INDOLIZINE DERIVATIVES FOR TREATING CANCER

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Serial No. 63/418,102, filed on October 21, 2022; which is incorporated herein by reference in its entirety.

SEQUENCE LISTING

This application contains a Sequence Listing that has been submitted electronically as an XML file named 50006-0109W01_ST26_SL.XML.” The XML file, created on October 19, 2023, is 2,257 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e g., a human).

BACKGROUND

The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates the expression of genes required for DNA repair, cell cycle arrest, senescence, and apoptosis, and p53 plays a critical role in mediating each of these processes (Alvarado-Ortiz et al., Frontiers in Cell and Developmental Biology (2021) 8, Article 607670; Vousden et al., Cell (2009) 137, 413-431; Bieging et al., Nat. Rev. Cancer (2014) 14, 359-370). TP53 is altered in over 50% of all human cancers, making it the most frequently mutated gene among oncogenes and tumor suppressor genes (Hainaut et al., Adv Cancer Res (2000) 77, 81-137; Joerger et al., Cold Spring Harb. Perspect. Biol. (2010) 2(6), Article a000919). Mutations in TP53 result in loss of its normal function, rendering cells incapable of responding to a variety of cellular stresses such as DNA damage or oncogene activation, making them susceptible to tumorigenesis (Joerger et al., Oncogene (2007) 26, 2226-2242). The great majority of TP53 mutations are missense mutations, located within or proximal to its DNA-binding domain (Baugh et al., Cell Death & Differentiation (2018) 25, 154-160). Mutations leading to p53 loss of function can be categorized into two main types: (1) DNA contact mutations, where the mutant protein loses its ability to bind DNA; (2) structural mutations, which destabilize the p53 protein (Brosh et al., Nat. Rev. Cancer (2009) 9, 701-713; Hollstein et al., Science (1991) 253, 49-53). Both classes of mutations prevent p53-driven transcriptional activation, thus abrogating p53-mediated tumor suppression (Zhu et al., Frontiers in Oncology (2020) 10, Article 595187).

Reactivation of the mutant p53 protein emerges as an attractive approach to treat TP53 mutant cancers (Degtjarik et al., Nature Communications (2021) 12, Article 7057; Bykov et al., FEBS Letters (2014) 588, 2622-2627). Theoretically, mutant p53 reactivation will restore its tumor suppressive functions, stimulating p53-dependent arrest or apoptosis and resulting in efficient elimination of tumor cells (Selivanova et al., Oncogene (2007) 26, 2243-2254). The p53 ^Y220C mutation occurs in -1% of human cancers; -100,000 new cancer cases per year worldwide (Joerger et al., Annu. Rev. Biochem. (2016) 85, 375-404; Bouaoun et al., Hum. Mutat. (2016) 37, 865-876). Stabilization of the mutant protein may restore and/or maintain the functional conformation of the protein (Baud et al., Eur J Med Chem. (2018) 25, 101-114; Rauf et al., Protein J (2013) 32, 68- 74). In some instances, such as the Y200C mutation, there is a small molecule binding pocket far away from the binding interface between p53 and DNA, such that small molecule engagement at this pocket will not disrupt DNA binding (Bauer et al., Future Med. Chem. (2019) 11, 2491-2504).

SUMMARY

Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is CR ¹ or N;

R ¹ is hydrogen, halogen, cyano, -OR ⁴ , -NR ⁴ R ⁵ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁴ , -C(=O)NR ⁴ R ⁵ , -SR ⁴ , -S(=O)R ⁴ , -S(O ₂ )R ⁴ , -NR ⁴ C(=O)R ⁵ , -R ⁴ C(-O)R ⁵ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X ² , X ³ , X ⁴ , and X ⁵ are CH, N, CR ² or CR ³ , wherein two or more of X ² , X ³ , X ⁴ , and X ⁵ are independently CH, CR ² , or CR ³ ; each of Y ¹ , Y ² , and Y ³ are C or N, wherein one of Y ¹ , Y ² , and Y ³ is N; R ^A is hydrogen, –OR ⁶ , -NR ⁶ R ⁷ , -C(=O)R ⁶ , -R ⁶ C(=O)R ⁷ , -OC(=O)R ⁶ , -OC(=O)NR ⁶ , –C(=O)OR ⁶ , –NR ⁶ C(=O)OR ⁷ , –C(=O)NR ⁶ R ⁷ , –SR ⁶ , –S(=O)R ⁶ , –S(O2)R ⁶ , –S(O2)NR ⁶ , –NR ⁶ S(O2)R ⁷ , -NR ⁶ C(=O)R ⁷ , -NR ⁶ C(=O)NR ⁷ , -SiR ⁶ R ⁷ R ⁸ , optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; R ^B is halogen, cyano, hydroxyl, –NR ⁸ R ⁹ , -OR ⁸ , –C(=O)NR ⁸ R ⁹ , –C(=O)R ⁸ , -C(=O)OR ⁸ , -NR ⁸ C(=O)OR ⁹ , –OC(=O)R ⁸ , –OC(=O)NR ⁸ , –C(=O)NR ⁸ R ⁹ , –NR ⁸ C(=O)R ⁹ , –NR ⁸ C(=O)NR ⁹ , –SR ⁸ , –S(=O)R ⁸ , –S(O2)R ⁸ , –S(O2)NR ⁸ , –NR ⁸ S(O2)R ⁹ , -R ⁸ C(=O)R ⁹ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ C(=O)NR ⁹ , optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each R ² is Z ¹ is a bo ally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z ² is CR ^2C , N, O, or a bond; wherein when Z ² is O, R ^2B is absent, and when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to Formula (I) via Z ¹ ; R ^2A and R ^2B are independently hydrogen, –C(=O)R ¹⁰ , –C(=O)OR ¹⁰ , –C(=O)NR ¹⁰ R ¹¹ , –S(=O)R ¹⁰ , –S(O2)R ¹⁰ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R ^2A and R ^2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z ² is O and R ^2B is absent;

R ^2C is hydrogen, halogen, or C1-C6 alkyl; each R ³ is independently halogen, cyano, -NR ¹² R ¹³ , -OR ¹² , -C(=O)NR ¹² R ¹³ , -C(=O)R ¹² , -C(=O)OR ¹² , -OC(=O)R ¹² , -NR ¹² (C=O)NR ¹³ R ¹⁴ , -SR ¹² , -S(=O)R ¹² , -S(O ₂ )R ¹² , -S(O ₂ )NR ¹² R ¹³ , -NR ¹² S(O ₂ )NR ¹³ R ¹⁴ , -R ¹ =O)R -NR ¹² C(=O)R ¹³ , optionally substituted Cl- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl;

L is an optionally substituted 4-6 membered heterocyclylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2; and each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Further provided herein is a method of treating a p53-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a p53-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

This disclosure also provides a method of treating a p53-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a p53 -associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.

This disclosure also provides a method for restoring p53 function in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Other embodiments include those described in the Detailed Description and/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and/or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a p53 protein-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular cancer or (iii) delay the onset of one or more symptoms of the particular cancer, described herein.

The term “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe etal., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

As used herein, the “subject” refers to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the cancer to be treated.

As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a cancer, diminishment of the extent of the cancer, stabilized (i.e., not worsening) state of disease, delay or slowing of cancer progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the cancer), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “substituted” the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more individually and independently selected group(s) that are stable and chemically acceptable for the group being substituted. Non-limiting examples of optional substituents are halogen, cyano, hydroxyl, nitro, nitroso, azido, sulfhydryl, acyl, alkyl, hydroxyalkyl, aminoalkyl, alkoxyamino, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, hydroxyalkoxy, alkoxyalkoxy, alkenoxy, alkynoxy, haloalkoxy, haloalkenoxy, haloalkynoxy, cycloalkyl, halocycloalkyl, cycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, aralkyl, cycloalkylalkyl, heteroaralkyl, alkoxyalkyl, heterocyclylalkyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, alkoxycarbonyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfenyl, halosulfenyl, sulfonyl, sulfinyl, sulfoximino, sulfonimidamido, phosphine oxide, C-carboxy, O- carboxy, arylalkoxy, cycloalkylalkoxy, carboxaldehyde, iminyl, trihalomethanesulfonyl, trihalomethanesulfonamido, phosphityl, phosphonityl, phosphorothioityl, phophoamidityl, phosphonamidityl, phosphinityl, phosphinyl, phosphonothioityl, phosphorodiamidityl, phosphinamidityl, phosphorodithioityl, phosphonodiamidityl, phosphorotriamidityl, phosphatyl, phosphinatyl, phosphonatyl, phosphoroamidatyl, phosphorodiamidatyl, phosphonodiamidatyl, phosphonamidatyl, phosphinamidatyl, phosphorotriamidatyl, phosphorothiatyl, dithiophosphinatyl, phosphorodithioatyl, phosphonothioatyl, thiophosphatyl, thiophosphinatyl, phosphorodithiatyl, thiophosphonatyl, phosphorofluoridatyl, bisphosphonatyl, triphosphatyl, pyrophosphatyl, tetraphosphatyl, and ureido. The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "hydroxyl" refers to an -OH radical. The term “sulfhydryl” refers to a –SH radical. The term "cyano" refers to a -CN radical. The term “azido” refers to a –N3 radical. The term “nitro” refers to a –NO2 radical. The term “nitroso” refers to a –N=O radical. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-C10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, /e/7-butyl, w-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.

The term “acyl” refers to a -C(=O)alkyl radical (e.g., acetyl), or a -C(=O)alkenyl radical

(e.g., -C(=0)-CH=CH2), or -C(=O)alkynyl radical (e.g., Acyl groups can be substituted with cyano or with 1-3 independently selected halogens.

As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

The term “cycloalkyl” as used herein refers to cyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l.l. l]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2. l]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S, P, B, and Si and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-J]pyrimidinyl, pyrrolo[2,3-/>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[d][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[/>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more

or and imidazolone (e.g., wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, P, S, B, or Si (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, P, S, B, or Si if monocyclic, bicyclic, or tricyclic, respectively), wherein one or more ring atoms may be substituted by 1-3 oxo (forming, e.g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting; and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by 1-2 substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, di hydrofuranyl, dihydrothiophenyl, oxaphosphinanyl oxide, azaphosphinanyl oxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[l.l.l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7- azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2- azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicyclo[l . l.l]pentane, 3-oxabicyclo[3.1.0]hexane, 5- oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2. l]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4- azaspiro[2.5]octane, l-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2- azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2- oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5- dioxaspiro[3.6]decane, l-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9- azaspiro[5.5]undecane and the like.

As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.

The term “halocycloalkyl” refers to a cycloalkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.

The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with hydroxyl.

The term “haloalkenyl” refers to an alkenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.

The term “haloalkynyl” refers to an alkynyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen.

The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

The term “alkoxyalkyl” refers to an alkyl, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy (e.g., methoxy ethyl).

The term “hydroxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with hydroxy.

The term “alkoxyalkoxy” refers to an alkoxy group, in which one or two hydrogen atoms is/are replaced with an independently selected alkoxy.

The term “alkoxyamino” refers to an -O-amino radical (e.g., -OCH2CH2N(CH3)2).

The term “haloalkoxy” refers to an -O-haloalkyl radical (e g., -OCF3).

The term “alkenoxy” refers to an -O-alkenyl radical (e.g., -O-allyl).

The term “haloalkenoxy” refers to an -O-haloalkenyl radical. The term “alkynoxy” refers to an -O-alkynyl radical (e.g., -O-propargyl). The term “haloalkynoxy” refers to an -O-haloalkynyl radical. The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O-cyclopropyl).

The term “aryloxy” refers to an -O-aryl radical (e.g., phenoxy).

The term “heteroaryloxy” refers to an -O-heteroaryl radical (e.g., pyridinoxy).

The term “heterocyclyloxy” refers to an -O-heterocyclyl radical (e.g., -O-pyrrolidinyl or -O-oxetanyl).

The term “aralkyl” refer to an aryl group connected, as a substituent, via an alkyl group (e.g., benzyl).

The term “cycloalkylalkyl” refers to a cycloalkyl group connected, as a substituent, via an alkyl group (e.g., ethylcyclobutyl).

The term “heteroaralkyl” refers to a heteroaryl group connected, as a substituent, via an alkyl group (e.g., methylpyrimidinyl).

The term “heterocyclylalkyl” refers to a heterocyclyl group connected, as a substituent, via an alkyl group (e.g., methyloxetanyl).

The term “aralkoxy” refers to an aryl group connected, as a substituent, via an alkoxy group (e.g., benzyl oxy).

The term “cycloalkylalkoxy” refers to a cycloalkyl connected, as a substituent, via an alkoxy group (e.g., methoxycyclopropyl).

The term “aminoalkyl” refers to an amino group connected, as a substituent, via an alkyl group (e.g., methyl(dimethylamino)).

A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

A “halosulfenyl” group refers to a sulfenyl, in which one or more hydrogen atoms is/are replaced with an independently selected halogen (e.g., -S(CFs) or -S(CHF2)).

A “sulfinyl” group refers to an “-S(=O)” group in which R can be the same as defined with respect to sulfenyl.

A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.

A “sulfoximine” group refers to an -S(=O)(=NR)R’, where R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

A “sulfonimidamido” group refers to an -S(=O)(=NR)NR’R” where R, R’, and R” are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl; and where R’ alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy.

A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy.

A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.

A “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(R’)-” group wherein each X is a halogen, and R’ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “S-sulfonamido” group refers to a “-S02N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “N-sulfonamido” group refers to a “RS02N(R’)-” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “O-carbamyl” group refers to a “-OC(=O)N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “N-carbamyl” group refers to an “ROC(=O)N(R’)-” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “O-thiocarbamyl” group refers to a “-OC(=S)N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “N-thiocarbamyl” group refers to an “ROC(=S)N(R’) — ” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

A “C-amido” group refers to a “-C(=O)N(RR’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

An “N-amido” group refers to a “RC(=O)N(R’)” group in which R and R’ are independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

The terms “ureido” or “urea” refer to an -NR(C=O)NR’R”” group, in which R, R’, and R” are independently hydrogen, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

The term “carboxaldehyde” refers to a -C(=O)H radical.

The term “imine” or “imino” refers to a -N=R radical, in which R is hydrogen, hydroxyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. The term “amino” refers to a -NRR’ radical, where R and R’ are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl. In some instances, an amino group is -NH2, a mono-alkyl amine (R is hydrogen and R’ is alkyl) or a dialkylamine (R and R’ are independently selected alkyl).

The term “phosphine oxide” refers to a -P(=O)RR’ radical, where R and R’ are independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aralkyl heteroaralkyl, heterocyclylalkyl, or cycloalkylalkyl.

As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms

(e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring systems) (e.g., , a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: ^{H 5} Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and/or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION

This disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, that restore p53 function. These compounds are useful, e.g., for treating a disease in which decreased p53 function contributes to the pathology and/or symptoms and/or progression of the disease (e.g., cancer) in a subject (e.g., a human).

Formulae (I) Compounds

Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is CR ¹ or N;

R ¹ is hydrogen, halogen, cyano, -OR ⁴ , -NR ⁴ R ⁵ , -C(=O)R ⁴ , -OC(=O)R ⁴ , -C(=O)OR ⁴ , C(=O)NR ⁴ R ⁵ , -SR ⁴ , S(=O)R ⁴ , -S(O ₂ )R ⁴ , -NR ⁴ C(=O)R ⁵ , -R ⁴ C(-O)R ⁵ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4- 12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; each of X ² , X ³ , X ⁴ , and X’ are CH, N, CR ² or CR ³ , wherein two or more of X ² , X ³ , X ⁴ , and X ⁵ are independently CH, CR ² , or CR ³ ; each of Y ¹ , Y ² , and Y ³ are C or N, wherein one of Y ¹ , Y ² , and Y ³ is N;

R ^A is hydrogen, -OR ⁶ , -NR ⁶ R ⁷ , -C(=O)R ⁶ , -R ⁶ C(=O)R ⁷ , -OC(=O)R ⁶ , -OC(=O)NR ⁶ , -C(=O)OR ⁶ , -NR ⁶ C(=O)OR ⁷ , -C(=O)NR ⁶ R ⁷ , -SR ⁶ , -S(=O)R ⁶ , -S(O ₂ )R ⁶ , -S(O ₂ )NR ⁶ , -NR ⁶ S(O ₂ )R ⁷ , -NR ⁶ C(=O)R ⁷ , -NR ⁶ C(=O)NR ⁷ , -SiR ⁶ R ⁷ R ⁸ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl;

R ^B is halogen, cyano, hydroxyl, -NR ⁸ R ⁹ , -OR ⁸ , -C(=O)NR ⁸ R ⁹ , -C(=O)R ⁸ , -C(=O)OR ⁸ , -NR ⁸ C(=O)OR ⁹ , -OC(=O)R ⁸ , -OC(=O)NR ⁸ , -C(=O)NR ⁸ R ⁹ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ C(=O)NR ⁹ , -SR ⁸ , -S(=O)R ⁸ , -S(O ₂ )R ⁸ , -S(O ₂ )NR ⁸ , -NR ⁸ S(O ₂ )R ⁹ , -R ⁸ C(=O)R ⁹ , -NR ⁸ C(=O)R ⁹ , -NR ⁸ C(=O)NR ⁹ , optionally substituted C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 3-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl; c R ^2A

^-Z ¹ -Z ² '

, , . ^X _R 2B each R is ; Z ¹ is a bond, -C=O-, -S(O2)-optionally substituted C1-C6 alkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 alkynylene, or an optionally substituted C3-C4 cycloalkylene; Z ² is CR ^2C , N, O, or a bond; wherein when Z ² is O, R ^2B is absent, and when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to Formula (I) via Z ¹ ; R ^2A and R ^2B are independently hydrogen, –C(=O)R ¹⁰ , –C(=O)OR ¹⁰ , –C(=O)NR ¹⁰ R ¹¹ , –S(=O)R ¹⁰ , –S(O2)R ¹⁰ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; or R ^2A and R ^2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl; or Z ² is O and R ^2B is absent; R ^2C is hydrogen, halogen, or C1-C6 alkyl; each R ³ is independently halogen, cyano, –NR ¹² R ¹³ , -OR ¹² , –C(=O)NR ¹² R ¹³ , –C(=O)R ¹² , -C(=O)OR ¹² , –OC(=O)R ¹² , –NR ¹² (C=O)NR ¹³ R ¹⁴ , –SR ¹² , –S(=O)R ¹² , –S(O2)R ¹² , –S(O2)NR ¹² R ¹³ , –NR ¹² S(O2)NR ¹³ R ¹⁴ , -R ¹² C(=O)R ¹³ , -NR ¹² C(=O)R ¹³ , optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl; L is an optionally substituted 4-6 membered heterocyclylene or an optionally substituted 5-6 membered heteroarylene; m is 0, 1, or 2; and each R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, one of X ² , X ³ , X ⁴ , and X ⁵ is N.

In some embodiments, two of X ² , X ³ , X ⁴ , and X ⁵ are N.

In some embodiments, X ¹ is CR ¹ .

In some embodiments, R ¹ is hydrogen.

In some embodiments, R ¹ is halogen.

In some embodiments, R ¹ is cyano.

In some embodiments, R ¹ is -OR ⁴ .

In some embodiments, R ¹ is -NR ⁴ R ⁵ .

In some embodiments, R ¹ is -C(=O)R ⁴ .

In some embodiments, R ¹ is -OC(=O)R ⁴ .

In some embodiments, R ¹ is -C(=O)OR ⁴ .

In some embodiments, R ¹ is -C(=O)NR ⁴ R ⁵ .

In some embodiments, R ¹ is -SR ⁴ .

In some embodiments, R ¹ is -S(=O)R ⁴ .

In some embodiments, R ¹ is -S(O2)R ⁴ .

In some embodiments, R ¹ is -NR ⁴ C(=O)R ³ . In some embodiments, R ¹ is -R ⁴ C( ^::: OHV.

In some embodiments, R ⁴ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁴ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ⁴ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁴ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁴ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ⁴ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, R ⁵ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁵ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R’ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁵ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁵ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ⁵ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, when R ⁴ and R ³ are attached to the same nitrogen atom, R ⁴ and R ⁵ are the same. In some embodiments, when R ⁴ and R ⁵ are attached to the same nitrogen atom, R ⁴ and R ⁵ are different. In some embodiments, when R ⁴ and R ³ are attached to the same nitrogen atom, R ⁴ and R ⁵ are each hydrogen. In some embodiments, when R ⁴ and R ³ are attached to the same nitrogen atom, R ⁴ and R ⁵ are each an independently selected C1-C6 alkyl.

In some embodiments, when R ⁴ and R ⁵ are attached to the same nitrogen atom, one of R ⁴ and R ⁵ is hydrogen and the other of R ⁴ and R ⁵ is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ⁴ and R ⁵ are attached to the same nitrogen atom, one of R ⁴ and R ³ is hydrogen and the other of R ⁴ and R ⁵ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ¹ is optionally substituted C1-C6 alkyl. In some embodiments, R ¹ is C1-C6 alkyl. In some embodiments, R ^x is methyl or ethyl.

In some embodiments, R ¹ is optionally substituted C2-C6 alkenyl. In some embodiments, R ¹ is C2-C6 alkenyl. In some embodiments, R ^x is optionally substituted C2-C3 alkenyl. In some embodiments, R ^x is C2-C3 alkenyl.

In some embodiments, R ¹ is optionally substituted C2-C6 alkynyl. In some embodiments, R ¹ is C2-C6 alkynyl. In some embodiments, R ⁴ is optionally substituted C2-C3 alkynyl. In some embodiments, R ^x is C2-C3 alkynyl.

In some embodiments, R ¹ is optionally substituted C3-C6 cycloalkyl. In some embodiments, R ^x is C3-C6 cycloalkyl.

In some embodiments, R ¹ is optionally substituted phenyl. In some embodiments, R ¹ is phenyl.

In some embodiments, R ¹ is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R ¹ is 4-6 membered heterocyclyl.

In some embodiments, R ¹ is optionally substituted 5-6 membered heteroaryl. In some embodiments, R ¹ is 5-6 membered heteroaryl.

In some embodiments, X ¹ is N. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

U), or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

ADa), and (I-AEa), or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

AA1), or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

AA2), or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

acceptable salt of any of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

AA21), (I-AC21), (I-AE21), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a

S-— . pharmaceutically acceptable salt thereof, is " ^CF3 (I-V21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

^CF 3 (I-W21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-X21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

(I-Y21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-Z21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (I-AA21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

(I-AC21). In some embodiments, the compound of Formula (I), or a

R ² R ¹ pharmaceutically acceptable salt thereof, is (I-AD21). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

of the foregoing.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

AA5), or a pharmaceutically acceptable salt of any of the foregoing, wherein R ^2B is hydrogen or an optionally substituted C1-C6 alkyl.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

AA6), or a pharmaceutically acceptable salt of any of the foregoing, wherein R ^2B is hydrogen or an optionally substituted C1-C6 alkyl.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

AA7), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

(I-AA8),

(I-AC8), pharmaceutically acceptable salt of any of the foregoing, wherein R ^2B is hydrogen or an optionally substituted C1-C6 alkyl. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

(I-W9),

(I-Y9),

(I-AA9),

(I-AC9), or a pharmaceutically acceptable salt of any of the foregoing, wherein R ^2B is hydrogen or an optionally substituted C1-C6 alkyl.

In some embodiments, R ^A is hydrogen.

In some embodiments, R ^A is -OR ⁶ .

In some embodiments, R ^A is -NR ⁶ R ⁷ . In some embodiments, R ^A is -C(=O)R ⁶ .

In some embodiments, R ^A is -R ⁶ C(=O)R ⁷ .

In some embodiments, R ^A is -OC(=O)R ⁶ .

In some embodiments, R ^A is -OC(=O)NR ⁶ .

In some embodiments, R ^A is -C(=O)OR ⁶ .

In some embodiments, R ^A is -NR ⁶ C(=O)OR ⁷ .

In some embodiments, R ^A is -C(=O)NR ⁶ R ⁷ .

In some embodiments, R ^A is -SR ⁶ .

In some embodiments, R ^A is -S(=O)R ⁶ .

In some embodiments, R ^A is -S(O2)R ⁶ .

In some embodiments, R ^A is -S(O2)NR ⁶

In some embodiments, R ^A is -NR ⁶ S(O2)R ⁷ .

In some embodiments, R ^A is -NR ⁶ C(=O)R ⁷ .

In some embodiments, R ^A is -NR ⁶ C(=O)NR ⁷ .

In some embodiments, R ^A is -SiR ⁶ R ⁷ R ⁸ .

In some embodiments, R ⁶ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁶ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ⁶ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁶ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁶ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ⁶ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R ⁷ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁷ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ⁷ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁷ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁷ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ⁷ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are the same. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are different. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are each hydrogen. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, R ⁶ and R ⁷ are each an independently selected C1-C6 alkyl.

In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, one of R ⁶ and R ⁷ is hydrogen and the other of R ⁶ and R ⁷ is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, one of R ⁶ and R ⁷ is hydrogen and the other of R ⁶ and R ⁷ is optionally substituted phenyl or optionally substituted 5-10 membered heteroaryl. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, one of R ⁶ and R ⁷ is hydrogen and the other of R ⁶ and R ⁷ is substituted phenyl or optionally 5-10 membered heteroaryl. In some embodiments, when R ⁶ and R ⁷ are attached to the same nitrogen atom, one of R ⁶ and R ⁷ is hydrogen and the other of R ⁶ and R ⁷ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R ⁸ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, R ^A is optionally substituted C1-C6 alkyl. In some embodiments, R ^A is C1-C6 alkyl. In some embodiments, R ^A is methyl, ethyl, or n-propyl.

In some embodiments, R ^A is C1-C6 haloalkyl. In some embodiments, R ^A is C1-C3 haloalkyl. In some embodiments, R ^A is trifluoromethyl.

In some embodiments, R ^A is optionally substituted C2-C6 alkenyl. In some embodiments, R ^A is C2-C6 alkenyl. In some embodiments, R ^A is optionally substituted C2-C3 alkenyl. In some embodiments, R ^A is C2-C3 alkenyl.

In some embodiments, R ^A is optionally substituted C2-C6 alkynyl. In some embodiments, R ^A is C2-C6 alkynyl. In some embodiments, R ^A is optionally substituted C2-C3 alkynyl. In some embodiments, R ^A is C2-C3 alkynyl.

In some embodiments, R ^A is optionally substituted C3-C10 cycloalkyl. In some embodiments, R ^A is optionally substituted C3-C6 cycloalkyl. In some embodiments, R ^A is C3- C10 cycloalkyl. In some embodiments, R ^A is C3-C6 cycloalkyl. In some embodiments, R ^A is optionally substituted phenyl. In some embodiments, R ^A is phenyl.

In some embodiments, R ^A is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ^A is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R ^A is 3-12 membered heterocyclyl. In some embodiments, R ^A is 4-8 membered heterocyclyl.

In some embodiments, R ^A is optionally substituted 5-10 membered heteroaryl. In some embodiments, R ^A is optionally substituted 5-6 membered heteroaryl. In some embodiments, R ^A is 5-10 membered heteroaryl. In some embodiments, R ^A is 5-6 membered heteroaryl. In some embodiments, R ^A is an optionally substituted 9-10 membered heteroaryl. In some embodiments, R ^A is a 9-10 membered heteroaryl.

In some embodiments, R ^A is phenyl optionally substituted with 1-3 independently selected R ^Ai . In some embodiments, R ^A is pyridinyl, pyrimidinyl, pyridizinyl, orpyrazinyl, each optionally substituted with 1-3 independently selected R ^A2 . In some embodiments, R ^A is a 9 membered heteroaryl optionally substituted with 1-3 independently selected R ^A3 .

In some embodiments, each R ^A1 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphoxide, and C-carboxy.

In some embodiments, each R ^A2 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.

In some embodiments, each R ^A3 is independently selected from halogen, cyano, amino, hydroxyl, sulfhydryl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, 4-5 membered heterocyclyloxy, C-amido, S-sulfonamido, sulfenyl, sulfonyl, sulfinyl, sulfoximine, sulfonimidamindo, phosphine oxide, and C-carboxy.

In some embodiments, each R ^A1 , R ^A2 and R ^A3 is independently selected from halogen, cyano, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkyl, (hydroxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3 alkoxy, (C1-C3 alkoxy)Cl-C3amino, 4-5 membered heterocyclyloxy, -C(=O)NRR’, -CO2H, -SO ₂ (C1-C3 alkyl), -S(=O)C1-C3 alkyl, -SO2NRR’, - S(=O)(=NR)NRR’, or -P(=O)(C1-C3 alkyl)2, wherein each R and R’ are independently hydrogen or Cl -C 3 alkyl.

In some embodiments, each R ^A1 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, 4-5 membered heterocyclyloxy, -SCh(Cl-C3 alkyl), -SO2NRR’, or -P(=O)(C1-C3 alkyl)2, wherein R and R’ are independently hydrogen or C1-C3 alkyl.

39 , , , , .or . In some embodiments, R ^A is , , , , , , , , , , , , , , , , , , , , , , , ,

In some embodiments, R ^A is In some embodiments, R ^A is ° , ° , ⁰ , ⁰ o o o o o o o o o o o o o O O O O o or o n some embodiments, R ^B is halogen. In some embodiments, R ^B is fluoro or chloro.

In some embodiments, R ^B is cyano.

In some embodiments, R ^B is hydroxyl. In some embodiments, R ^B is -NR ⁸ R ⁹ .

In some embodiments, R ^B is -OR ⁸ .

In some embodiments, R ^B is -C(=O)NR ⁸ R ⁹ .

In some embodiments, R ^B is -C(=O)R ⁸ .

In some embodiments, R ^B is -C(=O)OR ⁸ . In some embodiments, R ^B is -NR ⁸ C(=O)OR ⁹

In some embodiments, R ^B is -OC(=O)R ⁸ .

In some embodiments, R ^B is -OC(=O)NR ⁸ .

In some embodiments, R ^B is -C(=O)NR ⁸ R ⁹ . In some embodiments, R ^B is -NR ⁸ C(=O)R ⁹ .

In some embodiments, R ^B is -NR ⁸ C(=O)NR ⁹ .

In some embodiments, R ^B is -SR ⁸ .

In some embodiments, R ^B is -S(=O)R ⁸ .

In some embodiments, R ^B is -S(O2)R ⁸ .

In some embodiments, R ^B is -S(O2)NR ⁸ .

In some embodiments, R ^B is -NR ⁸ S(Ch)R ⁹ .

In some embodiments, R ^B is -R ⁸ C( ^:::; O)R ⁹ .

In some embodiments, R ^B is -NR ⁸ C(=O)R ⁹ .

In some embodiments, R ^B is -NR ⁸ C(=O)NR ⁹ .

In some embodiments, R ⁸ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁸ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 8-12 membered heterocyclyl. In some embodiments, R ⁸ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, R ⁹ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ⁹ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ⁹ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ⁹ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ⁹ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ⁹ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are the same. In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are different. In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are each hydrogen. In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, R ⁸ and R ⁹ are each an independently selected C1-C6 alkyl.

In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, one of R ⁸ and R ⁹ is hydrogen and the other of R ⁸ and R ⁹ is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ⁸ and R ⁹ are attached to the same nitrogen atom, one of R ⁸ and R ⁹ is hydrogen and the other of R ⁸ and R ⁹ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ^B is optionally substituted C1-C6 alkyl. In some embodiments, R ^B is C1-C6 alkyl. In some embodiments, R ^B is methyl, ethyl, or n-propyl.

In some embodiments, R ^B is C1-C6 haloalkyl. In some embodiments, R ^B is C1-C3 haloalkyl. In some embodiments, R ^B is a C1-C3 fluoroalkyl. In some embodiments, R ^B is trifluoromethyl or 2,2,2-trifluoroethyl. In some embodiments, R ^B is 2,2,2-trifluoroethyl.

In some embodiments, R ^B is optionally substituted C2-C6 alkenyl. In some embodiments, R ^B is C2-C6 alkenyl. In some embodiments, R ^B is optionally substituted C2-C3 alkenyl. In some embodiments, R ^B is C2-C3 alkenyl. In some embodiments, R ^B is optionally substituted C2-C6 alkynyl. In some embodiments, R ^B is C2-C6 alkynyl. In some embodiments, R ^B is optionally substituted C2-C3 alkynyl. In some embodiments, R ^B is C2-C3 alkynyl.

In some embodiments, R ^B is optionally substituted C3-C10 cycloalkyl. In some embodiments, R ^B is optionally substituted C3-C6 cycloalkyl. In some embodiments, R ^B is C3- C10 cycloalkyl. In some embodiments, R ^B is C3-C6 cycloalkyl.

In some embodiments, R ^B is optionally substituted phenyl. In some embodiments, R ^B is phenyl.

In some embodiments, R ^B is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ^B is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R ^B is 3-12 membered heterocyclyl. In some embodiments, R ^B is 4-8 membered heterocyclyl.

In some embodiments, R ^B is optionally substituted 5-10 membered heteroaryl. In some embodiments, R ^B is optionally substituted 5-6 membered heteroaryl. In some embodiments, R ^B is 5-10 membered heteroaryl. In some embodiments, R ^B is 5-6 membered heteroaryl.

In some embodiments, R ^B is methyl, ethyl, or n-propyl.

F F

-|-O— ( -|-O— ^-F

In some embodiments, R ^B is hydroxyl, ^F , or ^F .

In some embodiments, R ^B is or . In some embodiments, R ^B is ,

In some embodiments, R ^B is ^CF3 , . In some embodiments, R ^B is ^CFs , f o p

X CF ₃ X , or

In some embodiments, R ^B is In some embodiments, R ^B is

_T R ^2A

|-Z ¹ -Z ² '

7 •

In some embodiments, each R is ^X R ^2B .

In some embodiments, one of X ² , X ³ , X ⁴ , and X ⁵ is CR ² and the remaining X ² , X ³ , X ⁴ , and X ⁵ are CH, N, or CR ³ .

In some embodiments, Z ¹ is a bond.

In some embodiments, Z ¹ is -C=O-.

In some embodiments, Z ¹ is -S(O2)-.

In some embodiments, Z ¹ is optionally substituted C1-C6 alkylene. In some embodiments, Z ¹ is optionally substituted C1-C3 alkylene. In some embodiments, Z ¹ is C1-C6 alkylene. In some embodiments, Z ¹ is C1-C3 alkylene. In some embodiments, Z ¹ is methylene or ethylene.

In some embodiments, Z ¹ is optionally substituted C2-C6 alkenylene. In some embodiments, Z ¹ is optionally substituted C2-C3 alkenylene. In some embodiments, Z ¹ is C2-C6 alkenylene. In some embodiments, Z ¹ is C2-C3 alkenylene.

In some embodiments, Z ¹ is optionally substituted C2-C6 alkynylene. In some embodiments, Z ¹ is optionally substituted C2-C3 alkynylene. In some embodiments, Z ¹ is C2-C6 alkynylene. In some embodiments, Z ¹ is C2-C3 alkynylene.

In some embodiments, Z ¹ is an optionally substituted C3-C4 cycloalkylene. In some embodiments, Z ¹ is C3-C4 cycloalkylene.

In some embodiments, Z ² is N.

In some embodiments, Z ² is O and R ^2B is absent.

In some embodiments, Z ² is a bond.

In some embodiments, Z ² is CR ^2C .

In some embodiments, R ^2C is hydrogen. In some embodiments, R ^2C is halogen. In some embodiments, R ^2C is fluoro or chloro.

In some embodiments, R ^2C is C1-C6 alkyl. In some embodiments, R ^2C is C1-C3 alkyl. In some embodiments, R ^2C is methyl.

In some embodiments, when Z ¹ is a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to Formula (I) via Z ¹ . In some embodiments, when Z ² is a bond, R ^2B is absent and R ^2A is directly connected to Z ¹ . In some embodiments, Z ² is O and R ^2B is absent.

In some embodiments, R ² is -NR ^2A R ^2B , i.e., Z ¹ is a bond and Z ² is N. In some embodiments, R ² is R ^2B , i.e., Z ¹ and Z ² are both a bond, R ^2A is absent and R ^2B is directly connected to Formula (I) via Z ¹ .

In some embodiments, when Z ¹ is a not a bond and Z ² is a bond, R ^2B is absent and R ^2A is directly connected to Z ¹ .

In some embodiments, R ^2A is hydrogen.

In some embodiments, R ^2A is -C(=O)R ¹⁰ .

In some embodiments, R ^2A is -C(=O)OR ¹⁰ .

In some embodiments, R ^2A is -C(=O)NR ¹⁰ R ⁿ .

In some embodiments, R ^2A is -S(=O)R ¹⁰ .

In some embodiments, R ^2A is -S(O2)R ¹⁰ .

In some embodiments, R ¹⁰ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ¹⁰ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ¹⁰ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ¹⁰ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R ¹⁰ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-8 membered heterocyclyl. In some embodiments, R ¹⁰ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.

In some embodiments, R ¹¹ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ¹¹ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ^u is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ¹¹ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ¹¹ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ¹¹ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are the same. In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are different. In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ¹¹ are each hydrogen. In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, R ¹⁰ and R ⁿ are each an independently selected C1-C6 alkyl.

In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, one of R ¹⁰ and R ¹¹ is hydrogen and the other of R ¹⁰ and R ¹¹ is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ¹⁰ and R ¹¹ are attached to the same nitrogen atom, one of R ¹⁰ and R ¹¹ is hydrogen and the other of R ¹⁰ and R ¹¹ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-10 membered heteroaryl. In some embodiments, R ^2A is optionally substituted C1-C6 alkyl. In some embodiments, R ^2A is C1-C6 alkyl. In some embodiments, R ^2A is methyl or ethyl.

In some embodiments, R ^2A is C1-C6 haloalkyl. In some embodiments, R ^2A is C1-C3 haloalkyl. In some embodiments, R ^2A is trifluoromethyl.

In some embodiments, R ^2A is optionally substituted C2-C6 alkenyl. In some embodiments, R ^2A is C2-C6 alkenyl. In some embodiments, R ^2A is optionally substituted C2-C3 alkenyl. In some embodiments, R ^2A is C2-C3 alkenyl.

In some embodiments, R ^2A is optionally substituted C2-C6 alkynyl. In some embodiments, R ^2A is C2-C6 alkynyl. In some embodiments, R ^2A is optionally substituted C2-C3 alkynyl. In some embodiments, R ^2A is C2-C3 alkynyl.

In some embodiments, R ^2A is optionally substituted C3-C10 cycloalkyl. In some embodiments, R ^2A is optionally substituted C3-C6 cycloalkyl. In some embodiments, R ^2A is C3- C10 cycloalkyl. In some embodiments, R ^2A is C3-C6 cycloalkyl.

In some embodiments, R ^2A is optionally substituted phenyl. In some embodiments, R ^2A is phenyl.

In some embodiments, R ^2A is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ^2A is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R ^2A is 3-12 membered heterocyclyl. In some embodiments, R ^2A is 4-8 membered heterocyclyl.

In some embodiments, R ^2A is optionally substituted 5-10 membered heteroaryl. In some embodiments, R ^2A is optionally substituted 5-6 membered heteroaryl. In some embodiments, R ^2A is 5-10 membered heteroaryl. In some embodiments, R ^2A is 5-6 membered heteroaryl.

In some embodiments, R ^2B is hydrogen.

In some embodiments, R ^2B is -C(=O)R ¹⁰ .

In some embodiments, R ^2B is -C(=O)OR ¹⁰ .

In some embodiments, R ^2B is -C(=O)NR ¹⁰ R ¹¹ .

In some embodiments, R ^2B is -S(=O)R ¹⁰ .

In some embodiments, R ^2B is -S(O2)R ¹⁰ .

In some embodiments, R ^2B is optionally substituted C1-C6 alkyl. In some embodiments, R ^2B is C1-C6 alkyl. In some embodiments, R ^2B is methyl or ethyl.

In some embodiments, R ^2B is C1-C6 haloalkyl. In some embodiments, R ^2B is C1-C3 haloalkyl. In some embodiments, R ^2B is trifluoromethyl. In some embodiments, R ^2B is optionally substituted C2-C6 alkenyl. In some embodiments, R ^2B is C2-C6 alkenyl. In some embodiments, R ^2B is optionally substituted C2-C3 alkenyl. In some embodiments, R ^2B is C2-C3 alkenyl.

In some embodiments, R ^2B is optionally substituted C2-C6 alkynyl. In some embodiments, R ^2B is C2-C6 alkynyl. In some embodiments, R ^2B is optionally substituted C2-C3 alkynyl. In some embodiments, R ^2B is C2-C3 alkynyl.

In some embodiments, R ^2B is optionally substituted C3-C10 cycloalkyl. In some embodiments, R ^2B is optionally substituted C3-C6 cycloalkyl. In some embodiments, R ^2B is C3- C10 cycloalkyl. In some embodiments, R ^2B is C3-C6 cycloalkyl.

In some embodiments, R ^2B is optionally substituted phenyl. In some embodiments, R ^2B is phenyl.

In some embodiments, R ^2B is optionally substituted 3-12 membered heterocyclyl. In some embodiments, R ^2B is optionally substituted 4-8 membered heterocyclyl. In some embodiments, R ^2B is 3-12 membered heterocyclyl. In some embodiments, R ^2B is 4-8 membered heterocyclyl.

In some embodiments, R ^2B is optionally substituted 5-10 membered heteroaryl. In some embodiments, R ^2B is optionally substituted 5-6 membered heteroaryl. In some embodiments, R ^2B is 5-10 membered heteroaryl. In some embodiments, R ^2B is 5-6 membered heteroaryl.

In some embodiments, R ^2B is -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)NR ¹⁰ R ^u , -S(=O)R ¹⁰ , -S(C>2)R ¹⁰ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl; and R ^2B is hydrogen.

In some embodiments, one of R ^2A and R ^2B is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl, and the other of R ^2A and R ^2B is hydrogen, -C(=O)R ¹⁰ , -C(=O)OR ¹⁰ , -C(=O)NR ¹⁰ R ⁿ , -S(=O)R ¹⁰ , -S(O2)R ¹⁰ , optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl.

In some embodiments, one of R ^2A and R ^2B is hydrogen and the other of R ^2A and R ^2B is an optionally substituted 4-12 membered heterocyclyl or an optionally substituted 5-6 membered heteroaryl. In some embodiments, one of R ^2A and R ^2B is hydrogen and the other of R ^2A and R ^2B is an optionally substituted 4-12 membered heterocyclyl. In some embodiments, one of R ^2A and R ^2B is hydrogen and the other of R ^2A and R ^2B is a substituted 4-12 membered heterocyclyl.

In some embodiments, R ^2A and R ^2B together with the atom to which they are attached together form an optionally substituted 4-10 membered cycloalkyl, an optionally substituted phenyl, an optionally substituted 5-10 membered heteroaryl, or an optionally substituted 4-12 membered heterocyclyl.

R ^2A

In some embodiments, R ² is or ^CF ’ , i.e., Z ¹ is optionally

R2A

R2A

^N -R2B substituted alkylene and Z ² is N. In some embodiments, R ² is

R ^2A R ^2A R ^{2A N} 'R ^2B _V <R R ^{2B N} 'R ^{2B 2B} /y ^R

F CF ₃ , or ^CF NH 3 . In some embodiments, R ² is ^NHz , or

H N.

R _2B

, i.e., Z ¹ is optionally substituted alkylene, Z ² is a bond, and R ^2A is absent. In some

>O ^R2B </ ^R2B ^ ^R2B /^ ^R2B

NH embodiments, R ² is ^NHz , ^RH 2 , / ^NH , x R ^2B , or R ^2B O In some embodiments, R ^2A is hydrogen.

F F

OH

In some embodiments, R ^2B is , or . In some

OH

OH embodiments, R ^2B is , or ' F. F. F. F,

10 In some embodiments, R ^2B is

10

10

10 I

In some embodiments, R ² as defined herein, comprises an a, P-unsaturated system or an electrophilic group.

In some embodiments, X ³ is CR ² and R ² as defined herein comprises an a, 0-unsaturated system or an electrophilic group, as described herein.

In some embodiments, one of X ² , X ³ , X ⁴ , and X ⁵ is CR ² , one of X ² , X ³ , X ⁴ , and X ⁵ is CR ³ , and the remaining X ² , X ³ , X ⁴ , and X ⁵ are CH or N.

In some embodiments, one of X ² , X ³ , X ⁴ , and X ⁵ is CR ² , one of X ² , X ³ , X ⁴ , and X ⁵ is CR ³ , and the remaining X ² , X ³ , X ⁴ , and X ³ are CH. In some embodiments, R ³ is halogen. In some embodiments, R ³ is fluoro. In some embodiments, R ³ is chloro.

In some embodiments, R ³ is cyano.

In some embodiments, R ³ is -NR ¹² R ¹³ .

In some embodiments, R ³ is -OR ¹² .

In some embodiments, R ³ is -C(=O)NR ¹² R ¹³ .

In some embodiments, R ³ is -C(=O)R ¹² .

In some embodiments, R ³ is -C(=O)OR ¹² .

In some embodiments, R ³ is -OC(=O)R ¹² .

In some embodiments, R ³ is NR ¹² (C=O)NR ¹² R ¹³ .

In some embodiments, R ³ is -SR ¹² .

In some embodiments, R ³ is -S(=O)R ¹² .

In some embodiments, R ³ is -S(O2)R ¹² .

In some embodiments, R ³ is -S(O2)NR ¹² R ¹³ .

In some embodiments, R ³ is -NR ¹² S(O2)NR ¹³ R ¹⁴ .

In some embodiments, R ³ is -R ^!2 C(=O)R ¹³ .

In some embodiments, R ³ is -NR ¹² C(=O)R ¹³ .

In some embodiments, R ¹² is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ¹² is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ¹² is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ¹² is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R ¹² is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ¹² is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, R ¹³ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ^lj is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ¹³ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ¹³ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl.

In some embodiments, R ¹³ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ¹³ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, R ¹⁴ is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, R ¹⁴ is hydrogen, optionally substituted C1-C3 alkyl, optionally substituted C2-C3 alkenyl, optionally substituted C2-C3 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-8 membered heterocyclyl, or optionally substituted 5-6 membered heteroaryl.

In some embodiments, R ¹⁴ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ¹⁴ is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3- C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, or 5-6 membered heteroaryl. In some embodiments, R ¹⁴ is hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, or 4-12 membered heterocyclyl. In some embodiments, R ¹⁴ is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or 4-8 membered heterocyclyl.

In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are the same. In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are different. In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are each hydrogen. In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, R ¹² and R ¹³ are each an independently selected C1-C6 alkyl.

In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, one of R ¹² and R ¹³ is hydrogen and the other of R ¹² and R ¹³ is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ¹² and R ¹³ are attached to the same nitrogen atom, one of R ¹² and R ¹³ is hydrogen and the other of R ¹² andR ¹³ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are the same. In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are different. In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are each hydrogen. In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, R ¹³ and R ¹⁴ are each an independently selected C1-C6 alkyl.

In some embodiments, when R ¹³ and R ¹⁴ are attached to the same nitrogen atom, one of R ¹³ and R ¹⁴ is hydrogen and the other of R ¹³ and R ¹⁴ is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted phenyl, optionally substituted 4-12 membered heterocyclyl, or optionally substituted 5-10 membered heteroaryl.

In some embodiments, when R ^lj and R ¹⁴ are attached to the same nitrogen atom, one of R ¹³ and R ¹⁴ is hydrogen and the other of R ¹³ andR ¹⁴ is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, phenyl, 4-12 membered heterocyclyl, or 5-10 membered heteroaryl.

In some embodiments, R ³ is optionally substituted C1-C6 alkyl. In some embodiments, R ³ is C1-C6 alkyl. In some embodiments, R ³ is methyl or ethyl. In some embodiments, R ³ is optionally substituted C2-C6 alkenyl. In some embodiments, R ³ is C2-C6 alkenyl. In some embodiments, R ³ is optionally substituted C2-C3 alkenyl. In some embodiments, R ³ is C2-C3 alkenyl.

In some embodiments, R ³ is optionally substituted C2-C6 alkynyl. In some embodiments, R ³ is C2-C6 alkynyl. In some embodiments, R ³ is optionally substituted C2-C3 alkynyl. In some embodiments, R ³ is C2-C3 alkynyl.

In some embodiments, R ³ is optionally substituted C3-C6 cycloalkyl. In some embodiments, R ³ is C3-C6 cycloalkyl.

In some embodiments, R ³ is optionally substituted phenyl. In some embodiments, R ³ is phenyl.

In some embodiments, R ³ is optionally substituted 4-6 membered heterocyclyl. In some embodiments, R ³ is 4-6 membered heterocyclyl.

In some embodiments, R ³ is optionally substituted 5-6 membered heteroaryl. In some embodiments, R ³ is 5-6 membered heteroaryl.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

In some embodiments, L is an optionally substituted 5-6 membered heteroarylene. In some embodiments, L is a 5-6 membered heteroarylene. In some embodiments, L is a substituted 6 membered heteroarylene. In some embodiments, L is a 5 membered heteroarylene. In some embodiments, L is a 2,5-(l,3,4-oxadiazolyl)ene, a 2,5-(l,3,4-thiadiazolyl)ene, or a 3,5-(l,2,4- oxadiazolyl)ene. In some embodiments, L is

N- ^N

, wherein each represents a bond to either the cabon of the 5 -membered ring of

Formula (I) or the CH2 or R ^A of Formula (I).

In some embodiments, L is an optionally substituted 4-6 membered heterocyclylene. In some embodiments, L is a 4-6 membered heterocyclylene. In some embodiments, L is a 4 membered heterocyclylene.

Non-Limiting Exemplary Compounds

In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table 1, or a pharmaceutically acceptable salt thereof. w Table 1

Example

Structure

No.

1

X X ..-J /\

X . ' —A

XT A -

2 f . / 1

X _: . ' ^s x ^z N- ^: ”’ X ..A X X', /

r r" T

< / \ * / y

* > - ; y

■ J

HA ⁷ Q €i > x iv

/ f X

\ K ^

■ ^; ‘!

Z . L

Z J / Z 7 f I > L J

J X X

\ Y . _ xM J

'if

^F 6 x/ X f^YW V .= ^; X 1 ^.X _x xx j? X. -

F- _ /

/ \

I - yj ^ — X X X

J 1

1 1 r w u/

J x A/ J X ^X ' -- ^X

K, _fl r : r : v> _- / v i ’C \

X X/ N. // \ K-- ,-1 H X ! \

, ^s I ' t--^/ ^(>

\ rK ,/x x xx ^X N ^X

J

X x X,, s o .

¹ : i ;i< A : ■ /

-x >- x.^x /Z'-^z' ^K N V \ \ r r w ii " u 'z ^x x N. 'x /;/ \ O'- _N

$

/ f ^/ 1

X r rw 1 r\ .

X/M s 11 \

F->_ "x /

^F K ^S-- Xr , ^x z

'X-'■’ i ti " \ -i r \ \

X-x ' W ^::: -\ .„ ^M _X \

It f F \ / ^K / 'X--

\

^F K /V

HN^ ^x - ^X

L hj // \ J H / \

V ^: ""\ -'■ ^{1 N} —./ r f V -'- \

Z<v•N-- J V. / K■ "0 b

L %..- L ^; P r--^ K'- AX. _H n /-X (-.

/xj" J ^v

L J J . U. _A ri.„

1 "" r ^%/ S

,-y x J N- f f \ . / '?

L X / \ -i « i ''

X'" z\ ^ ^,u

In some embodiments, the compound is selected from the group consisting of the compounds delineated in List 1, or a pharmaceutically acceptable salt thereof.

List 1

N-((3-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyridin-2 -yl)- l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-o xadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazo l-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-o xadiazol-5-yl)methyl)-lH- pyrazole-4-carb oxami de; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)meth yl)-lH-pyrrole-3-carboxamide; 1- (tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4 -yl)amino)-3-vinylimidazo[l,2- a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-c arboxamide; l-(tert-butyl)-N-((3- (8-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-vinylimidazo[ 1 ,2-a]pyri din-2 -yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2- yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazo l-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2- yl)- 1 ,3 ,4-thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(8-(((3 S,4R)-3 -fluoro- 1 - methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyridin-2-y l)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl )amino)-3 -viny 1 pyrazol o[ 1 , 5 -a]pyri din-2-yl )- 1 , 3 ,4-thi adi azol -2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol-2-yl)-l,3,4-t hiadiazol-2-yl)methyl)-lH- pyrazol e-4-carb oxami de; 1 -(tert-butyl)-N-((5 -(7-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,3,4-thiadiazol-2-yl)met hyl)-lH-pyrrole-3-carboxamide; 1- (tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4 -yl)amino)-3-vinylimidazo[l,2- a]pyridin-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((5- (8-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-vinylimidazo[ 1 ,2-a]pyri din-2 -yl)- 1,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2- yl)-l,3,4-thiadiazol-2-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-vinylpyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiaz ol-2-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)a mino)-3-vinyl-2H- indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarbox amide; N-((3-(8-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-3 -vinylimidazof 1 ,2-a]pyrazin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3 -fluoro- 1-methylpiperi din-4- yl)amino)-3 -vinylpyrazolof 1 ,5 -a]pyrazin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3 S,4R)-3-fluoro- 1-methylpiperi din-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)meth yl)-l-(tert-butyl)-lH-pyrazole-4- carboxamide; N-((3-(5-amino-7-(((3 S,4R)-3-fluoro- 1-methylpiperi din-4-yl)amino)-3-vinyl-2H- indazol-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- 1 -(tert-butyl)- lH-pyrrole-3 -carboxamide; 1 -(tert- butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)am ino)-3-vinylimidazo[l,2-a]pyrazin- 2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide ; l-(tert-butyl)-N-((3-(8- (((3 S,4R)-3-fluoro- 1-methylpiperi din-4-yl)amino)-3 -vinylimidazof l,2-a]pyrazin-2-yl)- 1,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2- yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,2,4-oxadiazo l-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)a mino)-3-vinyl-2H- indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)cyclopropanecarbo xamide; N-((5-(8-(((3S,4R)-3- fluoro- 1-methylpiperi din-4-yl)amino)-3-vinylimidazo[l,2-a]pyrazin-2-yl)- 1,3, 4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,3,4-thiadiaz ol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -vinyl -2H-indazol-2-yl)-l, 3, 4-thiadiazol-2-yl)m ethyl)- 1 -(tert-butyl)- lH-pyrazole-4- carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)a mino)-3-vinyl-2H- indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-l-(tert-butyl)-l H-pyrrole-3-carboxamide; l-(tert- butyl)-N-((5-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-3-vinylimidazo[l,2-a]pyrazin-

2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxa mide; l-(tert-butyl)-N-((5-(8- (((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinylimid azo[l,2-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2- yl)-l,3,4-thiadiazol-2-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-vinylpyrazolo[l,5-a]pyrazin-2-yl)-l,3,4-thiadiaz ol-2-yl)methyl)-lH-pyrrole-3- carboxamide; N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl) amino)-3-vinyl-2H- indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarbox amide; l-(tert-butyl)-N-((3-(5- fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-

3-fluoro-l-methylpiperidin-4-yl)amino)-3-vinyl-2H-indazol -2-yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-vinyl-2H-indazol-2-yl)-l,3,4-thiadiazol-2-yl)met hyl)cyclopropanecarboxamide; 1- (tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpi peridin-4-yl)amino)-3-vinyl-2H- indazol-2-yl)-l,3,4-thiadiazol-2-yl)methyl)-lH-pyrazole-4-ca rboxamide; l-(tert-butyl)-N-((5-(5- fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- vinyl-2H-indazol-2-yl)- 1,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(prop-l-en-2-yl)-2H-indazol-2- yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -(prop- l-en-2-yl)imidazo[l,2-a]pyridin-2-yl)- 1,2, 4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3 -fluoro- l-methylpiperidin-4- yl)amino)-3 -(prop- 1 -en-2-yl)pyrazolo[ 1 ,5-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(prop-l -en-2-yl)-2H-indazol -2-yl)- 1,2, 4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-(prop-l-en-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiazo l-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-(prop- l-en-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)m ethyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-(prop-

1-en-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-y l)methyl)-lH-pyrrole-3-carboxamide;

1 -(tert-butyl)-N-((3 -(7-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3 -(prop- 1 -en-2- yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl) -lH-pyrazole-4-carboxamide; 1- (tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4 -yl)amino)-3-(prop-l-en-2- yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl) -lH-pyrrole-3-carboxamide; N-((3- (7-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-( 1 -fluorovinyl)-2H-indazol-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(l-fluorovinyl)imidazo[l,2-a]p yridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(l-fluorovinyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2, 4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- rnethylpiperidin-4-yl)amino)-3-(l-fluorovinyl)-2H-indazol-2- yl)-l,2,4-oxadiazol-5-yl)rnethyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-(l-fluorovinyl)-2H-indazol-2-yl)-l,2,4-oxadiazol -5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-(l- fluorovinyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-(l- fluorovinyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-(l- fluorovinyl)pyrazolo[ 1 , 5-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-(l- fluorovinyl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-y l)methyl)-lH-pyrrole-3- carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- ((E)-prop-l-en-l- yl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropan ecarboxamide; N-((3-(8-

(((3 S,4R)-3-fluoro- 1 -methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)imidazo[ 1 ,2-a]pyridin-

2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarboxamide ; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((E)-prop-l-en-l-yl)pyrazolo[l ,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((E)-prop-l-en-l-yl)-2H-indazo l-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)-2H-indazol-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)imidazo[ 1 ,2-a]pyri din-2 -yl)- 1 ,2,4-oxadiazol- 5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)imidazo[ 1 ,2-a]pyri din-2 -yl)- 1 ,2,4-oxadiazol- 5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)pyrazolo[ 1 ,5-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- 1 -methylpiperidin-4-yl)amino)-3 -((E)-prop- 1 -en- 1 -yl)pyrazolo[ 1 , 5-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-2H-indazol-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)imidazo[l,2-a]pyridin-2-yl)-l,2,4 -oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)pyrazolo[l,5-a]pyridin-2-yl)-l,2, 4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-2H-indazol-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- 1H- pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fl uoro-l- methylpiperidin-4-yl)amino)-2H-indazol-2-yl)-l,2,4-oxadiazol -5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fl uoro-l-rnethylpiperidin- 4-yl)amino)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl) methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-8-(((3S,4R)-3-fl uoro-l-methylpiperidin- 4-yl)amino)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl) methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fl uoro-l-methylpiperidin- 4-yl)amino)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(3-(2,2-difluorovinyl)-7-(((3S,4R)-3-fl uoro-l-methylpiperidin- 4-yl)amino)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lE[-pyrrole-3- carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- (l,2,2- trifluorovinyl)-2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl )cyclopropanecarboxamide; N-((3- (8-(((3 S,4R)-3 -fluoro- 1 -methylpiperidin-4-yl)amino)-3-( 1 ,2,2-trifluorovinyl)imidazo[ 1 ,2- a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecarb oxamide; N-((3-(7-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-3 -( 1 ,2,2-trifluorovinyl)pyrazolo[ 1 ,5 -a]pyri din-2 -yl)- 1 ,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; 2-(5-((((l-(tert-butyl)-lH-pyrazol-4-yl)(12- fluoraneylidene)methyl)amino)methyl)-l,2,4-oxadiazol-3-yl)-N -((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)-3-(l,2,2-trifluorovinyl)-2H-indazol-7- amine; l-(tert-butyl)-N-((3-(7- (((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)arnino)-3-(l,2,2-t rifluorovinyl)-2H-indazol-2-yl)- l,2,4-oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3- fluoro- 1 -methylpiperidin-4-yl)amino)-3 -( 1 ,2,2-trifluorovinyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3 -(1,2, 2-trifluorovinyl)imidazo[l,2-a]pyridin-2-yl)- 1,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(l,2,2-trifluorovinyl)pyrazolo [l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(l,2,2-trifluorovinyl)pyrazo lo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((R)-oxiran-2-yl)-2H-indazol-2 -yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-((S)-oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2 ,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-((R)-oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l, 2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((S)-oxiran-2-yl)-2H-indazol-2 -yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-((S)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiaz ol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-((R)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-((S)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrrole-3- carboxamide; l -(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)-3-((R)- oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-y l)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-((R)- oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-y l)methyl)-lH-pyrrole-3- carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- ((S)-oxiran-2-yl)- 2H-indazol-2-yl)-l,2,4-oxadiazol-5-yl)methyl)cyclopropanecar boxamide; N-((3-(8-(((3S,4R)-3- fluoro-l-methylpiperidin-4-yl)amino)-3-((R)-oxiran-2-yl)imid azo[l,2-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((S)-oxiran-2-yl)pyrazolo[l,5- a]pyridin-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-((R)-oxiran-2-yl)-2H-indazol-2 -yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-((R)-oxiran-2-yl)-2H-indazol-2-yl)-l,2,4-oxadiaz ol-5-yl)methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-((S)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-((R)- oxiran-2-yl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5-yl )methyl)-lH-pyrrole-3- carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4-yl)amino)-3-((S)- oxiran-2-yl)pyrazolo[l,5-a]pyridin-2-yl)-l,2,4-oxadiazol-5-y l)methyl)-lH-pyrrole-3- carboxamide; N-((3-(6-acrylamido-8-(((3S,4R)-3-fluoro-l-methylpiperidin-4 -yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- 1 -(tert-butyl)- 1H- pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-6-methacrylamido-3 -(2,2,2-trifluoroethyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(6-((E)-4- (dimethylamino)but-2-enamido)-8-(((3S,4R)-3-fluoro-l-methylp iperidin-4-yl)amino)-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5 -yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-6-((E)-4- (4-methylpiperazin-l-yl)but-2-enamido)-3-(2,2,2-trifluoroeth yl)imidazo[l,2-a]pyridin-2-yl)- l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3- fluoro-l-methylpiperidin-4-yl)amino)-6-(4-(methylamino)but-2 -ynamido)-3 -(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5 -yl)methyl)-lH-pyrazole-4- carboxamide; l -(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)-6-(2- fluoroacrylamido)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyri din-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-6-propiolamido-3-(2,2,2-trifluor oethyl)imidazo[l,2-a]pyridin-2-yl)- l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3- fluoro-l-methylpiperidin-4-yl)amino)-6-((E)-4-(methylamino)b ut-2-enamido)-3-(2,2,2- trifluoroethyl)imidazo[l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-5 -yl)methyl)-lH-pyrazole-4- carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3 -fluoro- l-methylpiperidin-4-yl)amino)-6-((E)-4- morpholinobut-2-enamido)-3-(2,2,2-trifluoroethyl)imidazo[l,2 -a]pyridin-2-yl)-l,2,4-oxadiazol- 5-yl)methyl)-lH-pyrazole-4-carboxamide; N-((3-(6-(but-2-ynamido)-8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[ l,2-a]pyridin-2-yl)-l,2,4-oxadiazol- 5-yl)methyl)-l-(tert-butyl)-lH-pyrazole-4-carboxamide; N-((3-(6-((E)-but-2-enamido)-8- (((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3-(2,2,2-tr ifluoroethyl)imidazo[l,2-a]pyridin- 2 -yl)-l, 2, 4-oxadiazol-5-yl)methyl)-l -(tert-butyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N- ((3-(6-((E)-4-(3,3-difluoroazetidin-l-yl)but-2-enamido)-8-(( (3S,4R)-3-fluoro-l-methylpiperidin-

4-yl)amino)-3 -(2,2,2-trifluoroethyl)imidazo[ 1 ,2-a]pyridin-2-yl)- 1 ,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(6-(4-(dimethylamino)but-2-ynamido)-8-

(((3 S,4R)-3-fluoro- 1 -methylpiperidin-4-yl)amino)-3 -(2,2,2-trifluoroethyl)imidazo[ 1 ,2-a]pyridin- 2-yl)-l,2,4-oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide ; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl )-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(7-(((3S/lR)-3 -fluoro- l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo[l,5-a]pyridin-2-y l)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)- lH-pyrrole-3 -carboxamide; 1 -(tert-butyl)-N-((3 -(8-(((3 S,4R)-3-fluoro- 1 - methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[ l,2-a]pyridin-2-yl)-l,2,4-oxadiazol-

5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[ l,2-a]pyridin-2-yl)-l ,2,4-oxadiazol- 5-yl)methyl)-lH-pyrrole-3-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo [l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazo lo[l,5-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[l,2-a]pyridin-2-yl )-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[ l,2-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidaz o[l,2-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo [l,5-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo [l,5-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazo lo[l,5-a]pyridin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -(2, 2, 2-trifluoroethyl)-2H-indazol-2-yl)-l, 2, 4-oxadiazol-5-yl)methyl)-l -(tert-butyl)- lH-pyrazole-4-carboxamide; N-((3-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3 -(2, 2, 2-trifluoroethyl)-2H-indazol-2-yl)-l, 2, 4-oxadiazol-5-yl)methyl)-l -(tert-butyl)- lH-pyrrole-3-carboxamide; N-((3-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- (2,2,2- trifluoroethyl)imidazo[ 1 ,2-a]pyrazin-2-yl)- 1 ,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro-l - methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[ l,2-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidaz o[l,2-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo [l,5-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo [l,5-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazo lo[l,5-a]pyrazin-2-yl)-l,2,4- oxadiazol-5-yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4-th iadiazol-2-yl)methyl)-l-(tert-butyl)- lH-pyrrole-3-carboxamide; N-((5-(8-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- (2,2,2- trifluoroethyl)imidazo[l,2-a]pyrazin-2-yl)-l,3,4-thiadiazol- 2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidazo[ l,2-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(8-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)imidaz o[l,2-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazolo [l,5-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)cyclopropanecarboxamide; N-((5-(5-amino-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-l -(tert-butyl)- lH-pyrazole-4-carboxami de; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazo lo[l,5-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro- l-methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)pyrazo lo[l,5-a]pyrazin-2-yl)-l,3,4- thiadiazol-2-yl)methyl)-lH-pyrrole-3 -carboxamide; N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3 -fluoro- 1- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,2,4-oxadiazol-5- yl)methyl)-lH-pyrrole-3-carboxamide; N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l-methylpiperidin- 4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-indazol-2-yl)-l,3,4- thiadiazol-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((5-(5-fluoro-7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(2,2,2-trifluoroethyl)-2H-inda zol-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrrole-3-carboxamide; N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazo l-5- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)-2H-indazol-2- yl)-l,2,4-oxadiazol-5-yl)methyl)- lH-pyrazole-4-carboxamide; l-(tert-butyl)-N-((3-(7-(((3S,4R)-3-fluoro-l-methylpiperidin -4- yl)amino)-3-(perfluoroethyl)-2H-indazol-2-yl)-l,2,4-oxadiazo l-5-yl)methyl)-lH-pyrrole-3- carboxamide; N-((5-(7-(((3S,4R)-3-fluoro-l-methylpiperidin-4-yl)amino)-3- (perfluoroethyl)pyrazolo[l,5-a]pyridin-2-yl)-l,3,4-thiadiazo l-2- yl)methyl)cyclopropanecarboxamide; l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[l,5-a ]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrazole-4-carboxamide; and l-(tert-butyl)-N-((5-(7-(((3S,4R)-3-fluoro-l- methylpiperidin-4-yl)amino)-3-(perfluoroethyl)pyrazolo[l,5-a ]pyridin-2-yl)-l,3,4-thiadiazol-2- yl)methyl)-lH-pyrrole-3-carboxamide.

Pharmaceutical Compositions

Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

Methods of Treatment

Provided herein are methods for restoring p53 function, encoded by TP53 gene. For example, provided herein are compounds that restore p53 function that are useful for treating or preventing diseases associated with dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same (i.e., a p53 -associated disease), such as cancer (e.g., p53-associated cancer).

The terms “restore” or “restoration of’ means to increase the activity and/or function of the specified target by a measurable amount. For example, restoration of a mutant p53 with a compound of Formula (I) refers to increasing the function of the mutant p53 in the presence of the compound to a higher level than the function of the mutant p53 in the absence of the compound.

The ability of test compounds to act as a p53 restorer may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as p53 restorers can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine activation of the protein and/or a change in its conformation. Potency of a p53 restorer as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent p53 restorer relative to a compound with a higher EC50 value.

Indications

Compounds of Formula (I), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a p53 restorer, such as p53-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors). In some embodiments, the p53 -associated disease or disorder is Li -Fraumeni syndrome.

Some embodiments provide a method of treating cancer in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a p53 -associated cancer.

Some embodiments provide a method of treating cancer in a subj ect that has been identified or diagnosed as having a p53 -associated cancer, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the p53 -associated cancer harbors a Y220C mutation.

Some embodiments provide a method of treating a p53 -associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one of the compound of Examples 1 -1 10, or a pharmaceutically acceptable salt thereof. In some embodiments, the p53-associated cancer harbors a Y220C mutation.

Some embodiments provide a method of treating cancer in a subject in need thereof, comprising (a) determing that the subject has a p53 -associated cancer, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject that has been identified or diagnosed as having Li-Fraumeni syndrome, compirising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method of treating Li-Fraumeni syndrome in a subject in need thereof, comprising (a) determing that the subject has Li-Fraumeni syndrome, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome. In some embodiments, a therapeutically effective amount of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prophylactically to a subject with Li-Fraumeni syndrome.

The term “p53 -associated disease” as used herein refers to diseases associated with or having a dysregulation of a TP53 gene, a p53 protein, or the activity of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a TP53 gene, or a p53 protein, or the activity of any of the same described herein). Non-limiting examples of a p53-associated disease include, for example, cancer (e.g., p53-associated cancer).

The term “p53 -associated cancer” as used herein refers to cancers associated with or having a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. Non-limiting examples of p53-associated cancers are described herein. The term “wild type” or “wild-type” describes a nucleic acid (e.g., a TP53 gene or a p53 mRNA) or protein (e.g., a p53) sequence that is typically found in a subject that does not have a cancer related to the reference nucleic acid or protein.

Provided herein is a method of treating cancer (e.g., a p53-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating p53- associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more a p53 protein substitutions/point mutations/insertions. Non-limiting examples of p53 protein substitutions/insertions/deletions are described in Table 1.

In some embodiments, the p53 protein substitution / insertion / deletion is Y220X, where X is any amino acid other than Y. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C, Y220S, Y220N, Y220D, and combinations thereof. In some embodiments, the p53 protein substitution/insertion/deletion is selected from the group consisting of Y220C or Y220S, or a combination thereof. In some embodiments, the p53 protein substitution/insertion/deletion is Y220C. In some embodiments, the p53 protein substitution/insertion/deletion is Y220S.

In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, includes at least one point mutation in a TP53 gene that results in the production of a p53 protein that has one or more amino acid substitutions or insertions or deletions in a TP53 gene that results in the production of a p53 protein that has one or more amino acids inserted or removed, as compared to the wild type p53 protein. In some cases, the resulting mutant p53 protein has reduced function, as compared to a wild type p53 protein or a p53 protein not including the same mutation. In some embodiments, the compounds described herein restore the resulting mutant p53 protein function relative to the mutant p53 protein function in the absence of the compounds described herein, for example, by stabilizing the mutant protein into an active conformation.

Exemplary Sequence of Human p53 (UniProtKB entry P04637-1) (SEQ ID NO: 1) MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGP DEAPRMPE AAPP VAPAP AAPTP AAPAPAP S WPL S S S VP SQKTYQGS YGFRLGFLHSGTA KSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCP HHERC SD SDGL APPQHLIRVEGNLRVEYLDDRNTFRHS VVVP YEPPE VGSDCTTIHYNY MCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPH HELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAG KEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

In some embodiments, compounds of Formula (I), or pharmaceutically acceptable thereof, are useful for treating a cancer that has been identified as having one or more p53 mutations. Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Also provided herein are methods for treating a subject identified or diagnosed as having a p53 -associated cancerthat include administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a p53 -associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the nonlimiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer.

Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a p53-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., an immunotherapy). In some embodiments, the subj ect was previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a p53-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an p53-associated cancer.

Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a p53-associated cancer in a subject identified or diagnosed as having a p53 -associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, where the presence of a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, identifies that the subject has a p53-associated cancer.

Also provided is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a p53-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a p53 -associated cancer. In some embodiments, a subject is identified or diagnosed as having a p53-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a TP53 gene, a p53 protein, or activity of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a p53-associated cancer includes those described herein and known in the art.

In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a p53-associated cancer. In some embodiments, provided herein are methods for treating a p53 -associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a TP53 gene, a p53 protein, or the activity of any of the same includes one or more p53 protein point mutations/insertions/deletions, as described herein. In some embodiments, the cancer with a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor with a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.

In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a TP 53 gene, a p53 protein, or activity of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a TP53 gene, a p53 protein, or activity of any of the same.

Also provided is a method for restoring p53 function in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant p53 function. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a p53-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moi eties in an in vitro system or an in vivo system. For example, "contacting" a p53 protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a p53 protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the p53 protein.

Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from a hematological cancer and a solid tumor.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is a hematological cancer. In some embodiments, the hematological cancer is a leukemia. In some embodiments, the hematological cancer is a lymphoma. In some embodiments, the hematological cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or hairy cell leukemia (HCL). In some embodiments, the hematological cancer is acute myeloid leukemia (AML).

In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from brain cancer, bladder cancer, breast cancer, colorectal cancer, skin cancer, esophageal cancer, lung cancer, gastric cancer, kidney cancer, uterine cancer, ovarian cancer, liver cancer, pancreatic cancer, prostate cancer, leiomyosarcoma, and head and neck squamous cell carcinoma.

In some embodiments of any of the methods or uses described herein, the cancer (e.g., p53- associated cancer) is selected from colorectal cancer, ovarian cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, small cell lung cancer, endometrial cancer, and bladder cancer.

In some embodiments, the brain cancer is astrocytoma, oligoastrocytoma, oligodendroglioma, or glioblastoma multiforme.

In some embodiments, the bladder cancer is bladder urothelial carcinoma.

In some embodiments, the esophageal cancer is esophageal adenocarcinoma or esophageal squamous cell carcinoma.

In some embodiments, the skin cancer is cutaneous melanoma.

In some embodiments, the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is lung adenocarcinoma or lung squamous cell carcinoma.

In some embodiments, the gastric cancer is mucinous stomach adenocarcinoma or intestinal type stomach adenocarcinoma.

In some embodiments, the breast cancer is breast invasive ductal carcinoma.

In some embodiments, the uterine cancer is uterine mixed endometrial carcinoma, uterine endometrioid carcinoma, uterine serous carcinoma, or uterine papillary serous carcinoma.

In some embodiments, the ovarian cancer is serous ovarian cancer.

In some embodiments, the kidney cancer is chromophobe renal cell carcinoma.

In some embodiments, the colorectal cancer is colon adenocarcinoma.

In some embodiments, the liver cancer is hepatocellular carcinoma.

In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma.

In some embodiments, the cancer is prostate cancer.

In some embodiments of any of the methods or uses described herein, the p53-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the p53 -associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the p53-associated cancer is lung cancer.

In some embodiments of any of the methods or uses described herein, the p53-associated cancer is selected from the cancers described in Table 1.

Table 1. p53 Protein Amino Acid Substitutions/Insertions/Deletions ^A

Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

1 Ml Head and Neck Squamous Cell Carcinoma (translation start site)

4 P4L Mucinous Stomach Adenocarcinoma

10 XIO splice (splice site) Acute Myeloid Leukemia

11 Ell* (nonsense mutation) Breast Invasive Ductal Carcinoma E11K Renal Clear Cell Carcinoma

20 S20* Bladder Urothelial Carcinoma S20Qfs*24 Intestinal Type Stomach Adenocarcinoma (frame shift, additional amino acids)

22 L22Yfs*22 Bladder Urothelial Carcinoma

23 W23* Cervical Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

25 X25_splice Adrenocortical Carcinoma

Head and Neck Squamous Cell Carcinoma Tubular Stomach Adenocarcinoma

27 P27L Adrenocortical Carcinoma P27Lfs*17 Astrocytoma P27S Breast Invasive Ductal Carcinoma

Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Cutaneous Melanoma

Head and Neck Squamous Cell Carcinoma

Mucinous Carcinoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

30 N30del Colon Adenocarcinoma (in frame deletion)

32 L32Cfs*12 Astrocytoma

X32_splice Chromophobe Renal Cell Carcinoma Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma Oligoastrocytoma

Renal Clear Cell Carcinoma

33 S33Ffs*10 Astrocytoma

X33_splice Bladder Urothelial Carcinoma

Breast Invasive Ductal Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

35 L35Cfs*9 Bladder Urothelial Carcinoma

L35Ffs*7 Colon Adenocarcinoma

L35Ffs*8 Lung Adenocarcinoma

L35Pfs*10 Lung Squamous Cell Carcinoma Pancreatic Adenocarcinoma Papillary Stomach Adenocarcinoma Rectal Adenocarcinoma

Tubular Stomach Adenocarcinoma Uterine Endometrioid Carcinoma

36 P36Wfs*4 Serous Ovarian Cancer

37 S37Vfs*6 Lung Squamous Cell Carcinoma

38 Q38* Colon Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Q38Kfs*6 Head and Neck Squamous Cell Carcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

40 M40Lfs*7 Acute Myeloid Leukemia

42 D42Ifs*2 Esophageal Squamous Cell Carcinoma

43 L43* Hepatocellular Carcinoma

L43Afs*7 Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

44 M44Ifs*79 Bladder Urothelial Carcinoma

M44Tfs*75 Lung Squamous Cell Carcinoma

46 S46* Lung Squamous Cell Carcinoma

S46Tfs*5

47 P47Rfs*76 Serous Ovarian Cancer

48 D48Gfs*4 Cutaneous Melanoma D48N Head and Neck Squamous Cell Carcinoma D48Nfs*72 Lung Adenocarcinoma D48Tfs*75 Lung Squamous Cell Carcinoma

49 D49Sfs*69 Lung Squamous Cell Carcinoma

51 E51* Breast Invasive Ductal Carcinoma

E51Gfs*6 Esophageal Adenocarcinoma Serous Ovarian Cancer

52 Q52* Breast Invasive Ductal Carcinoma

Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma

53 W53* Bladder Urothelial Carcinoma

W53Cfs*4 Diffuse Type Stomach Adenocarcinoma

W53Mfs*4 Glioblastoma Multiforme

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

54 F54Sfs*69 Lung Adenocarcinoma

56 E56* Adrenocortical Carcinoma

E56Kfs*67 Breast Invasive Ductal Carcinoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Squamous Cell Carcinoma

57 D57Kfs*67 Lung Adenocarcinoma

D57N Pancreatic Adenocarcinoma

58 P58Qfs*65 Head and Neck Squamous Cell Carcinoma

61 D61* Uterine Endometrioid Carcinoma

D61G Uterine Mixed Endometrial Carcinoma

62 E62* Cervical Squamous Cell Carcinoma

E62K Lung Squamous Cell Carcinoma

E62Kfs*61 Pancreatic Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Serous Ovarian Cancer

64 P64Qfs*84 Esophageal Squamous Cell Carcinoma

P64Sfs*59 Lung Squamous Cell Carcinoma

P64T Uterine Endometrioid Carcinoma

65 R65* Head and Neck Squamous Cell Carcinoma

R65Efs*58 Lung Adenocarcinoma

R65Qfs*84 Lung Squamous Cell Carcinoma

66 M66Tfs*60 Serous Ovarian Cancer

67 P67S Uterine Endometrioid Carcinoma

68 E68* Bladder Urothelial Carcinoma

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

69 A69Gfs*80 Lung Adenocarcinoma

72 P72Rfs*51 Cutaneous Melanoma

P72S Diffuse Type Stomach Adenocarcinoma

Lung Adenocarcinoma

73 V73Rfs*76 Adrenocortical Carcinoma

V73Wfs*50 Colon Adenocarcinoma

Head and Neck Squamous Cell Carcinoma

Leiomyosarcoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Tubular Stomach Adenocarcinoma

74 A74T Prostate Adenocarcinoma

75 P75Lfs*48 Lung Squamous Cell Carcinoma

76 A76Hfs*47 Serous Ovarian Cancer

77 P77Cfs*73 Breast Invasive Ductal Carcinoma

P77Gfs*65 Lung Adenocarcinoma

P77L

79 A79Pfs*70 Colon Adenocarcinoma

A79V Head and Neck Squamous Cell Carcinoma

82 P82L Prostate Adenocarcinoma P82Rfs*41 Stomach Adenocarcinoma

83 A83Gfs*66 Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

84 A84Pfs*39 Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma

85 P85Lfs*38 Head and Neck Squamous Cell Carcinoma

86 A86Cfs*63 Breast Invasive Ductal Carcinoma

A86Pfs*34 Prostate Adenocarcinoma

A86Vfs*55 Serous Ovarian Cancer

I ll Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

90 S90Ffs*53 Astrocytoma

S90Pfs*33 Breast Invasive Ductal Carcinoma

S90Pfs*34 Head and Neck Squamous Cell Carcinoma

S90Vfs*55 Hepatocellular Carcinoma

Lung Adenocarcinoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

91 W91* Astrocytoma

Bladder Urothelial Carcinoma

Breast Invasive Ductal Carcinoma

Colon Adenocarcinoma

Esophageal Adenocarcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Papillaty Renal Cell Carcinoma

Stomach Adenocarcinoma

92 P92Afs*57 Bladder Urothelial Carcinoma

P92S Uterine Endometrioid Carcinoma

93 L93Vfs*55 Breast Invasive Ductal Carcinoma

94 S94* Bladder Urothelial Carcinoma S94Cfs*30 Colon Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Rectal Adenocarcinoma

Stomach Adenocarcinoma

96 S96Ffs*25 Diffuse Type Stomach Adenocarcinoma

97 V97D Cutaneous Melanoma

V97Efs*48 Hepatocellular Carcinoma

V97Sfs*26 Tubular Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

98 P98Afs*51 Stomach Adenocarcinoma

99 S99Rfs*23 Head and Neck Squamous Cell Carcinoma Serous Ovarian Cancer

100 Q100* Colon Adenocarcinoma Q100Gfs*37 Lung Squamous Cell Carcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

101 K101* Head and Neck Squamous Cell Carcinoma

102 T102Pfs*21 Glioblastoma Multiforme Serous Ovarian Cancer

103 Y103* Head and Neck Squamous Cell Carcinoma

Y103Lfs*46 Hepatocellular Carcinoma

Y103Tfs*20 Lung Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Stomach Adenocarcinoma

104 Q104* Esophageal Adenocarcinoma

Q104H Head and Neck Squamous Cell Carcinoma

Q104Tfs*20 Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

105 G105C Bladder Urothelial Carcinoma G105D Glioblastoma Multiformc G105R Head and Neck Squamous Cell Carcinoma G105S Lung Adenocarcinoma

G105V Lung Squamous Cell Carcinoma

Serous Ovarian Cancer

106 S106R Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Hepatocellular Carcinoma Lung Squamous Cell Carcinoma

107 Y107Cfs*16 Breast Invasive Ductal Carcinoma

Y107D Colon Adenocarcinoma

Stomach Adenocarcinoma

108 G108Ffs*40 Breast Invasive Ductal Carcinoma G108S Glioblastoma Multiforme G108Vfs*15 Uterine Endometrioid Carcinoma

109 F109C Colon Adenocarcinoma

F109Lfs*36 Esophageal Squamous Cell Carcinoma

F109S Lung Adenocarcinoma

F109V Lung Squamous Cell Carcinoma

Oligoastrocytoma

Oligodendroglioma

Rectal Adenocarcinoma

110 R110_G112del Bladder Urothelial Carcinoma

R110C Breast Invasive Ductal Carcinoma RllOdel Cutaneous Melanoma

R110L Esophageal Squamous Cell Carcinoma

R110P Head and Neck Squamous Cell Carcinoma

R110Sfs*14 Lung Adenocarcinoma R110Vfs*13 Lung Squamous Cell Carcinoma R110Wfs*12 Oligoastrocytoma

Pancreatic Adenocarcinoma Serous Ovarian Cancer

111 L111P Bladder Urothelial Carcinoma

L111Q Breast Invasive Ductal Carcinoma

L111R Diffuse Type Stomach Adenocarcinoma Lung Squamous Cell Carcinoma Papillary Renal Cell Carcinoma

113 F113C Astrocytoma F113del Breast Invasive Carcinoma (NOS) F113L Breast Invasive Ductal Carcinoma F113V Colon Adenocarcinoma Esophageal Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Oligodendroglioma

114 L114* Breast Invasive Carcinoma (NOS)

115 H115Ifs*8 Breast Invasive Ductal Carcinoma

118 T118Dfs*31 Breast Invasive Ductal Carcinoma

T118Qfs*5 Head and Neck Squamous Cell Carcinoma Serous Ovarian Cancer

120 K120E Cutaneous Melanoma

K120Sfs*3 Lung Adenocarcinoma

K120Tfs*2 Lung Squamous Cell Carcinoma

Oligoastrocytoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

121 S121Cfs*27 Bladder Urothelial Carcinoma

S121Y Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

122 V122Cfs*27 V122Dfs*26 Astrocytoma

V122Lfs*25 Breast Invasive Ductal Carcinoma Colon Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Leiomyosarcoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma Rectal Adenocarcinoma Serous Ovarian Cancer

123 T123Dfs*26 Glioblastoma Multiforme

T123Lfs*47 Pancreatic Adenocarcinoma

T123Rfs*48 Serous Ovarian Cancer

124 C124* Breast Invasive Ductal Carcinoma C124Afs*46 Colon Adenocarcinoma C124G Esophageal Squamous Cell Carcinoma C124Wfs*25 Prostate Adenocarcinoma

Serous Ov arian Cancer

125 T125= Acute Myeloid Leukemia (splice region) Adrenocortical Carcinoma

Astrocytoma

T125M Bladder Urothelial Carcinoma

T125P Breast Invasive Ductal Carcinoma

X125_splice Colon Adenocarcinoma

Cutaneous Melanoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma

126 Y126_M133del Acute Myeloid Leukemia

Y126C Breast Invasive Ductal Carcinoma

Y126D Cutaneous Melanoma

Y126H Esophageal Squamous Cell Carcinoma

Y126N Glioblastoma Multiforme Y126S Head and Neck Squamous Cell Carcinoma X126_splice Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Stomach Adenocarcinoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of the Stomach

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

127 S127C Astrocytoma

S127F Breast Invasive Ductal Carcinoma

S127P Colon Adenocarcinoma

S127T Cutaneous Melanoma

S127Y Glioblastoma Multiforme S127Yfs*43 Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

128 P128del Astrocytoma P128Lfs*42 Breast Invasive Ductal Carcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma

129 A129Vfs*20 Lung Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

130 L130Cfs*20 Astrocytoma

L130F Breast Invasive Lobular Carcinoma

L130P Colon Adenocarcinoma

L130R Diffuse Type Stomach Adenocarcinoma

L130V Esophageal Squamous Cell Carcinoma Glioblastoma Multiforme

Lung Adenocarcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Uterine Mixed Endometrial Carcinoma

131 N131del Astrocytoma N131I Breast Invasive Ductal Carcinoma N131Kfs*39 Lung Adenocarcinoma

N131Qfs*17 Lung Squamous Cell Carcinoma N131S Pancreatic Adenocarcinoma N131Tfs*39 Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Mixed Endometrial Carcinoma

132 K132E Adrenocortical Carcinoma

K132M Astrocytoma K132N Bladder Urothelial Carcinoma K132Q Breast Invasive Ductal Carcinoma K132R Cervical Squamous Cell Carcinoma

K132T Colon Adenocarcinoma K132Vfs*15 Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pleural Mesothelioma, Epithelioid Type

Serous Ovarian Cancer

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian Tumor

133 M133K Breast Invasive Carcinoma (NOS)

M133R Head and Neck Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

134 F134L Cutaneous Melanoma

F134V Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

135 C135* Adrenocortical Carcinoma

C135Afs*35 Bladder Urothelial Carcinoma C135F Breast Invasive Ductal Carcinoma

C135Lfs*14 Colon Adenocarcinoma

C135R Diffuse Type Stomach Adenocarcinoma

C135W Esophageal Adenocarcinoma C135Y Esophageal Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Papillary Stomach Adenocarcinoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Endometrioid Carcinoma

136 Q136* Astrocytoma Q136_C141del Breast Invasive Ductal Carcinoma Q136del Glioblastoma Multiforme Q136E Head and Neck Squamous Cell Carcinoma Q136H Hepatocellular Carcinoma Q136P Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Metaplastic Breast Cancer

Mucinous Stomach Adenocarcinoma

Oligodendroglioma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

137 L137Pfs*32 Head and Neck Squamous Cell Carcinoma L137Q

138 A138_L145dcl Breast Invasive Ductal Carcinoma

A138_P142del Esophageal Adenocarcinoma

A138Cfs*27 Glioblastoma Multiforme

A138T Lung Adenocarcinoma

A138V Rectal Adenocarcinoma Serous Ovarian Cancer Uterine Endometrioid Carcinoma

139 K139_P142del Bladder Urothelial Carcinoma K139_P142delinsT Breast Invasive Carcinoma (NOS) K139Afs*5 Esophageal Squamous Cell Carcinoma K139Cfs*6 Glioblastoma Multiforme K139N Head and Neck Squamous Cell Carcinoma K139Nfs*9 Hepatocellular Carcinoma K139Rfs*31 Lung Adenocarcinoma

Uterine Endometrioid Carcinoma

140 T140Mfs*28 Serous Ovarian Cancer

141 C141* Acute Myeloid Leukemia C141Afs*29 Astrocytoma C141F Bladder Urothelial Carcinoma C141G Breast Invasive Ductal Carcinoma

C141R Chromophobe Renal Cell Carcinoma C141S Colon Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

C141W Cutaneous Melanoma

C141Y Head and Neck Squamous Cell Carcinoma

Intrahepatic Cholangiocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

142 P142del Lung Squamous Cell Carcinoma P142L Oligoastrocytoma P142Lfs*28 Uterine Mixed Endometrial Carcinoma

143 V143A Bladder Urothelial Carcinoma V143Afs*29 Colon Adenocarcinoma V143E Cutaneous Melanoma V143G Esophageal Adenocarcinoma V143M Head and Neck Squamous Cell Carcinoma V143Rfs*18 Hepatocellular Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

144 Q144* Bladder Urothelial Carcinoma Q144_L145dup Breast Invasive Lobular Carcinoma Q144Afs*16 Colon Adenocarcinoma Q144Gfs*24 Head and Neck Squamous Cell Carcinoma Q144H Hepatocellular Carcinoma Q144L Lung Adenocarcinoma Q144Lfs*5 Lung Squamous Cell Carcinoma Q144P Prostate Adenocarcinoma Q144Tfs*5 Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

145 L145P Colon Adenocarcinoma

L145Q Oligoastrocytoma

L145R Serous Ovarian Cancer

Signet Ring Cell Carcinoma of the Stomach

146 W146* Astrocytoma

W146S Bladder Urothelial Carcinoma

W146Vfs*3 Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligodendroglioma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

147 V147_D148dup Breast Invasive Ductal Carcinoma V147G Esophageal Adenocarcinoma V147Lfs*23 Serous Ovarian Cancer

148 D148Ifs*22 Bladder Urothelial Carcinoma

D148N Lung Adenocarcinoma

149 S149Ffs*32 Pancreatic Adenocarcinoma

S149Pfs*21 Prostate Adenocarcinoma Serous Ovarian Cancer

150 T150Afs*16 Stomach Adenocarcinoma

151 P151A Astrocytoma

P151H Bladder Urothelial Carcinoma

P151L Breast Invasive Ductal Carcinoma

P151R Colon Adenocarcinoma

P151Rfs*27 Cutaneous Melanoma

P151S Esophageal Squamous Cell Carcinoma

P151T Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

152 P152Afs*14 Astrocytoma P152L Bladder Urothelial Carcinoma P152Lfs*18 Breast Invasive Ductal Carcinoma P152Q Cutaneous Melanoma P152Rfs*18 Diffuse Type Stomach Adenocarcinoma P152S Glioblastoma Multiforme P152Wfs*10 Head and Neck Squamous Cell Carcinoma Intestinal Type Stomach Adenocarcinoma Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of the Stomach Tubular Stomach Adenocarcinoma

153 P153Afs*28 Bladder Urothelial Carcinoma

P153Rfs* 18 Lung Squamous Cell Carcinoma Oligoastrocytoma

Stomach Adenocarcinoma

154 G154Afs*16 Bladder Urothelial Carcinoma

G154Rfs*27 Esophageal Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

G154V Head and Neck Squamous Cell Carcinoma

G154Wfs*10 Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligodendroglioma

Pancreatic Adenocarcinoma Serous Ovarian Cancer

155 T155_A161dcl Astrocytoma T155_R156del Bladder Urothelial Carcinoma

T155_R156delinsN Breast Invasive Ductal Carcinoma T155_R158del Colon Adenocarcinoma

T155_R158delinsC Glioblastoma Multiforme T155I Head and Neck Squamous Cell Carcinoma T155N Lung Adenocarcinoma T155P Lung Squamous Cell Carcinoma

Oligoastrocytoma

Serous Ovarian Cancer

156 R156Afs*12 Astrocytoma R156C Bladder Urothelial Carcinoma R156del Breast Invasive Ductal Carcinoma R156G Glioblastoma Multiforme R156H Head and Neck Squamous Cell Carcinoma R156Hfs*26 Hepatocellular Carcinoma R156P Leiomyosarcoma

R156Pfs*13 Lung Adenocarcinoma

Serous Ovarian Cancer

Uterine Serous Carcinoma/Uterine Papil la ry Serous Carcinoma

157 V157_P177del Breast Invasive Ductal Carcinoma V157_R158dup Colon Adenocarcinoma V157Afs*24 Esophageal Squamous Cell Carcinoma V157D Glioblastoma Multiformc V157F Head and Neck Squamous Cell Carcinoma V157G Hepatocellular Carcinoma V157Hfs*21 Lung Adenocarcinoma

V157L Lung Squamous Cell Carcinoma

V157Pfs*23 Oligodendroglioma V157Sfs*13 Prostate Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

158 R158Afs*12 Astrocytoma

R158C Bladder Urothelial Carcinoma R158G Breast Invasive Ductal Carcinoma R158H Colon Adenocarcinoma R158L Diffuse Type Stomach Adenocarcinoma R158P Esophageal Squamous Cell Carcinoma

R158S Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma Leiomyosarcoma

Lung Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Lung Squamous Cell Carcinoma Oligoastrocytoma Oligodendroglioma

Prostate Adenocarcinoma Stomach Adenocarcinoma Uterine Endometrioid Carcinoma

159 A159P Astrocytoma

A159V Bladder Urothelial Carcinoma

Cervical Squamous Cell Carcinoma

Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Cutaneous Melanoma

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

160 M160I Lung Squamous Cell Carcinoma

161 A161_H62del Astrocytoma A161D Bladder Urothelial Carcinoma A161Gfs*3 Breast Invasive Ductal Carcinoma A161P Colon Adenocarcinoma A161S Cutaneous Melanoma A161T Head and Neck Squamous Cell Carcinoma A161V Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Serous Ovarian Cancer

162 I162_Y163delinsN Breast Invasive Ductal Carcinoma

I162dup Colon Adenocarcinoma I162F Lung Squamous Cell Carcinoma I162Hfs*12 Tubular Stomach Adenocarcinoma I162N Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma I162Tfs*8 I162Wfs*10

163 Y163* Astrocytoma

Y163D Breast Invasive Ductal Carcinoma

Y163H Colon Adenocarcinoma Y163Lfs*18 Esophageal Squamous Cell Carcinoma

Y163N Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Malignant Peripheral Nerve Sheath Tumor

Oligoas trocy to ma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

164 K164E Esophageal Squamous Cell Carcinoma

K164Sfs*5 Glioblastoma Multiforme

K164Sfs*6 Lung Squamous Cell Carcinoma Mucinous Carcinoma Rectal Adenocarcinoma Serous Ovarian Cancer

165 Q165* Breast Invasive Ductal Carcinoma Q165Afs*6 Lung Adenocarcinoma Q165Hfs*17 Prostate Adenocarcinoma

166 S166* Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Pancreatic Adenocarcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

167 Q167* Bladder Urothelial Carcinoma Q167Hfs*3 Breast Invasive Ductal Carcinoma Q167Tfs*14 Esophageal Adenocarcinoma

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Endometrioid Carcinoma

168 H168Cfs*8 Adrenocortical Carcinoma

H168L Breast Invasive Ductal Carcinoma

H168P Esophageal Squamous Cell Carcinoma

H168R Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Stomach Adenocarcinoma

169 M169I Bladder Urothelial Carcinoma

M169T Breast Invasive Lobular Carcinoma Stomach Adenocarcinoma

171 E171* Bladder Urothelial Carcinoma

E171Gfs*3 Breast Invasive Ductal Carcinoma

E171Gfs*4 Cutaneous Melanoma

E171K Diffuse Large B-Cell Lymphoma, NOS

E171Lfs*2 Glioblastoma Multiforme

E171Rfs*3 Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pleural Mesothelioma. Epithelioid Type

Rectal Adenocarcinoma

172 V172D Esophageal Adenocarcinoma

V172F Glioblastoma Multiforme

V172G Head and Neck Squamous Cell Carcinoma

V172Lfs*2 Lung Squamous Cell Carcinoma

Pleural Mesothelioma, Epithelioid Type

173 V173* Acute Myeloid Leukemia Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

V173_R175del Adrenocortical Carcinoma V173A Astrocytoma V173Afs*69 Breast Invasive Ductal Carcinoma

V173dup Colon Adenocarcinoma V173Efs*7 Esophageal Adenocarcinoma V173G Head and Neck Squamous Cell Carcinoma V173L Lung Adenocarcinoma V173M Lung Squamous Cell Carcinoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of the Stomach

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

174 R174Sfs*73 Breast Invasive Ductal Carcinoma

R174W Esophageal Squamous Cell Carcinoma Hepatocellular Carcinoma

Uterine Endometrioid Carcinoma

175 R175C Astrocytoma

R175G Bladder Urothelial Carcinoma

R175H Breast Invasive Ductal Carcinoma

R175L Colon Adenocarcinoma

Cutaneous Melanoma

Diffuse Type Stomach Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

176 C176* Acute Myeloid Leukemia Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

C176dup Bladder Urothelial Carcinoma C176F Breast Invasive Carcinoma (NOS) C176G Breast Invasive Ductal Carcinoma C176R Chromophobe Renal Cell Carcinoma C176S Colon Adenocarcinoma C176Sfs*71 Diffuse Type Stomach Adenocarcinoma C176W Esophageal Adenocarcinoma C176Y Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Oligodendroglioma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

177 P177_C182del Astrocytoma

P177_H178del Colon Adenocarcinoma

P177H Cutaneous Melanoma

P177L Esophageal Adenocarcinoma

P177R Head and Neck Squamous Cell Carcinoma

P177S Lung Adenocarcinoma

P177T Prostate Adenocarcinoma

Serous Ovarian Cancer

178 H178_S183del Bladder Urothelial Carcinoma

H178D Chromophobe Renal Cell Carcinoma H178Pfs*3 Colon Adenocarcinoma H178Pfs*70 Glioblastoma Multiforme

H178Q Head and Neck Squamous Cell Carcinoma H178Qfs*3 Lung Adenocarcinoma H178Sfs*69 Lung Squamous Cell Carcinoma

H178Tfs*69 Pancreatic Adenocarcinoma

Renal Clear Cell Carcinoma Stomach Adenocarcinoma Uterine Endometrioid Carcinoma

179 H179D Acute Myeloid Leukemia H179L Astrocytoma H179N Bladder Urothelial Carcinoma H179P Breast Invasive Ductal Carcinoma H179Q Colon Adenocarcinoma H179R Cutaneous Melanoma H179Y Diffuse Type Stomach Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

180 E180* Adrenocortical Carcinoma

E180_D184del Bladder Urothelial Carcinoma

E180_S185del Head and Neck Squamous Cell Carcinoma

E180K Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Rectal Adenocarcinoma

181 R181C Astrocytoma

R181H Bladder Urothelial Carcinoma

R181P Colon Adenocarcinoma

Lung Squamous Cell Carcinoma

Prostate Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

183 S183* Bladder Urothelial Carcinoma

Breast Invasive Ductal Carcinoma

Cervical Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

184 D184Afs*62 Head and Neck Squamous Cell Carcinoma

186 D186Vfs*61 Pancreatic Adenocarcinoma

187 G187S Bladder Urothelial Carcinoma X187_splice Breast Invasive Carcinoma (NOS) Breast Invasive Ductal Carcinoma Chromophobe Renal Cell Carcinoma Colon Adenocarcinoma Cutaneous Melanoma

Esophageal Squamous Cell Carcinoma Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma Oligoastrocytoma

Pancreatic Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian Tumor

Uterine Endometrioid Carcinoma

188 L188Gfs*20 Lung Squamous Cell Carcinoma

L188Tfs*21 Serous Ovarian Cancer

189 A189Dfs*14 Bladder Urothelial Carcinoma

A189Pfs*58 Leiomyosarcoma

Lung Squamous Cell Carcinoma

190 P190L Astrocytoma

P190R Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Glioblastoma Multiforme

Lung Squamous Cell Carcinoma

191 P191del Astrocytoma P191L Colon Adenocarcinoma P191Qfs*51 Cutaneous Melanoma

Diffuse Type Stomach Adenocarcinoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Oligodendroglioma

Serous Ovarian Cancer

Stomach Adenocarcinoma

192 Q192* Bladder Urothelial Carcinoma Q192_H193del Breast Invasive Ductal Carcinoma Q192del Cervical Squamous Cell Carcinoma Q192R Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Papillary Thyroid Cancer

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

193 H193D Acute Myeloid Leukemia H193L Astrocytoma H193N Bladder Urothelial Carcinoma H193P Breast Invasive Carcinoma (NOS) H193R Breast Invasive Ductal Carcinoma H193Y Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Metaplastic Breast Cancer

Oligoastrocytoma

Papillary Renal Cell Carcinoma

Prostate Adenocarcinoma

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/Utcrinc Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

194 L194Efs*51 Bladder Urothelial Carcinoma

L194F Breast Invasive Ductal Carcinoma

L194H Endometrioid Carcinoma

L194P Glioblastoma Multiforme

L194Pfs*13 Head and Neck Squamous Cell Carcinoma

L194R Hepatocellular Carcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Thymoma

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

195 I195F Acute Myeloid Leukemia I195Ffs*52 Astrocytoma 1195Lfs*53 Breast Invasive Ductal Carcinoma

I195M Colon Adenocarcinoma

I195N Cutaneous Melanoma I195Nfs*14 Esophageal Squamous Cell Carcinoma

I195S Glioblastoma Multiforme

I195Sfs*52 Head and Neck Squamous Cell Carcinoma

I195T Hepatocellular Carcinoma I195Yfs*14 Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Oligodendroglioma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

196 R196* Astrocytoma

R196P Breast Invasive Carcinoma (NOS)

Breast Invasive Ductal Carcinoma

Cervical Squamous Cell Carcinoma

Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Cutaneous Melanoma

Esophageal Adenocarcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Oligodendroglioma

Pancreatic Adenocarcinoma

Pleural Mesothelioma. Epithelioid Type

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

197 V197G Breast Invasive Ductal Carcinoma V197Ifs*42 Esophageal Squamous Cell Carcinoma V197L Head and Neck Squamous Cell Carcinoma V197M Hepatocellular Carcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

198 E198* Breast Invasive Ductal Carcinoma

E198Gfs*ll Colon Adenocarcinoma

Cutaneous Melanoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

199 G199* Bladder Urothelial Carcinoma

G199Efs*48 Breast Invasive Ductal Carcinoma

G1991fs*47 Colon Adenocarcinoma

G199V Head and Neck Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Uterine Endometrioid Carcinoma

200 N2001fs*47 Head and Neck Squamous Cell Carcinoma Oligoastrocytoma

201 L201* Breast Invasive Ductal Carcinoma L201Ffs*8 Head and Neck Squamous Cell Carcinoma

202 R202 L206del Head and Neck Squamous Cell Carcinoma

203 V203Gfs*44 Head and Neck Squamous Cell Carcinoma

V203Gfs*5 Leiomyosarcoma

V203L Mucinous Adenocarcinoma of the Colon and Rectum V203Wfs*44 Prostate Adenocarcinoma

204 E204* Bladder Urothelial Carcinoma

E204D Breast Invasive Ductal Carcinoma

E204Q Esophageal Squamous Cell Carcinoma

E204Sfs*43 Head and Neck Squamous Cell Carcinoma

E204Vfs*4 Hepatocellular Carcinoma Lung Squamous Cell Carcinoma Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

205 Y205* Astrocytoma Y205C Breast Invasive Ductal Carcinoma Y205D Chromophobe Renal Cell Carcinoma Y205F Colon Adenocarcinoma Y205H Esophageal Squamous Cell Carcinoma

Y205N Glioblastoma Multiforme Y205S Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

206 L206Wfs*41 Head and Neck Squamous Cell Carcinoma

207 D207Ffs*35 Lung Squamous Cell Carcinoma D207Mfs*40

208 D208G Bladder Urothelial Carcinoma

D208N Breast Invasive Ductal Carcinoma

D208V Oligoastrocytoma

Serous Ovarian Cancer

209 R209* Bladder Urothelial Carcinoma R209Hfs*5 Breast Invasive Carcinoma (NOS) R209I Breast Invasive Ductal Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

R209K Esophageal Adenocarcinoma R209Kfs*6 Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Leiomyosarcoma

Lung Adenocarcinoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of tire Stomach Uterine Endometrioid Carcinoma

210 N210Tfs*37 Serous Ovarian Cancer

211 T211_H214del Breast Invasive Carcinoma (NOS) T211A Breast Invasive Ductal Carcinoma T211Ffs*4 Colon Adenocarcinoma T211I Glioblastoma Multiforme T211Lfs*36 Head and Neck Squamous Cell Carcinoma

Lung Squamous Cell Carcinoma

Rectal Adenocarcinoma

Uterine Endometrioid Carcinoma

212 F212Sfs*3 Astrocytoma F212Yfs*34 Breast Invasive Ductal Carcinoma Glioblastoma Multiforme Lung Squamous Cell Carcinoma

213 R213* Adrenocortical Carcinoma R213Dfs*34 Astrocytoma R213G Bladder Urothelial Carcinoma R213L Breast Invasive Carcinoma (NOS) R213P Breast Invasive Ductal Carcinoma

R213Q Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Cutaneous Melanoma

Dedifferentiated Liposarcoma

Diffuse Type Stomach Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Myxofibrosarcoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor

Uterine Endometrioid Carcinoma

214 H214L Astrocytoma H214Qfs*33 Bladder Urothelial Carcinoma H214R Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Serous Carcinoma/Uterine Papi 1 la ry Serous Carcinoma

215 S215G Acute Myeloid Leukemia

S215I Astrocytoma

S215Kfs*7 Breast Invasive Ductal Carcinoma

S215N Colon Adenocarcinoma

S215R Cutaneous Melanoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

216 V216E Astrocytoma

V216G Breast Invasive Ductal Carcinoma

V216L Colon Adenocarcinoma V216M Esophageal Adenocarcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pleural Mesothelioma, Biphasic Type

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

217 V217Gfs*31 Pancreatic Adenocarcinoma

218 V218Cfs*29 Bladder Urothelial Carcinoma V218del Cutaneous Melanoma V218E Head and Neck Squamous Cell Carcinoma V218G Lung Squamous Cell Carcinoma

Serous Ovarian Cancer Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

219 P219Afs*3 Bladder Urothelial Carcinoma

P219Lfs*2 Head and Neck Squamous Cell Carcinoma

P219T Rectal Adenocarcinoma

220 Y220* Astrocytoma

Y220C Bladder Urothelial Carcinoma

Y220D Breast Invasive Carcinoma (NOS)

Y220H Breast Invasive Ductal Carcinoma Y220Mfs*27 Cervical Squamous Cell Carcinoma Y220S Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Cutaneous Melanoma

Dedifferentiated Liposarcoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Papillary Renal Cell Carcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

221 E221* Bladder Urothelial Carcinoma E221Afs*2 Breast Invasive Ductal Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Squamous Cell Carcinoma

Serous Ovarian Cancer

223 P223* Acute Myeloid Leukemia P223Rfs*4 Serous Ovarian Cancer X223_splice Tubular Stomach Adenocarcinoma

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

224 E224* Astrocytoma

E224D Bladder Urothelial Carcinoma E224Gfs*4 Breast Invasive Ductal Carcinoma X224 splice Colon Adenocarcinoma

Cutaneous Melanoma

Diffuse Type Stomach Adenocarcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Hepatocellular Carcinoma Leiomyosarcoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Myxofibrosarcoma

Oligoastrocytoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

225 V225Rfs*23 Acute Myeloid Leukemia

X225_splice Astrocytoma

Breast Invasive Ductal Carcinoma

Chromophobe Renal Cell Carcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pleural Mesothelioma, Epithelioid Type

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

226 G226Afs*21 Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

227 S227* Oligoastrocytoma

228 D228* Bladder Urothelial Carcinoma

D228E Hepatocellular Carcinoma

D228N Serous Ovarian Cancer D228Vfs*18 Tubular Stomach Adenocarcinoma

229 C229* Bladder Urothelial Carcinoma C229_I232del Chromophobe Renal Cell Carcinoma C229Lfs*18 Colon Adenocarcinoma C229Yfs*10 Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Serous Ovarian Cancer

230 T230_T231del Hepatocellular Carcinoma

T230Hfs*9 Lung Squamous Cell Carcinoma T230P Oligoastrocytoma

232 I232F Astrocytoma

I232N Breast Invasive Ductal Carcinoma

I232S Colon Adenocarcinoma

I232T Diffuse Large B-Cell Lymphoma, NOS

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

234 Y234* Adrenocortical Carcinoma

Y234C Astrocytoma

Y234H Breast Invasive Ductal Carcinoma

Y234N Colon Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Y234Pfs*7 Glioblastoma Multiforme Y234S Head and Neck Squamous Cell Carcinoma Y234Tfs*ll Intrahepatic Cholangiocarcinoma

Leiomyosarcoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pleural Mesothelioma. Biphasic Type

Rectal Adenocarcinoma

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

236 Y236* Astrocytoma Y236C Bladder Urothelial Carcinoma Y236D Colon Adenocarcinoma Y236del Head and Neck Squamous Cell Carcinoma

Y236H Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Serous Ovarian Cancer

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

237 M237_N239del Astrocytoma M237Cfs*10 Bladder Urothelial Carcinoma M237Gfs*20 Breast Invasive Ductal Carcinoma M237I Colon Adenocarcinoma M237K Dedifferentiated Liposarcoma M237L Esophageal Adenocarcinoma M237V Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Intrahepatic Cholangiocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Myxofibrosarcoma

Oligoastrocytoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillaiy Serous Carcinoma

238 C238* Astrocytoma C238_M243del Bladder Urothelial Carcinoma C238_N239delinsY Breast Invasive Ductal Carcinoma C238F Endocervical Adenocarcinoma C238G Esophageal Squamous Cell Carcinoma

C238Lfs*9 Glioblastoma Multiforme

C238R Head and Neck Squamous Cell Carcinoma C238S Hepatocellular Carcinoma C238W Intestinal Type Stomach Adenocarcinoma C238Y Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma Oligodendroglioma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Pancreatic Adenocarcinoma

Pleural Mesothelioma, Epithelioid Type

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

239 N239* Astrocytoma

N239_S240del Breast Invasive Ductal Carcinoma

N239_S241del Chromophobe Renal Cell Carcinoma

N239D Colon Adenocarcinoma

N239Qfs*24 Esophageal Adenocarcinoma

N239S Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

240 S240 C242del Bladder Urothelial Carcinoma S240G Colon Adenocarcinoma

S240Gfs*20 Head and Neck Squamous Cell Carcinoma

S240Kfs*24 Stomach Adenocarcinoma

S240R Uterine Endometrioid Carcinoma

241 S241A Bladder Urothelial Carcinoma S241C Breast Invasive Ductal Carcinoma S241dup Cervical Squamous Cell Carcinoma S241F Cutaneous Melanoma S241P Esophageal Adenocarcinoma S241Pfs*6 Glioblastoma Multiforme

S241Y Head and Neck Squamous Cell Carcinoma

Invasive Breast Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma

Papillary Renal Cell Carcinoma

Papillary Stomach Adenocarcinoma

Perihilar Cholangiocarcinoma

Serous Ovarian Cancer

Serous Ovarian Cancer

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

242 C242* Bladder Urothelial Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

C242Afs*5 Breast Invasive Ductal Carcinoma

C242F Colon Adenocarcinoma C242G Diffuse Type Stomach Adenocarcinoma C242R Esophageal Adenocarcinoma C242S Esophageal Squamous Cell Carcinoma

C242Y Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian Tumor

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

243 M243I Bladder Urothelial Carcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

244 G244* Colon Adenocarcinoma G244C Glioblastoma Multiforme G244D Head and Neck Squamous Cell Carcinoma

G244S Leiomyosarcoma G244V Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pleural Mesothelioma, Epithelioid Type

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

245 G245C Astrocytoma G245D Bladder Urothelial Carcinoma G245R Breast Invasive Ductal Carcinoma G245S Colon Adenocarcinoma

G245V Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Oligodendroglioma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Pancreatic Adenocarcinoma

Pleural Mesothelioma, Epithelioid Type

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of the Stomach

Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

246 M246I Bladder Urothelial Carcinoma

M246R Breast Invasive Lobular Carcinoma

M246T Chromophobe Renal Cell Carcinoma

M246V Esophageal Adenocarcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Tubular Stomach Adenocarcinoma

Uterine Mixed Endometrial Carcinoma

247 N247I Breast Invasive Ductal Carcinoma Lung Adenocarcinoma

248 R248G Acute Myeloid Leukemia R248Hfs*13 Astrocytoma R248L Bladder Urothelial Carcinoma R248P Breast Invasive Carcinoma (NOS)

R248Q Breast Invasive Ductal Carcinoma R248W Cholangiocarcinoma

Colon Adenocarcinoma

Cutaneous Melanoma

Diffuse Large B-Cell Lymphoma, NOS

Diffuse Type Stomach Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Thymoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

249 R249Ffs*96 Astrocytoma R249G Bladder Urothelial Carcinoma R249Gfs*96 Esophageal Squamous Cell Carcinoma R249M Glioblastoma Multiforme R249S Head and Neck Squamous Cell Carcinoma R249T Hepatocellular Carcinoma R249W Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Prostate Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

250 P250_I251delinsL Astrocytoma

P250Hfs*13 Breast Invasive Ductal Carcinoma

P250L Chromophobe Renal Cell Carcinoma

P250R Esophageal Squamous Cell Carcinoma Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma Serous Ovarian Cancer

251 125 IF Breast Invasive Ductal Carcinoma

125 IN Head and Neck Squamous Cell Carcinoma

125 IS Hepatocellular Carcinoma I251Sfs*94 Lung Squamous Cell Carcinoma

Serous Ov arian Cancer

252 L252_I254del Breast Invasive Ductal Carcinoma L252_T253delinsP Esophageal Squamous Cell Carcinoma L252del Lung Squamous Cell Carcinoma L252P Myxofibrosarcoma L252Sfs*93 Uterine Mixed Endometrial Carcinoma

253 T253A Breast Invasive Ductal Carcinoma T253dup Esophageal Adenocarcinoma T253Hfs*ll Hepatocellular Carcinoma T253I Papillary Stomach Adenocarcinoma T253N Serous Ovarian Cancer

254 I254S Glioblastoma Multiforme

Intestinal Type Stomach Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Pancreatic Adenocarcinoma

255 1255del Breast Invasive Lobular Carcinoma I255F Esophageal Adenocarcinoma I255N Esophageal Squamous Cell Carcinoma I255S Glioblastoma Multiforme I255T Glioblastoma Multiforme

Lung Adenocarcinoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Papillary Renal Cell Carcinoma

256 T256del Breast Invasive Ductal Carcinoma T256Hfs*8 Head and Neck Squamous Cell Carcinoma T256I Prostate Adenocarcinoma T256Ifs*90 Serous Ovarian Cancer T256Nfs*8 Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Endometrioid Carcinoma

257 L257P Bladder Urothelial Carcinoma L257Pfs*7 Breast Invasive Ductal Carcinoma L257Q Esophageal Adenocarcinoma L257R Hepatocellular Carcinoma Serous Ovarian Cancer

258 E258* Bladder Urothelial Carcinoma

E258A Breast Invasive Ductal Carcinoma

E258D Esophageal Adenocarcinoma

E258G Head and Neck Squamous Cell Carcinoma

E258K Hepatocellular Carcinoma

E258Q Lung Adenocarcinoma E258Qfs*3 Lung Squamous Cell Carcinoma X258_splice Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

259 D259Efs*86 Bladder Urothelial Carcinoma

D259N Colon Adenocarcinoma

D259V Head and Neck Squamous Cell Carcinoma

D259Y Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Tubular Stomach Adenocarcinoma

260 S260_L264dup Serous Ovarian Cancer S260Lfs*4

261 S261Vfs*84 Breast Invasive Ductal Carcinoma

X261_splicc Esophageal Adenocarcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma Oligoastrocytoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of the Stomach

Stomach Adenocarcinoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian

Tumor

262 G262dcl Head and Neck Squamous Cell Carcinoma G262V Hepatocellular Carcinoma G262Vfs*83 Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Endometrioid Carcinoma

263 N263Ifs*82 Hepatocellular Carcinoma N263Kfs*9 Oligoastrocytoma N263Sfs*8

264 L264Yfs*81 Glioblastoma Multiforme

265 L265P Astrocytoma

L265R Bladder Urothelial Carcinoma

L265Tfs*7 Breast Invasive Ductal Carcinoma

Head and Neck Squamous Cell Carcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Serous Ov arian Cancer

Tubular Stomach Adenocarcinoma

266 G266* Breast Invasive Ductal Carcinoma G266Dfs*79 Colon Adenocarcinoma

G266E Cutaneous Melanoma

G266R Glioblastoma Multiforme

G266V Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

267 R267G Astrocytoma R267L Chromophobe Renal Cell Carcinoma R267P Colon Adenocarcinoma R267Q Glioblastoma Multiforme R267W Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Oligoastrocytoma

Tubular Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

268 N268* Head and Neck Squamous Cell Carcinoma N268_R273dcl Lung Squamous Cell Carcinoma N268Kfs*77 Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous N268Tfs*77 Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Carcinosarcoma/U terine Malignant Mixed Mullerian Tumor

269 S269_E271delinsK Oligodendroglioma

S269Ifs*2 Pancreatic Adenocarcinoma

270 F270C Astrocytoma

F270I Breast Invasive Ductal Carcinoma

F270L Head and Neck Squamous Cell Carcinoma

F270Lfs*2 Intestinal Type Stomach Adenocarcinoma

F270S Leiomyosarcoma

F270V Lung Adenocarcinoma

Oligodendroglioma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Tubular Stomach Adenocarcinoma

271 E271* Bladder Urothelial Carcinoma

E271K Breast Invasive Ductal Carcinoma

E271Q Colon Adenocarcinoma

E271V Endometrioid Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

272 V272A Astrocytoma

V272Cfs*73 Breast Invasive Carcinoma (NOS)

V272G Breast Invasive Ductal Carcinoma V272L Cervical Squamous Cell Carcinoma V272M Colon Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

273 R273C Acute Myeloid Leukemia

R273G Adrenocortical Carcinoma

R273H Astrocytoma

R273L Bladder Urothelial Carcinoma R273Lfs*72 Breast Invasive Carcinoma (NOS)

R273P Breast Invasive Ductal Carcinoma

R273S Colon Adenocarcinoma

Diffuse Large B-Cell Lymphoma, NOS

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Pleural Mesothelioma, Biphasic Type

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Thymoma

Tubular Stomach Adenocarcinoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

274 V274_C275dup Astrocytoma V274_G279del Breast Invasive Ductal Carcinoma V274D Colon Adenocarcinoma V274dup Esophageal Adenocarcinoma V274F Esophageal Squamous Cell Carcinoma V274G Head and Neck Squamous Cell Carcinoma V274L Intestinal Type Stomach Adenocarcinoma Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma Serous Ovarian Cancer

275 C275* Adrenocortical Carcinoma C275_R282delinsW Astrocytoma C275F Bladder Urothelial Carcinoma C275G Breast Invasive Ductal Carcinoma C275Lfs*67 Chromophobe Renal Cell Carcinoma C275Lfs*70 Colon Adenocarcinoma C275R Cutaneous Melanoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

C275S Esophageal Squamous Cell Carcinoma

C275Vfs*70 Glioblastoma Multiforme

C275W Head and Neck Squamous Cell Carcinoma C275Y Hepatocellular Carcinoma

Leiomyosarcoma

Low-Grade Glioma (NOS)

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma

276 A276D Breast Invasive Ductal Carcinoma

A276G Cutaneous Melanoma

A276Lfs*29 Head and Neck Squamous Cell Carcinoma

A276Lfs*31 Hepatocellular Carcinoma

A276P Lung Squamous Cell Carcinoma

Pleural Mesothelioma, Biphasic Type

Serous Ovarian Cancer

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

277 C277* Astrocytoma

C277dup Bladder Urothelial Carcinoma

C277F Head and Neck Squamous Cell Carcinoma

C277G Lung Adenocarcinoma

C277Vfs*68 Oligoastrocytoma

C277W Oligodendroglioma

C277Y Serous Ovarian Cancer

Serous Ovarian Cancer

278 P278A Astrocytoma

P278H Bladder Urothelial Carcinoma P278L Breast Invasive Ductal Carcinoma P278Lfs*67 Colon Adenocarcinoma P278Lfs*68 Cutaneous Melanoma

P278R Esophageal Squamous Cell Carcinoma P278S Head and Neck Squamous Cell Carcinoma P278T Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Metaplastic Breast Cancer

Mucinous Adenocarcinoma of the Colon and Rectum

Mucinous Carcinoma

Myxofibrosarcoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

279 G279E Bladder Urothelial Carcinoma G279Pfs*69 Breast Invasive Ductal Carcinoma G279R Lung Squamous Cell Carcinoma Oligoastrocytoma

Prostate Adenocarcinoma Serous Ovarian Cancer

Uterine Endometrioid Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

280 R280* Acute Myeloid Leukemia R280Efs*65 Astrocytoma R280G Bladder Urothelial Carcinoma R280I Breast Invasive Carcinoma (NOS) R280K Breast Invasive Ductal Carcinoma R280Kfs*59 Cervical Squamous Cell Carcinoma R280S Cutaneous Melanoma R280T Esophageal Adenocarcinoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Metaplastic Breast Cancer

Oligoastrocytoma

Oligodendroglioma

Serous Ovarian Cancer

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

281 D281A Astrocytoma

D281Afs*62 Bladder Urothelial Carcinoma

D281Afs*64 Breast Invasive Ductal Carcinoma

D281Afs*66 Diffuse Type Stomach Adenocarcinoma

D281E Glioblastoma Multiforme

D281Efs*26 Head and Neck Squamous Cell Carcinoma

D281Gfs*63 Hepatocellular Carcinoma

D281H Leiomyosarcoma

D281N Lung Adenocarcinoma

D281V Lung Squamous Cell Carcinoma

D281Y Metaplastic Breast Cancer

Renal Clear Cell Carcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Thymoma

Uterine Carcinosarcoma/Uterine Malignant Mixed Mullerian

Tumor

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

282 R282_R283del Astrocytoma R282G Bladder Urothelial Carcinoma R282Gfs*63 Breast Invasive Carcinoma (NOS) R282Q Breast Invasive Ductal Carcinoma R282W Cervical Squamous Cell Carcinoma

Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Diffuse Type Stomach Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Signet Ring Cell Carcinoma of tire Stomach

Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

Uterine Mixed Endometrial Carcinoma

Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma

283 R283Afs*62 Bladder Urothelial Carcinoma

R283H Head and Neck Squamous Cell Carcinoma

R283P Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

284 T284Hfs*22 Serous Ovarian Cancer

T284Kfs*61 Tubular Stomach Adenocarcinoma

T284Qfs*61

285 E285* Bladder Urothelial Carcinoma

E285K Breast Invasive Ductal Carcinoma

E285Q Breast Invasive Lobular Carcinoma E285Rfs*54 Cervical Squamous Cell Carcinoma

E285V Colon Adenocarcinoma

Diffuse Type Stomach Adenocarcinoma Esophageal Squamous Cell Carcinoma Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Carcinoma

Pheochromocytoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Stomach Adenocarcinoma

286 E286* Acute Myeloid Leukemia E286_E287del Bladder Urothelial Carcinoma E286A Breast Invasive Carcinoma (NOS) E286G Breast Invasive Ductal Carcinoma E286K Colon Adenocarcinoma E286Q Cutaneous Melanoma E286V Diffuse Type Stomach Adenocarcinoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Endometrioid Carcinoma

287 E287* Bladder Urothelial Carcinoma

E287D Breast Invasive Ductal Carcinoma

E287Pfs*9 Cervical Squamous Cell Carcinoma

E287Q Lung Squamous Cell Carcinoma Rectal Adenocarcinoma

288 N288Efs*18 Astrocytoma

N288Kfs*59 Myxofibrosarcoma

289 L289F Breast Invasive Ductal Carcinoma

290 R290C Colon Adenocarcinoma

R290Kfs*53 Cutaneous Melanoma

R290Sfs*56 Head and Neck Squamous Cell Carcinoma

291 K291Sfs*51 Lung Squamous Cell Carcinoma

292 K292* Breast Invasive Ductal Carcinoma K292Gfs*52 Chromophobe Renal Cell Carcinoma Hepatocellular Carcinoma

294 E294* Astrocytoma E294Sfs*51 Bladder Urothelial Carcinoma

Breast Invasive Ductal Carcinoma

Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Serous Ovarian Cancer

Tubular Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

296 H296Tfs*49 Lung Adenocarcinoma

297 H297Pfs*48 Astrocytoma

Head and Neck Squamous Cell Carcinoma

298 E298* Bladder Urothelial Carcinoma

Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

299 L299Afs*7 Breast Invasive Ductal Carcinoma

301 P301Qfs*44 Bladder Urothelial Carcinoma P301T Colon Adenocarcinoma

Cutaneous Melanoma

Lung Squamous Cell Carcinoma

Stomach Adenocarcinoma

302 G302Afs*31 Colon Adenocarcinoma

G302Efs*3 Glioblastoma Multiforme

G302Rfs*4 Head and Neck Squamous Cell Carcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Hepatocellular Carcinoma Pancreatic Adenocarcinoma

303 S303Afs*42 Breast Invasive Ductal Carcinoma

304 T3041fs*41 Breast Invasive Ductal Carcinoma

305 K3O5* Head and Neck Squamous Cell Carcinoma K305Efs*39 Lung Adenocarcinoma X305_splice Lung Squamous Cell Carcinoma

Serous Ovarian Cancer

306 R306* Astrocytoma R306Afs*31 Bladder Urothelial Carcinoma

Breast Invasive Lobular Carcinoma

Colon Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Mucinous Stomach Adenocarcinoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

307 X307_splice Adrenocortical Carcinoma

Astrocytoma

Breast Invasive Carcinoma (NOS)

Chromophobe Renal Cell Carcinoma

Colon Adenocarcinoma

Diffuse Type Stomach Adenocarcinoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Prostate Adenocarcinoma

Serous Ovarian Cancer

308 L308Afs*28 Breast Invasive Ductal Carcinoma

L308Qfs*27 Esophageal Adenocarcinoma

310 N310Tfs*35 Diffuse Type Stomach Adenocarcinoma

313 S313Afs*32 Glioblastoma Multiforme

Lung Adenocarcinoma

Uterine Endometrioid Carcinoma

315 S315C Lung Squamous Cell Carcinoma

S315Lfs*30 Uterine Endometrioid Carcinoma

316 P316Sfs*21 Serous Ovarian Cancer Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

317 Q317* Acute Myeloid Leukemia Q317Afs*19 Astrocytoma Q317Pfs*20 Bladder Urothelial Carcinoma

Cutaneous Melanoma

Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Serous Ovarian Cancer

Uterine Serous Carcinoma/U terine Papillary Serous Carcinoma

318 P318Tfs*15 Breast Invasive Ductal Carcinoma

319 K319* Bladder Urothelial Carcinoma K319Afs*19 Cervical Squamous Cell Carcinoma

K319N Prostate Adenocarcinoma K319Rfs*26 Rectal Adenocarcinoma

320 K320E Head and Neck Squamous Cell Carcinoma

K320Gfs*22 Lung Squamous Cell Carcinoma

K320Nfs*19 Serous Ovarian Cancer

K320Rfs*25

321 K321* Astrocytoma K321Efs*16 Serous Ovarian Cancer

322 P322Hfs*23 Colon Adenocarcinoma

325 G325* Esophageal Adenocarcinoma

327 Y327* Cutaneous Melanoma Glioblastoma Multiforme Serous Ovarian Cancer

328 F328Sfs*17 Breast Invasive Ductal Carcinoma Hepatocellular Carcinoma

329 T329Hfs*8 Head and Neck Squamous Cell Carcinoma

T329Rfs*14 Hepatocellular Carcinoma

330 L33OFfs*15 Cutaneous Melanoma

L330I Head and Neck Squamous Cell Carcinoma

L330R Serous Ovarian Cancer

331 Q331* Astrocytoma

Q331H Bladder Urothelial Carcinoma

Q331Sfs*6 Breast Invasive Ductal Carcinoma

X331_splice Colon Adenocarcinoma

Cutaneous Melanoma

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Mucinous Carcinoma

Pancreatic Adenocarcinoma

Pleural Mesothelioma, Epithelioid Type

Prostate Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Rectal Adenocarcinoma

Serous Ovarian Cancer

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

332 I332F Astrocytoma X332_splice Diffuse Large B-Cell Lymphoma, NOS

Esophageal Squamous Cell Carcinoma

Head and Neck Squamous Cell Carcinoma

Hepatocellular Carcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Oligoastrocytoma

Serous Ovarian Cancer

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

333 R333C Breast Invasive Ductal Carcinoma R333Vfs*12 Cervical Squamous Cell Carcinoma

Mucinous Adenocarcinoma of the Colon and Rectum

Serous Ovarian Cancer

334 G334V Lung Adenocarcinoma

G334W Lung Squamous Cell Carcinoma

Seminoma

Uterine Serous Carcinoma/Uterine Papillary' Serous Carcinoma

335 R335Lfs*10 Adrenocortical Carcinoma R335Qfs*2 Colon Adenocarcinoma

R335Vfs*10 Oligoastrocytoma

Rectal Adenocarcinoma

Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous

Histiocytoma/High-Grade Spindle Cell Sarcoma

336 E336* Bladder Urothelial Carcinoma E336 R337del Colon Adenocarcinoma E336Afs*10 Head and Neck Squamous Cell Carcinoma

E336Sfs*9 Leiomyosarcoma

Lung Adenocarcinoma

337 R337C Acute Myeloid Leukemia R337H Adrenocortical Carcinoma R337L Bladder Urothelial Carcinoma R337P Cervical Squamous Cell Carcinoma

R337S Chromophobe Renal Cell Carcinoma Colon Adenocarcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma Intestinal Type Stomach Adenocarcinoma Leiomyosarcoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Oligodendroglioma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Stomach Adenocarcinoma

338 F3381 Chromophobe Renal Cell Carcinoma

F338Lfs*7 Serous Ovarian Cancer

339 E339* Adrenocortical Carcinoma

E339Afs*8 Breast Invasive Ductal Carcinoma

E339Rfs*6 Head and Neck Squamous Cell Carcinoma

Lung Adenocarcinoma

Oligodendroglioma

Stomach Adenocarcinoma

340 M340Sfs*8 Serous Ovarian Cancer

341 F341Efs*7 Head and Neck Squamous Cell Carcinoma

F341L Hepatocellular Carcinoma

F341V Lung Adenocarcinoma

342 R342* Acute Myeloid Leukemia

R342Efs*2 Astrocytoma

R342Efs*3 Breast Invasive Ductal Carcinoma

R342P Colon Adenocarcinoma

Cutaneous Melanoma

Esophageal Adenocarcinoma

Esophageal Squamous Cell Carcinoma

Glioblastoma Multiforme

Head and Neck Squamous Cell Carcinoma

Intestinal Type Stomach Adenocarcinoma

Lung Adenocarcinoma

Lung Squamous Cell Carcinoma

Myxofibrosarcoma

Oligoastrocytoma

Pancreatic Adenocarcinoma

Prostate Adenocarcinoma

Rectal Adenocarcinoma

Serous Ovarian Cancer

Stomach Adenocarcinoma

Uterine Endometrioid Carcinoma

Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

343 E343* Esophageal Squamous Cell Carcinoma E343Gfs*2 Head and Neck Squamous Cell Carcinoma Lung Adenocarcinoma Serous Ovarian Cancer

345 N345D Mucinous Stomach Adenocarcinoma

N345Mfs*25 Serous Ovarian Cancer

N345Sfs*2 Tubular Stomach Adenocarcinoma

346 E346* Lung Adenocarcinoma Oligoastrocytoma

347 A347V Uterine Mixed Endometrial Carcinoma

348 L348* Head and Neck Squamous Cell Carcinoma

L348F Lung Squamous Cell Carcinoma

L348S Serous Ovarian Cancer L348Wfs*22

351 K351* Leiomyosarcoma

K351E Lung Adenocarcinoma Amino Acid Non-Limiting Non-Limiting Exemplary p53 Position Exemplary Mutations Associated Cancer(s)

Lung Squamous Cell Carcinoma

354 Q354* Lung Adenocarcinoma

355 A355T Lung Adenocarcinoma

367 X367_splice Bladder Urothelial Carcinoma

Head and Neck Squamous Cell Carcinoma

Uterine Mixed Endometrial Carcinoma

375 Q375* Bladder Urothelial Carcinoma

Q375K Glioblastoma Multiforme Papillary Thyroid Cancer

376 S376C Cervical Squamous Cell Carcinoma

379 R379C Uterine Serous Carcinoma/Uterine Papillary Serous Carcinoma

382 K382Nfs*40 Bladder Urothelial Carcinoma

Oligoastrocytoma

Uterine Endometrioid Carcinoma Uterine Mixed Endometrial Carcinoma

383 L383Cfs*38 Head and Neck Squamous Cell Carcinoma

385 F385L Bladder Urothelial Carcinoma

390 P390Qfs*32 Esophageal Squamous Cell Carcinoma

392 S392Tfs*76 Intestinal Type Stomach Adenocarcinoma

^A Unless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pH (2013).

Combinations

In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies, or combinations of any of the foregoing. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject has undergone prior therapy. In some embodiments, a subject is naive to p53 restoration therapy. In some embodiments, a subject is not naive to p53 restoration therapy. In some embodiments, a subject is kinase inhibitor naive. In some embodiments, a subject is not kinase inhibitor naive.

In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents described herein. For example, in some embodiments, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with one, two, or three independently selected additional therapeutic agents as described herein.

Non-limiting examples of additional therapeutic agents include small molecules, antibodies, and antibody-drug conjugates such as EGFR inhibitors, HER2 inhibitors, RAS pathway targeted therapeutic agents (as described herein), PARP inhibitors, CDK4/6 inhibitors, FGFR inhibitors, ALK inhibitors, NTRK/ROS inhibitors, MET inhibitors, RET inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase-targeted therapeutic agents (e.g., multi-kinase inhibitors)), selective estrogen receptor modulators or degraders (SERMs / SERDs), antiandrogens, checkpoint inhibitors; cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.

In some embodiments, the CDK4/6 inhibitor is palbociclib (IBRANCE®, PD-0332991), ribociclib (KISQALI®, LEE-011), abemaciclib (VERZENIO®, LY-2835219), trilaciclib (COSELA™, G1T28), lerociclib (G1T38), dalpiciclib (SHR-6390), or BPI-16350.

In some embodiments, the FGFR inhibitor is pemigatinib (PEMAZYRE®, INCB-054828), infigratinib (TRUSELTIQ®, BGJ-398, NVP-BGJ398), futibatinib (LYTGOBI®, TAS- 120), erdafitinib (BAL VERSA®, JNJ-42756493), AZD4547, derazantinib (ARQ-087), AZD4547, ferulic acid-13C3, FGFR-IN-7, PP58, FGFR3-IN-1, ENMD-2076 tartrate, R1530, FGFR3-IN-3, ryrosine kinase-IN-1, SU4984, roblitinib (FGF-401), PD173074, FGFR4-IN-8, lucitanib (E-3810), masitinib (AB1010), zoligratinib (debio 1347, CH5183284), FGFR4-IN-4, BLU9931, SMI-71, TG 100801, FGFR1 inhibitor-6, or TG 100572.

In some embodiments, the ALK inhibitor is crizotinib (X.kl.KORI®. PF-02341066), ceritinib (ZYKADIA®, LDK-378), alectinib (ALECENSA®, CH5424802, RO5424802, AF802), brigatinib (ALUNBRIG®, AP-26113), lorlatinib (LORBRENA®, PF-06463922), entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), ASP3026, TSR-01 L PF-06463922, ensartinib (X- 396), or CEP-37440.

In some embodiments, the NTRK/ROS inhibitor is entrectinib (NMS-E628, RXDX-101, ROZLYTREK®), taletrectinib (DS-6051b, AB-106), or repotrectinib (TPX-0005),

In some embodiments, the MET inhibitor is capmatinib (TABRECTA®, INC280; INCB28060), tepotinib (TEPMETKO®), tivantinib (ARQ197), savolitinib (ORPATHYS®, Volitinib, HMPL-504, AZD-6094), foretinib (XL880, GSK1363089, GSK089, EXEL-2880), pamufetinib (TAS-115), c-Met-IN-2, PHA-665752, SU11274, SYN1143, or amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride).

In some embodiments, the RET inhibitor is selpercatinib (RETEVMO®, LOXO-292), zeteletinib (BOS- 172738, DS-5010), GSK3179106, amuvatinib hydrochloride (MP470 hydrochloride, HPK 56 hydrochloride), TPX-0046, or pralsetinib (GAVRETO®, BLU-667).

In some embodiments, the EGFR inhibitor is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS-816), mavelertinib (PF-06747775), icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetyl shikonin, P,P-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM- 151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ-61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

Exemplary HER2 inhibitors include trastuzumab (e g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 22261 1, and AEE-788.

A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e g., KRAS, HRAS, and NRAS), RAF (ARAF, BRAF, CRAF), MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor.

Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include sotorasib (AMG510, LUMAKRAS®), BI 1701963, BI 1823911, ARS-853, ARS-3248, ARS-1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, GDC-6036, D-1553, AA12, JDQ443, and adagrasib (MRTX-849).

Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVI®), BMS-908662 (XL281), sorafenib, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC-0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof.

In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK 162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI 1040 (PD 184352), hypothemycin, or a combination thereof.

In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-1 le, 25-OH-D3-3- BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ- 13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK-8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG-7482), ASN007, FR148083, 5- 7-Oxozeaenol, 5 -iodotuberci din, GDC0994, ONC201, or a combination thereof. In some embodiments, the PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ- 235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC-907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI-402, wortmannin, LY294002, PI- 103, rigosertib, XL-765, LY2023414, SAR260301, KIN-193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2- aminoprop-2-yl)phenyl]-3 -phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2- aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

In some embodiments, the mTOR inhibitor is selected from MLN0128, vistusertib (AZD- 2014), onatasertib (CC-223), CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), ridaforolimus (MK-8669), or a combination thereof.

In some embodiments, a chemotherapeutic agent includes an anthracycline, a topoisomerase inhibitors, an antimetabolite, an alkylating agent, a taxane, a platinum-based agent, mitomycin, eribulin (HALAVEN™), or combinations thereof.

In some embodiments, the topoisomerase inhibitor is irinotecan (CAMPTOSAR®), camptothecin, topotecan, etoposide, or teniposide.

In some embodiments, the alkylating agent is cyclophosphamide, Melphalan, chlorambucil, ifosfamide, bendamustine, carmustine, lomustine, or busulfan. In some embodiments, the alkylating agent is cyclophosphamide. In some embodiments, the antimetabolite is methotrexate, pemetrexed (ALIMTA®), 5- fluorouracil (5-FU), 6-Mercaptopurine (6-MP), capecitabine (XELODA®), cytarabine (Ara-C®), floxuridine, fludarabine, gemcitabine (GEMZAR®), hydroxycarbamide, phototrexate, or a combination of any of the foregoing. In some embodiments, the antimetabolite is methotrexate, pemetrexed, or 5-FU.

Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, aclarubicin, and combinations thereof.

In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.

Non-limiting examples of P ARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF- 01367338, INO-1001, and JPI-289.

Non-limiting examples of selective estrogen receptor modulators or degraders (SERMs / SERDs) include tamoxifen, fulvestrant, brilanestrant, elacestrant, giredestrant, amcenestrant (SAR439859), AZD9833, rintodestrant, LSZ102, LY3484356, ZN-c5, D-0502, and SHR9549.

Non-limiting examples of anti-androgens include enzalutamide (XTANDI®), leuprolide (LUPRON®, ELIGARD®), goserelin (ZOLDEX®), triptorelin (TRELSTAR®), leuprolide mesylate (CAMCEVI®), flutamide (EULEXIN®), bicalutamide (CASXODEX®), nilutamide (NILANDRON®), degarelix (FIRMAGON®), relugolix (ORGOVYX®), and abiraterone (ZYTIGA®).

Non-limiting examples of immunotherapy include immune checkpoint therapies, such as inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), vopratelimab (JTX-4014), spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IB 1308), tislelizumab (BGB-A317), toripalimab (JS 001), INCMGA00012, AMP-224, AMP-514 (MEDI0680), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), KN035, cosibelimab (CK-301), AUNP12, CA-170, BMS-986189, or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is INJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin- Acevedo, et al., J Hematol Oncol. 11: 39 (2018).

In some embodiments, the additional therapy or therapeutic agent is selected from 5-FU, irinotecan, cisplatin, carboplatin, oxaliplatin, doxorubicin, epirubicin, gemcitabine, methotrexate, pemetrexed, cyclophosphamide, olaparib, rucaparib, niraparib, pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), dostarlimab (JEMPERLI®), atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), radiation therapy, and combinations of any of the foregoing.

In some embodiments, additional therapeutic agents may also be administereted to treat potential side-effects for particular anticancer therapies and/or as palliative therapy, for example, opioids and corticosteroids.

EXAMPLES

Compound Preparation

The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents.

Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.

The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

The compounds described herein can be synthesized, for example, using the procedure shown in Scheme 1, Scheme 2, or Scheme 3 below, using different coupling partners from diversifiable intermediate 8, intermediate 16, or intermediate 29.

Example 1 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-

[(trifluoromethyl)sulfanyl] imidazo [1 ,2-a] pyridin-2-yl)- 1 ,2,4-oxadiazol-5- yl]methyl}cyclopropanecarboxamide

Step 1: To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2- a]pyridine-2-carboxylic acid (1.00 g, 2.93 mmol, 1.00 equiv) in DMF (3.00 mL) was added HATU (1.67 g, 4.39 mmol, 1.50 equiv), NaHCCh (1.23 g, 14.66 mmol, 5.00 equiv) and NFhCl (470.5 mg, 8.79 mmol, 3.00 equiv). The resulting mixture was stirred for 1 h at room temperature. The resulted solution was purified reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) to afford 8- bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2- carboxamide (800 mg, 80.23%) as a white solid. LC-MS: [M+H] ⁺ found found 339.9.

Step 2: A solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine- 2- carboxamide (780.0 mg, 2.29 mmol, 1.00 equiv) in POCh (5 mb) was stirred for 30 min at 110°C. The solvent was removed under vacuum. The residue was quenched by ice and basified to pH 7 with saturated NaHCCh at 0°C. The resulted mixture was poured into water and extracted with EA. The organic layer was washed with brine, dried over Na2SOr and evaporated to give 8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine-2-carbonit rile (700 mg, 94.76%) as a yellow solid. LC-MS: [M+H] ⁺ found found 321.8.

Step 3: To a solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine- 2- carbonitrile (500.0 mg, 1.55 mmol, 1.00 equiv) in EtOH (5.00 mL) was added hydroxylamine (50%, 205.1 mg, 3.10 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. This resulted in 8-bromo-N'- hydroxy-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridine- 2-carboximidamide (500 mg, 90.7%) as a white solid. LC-MS: [M+H] ⁺ found found 354.9.

Step 4: To a stirred solution of 8-bromo-N'-hydroxy-3-

[(trifhioromethyl)sulfanyl]imidazo[l,2-a]pyridine-2-carbo ximidamide (500.0 mg, 1.40 mmol, 1.00 equiv) in DMF (6.0 mL) were added (tert-butoxycarbonyl)glycine (369.3 mg, 2.11 mmol, 1.50 equiv), HATU (801.8 mg, 2.11 mmol, 1.50 equiv) and TEA (569.9 mg, 5.63 mmol, 4.00 equiv). After stirring at room temperature for 1 h, the reaction mixture was heated at 100°C for another 4 h. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in tert-butyl N-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}-l,2,4 -oxadiazol-5-yl)methyl]carbamate (300 mg, 43.11%) as a yellow solid. LC-MS: [M+H] found 494.1.

Step 5: To a stirred solution of tert-butyl N-[(3-{8-bromo-3-

[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl}-l, 2,4-oxadiazol-5-yl)methyl]carbamate (280.0 mg, 0.56 mmol, 1.00 equiv) in THF (3.0 mL) were added (3 S,4R)-3 -fluoro- 1- methylpiperidin-4-amine dihydrochloride (232.4 mg, 1.13 mmol, 2.00 equiv), tBuXPhos Pd G3 (90.0 mg, 0.11 mmol, 0.20 equiv) and t-BuONa (272.2 mg, 2.83 mmol, 5.00 equiv). The resulting mixture was stirred for 2 h at 65°C under nitrogen atmosphere, then purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm). This resulted in tert-butyl N-{ [3-(8-{[(3S,4R)-3-fluoro- l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]i midazo[l,2-a]pyridin-2-yl)-l,2,4- oxadiazol-5-yl]methyl}carbamate (40 mg, 12.94%) as a yellow oil. LC-MS: [M+H] ⁺ found 546.3.

Step 6: To a stirred solution of tert-butyl N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyrid in-2-yl)-l,2,4-oxadiazol-5- yl]methyl} carbamate (40.0 mg, 0.06 mmol, 1.00 equiv) in MeOH (1.00 mL) was added HC1 (4M in dioxane, 3.00 mL). The resulting mixture was stirred for 1 h at room temperature. The solvent was removed under vacuum. This resulted in (3S,4R)-N-{2-[5-(aminomethyl)-l,2,4-oxadiazol-3- yl]-3-[(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-8-yl} -3-fluoro-l-methylpiperidin-4-amine hydrochloride (40 mg, crude) as a yellow solid. LC-MS: [M+H] ⁺ found 446.1.

Step 7: To a stirred solution of (3S,4R)-N-{2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-3- [(trifluoromethyl)sulfanyl] imidazo[l,2-a]pyridin-8-yl}-3-fluoro-l-methylpiperidin-4-ami ne hydrochloride (40.0 mg, 0.09 mmol, 1.00 equiv) in DMF (3.0 mL) were added cyclopropanecarboxylic acid (10.5 mg, 0.12 mmol, 1.30 equiv), HATU (45.6 mg, 0.12 mmol, 1.30 equiv) and NaHCCh (47.1 mg, 0.55 mmol, 6 equiv). The resulting mixture was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NFh H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 23% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT(min): 6.75). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]imidazo[l,2-a]pyridin-2-yl)-l,2,4 -oxadiazol-5- yl]methyl}cyclopropanecarboxamide (12.8 mg, 26.24%) as a white solid. LC-MS: [M+H] ⁺ found 514.25. ^X H NMR (400 MHz, DMSO-tA) 8 9.02 (t, J= 5.8 Hz, 1H), 8.05 (d, J= 6.7 Hz, 1H), 7.13 (t, J= 7.2 Hz, 1H), 6.72 (d, J= 7.7 Hz, 1H), 5.62 (d, J= 9.1 Hz, 1H), 4.89 (d, J = 49.3 Hz, 1H), 4.70 (d, J= 5.7 Hz, 2H), 3.81 (dt, J = 27.0, 8.4 Hz, 1H), 3.08 (t, J = 11.5 Hz, 1H), 2.80 (d, J= 10.8 Hz, 1H), 2.36-2.23 (m, 1H), 2.21 (s, 3H), 2.13 (td, J= 10.9, 4.0 Hz, 1H), 1.88 (td, J= 10.5, 4.0 Hz, 2H), 1.68 (m, 1H), 0.79-0.67 (m, 4H). Example 3 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5 - yl]methyl}cyclopropanecarboxamide

HN

> O H N

,S

Step 1 : A mixture of ethyl 8-bromoindolizine-2-carboxylate (2 g, 7.46 mmol, 1 equiv), 2- [(trifluoromethyl) sulfanyl]isoindole-l, 3-dione (2.21 g, 8.95 mmol, 1.20 equiv), NaCl (87.19 mg, 1.49 mmol, 0.2 equiv) in DMF (10 mb) was stirred for 4 h at 90°C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mb), washed with brine, and dried over anhydrous Na2SO-r After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100:1) to afford ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylat e (1.8 g, 65.54%) as a light yellow solid. LC-MS: (M+H) ⁺ found 368.1.

Step 2: A solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylat e (1.8 g, 4.89 mmol, 1 equiv) and caustic soda (1 g, 24.45 mmol, 5 equiv) in MeOH (7 mL)/THF (7 mL)/H20 (6 mb) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with HC1 (3N). The precipitated solids were collected by filtration and dried under vacuum to afford 8-bromo-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboxylic acid (1.8 g) as a light yellow solid. LC-MS: (M+H) ⁺ found 340.1.

Step 3: To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxylic acid (1 g, 2.94 mmol, 1 equiv), EtsN (0.89 g, 8.82 mmol, 3 equiv), and NH-iCl (1.57 g, 29.40 mmol, 10 equiv) in DMF (10 mL) was added HATU (1.68 g, 4.41 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with ethyl acetate (100 mL), then washed with 3*100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vaccum. The residue was washed with MeOH (3 mL) and filtered to give 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxamide (850 mg, 85.25%) as a white solid. LC-MS: (M+H) ⁺ found 339.2.

Step 4: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxamid e (1 g, 2.95 mmol, 1 equiv) and POCh (0.99 g, 6.49 mmol, 2.2 equiv) in toluene (10 mL) was stirred at 110 °C for 1 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitri le (0.8 g, 84.49%) as a white solid. LC-MS: (M+H) ⁺ found 321.1.

Step 5: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitri le (1 g, 3.11 mmol, 1 equiv), NH2OHHCI (770 mg, 4.67 mmol, 1.5 equiv) and EtsN (0.95 g, 9.34 mmol, 3 equiv) in EtOH (10 mL) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (Z)-8-bromo-N'-hydroxy-3-[(trifluoromethyl)sulfanyl]indolizi ne-2- carboximidamide (700 mg, 63.47%) as a white solid. LC-MS: (M+H) ⁺ found 354.2.

Step 6: To a stirred solution of (Z)-8-bromo-N'-hydroxy-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboximidamide (2 g, 5.65 mmol, 1 equiv), DIEA (7.30 g, 56.47 mmol, 10 equiv), and [(tert-butoxycarbonyl)amino]acetic acid (1.19 g, 6.77 mmol, 1.2 equiv) in DMF (20 mL) were added HOBT (1.53 g, 11.29 mmol, 2 equiv) and EDCI (2.17 g, 11.29 mmol, 2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 h and then 80°C for 16 h. The mixture was purified by reversed-phase flash chromatography directly (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}- l,2,4- oxadiazol-5-yl)methyl] carbamate (1.8 g, 64.61%) as a white solid. LC-MS: (M+H) ⁺ found 493.3.

Step 7: A mixture of tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}-l,2,4-oxadiazol-5-yl)methyl]carbamate vanadium (500 mg, 0.92 mmol, 1 equiv), (3S,4R)-3- fluoro-l-methylpiperidin-4-amine dihydrochloride (283 mg, 1.38 mmol, 1.5 equiv), RAC-BINAP- PD-G3 (183 mg, 0.18 mmol, 0.2 equiv), BINAP (228 mg, 0.37 mmol, 0.4 equiv), and CS2CO3 (1.5 g, 4.59 mmol, 5 equiv) in dioxane (5 mL) were added was stirred for 6 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford tertbutyl N-{[3-(8-{[(3S)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(t rifluoromethyl) sulfanyl]indolizin-2-yl)-l ,2,4-oxadiazol-5-yl]methyl)carbamate (300 mg, 59.96%) as a light brown solid. LC-MS: (M+H) ⁺ found 545.2.

Step 8: A solution of tert-butyl N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-l, 2, 4-oxadiazol-5-yl]methyl (carbamate (280 mg, 0.51 mmol, 1 equiv) and 4M HC1 (gas) in 1,4-dioxane (0.6 mL) in DCM (3 mL) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro - l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indoliz in-8-amine (280 mg, crude) as a brown solid. LC-MS: (M+H) ⁺ found 454.2.

Step 9: To a stirred solution of cyclopropanecarboxylic acid (14.5 mg, 0.17 mmol, 1.5 equiv), 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -l-methylpiperidin-4-yl]- 3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), and DIEA (0.10 mL, 0.56 mmol, 5 equiv) in DMF (1 mL) was added HATU (64.2 mg, 0.17 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for additional 1 h at room temperature, then diluted with EtOAc (20 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CILCh/MeOHM 0: 1) and Prep-HPLC (Column: XB ridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 32% B to 57% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.73) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl}cyclopropanecarboxamide (20.4 mg, 35.10%) as a light yellow solid. LC-MS: (M+H) ⁺ found 513.15. 'HNMR (400 MHz, DMSO-i/s) 8 8.99 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.79 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.29 (d, J= 8.0 Hz, 1H), 6.21 (d, J= 7.6 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.67 (d, J= 5.7 Hz, 2H), 3.63 (d, J= 29.1 Hz, 1H), 3.05 (t, J= 11.2 Hz, 1H), 2.83 (s, 1H), 2.20 (s, 4H), 2.08 (t, J= 8.9 Hz, 2H), 1.76 - 1.60 (m, 2H), 0.73 (m, 4H).

Example 4 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-thiadiazol- 5- yl] methyl} cyclopropanecarboxamide

Step 1 : A solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxamid e (2 g, 5.89 mmol, 1 equiv) and chloro(chlorosulfanyl)methanone (803.3 mg, 6.13 mmol, 1.04 equiv) in THF (20 mL) was stirred for 1 h at 65°C. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100: 1) to afford 5-{8-bromo- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,3,4-oxathiazo l-2-one (800 mg, 34.15%) as a light yellow solid. LC-MS: (M+H) ⁺ found 397.3.

Step 2: A solution of 5-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,3, 4- oxathiazol-2-one (800 mg, 2.01 mmol, 1 equiv) and 2-ethoxy-2-oxoacetonitrile (399.2 mg, 4.03 mmol, 2.00 equiv) in M-xylene (4 mL) was irradiated with microwave radiation for 15 min at 180°C. The solution was allowed to cool down to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/ EA (10:1) to afford ethyl 3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2, 4-thiadiazole-5- carboxylate (600 mg, 65.87%) as a light yellow solid. LC-MS: (M+H) ⁺ found 451.1.

Step 3: A mixture of NaBEh (501.9 mg, 13.27 mmol, 10 equiv) in THF (5 mL) was stirred for 5 min at 0°C. To the above mixture was added ethyl 3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazole -5-carboxylate (600 mg, 1.33 mmol, 1 equiv) in portions. The resulting mixture was stirred overnight at room temperature, then quenched with MeOH at 0°C and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), 0% to 70% gradient in 20 min; detector, UV 254 nm) to afford (3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazol- 5-yl)methanol (400 mg, 73.50%) as a light yellow solid. LC-MS: (M+H) ⁺ found 410.2. Step 4: A solution of (3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l ,2,4- thiadiazol-5-yl)methanol (400 mg, 0.98 mmol, 1 equiv), TEA (296.0 mg, 2.93 mmol, 3 equiv) and TsCl (185.9 mg, 0.98 mmol, 1 equiv) in DCM (3 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous NaiSOu After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (3 mL) and added to a stirred NHs(g) in MeOH (6 mL) at room temperature. The resulting solution was stirred for 3 h at 40°C under, then concentrated under reduced pressure to afford 1 -(3 -{8-bromo-3 -[(trifluoromethyl) sulfanyl]indolizin-2-yl}-l,2,4-thiadiazol-5-yl)methanamine (300 mg, 75.18%) as a light yellow solid. LC-MS: (M+H) ⁺ found 409.1.

Step 5: A solution of l-(3-{8-bromo-3-[(trifhioromethyl)sulfanyl]indolizin-2-yl}-l ,2,4- thiadiazol-5-yl)methanamine (100 mg, 0.24 mmol, 1 equiv), cyclopropanecarboxylic acid (25.2, 0.29 mmol, 1.2 equiv), DIEA (94.8 mg, 0.73 mmol, 3.00 equiv) and HATU (92.9 mg, 0.244 mmol, 1.00 equiv) in DMF (1 mL) was stirred for Ih at room temperature. The resulting solution was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined organic layers were dried over anhydrous Na2SO-i. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH 15 : 1 ) to afford N-[(3-{ 8-bromo- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l,2,4-thiadiazo l-5- yl)methyl]cyclopropanecarboxamide (80 mg, 68.59%) as a light brown solid. LC-MS: (M+H) ⁺ found 477.1.

Step 6: A mixture of N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}- l,2,4- thiadiazol-5-yl)methyl] cyclopropanecarboxamide (80 mg, 0.17 mmol, 1 equiv), (3S,4R)-3-fluoro- l-methylpiperidin-4-amine dihydrochloride (68.8 mg, 0.34 mmol, 2 equiv), Pd-PEPPSLIHeptCl 3 -chloropyridine (81.6 mg, 0.08 mmol, 0.5 equiv) and CS2CO3 (327.6 mg, 1.01 mmol, 6 equiv) in dioxane (1 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / (7 M NH3 in MeOH = 20/1) and Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05% NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 36% B to 61% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.4) to afford N-{[3- (8-{[(3S,4R)-3-fhjoro-l-methylpiperidin-4-yl]amino}-3-[(trif luoromethyl)sulfanyl]indolizin-2- yl)-l,2,4-thiadiazol-5-yl]methyl}cyclopropanecarboxamide (3.4 mg, 3.84%) as a light yellow solid. LC-MS: (M+H) ⁺ found 529.15. ^ NMR ^OO MHz, DMSO4) 8 9.17 (t, J= 5.8 Hz, 1H), 8.02 (d, J= 6.9 Hz, 1H), 7.84 (s, 1H), 6.82 (t, J= 7.2 Hz, 1H), 6.19 (t, J= 8.9 Hz, 2H), 5.02 - 4.69 (m, 3H), 3.63 (d, J= 29.8 Hz, 1H), 3.05 (t, J= 11.3 Hz, 1H), 2.83 (s, 1H), 2.20 (s, 4H), 2.10 (d, J = 8.3 Hz, 2H), 1.69 m, 2H), 0.77 (d, J= 5.2 Hz, 4H).

Example 55 - Preparation of N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl] amino}-3- [(trifluor omethyl)sulfanyl] indolizin-2-yl)- 1 ,2, 4-oxadiazol-5-yl] -2- hydroxyethyljcyclopropanecarboxamide y—O OH

S HN

Step 1 : A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitri le (1 g,

3.11 mmol, 1 equiv), (3S,4R)-3-fluoro-l-methylpiperidin-4-amine dihydrochloride (958.1 mg, 4.67 mmol, 1.5 equiv), CS2CO3 (5.07 g, 15.57 mmol, 5 equiv) and Pd-PEPPSI-IHeptCl 3- chloropyridine (303.3 mg, 0.31 mmol, 0.1 equiv) in 1,4-dioxane (10 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (15: 1) to afford 8-{[(3S,4R)-3- fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sul fanyl]indolizine-2-carbonitrile (1.2 g, 103.48%) as a yellow solid. LC-MS: (M+H) ⁺ found 373.2.

Step 2: A solution of 8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizine-2-carbonitrile (1.2 g, 3.22 mmol, 1 equiv), TEA (1.63 g,

16.11 mmol, 5 equiv) and NH2OHHCI (0.67 g, 9.67 mmol, 3 equiv) in EtOH (10 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. The solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (1.1g) was used in the next step directly without further purification. LC-MS: (M+H) ⁺ found 406.3. Step 3: A solution of (Z)-8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-N'- hydroxy-3 -[(trifluoromethyl) sulfanyl]indolizine-2-carboximidamide (300 mg, 0.74 mmol, 1 equiv), (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoic acid (182.2 mg, 0.89 mmol, 1.2 equiv), HOBT (200 mg, 1.48 mmol, 2 equiv), EDCI (283.7 mg, 1.48 mmol, 2 equiv) and DIEA (956.4 mg, 7.40 mmol, 10 equiv) in DMF (6 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH 15: 1) to afford tert-butyl N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]am ino}-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl)-l, 2, 4-oxadiazoL5-yl]-2-hydroxy ethylcarbamate (190 mg, 44.69%) as a yellow solid. LC-MS: (M+H) ⁺ found 575.2.

Step 4: To a stirred solution of tert-butyl N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5-yl]- 2-hydroxyethyl]carbamate (190 mg, 0.33 mmol, 1 equiv) in DCM (5 mL) were added HC1 (gas) in 1,4-dioxane (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for 0.5 h at room temperature, then basified to pH 8 with sat.NaHCOi. The resulting mixture was extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (170 mg) was used in the next step directly without further purification. LC-MS: (M+H) ⁺ found 409.1.

Step 5: A solution of (2S)-2-amino-2-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(triftaoromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]ethanol (170 mg, 0.36 mmol, 1 equiv), cyclopropanecarboxylic acid (37.0 mg, 0.43 mmol, 1.2 equiv), PyBOP (223.7 mg, 0.43 mmol, 1.2 equiv) and DIEA (231.5 mg, 1.79 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was extracted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / 7 M NH ₃ in MeOH 15: 1) (Column: CHIRALPAKIC-34.6*50mm, 3.0um; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1 : l)=60: 40; Gradient: isocratic ; Injection Volume: 5.0L mL) to afford N-[(lS)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]am ino}-3-

[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazo l-5-yl]-2- hydroxyethyl]cyclopropanecarboxamide (17.2 mg, 8.85%) as a light yellow solid. LC-MS: (M+H) ⁺ found 543.15. ^X H NMR (400 MHz, DMSO-fifc) 8 8.96 (d, J= 7.2 Hz, 1H), 8.08 (d, J= 6.9 Hz, 1H), 7.77 (s, 1H), 6.90 (t, J= 7.2 Hz, 1H), 6.52 (d, J= 7.8 Hz, 1H), 6.25 (d, J= 7.7 Hz, 1H), 5.38 (s, 1H), 5.34 - 5.02 (m, 2H), 4.09 - 3.66 (m, 4H), 3.47 (s, 2H), 3.12 (s, 1H), 2.80 (s, 3H), 2.39 - 2.18 (m, 1H), 1.99 (d, J= 13.9 Hz, 1H), 1.85 - 1.70 (m, 1H), 0.72 (m, 4H).

Example 53 - Preparation of N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]-2- hydroxyethyljcyclopropanecarboxamide

Step 1 : A solution of (Z)-8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-N'- hydroxy-3 -[(trifluoromethyl) sulfanyl]indolizine-2-carboximidamide (400 mg, 0.99 mmol, 1 equiv), HOBT (266.6 mg, 1.97 mmol, 2 equiv), EDCI (378.3 mg, 1.97 mmol, 2 equiv) and DIEA (1.28 g, 9.87 mmol, 10 equiv) in DMF (5 mL) was stirred for 3 h at room temperature, then stirred overnight at 80°C. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH 15: 1) to afford tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]am ino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5 -yl]-2-hydroxyethyl]carbamate (188 mg, 33.16%) as a light yellow solid. LC-MS: (M+Hf found 575.2.

Step 2: To a stirred solution of tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5-yl]- 2-hydroxyethyl]carbamate (188 mg, 0.33 mmol, 1 equiv) in DCM (5 mL) was added HC1 (gas) in 1,4-dioxane (0.5 mL) dropwise at room temperature. The resulting mixture was stirred for 0.5 h at room temperature, then basified to pH 8 with sat.NaHCOs. The resulting mixture was extracted with CH2CI2. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue (140 mg) was used in the next step directly without further purification. LC-MS: (M+H) ⁺ found 409.1.

Step 3: A solution of (2R)-2-amino-2-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]ethanol (140 mg, 0.30 mmol, 1 equiv), cyclopropanecarboxylic acid (27.9 mg, 0.33 mmol, 1.10 equiv), PyBOP (184.3 mg, 0.35 mmol, 1.2 equiv) and DIEA (190.7 mg, 1.48 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2CI2 / 7 MNH ₃ in MeOH 15: 1) and Prep-HPLC (Column: CHIRALPAKIC-34.6*50mm, 3.0um; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1 : 1) = 60: 40; Gradient: isocratic ; Injection Volume: 5.0 L mL) to afford N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]-2- hydroxyethyl]cyclopropanecarboxamide (37 mg, 23.11%) as a light yellow solid. LC-MS: (M+H) found 543.30. ‘HNMR (400 MHz, DMSO-rL) 5 8.94 (d, J= 7.5 Hz, 1H), 8.03 (d, J= 6.9 Hz, 1H), 7.79 (s, 1H), 6.86 (t, J= 7.2 Hz, 1H), 6.32 (d, J= 8.1 Hz, 1H), 6.21 (d, J= 7.6 Hz, 1H), 5.35 (t, J = 5.7 Hz, 1H), 5.24 (m 1H), 4.88 (d, J = 49.2 Hz, 1H), 3.99 - 3.78 (m, 2H), 3.64 (d, J = 29.0 Hz, 1H), 3.06 (s, 1H), 2.85 (s, 1H), 2.21 (s, 4H), 2.11 (d, J = 9.1 Hz, 2H), 1.74 (m 2H), 0.72 (m 4H).

Example 51 - Preparation of N-[(lR*)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2 ,4-oxadiazol-5- yl] ethyl] cyclopropanecarboxamide

Step 1 : To a stirred mixture of (Z)-8-bromo-N'-hydroxy-3-

[(trifluoromethyl)sulfanyl]indolizine-2-carboximidamide (1 g, 2.82 mmol, 1 equiv), (2R)-2-[(tert- butoxycarbonyl)amino]propanoic acid (801.4 mg, 4.24 mmol, 1.5 equiv) and DIEA (3.65 g, 28.240 mmol, 10 equiv) in DMF (1 mL) were added HOBT (763.1 mg, 5.65 mmol, 2 equiv) and EDCI (1.08 g, 5.65 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 3 h at room temperature and then overnight at 80°C. The resulting mixture was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6: 1) to afford tert-butyl N-[(lR)-l-(3-{ 8- bromo-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl}-l,2,4-oxadiazol-5-yl)ethyl]carbamat e (350 mg, 24.43%, 88 ee%) as a white solid. LC-MS: (M+H) ⁺ found 507.1.

Step 2: A mixture of tert-butyl N-[(lR)-l-(3-{8-bromo-3-

[(trifluoromethyl)sulfanyl]indolizin-2-yl}-l ,2,4-oxadiazol-5-yl)ethyl]carbamate (460 mg, 0.91 mmol, 1 equiv), (3 S,4R)-3 -fluoro- l-methylpiperidin-4-amine dihydrochloride (279 mg, 1.36 mmol, 1.50 equiv), BINAP (282.3 mg, 0.45 mmol, 0.50 equiv), CS2CO3 (1.48 g, 4.54 mmol, 5 equiv) and RAC-BINAP-PD-G3 (90 mg, 0.09 mmol, 0.10 equiv) in dioxane (4 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ACN. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeOH in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) and Prep-TLC (CH2CI2 / MeOH 20: 1) to afford tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]am ino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5 -yl]ethyl] carbamate (120 mg, 23.69%, 45 ee%) as a grey solid. LC-MS: (M+H) ⁺ found 559.2.

Step 3: To a stirred solution of tert-butyl N-[(lR)-l-[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5- yl]ethyl]carbamate (120 mg, 0.21 mmol, 1 equiv) in DCM (2 mL) were added TFA (0.4 mL) at room temperature. The resulting solution was stirred for 0.5 h at room temperature, then basified to pH 8 with sat.NaHCOs. The resulting mixture was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-{5-[(lR)-l-aminoethyl]-l,2,4-oxadiazol-3-yl}-N- [(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]-3-[(trifluoromethy l)sulfanyl]indolizin-8-amine (120 mg, crude) as a yellow oil. LC-MS: (M+H) ⁺ found 459.2. Step 4: A solution of 2-{5-[(1R)-1-aminoethyl]-1,2,4-oxadiazol-3-yl}-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (120 mg, 0.26 mmol, 1 equiv), cyclopropanecarboxylic acid (27.0 mg, 0.31 mmol, 1.2 equiv), DIEA (169.1 mg, 1.31 mmol, 5.00 equiv) and PyBOP (163.4 mg, 0.31 mmol, 1.20 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 20 min; detector, UV 254 nm) and Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH 20:1) to afford N- [(1R)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amin o}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]ethyl]cyclopropanecarboxamide (42 mg, 30.48%, 45 ee%) as a off-white solid. LC-MS: (M+H) ⁺ found 527.2. Step 5: The crude product (42 mg) was purified by Prep-HPLC (Column: CHIRALPAKIA3; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1: 1)=80: 20; Flow rate: 1mL/min mL/min; Gradient: isocratic ; Injection Volume: 3μL mL) to afford N-[(1R*)-1-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluo romethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]ethyl]cyclopropanecarboxamide (18.7 mg, 44.52%, 100 ee%) as a white solid. LC-MS: (M+H) ⁺ found 527.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 5.27 (m, 1H), 4.89 (d, J = 49.2 Hz, 1H), 3.83 – 3.57 (m, 1H), 3.11 (s, 1H), 2.89 (d, J = 10.4 Hz, 1H), 2.49 – 1.98 (m, 6H), 1.75 – 1.69 (m, 1H), 1.69 – 1.44 (m, 4H), 0.84 – 0.57 (m, 4H). Example 52 – Preparation of N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5- yl]ethyl]cyclopropanecarboxamide

Step 1: A solution of (Z)-8-bromo-N'-hydroxy-3-[(trifluoromethyl)sulfanyl]indolizi ne-2- carboximidamide (1 g, 2.82 mmol, 1 equiv), (2S)-2-[(tert-butoxycarbonyl)amino]propanoic acid (0.64 g, 3.39 mmol, 1.2 equiv), HOBT (0.76 g, 5.65 mmol, 2 equiv), EDCI (1.08 g, 5.65 mmol, 2 equiv) and DIEA (3.65 g, 28.24 mmol, 10 equiv) in DMF (10 mL) was stirred for 1 h at room temperature. Then the solution was heated at 80°C for 5 h. The reaction was diluted with EA (100 mL) and washed with brine (3*100 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford tert-butyl N-[(1S)-1-(3-{8- bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-oxa diazol-5-yl)ethyl]carbamate (1.152 g, 80.42%, 89.4 ee%) as a white solid. LC-MS: (M+H) ⁺ found 507.1. Step 2: A solution of tert-butyl N-[(1S)-1-(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-oxadiazol-5 -yl)ethyl]carbamate (1 g, 1.97 mmol, 1 equiv), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine dihydrochloride (0.61 g, 2.96 mmol, 1.5 equiv), RAC-BINAP-PD-G3 (0.39 g, 0.39 mmol, 0.2 equiv), BINAP (0.61 g, 0.99 mmol, 0.5 equiv) and Cs2CO3 (3.21 g, 9.86 mmol, 5 equiv) in dioxane (10 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM. The filtrate was washed with brine (50 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 50 min; detector, UV 254 nm). This resulted in tert-butyl N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]ethyl]carbamate (600 mg, 54.49%) as a yellow solid. LC-MS: (M+H) ⁺ found 559.2. Step 3: A solution of tert-butyl N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]ethyl]carbamate (300 mg, 0.54 mmol, 1 equiv) and TFA (0.6 mL, 8.08 mmol, 15.04 equiv) in DCM (3 mL) was stirred for 1 h at room temperature. The mixture was basified to pH 7 with saturated NaHCO3, and then extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ² Cl ² / 7 M NH ³ in MeOH (25:1) to afford 2-{5-[(1S)-1-aminoethyl]-1,2,4-oxadiazol-3-yl}-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4- yl]-3-[(trifluoromethyl)sulfanyl]indolizin-8-amine (68 mg, 27.62%) as a yellow solid. LC-MS: (M+H) ⁺ found 459.2. Step 4: A solution of 2-{5-[(1S)-1-aminoethyl]-1,2,4-oxadiazol-3-yl}-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (55 mg, 0.12 mmol, 1 equiv), cyclopropanecarboxylic acid (12.4 mg, 0.14 mmol, 1.2 equiv), PyBOP (81.2 mg, 0.16 mmol, 1.3 equiv) and DIEA (77.5 mg, 0.60 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EA (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 38% B to 63% B in 8 min; Wave Length: 220nm nm; RT1(min): 6.85) to afford N-[(1S)-1-[3-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]i ndolizin-2-yl)-1,2,4-oxadiazol-5- yl]ethyl]cyclopropanecarboxamide (26 mg, 40.72%, 8 ee%) as a white solid. LC-MS: (M+H) ⁺ found 527.15. Step 5: The crude product (26 mg) was purified by CHIRAL-HPLC (Column: CHIRALPAKIA3; Mobile Phase A: Hex(0.2%DEA): (EtOH: DCM=1: 1)=80: 20; Flow rate: 1mL/min mL/min; Gradient: isocratic ; Injection Volume: 3μL mL) to afford N-[(1S)-1-[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluo romethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]ethyl]cyclopropanecarboxamide (8.3 mg, 31.92%, 100 ee%) as a light brown solid. LC-MS: (M+H) ⁺ found 527.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.41 – 6.29 (m, 1H), 6.21 (d, J = 7.6 Hz, 1H), 5.27 (m, 1H), 4.90 (d, J = 49.2 Hz, 1H), 3.66 (d, J = 28.5 Hz, 1H), 3.13 (s, 1H), 2.90 (d, J = 10.2 Hz, 1H), 2.47 – 1.93 (m, 6H), 1.73 (d, J = 10.8 Hz, 1H), 1.64 (m, 1H), 1.57 (d, J = 7.1 Hz, 3H), 0.79 – 0.62 (m, 4H). Example 54 – Preparation of 6-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}amino)- N-methylpyridine-3-carboxamide

Step 1 : A mixture of ethyl 8-bromoindolizine-2-carboxylate (2 g, 7.46 mmol, 1 equiv), 2- [(trifhioromethyl)sulfanyl] isoindole- 1,3-dione (2.21 g, 8.95 mmol, 1.20 equiv), NaCl (87.19 mg, 1.49 mmol, 0.2 equiv) in DMF (10 mb) was stirred for 4 h at 90°C under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (100 mb), washed with brine, and dried over anhydrous Na2SO-L After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100:1) to afford ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylat e (1.8 g, 65.54%) as a light yellow solid. LC-MS: (M+H) ⁺ found 368.1.

Step 2: A solution of ethyl 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxylat e (1.8 g, 4.89 mmol, 1 equiv) and caustic soda (1 g, 24.45 mmol, 5 equiv) in MeOH (7 mL)/THF (7 mL)/H20 (6 mb) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with HC1 (3N). The precipitated solids were collected by filtration and dried under vacuum to afford 8-bromo-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboxylic acid (1.8 g) as a light yellow solid. LC-MS: (M+H) ⁺ found 340.1.

Step 3: To a stirred solution of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxylic acid (1 g, 2.94 mmol, 1 equiv), EtsN (0.89 g, 8.82 mmol, 3 equiv), and NH4CI (1.57 g, 29.40 mmol, 10 equiv) in DMF (10 mb) was added HATU (1.68 g, 4.41 mmol, 1.5 equiv) at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was diluted with ethyl acetate (100 mL), then washed with 3*100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vaccum. The residue was washed with MeOH (3 mL) and filtered to give 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2- carboxamide (850 mg, 85.25%) as a white solid. LC-MS: (M+H) ⁺ found 339.2. Step 4: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carboxamid e (1 g, 2.95 mmol, 1 equiv) and POCh (0.99 g, 6.49 mmol, 2.2 equiv) in toluene (10 mb) was stirred at 110 °C for 1 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitri le (0.8 g, 84.49%) as a white solid. LC-MS: (M+H) ⁺ found 321.1.

Step 5: A mixture of 8-bromo-3-[(trifluoromethyl)sulfanyl]indolizine-2-carbonitri le (1 g, 3.11 mmol, 1 equiv), NH2OHHCI (770 mg, 4.67 mmol, 1.5 equiv) and EtsN (0.95 g, 9.34 mmol, 3 equiv) in EtOH (10 mb) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (Z)-8-bromo-N'-hydroxy-3-[(trifluoromethyl)sulfanyl]indolizi ne-2- carboximidamide (700 mg, 63.47%) as a white solid. LC-MS: (M+H) ⁺ found 354.2.

Step 6: To a stirred solution of (Z)-8-bromo-N'-hydroxy-3- [(trifluoromethyl)sulfanyl]indolizine-2-carboximidamide (2 g, 5.65 mmol, 1 equiv), DIEA (7.30 g, 56.47 mmol, 10 equiv), and [(tert-butoxycarbonyl)amino]acetic acid (1.19 g, 6.77 mmol, 1.2 equiv) in DMF (20 mL) were added HOBT (1.53 g, 11.29 mmol, 2 equiv) and EDCI (2.17 g, 11.29 mmol, 2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 1 h and then 80°C for 16 h. The mixture was purified by reversed-phase flash chromatography directly (column, Cl 8 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to give tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}- l,2,4- oxadiazol-5-yl)methyl] carbamate (1.8 g, 64.61%) as a white solid. LC-MS: (M+H) ⁺ found 493.3.

Step 7: A mixture of tert-butyl N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2- yl}-l,2,4-oxadiazol-5-yl)methyl]carbamate vanadium (500 mg, 0.92 mmol, 1 equiv), (3S,4R)-3- fluoro-l-methylpiperidin-4-amine dihydrochloride (283 mg, 1.38 mmol, 1.5 equiv), RAC -BINAP - PD-G3 (183 mg, 0.18 mmol, 0.2 equiv), BINAP (228 mg, 0.37 mmol, 0.4 equiv), and CS2CO3 (1.5 g, 4.59 mmol, 5 equiv) in dioxane (5 mL) were added was stirred for 6 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford tertbutyl N-{[3-(8-{[(3S)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(t rifluoromethyl) sulfanyl]indolizin-2-yl)-l ,2,4-oxadiazol-5-yl]methyl(carbamate (300 mg, 59.96%) as a light brown solid. LC-MS: (M+H) ⁺ found 545.2.

Step 8: A solution of tert-butyl N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l, 2, 4-oxadiazol-5-yl]methyl (carbamate (280 mg, 0.51 mmol, 1 equiv) and 4M HC1 (gas)in 1,4-dioxane (0.6 mL) in DCM (3 mL) was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford crude product 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro - l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indoliz in-8-amine (280 mg, crude) as a brown solid. LC-MS: (M+H) ⁺ found 445.2.

Step 9: A solution of 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -l- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (80 mg, 0.18 mmol, 1 equiv), TEA (54.6 mg, 0.54 mmol, 3 equiv) and methyl 6-fluoropyridine-3 -carboxylate (41.9 mg, 0.27 mmol, 1.5 equiv) in NMP (2 mL) was stirred overnight at 90°C. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV 254 nm) to afford methyl 6-({[3-(8-{[(3S,4R)-3- fluoro- 1-methylpiperi din-4-yl]amino(-3-[(tri fluoromethyl)sulfanyl]indolizin-2-yl)- 1,2,4- oxadiazol-5-yl]methyl( amino)pyridine-3-carboxylate (40 mg, 35.28%) as ayellow solid. LC-MS: (M+H) ⁺ found 580.2.

Step 10: A solution of methyl 6-({ [3 -(8- {[(3 S,4R)-3 -fluoro- 1-methylpiperi din-4- yl]amino(-3-[(trifhioromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl(amino)pyridine-3-carboxylate (40 mg, 0.07 mmol, 1 equiv) and NaOH (13.8 mg, 0.35 mmol, 5 equiv) in THF (0.2 mL)/MeOH (0.4 mL)/H20 (0.4 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (10 mL) and acidfied to pH 5 with IM HC1, then extracted with EtOAc (3*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-({[3-(8-{[(3S,4R)- 3-fluoro- 1-methylpiperi din-4-yl]amino(-3-[(tri fhioromethyl)sulfanyl]indolizin-2-yl)-l, 2,4- oxadiazol-5-yl]methyl( amino)pyridine-3-carboxylic acid (35 mg) as a white solid. LC-MS: (M+H) ⁺ found 566.0. Step 11: A solution of 6-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl](methyl)amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}amino)pyridine-3-carboxylic acid (40 mg, 0.07 mmol, 1 equiv), methanamine, hydrochloride (14.0 mg, 0.21 mmol, 3 equiv), HATU (31.5 mg, 0.08 mmol, 1.2 equiv) and TEA (34.9 mg, 0.35 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with water (10 mL) and extracted with CH2Cl (2*10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 54% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.77) to afford 6-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3 - [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}amino)-N- methylpyridine-3-carboxamide (6.3 mg, 15.45%) as a white solid. LC-MS: (M+H) ⁺ found 579.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.3 Hz, 1H), 8.15 (d, J = 4.7 Hz, 1H), 8.01 (d, J = 6.9 Hz, 1H), 7.94 – 7.83 (m, 2H), 7.74 (s, 1H), 6.84 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.21 (dd, J = 16.2, 7.9 Hz, 2H), 4.97 – 4.72 (m, 3H), 3.62 (d, J = 28.9 Hz, 1H), 3.04 (t, J = 11.3 Hz, 1H), 2.84 (dd, J = 14.9, 6.6 Hz, 1H), 2.72 (d, J = 4.5 Hz, 3H), 2.19 (s, 4H), 2.13 – 2.00 (m, 2H), 1.68 (d, J = 10.4 Hz, 1H). Example 50 – Preparation of 2-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}amino)- N-methylpyrimidine-5-carboxamide Step 1: A mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (130 mg, 0.29 mmol, 1 equiv), methyl 2-chloropyrimidine-5-carboxylate (55.5 mg, 0.32 mmol, 1.1 equiv), and KF (34.0 mg, 0.58 mmol, 2 equiv) in DMSO (1 mL) stirred for 40 min at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2*50 mL). The combined organic layers were dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CFLCh/MeOHMO: !) to afford methyl 2-({[3-(8-{ [(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3-[(trifluor omethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}amino)pyrimidine -5-carboxylate (90 mg, 53.00%) as a yellow solid. LC-MS: (M+H)+ found 581.2.

Step 2: To a stirred solution of methyl 2-({[3-(8-{[(3S,4R)-3-fhioro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l ,2,4-oxadiazol-5- yl]methyl}amino)pyrimidine-5-carboxylate (40 mg, 0.07 mmol, 1 equiv) in THF (1 mL)/H20 (0.25 mL) was added LiOH (10 mg, 0.08 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature, then acidified to pH 5 with HC1 (aq.). The resulting solution was extracted with DCM (3*20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-({[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3 - [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5 -yl]methyl}amino)pyrimidine-5- carboxylic acid (23 mg, 58.92%) as a brown oil. LC-MS: (M+H)+ found 567.1.

Step 3: A solution of 2-({[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3 - [(trifluorom ethyl) sulfanyl]indolizin-2-yl)- 1 ,2,4-oxadiazol-5-yl]methyl } amino)pyrimidine-5 - carboxylic acid (50 mg, 0.09 mmol, 1 equiv), methanamine hydrochloride (7.8 mg, 0.11 mmol, 1.3 equiv), DIEA (57.0 mg, 0.44 mmol, 5 equiv), and HATU (43.6 mg, 0.11 mmol, 1.3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution purified by Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NHIHC03+0.05%NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7min; Wave Length: 254nm/220nm nm; RTl(min): 6.7; Number Of Runs: 2) to afford 2-({[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3 -

[(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazo l-5-yl]methyl}amino)-N- methylpyrimidine-5-carboxamide (4.9 mg, 9.48%) as a white solid. LC-MS: (M+H)+ found 580.35. 'H NMR (400 MHz, DMSO-d6) 5 8.72 (d, J= 29.1 Hz, 2H), 8.51 (t, J= 6.0 Hz, 1H), 8.33 (m, 1H), 8.01 (d, J= 6.9 Hz, 1H), 7.74 (s, 1H), 6.84 (t, J= 7.2 Hz, 1H), 6.23 (dd, J= 26.3, 7.9 Hz, 2H), 4.98 - 4.74 (m, 3H), 3.62 (d, J= 28.8 Hz, 1H), 3.04 (t, J= 11.1 Hz, 1H), 2.83 (d, J= 8.3 Hz, 1H), 2.74 (d, J= 4.5 Hz, 3H), 2.39 - 2.26 (m, 1H), 2.19 (s, 3H), 2.10 - 2.01 (m, 2H), 1.68 (d, J = 9.5 Hz, 1H).

Example 2 - Preparation of l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5- yljmethyl}pyrazole-4-carboxamide

Step 1 : To a stirred solution of l-tert-butylpyrazole-4-carboxylic acid (29 mg, 0.17 mmol, 1.5 equiv), DIEA (0.20 mL, 1.12 mmol, 10 equiv), and 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]- N-[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]-3-[(trifluoromet hyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) in DMF (1 mL) was added HATU (65 mg, 0.17 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature, then diluted with EtOAc (20 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2C12/MeOH=10: 1) and Prep-HPLC (Column: XB ridge Prep OBD C 18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH ₄ HC03+0.05% NH ₃ H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 36% B to 61% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.62) to afford l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5- yl]methyl}pyrazole-4-carboxamide (25.8 mg, 38.45%) as a light yellow solid. LC-MS: (M+H)~ found 595.20. E NMR (400 MHz, DMSO-e/e) S 8.98 (t, J = 5.7 Hz, 1H), 8.34 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.28 (d, J= 8.1 Hz, 1H), 6.20 (d, J= 7.7 Hz, 1H), 4.96 - 4.75 (m, 3H), 3.62 (d, J= 28.4 Hz, 1H), 3.04 (t, J= 11 .3 Hz, 1H), 2.83 (d, J= 8.1 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J= 10.9 Hz, 2H), 1.68 (d, J= 10.3 Hz, 1H), 1.54 (s, 9H).

Example 7 - Preparation of l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-l- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-l,2,4-oxadiazol-5- yl] methyl} pyrrole-3-carboxamide

^N -0 ' ^u H

N

S F-V

Step 1 : To a stirred solution of l-tert-butylpyrrole-3 -carboxylic acid (29 mg, 0.17 mmol, 1.5 equiv), 2-[5-(aminomethyl)- 1 ,2,4-oxadiazol-3 -yl]-N-[(3 S,4R)-3 -fluoro- 1 -methylpiperidin-4- yl]-3-[(trifluoromethyl) sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) and DIEA (0.20 mb, 1.12 mmol, 10 equiv) in DMF (1 mL) was added HATU (64.2 mg, 0.17 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHiCh/MeOHMOT) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03+0.05%NH3 H20), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 62% B in 7min; Wave Length: 254nm/220 nm nm; RTl(min): 6.67; Number Of Runs: 2) to afford l-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fhroro-l-methylpiperidin-4 -yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5 -yl]methyl}pyrrole-3-carboxamide (19.7 mg, 29.26%) as a light yellow solid. LC-MS: (M+H) ⁺ found 594.25. 'H NMR (400 MHz, DMSO-tA) 8 8.66 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (s, 1H), 7.55 (t, J= 2.1 Hz, 1H), 6.99 (t, J = 2.7 Hz, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.50 (dd, J= 3.0, 1.8 Hz, 1H), 6.24 (dd, J = 30.8, 7.9 Hz, 2H), 4.98 - 4.66 (m, 3H), 3.62 (d, J= 28.7 Hz, 1H), 3.12 - 2.97 (m, 1H), 2.87 - 2.78 (m, 1H), 2.19 (s, 4H), 2.13 - 2.01 (m, 2H), 1.73 - 1.64 (m, 1H), 1.49 (s, 9H). Example 27 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}-l,2- thiazole-5-carboxamide

Step 1 : To a stirred solution of 2-[5-(aminomethyl)-l,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-l-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), l,2-thiazole-5-carboxylic acid (29.1 mg, 0.22 mmol, 2 equiv) and DIEA (145.4 mg, 1.12 mmol, 10 equiv) in DMF (1 mL) was added HATU (51.3 mg, 0.13 mmol, 1.2 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol/L NH4HC03)+0.05%NH ₃ H ₂ 0, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RTl(min): 7.48) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4-yl]amino}-3- [(trifluorom ethyl) sulfanyl]indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl }-l,2-thiazole-5- carboxamide (17.7 mg, 28.26%) as a white solid. LC-MS: (M+H) ⁺ found 556.30. NMR (400 MHz, DMSO4) 5 9.87 (t, J= 5.7 Hz, 1H), 8.72 (d, J= 1.8 Hz, 1H), 8.07 - 7.94 (m, 2H), 7.77 (d, J= 0.8 Hz, 1H), 6.85 (t, J= 7.2 Hz, 1H), 6.24 (dd, J= 29.7, 7.9 Hz, 2H), 4.95 - 4.72 (m, 3H), 3.63 (d, J= 29.2 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.83 (d, J= 8.0 Hz, 1H), 2.19 (s, 4H), 2.14 - 1.94 (m, 2H), 1.68 (d, J= 10.5 Hz, 1H).

Example 30 - Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-l-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-l,2,4-oxadiazol-5-yl]methyl}-3- methylthiophene-2-carboxamide

Step 1: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv), 3-methylthiophene-2-carboxylic acid (32.0 mg, 0.22 mmol, 2 equiv) and DIEA (145.4 mg, 1.12 mmol, 10 equiv) in DMF (1 mL) was added HATU (51.3 mg, 0.13 mmol, 1.2 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 41% B to 66% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.5) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- methylthiophene-2-carboxamide (17.5 mg, 27.30%) as a white solid. LC-MS: (M+H) ⁺ found 569.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 5.0 Hz, 1H), 7.01 (d, J = 5.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.92– 4.78 (m, 3H), 3.63 (d, J = 28.0 Hz, 1H), 3.13 – 2.98 (m, 1H), 2.83 (d, J = 7.6 Hz, 1H), 2.46 (s, 3H), 2.34 – 2.19 (m, 4H), 2.07 (t, J = 10.7 Hz, 2H), 1.69 (d, J = 9.2 Hz, 1H). Example 13 – Preparation of 2-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-1,3-oxazole-5-carboxamide

l)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 2-tert-butyl-1,3-oxazole-5-carboxylic acid (22.8 mg, 0.13 mmol, 1.2 equiv), HATU (64.1 mg, 0.17 mmol, 1.5 equiv) and DIEA (145.4 mg, 1.12 mmol, 10 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with 3*50 mL of brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2 / MeOH 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 65% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.28) to afford 2-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4 - yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3- oxazole-5-carboxamide (11 mg, 16.14%) as a off-white solid. LC-MS: (M+H) ⁺ found 596.15. ¹ H NMR (400 MHz, DMSO-d6) δ 9.41 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.83 – 7.68 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.76 (m, 3H), 3.62 (d, J = 28.8 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 8.1 Hz, 1H), 2.19 (s, 4H), 2.06 (t, J = 11.1 Hz, 2H), 1.68 (d, J = 9.9 Hz, 1H), 1.37 (s, 9H). Example 14 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-5- methyl-4-oxo-3H-thieno[2,3-d]pyrimidine-6-carboxamide

o[2,3-d]pyrimidine-6-carboxylic acid (47.3 mg, 0.23 mmol, 1 equiv), HATU (102.6 mg, 0.27 mmol, 1.2 equiv), DIEA (116.3 mg, 0.90 mmol, 4 equiv) in DMF (2 mL) was added 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N- [(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethy l)sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ⁴ HCO ³ )+0.05%NH ^3. H ² O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.82) to afford N-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluo romethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]methyl}-5-methyl-4-oxo-3H-thieno[2,3-d] pyrimidine-6-carboxamide (13.6 mg, 9.36%) as a yellow solid. LC-MS: (M+H) ⁺ found 637.10. ¹ H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 9.06 (t, J = 5.6 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 17.0, 7.9 Hz, 2H), 4.98 – 4.74 (m, 3H), 3.63 (d, J = 27.8 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.78 (s, 4H), 2.19 (s, 4H), 2.07 (t, J = 11.2 Hz, 2H), 1.69 (d, J = 9.8 Hz, 1H). Example 16 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2-oxo- 1,3-dihydroindole-6-carboxamide

zol-3-yl]-N-[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (80 mg, 0.18 mmol, 1 equiv), 2-oxo-1,3-dihydroindole-6-carboxylic acid (31.9 mg, 0.18 mmol, 1 equiv), DIEA (93.1 mg, 0.72 mmol, 4 equiv), and HATU (88.9 mg, 0.23 mmol, 1.3 equiv) in DMF (4 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with briner (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=8:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.47; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-2-oxo-1,3-dihydroindole-6-carboxamide (11.7 mg, 10.47%) as a light yellow solid. LC-MS: (M+H) ⁺ found 604.10. ¹ H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.38 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.53 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 – 7.30 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.95 – 4.76 (m, 3H), 3.56 (s, 3H), 3.11 – 2.98 (m, 1H), 2.82 (d, J = 8.2 Hz, 1H), 2.41 – 1.96 (m, 6H).1.68 (d, J = 10.1 Hz, 1H). Example 17 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo- 1,3-dihydroindole-7-carboxamide

aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- flu oro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]ind olizin-8-amine (120 mg, 0.27 mmol, 1 equiv), DIEA (0.24 mL, 1.35 mmol, 5 equiv), and 2-oxo-1,3-dihydroindole-7-carboxylic acid (52.6 mg, 0.30 mmol, 1.1 equiv) in DMF (2 mL) was added HATU (154.0 mg, 0.41 mmol, 1.5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 59% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.57) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-oxo- 1,3- dihydroindole-7-carboxamide (23.7 mg, 14.24%) as a white solid. LC-MS: (M+H) ⁺ found 604.15. ¹ H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.48 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.75 (dd, J = 7.3, 1.0 Hz, 2H), 7.44 – 7.38 (m, 1H), 7.08 (dd, J = 8.1, 7.3 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (dd, J = 15.3, 7.8 Hz, 2H), 4.95 – 4.77 (m, 3H), 3.55 (s, 3H), 3.04 (t, J = 11.2 Hz, 1H), 2.82 (d, J = 8.5 Hz, 1H), 2.33 – 1.95 (m, 6H), 1.68 (d, J = 10.5 Hz, 1H). Example 18 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2-oxo- 1,3-dihydroindole-5-carboxamide

Step 1: To a stirred solution of 2-oxo-1,3-dihydroindole-5-carboxylic acid (35.9 mg, 0.20 mmol, 1 equiv), DIEA (130.9 mg, 1.01 mmol, 5 equiv) and 2-[5-(aminomethyl)-1,2,4-oxadiazol- 3-yl]-N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-3-[(triflu oromethyl)sulfanyl]indolizin-8- amine (90 mg, 0.20 mmol, 1 equiv) in DMF (1.5 mL) was added PyBOP (115.9 mg, 0.22 mmol, 1.1 equiv) at 0°C. The mixture was stirred at 25°C for 30 min. The resulting solution was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.77; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-2-oxo-1,3- dihydroindole-5-carboxamide (20.4 mg, 16.36%) as an off-white solid. LC-MS: (M+H) ⁺ found 604.35. ¹ H NMR (400 MHz, DMSO-d6) 10.67 (s, 1H), 9.23 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.85-7.73 (m, 3H), 6.93-6.81 (m, 2H), 6.23 (dd, J = 22.5, 7.8 Hz, 2H), 4.96-4.71 (m, 3H), 3.56 (s, 3H), 3.04 (t, J = 11.1 Hz, 1H), 2.83 (d, J = 8.7 Hz, 1H),2.35- 2.19 (m, 4H), 2.14-1.99 (m, 2H), 1.68 (d, J = 11.0 Hz, 1H). Example 19 – Preparation of 3-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H- indole-5-carboxamide

Step 1: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv), DIEA (290.8 mg, 2.25 mmol, 10 equiv) and 3-cyano-1H-indole-5-carboxylic acid (20.9 mg, 0.11 mmol, 0.5 equiv) in DMF (1 mL) was added PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) at 0 °C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220 nm nm; RT1(min): 7.78) to afford 3-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]a mino}- 3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1H-ind ole-5- carboxamide (27.2 mg, 19.73%) as an off-white solid. LC-MS: (M+H) ⁺ found 613.40. ¹ H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 9.51 (t, J = 5.6 Hz, 1H), 8.41 – 8.33 (m, 2H), 8.02 (d, J = 6.8 Hz, 1H), 7.88 (dd, J = 8.7, 1.7 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 23.3, 7.9 Hz, 2H), 4.94 – 4.77 (m, 3H), 3.61 (d, J = 28.5 Hz, 1H), 3.03 (t, J = 11.3 Hz, 1H), 2.82 (d, J = 8.4 Hz, 1H), 2.18 (s, 4H), 2.05 (t, J = 11.3 Hz, 2H), 1.66 (s, 1H). Example 20 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2- (morpholin-4-yl)-1,3-thiazole-4-carboxamide

Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (100 mg, 0.23 mmol, 1 equiv), 2-(morpholin-4-yl)-1,3-thiazole-4-carboxylic acid (33.7 mg, 0.16 mmol, 0.7 equiv), HATU (85.5 mg, 0.23 mmol, 1 equiv) and DIEA (145.4 mg, 1.13 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (20 mL) and washed with brine (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (CH2Cl2/MeOH 10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 57% B to 82% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.77; Number Of Runs: 4) to afford N-{[3-(8-{[(3S,4R)-3-fluoro- 1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]i ndolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-2-(morpholin-4-yl)-1,3-thiazole-4-carboxamide (18.8 mg, 12.72%) as a off-white solid. LC-MS: (M+H) ⁺ found 641.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.0 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.55 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 28.4, 7.9 Hz, 2H), 4.96 – 4.74 (m, 3H), 3.74 (t, J = 4.9 Hz, 4H), 3.62 (d, J = 29.4 Hz, 1H), 3.48 (t, J = 4.9 Hz, 4H), 3.04 (t, J = 11.1 Hz, 1H), 2.83 (d, J = 8.3 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 11.2 Hz, 2H), 1.68 (d, J = 10.9 Hz, 1H). Example 32 – Preparation of 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide

Step 1: A mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (60 mg, 0.14 mmol, 1 equiv), 3-fluorothiophene-2-carboxylic acid (23.7 mg, 0.16 mmol, 1.2 equiv), DIEA (87.2 mg, 0.67 mmol, 5 equiv) and HATU (77mg, 020 mmol, 1.5 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 65% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.4; Number Of Runs: 2) to afford 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}thiophe ne- 2-carboxamide (18.4 mg, 23.52%) as a off-white solid. LC-MS: (M+H) ⁺ found 573.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.87 (dd, J = 5.5, 4.0 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.16 (d, J = 5.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.95 – 4.74 (m, 3H), 3.62 (d, J = 29.1 Hz, 1H), 3.04 (t, J = 10.7 Hz, 1H), 2.82 (s, 1H), 2.19 (s, 4H), 2.13 – 2.00 (m, 2H), 1.68 (d, J = 10.0 Hz, 1H). Example 43 – Preparation of 2-(4-cyanophenoxy)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}acetamide

Step 1: A mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (60 mg, 0.14 mmol, 1 equiv), P-cyanophenoxyacetic acid (28.7 mg, 0.16 mmol, 1.2 equiv), HATU (77.0 mg, 0.20 mmol, 1.5 equiv) and DIEA (87.2 mg, 0.67 mmol, 5 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.85) to afford 2-(4-cyanophenoxy)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiper idin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}acetamide (17 mg, 20.59%) as a yellow solid. LC-MS: (M+H) ⁺ found 604.10. ¹ H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.88 – 7.71 (m, 3H), 7.25 – 7.09 (m, 2H), 6.86 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.80 – 4.71 (m, 4H), 3.63 (d, J = 28.4 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.82 (s, 1H), 2.20 (s, 4H), 2.07 (t, J = 10.2 Hz, 2H), 1.70 (d, J = 9.5 Hz, 1H). Example 23 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1- methyl-3-oxo-2,4-dihydroquinoxaline-6-carboxamide

Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (100 mg, 0.225 mmol, 1 equiv) in DMF (1 mL) was treated with DIEA (203.6 mg, 1.58 mmol, 7 equiv) and PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) for 2 min at 0°C followed by the addition of 1-methyl-3-oxo-2,4- dihydroquinoxaline-6-carboxylic acid (46.4 mg, 0.23 mmol, 1 equiv) at room temperature. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.70) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1-methyl-3-oxo- 2,4- dihydroquinoxaline-6-carboxamide (29.8 mg, 20.94%) as an off-white solid. LC-MS: (M+H) ⁺ found 633.15. ¹ H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.10 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.78 (d, J = 5.6 Hz, 3H), 3.79 (s, 2H), 3.62 (d, J = 30.2 Hz, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.86 (s, 4H), 2.19 (s, 4H), 2.14 – 2.01 (m, 2H), 1.68 (d, J = 11.0 Hz, 1H). Example 31 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-3-(1- methylcyclopropyl)prop-2-ynamide

Step 1: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv), 3-(1-methylcyclopropyl) prop-2-ynoic acid (25.1 mg, 0.20 mmol, 1 equiv) and DIEA (0.18 mL, 1.01 mmol, 5 equiv) in DMF (1 mL) was added PyBOP (137.0 mg, 0.26 mmol, 1.3 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=10:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 44% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.42; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-3-(1- methylcyclopropyl)prop-2-ynamide (29 mg, 25.80%) as a light yellow solid. LCMS: (M+H) ⁺ found 551.40. ¹ H NMR (400 MHz, DMSO-d6) δ 9.32 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.25 (dd, J = 34.0, 7.9 Hz, 2H), 4.87 (d, J = 48.8 Hz, 1H), 4.65 (d, J = 5.8 Hz, 2H), 3.63 (d, J = 29.3 Hz, 1H), 3.10 – 2.99 (m, 1H), 2.83 (s, 1H), 2.30 – 2.20 (m, 4H), 2.14 – 2.03 (m, 2H), 1.70 (d, J = 9.0 Hz, 1H), 1.28 (s, 3H), 0.98 (m, 2H), 0.80 (m, 2H). Example 33 – Preparation of 3-amino-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2 ,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide

Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (40 mg, 0.09 mmol, 1 equiv), 3-aminothiophene-2-carboxylic acid (12.9 mg, 0.09 mmol, 1 equiv), HATU (34.2 mg, 0.09 mmol, 1 equiv) and DIEA (34.9 mg, 0.27 mmol, 3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 in MeOH 20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 53% B to 77% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.78; Number Of Runs: 5) to afford 3-amino-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide (3.1 mg, 6.05%) as a white solid. LC-MS: (M+H) ⁺ found 570.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J = 5.5 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 7.46 (d, J = 5.3 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 5.3 Hz, 1H), 6.51 (s, 2H), 6.28 (d, J = 8.2 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.86 (d, J = 49.2 Hz, 1H), 4.69 (d, J = 5.5 Hz, 2H), 3.62 (d, J = 28.5 Hz, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.82 (s, 1H), 2.19 (s, 4H), 2.07 (t, J = 9.8 Hz, 2H), 1.69 (s, 1H). Example 34 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl] methyl}-6- methoxyquinoline-2-carboxamide

Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 6-methoxyquinoline-2-carboxylic acid (22.9 mg, 0.11 mmol, 1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5.00 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 45% B to 70% B in 8 min; Wave Length: 220nm nm; RT1(min): 8.17) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl] methyl}-6-methoxyquinoline-2- carboxamide (10.9 mg, 15.39%) as a white solid. LC-MS: (M+H) ⁺ found 630.20. ¹ H NMR (400 MHz, DMSO-d6) δ 9.69 (t, J = 6.1 Hz, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.75 (s, 1H), 7.55 – 7.51 (m, 2H), 6.84 (t, J = 7.2 Hz, 1H), 6.21 (m 2H), 5.10 – 4.58 (m, 3H), 3.95 (s, 3H), 3.61 (d, J = 29.3 Hz, 1H), 3.03 (t, J = 11.2 Hz, 1H), 2.81 (d, J = 9.7 Hz, 1H), 2.18 (s, 4H), 2.11 – 1.90 (m, 2H), 1.66 (d, J = 11.8 Hz, 1H). Example 37 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-4- methoxythiophene-2-carboxamide

Step 1: To a stirred solution of 4-methoxythiophene-2-carboxylic acid (32.0 mg, 0.20 mmol, 1 equiv) in DMF (1.5 mL) was added PyBOP (158.1 mg, 0.30 mmol, 1.5 equiv), DIEA (130.9 mg, 1.01 mmol, 5 equiv) and 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoro-methyl) sulfanyl]indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv) at 0°C. The reaction solution was stirred at r.t. for 1 h. The resulting mixture was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.57; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-4-methoxythiophene-2-carboxamide (43.3 mg, 36.54%) as an off-white solid. LC-MS: (M+H) ⁺ found 585.30. ¹ H NMR (400 MHz, DMSO-d6) 9.39 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 6.98-6.81 (m, 2H), 6.23 (dd, J = 23.1, 7.9 Hz, 2H), 4.96- 4.77 (m, 3H), 3.78 (s, 3H), 3.63 (d, J = 28.4 Hz, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.82 (d, J = 7.9 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 10.8 Hz, 2H), 1.68 (d, J = 9.7 Hz, 1H). Example 38 – Preparation of 4-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2 ,4-oxadiazol-5-yl]methyl} thiophene-2-carboxamide Attorney Docket No.50006-0109WO1 Step 1: To a stirred solution of 4-cyanothiophene-2-carboxylic acid (33 mg, 0.22 mmol, 1.2 equiv), 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1-methylpiperidin-4- yl]-3-[(trifluoromethyl) sulfanyl]indolizin-8-amine (80 mg, 0.18 mmol, 1 equiv), and DIEA (0.16 mL, 0.90 mmol, 5 equiv) in DMF (1 mL) was added PyBOP (112 mg, 0.22mmol, 1.2 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature, then diluted with EtOAc (20 mL) and washed with brine (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH=10:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 38% B to 63% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.7) to afford 4-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl} thiophene-2-carboxamide (36.2 mg, 34.70%) as a light yellow solid. LC-MS: (M+H) ⁺ found 580.00. ¹ H NMR (400 MHz, DMSO-d6) δ 9.70 (t, J = 5.7 Hz, 1H), 8.80 (d, J = 1.3 Hz, 1H), 8.18 (d, J = 1.3 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.78 (m, 3H), 3.63 (d, J = 28.9 Hz, 1H), 3.04 (t, J = 11.0 Hz, 1H), 2.92 – 2.78 (m, 1H), 2.19 (s, 4H), 2.12 – 1.97 (m, 2H), 1.68 (d, J = 9.5 Hz, 1H). Example 39 – Preparation of 5-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2 ,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide Attorney Docket No.50006-0109WO1 Step 1: To a stirred solution of 5-cyanothiophene-2-carboxylic acid (31.0 mg, 0.20 mmol, 1 equiv) in DMF (1.5 mL) was added PyBOP (126.5 mg, 0.24 mmol, 1.2 equiv), DIEA (130.9 mg, 1.01 mmol, 5 equiv) and 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoro-methyl) sulfanyl]indolizin-8-amine (90 mg, 0.20 mmol, 1 equiv) at 0°C. The reaction solution was stirred at r.t. for 1 h. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 62% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.73; Number Of Runs: 2) to afford 5-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide (37.5 mg, 31.63%) as a yellow solid. LC-MS: (M+H) ⁺ found 580.30. ¹ H NMR (400 MHz, DMSO-d6) 9.85 (t, J = 5.6 Hz, 1H), 8.07-7.99 (m, 2H), 7.95 (d, J = 4.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 23.5, 7.9 Hz, 2H), 4.94- 4.73 (m, 3H), 3.62 (d, J = 28.1 Hz, 1H), 3.04 (t, J = 11.0 Hz, 1H), 2.83 (d, J = 8.4 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 11.6 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H). Example 41 – Preparation of 3-(difluoromethoxy)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}thiophene-2-carboxamide Attorney Docket No.50006-0109WO1 Step 1: To a stirred solution of 3-(difluoromethoxy)thiophene-2-carboxylic acid (48.1 mg, 0.25 mmol, 1.1 equiv), PyBOP (140.5 mg, 0.27 mmol, 1.2 equiv) and DIEA (0.20 mL, 1.13 mmol, 5 equiv) in DMF (1 mL) was added 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl]indolizin-8-amine (100 mg, 0.23 mmol, 1 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 42% B to 67% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.62) to afford 3-(difluoromethoxy)-N-{[3-(8- {[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluo romethyl)sulfanyl]indolizin-2-yl)- 1,2,4-oxadiazol-5-yl]methyl}thiophene-2-carboxamide (32.4 mg, 23.18%) as a white solid. LC- MS: (M+H) ⁺ found 621.00. ¹ H NMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.90 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.54 – 7.16 (m, 2H), 6.85 (t, J = 7.3 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.94 – 4.74 (m, 3H), 3.63 (d, J = 29.1 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 7.5 Hz, 1H), 2.19 (s, 4H), 2.15 – 1.99 (m, 2H), 1.68 (d, J = 10.4 Hz, 1H). Example 44 – Preparation of tert-butyl N-{1-[2-({[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)eth-1-yn-1-yl]cyclopropyl}carbamate Attorney Docket No.50006-0109WO1 Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (80 mg, 0.18 mmol, 1 equiv), 3-{1-[(tert-butoxycarbonyl) amino]cyclopropyl}prop-2-ynoic acid (40.5 mg, 0.18 mmol, 1 equiv), PyBOP (121.8 mg, 0.23 mmol, 1.3 equiv) and DIEA (116.3 mg, 0.90 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at r.t.. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 41% B to 66% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.68) to afford tert-butyl N-{1-[2-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]am ino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}carbamoyl)eth-1-yn-1- yl]cyclopropyl}carbamate (14.1 mg, 11.77%) as a white solid. LC-MS: (M+H) ⁺ found 652.30. ¹ H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 18.5 Hz, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.97 – 4.76 (m, 1H), 4.66 (d, J = 5.8 Hz, 2H), 3.63 (d, J = 28.8 Hz, 1H), 3.05 (t, J = 10.9 Hz, 1H), 2.84 (d, J = 7.0 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 9.4 Hz, 2H), 1.70 (s, 1H), 1.39 (s, 9H), 1.24 – 1.16 (m, 2H), 1.14 – 1.06 (m, 2H) ^. Example 56 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-5-(2H- pyrazol-3-yl)thiophene-2-carboxamide Attorney Docket No.50006-0109WO1 Step 1: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (100 mg, 0.23 mmol, 1 equiv) in DMF (1.2 mL) was treated with DIEA (203.6 mg, 1.58 mmol, 7 equiv) and PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) for 2 min at 0 °C followed by the addition of 5-(2H-pyrazol-3- yl)thiophene-2-carboxylic acid (30.6 mg, 0.16 mmol, 0.7 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3) +0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 58% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.77) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-5-(2H-pyrazol-3- yl)thiophene-2-carboxamide (40.5 mg, 29.00%) as an off-white solid. LC-MS: (M+H) ⁺ found 621.10. ¹ H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.40 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.85 – 7.75 (m, 3H), 7.45 (d, J = 3.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.71 (t, J = 2.1 Hz, 1H), 6.24 (dd, J = 29.1, 7.9 Hz, 2H), 4.96 – 4.75 (m, 3H), 3.62 (d, J = 28.7 Hz, 1H), 3.04 (t, J = 11.0 Hz, 1H), 2.82 (d, J = 7.6 Hz, 1H), 2.19 (s, 4H), 2.13 – 1.98 (m, 2H), 1.68 (d, J = 10.7 Hz, 1H). Example 59 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5- yl]methyl}acetamide Attorney Docket No.50006-0109WO1 Step 1: To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (70 mg, 0.16 mmol, 1 equiv) in DCM (0.7 mL) were added TEA (0.04 mL, 0.31 mmol, 2 equiv) and acetic anhydride (48.2 mg, 0.47 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred for 1 h at 0°C. The resulting solution was diluted with EA (30 mL) and washed with sat.NaHCO3 (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 28% B to 53% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.5) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}acetamide (29.6 mg, 38.21%) as a light yellow solid. LCMS: (M+H) ⁺ found 487.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 28.5, 7.8 Hz, 2H), 4.87 (d, J = 49.7 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.63 (d, J = 29.2 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.1 Hz, 1H), 2.20 (s, 4H), 2.09 (d, J = 8.6 Hz, 2H), 1.93 (s, 3H), 1.70 (d, J = 8.7 Hz, 1H). Example 10 – Preparation of 3,3-difluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}cyclobutane-1-carboxamide

Attorney Docket No.50006-0109WO1 Step 1: To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added PyBOP (81.1 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.04 mmol, 10.00 equiv) and 3,3-difluorocyclobutane-1-carboxylic acid (17.0 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 35% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.3). This resulted in 3,3-difluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}cyclobutane-1-carboxamide (FA salt; 17.5 mg, 29.4%) as a light yellow solid. LC-MS: (M+H) ⁺ found 563.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.87 (d, J = 48.0 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 3.75-3.58 (m, 1H), 3.08-2.96 (m, 2H), 2.84 (s, 1H), 2.81-2.70 (m, 4H), 2.21 (s, 4H), 2.13-2.03 (m, 2H), 1.70 (d, J = 11.0 Hz, 1H). Example 15 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-3,3- dimethyl-2-oxo-1H-indole-5-carboxamide

Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 3,3-dimethyl-2-oxo-1H-indole-5-carboxylic acid (23.1 mg, 0.11 mmol, 1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv), and DIEA (87.2 mg, 0.67 mmol, 6 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50mL) and washed with brine (2*50mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7 min; Wave Length: 254nm/220nm nm; RT1(min): 6.47; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-3,3-dimethyl-2-oxo-1H- indole-5-carboxamide (41.9 mg, 58.73%) as a white solid. LC-MS: (M+H) ⁺ found 632.35. ¹ H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 9.25 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.84 – 7.72 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.98 – 4.71 (m, 3H), 3.62 (d, J = 27.7 Hz, 1H), 3.04 (t, J = 11.2 Hz, 1H), 2.82 (d, J = 8.4 Hz, 1H), 2.19 (s, 4H), 2.13 – 2.03 (m, 2H), 1.69 (s, 1H), 1.29 (s, 6H). Example 21 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-5- methoxy-1H-indazole-3-carboxamide Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added 5-methoxy-1H-indazole-3-carboxylic acid 5 (21.6 mg, 0.11 mmol, 1.00 equiv), DIEA (145.4 mg, 1.12 mmol, 10.00 equiv) and PyBOP (87.8 mg, 0.17 mmol, 1.50 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: MeOH; Flow rate: 25 mL/min; Gradient: 58% B to 83% B in 10min; Wave Length: 254nm/220nm; RT(min): 9.73; Number Of Runs: 3). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-5-methoxy-1H-indazole- 3-carboxamide (17.7 mg, 24.54%) as a white solid. LC-MS: (M+H) ⁺ found 619.35. ¹ H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 9.20 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.51 (m, 2H), 7.08 (dd, J = 9.0, 2.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 5.10-4.46 (m, 3H), 3.79 (s, 3H), 3.40 (d, J = 11.2 Hz, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.81 (d, J = 8.6 Hz, 1H), 2.38-2.18 (m, 4H), 2.17-1.85 (m, 2H), 1.66 (d, J = 10.4 Hz, 1H). Example 22 – Preparation of tert-butyl N-[1-({[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)cyclopropyl]carbamate Attorney Docket No.50006-0109WO1 To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added PyBOP (81.1 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.0 mmol, 10.00 equiv) and 1-[(tert-butoxycarbonyl)amino]cyclopropane-1-carboxylic acid (25.1 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22% B to35% B in 7 min; Wave Length: 254nm/220nm; RT(min): 6.9). This resulted in tert-butyl N-[1-({[3-(8-{[(3S,4R)- 3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)s ulfanyl]indolizin-2-yl)-1,2,4- oxadiazol-5-yl]methyl}carbamoyl)cyclopropyl]carbamate (FA salt; 14.2 mg, 21.1%) as a light yellow solid. LC-MS: (M+H) ⁺ found 628.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.82-8.50 (m, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 7.49-7.19 (m, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.35-6.13 (m, 2H), 4.88 (d, J = 49.6 Hz, 1H), 4.64 (d, J = 5.7 Hz, 2H), 3.75 (s, 1H), 3.06 (t, J = 10.8 Hz, 1H), 2.85 (d, J = 9.2 Hz, 1H), 2.38-2.20 (m, 4H), 2.19-2.00 (m, 2H), 1.75-1.67 (m, 1H), 1.39 (d, J = 10.0 Hz, 9H), 1.27 (m, 2H), 0.94 (m, 2H). Example 24 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1- hydroxycyclopropane-1-carboxamide Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added 1-hydroxycyclopropane-1-carboxylic acid (10.6 mg, 0.10 mmol, 1.00 equiv), PyBOP (81.2 mg, 0.15 mmol, 1.50 equiv) and DIEA (134.4 mg, 1.04 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.23). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1-hydroxycyclopropane-1-carboxamide (22.3 mg, 40.26%) as a white solid. LC-MS: (M+H) ⁺ found 529.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.39 (s, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.87 (d, J = 49.4 Hz, 1H), 4.68 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 28.1 Hz, 1H), 3.05 (t, J = 11.0 Hz, 1H), 2.83 (s, 1H), 2.35-2.19 (m, 4H), 2.18- 1.98 (m, 2H), 1.80-1.62 (m, 1H), 1.11-1.00 (m, 2H), 0.91-0.88 (m, 2H). Example 25 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}oxetane- 3-carboxamide Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (40 mg, 0.09 mmol, 1 equiv), DIEA (0.05 mL, 0.27 mmol, 3 equiv) and oxetane-3-carboxylic acid (9.2 mg, 0.09 mmol, 1 equiv) in DMF (1 mL) was added PyBOP (60.9 mg, 0.12 mmol, 1.3 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 27% B to 54% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.27) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}oxetane-3-carboxamide (8.2 mg, 16.98%) as a light yellow solid. LCMS: (M+H) ⁺ found 529.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.85 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 21.2, 7.8 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.73 – 4.56 (m, 6H), 3.86 (tt, J = 8.5, 6.6 Hz, 1H), 3.63 (d, J = 28.7 Hz, 1H), 3.06 (dt, J = 12.2, 6.5 Hz, 1H), 2.84 (d, J = 7.9 Hz, 1H), 2.30 – 2.20 (m, 4H), 2.14 – 2.00 (m, 2H), 1.70 (d, J = 9.7 Hz, 1H). Example 26 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-1- methoxycyclopropane-1-carboxamide Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv) in DMF (1.5 mL) was added 1-methoxycyclopropane-1-carboxylic acid (19.6 mg, 0.17 mmol, 1.5 equiv), DIEA (72.7 mg, 0.56 mmol, 5 equiv) and PyBOP (87.8 mg, 0.17 mmol, 1.5 equiv) at 0°C. The reaction solution was stirred at room temperature for 1 h. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.67; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-1-methoxycyclopropane-1-carboxamide (24.9 mg, 40.47%) as an off-white solid. LC- MS: (M+H) ⁺ found 543.15. ¹ H NMR (400 MHz, DMSO-d6) 8.94 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 16.0, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.70 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 28.3 Hz, 1H), 3.34 (s, 3H), 3.05 (t, J = 11.1 Hz, 1H), 2.84 (d, J = 8.0 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 10.9 Hz, 2H), 1.70 (d, J = 9.5 Hz, 1H), 1.08 (m, 4H). Example 28 – Preparation of 1-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2 ,4-oxadiazol-5- yl]methyl}cyclopropane-1-carboxamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv) in DMF (1.5 mL) was treated with DIEA (72.7 mg, 0.56 mmol, 5 equiv) and PyBOP (87.8 mg, 0.17 mmol, 1.5 equiv) for 2 min at 0 °C followed by the addition of 1-cyanocyclopropane-1- carboxylic acid (12.5 mg, 0.11 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resultingsolution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78) to afford 1-cyano-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]a mino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}cyclopropane-1- carboxamide (18.4 mg, 30.43%) as an off-white solid. LC-MS: (M+H) ⁺ found 538.35. ¹ H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.25 (dd, J = 30.1, 7.9 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H), 3.63 (d, J = 30.6 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 6.7 Hz, 1H), 2.30 (d, J = 13.1 Hz, 1H), 2.20 (s, 3H), 2.14 – 2.01 (m, 2H), 1.68 (m, 3H), 1.56 (m, 2H). Example 35 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-6- methoxy-1-methylindole-2-carboxamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (60 mg, 0.14 mmol, 1 equiv), 6-methoxy-1-methylindole-2-carboxylic acid (30.5 mg, 0.15 mmol, 1.1 equiv), PyBOP (84.3 mg, 0.16 mmol, 1.2 equiv) and DIEA (87.2 mg, 0.68 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (15 mL) and washed with brine (4*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2/MeOH=20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 45% B to 70% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.8) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-6-methoxy-1- methylindole-2-carboxamide (23.7 mg, 27.65%) as a off-white solid. LC-MS: (M+H) ⁺ found 632.15. ¹ H NMR (400 MHz, DMSO-d6) δ 9.26 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.78 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.20 (s, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.77 (dd, J = 8.7, 2.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.74 (m, 3H), 3.98 (s, 3H), 3.84 (s, 3H), 3.62 (d, J = 28.4 Hz, 1H), 3.04 (t, J = 11.5 Hz, 1H), 2.81 (s, 1H), 2.19 (s, 4H), 2.06 (t, J = 11.4 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H). Example 36 – Preparation of 4-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin- 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2 ,4-oxadiazol-5-yl]methyl} oxane- 4-carboxamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (70 mg, 0.16 mmol, 1 equiv), PyBOP (98.4 mg, 0.19 mmol, 1.2 equiv), DIEA (0.14 mL, 0.79 mmol, 5 equiv) and 4- fluorooxane-4-carboxylic acid (25.7 mg, 0.17 mmol, 1.1 equiv) in DMF (0.7 mL) was stirred for 0.5 h at room temperature. The solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.2) to afford 4-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl} oxane-4-carboxamide (17.7 mg, 19.34%) as a white solid. LC-MS: (M+H) ⁺ found 575.15. ¹ H NMR (400 MHz, DMSO- d6) δ 9.09 (td, J = 5.8, 2.4 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 14.8, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 3.83 (m, 2H), 3.59 (td, J = 11.8, 2.3 Hz, 3H), 3.05 (t, J = 11.0 Hz, 1H), 2.84 (d, J = 10.1 Hz, 1H), 2.20 (s, 4H), 2.18 – 1.97 (m, 4H), 1.83 – 1.64 (m, 3H). Example 40 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-1,3- benzothiazole-6-carboxamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 1,3-benzothiazole-6-carboxylic acid (22.2 mg, 0.12 mmol, 1.1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.67; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}- 3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol -5-yl]methyl}-1,3-benzothiazole-6- carboxamide (18.0 mg, 26.42%) as a light yellow solid. LC-MS: (M+H) ⁺ found 606.05. ¹ H NMR (400 MHz, DMSO-d6) δ 9.58 (d, J = 7.8 Hz, 2H), 8.76 (d, J = 1.7 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.09 (m, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.98 – 4.73 (m, 3H), 3.62 (d, J = 28.2 Hz, 1H), 3.05 (d, J = 11.2 Hz, 1H), 2.82 (d, J = 8.8 Hz, 1H), 2.19 (s, 4H), 2.05 (t, J = 11.4 Hz, 2H), 1.67 (d, J = 11.0 Hz, 1H). Example 42 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-4- methanesulfonylbenzamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (60 mg, 0.14 mmol, 1 equiv), P-methylsulfonylbenzoic acid (29.7 mg, 0.15 mmol, 1.1 equiv), PyBOP (84.3 mg, 0.16 mmol, 1.2 equiv) and DIEA (87.2 mg, 0.68 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (15 mL) and washed with brine (4*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 /MeOH=20:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 34% B to 59% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.6) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-4- methanesulfonylbenzamide (21.6 mg, 25.41%) as a off-white solid. LC-MS: (M+H) ⁺ found 627.05. ¹ H NMR (400 MHz, DMSO-d6) δ 9.72 (t, J = 5.6 Hz, 1H), 8.21 – 8.13 (m, 2H), 8.13 – 8.06 (m, 2H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.97 – 4.72 (m, 3H), 3.71 – 3.54 (m, 1H), 3.29 (s, 3H), 3.04 (t, J = 11.4 Hz, 1H), 2.82 (d, J = 7.5 Hz, 1H), 2.19 (s, 4H), 2.06 (t, J = 11.2 Hz, 2H), 1.68 (d, J = 10.3 Hz, 1H). Example 45 – Preparation of tert-butyl N-[3-({[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]carbamate Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (80 mg, 0.18 mmol, 1 equiv), 3-[(tert-butoxycarbonyl) amino]bicyclo[1.1.1]pentane-1-carboxylic acid (40.9 mg, 0.18 mmol, 1 equiv), PyBOP (112.4 mg, 0.22 mmol, 1.2 equiv) and DIEA (116.3 mg, 0.90 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with DCM (3*30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: MEOH; Flow rate: 25 mL/min mL/min; Gradient: 60% B to 83% B in 10min; Wave Length: 254nm/220nm nm; RT1(min): 9.27) to afford tert-butyl N-[3-({[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl) sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}carbamoyl)bicyclo[1.1.1]pentan-1-yl]carbamate (16.5 mg, 13.69%) as a white solid. LC-MS: (M+H) ⁺ found 654.45. ¹ H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 7.60 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 19.7, 7.8 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.61 (d, J = 5.7 Hz, 2H), 3.63 (d, J = 29.8 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.83 (s, 1H), 2.20 (s, 4H), 2.11 (s, 8H), 1.70 (d, J = 9.3 Hz, 1H), 1.38 (s, 9H). Example 46 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-1-(4- fluorophenyl)cyclopropane-1-carboxamide Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (90 mg, 0.20 mmol, 1 equiv), PyBOP (126.5 mg, 0.24 mmol, 1.2 equiv) and DIEA (130.9 mg, 1.01 mmol, 5 equiv) in DMF (1.0 mL) was added 1-(4-fluorophenyl)cyclopropane-1-carboxylic acid (40.1 mg, 0.22 mmol, 1.1 equiv) at 0°C. The resulting solution was stirred for 0.5 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 47% B to 74% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.02) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-1-(4- fluorophenyl)cyclopropane-1-carboxamide (40.4 mg, 32.46%) as a white solid. LC-MS: (M+H) ⁺ found 607.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.67 (t, J = 5.7 Hz, 1H), 7.48 – 7.41 (m, 2H), 7.25 – 7.17 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 13.6, 7.9 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.64 (d, J = 28.8 Hz, 1H), 3.05 (t, J = 11.1 Hz, 1H), 2.88 – 2.78 (m, 1H), 2.20 (s, 4H), 2.08 (t, J = 11.1 Hz, 2H), 1.70 (d, J = 9.7 Hz, 1H), 1.40 (m, 2H), 1.05 (m, 2H). Example 47 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl] methyl}-1- (trifluoromethyl)cyclopropane-1-carboxamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (70 mg, 0.16 mmol, 1 equiv), 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (24.3 mg, 0.16 mmol, 1 equiv), PyBOP (98.4 mg, 0.19 mmol, 1.2 equiv) and DIEA (101.8 mg, 0.79 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 44% B to 68% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.25) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl] methyl}-1- (trifluoromethyl)cyclopropane-1-carboxamide (35.5 mg, 38.67%) as a white solid. LC-MS: (M+H) ⁺ found 581.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.5 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 18.6, 7.8 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.66 (d, J = 5.6 Hz, 2H), 3.64 (d, J = 28.9 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.6 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 10.8 Hz, 2H), 1.70 (d, J = 9.8 Hz, 1H), 1.38 (d, J = 7.5 Hz, 2H), 1.36 – 1.27 (m, 2H). Example 49 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2- hydroxy-2-methylpropanamide Attorney Docket No.50006-0109WO1 To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (80 mg, 0.18 mmol, 1 equiv) in anhydrous DMF (1 mL) was added acetonate (28.1 mg, 0.27 mmol, 1.5 equiv), PyBOP (140.5 mg, 0.27 mmol, 1.5 equiv) and DIEA (116.3 mg, 0.90 mmol, 5 equiv) at 0°C. The reaction solution was stirred at room temperature for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 56% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.18) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-2-hydroxy-2- methylpropanamide (42.1 mg, 42.67%) as a yellow solid. LC-MS: (M+H) ⁺ found 531.40. ¹ H NMR (400 MHz, DMSO-d6) 8.55 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 8.8 Hz, 2H), 5.53 (s, 1H), 4.87 (d, J = 49.5 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 28.3 Hz, 1H), 3.05 (t, J = 11.1 Hz, 1H), 2.83 (d, J = 7.8 Hz, 1H), 2.20 (s, 4H), 2.08 (t, J = 11.0 Hz, 2H), 1.70 (d, J = 9.6 Hz, 1H), 1.30 (s, 6H). Example 57 – Preparation of N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-N4- methylbenzene-1,4-dicarboxamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 4-(methylcarbamoyl)benzoic acid (22.2 mg, 0.12 mmol, 1.1 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 56% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.23) to afford N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3 - [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-N4-methylbenzene-1,4- dicarboxamide (15.7 mg, 23.04%) as a white solid. LC-MS: (M+H) ⁺ found 606.15. ¹ H NMR (400 MHz, DMSO-d6) δ 9.54 (t, J = 5.6 Hz, 1H), 8.60 (d, J = 4.7 Hz, 1H), 8.16 – 7.83 (m, 5H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 5.00 – 4.71 (m, 3H), 3.62 (d, J = 29.4 Hz, 1H), 3.04 (t, J = 11.4 Hz, 1H), 2.81 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.14 – 1.97 (m, 2H), 1.68 (d, J = 9.9 Hz, 1H). Example 58 – Preparation of N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-N3- methylbenzene-1,3-dicarboxamide Attorney Docket No.50006-0109WO1 Step 1: A mixture of isophthalic acid, methyl ester (1 g, 5.55 mmol, 1 equiv), HATU (3.2 g, 8.32 mmol, 1.5 equiv) CH3NH2 ^. HCl (0.5 g, 6.66 mmol, 1.2 equiv) and DIEA (2.9 g, 22.20 mmol, 4 equiv) in DMF (5 mL) was stirred for 1 h at room temperature. The resulting solution was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0 to 100% gradient in 20 min; detector, UV 254 nm) to afford methyl 3- (methylcarbamoyl)benzoate (1 g, 93.25%) as a off-white solid. LC-MS: (M+H) ⁺ found 193.2. Step 2: A mixture of methyl 3-(methylcarbamoyl)benzoate (1 g, 5.18 mmol, 1 equiv) and NaOH (2.1 g, 51.76 mmol, 10 equiv) in H2O (10 mL)/MeOH (20 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL) and acidified to pH 2 with 1M HCl. The aqueous layer was extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(methylcarbamoyl)benzoic acid (820 mg, 88.42%) as a off-white solid. LC-MS: (M+H) ⁺ found 179.1. Step 3: A mixture of 3-(methylcarbamoyl)benzoic acid (24.2 mg, 0.13 mmol, 1.2 equiv), 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1-methylpiperidin-4-yl]-3- [(trifluoromethyl)sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1.00 equiv), PyBOP (87.8 mg, 0.17 mmol, 1.5 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting solution was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.75; Number Of Runs: 2) to afford N1-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3 - [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-N3-methylbenzene-1,3- dicarboxamide (15.6 mg, 22.90%) as a yellow solid. LC-MS: (M+H) ⁺ found 606.15. ¹ H NMR (400 Attorney Docket No.50006-0109WO1 MHz, DMSO-d6) δ 9.55 (t, J = 5.6 Hz, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.12 – 7.92 (m, 3H), 7.76 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.96 – 4.73 (m, 3H), 3.62 (d, J = 28.7 Hz, 1H), 3.04 (t, J = 11.1 Hz, 1H), 2.80 (d, J = 4.5 Hz, 4H), 2.19 (s, 4H), 2.06 (t, J = 11.5 Hz, 2H), 1.68 (d, J = 10.4 Hz, 1H). Example 60 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2- methylpropanamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (100 mg, 0.23 mmol, 1 equiv) in DMF (1.5 mL) was treated with DIEA (145.4 mg, 1.13 mmol, 5 equiv) and PyBOP (175.6 mg, 0.34 mmol, 1.5 equiv) for 2 min at 0 °C followed by the addition of isobutyric acid (19.8 mg, 0.23 mmol, 1 equiv). The resulting solution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78) to afford N-{[3- (8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[(trif luoromethyl)sulfanyl]indolizin-2- yl)-1,2,4-oxadiazol-5-yl]methyl}-2-methylpropanamide (28.3 mg, 24.45%) as an off-white solid. LC-MS: (M+H) ⁺ found 515.35. ¹ H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 16.8, 7.8 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.63 (d, J = 29.3 Hz, 1H), 3.05 (t, J = 11.3 Hz, 1H), 2.83 (s, 1H), 2.50 – 2.42 (m, 1H), 2.20 (s, 4H), 2.16 – 2.00 (m, 2H), 1.70 (d, J = 10.4 Hz, 1H), 1.06 (d, J = 6.8 Hz, 6H). Attorney Docket No.50006-0109WO1 Example 61 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2- methoxy-2-methylpropanamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 2-methoxy-2-methylpropanoic acid (13.3 mg, 0.11 mmol, 1 equiv), pybop (76.1 mg, 0.15mmol, 1.3 equiv) and DIEA (0.06 mL, 0.34 mmol, 3 equiv) in DMF (1 mL) was stirred for 1 at room temperature. The resultingsolution was diluted with water (30 mL) and extracted with EtOAc (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.13; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-2-methoxy-2- methylpropanamide (18.1 mg, 29.49%) as a light yellow solid. LCMS: (M+H) ⁺ found 545.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.23 (dd, J = 12.2, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.64 (d, J = 5.9 Hz, 2H), 3.64 (d, J = 28.1 Hz, 1H), 3.23 (s, 3H), 3.05 (t, J = 11.1 Hz, 1H), 2.84 (d, J = 7.7 Hz, 1H), 2.30 (d, J = 13.2 Hz, 1H), 2.20 (s, 3H), 2.13 – 2.01 (m, 2H), 1.70 (d, J = 9.7 Hz, 1H), 1.31 (s, 6H). Example 63 – Preparation of (3R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-3- hydroxybutanamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (60 mg, 0.14 mmol, 1 equiv), (-)-3-hydroxybutyric acid (15.5 mg, 0.15 mmol, 1.1 equiv), PyBOP (84.3 mg, 0.16 mmol, 1.2 equiv) and DIEA (87.2 mg, 0.68 mmol, 5 equiv) in DMF (1 mL) was stirred for 30 min at room temperature. The resulting mixture was diluted with EtOAc (10 mL) and washed with brine (4*10 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 53% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.37) to afford (3R)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[( trifluoromethyl)sulfanyl]indolizin- 2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxybutanamide (16.5 mg, 22.65%) as a light yellow solid. LC-MS: (M+H) ⁺ found 531.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.79 – 7.73 (m, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (dd, J = 11.2, 7.9 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.75 – 4.55 (m, 3H), 4.00 (dt, J = 12.0, 6.2 Hz, 1H), 3.63 (d, J = 28.8 Hz, 1H), 3.05 (s, 1H), 2.83 (d, J = 8.0 Hz, 1H), 2.41 – 2.28 (m, 1H), 2.22 (d, J = 19.4 Hz, 5H), 2.16 – 1.99 (m, 2H), 1.70 (d, J = 9.9 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H). Example 64 – Preparation of (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-3- hydroxybutanamide Attorney Docket No.50006-0109WO1 A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), (S)-3-hydroxybutanoic acid (14.1 mg, 0.13 mmol, 1.2 equiv), PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was stirred for 1 h at room temperature under. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3 ^. H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 26% B to 50% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.75) to afford (3S)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3-[( trifluoromethyl)sulfanyl]indolizin- 2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxybutanamide (19.6 mg, 32.84%) as a light yellow solid. LC-MS: (M+H) ⁺ found 531.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (m, 2H), 4.86 (d, J = 49.3 Hz, 1H), 4.76 – 4.55 (m, 3H), 4.00 (m, 1H), 3.63 (d, J = 28.9 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 8.1 Hz, 1H), 2.34 (m, 1H), 2.22 (d, J = 19.5 Hz, 5H), 2.08 (t, J = 10.9 Hz, 2H), 1.70 (d, J = 9.6 Hz, 1H), 1.10 (d, J = 6.1 Hz, 3H). Example 65 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-3- hydroxy-3-methylbutanamide Attorney Docket No.50006-0109WO1 To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 3-hydroxyisovaleric acid (14.6 mg, 0.12 mmol, 1.1 equiv) and DIEA (72.7 mg, 0.56 mmol, 5 equiv) in DMF (1 mL) was added PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 1h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 31% B to 56% B in 8 min; Wave Length: 220nm nm; RT1(min): 6.98) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-3-hydroxy-3- methylbutanamide (9.9 mg, 15.79%) as a white solid. LC-MS: (M+H) ⁺ found 545.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 9.2 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.74 (s, 1H), 4.66 (d, J = 5.7 Hz, 2H), 3.64 (d, J = 29.7 Hz, 1H), 3.06 (t, J = 11.3 Hz, 1H), 2.84 (d, J = 8.5 Hz, 1H), 2.32 (s, 2H), 2.20 (s, 3H), 2.08 (t, J = 11.3 Hz, 2H), 1.70 (d, J = 10.5 Hz, 1H), 1.20 (s, 6H). Example 8 – Preparation of (1r,3r)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3- hydroxycyclobutane-1-carboxamide Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added trans-3-hydroxycyclobutanecarboxylic acid (12.8 mg, 0.01 mmol, 1.00 equiv), PyBOP (75.4 mg, 0.15 mmol, 1.50 equiv) and DIEA (124.9 mg, 0.97 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 52% B in 8 min; Wave Length: 220 nm; RT(min): 7.17). This resulted in (1r,3r)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-3-hydroxycyclob utane- 1-carboxamide (20.2 mg, 38.10%) as a white solid. LC-MS: (M+H) ⁺ found 543.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.64 (t, J = 5.8 Hz, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.28-6.10 (m, 2H), 5.06 (d, J = 6.2 Hz, 1H), 4.92 (d, J = 49.0 Hz, 1H), 4.63 (d, J = 5.7 Hz, 2H), 4.26 (t, J = 6.8 Hz, 1H), 3.68 (d, J = 29.2 Hz, 1H), 3.28 (s, 1H), 2.98-2.87 (m, 2H), 2.42- 2.20 (m, 6H), 2.19-1.95 (m, 4H), 1.90-1.60 (m, 1H). Example 9 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-2-(5- methoxy-1H-indazol-3-yl)acetamide Attorney Docket No.50006-0109WO1 To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.0 mL) were added PyBOP (81.2 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.04 mmol, 10.00 equiv) and (5-methoxy-1H-indazol-3-yl)acetic acid (25.7 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 60% B in 7min; Wave Length: 254 nm/220 nm; RT1(min): 7.68). This resulted in N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-2-(5-methoxy-1H- indazol-3-yl)acetamide (28.5 mg, 43.0%) as an off-white solid. LC-MS: (M+H) ⁺ found 633.20. ¹ H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 9.02 (t, J = 5.8 Hz, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 9.0, 2.4 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.26-6.21 (m, 2H), 4.87 (d, J = 49.6 Hz, 1H), 4.69 (d, J = 5.7 Hz, 2H), 3.88 (s, 2H), 3.76 (s, 3H), 3.75-3.56 (m, 1H), 3.05 (t, J = 11.1 Hz, 1H), 2.84 (d, J = 7.4 Hz, 1H), 2.35-2.18 (m, 4H), 2.08 (t, J = 9.7 Hz, 2H), 1.71 (d, J = 9.4 Hz, 1H). Example 11 – Preparation of (2S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1,4- dioxane-2-carboxamide Attorney Docket No.50006-0109WO1 To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added (2S)-1,4-dioxane-2-carboxylic acid (13.7 mg, 0.10 mmol, 1.00 equiv), PyBOP (81.2 mg, 0.16 mmol, 1.50 equiv) and DIEA (134.4 mg, 1.04 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 57% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.52). This resulted in (2S)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1,4-dioxane-2-carboxamide (11.6 mg, 19.94%) as a white solid. LC-MS: (M+H) ⁺ found 559.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.35-6.10 (m, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.73-4.58 (m, 2H), 4.16 (dd, J = 9.4, 3.1 Hz, 1H), 3.89 (td, J = 11.1, 10.7, 2.9 Hz, 2H), 3.76-3.65 (m, 3H), 3.62-3.42 (m, 2H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.9 Hz, 1H), 2.40-2.18 (m, 4H), 2.17-2.02 (m, 2H), 1.70 (d, J = 9.4 Hz, 1H). Example 12 – Preparation of 2-(dimethylamino)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-1,3-oxazole-5-carboxamide Attorney Docket No.50006-0109WO1 Step 1: A mixture of ethyl 2-amino-1,3-oxazole-5-carboxylate (400 mg, 2.56 mmol, 1 equiv), dimethylamine hydrochloride (626.7 mL, 7.69 mmol, 3 equiv) and K2CO3 (1.77 g, 12.81 mmol, 5 equiv) in ACN (10 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water (50 mL) and extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in ethyl 2-(dimethylamino)-1,3-oxazole-5-carboxylate (400 mg, 84.77%) as a light yellow oil. LC-MS: (M+H) ⁺ found 185.1. Step 2: To a stirred mixture of ethyl 2-(dimethylamino)-1,3-oxazole-5-carboxylate (500 mg, 2.72 mmol, 1 equiv) in THF (2 mL)/H2O (2 mL) was added NaOH (108.6 mg, 2.72 mmol, 1 equiv) at 0°C. The resulting mixture was stirred for 2 h at room temperature, then acidified to pH 3 with 1 M HCl. The resulting solution was extracted with DCM (3*50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(dimethylamino)-1,3-oxazole-5-carboxylic acid (400 mg, 94.37%) as an off-white solid. LC-MS: (M+H) ⁺ found 157.1. Step 3: A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (60 mg, 0.14 mmol, 1.00 equiv), DIEA (122.1 mg, 0.95 mmol, 7 equiv), 2-(dimethylamino)-1,3-oxazole-5-carboxylic acid (42.2 mg, 0.27 mmol, 2 equiv) and PyBOP (105.4 mg, 0.20 mmol, 1.5 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (20 mL) and washed with briner (3*20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH ⁴ HCO ³ +0.05% NH ^3. H ² O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 35% B to 60% B in 8 min; Wave Length: 220nm nm; RT1(min): 7.78 ) to afford 2- Attorney Docket No.50006-0109WO1 (dimethylamino)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidi n-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-1,3-oxazole-5- carboxamide (26.6 mg, 33.82%) as a off-white solid. LC-MS: (M+H) ⁺ found 583.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.96 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.79 – 7.74 (m, 1H), 7.53 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.28 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.7 Hz, 1H), 4.98 – 4.68 (m, 3H), 3.62 (d, J = 29.0 Hz, 1H), 3.07 (s, 7H), 2.83 (d, J = 7.5 Hz, 1H), 2.19 (s, 4H), 2.07 (t, J = 10.2 Hz, 2H), 1.68 (d, J = 9.2 Hz, 1H). Example 29 – Preparation of (2R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-1,4- dioxane-2-carboxamide To a solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (1.00 mL) were added (2S)-1,4-dioxane-2-carboxylic acid (13.7 mg, 0.10 mmol, 1.00 equiv), PyBOP (81.2 mg, 0.16 mmol, 1.50 equiv) and DIEA (134.4 mg, 1.04 mmol, 10.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and Prep-HPLC (XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 57% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.52). This resulted in (2S)-N- {[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl] methyl}-1,4-dioxane-2-carboxamide (11.6 mg, 19.94%) as a white solid. LC-MS: (M+H) ⁺ found 559.10. ¹ H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.35-6.10 (m, 2H), 4.87 Attorney Docket No.50006-0109WO1 (d, J = 49.5 Hz, 1H), 4.73-4.58 (m, 2H), 4.16 (dd, J = 9.4, 3.1 Hz, 1H), 3.89 (td, J = 11.1, 10.7, 2.9 Hz, 2H), 3.76-3.65 (m, 3H), 3.62-3.42 (m, 2H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 7.9 Hz, 1H), 2.40-2.18 (m, 4H), 2.17-2.02 (m, 2H), 1.70 (d, J = 9.4 Hz, 1H). Example 29 – Preparation of 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-5 4-yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2 ,4-oxadiazol-5- yl]methyl}bicyclo[1.1.1]pentane-1-carboxamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (17.6 mg, 0.13 mmol, 1.2 eq), DIEA (72.7 mg, 0.56 mmol, 5 equiv) and PyBOP (70.3 mg, 0.13 mmol, 1.2 equiv) in DMF (1.5 mL) was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 37% B to 60% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.52; Number Of Runs: 2) to afford 3-fluoro-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl] amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}bicyclo[1.1.1]pentane-1- carboxamide (19.6 mg, 31.02%) as a white solid. LC-MS: (M+H) ⁺ found 557.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.90 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.78 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.24 (m, 2H), 4.87 (d, J = 49.3 Hz, 1H), 4.65 (d, J = 5.7 Hz, 2H), 3.64 (d, J = 29.0 Hz, 1H), 3.05 (t, J = 11.2 Hz, 1H), 2.84 (d, J = 8.1 Hz, 1H), 2.33 (d, J = 2.6 Hz, 7H), 2.20 (s, 3H), 2.14 – 2.00 (m, 2H), 1.70 (d, J = 9.7 Hz, 1H). Attorney Docket No.50006-0109WO1 Example 62 – Preparation of (1s,3s)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-3- hydroxycyclobutane-1-carboxamide To a stirred mixture of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine hydrochloride (50.0 mg, 0.10 mmol, 1.00 equiv) in DMF (2.00 mL) were added PyBOP (81.2 mg, 0.15 mmol, 1.50 equiv), DIEA (134.4 mg, 1.04 mmol, 10.00 equiv) and (1s,3s)-3-hydroxycyclobutane-1-carboxylic acid (14.5 mg, 0.12 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at room temperature. The resulted solution was purified by reverse flash chromatography (Mobile Phase A: Water, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 0% B to 100% B in 30 min; 254/220 nm) and prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.05% NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 52% B in 7min; Wave Length: 254nm/220nm; RT(min): 7.63). This resulted in (1s,3s)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]a mino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-oxadiazol-5 -yl]methyl}-3-hydroxycyclobutane- 1-carboxamide (14.9 mg, 25.9%) as an off-white solid. LC-MS: (M+H) ⁺ found 543.15. ¹ H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 5.7 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.77 (s, 1H), 6.86 (t, J = 7.2 Hz, 1H), 6.32-6.16 (m, 2H), 5.15 (d, J = 6.9 Hz, 1H), 4.87 (d, J = 49.6 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.95 (m, 1H), 3.76-3.57 (m, 1H), 3.05 (t, J = 10.8 Hz, 1H), 2.84 (d, J = 7.7 Hz, 1H), 2.47-2.02 (m, 9H), 1.97 (m, 2H), 1.70 (d, J = 10.0 Hz, 1H). Example 66 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2- (morpholin-4-yl)-1,3-oxazole-5-carboxamide Attorney Docket No.50006-0109WO1 Step 1: A mixture of ethyl 2-chloro-1,3-oxazole-5-carboxylate (500 mg, 2.85 mmol, 1 equiv), morpholine (496.2 mg, 5.69 mmol, 2 equiv) and K2CO3 (1.18 g, 8.54 mmol, 3 equiv) in MeCN (8 mL) was stirred at 80°C for 2 h. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was diluted with water (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylate (600 mg, 93.13%) as a yellow oil. LC-MS: (M+H) ⁺ found 227.2. Step 2: To a stirred solution of ethyl 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylate (590 mg, 2.61 mmol, 1 equiv) in THF (4 mL)/water (4 mL) was added NaOH (208.6 mg, 5.22 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture concentrated under reduced pressure and then acidified to pH 6 with 1 M HCl. The precipitated solids were collected by filtration to afford 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylic acid (500 mg, 96.74%) as an off-white solid. LC-MS: (M+H) ⁺ found 199.0. Step 3: To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3- fluoro-1-methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] indolizin-8-amine (55 mg, 0.12 mmol, 1 equiv) in DMF (1.5 mL) was added 2-(morpholin-4-yl)-1,3-oxazole-5-carboxylic acid (49.1 mg, 0.25 mmol, 2 equiv), PyBOP (96.6 mg, 0.19 mmol, 1.5 equiv) and DIEA (80.0 mg, 0.62 mmol, 5 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EA (30 mL) and washed with brine (3*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3)+0.05%NH3.H2O, Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 7.53) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- Attorney Docket No.50006-0109WO1 [(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-2-(morpholin-4- yl)-1,3- oxazole-5-carboxamide (24.5 mg, 31.19%) as an off-white solid. LC-MS: (M+H) ⁺ found 625.35. 1H NMR (400 MHz, DMSO-d6)9.03 (t, J = 5.8 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (s, 1H), 7.57 (s, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.94- 4.75 5 (m, 3H), 3.61 (dt, J = 66.7, 4.7 Hz, 9H), 3.05 (t, J = 11.3 Hz, 1H), 2.82 (s, 1H), 2.20 (s, 4H), 2.07 (t, J = 10.8 Hz, 2H), 1.69 (d, J = 9.9 Hz, 1H). Example 67 – Preparation of N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5- yl]methyl}morpholine-4-carboxamide Step 1: To a stirred mixture of triphosgene (120.2 mg, 0.40 mmol, 1.2 equiv) in DCM (2 mL) was added 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl) sulfanyl] indolizin-8-amine (150 mg, 0.34 mmol, 1 equiv) and DIEA (174.5 mg, 1.35 mmol, 4 equiv) dropwise at 0°C. Then the resulting mixture was concentrated under reduced pressure. This resulted in N-[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]-2-[5-(isocyanatomethyl)-1,2,4-oxadiazol-3-yl]-3-[(triflu oromethyl)sulfanyl] indolizin-8- amine (100 mg, 62.98%) as a yellow solid. LC-MS: (M+H) ⁺ found 471.1. Step 2: A solution of N-[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]-2-[5- (isocyanatomethyl)-1,2,4-oxadiazol-3-yl]-3-[(trifluoromethyl )sulfanyl]indolizin-8-amine (50 mg, 0.11 mmol, 1 equiv) in DCM (1 mL) was treated with morpholine (18.5 mg, 0.21 mmol, 2 equiv) for 30 min at 0°C .The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 50% B in 7min; Wave Length: 254nm/220nm nm;25 RT1(min): 6.53; Number Of Runs: 2) to afford N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- Attorney Docket No.50006-0109WO1 yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}morpholine- 4-carboxamide (19.7 mg, 33.24%) as an off-white solid. LC-MS: (M+H) ⁺ found 558.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.52 (t, J = 5.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.24 (dd, J = 29.1, 7.8 Hz, 2H), 4.87 (d, J = 49.5 Hz, 1H), 4.58 (d, J 5 = 5.4 Hz, 2H), 3.75 – 3.53 (m, 5H), 3.32 (s, 4H), 3.05 (t, J = 11.2 Hz, 1H), 2.83 (d, J = 7.0 Hz, 1H), 2.39 – 2.14 (m, 4H), 2.08 (t, J = 9.3 Hz, 2H), 1.69 (d, J = 7.9 Hz, 1H). Example 68 – Preparation of (3R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4- methylmorpholine-3-carboxamide A solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), (3R)-4-methylmorpholine-3-carboxylic acid hydrochloride (24.5 mg, 0.13 mmol, 1.2 equiv), DIEA (43.6 mg, 0.34mmol, 3 equiv), and PyBOP (76.1 mg, 0.15 mmol, 1.3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brien (2*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.27; Number Of Runs: 2) to afford (3R)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amin o}-3- [(trifluoromethyl)sulfanyl] indolizin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-4-methylmorphol ine-3- carboxamide (38.7 mg, 60.06%) as a white solid. LC-MS: (M+H) ⁺ found 572.30. ¹ H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.75 (d, J = 0.9 Hz, 1H), 25 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 7.8 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.75 – 4.53 (m, 2H), Attorney Docket No.50006-0109WO1 3.79 (dt, J = 10.8, 3.5 Hz, 2H), 3.63 (d, J = 28.7 Hz, 1H), 3.52 (td, J = 11.4, 2.4 Hz, 1H), 3.44 – 3.38 (m, 1H), 3.10 – 3.01 (m, 1H), 2.88 – 2.66 (m, 3H), 2.25 (s, 3H), 2.19 (d, J = 4.7 Hz, 4H), 2.09 (d, J = 8.8 Hz, 3H), 1.70 (d, J = 9.5 Hz, 1H). Example 69 – Preparation of (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- 5 yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-4- methylmorpholine-3-carboxamide To a stirred solution of 2-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-N-[(3S,4R)-3-fluoro -1- methylpiperidin-4-yl]-3-[(trifluoromethyl)sulfanyl]indolizin -8-amine (50 mg, 0.11 mmol, 1 equiv), (3S)-4-methyl-3-morpholinecarboxylic acid hydrochloride (25 mg, 0.13 mmol, 1.2 equiv) and DIEA (0.10 mL, 0.57 mmol, 5.10 equiv) in DMF (1 mL) was added PyBOP (71 mg, 0.13 mmol, 1.2 equiv) at 0°C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with EtOAc (30 mL) and washed with brine (2*30 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 30% B to 55% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.27) to afford (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-oxadiazol-5- yl]methyl}-4-methylmorpholine-3-carboxamide (33.9 mg, 52.35%) as a off-white solid. LC-MS: (M+H) ⁺ found 572.25. ¹ H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.22 (t, J = 8.5 Hz, 2H), 4.87 (d, J = 49.4 Hz, 1H), 4.73 – 4.56 (m, 2H), 3.79 (dt, J = 11.3, 3.5 Hz, 2H), 3.72 – 3.45 (m, 2H), 3.39 (dd, J = 11.1, 10.1 Hz, 1H), 3.05 (t, J = 11.4 Hz, 1H), 2.89 – 2.61 (m, 3H), 2.36 – 2.14 (m, 8H), 2.13 – 25 2.01 (m, 2H), 1.70 (d, J = 9.9 Hz, 1H). Attorney Docket No.50006-0109WO1 Example 5 – Preparation of (3S)-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4 -oxadiazol-5-yl]methyl}-4- methylmorpholine-3-carboxamide Step 1: A mixture of 1-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1 ,2,4- thiadiazol-5-yl)methanamine (100 mg, 0.24 mmol, 1 equiv), 1-tert-butylpyrazole-4-carboxylic acid (49.3 mg, 0.29 mmol, 1.2 equiv), HATU (92.9 mg, 0.24 mmol, 1 equiv) and DIEA (94.8 mg, 0.73 mmol, 3 equiv) in DMF (1 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 2:1) to afford N-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-thiadiazol- 5-yl)methyl]-1-tert-butylpyrazole-4- carboxamide (60 mg, 43.89%) as a light yellow solid. LC-MS: (M+H) ⁺ found 559.3. Step 2: A mixture of N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}- 1,2,4- thiadiazol-5-yl)methyl]-1-tert-butylpyrazole-4-carboxamide (60 mg, 0.11 mmol, 1 equiv), Pd- PEPPSI-IHeptCl 3-chloropyridine (52.2 mg, 0.05 mmol, 0.5 equiv) and Cs2CO3 (209.7 mg, 0.64 mmol, 6 equiv) in dioxane (1 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7 M NH3 in MeOH = 20:1) and Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.05%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 40% B to 63% B in 7min; Wave Length: 254nm/220nm nm; RT1(min): 6.47; Number Of Runs: 1) to afford 1-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-thiadiazol-5-25 yl]methyl}pyrazole-4-carboxamide (8.6 mg, 13.13%) as a light yellow solid. to afford 1-tert-butyl- Attorney Docket No.50006-0109WO1 N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-thiadiazol- 5-yl]methyl}pyrazole-4-carboxamide (8.6 mg, 13.13%) as a light yellow solid. LC-MS: (M+H) ⁺ found 611.15. ¹ H NMR (400 MHz, DMSO-d6) δ 9.16 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 8.03 (d, J = 6.9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 5 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.20 m, 2H), 5.00 – 4.78 (m, 3H), 3.82 – 3.52 (m, 1H), 3.08 (s, 1H), 2.86 (s, 1H), 2.23 (s, 4H), 2.19 – 2.03 (m, 2H), 1.72 (d, J = 11.6 Hz, 1H), 1.54 (s, 9H). Example 6 – Preparation of 1-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1- methylpiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl]ind olizin-2-yl)-1,2,4-thiadiazol-5- yl]methyl}pyrrole-3-carboxamide Step 1: A mixture of 1-(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}-1 ,2,4- thiadiazol-5-yl)methanamine (100 mg, 0.244 mmol, 1 equiv), 1-tert-butylpyrrole-3-carboxylic acid (49.0 mg, 0.29 mmol, 1.20 equiv), HATU (92.91mg, 0.24 mmol, 1.00 equiv) and DIEA (94.8 mg, 0.73 mmol, 3.00 equiv) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc (50 mL) and washed with brine (3*50 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 2:1) to afford N-[(3-{8-bromo-3- [(trifluoromethyl)sulfanyl]indolizin-2-yl}-1,2,4-thiadiazol- 5-yl)methyl]-1-tert-butylpyrazole-4- carboxamide (40 mg, 29.26%) as a light yellow solid. LC-MS: (M+H) ⁺ found 558.3. Step 2: A mixture of N-[(3-{8-bromo-3-[(trifluoromethyl)sulfanyl]indolizin-2-yl}- 1,2,4- thiadiazol-5-yl)methyl]-1-tert-butylpyrrole-3-carboxamide (40 mg, 0.07 mmol, 1 equiv), Pd- PEPPSI-IHeptCl 3-chloropyridine (34.9 mg, 0.04 mmol, 0.5 equiv) and Cs2CO3 (140.0 mg, 0.43 mmol, 6 equiv) in dioxane (1 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN. The filtrate was 25 concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / 7M NH3 Attorney Docket No.50006-0109WO1 in MeOH 20:1) and Prep-HPLC (Column: Waters Xbridge C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.5%NH3 ^. H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 43% B to 70% B in 7min; Wave Length: 254/220 nm; RT1(min): 6.28) to afford 1-tert-butyl-N-{[3-(8-{[(3S,4R)-3-fluoro-1-methylpiperidin-4 -yl]amino}-3- 5 [(trifluoromethyl)sulfanyl]indolizin-2-yl)-1,2,4-thiadiazol- 5-yl]methyl}pyrrole-3-carboxamide (1.5 mg, 3.43%) as a light yellow solid. LC-MS: (M+H) ⁺ found 610.20. ¹ H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.84 (s, 1H), 7.57 (s, 1H), 7.01 (d, J = 2.8 Hz, 1H), 6.82 (t, J = 7.1 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.19 (t, J = 8.3 Hz, 2H), 5.05 – 4.69 (m, 3H), 3.72 (m, 1H), 3.06 (s, 1H), 2.85 (s, 1H), 2.21 (s, 4H), 2.09 (d, J = 10.5 Hz, 2H), 1.72 ¹⁰ (s, 1H), 1.50 (s, 9H). Assays Surface Plasmon Resonance (SPR) Assay Protocol SPR experiments are performed on a Biacore 8K instrument. Biotinylated recombinant p53 Y220C mutant protein (amino acid residues 94-293) is immobilized onto a streptavidin sensor chip (Sensor Chip SA), by flowing the protein solution through the sensor chip at typically 10 ^g/mL concentration, 5 ^L/min flow rate for 70 seconds. Compounds are 2-fold, 7-point serial diluted; the top concentration varies depending on the potency. Compound binding affinities are measured in the multi-cycle kinetics mode, at 30 μL/min flow rate with 60 seconds association time and 120 seconds dissociation time. The running buffer contains 50 mM Tris, pH 7.5, 100 mM NaCl, 1 mM DTT, 0.01% Brij35, 0.05% Tween-20 and 1% DMSO. The assay temperature is maintained at 16 or 20 ^o C and data are fit into the 1:1 binding model using the Biacore Insight Evaluation software. Thermal shift assay protocol 5 ^M recombinant p53 Y220C mutant protein (amino acid residues 94-293) is incubated with 100 ^M compound for 3 hours at 20 ^o C in buffer containing 20 mM HEPES, pH7.4, 100 mM NaCl, 0.01% Pluronic F-127, and 1% DMSO in the presence of 400-fold diluted Sypro Orange (ThermoFisher Scientific catalog number 4461146), on a 384-well PCR plate (Applied Biosystems catalog number 4483285). The volume is 5 ^L/well. The sealed plate is then loaded onto a 30 QuantStudio 7 Flex instrument for melting temperature (TM) measurement. The temperature is Attorney Docket No.50006-0109WO1 increased from 30 ^o C to 50 ^o C, at a rate of 0.03 ^o C/second. Data are fit into a Boltzmann two-state model to determine the TM. Luciferase reporter assay protocol 5 Luciferase reporter (Luc) driven by p53 response element (LTV-p53-Luc (SKU#: LTLR007); G&P Biosciences) and inducible p53 Y220C construct (Tet-One inducible expression system; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. The cells were then used for p53 reporter assay. 5,000 cells were seeded in each well of 384 plate and cultured in 0.5 ug/mL doxycycline (D3072; Sigma) containing medium for 24 hours before ¹⁰ compound treatment. After 6 hour of compound treatment, equal volume of One-Glo reagent (E6110; Promega) was added to each well and the plate was incubated for 5 minutes with shaking at room temperature. The luciferase activity was immediately measured with PheraStar microplate reader. Luciferase activity was stimulated by 10 uM of a tool compound as positive control and AC50 was calculated. Cell proliferation assay Inducible p53 Y220C and R273H constructs (Tet-One inducible expression system; Takara) were stably expressed in NCIH1299 cells by lentiviral transduction. NUGC3, A549, BxPC3, T3M4, HuH7, HCC2935, MFE296, NCIH1299, NCIH1299-inducible p53 Y220C, and NCIH1299-inducible p53 R273H cell lines were used for cell proliferation assay. 250-500 cells were seeded in each well of 384 plate and then compounds were dispensed into each well using Echo or Tecan. After 5 days of incubation, equal volume of CellTiter-Glo reagent (G7570; Promega) was added into each well and the plate was incubated at room temperature for 10 minutes with shaking. The luminescent signal was measured by PheraStar microplate reader and IC50 was calculated. Table A shows results of the SPR p53 Y220C Kd_kinetic (nM), TSA p53 Y220C dTM (deg C), Luc p53 Y220C AC50 (nM), CTG H1299 p53 Y220C IC50 (nM), CTG H1299 p53 R273H IC50 (nM), and CTG NUGC3 p53 Y220C IC50 (nM) assays. Activity categories are as follows: 30 • SPR p53 Y220C Kd_kinetic (nM): D ≥ 1000 > C ≥ 100 > B ≥ 10 > A • TSA p53 Y220C dTM (deg C, 100 µM): A ≥ 10 > B ≥ 5 > C ≥ 1 > D Attorney Docket No.50006-0109WO1 • TSA p53 Y220C dTM (deg C, 10 µM): A ≥ 10 > B ≥ 5 > C ≥ 1 > D • CTG NUGC3 p53 Y220C IC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • CTG H1299 p53 Y220C IC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A • CTG H1299 p53 R273H IC50 (nM): A ≥ 10000 > B ≥ 8000 > C ≥ 5000 > D 5 • Luc p53 Y220C AC50 (nM): D ≥ 3000 > C ≥ 1500 > B ≥ 750 > A Table A Example SPR P53 TSA TSA Luc CTG CTG CTG No. Y220C P53 P53 P53 NUGC3 H1299 H1299 Kd_kinetic Y220C Y220C Y220C P53 P53 P53 (nM) dTM dTM AC50 Y220C Y220C R273H (deg (deg (nM) IC50 IC50 IC50 C) C, 10 (nM) (nM) (nM) uM) 1 B B B D D D A 2 A A A A 3 A A A A 4 B D D D 5 C D D D 6 D D D D 7 A A A A 8 A C C B 9 C D C C 10 B C D D 11 A B B B 12 A A A A 13 A A A A 14 B C B B 15 A A A A 16 A B A B 17 A A A B 18 A B A B 19 B B A A 20 A A A A 21 C C C C 22 B D C D 23 A A A A 24 A A B B 25 A C C C 26 B C C C 27 A A A B Attorney Docket No.50006-0109WO1 28 A A A A 29 A B B B 30 B B C C 31 A A A A 32 A A A A 33 A A A A 34 B D C C 35 B D C C 36 B C C C 37 A A A A 38 B B A A 39 B B A A 40 B A A A 41 B B B B 42 A A A A 43 B B B B 44 A A B A 45 B D C D 46 C D D D 47 B D D D 48 B D D D 49 B C D C 50 A A B 51 B D D D 52 B D D D 53 B D D 54 A A A A 55 B D D 56 B B A A 57 A A A A 58 A A A A 59 A B B A 60 B C C C 61 B D D D 62 A C C B 63 A C C D 64 B D D D 65 B D D D 66 A A A A 67 A B C B 68 B D D 69 B D D 70 A A A Attorney Docket No.50006-0109WO1 71 A A A 72 A A A 73 A A B 74 A B C 75 A B B 76 A A B 77 A A A 78 A A A 79 A A A 80 A C C 81 A A B 82 A A A 83 A B B 84 B D D 85 A A A 86 A A 87 A B 88 B A 89 A A A 90 A A 91 A A 92 A A 93 A A A 94 A A A 95 A A 96 A A 97 A A 98 A B B 99 100 101 102 103 104 105 106 107 108 109 110