkyl substituted with halogen and —-OH.

9. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of Rs, Rs, R7, Rg, and Ry is halogen, and one to three of Rs, Rs, Ry, Rg, and Ro is C16 alkyl substituted with halogen.

10. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one to three of Rs, Rs, R7, Rs, and Rog is —-NH,.

11. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein one of Rs, Rs, R7, Rg, and Ry is —NH,; and one of Rs, Rg, R7, Rg, and Ry is C14 alkyl substituted with halogen.

12. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein any two adjacent R®, R®, R”, R®, and R’ forms a 3-14 membered fused ring, wherein the fused ring is substituted with halogen.

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

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is Cs alkyl.

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is Cy.¢ alkyl substituted with 5-6 membered heterocyclyl.

16. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is C,.¢ alkyl substituted with -NHR;,, wherein Rj, is C1 alkyl or 3-6 membered heterocyclyl.

17. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is C,.¢ alkyl substituted with -OR,,, wherein Rj, is C1 alkyl, 18. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is -NHRy,, wherein Ry, is Ci. 6 alkyl.

19. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R; is ~ORy,, wherein Ry, is Ci alkyl.

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

21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Rj is C.; alkyl substituted with —-OH.

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

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

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L; is selected from the group 0 1 2 consisting of bond, —C(0)-, —~C(0)0-, ~C(O)NH(CH,),—,-NH-, —S—, -S(0)>-, - = C,.¢ alkyl 2 CE , —~(CHa),—, and —O—; wherein ois 0, 1, or 2; and wherein p is a number from1to6.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L, is a bond.

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

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein L4 is -(CH,),—.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein R, is selected from the group consisting of H, Cy alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each Cis 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 Cj alkyl “OR4,, =O, halogen, —C(O)Ry,, —C(OO)R4,, —C(O)NRypR4c, -CN, — NRypR4,3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5- 10 membered heteroaryl.

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

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

32. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, isomer, prodrug, or tautomer thereof, wherein Ry is 3-14 membered heterocyclyl substituted with Cy alkyl.

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

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

35. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 1.

36. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 2.

37. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 3.

38. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 4.

39. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, selected from the group consisting of compounds of Collection 5.

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

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

42. A method of inhibiting SOS1 in a subject, comprising administering to the subject a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, 43. A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC in a cell, comprising administering to the cell a compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof, 44. A method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC, the method comprising administering to a subject in need thereof an effective amount of a compound of any of claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof 45. A method 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 claims 1-40, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or isomer thereof 46. The method of claim 44 or 45, wherein the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas.

47. The method of claim 44, wherein the disease is a RASopathy.

48. The method of claim 47, 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 Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, and Hereditary gingival fibromatosis.

49. The method of claim 45 or 46, wherein the cancer comprises a Ras™"” or an NF1YF mutation.