Compounds targeting mutations in p53 and uses thereof

Abstract

The present disclosure relates to compounds that target mutations in p53, specifically the Y220C mutation, to pharmaceutical compositions comprising said compounds, and to the use of said compounds and compositions as medicaments, such as in the treatment of cancer, and related aspects. Such compounds may bind, stabilise, and restore the level of correctly folded p53 by stabilising an active p53 conformation and restoring wild type-like transcriptional function of mutant p53.

Description

25972-WO-PCT 12617.0005-00304 COMPOUNDS TARGETING MUTATIONS IN P53 AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 675,131, filed July 24, 2024, the contents of which is incorporated by reference in its entirety. SEQUENCE LISTINGS

[0002] The instant application contains a Sequence Listing XML which has been submitted electronically in ST.26 XML format and is hereby incorporated by reference in its entirety. The XML copy, created on July 23, 2025, is named 25972-WO-PCT.xml and is 3,275 bytes in size. FIELD

[0003] The invention relates to compounds, to pharmaceutical compositions comprising said compounds, and to the use of said compounds as medicaments, such as in the treatment of cancer, and related aspects. BACKGROUND

[0004] The tumor suppressor p53 is a 393 amino acid protein that, upon tetramer formation, acts as a transcription factor that regulates cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage. There are various p53 mediated mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis or ferroptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. A large number of cancers harbor cells in which TP53, the gene that encodes for p53, is mutated resulting in a loss of the protein’s tumour suppressor function and sometimes even in p53 protein versions that gain novel oncogenic functions. The loss of function results from the mutant p53 being unable to bind to DNA either by loss of residue contact to DNA or loss of the ability to fold into its active conformation required for binding to DNA.

[0005] Approximately fifty percent of human cancers harbor mutations in p53, and almost all cancers exhibit malfunction along the p53 pathway. Homozygous loss of the p53 gene occurs in almost all types of cancer, including carcinomas of the breast, colon, and lung. The presence of certain p53 mutations in several types of human cancer can correlate with less favorable patient prognosis. - 1 -25972-WO-PCT 12617.0005-00304

[0006] In the absence of stress signals, p53 levels are maintained at low levels via the interaction of p53 with Mdm2, an E3 ubiquitin ligase. In an unstressed cell, Mdm2 can target p53 for degradation by the proteasome. Under stress conditions, the interaction between Mdm2 and p53 is disrupted, and p53 accumulates. The critical event leading to the activation of p53 is phosphorylation of the N-terminal domain of p53 by protein kinases. The phosphorylation of p53 leads to a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors. The activation of p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair. The p53 protein can activate proteins involved in the above pathways including, for example, Fas / Apo1, KILLER / DRS, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAFl). Additionally, p53 can repress the transcription of a variety of genes including, for example, c-MYC, Cyclin B, VEGF, RAD5 l, and hTERT.

[0007] In its active conformation, the p53 protein is a homotetramer formed by four identical chains of 393 residues each. Each monomer is structurally and functionally divided into multiple domains. At the N-terminus, the transactivation domain (TAD) contains two subdomains (TAD1 and TAD2) that act as transactivation sites. TAD1 binds Mdm2, which sterically blocks p53 dependent transcription and leads to polyubiquitination and degradation of the p53 protein. The TAD domain is followed by a proline rich domain. At the core of the protein, there is a sequence specific DNA binding domain (DBD). The carboxy terminal region (301-393) of p53 contains a tetramerisation domain and an intrinsically disordered C-terminal domain (CTD) that has a strong regulatory effect on p53 activity through lysine methylation (inactivation) or acetylation (activation).

[0008] About 90% of oncogenic mutations found in TP53 from human cancers reside in the DBD. X-ray and NMR structures of the DBD show a compact immunoglobulin-like β-sandwich architecture. The DNA-binding surface is composed of two β-turn loops, L2 and L3, which are stabilised by a zinc ion, interacting with Cys176, Cys238, Cys242, and His179, and a loop-sheet helix motif. Altogether, these structural elements form an extended DNA-binding surface that is rich in positively charged amino acids, such as Arg248 and Arg273, and makes specific contact with various p53 response elements.

[0009] Mutations in p53 located in the core of the DBD or periphery of the DNA-binding interface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282. Some p53 mutations that can abrogate the activity of p53 include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H, R273C, and R282W. - 2 -25972-WO-PCT 12617.0005-00304 These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilise the folded protein at physiological temperature.

[0010] Wild type function of p53 mutants can be recovered by binding of the p53 mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization and / or enhance the interaction between p53 and its DNA target. It is highly desirable to find small molecules that can bind, stabilize, and restore the level of correctly folded p53 by stabilising an active p53 conformation and restoring wild type like transcriptional function of mutant p53.

[0011] Y220C is a common mutation outside the DNA-binding surface of p53. Although the Y220C mutation is located at the far end of the β-sandwich, remote from functional areas of the protein, the p53 protein is highly destabilised as a result of the mutation; p53 wild type function is compromised by a Y220C mutation.

[0012] There remains a need to provide compounds that restore function of the Y220C mutant of p53 and that can be used as medicaments. More specifically, there remains a need to provide compounds that bind to the Y220C p53 mutant and can restore wild type activity of the p53 mutant including, for example, DNA binding function and activation of downstream targets involved in tumor suppression, and that can stabilize the Y220C mutant to reduce the likelihood of denaturation of the protein at body temperature.

[0013] Furthermore there remains a need to provide compounds that may demonstrate advantages over known compounds, such as one or more of the following aspects: i. potency; ii. in vivo efficacy iii. pharmacokinetic properties; iv. metabolic stability; v. oral bioavailability; vi. physiochemical properties; and vii. safety profile or therapeutic index (TI). Novel compounds that demonstrate a desirable profile over a plurality of the above aspects may also be of benefit over known compounds. SUMMARY

[0014] The present disclosure relates to novel compounds of Formula I: - 3 -25972-WO-PCT 12617.0005-00304and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof.

[0015] The disclosure also provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof, for use as a medicament.

[0016] The disclosure also provides use of compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof, in the manufacture of a medicament.

[0017] The disclosure also provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof, for use in the prophylaxis or treatment of a disease or disorder associated with p53 mutation.

[0018] The disclosure additionally provides use of compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof, in the manufacture of a medicament for the prophylaxis or treatment of a disease or disorder associated with p53 mutation.

[0019] The disclosure further provides a method for the treatment of a disease or disorder associated with p53 mutation, said method comprising administering to a subject compounds of Formula I, or pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof.

[0020] The disclosure further provides a method for the prophylaxis of a disease or disorder associated with p53 mutation, said method comprising administering to a subject compounds of Formula I, or pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof.

[0021] Also provided are pharmaceutical compositions comprising compounds of Formula I, or pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof, and a pharmaceutically acceptable carrier or excipient.

[0022] Also provided are processes for preparing compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof, and novel intermediates of use in the preparation of compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof.

[0023] The summary of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims. - 4 -25972-WO-PCT 12617.0005-00304 DETAILED DESCRIPTION

[0024] The present disclosure is directed to a compound of Formula I:or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y1and Y2are independently N or C; X1, X2, X3, and X4are independently N, S, or CR, and each R is independently H, halogen, CH3, OCH3, CH3substituted by 1 to 3 halogen, or OCH3substitued by 1 to 3 halogen;R6is a) H; b) C1-C6alkyl; c) C1-C6 alkyl substituted by OH; d) C3-C6cycloalkyl; e) C3-C6cycloalkyl substituted by CH3, C(O)NHCH3, CN, or F; f) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; g) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; h) NH2; - 5 -25972-WO-PCT 12617.0005-00304 i) NHCH3; or j) N(CH3)2; X7, X8, and X9are independently N, CH, or CF, and at least one of X7, X8, and X9is not N;wherein each R7is independently a) H; b) C1-C6 alkyl; c) C1-C6 alkyl substituted by OH; d) C3-C6cycloalkyl; e) C3-C6 cycloalkyl substituted by CH3 or OH; f) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; g) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; h) NH2; i) NHCH3; or j) N(CH3)2; R5is H, halogen, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl; R2is a) monocyclic C3-8 cycloalkyl; b) bicyclic C4-8 cycloalkyl; c) C5-10spiro-cycloalkyl; d) tricyclic C6-9 cycloalkyl; e) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; or f) 4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; wherein said R2group is unsubstituted or substituted with 1 to 5 substituents independently selected from R8, and each R8is independently - 6 -25972-WO-PCT 12617.0005-00304 a) halogen; b) C1-3 alkyl; c) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; d) 4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; e) 5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; f) NH2; g) NH-C1-3alkyl; h) NH-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); i) NH-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); j) NH(5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); or k) N(C1-3alkyl)2; wherein said R8group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, oxo, CN, CH3, CONH2, CONHCH3, CON(CH3)2, and OCH3.

[0025] The disclosure includes numerous embodiments, which are summarized below. The disclosure includes the compounds as shown and also includes individual diastereoisomers, enantiomers, and epimers of the compounds, and mixtures of diastereoisomers and / or enantiomers thereof, including racemic mixtures.

[0026] A first embodiment is directed to compounds of Formula I, wherein- 7 -25972-WO-PCT 12617.0005-00304 , , , or, and wherein each R is independently H, halo, CH3, OCH3, CH3substituted by 1 to 3 halo, or OCH3substituted by 1 to 3 halo. In aspects of this first embodiment, , , . In aspects of the first embodiment,, , or . In a particular aspect of the embodiment, is .- 8 -25972-WO-PCT 12617.0005-00304embodiment,. particular aspect of the embodiment,. particular aspect of the embodiment,. particular aspect of the embodiment,.

[0027] In a second embodiment,

[0028] In a first aspect of the second embodiment, R1is C(=O)R3, wherein R3is R6,, , wherein R6is H; C1-C6alkyl; C1-C6alkyl substituted by OH; - 9 -25972-WO-PCT 12617.0005-00304 C3-C6cycloalkyl; C3-C6cycloalkyl substituted by CH3, F, CN, or CONHCH3; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; 4- membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; NH2; NHCH3; or N(CH3)2. In instances of this first aspect, R1is,- 10 -25972-WO-PCT 12617.0005-00304

[0029] In a second aspect of the second embodiment,, wherein X7, X8, and X9are independently N, CH, or CF, and at least one of X7,, wherein each R7is H; C1-C6 alkyl; C1-C6 alkyl substituted by OH; C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by CH3; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; NH2; NHCH3; or N(CH3)2; R5is H, halogen, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl. In instances of this second aspect,

[0030] In a first instance of the second aspect, R4is , ,, ,wherein each R7 is H; C1-C6 alkyl; C1-C6 alkyl substituted byOH; C3-C6 cycloalkyl; C3-C6 cycloalkyl substituted by CH3 or OH; 4-membered monocyclic - 11 -25972-WO-PCT 12617.0005-00304 heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; NH2; NHCH3; or N(CH3)2. In specific instances, R4is, , or.

[0031] In a second instance of the second aspect, R5is H, halogen, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl. In specific instances, R5is H, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl. In more specific instances, R5is OCH3..

[0033] In a third embodiment, R2is monocyclic C3-8cycloalkyl; bicyclic C4-8cycloalkyl; C5-10spiro-cycloalkyl; tricyclic C6-9 cycloalkyl; 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; or 4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; wherein said R2group is unsubstituted or substituted with 1 to 5 substituents independently selected from R8, and R8is halogen; C1-3 alkyl; 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; 4- to 9-membered bicyclic heterocycloalkyl - 12 -25972-WO-PCT 12617.0005-00304 containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; 5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; NH2; NH- C1-3 alkyl; NH-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); NH-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); NH(5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); or N(C1-3alkyl)2; wherein said R8group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, oxo, CN, CH3, CONH2, CONHCH3, CON(CH3)2, andsaid R2group is unsubstituted or substituted with 1 to 2 R8groups. In instances of aspects of the third embodiment, each R8is independently H, F, CH3, NH2, NH(CH3), N(CH3)2, NH(CH2CH2F), NH(CH2CH2OH), NH(CH2CHF2), CH2CH2F, CH2CHF2, CH2CH2OH,- 13 -25972-WO-PCT 12617.0005-00304

[0034] The disclosure further provides a salt of a compound of Formula I, in particular a pharmaceutically acceptable salt of a compound of Formula I. The disclosure also provides a solvate of a compound of Formula I, in particular a pharmaceutically acceptable solvate of a compound of Formula I. The disclosure further provides a salt and solvate of a compound of Formula I, in particular a pharmaceutically acceptable salt and solvate of a compound of Formula I (i.e., a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt). The compounds of Formula I, and salts and / or solvates thereof, may be referred to herein as compounds of the invention. - 14 -25972-WO-PCT 12617.0005-00304

[0035] Unless the context indicates otherwise, references to Formula I in all sections of this disclosure (including the uses, methods and other aspects of the invention) include references to all other sub-formula, sub-groups, preferences and examples as defined herein.

[0036] Aspects set out below relating to relative stereochemistry and the nature of groups, including Y1, Y2, X1, X2, X3, X4, X7, X8, X9, L, R1, R2, R3, R4, R5, R6, R7, and R8, are envisaged as being independently, fully combinable with one another to form further combinations of the disclosure. Such aspects apply equally to intermediates that may be of use in the synthesis of a compound of Formula I, and salts, such as pharmaceutically acceptable salts, of any thereof.

[0037] It will be appreciated that the selection of combinations of functional groups for compounds of Formula I should result in chemically sensible structures. For example, the positioning of heteroatoms in inappropriate proximity may cause instability.

[0038] Illustrative, but non-limiting, examples of compounds of embodiments that are useful to restore the function of the Y220C mutation of p53 are the following compounds, and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof: (1) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (2) 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (3) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (4) 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (5) 1-(tert-butyl)-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (6) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (7) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; - 15 -25972-WO-PCT 12617.0005-00304 (8) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methylthiazole-5-carboxamide; (9) N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (10) 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (11) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (12) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2-methylthiazole-5-carboxamide; (13) 1-cyclopropyl-N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (14) 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (15) 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (16) 1-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (17) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (18) 2-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (19) 2-methyl-N-(3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; - 16 -25972-WO-PCT 12617.0005-00304 (20) 1-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (21) 1-methyl-N-(3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (22) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (23) 2-methyl-N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (24) 2-methyl-N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (25) 1-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (26) 1-methyl-N-(3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (27) 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (28) 4-methoxy-N-methyl-3-((3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (29) 2-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (30) 3-methoxy-N-methyl-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; - 17 -25972-WO-PCT 12617.0005-00304 (31) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (32) 3-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; (33) 3-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (34) 4-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (35) 4-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (36) 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((S)-2-hydroxypropyl)- 3-methoxybenzamide; (37) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl) indolizin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (38) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl) indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (39) 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (40) 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (41) 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide; (42) (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3- hydroxy-3-methylazetidin-1-yl)methanone; - 18 -25972-WO-PCT 12617.0005-00304 (43) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-((R)- tetrahydrofuran-3-yl)benzamide; (44) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)- 3-methoxybenzamide; (45) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide; (46) 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (47) 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)- 4-methoxybenzamide; (48) 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)- 4-methoxybenzamide; (49) 4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (50) 3-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-(3- methyloxetan-3-yl)benzamide; (51) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2-methylpropyl)- 1H-pyrazole-4-carboxamide; (52) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole-4- carboxamide; (53) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2-methylthiazole-4-carboxamide; - 19 -25972-WO-PCT 12617.0005-00304 (54) 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzamide; (55) 1-(tert-butyl)-N-(3-(1-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (56) 1-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-3-methylurea; (57) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (58) 5-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; (59) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)acetamide; (60) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole-4- carboxamide, 2,2,2-trifluoroacetate salt; (61) 5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide, 2,2,2-trifluoroacetate salt; (62) N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl) phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7- amine, 2,2,2-trifluoroacetate salt; (63) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2-methylpropyl)- 1H-pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt; (64) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2- yn-1-yl)amino)phenyl)methanone; (65) (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3-hydroxy-3- methylazetidin-1-yl)methanone; - 20 -25972-WO-PCT 12617.0005-00304 (66) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)-3- methoxybenzamide; (67) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamide; (68) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamide; (69) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamide; (70) 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamide; (71) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (72) 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (73) 3-methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (74) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (75) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo [3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- 2-yn-1-yl)amino)benzamide; (76) 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamide; (77) 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; - 21 -25972-WO-PCT 12617.0005-00304 (78) 4-((3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (79) 3-methoxy-N-methyl-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (80) 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan-3- yl)benzamide; (81) N-(3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (82) 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (83) 4-((3-(7-(((1S,2R,5R,7R)-7-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (84) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl) amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzamide; (85) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2- yn-1-yl)amino)benzamide; (86) 1-(tert-butyl)-N-(3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (87) 1-(tert-butyl)-N-(3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (88) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan- 6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; - 22 -25972-WO-PCT 12617.0005-00304 (89) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan- 6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (90) N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole-4- carboxamide; (91) N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole-4- carboxamide; (92) 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (93) 1-cyclopropyl-N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (94) 1-cyclopropyl-N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (95) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (96) N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)acetamide; (97) 2-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)thiazole-5-carboxamide; (98) 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (99) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl) indolizin-2-yl)prop-2-yn-1-yl)-2-methylthiazole-5-carboxamide; (100) 1-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (101) 1-cyclopropyl-N-(3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; - 23 -25972-WO-PCT 12617.0005-00304 (102) 1-methyl-N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (103) 1-methyl-N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (104) N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (105) N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (106) N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (107) 4-methoxy-N-methyl-3-((3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (108) 4-methoxy-N-methyl-3-((3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (109) 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide; (110) (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (111) 1-methyl-3-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)urea; (112) 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)- 3-methoxybenzamide; (113) (3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxyphenyl)(3-hydroxy-3- methylazetidin-1-yl)methanone; - 24 -25972-WO-PCT 12617.0005-00304 (114) 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (115) 4-methoxy-N-methyl-5-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)picolinamide; (116) N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (117) N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (118) (4-((3-(7-(((1R,5S,6S)-5-fluoro-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone; (119) (4-((3-(7-(((1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone; (120) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (121) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (122) 4-((3-(7-((3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (123) N-(3-(7-((3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (124) N-(3-(7-((3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; - 25 -25972-WO-PCT 12617.0005-00304 (125) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (126) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (127) 3-methoxy-N-methyl-4-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (128) 3-((3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (129) 4-((3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (130) 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo [1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (131) 3-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (132) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (133) 1-(tert-butyl)-N-(3-(1-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8- azabicyclo[3.2.1] octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (134) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide; (135) 1-(tert-butyl)-N-(3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; - 26 -25972-WO-PCT 12617.0005-00304 (136) 1-(tert-butyl)-N-(3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (137) 3-((3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (138) 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (139) 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (140) 3-((3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (141) 4-methoxy-N-methyl-3-((3-(1-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (142) 4-methoxy-N-methyl-3-((3-(1-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (143) N-(3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4- carboxamide; (144) 4-((3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzamide; (145) 3-((3-(1-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (146) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (147) 1-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-3-methylurea; - 27 -25972-WO-PCT 12617.0005-00304 (148) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (149) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (150) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (151) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (152) 1-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-3-methylurea; (153) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (154) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (155) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (156) 3-methoxy-N-methyl-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; and (157) 2-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide.

[0039] Illustrative, but non-limiting, examples of compounds of embodiments that are useful to restore the function of Y220C mutant of p53 are compounds of the following structures: - 28 -25972-WO-PCT 12617.0005-00304- 29 -25972-WO-PCT 126170005-00304- 30 -25972-WO-PCT 12617.0005-00304- 31 -25972-WO-PCT 12617.0005-00304, , , , , , , , , - 32 -25972-WO-PCT 12617.0005-00304- 33 -25972-WO-PCT 12617.0005-00304- 34 -25972-WO-PCT 12617.0005-00304- 35 -25972-WO-PCT 12617.0005-00304and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof.

[0040] Although the specific stereochemistries described above are preferred, other stereoisomers, including diastereoisomers, enantiomers, epimers, and mixtures of these may also have utility in restoring the function of Y220C mutant of p53.

[0041] Synthetic methods for making the compounds are disclosed in the Examples shown below. Where synthetic details are not provided in the examples, the compounds are readily made by a person of ordinary skill in the art of medicinal chemistry or synthetic organic chemistry by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such compounds, the individual stereoisomers, including enantiomers, diastereoisomers, and mixtures of these are also compounds of the disclosure. Definitions

[0042] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. - 36 -25972-WO-PCT 12617.0005-00304

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0044] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0045] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0046] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0047] As used herein, the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of” and “consisting essentially of” the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0048] “Alkyl” means monovalent, saturated carbon chains, which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the prefix “alk”, such as alkoxy and alkanoyl, also may be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0049] “Alkylene” means bivalent saturated carbon chains, which may be linear, branched, or combinations thereof. - 37 -25972-WO-PCT 12617.0005-00304

[0050] “Cycloalkyl” means a saturated monocyclic, bicyclic, tricyclic carbocyclic ring, having a specified number of carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Bicyclic carbocyclic rings, which feature two joined rings, may be fused (in which adjacent rings share at least two atoms and bridgehead carbons are directly connected, such asor bridged (in which one or more atoms spans or bridges another ring of atoms, such as ). Tricyclic carbocyclic rings similarly feature three fused or bridged rings. Spirocyclic rings, in which a single carbon atom is shared by either two rings (such asare also contemplated herein and may be formed by two substituents attached to the same carbon atom.

[0051] “Heterocycloalkyl” means monocyclic, bicyclic, or tricyclic ring or ring system having 3 to 14 ring atoms and containing at least one ring heteroatom selected from N (including NH and NR*, where R*is a substituent such as an alkyl group), S (including SO and SO2), O, and P (including PO, PO2, and POR*, where R*is a substituent such as an alkyl group). The heterocycloalkyl ring may be substituted on the ring carbons and / or the ring nitrogen, sulfur, or phosphorus. Heterocycloalkyl rings may be non-aromatic or partially aromatic, in the case of bicyclic or tricyclic ring systems. Bicyclic heterocycloalkyls, which feature two joined rings, may be fused (in which adjacent rings share at least two atoms and bridgehead atoms are directly connected, such asor bridged (in which one or more atoms spans or bridges another ring of atoms, such asTricyclic heterocycloalkyls similarly feature three fused or bridged rings. Spirocyclic rings, in which a single atom is shared by either two rings (such asare also contemplated herein and may be formed by two substituents attached to the same atom. Non-limiting examples of heterocycloalkyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydropyranyl, thiomorpholine, tetrahydropyran, octahydro-1H- pyrrolo[2,3-c]pyridine, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 4,5,6,7-tetrahydro-1H- benzo[d][1,2,3]triazole, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptane, 1-oxa-7- azaspiro[4.4]nonane, 1-oxa-8-azaspiro[4.5]decane, 3-oxa-1,8-diazaspiro[4.5]decane, 2,8- diazaspiro[4.5]decane, 1-oxa-3,8-diazaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1,8- diazaspiro[4.5]decane, and 1-oxa-4,9-diazaspiro[5.5]undecane. - 38 -25972-WO-PCT 12617.0005-00304

[0052] “Aryl” means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 6 to 14 carbon atoms, wherein at least one of the rings is aromatic. Non- limiting examples of aryl include phenyl and naphthyl.

[0053] “Heteroaryl” means a monocyclic, bicyclic, or tricyclic ring or ring system containing 5 to14 ring atoms and containing at least one ring heteroatom selected from N (including NH and NR*, where R*is a substituent such as an alkyl group), S (including SO and SO2), O, and P (including PO, PO2, and POR*, where R*is a substituent such as an alkyl group), wherein at least one of the heteroatom containing rings is aromatic. In embodiments, a heteroaryl group is monocyclic and has 5 or 6 ring atoms (“5- or 6-membered monocyclic heteroaryl”). In other embodiments, a heteroaryl group is bicyclic and has 8 to 10 ring atoms (“8- to 10-membered bicyclic heteroaryl”). In other embodiments, a heteroaryl group is bicyclic and has 9 to 11 ring atoms (“9- to 11-membered bicyclic heteroaryl”). Non-limiting examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.

[0054] “Halogen” or “halo” includes fluorine, chlorine, bromine, and iodine. In one embodiment, halogen is fluorine, chorine, or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is chlorine or bromine. In another embodiment, halogen is fluorine or bromine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine.

[0055] “Saturated” means containing only single bonds.

[0056] “Unsaturated” means containing at least one double or triple bond. In one embodiment, unsaturated means containing at least one double bond. In another embodiment, unsaturated means containing at least one triple bond.

[0057] When any variable (e.g., Raetc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A squiggly or wavy line at the end of or across a bond in a substituent variable (such asrepresents the point of attachment. - 39 -25972-WO-PCT 12617.0005-00304

[0058] Under nomenclature used throughout this disclosure, the point of attachment is described first, followed by the terminal portion of the designated side chain. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to:.

[0059] In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

[0060] The term “substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0061] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, salts and / or dosage forms that are, using sound medical judgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.

[0062] Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present disclosure is meant to encompass all such isomeric forms of the compounds of Formula I.

[0063] The independent syntheses of optical isomers and diastereoisomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the X- ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration or sufficient heavy atoms to make an absolute assignment.

[0064] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereoisomeric - 40 -25972-WO-PCT 12617.0005-00304 derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0065] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0066] Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.

[0067] In the compounds of general Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The present disclosure is meant to include all suitable isotopic variations of the compounds of structural Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies. Isotopically-enriched compounds within structural Formula I, can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0068] Furthermore, some of the crystalline forms for compounds of the present disclosure may exist as polymorphs and as such are intended to be included in the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this disclosure.

[0069] It is generally preferable to administer compounds of the present disclosure as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, - 41 -25972-WO-PCT 12617.0005-00304 derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts. Salts

[0070] It will be understood that, as used herein, references to the compounds of the present disclosure are meant to also include the pharmaceutically acceptable salts and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

[0071] The compounds of the present disclosure may be administered in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention that are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present disclosure include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, formic, fumarate, gluceptate, gluconate, glutamate, glycollylars-anilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate, and valerate. Where the compounds of the disclosure carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, - 42 -25972-WO-PCT 12617.0005-00304 procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0072] Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present disclosure, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0073] The term “prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of Formula I to a compound of Formula I, or to a salt thereof; a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. This invention includes prodrugs of the novel compounds of this disclosure. Solvates, and in particular, hydrates of the compounds of the present disclosure are included in the present invention as well. Utilities

[0074] The present disclosure also provides a method for the treatment of a disease, disorder or condition in which restoration of wild type activity of p53 is needed, which method comprises administration to a patient in need of such treatment with a therapeutically effective amount of a compound of Formula I.

[0075] In a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I, together with at least one pharmaceutically acceptable carrier or excipient.

[0076] The term "therapeutically effective amount" means the amount the compound of structural Formula I that will elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this disclosure are for disorders known to those skilled in the art. The term “mammal” includes humans, and companion animals such as dogs and cats. Administration and Dose Ranges

[0077] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present disclosure. For example, - 43 -25972-WO-PCT 12617.0005-00304 oral, intravenous, infusion, subcutaneous, transcutaneous, intramuscular, intradermal, transmucosal, intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of the present disclosure are administered orally.

[0078] In the treatment or prevention of disorders, diseases and / or conditions that require restoration of p53 wild type activity by restoring function of the Y220C mutant, a suitable dosage level will generally be about 0.0001 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In one embodiment, a suitable dosage level may be about 0.001 to about 500 mg per kg patient body weight per day. In another embodiment, a suitable dosage level may be about 0.001 to about 250 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.01 to about 250 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.1 to about 100 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.05 to about 100 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.1 to about 50 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.05 to about 0.5 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.5 to about 5 mg / kg per day. In another embodiment, a suitable dosage level may be about 5 to about 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing about 0.01 to about 1000 mg of the active ingredient, particularly about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1.0, about 2.5, about 5.0, about 7.5, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 8 times per day; preferably, 1 to 4 times a day; more preferably once or twice per day, even more preferably once a day. This dosage regimen may be adjusted to provide the optimal therapeutic response.

[0079] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode, and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy. - 44 -25972-WO-PCT 12617.0005-00304

[0080] The compounds of this disclosure may be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier. The compounds of this disclosure may be used in pharmaceutical compositions in which the compound of the present disclosure or a pharmaceutically acceptable salt thereof is the only active ingredient. The compounds of this disclosure may also be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients.

[0081] The term “composition,” as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0082] Compounds of the present disclosure may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of the present disclosure are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure.

[0083] The combination therapy also includes therapies in which the compound of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0084] Examples of other active ingredients that may be administered in combination with a compound of the present disclosure, and either administered separately or in the same pharmaceutical composition, include but are not limited to: i. immunooncology agent; ii. anti-neovascular agents; iii. checkpoint inhibitors, including anti-PD1 and anti-PDL1 inhibitors; iv. chemotherapy procedures; - 45 -25972-WO-PCT 12617.0005-00304 v. radiation therapy; vi. surgical procedures; vii. anti-fibrotics; viii. JAK inhibitors; ix. TNF-alpha inhibitors; x. antibody-drug conjugates; xi. radionuclide therapies; xii. local ablative procedures, such as chemoembolization and radioembolization; xiii. oncolytic viral therapies; xiv. RAS inhibitors, such as (but not limited to) sotorasib and adagrasib; xv. other inhibitors of the MAP kinase pathway, such as trametinib, tyrosine kinase inhibitors such as osimertinib, alectinib, brigatinib, and lorlatinib; xvi. MDM2 inhibitors / degraders, such as milamedetan; xvii. PI3K inhibitors, such as alpelisib; xviii. hormonal therapies, such as anastrazole and fulvestrant; xix. P53 overexpression therapies; xx. T cell therapies targeting mutant p53; xxi. mutation-specific inhibitors, such sotorasib, alectinib, etc.; xxii. inhibitors promoting synthetic lethality, such as PARP inhibitors in BRCA mutant cancers; xxiii. pro-apoptotic drugs as a class for combination, such as BCL-2 inhibitors; xxiv. STING / cGAS antagonists; xxv. inhibitors of CDK4 / 6, CDK4, and / or CDK2; and xxvi. pharmaceutically acceptable salts thereof.

[0085] In another embodiment, the pharmaceutical composition comprises: 1) a compound as disclosed herein, or a pharmaceutically acceptable salt thereof; 2) one or more compounds, or pharmaceutically acceptable salts thereof, selected from the group: a. immunooncology agent; b. anti-neovascular agents; c. checkpoint inhibitors, including anti-PD1 and anti-PDL1 inhibitors; d. chemotherapy procedures; e. radiation therapy; f. surgical procedures; - 46 -25972-WO-PCT 12617.0005-00304 g. anti-fibrotics; h. JAK inhibitors; i. TNF-alpha inhibitors; j. antibody-drug conjugates; k. radionuclide therapies; l. local ablative procedures, such as chemoembolization and radioembolization; m. oncolytic viral therapies; n. RAS inhibitors, such as (but not limited to) sotorasib and adagrasib; o. other inhibitors of the MAP kinase pathway, such as trametinib, tyrosine kinase inhibitors such as osimertinib, alectinib, brigatinib, and lorlatinib; p. MDM2 inhibitors / degraders, such as milamedetan; q. PI3K inhibitors, such as alpelisib; r. hormonal therapies, such as anastrazole and fulvestrant; s. P53 overexpression therapies; t. T cell therapies targeting mutant p53; u. mutation-specific inhibitors, such sotorasib, alectinib, etc.; v. inhibitors promoting synthetic lethality, such as PARP inhibitors in BRCA mutant cancers; w. pro-apoptotic drugs as a class for combination, such as BCL-2 inhibitors; x. STING / cGAS antagonists; y. inhibitors of CDK4 / 6, CDK4, and / or CDK2; and z. pharmaceutically acceptable salts thereof; and 3) a pharmaceutically acceptable carrier.

[0086] Suitable immune-oncology agents include, but are not limited to, PD-L1 inhibitors and PD-1 inhibitors, and STING antagonists. In one embodiment, the immune-oncology agents include PD-L1 inhibitors and PD-1 inhibitors.

[0087] Suitable anti-neovascular agents include, but are not limited to, anti-VEG-F treatment.

[0088] The above combinations include combinations of a compound of the present disclosure not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include combinations of compounds with two or more active compounds selected from those listed above.

[0089] The present disclosure also provides a method for the treatment of a disease, disorder or condition in which restoration of wild type activity of p53 is needed, which method comprises administration to a patient in need of such treatment with a therapeutically effective amount of a - 47 -25972-WO-PCT 12617.0005-00304 compound of Formula I and an amount of one or more active ingredients, such that together they give effective relief.

[0090] In a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula I and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.

[0091] Thus, according to a further aspect of the present disclosure there is provided the use of a compound of Formula I and one or more active ingredients for the manufacture of a medicament for the treatment of a disease, disorder or condition in which restoration of wild type activity of p53. In a further or alternative aspect of the present disclosure, there is therefore provided a product comprising a compound of Formula I and one or more active ingredients as a combined preparation for simultaneous, separate, or sequential use in the treatment of a disease, disorder or condition in which restoration of wild type activity of p53. Such a combined preparation may be, for example, in the form of a twin pack.

[0092] It will be appreciated that for the treatment of cancer, a compound of the present disclosure may be used in conjunction with another pharmaceutical agent effective to treat that disease, disorder, or condition.

[0093] The term "therapeutically effective amount" means the amount the compound of structural Formula I that will elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this disclosure are for disorders known to those skilled in the art. The term “mammal” includes humans, and companion animals such as dogs and cats.

[0094] The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an anti-steatotic agent, the weight ratio of the compound of the Formula I generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. Methods of Synthesis

[0095] The following reaction schemes and Examples illustrate methods that may be employed for the synthesis of the compounds of Formula I described in this disclosure. These reaction schemes and Examples are provided to illustrate the invention and are not to be construed as - 48 -25972-WO-PCT 12617.0005-00304 limiting the invention in any manner. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the compounds of Formula I. The scope of the invention is defined by the appended claims. Compound names were generated in Chemdraw Version 21.0.0.28. EXAMPLES

[0096] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0097] Abbreviations used herein are set forth in Table 1. Table 1- 49 -25972-WO-PCT 12617.0005-00304- 50 -25972-WO-PCT 12617.0005-00304- 51 -25972-WO-PCT 12617.0005-00304

[0098] The compounds of the present disclosure can be prepared according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthesis procedures. It is also possible to make use of variants that are themselves known to those of ordinary skill in this art but are not mentioned in detail. The general procedures for making the compounds claimed in this disclosure can be readily understood by one skilled in the art from viewing the following schemes and descriptions.

[0099] Unless otherwise noted, all reactions are magnetically stirred. Unless otherwise noted, “concentrated” and / or “solvent removed under reduced pressure” means evaporating the solvent from a solution or mixture using a rotary evaporator or vacuum pump. Unless otherwise noted, flash chromatography is carried out on a Teledyne Isco (Lincoln, NE), Analogix (Burlington, WI), or Biotage (Stockholm, SWE) automated chromatography system using a commercially available cartridge as the column. Columns may be purchased from Teledyne Isco, Analogix, Biotage, Varian (Palo Alto, CA), or Supelco (Bellefonte, PA) and are usually filled with silica gel as the stationary phase. Aqueous solutions were concentrated on a Genevac (Ipswich, ENG) or by freeze-drying / lyophilization.

[0100] The compounds of the disclosure may be prepared by methods known in the art of organic synthesis as set forth in part by the following general synthetic schemes and specific preparative examples. Starting materials are available commercially or may be prepared by known methods. - 52 -25972-WO-PCT 12617.0005-00304 General Schemes Scheme 1

[0101] In Scheme 1, commercially available anilines were reacted with 3-bromoprop-1-yne to afford functionalilzed anilines. Representative preparative examples from each sequence are described in more detail below. Scheme 2

[0102] In Scheme 2, commercially available carboxylic acids were amide coupled with prop-2- yn-1-amine to afford functionalized amides. Representative preparative examples from each sequence are described in more detail below. Scheme 3

[0103] According to Scheme 3, trifluoromethylselenide substituted fused bicyclic aromatic systems with bromo or iodo substitution are coupled to propargyl amides prepared as described in Scheme 2, for example using transition metal catalysis as in the well-known Sonogashira reaction. The resulting intermediates, bearing a halogen, are then reacted with alkyl amines that are commercially available or prepared as described herein using direct SNAr reaction, for example by heating in a suitable solvent, or by transition metal mediated C-N coupling chemistry. - 53 -25972-WO-PCT 12617.0005-00304 Scheme 4

[0104] According to Scheme 4, trifluoromethylselenide-substituted fused bicyclic aromatic systems with chloro or bromo substitution are coupled with alkyl amines that are commercially available or prepared as described herein using direct SNAr reaction, for example by heating in a suitable solvent, or by transition metal mediated C-N coupling chemistry. The resulting intermediates are coupled to propargyl amides prepared as described in Scheme 2, for example using transition metal catalysis as in the well-known Sonogashira reaction to provide target compounds. Alternatively, the intermediates can be coupled to propargyl arylamines, prepared as described in Scheme 1, for example using transition metal catalysis as in the well-known Sonogashira reaction, to provide target compounds. SYNTHESIS OF INTERMEDIATES Intermediate 1: 7-chloro-2-iodopyrazolo[1,5-a]pyridineStep 1: 2-iodopyrazolo a]pyridine

[0105] A 1000 mL round-bottom flask was charged with pyrazolo[1,5-A]pyridine (25 g, 211.61 mmol) amd THF (375 mL). The reaction vessel was cooled in an ice bath to 0°C, and boron trifluoride diethyl etherate (28.73 mL, 232.77 mmol) was added dropwise. The reaction mixture was stirred in the ice bath for 45 min after which the reaction vessel was cooled to -70°C in a dry ice / acetone bath. TMPMgCl·LiCl (1M in THF / toluene; 253.9 mL, 253.94 mmol) was added dropwise, and the mixture was stirred at -70°C for 2 h. A solution of iodine (80.6 g, 317.42 mmol) in THF (125 mL) was added dropwise, and the reaction mixture was allowed to warm to - 54 -25972-WO-PCT 12617.0005-00304 RT. At 16 h, the reaction mixture was quenched with sat. Na2CO3(250 mL) and water (250 mL), and the mixture was stirred for 1 h. The mixture was extracted with Et2O (250 mL x 2). The organic phases were combined and poured into 500 mL of 0.66 M Na2S2O5. The mixture was stirred until complete color change was observed, after which the organic phase was recovered, and the aqueous phase extracted with 125 mL of Et2O. The organic phases were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by silica column chromatography to obtain 2-iodopyrazolo[1,5-a]pyridine. MS (m / z) 245.0 [M+H]+. Step 2: 7-chloro-2-iodopyrazolo[1,5-a]pyridine

[0106] A 1000 mL round bottom flask was charged with 2-iodopyrazolo[1,5-a]pyridine (37.96 g, 155.55 mmol) and THF (314 mL). The reaction vessel was cooled to -70°C in a dry ice / acetone bath. TMPMgCl·LiCl (1M in THF / toluene; 211.24 mL, 211.24 mmol) was added dropwise, and the mixture was stirred at -70°C for 30 min. A solution of 1,1,1,2,2,2- hexachloroethane (53.6 g, 226.32 mmol) in THF (70.3 mL) was added dropwise, and the reaction mixture was slowly warmed to RT overnight. At 16 h, the reaction mixture was quenched with an aq.10% Na2S2O3 solution (300 mL) and extracted with Et2O (150 mL x 2). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo, and the product was purified via silica column chromatography to obtain 7-chloro-2-iodo-pyrazolo[1,5-a]pyridine. MS (ESI) m / z = 278.9 - 281.0 [M+H]+. Intermediate 2: 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzeneStep 1: 1-(selenocyanatomethyl)-4-(trifluoromethyl)benzene

[0107] To a mixture of 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.825 g, 7.63 mmol) in acetone (69.4 mL) was added potassium selenocyanate (1 g, 6.94 mmol) at 20°C. The resulting mixture was stirred at 80°C for 5 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0~20% ethyl acetate / petroluem ether gradient) to give 1-(selenocyanatomethyl)-4- (trifluoromethyl)benzene.1H NMR (400 MHz, CDCl3) δ = 7.69 - 7.61 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 4.33 - 4.28 (m, 2H). - 55 -25972-WO-PCT 12617.0005-00304 Step 2: (trifluoromethyl)(4-(trifluoromethyl)benzyl)selane

[0108] To a mixture of 1-(selenocyanatomethyl)-4-(trifluoromethyl)benzene (1.52 g, 5.75 mmol) in THF (11.51 mL) was added trimethyl(trifluoromethyl)silane (1.689 mL, 11.51 mmol) at 0°C under N2, then TBAF (1.151 mL, 1.151 mmol) (1 M in THF) was added at 0°C dropwise. After 10 min at 0°C, the reaction was allowed to warm to 20°C and stirred for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0~20% ethyl acetate / petroleum ether gradient) to give (trifluoromethyl)(4-(trifluoromethyl)benzyl) selane.1H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 4.29 - 4.25 (m, 2H).19F NMR (376 MHz, CDCl3) δ = - 34.30 (s, 3F), -62.66 (s, 3F). Step 3: 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene

[0109] To a mixture of (trifluoromethyl)(4-(trifluoromethyl)benzyl)selane (1.13 g, 3.68 mmol) in DCM (3.68 mL) was added 3-chlorobenzoperoxoic acid (0.667 g, 3.86 mmol) at 0°C, After 10 min at 0°C, the reaction was allowed to warm to 20°C and stirred for 16 h. The reaction was then quenched with sat. aq. Na2CO3 (30 mL) at 0°C, and the aqueous phase was extracted with CH2Cl2(20 mL x 2), the organic layers were washed with sat. aq. Na2CO3(20 mL x 2). The combined organic layers were dried with Na2SO4and concentrated in vacuo to give 1- (trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene.1H NMR (400 MHz, CDCl3) δ = 7.69 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 4.48 (d, J = 11.8 Hz, 1H), 4.34 (d, J = 11.9 Hz, 1H).19F NMR (376 MHz, CDCl3) δ = -61.63 (s, 3F), -62.91 (s, 3F). Intermediate 3: 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene

[0110] To a mixture of 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene (200 mg, 0.619 mmol) and 7-chloro-2-iodopyrazolo[1,5-a]pyridine (207 mg, 0.743 mmol) in 2- - 56 -25972-WO-PCT 12617.0005-00304 propanol (6190 µL) was added trifluoromethanesulfonic anhydride (125 µL, 0.743 mmol) at 20°C. The resulting mixture was stirred at 20°C for 2 h. The residue was purified by Prep-TLC (silica gel, ethyl acetate / petroleum ether = 1 / 5, v / v) to give 7-chloro-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine. MS (ESI) m / z: calc’d for C8H4ClF3IN2Se+[M+H]+: 427.1 / 429.1, found: 426.8 / 428.8 [M+H]+, tR=0.803 min. Intermediate 4: (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amineStep 1: tert-butyl (3S,4R)-4-(dibenzylamino)-3-fluoropiperidine-1-carboxylate

[0111] To a mixture of tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (2 g, 9.16 mmol) and potassium carbonate (1.27 g, 9.16 mmol), potassium iodide (1.521 g, 9.16 mmol), N- benzyl-N,N-diethylethanaminium chloride (2.09 g, 9.16 mmol) in MeCN (25 mL) was added (bromomethyl)benzene (2.351 g, 13.74 mmol) at 20°C. The resulting mixture was stirred at 80°C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0~15% ethyl acetate / petroleum ether gradient) to give tert-butyl (3S,4R)-4-(dibenzylamino)-3-fluoropiperidine-1-carboxylate. MS (ESI) m / z: calc’d for C24H32FN2O2+[M+H]+: 399.1, found: 399.2 [M+H]+, tR=0.718 min. Step 2: (3S,4R)-N,N-dibenzyl-3-fluoropiperidin-4-amine

[0112] A mixture of tert-butyl (3S,4R)-4-(dibenzylamino)-3-fluoropiperidine-1-carboxylate (2.3 g, 5.77 mmol) and 2 M HCl (25 mL, 50.0 mmol) in MeOH was stirred at 20°C for 16 h. The mixture was concentrated and dissolved in water (20 mL); the pH was adjusted to 9 with sat. aq. NaHCO3. THe mixture was extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under - 57 -25972-WO-PCT 12617.0005-00304 reduced pressure to give (3S,4R)-N,N-dibenzyl-3-fluoropiperidin-4-amine, which was used in next step directly. MS (ESI) m / z: calc’d for C19H24FN2+[M+H]+: 299.1, found: 299.2 [M+H]+, tR=0.624 min. Step 3: 3-((3S,4R)-4-(dibenzylamino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile

[0113] To a solution of (3S,4R)-N,N-dibenzyl-3-fluoropiperidin-4-amine (1.7 g, 5.70 mmol) and oxetan-3-one (0.668 mL, 11.39 mmol) in DCE (25 mL) was added AcOH (0.065 mL, 1.139 mmol) at 20°C, the mixture was stirring at 50°C for 30 min. After cooling to RT, trimethylsilanecarbonitrile (1.488 mL, 11.89 mmol) was added to the mixture at RT. The resulting mixture was stirred for another 20 h. The reaction mixture was quenched with sat. NaHCO3 (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0~25% ethyl acetate / petroleum ether gradient) to give 3-((3S,4R)-4-(dibenzylamino)-3-fluoropiperidin-1- yl)oxetane-3-carbonitrile. MS (ESI) m / z: calc’d for C23H27FN3O+[M+H]+: 380.1, found: 380.2 [M+H]+, tR=0.699 min. Step 4: (3S,4R)-N,N-dibenzyl-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine

[0114] To a solution of 3-((3S,4R)-4-(dibenzylamino)-3-fluoropiperidin-1-yl)oxetane-3- carbonitrile (890 mg, 2.345 mmol) in THF (15 mL) was added MeMgBr (4.69 mL, 14.07 mmol) at 0°C over 10 min under N2, the mixture was stirring at 0°C for 10 min then warmed to 40°C and stirred for 12 h. After cooling to RT, the reaction mixture was quenched with sat. aq. NH4Cl (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give (3S,4R)-N,N-dibenzyl-3-fluoro-1-(3- methyloxetan-3-yl)piperidin-4-amine. MS (ESI) m / z: calc’d for C23H30FN2O+[M+H]+: 369.1, found: 369.2 [M+H]+, tR= 0.677 min. - 58 -25972-WO-PCT 12617.0005-00304 Step 5: (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine

[0115] (3S,4R)-N,N-dibenzyl-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine (250 mg, 0.678 mmol) was dissolved in MeOH (25 mL) and THF (25 mL). The solution was added 5% Pd(OH)2 in Al2O3 (1.91 g, 1 eq) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred under H2 (Pressure: 1.0 MPa) at 35°C for 2 h. The reaction mixture was filtered through a pad of diatomaceous earth, which was washed with MeOH (20 mL x 3). The combined filtrate was concentrated under reduced pressure to give (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine, which was used in next step directly. MS (ESI) m / z: calc’d for C9H18FN2O+[M+H]+: 189.1, found: 189.1 [M+H]+, tR= 0.087 min.1H NMR (400 MHz, MeOD) δ = 4.70 - 4.52 (m, 3H), 4.22 (d, J = 5.6 Hz, 2H), 2.85 - 2.69 (m, 2H), 2.59 - 2.50 (m, 1H), 2.42 - 2.28 (m, 1H), 2.24 - 2.16 (m, 1H), 1.79 - 1.69 (m, 2H), 1.37 (s, 3H). Intermediate 5: N-(prop-2-yn-1-yl)acetamide

[0116] In a 250 mL round-bottom flask, acetyl chloride (1.16 mL, 16.34 mmol) was added dropwise to a stirred solution of 2-propyn-1-amine (1.16 mL, 18.16 mmol), DMAP (221.8 mg, 1.82 mmol) and TEA (2.78 mL, 19.97 mmol) in DCM (33 mL). The reaction mixture was stirred at RT overnight. At 16 h, DCM (33 mL) and aq. NaOH 1M (66 mL) were added. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to afford N-(prop-2-yn-1-yl)acetamide. MS (ESI) m / z = 98.2 [M+H]+.1H NMR (400 MHz, DMSO- d6) d ppm 1.81 - 1.84 (3H, m) 3.07 - 3.09 (1H, m) 3.80 - 3.86 (2H, m) 8.26 (1H, t, J = 6.27 Hz). Intermediate 6: 4-dimethylphosphoryl-2-methoxy-N-prop-2-ynyl-aniline

[0117] A 40 mL vial was charged with 4-dimethylphosphoryl-2-methoxy-aniline (308.0 mg, 1.55 mmol) and DMF (5 mL).3-Bromo-1-propyne (80 wt% in toluene; 0.21 mL, 1.86 mmol) and potassium carbonate (641.13 mg, 4.64 mmol) were added, and the reaction mixture was stirred at 70°C overnight. At 16 h, the mixture was allowed to reach RT and then partitioned between EtOAc and H2O. The aqueous layers was further extracted with EtOAc (x3) and then - 59 -25972-WO-PCT 12617.0005-00304 DCM:MeOH 9:1 (x3). The combined organic factions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified through flash chromatography to afford 4-dimethylphosphoryl-2-methoxy-N-prop-2-ynyl-aniline. MS (ESI) m / z = 238.45 [M+H]+.

[0118] Each of the intermediates presented in Table 2 below were prepared in accordance with the synthetic route demonstrated in Scheme 1, using procedures analogous to those described above.Intermediate 10: 1-(tert-butyl)-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide

[0119] A 1000 mL round-bottom flask was charged with 1-(tert-butyl)-1H-pyrazole-4- carboxylic acid (16 g, 95 mmol), DIEA (33.2 ml, 190 mmol) and HATU (39.8 g, 105 mmol). DMF (120 ml) was added, and the reaction mixture was stirred at 25°C for 5 min, after which prop-2-yn-1-amine (7.86 g, 143 mmol) was added dropwise. The resulting mixture was stirred at RT overnight. At 16 h, the reaction mixture was quenched with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0~30% ethyl acetate / petroleum ether gradient) to give 1-(tert-butyl)-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide. LCMS (ESI) m / z: 206 [M+H]+. - 60 -25972-WO-PCT 12617.0005-00304

[0120] Each of the intermediates presented in Table 3 below were prepared in accordance with the synthetic route demonstrated in Scheme 2, using procedures analogous to those described above.Intermediate 16: Synthesis of 8-bromo-2-iodo-imidazo[1,2-a]pyridineStep 1: Synthesis of 2-amino-3-bromo-1-(2-ethoxy-2-oxoethyl)pyridin-1-ium (1:1 Bromide)

[0121] A 500 mL round-bottom flask equipped with an air refrigerator, was charged with a solution of 3-bromo-2-pyridinamine (10.0 g, 57.8 mmol) in 2-bromoacetic acid ethyl ester (50.0 mL, 450.9 mmol). The reaction mixture was stirred at 50°C overnight for 16 h under N2. At 16 h, the reaction mixture became a suspension, and the reaction mixture was diluted with Et2O and filtered. The resulting filtrate was washed with Et2O and dried under high vacuum affording 2- amino-3-bromo-1-(2-ethoxy-2-oxoethyl)pyridin-1-ium (1:1 Bromide).1H NMR (400 MHz, - 61 -25972-WO-PCT 12617.0005-00304 DMSO) δ 1.26 (t, J = 7.1 Hz, 3H), 4.21 (q, J = 7.1 Hz, 2H), 5.30 (s, 2H), 6.94 (dd, J = 7.7, 6.7 Hz, 1H), 8.16 (dd, J = 6.7, 1.4 Hz, 1H), 8.43 (dd, J = 7.7, 1.4 Hz, 1H), 8.73 (s, 2H). Step 2: Synthesis of 8-bromo-2-chloro-imidazo[1,2-a]pyridine

[0122] A 500 mL round-bottom flask equipped with an air refrigerator was charged with a suspension of 2-amino-3-bromo-1-(2-ethoxy-2-oxoethyl)pyridin-1-ium (1:1 Bromide, 9.75 g, 28.68 mmol) in phosphorus(V) oxychloride (40.0 mL, 429.14 mmol). The reaction mixture was refluxed (105°C) for 3 h under N2. POCl3was evaporated under reduced pressure, and the reaction mixture was cooled using an ice water bath. The residual POCl3 was quenched carefully using crushed ice and ammonium hydroxide solution to pH 8. The resulting suspension was filtered, washed with water and cyclohexane. The resulting material was then dried in an oven at 50°C overnight, affording 8-bromo-2-chloro-imidazo[1,2-a]pyridine. (ESI) m / z = 230.94 / 232.94 / 234.94 [M+H]+(Combined bromine / chlorine pattern).1H NMR (400 MHz, DMSO) δ 6.90 – 6.95 (m, 1H), 7.68 (dd, J = 7.5, 1.0 Hz, 1H), 8.20 (s, 1H), 8.54 (dd, J = 6.8, 1.0 Hz, 1H). Step 3: Synthesis of 8-bromo-2-iodo-imidazo[1,2-a]pyridine

[0123] A 40 mL vial was charged with sodium iodide (2410.56 mg, 16.08 mmol) and 8-bromo- 2-chloro-imidazo[1,2-a]pyridine (744.0 mg, 3.21 mmol). The reaction vessel was degassed with three vacuum N2 cycles. Anhydrous MeCN (4 mL) was added, and the resulting suspension was degassed. Hydriodic acid (3.0 mL, 39.87 mmol) was added under positive flow of N2, and the reaction vessel was stirred at 85°C overnight. At 16 h, the reaction was cooled with an ice water bath, and a 2:1 solution 12 M NaOH / sat. Na2S2O3was added until pH 10-12 was reached. The resulting suspension was filtered, washed with water and cyclohexane, and dried in an oven at 50°C overnight affording 8-bromo-2-iodo-imidazo[1,2-a]pyridine. (ESI) m / z = 322.98 / 324.98 [M+H]+(Bromine pattern).1H NMR (400 MHz, DMSO) δ 6.85 (t, J = 7.4, 6.8 Hz, 1H), 7.60 (dd, J = 7.4, 1.0 Hz, 1H), 8.27 (s, 1H), 8.52 (dd, J = 6.8, 1.0 Hz, 1H). - 62 -25972-WO-PCT 12617.0005-00304 Intermediate 17: 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazineStep 1: methyl 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyr role-2-carboxylate

[0124] To a solution of methyl 4-iodo-1H-pyrrole-2-carboxylate (1.9 g, 7.57 mmol) in DMF (20 mL) were added cesium carbonate (6.29 g, 19.30 mmol) and 2-bromo-1,1-dimethoxyethane (2.70 g, 15.97 mmol), and the mixture was reacted at 100°C for 16 h. Water (200 mL) was added to the reaction, and the mixture was extracted with EtOAc (200 mL x 2). The organic phase was collected combined, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether / ethyl acetate (5 / 1)) to give methyl 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxylate. MS (ESI) m / z: calc’d for C10H15INO4+[M+H]+: 340.0, found 307.9 [M-OMe]+, tR = 0.743 min. Step 2: 1-(2,2-dimethoxyethyl)- 4-iodo-1H-pyrrole-2-carboxylic acid

[0125] A mixture of LiOH (0.424 g, 17.69 mmol) and methyl 1-(2,2-dimethoxyethyl)-4-iodo- 1H-pyrrole-2-carboxylate (2 g, 5.90 mmol) in MeOH (10 mL), water (10 mL) was stirred at 20°C for 1 h. The solvent was removed under reduced pressure, and the water phase was adjusted pH to 3 with 1 N HCl. Then, EtOAc (5 mL) was added to the water phase. The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxylic - 63 -25972-WO-PCT 12617.0005-00304 acid, which was used for next step without further purification. MS (ESI) m / z: calc’d for C9H13INO4+[M+H]+: 325.0, found 293.9 [M-OMe]+, tR = 0.661 min. Step 3: 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxamide

[0126] To a solution of 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxylic acid (1.9 g, 5.84 mmol), HATU (2.89 g, 7.60 mmol), and DIEA (4.08 mL, 23.38 mmol) in DMF (10 mL) was added ammonium chloride (0.938 g, 17.53 mmol). The mixture was stirred at 20°C for 4 h, and the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxamide. MS (ESI) m / z: calc’d for C9H14IN2O3+[M+H]+: 325.0, found: 293.0 [M-OMe]+, tR = 0.626 min. Step 4: 7-iodopyrrolo[1,2-a]pyrazin-1(2H)-one

[0127] A mixture of 4-bromo-1-(2,2-dimethoxyethyl)-1H-imidazole-2-carboxamide (1.15 g, 4.14 mmol) in AcOH (2 mL) was stirred at 100°C for 12 h. The reaction was filtered, and the filtrate was concentrated in vacuum to give the residue 2-bromoimidazo[1,2-a]pyrazin-8(7H)- one. LCMS (ESI) m / z: calc’d for C7H6IN2O+[M+H]+: 260.9, found: 260.9 [M+H]+. tR = 0.622 min. Step 5: 1-chloro-7-iodopyrrolo[1,2-a]pyrazine

[0128] To a mixture of 7-iodopyrrolo[1,2-a]pyrazin-1(2H)-one (800 mg, 3.08 mmol) in POCl3 (1434 µL, 15.38 mmol) was added DIEA (1075 µL, 6.15 mmol) at 20°C. The resulting mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated in vacuum. The solid was basified with sat. NaHCO3 (30 mL) to adjust the pH to 8. The mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue 1- - 64 -25972-WO-PCT 12617.0005-00304 chloro-7-iodopyrrolo[1,2-a]pyrazine without further work-up and used in next step. LCMS (ESI) m / z: calc’d for C7H5ClIN2+[M+H]+: 278.9, found: 278.9 [M+H]+. tR = 0.774 min. Step 6: 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine

[0129] To a mixture of 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene (280 mg, 0.867 mmol) and 1-chloro-7-iodopyrrolo[1,2-a]pyrazine (241 mg, 0.867 mmol) in 2- propanol (2.5 mL) was added chlorotrimethylsilane (0.143 ml, 1.127 mmol) at 20°C. The resulting mixture was stirred at 20°C for 12 h. The solvent was removed under reduced pressure, and the concentrate was purified by silica gel chromatography to afford 1-chloro-7-iodo-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazine. MS (ESI) m / z: calc'd for C8H4ClF3IN2Se+[M+H]+426.8 / 428.8, found [M+H]+426.8 / 428.8, tR = 0.862 min. Intermediate 18: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amineStep 1: 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine

[0130] A 250 mL flask was charged with 1-chloro-7-iodopyrrolo[1,2-a]pyrazine (4.83 g, 1.1 eq, 17.3 mmol), 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene (5.00 g, 1 eq, 15.5 mmol), and iPrOH (60 mL). The suspension was cooled to 0 °C with an ice-bath, then Tf2O (5.24 g, 3.14 mL, 1.2 eq, 18.6 mmol) was added dropwise over 10 min. The mixture was warmed to RT and stirred for 30 min. The reaction mixture was quenched with sat. aq. NaHCO3(~100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (220 g column, 0% to 40% EtOAc in heptanes, product eluted with 8% EtOAc). The corresponding fractions were combined and reduced under vacuum to afford 1-chloro-7- iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine. - 65 -25972-WO-PCT 12617.0005-00304 Step 2: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine

[0131] A 10 ml round bottom flask was charged with 1-chloro-7-iodo-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazine (300 mg, 1 eq, 705 μmol), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (140 mg, 1.5 eq, 1.06 mmol), CsF (321 mg, 3.0 eq, 2.12 mmol), flushed with N2, and DMSO (3.00 mL) was added. The mixture was stirred at 110 °C for 2 h and left at 23 °C for 16 h. The reaction mixture was diluted with EtOAc (25 ml), washed with water (3 x 25 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by normal phase flash chromatography (25 g SiO2 cartridge, 0 to 20% MeOH in CH2Cl2 over 15 CV, product eluted at 8% MeOH) to afford N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine. MS (ESI) m / z: Calc’d for C14H16F4IN4Se+[M+H]+: 522.95 found: 523.1. Intermediate 19: 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amineStep 1: tert-butyl (1R,2R,5R)-2-((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-1-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0132] A flame dried microwave vial with stirring was charged with 1-chloro-7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine (500 mg, 1 eq, 1.18 mmol), tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (399 mg, 1.5 eq, 1.76 mmol), and then cesium fluoride (536 mg, 3.0 eq, 3.53 mmol) was added. The mixture was purged with N2, and DMSO (5.0 mL) was added. The vial was sealed and stirred at 110 °C for 3 h. After cooling to RT, reaction mixture was diluted with water (20 mL) and EtOAc (30 mL). The aqueous and organic layers were separated. The aqueous layer was extracted by EtOAc (20 mL x 2). The combined organic layers were then dried (Na2SO4) and concentrated under reduced pressure. - 66 -25972-WO-PCT 12617.0005-00304 Purification by silica gel chromatography (40 g cartridge, using EtOAc in Heptanes, 0-100%) afforded tert-butyl (1R,2R,5R)-2-((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z: Calc’d for C20H25F3IN4O2Se+[M+H]+: 617.014 found: 617.3. Step 2: (1R,2R,5R)-2-((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1- yl)amino)-8-azabicyclo[3.2.1]octan-8-ium 2,2,2-trifluoroacetate

[0133] A dry 50 mL round bottom flask was charged with tert-butyl (1R,2R,5R)-2-((7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (100 mg, 1 eq, 163 μmol) and then 1,1,1,3,3,3-hexafluoroisopropanol (3 mL) was added. TFA (55.6 mg, 37.6 μL, 3 eq, 488 μmol) was added dropwise at RT. The mixture was stirred at 25 °C until complete consumption of starting material. The volatiles were removed under reduced pressure and co-evaporated with CH2Cl2 (25 mL x 3). The crude (1R,2R,5R)-2- ((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-yl)amino)-8-azabicyclo[3.2.1]octan- 8-ium 2,2,2-trifluoroacetate was obtained, which was used in the next step without further purification. MS (ESI) m / z: Calc'd for free base C15H18F3IN4O2Se+[M+H]+: 517.196 found: 517.3. Step 3: 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine

[0134] A 50 mL round-bottom flask was charged with (1R,2R,5R)-2-((7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-yl)amino)-8-azabicyclo[3.2.1]octan-8-ium 2,2,2-trifluoroacetate (153 mg, 1 eq, 244 μmol) and then CH2Cl2(1.50 mL) was added followed by formaldehyde (37wt% in water) (11.0 mg, 27.3 μL, 1.5 eq, 366 μmol) at RT. This was stirred for 5 min, and sodium triacetoxyhydroborate (103 mg, 2.0 eq, 488 μmol) was added. The mixture was stirred at 25 °C until full consumption of starting material. The mixture was quenched by adding aqueous solution of 10 wt% of K2CO3 solution (10 mL) and extracted using CH2Cl2 (10 mL x 3). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine was obtained and used in the next reaction without further purification. MS (ESI) m / z: Calc'd for C16H19F3IN4O2Se+[M+H]+: 530.977 found: 531.2. - 67 -25972-WO-PCT 12617.0005-00304 Intermediate 20: 7-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-1-amineStep 1: tert-butyl 6-((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1- yl)amino)-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0135] A mixture of 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine (666 mg, 1.57 mmol), tert-butyl 6-amino-3-azabicyclo[4.1.0]heptane-3-carboxylate (399 mg, 1.88 mmol) and CsF (523 mg, 3.44 mmol) in DMSO (5 mL) was stirred at 110 °C for 20 h. The mixture was cooled to RT and was partitioned between water (25 mL) and EtOAc (25 mL). The aqueous and organic layers were separated. The organic layer was washed with water (15 mL) and brine (15 mL), dried over sodium sulfate and reduced under vacuum to afford the crude product. The crude product was loaded on silica and purified by flash-chromatography (40 g column, 0% to 100% EtOAc in heptanes) to afford tert-butyl 6-((7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-azabicyclo[4.1.0]heptane-3- carboxylate. MS (ESI) m / z: calc'd for C19H23F3IN4O2Se+[M+H]+: 603.0, found: 603.3. Step 2: N-(3-azabicyclo[4.1.0]heptan-6-yl)-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo [1,2-a]pyrazin-1-amine

[0136] A mixture of tert-butyl 6-((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1- yl)amino)-3-azabicyclo[4.1.0]heptane-3-carboxylate (440 mg, 732 μmol) and TFA (169 μL, 2.20 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (10 mL) was stirred at RT for 16 h. The reaction mixture was concentrated to dryness and co-evaporated with CH2Cl2 (15 mL x 2) to afford the crude N-(3-azabicyclo[4.1.0]heptan-6-yl)-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-1-amine used directly in the next step. MS (ESI) m / z: calc'd for C14H16F3IN4Se+[M+H]+: 502.9, found: 503.2. Step 3: 7-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine

[0137] To a solution of N-(3-azabicyclo[4.1.0]heptan-6-yl)-7-iodo-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine (367 mg, 732 μmol) (crude) in CH2Cl2(7 mL) and MeOH (7 mL) was added paraformaldehyde (55.0 mg, 1.83 mmol). After 30 min, sodium triacetoxyborohydride (310 mg, 1.46 mmol) was added in one portion. The mixture was stirred at RT for 2 h. Volatiles were removed under reduced pressure, and the residue was dissolved in CH2Cl2 (35 mL) and - 68 -25972-WO-PCT 12617.0005-00304 washed with saturated NaHCO3(2 x 25 mL). The organic layer was dried over sodium sulfate and reduced under vacuum to afford the crude product. Purification by flash chromatography (40 g column, 0% to 50% MeOH in CH2Cl2) afforded 7-iodo-N-(3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine. MS (ESI) m / z: calc'd for C15H17F3IN4Se+[M+H]+: 515.9, found: 515.2. Intermediate 21: 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamideStep 1: 4-methoxy-3-nitrobenzoic acid

[0138] A 500 mL round-bottom flask was charged with methyl 4-methoxy-3-nitrobenzoate (10.0 g, 1 eq, 47.4 mmol), H2O (80.0 mL), and THF (80.0 mL), and the mixture was cooled in a water-ice bath. Lithium hydroxide hydrate (2.98 g, 1.5 eq, 71.0 mmol) was added, and the mixture was stirred at 25 °C until full consumption of starting material. The reaction mixture was concentrated under vacuo, and a solution of HCl (4.00 N in H2O) was added to the residue until pH 2-3. The mixture was filtered over suction and air dried to afford 4-methoxy-3-nitrobenzoic acid. MS (ESI) m / z: calc'd for C8H6O5N- [M-H]-: 196.0 found: 196.1. Step 2: 4-methoxy-N-methyl-3-nitrobenzamide

[0139] A 250 mL round-bottom flask was charged with 4-methoxy-3-nitrobenzoic acid (5.0 g, 1 eq, 25 mmol) and CH2Cl2(80 mL).2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethylisouronium hexafluorophosphate(V) (14 g, 1.5 eq, 38 mmol) was added at 0 °C. The mixture was stirred on ice bath for 10 min. Methanamine hydrochloride (3.4 g, 2.0 eq, 51 mmol) and N-ethyl-N-isopropylpropan-2-amine (16 g, 23 mL, 5.0 eq, 0.13 mol) were added successively. The solution was stirred at 25 °C until full consumption of starting material. The reaction mixture was diluted with sat. aq. solution of NaHCO3 (20 mL) and extracted with CH2Cl2(3 x 40 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. Purification by silica gel column chromatography (80 g cartridge, - 69 -25972-WO-PCT 12617.0005-00304 CH2Cl2 / heptanes, 0-100%) gave the desired product 4-methoxy-N-methyl-3-nitrobenzamide. MS (ESI) m / z: calc'd for C9H11O4N2+[M+H]+: 211.1 found: 211.1. Step 3: 3-amino-4-methoxy-N-methylbenzamide

[0140] A 250 mL round-bottom flask was charged with 4-methoxy-N-methyl-3-nitrobenzamide (3.1 g, 1 eq, 15 mmol), EtOAc (100 mL), and THF (30 mL). The homogenous solution was then purged with N2 for 10 min. To this, palladium hydroxide (20 wt.% Pd / C, 300 mg, 0.029 eq, 427 μmol) was added and again purged with N2for 5 more min. The N2was replaced with H2at 1 atm, and the reaction mixture was stirred at 23 °C until full consumption of starting material. The reaction mixture was filtered over diatomaceous earth (CELITE®) and washed with EtOAc (40 mL x 2). The combined organic layers were concentrated under reduced pressure to afford 3- amino-4-methoxy-N-methylbenzamide which was used in the next reaction without further purification. MS (ESI) m / z: calc'd for C9H13O2N2+[M+H]+: 181.1 found: 181.1. Step 4: 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide

[0141] A 250 mL round-bottom flask was charged with 3-amino-4-methoxy-N- methylbenzamide (2.5 g, 1 eq, 14 mmol) and DMF (20 mL). To the solution, solid potassium carbonate (3.8 g, 2 eq, 28 mmol) was added, followed by 3-bromoprop-1-yne (1.5 g, 80 wt%, 0.75 eq, 10 mmol), and the mixture was stirred at RT. After stirring for 48 hours, reaction mixture was filtered over suction, and the filtrate was concentrated under reduced pressure. The crude mixture was directly loaded on the reverse phase column (i-LOK SNAP C18, 120 g column using 10mM AmF in H2O / ACN, 0-100%) to afford 4-methoxy-N-methyl-3-(prop-2-yn- 1-ylamino)benzamide. MS (ESI) m / z: calc'd for C12H15O2N2+[M+H]+: 219.1 found: 219.2. Intermediate 22: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0142] To a mixture of 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (200 mg, 0.470 mmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (93 mg, 0.705 mmol) in DMSO (3 mL) was added DIEA (0.164 mL, 0.940 mmol), and CsF (143 mg, 0.940 mmol) at 20°C. The resulting mixture was stirred at 100°C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under - 70 -25972-WO-PCT 12617.0005-00304 reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 100% EtOAc gradient) to give N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine. MS (ESI) m / z: calc'd for C14H16F4IN4Se+[M+H]+: 520.9 / 522.9, found: 520.9 / 522.9, tR=0.689 min.1H NMR (CDCl3, 400 MHz): δ (ppm) 7.28-7.33 (m, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.27 (br d, J = 8.9 Hz, 1H), 5.94 (d, J = 7.7 Hz, 1H), 4.81-4.98 (m, 1H), 3.54-3.70 (m, 1H), 3.20-3.32 (m, 1H), 2.92-3.02 (m, 1H), 2.38 (s, 3H), 2.25-2.35 (m, 1H), 2.08-2.24 (m, 3H). Intermediate 23: 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amineStep 1: tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0143] In a 50 mL round bottom flask were added 7-chloro-2-iodo-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridine (300 mg, 1 eq, 705 μmol), tert-butyl (1R,2R,5R)-2-amino-8- azabicyclo[3.2.1]octane-8-carboxylate (192 mg, 1.2 eq, 846 μmol), and cesium fluoride (236 mg, 2.2 eq, 1.55 mmol), followed by DMSO (4 mL). The reaction mixture was heated at 110 °C for 3.5 h. The mixture was cooled to RT and diluted with water (10 mL) and EtOAC (10 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (25 ml x 2) and combined organic layers were washed thoroughly with water (2 x 10 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography (30 g silica, 0 to 100% EtOAc in Heptanes over 7 CV) afforded tert-butyl (1R,2R,5R)-2-((2-iodo- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) m / z: calc'd for C20H25F3IN4O2Se+[M+H]+: 617.0 found: 617.4. Step 2: N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-7-amine trifluoroacetic acid salt

[0144] To a solution of tert-butyl (1R,2R,5R)-2-((2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (383 mg, 1 eq, 622 μmol) in 1,1,1,3,3,3-hexafluoroisopropanol (12 mL) was added dropwise TFA (142 mg, 95.9 μL, 2 eq, 1.24 mmol). The reaction was stirred at RT for 1 h. The volatiles were removed under vacuum, then co-evaporated with CH2Cl2(3 x 15 mL) to afford the crude N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3- - 71 -25972-WO-PCT 12617.0005-00304 ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine trifluoroacetic acid salt, which was used in the next reaction without further purification. MS (ESI) m / z: calc'd for free base C15H17F3IN4Se+[M+H]+: 516.96 found: 517.2. Step 3: 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0145] To a solution of crude N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine trifluoacetic acid salt (536 mg, 1 eq, 1.04 mmol) in CH2Cl2 (15 mL) and MeOH (15 mL) was added paraformaldehyde (62.5 mg, 2 eq, 2.08 mmol). After 30 min, sodium triacetoxyborohydride (551 mg, 2.5 eq, 2.60 mmol) was added in one portion, and the reaction mixture was stirred overnight at RT. To this reaction was added paraformaldehyde (62.5 mg, 2 eq, 2.08 mmol) followed by sodium triacetoxyborohydride (551 mg, 2.5 eq, 2.60 mmol), and stirring was continued at RT for 1 h. The reaction mixture was reduced to dryness under vacuum, and the resulting product was suspended in CH2Cl2 (100 mL), washed with sat. NaHCO3(2 x 70 mL) and sat. NH4Cl (100 mL), dried over Na2SO4, reduced under vacuum to afford the crude 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine. MS (ESI) m / z: calc'd for C16H19F3IN4Se+[M+H]+: 530.97 found: 531.3 Intermediate 24: 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0146] 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)selanyl)pyrazolo [1,5-a]pyridin-7-amine was prepared in a similar fashion to N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-amine and 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine. - 72 -25972-WO-PCT 12617.0005-00304 Intermediate 25: tert-butyl (S)-(4-((2-hydroxypropyl)carbamoyl)-2-methoxyphenyl)(prop-2- yn-1-yl)carbamateStep 1: methyl 4-((tert-butoxycarbonyl)amino)-3-methoxybenzoate

[0147] In a 250 mL round bottom flask was added methyl 4-amino-3-methoxybenzoate (6 g, 1 eq, 0.03 mol) and di-tert-butyl dicarbonate (29 g, 30 mL, 4 eq, 0.13 mol). This was heated at 110 °C for 3 h. The mixture was cooled to RT, and the volatiles were removed under reduced pressure. The crude was poured onto ice-water and stirred for 30 min. The precipitate was filtered and dried under vacuum overnight to give the desired product methyl 4-((tert- butoxycarbonyl)amino)-3-methoxybenzoate.1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.5, 1.7 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.27 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 1.53 (s, 9H). MS (ESI) m / z: Calcd C14H18NO5- [M-H]-: 280.3 found: 280.1. Step 2: 4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxybenzoate

[0148] In a 250 mL round bottom flask was added cesium carbonate (6.949 g, 1.707 mL, 3 eq, 21.33 mmol) to a suspension of methyl methyl 4-((tert-butoxycarbonyl)amino)-3- methoxybenzoate (2 g, 1 eq, 7.110 mmol) and propargyl bromide (3.17 g, 2.31 mL, 80 wt%, 3 eq, 21.33 mmol) in DMF (30 mL). The suspension was stirred at 23 °C for 3 h. The mixture was poured onto ice-water (100 mL). This was stirred for 1 h at 23 °C. MTBE (40 mL) was added, and the aqueous and organic layers were separated. The aqueous layer was extracted with MTBE (3 x 25 mL). The combined organic layers were washed with brine (75 mL), dried over Na2SO4, and concentrated to give the desired compound methyl 4-((tert-butoxycarbonyl)(prop-2-yn-1- yl)amino)-3-methoxybenzoate, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 8.1, 1.8 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 4.73 - 4.10 (br m, 2H), 3.90 (d, J = 3.5 Hz, 3H), 3.86 (d, J = 3.0 Hz, 3H), 2.15 (d, J = 2.1 Hz, 1H), 1.35 (br s, 9H). Step 3: 4-((tert-butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxybenzoic acid

[0149] In a 250 mL round bottom flask containing methyl 4-((tert-butoxycarbonyl)(prop-2-yn- 1-yl)amino)-3-methoxybenzoate (2.27 g, 1 eq, 7.11 mmol) in MeOH (60 mL) was added lithium - 73 -25972-WO-PCT 12617.0005-00304 hydroxide monohydrate (1.49 g, 5 eq, 35.5 mmol). This was heated at 45 °C for 16 h. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in water (25 mL), and this was washed with MTBE (2 x 10 mL). The aqueous layer was cooled to 0 °C, and HCl (1.00 M in water) was added slowly until pH = 2-3. The mixture was filtered, washed with cold water (3 x 10 mL), and dried overnight to give desired compound 4-((tert- butoxycarbonyl)(prop-2-yn-1-yl)amino)-3-methoxybenzoic acid. This was used in the next reaction without further purification. MS (ESI) m / z: Calcd C16H18NO5- [M-H]-: 304.1 found: 304.2. Step 4: tert-butyl (S)-(4-((2-hydroxypropyl)carbamoyl)-2-methoxyphenyl)(prop-2-yn-1- yl)carbamate

[0150] In a 100 mL round bottom flask containing 4-((tert-butoxycarbonyl)(prop-2-yn-1- yl)amino)-3-methoxybenzoic acid (700 mg, 1 Eq, 2.29 mmol) in DMF (5 mL) was added (S)-1- aminopropan-2-ol (172 mg, 1 eq, 2.29 mmol), diisopropylethylamine (889 mg, 1.18 mL, 3 eq, 6.88 mmol), and HATU (1.05 g, 1.2 eq, 2.75 mmol). This was stirred at RT for 2 h. The reaction was poured onto ice-water (15 mL). This mixture was stirred at RT for 10 min. The mixture was diluted with EtOAc (20 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with sat aq NaHCO3 (3 x 10 mL), brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (40 g, 0 to 10% of CH3CN in CH2Cl2 over 15 CV) afforded tert-butyl (S)-(4-((2-hydroxypropyl)carbamoyl)-2-methoxyphenyl)(prop-2-yn-1- yl)carbamate. MS (ESI) m / z: Calcd C19H27N2O5+[M+H]+: 363.2 found: 363.4. Intermediate 26: 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine- 74 -25972-WO-PCT 12617.0005-00304 Step 1: Methyl 2 bromopyridin-2-yl)(hydroxy)methyl)acrylate

[0151] In a 2 L round bottom flask was added 1,4-diazabicyclo[2.2.2]octane (6.03 g, 0.1 eq, 53.8 mmol) to a suspension of 3-bromopicolinaldehyde (100 g, 1 eq, 538 mmol) and methyl acrylate (55.5 g, 58.1 mL, 1.2 eq, 645 mmol) in 1,4-dioxane (748 mL) and water (249 mL). The suspension became a solution in a few minutes, and it was stirred at RT for 17 h. The volatiles were removed. Water (250 mL) and EtOAc (500 mL) were added. The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to afford methyl 2-((3-bromopyridin-2-yl)(hydroxy)methyl)acrylate.1H NMR (400 MHz, DMSO- d6): δ 8.44 (dd, J = 4.6, 1.4 Hz, 1H), 8.07 (dd, J = 8.1, 1.5 Hz, 1H), 7.25 (dd, J = 8.0, 4.6 Hz, 1H), 6.33 (t, J = 1.6 Hz, 1H), 6.01 (t, J = 1.7 Hz, 1H), 5.90 (d, J = 7.0 Hz, 1H), 5.84 (dt, J = 7.0, 1.6 Hz, 1H), 3.55 (s, 3H). MS (ESI) m / z: Calcd. C10H11BrNO3+[M+H]+: 271.99; found: 272.0. Step 2: Methyl 8-bromoindolizine-2-carboxylate

[0152] In a 2 L round bottom flask, acetic anhydride (439 mL) was added to methyl 2-((3- bromopyridin-2-yl)(hydroxy)methyl)acrylate (146.3 g, 1 eq, 537.7 mmol). The solution was heated at 120 °C over 30 min, and heating was continued at 120 °C for 3.5 h. The reaction was cooled to RT to afford a slurry. The reaction mixture was concentrated, diluted with acetone (200 mL), and concentrated again. This dilution and concentration was repeated 3 times. The final slurry was suspended in acetone (300 mL) and poured into 2 L water while stirring. The suspension was stirred vigorously for 1 h. The suspension was filtered and washed with water (~500 mL). The residue was transferred into a beaker, and water (~500 mL) was added. The mixture was stirred for 10 min, filtered, washed with water (30 mL), and dried under air circulation, yielding methyl 8-bromoindolizine-2-carboxylate.1H NMR (400 MHz, DMSO-d6): δ 8.36 (dt, J = 7.0, 0.8 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 7.15 (dd, J = 7.0, 0.4 Hz, 1H), 6.76 (dd, J = 1.6, 1.0 Hz, 1H), 6.63 (t, J = 7.1 Hz, 1H), 3.81 (s, 3H). MS (ESI) m / z: Calcd. C10H9BrNO2+[M+H]+: 253.98 / 255.98; found: 254.1 / 256.0. Step 3: Methyl 8-bromo-3-((trifluoromethyl)selanyl)indolizine-2-carboxylate

[0153] In a 250 mL round bottom flask was added chlorotrimethylsilane (2.57 g, 3.00 mL, 2 eq, 23.6 mmol) to a suspension of methyl 8-bromoindolizine-2-carboxylate (3.00 g, 1 eq, 11.8 mmol) and 2-((trifluoromethyl)selanyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (3.90 g, 1 eq, 11.8 mmol) in acetonitrile (60.0 mL). The suspension was stirred at RT for 5 min.2- ((trifluoromethyl)selanyl) benzo[d]isothiazol-3(2H)-one 1,1-dioxide) (200 mg, 0.605 mmol) was added after 10 min followed by another addition of 2- ((trifluoromethyl)selanyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide) (200 mg, 0.605 mmol) in 20 - 75 -25972-WO-PCT 12617.0005-00304 min. The mixture was diluted with sat. aq. NaHCO3(100 mL) and EtOAc (100 mL). The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by flash chromatography (dry load, 120 g normal phase column, 0 to 15% of EtOAc in Heptanes) gave methyl 8-bromo-3- ((trifluoromethyl)selanyl)indolizine-2-carboxylate.1H NMR (400 MHz, DMSO-d6): δ 8.64 (d, J = 7.1 Hz, 1H), 7.46 (d, J = 6.7 Hz), 7.10 (d, J = 0.9 Hz), 6.93 (t, J = 7.2 Hz), 3.86 (s).19F NMR (376 MHz, DMSO-d6): δ -36.57 (s, 3F).; MS (ESI) m / z: Calcd. C11H8BrF3NO2Se+[M+H]+: 401.89 / 403.89; found: 402.0 / 404.0. Step 4: (8-Bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)methanol

[0154] In a 500 mL round bottom flask, diisobutylaluminum hydride (10.0 g, 70.3 mL, 1.00 M in THF, 6 eq, 70.3 mmol) was added to a solution of methyl 8-bromo-3- ((trifluoromethyl)selanyl) indolizine-2-carboxylate (4.70 g, 1 eq, 11.7 mmol) in THF (70.5 mL) at -78 °C. The solution was stirred at -78 °C for 5 min, then the reaction was raised to 0 °C and stirred for another 3 h at 0 °C. Water was added slowly to the mixture, followed by addition of sat. aq. Rochelle salt (200 mL) and EtOAc (50 mL). This was stirred at RT overnight. The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4 and concentrated to obtain crude (8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)methanol, which was used without further purification in the next step. MS (ESI) m / z Calcd. C10H8BrF3NOSe+[M+H]+: 373.89 / 375.89; found: 374.1 / 376.1. Step 5: (8-Bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)methanol

[0155] In a 250 mL round bottom flask was added 1-hydroxy-1,2-benziodoxol-3(1H)-one 1- oxide (9.71 g, 3 eq, 34.7 mmol) to a suspension of (8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)methanol (4.31 g, 1 eq, 11.6 mmol) in EtOAc (43.1 mL). The suspension was heated at 80 °C overnight. The mixture was cooled to RT, filtered through diatomaceous earth (CELITE®), washed with EtOAc (3 x 20 mL). The filtrate was concentrated to afford 8-bromo-3-((trifluoromethyl)selanyl)indolizine-2-carbaldehyde used without further purification.1H NMR (400 MHz, DMSO-d6): δ 10.25 (s, 1H), 8.65 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 0.8 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H).;19F NMR (376 MHz, DMSO- d6): δ -37.00 (s, 3F). Step 6: 8-Bromo-2-ethynyl-3-((trifluoromethyl)selanyl)indolizine

[0156] In a 100 mL round bottom flask was added potassium carbonate (1.77 g, 2.5 eq, 12.8 mmol) to a beige suspension of 8-bromo-3-((trifluoromethyl)selanyl)indolizine-2-carbaldehyde - 76 -25972-WO-PCT 12617.0005-00304 (1.90 g, 1 eq, 5.12 mmol) and Bestmann-Ohira reagent (1.48 g, 1.42 mL, 1.5 eq, 7.68 mmol) in MeOH (19.00 mL) at 0 °C. The suspension was stirred at 0 °C for 5 min, then was warmed to RT and stirred for 2 h. The reaction was concentrated under reduced pressure. EtOAc (20 mL), water (10 mL), and aqueous NH4Cl (10 mL) were added. The aqueous and organic layers were separated. The aqueous layer was extracted by EtOAc (2 x 20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain 8-bromo-2-ethynyl-3- ((trifluoromethyl)selanyl)indolizine.1H NMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 7.1 Hz, 1H), 7.41 (dd, J = 7.2, 0.6 Hz, 1H), 6.87 (dd, J = 10.2, 4.0 Hz, 1H), 4.43 (s, 1H).;19F NMR (376 MHz, DMSO-d6): δ -36.65 (s, 3F). Step 7: 3-(8-Bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-ol

[0157] In a 250 mL round bottom flask was added TEA (2.90 g, 3.99 mL, 2.2 eq, 28.6 mmol) to a suspension of zinc(II)trifluoromethanesulphonate (10.4 g, 2.2 eq, 28.6 mmol) and TMEDA (3.33 g, 4.32 mL, 2.2 eq, 28.6 mmol) in toluene (47.8 mL) at RT. The suspension was stirred at RT for 1 h. A solution of 8-bromo-2-ethynyl-3-((trifluoromethyl)selanyl)indolizine (4.78 g, 1 eq, 13.02 mmol) in toluene (4.780 mL) was added to the suspension and was heated at 60 °C for 1 h. Paraformaldehyde (1.17 g, 3 eq, 39.1 mmol) was added, and the solution was heated at 60 °C for 1 h. The mixture was cooled down to RT. EtOAc (100 mL), water (40 mL) and aqueous HCl (1.00 M in H2O, 210 mL) were added. The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4and concentrated. Purification by flash chromatography (120 g normal phase column, 0 to 30% of EtOAc in Heptanes) afforded 3-(8-bromo-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-ol 8.1H NMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 7.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.85 (t, J = 7.1 Hz, 1H), 6.82 (s, 1H), 5.40 (t, J = 6.0 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H);19F NMR (376 MHz, DMSO-d6): δ -36.57 (s, 3F).; LCMS (ESI) m / z: Calcd. C12H8BrF3NOSe+[M+H]+: 397.89; found: 398.1. Step 8: 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine

[0158] In a 250 mL round bottom flask was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.265 g, 1.24 mL, 1.1 eq, 8.31 mmol) to a solution of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin- 2-yl)prop-2-yn-1-ol 8 (3.00 g, 1 eq, 7.56 mmol) and diphenylphosphoryl azide (4.159 g, 3.26 mL, 2 eq, 15.1 mmol) in THF (30.0 mL) at RT. The solution was heated at 60 °C for 2 h. The reaction was cooled to RT. EtOAc (50 mL) and NH4Cl (50 mL) were added. The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (120 g column with 0-10% EtOAc in hexane) to obtain 2-(3- - 77 -25972-WO-PCT 12617.0005-00304 azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine.1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J = 7.1 Hz, 1H), 7.42 (dd, J = 7.2, 0.6 Hz, 1H), 6.91 - 6.84 (m, 2H), 4.46 (s, 2H).;19F NMR (376 MHz, DMSO-d6): δ -36.59 (s, 3F).; MS (ESI) m / z: Calcd. C12H7BrF3N2Se+[M-N2+H]+: 394.89; found: 395.0 Step 9: 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine

[0159] In a 250 mL round bottom flask was added triphenylphosphine (3.107 g, 2.62 mL, 2 eq, 11.8 mmol) to a solution of crude 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3- ((trifluoromethyl)selanyl) indolizine 9 (2.5 g, 1 eq, 5.92 mmol) in a mixture of THF (45.0 mL) and water (5.00 mL) at RT. The solution was heated at 60 °C for 2 h. The solution was concentrated, and the crude residue was co-evaporated with toluene (5 mL x 2) times to remove water. The residue was purified by reverse phase chromatography (iLOK C18120 g, with 2 mL DMSO loading, eluted with 5-70% of ACN in 10 mM AmB) to obtain 3-(8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine.1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 7.1 Hz, 1H), 7.39 (dd, J = 7.2, 0.6 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 6.78 (d, J = 0.8 Hz, 1H), 3.57 (s, 2H).19F NMR (376 MHz, DMSO-d6): δ -36.54 (s, 3F). MS (ESI) m / z: Calcd. C12H6BrF3NSe+[M-NH2]+: 379.88; found: 380.0 Intermediate 27: 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acidStep 1: methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate

[0160] To a solution of methyl 4-amino-3-methoxybenzoate (20 g, 110 mmol) in DMF (200 mL) was added K2CO3 (15.26 g, 110 mmol), 3-bromoprop-1-yne (18.06 g, 121 mmol), and potassium iodide (18.32 g, 110 mmol), the mixture was stirred for 12 h at 80 °C under N2. LCMS showed the starting material was consumed, and the desired mass peak was observed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purfied by C18 flash silica gel chromatography (Eluent of 0 ~ 50% ACN / water gradient @ 80 mL / min) to give methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate. MS (ESI) m / z: calc'd for C12H14NO3+[M+H]+220.1, found 220.1 [M+H]+. Step 2: 3-methoxy-4- 2-yn-1-ylamino)benzoic acid

[0161] To a solution of methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate (6.96 g, 31.7 mmol) in MeOH (60 mL) and water (60 mL) was added lithium hydroxide hydrate (2.66 g, 63.5 mmol) , The mixture was stirred for 2 h at 50 °C. LCMS showed the starting material was consumed and desired mass peak was observed. The resulting mixture was concentrated under - 78 -25972-WO-PCT 12617.0005-00304 reduced pressure to removed MeOH. Then the concentrate was acidified to pH = 6 by 2 N HCl and filtered, and the filter cake was washed by H2O (30 mL). The filter cake was dried to give 3- methoxy-4-(prop-2-yn-1-ylamino)benzoic acid. MS (ESI) m / z: calc'd for C11H12NO3+[M+H]+206.1, found 206.1 [M+H]+. Intermediate 28: tert-butyl (3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)carbamateStep 1: tert-butyl (3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)carbamate

[0162] In a 2 dram vial, N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-1-amine (200 mg, 1 eq, 384 μmol), tert-butyl prop-2-yn-1-ylcarbamate (119 mg, 2 eq, 768 μmol), CuI (14.6 mg, 0.2 eq, 76.8 μmol), and tetrakis(triphenylphosphine) palladium(0) (88.7 mg, 0.2 eq, 76.8 μmol) were dissolved in DMSO (1000 μL). The vial was purged and backfilled with N2 three times. DIPEA (397 mg, 535 μL, 8 eq, 3.07 mmol) was added, and the reaction was allowed to stir at 50 °C for 2 h. After stirring, LCMS showed formation of product. A palladium scavenger was added to the reaction, which was stirred for 30 minutes at RT. After stirring, the reaction material was filtered and diluted further in DMSO. The solution was submitted for NH4 HPLC purification (C18, 19x150, 44-74% MPB). tert-butyl (3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)carbamate. MS (ESI) m / z [M+H]+: 548.1 / 550.1. Step 2: 7-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine

[0163] In a 40 mL vial, tert-butyl (3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)carbamate (200 mg, 1 eq, 365 μmol) was dissolved in DCM (2 mL). TFA (296 mg, 200 μL, 7.12 eq, 2.60 mmol) was added, and the reaction mixture was allowed to stir for 3 hours at RT. After stirring, LCMS showed full formation of product. The reaction was neutralized and extracted with saturated sodium bicarbonate. The organic layer was separated from the aqueous layer through a phase separator. The organic material was concentrated under reduced pressure to afford 7-(3- - 79 -25972-WO-PCT 12617.0005-00304 aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine. MS (ESI) m / z [M+H]+: 448.1 / 450.1. Intermediate 29: tert-butyl (1R,5S,6S)-6-amino-5-fluoro-3-azabicyclo[4.1.0]heptane-3- carboxylate (relative stereochemistry)Step 1: tert-Butyl 4-(dibenzylamino)-3-fluoro-3,6-dihydropyridine-1(2H)-carboxylate

[0164] A 50 ml round bottom flask equipped drying tube containing sodium sulfate under N2 was charged with tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate 1 (2.00 g, 1 eq, 9.21 mmol), PhCH3(20.0 mL), dibenzylamine (1.82 g, 1.77 mL, 1 eq, 9.21 mmol) and heated to a strong reflux (130 °C oil bath) for 24 h (required to achieve full conversion). The mixture was cooled and concentrated under reduced pressure, co-evaporated with heptanes (25 ml, 65 °C water bath temperature) to afford tert-butyl 4-(dibenzylamino)-3-fluoro-3,6-dihydropyridine-1(2H)- carboxylate, which was used directly in the next step.1H NMR (400 MHz, DMSO-d6): δ 7.38 - 7.17 (m, 10H), 5.35 (d, J = 48.8 Hz, 1H), 4.59 (s, 1H), 4.40 - 4.02 (m, 6H), 3.62 - 3.36 (m, 1H), 3.25 - 2.89 (m, 1H), 1.39 (s, 9H).19F NMR (376 MHz, DMSO-d6): δ -168.89 (t, J = 44.6 Hz, 1F). LCMS (ESI) m / z: Calcd. C24H30FN2O2[M+H]+: 397.23; found: 397.4. Step 2: rel-tert-Butyl (1R,5S,6S)-6-(dibenzylamino)-5-fluoro-3-azabicyclo[4.1.0]heptane- 3-carboxylate

[0165] A flame dried 250 ml round bottom flask equipped with an internal temperature probe under N2 was charged with CH2Cl2 (60.0 mL), cooled to 0 °C using an ice bath, and diethylzinc (1.00 M in hexanaes) (1.87 g, 15.1 mL, 1.00 molar, 2 eq, 15.1 mmol) was added. Trifluoroacetic acid (1.73 g, 1.15 mL, 2 eq, 15.1 mmol) in CH2Cl2(10.0 mL) was added dropwise over 12 min (Tint.0.8 to 4 °C). The mixture was stirred at 0 °C for 20 min. Methylene iodide (4.05 g, 1.22 mL, 2 eq, 15.1 mmol) in CH2Cl2 (10.0 mL) was added at 0 °C over 4 min ((Tint.0.8 to 2.5 °C), and the mixture was further stirred for 20 min. tert-Butyl 4-(dibenzylamino)-3-fluoro-3,6- dihydropyridine-1(2H)-carboxylate 2 (3.00 g, 1 eq, 7.57 mmol) in CH2Cl2(10.0 mL) was added at 0 °C over 5 min (Tint.1.1 to 3.5 °C), and the mixture was stirred at 0 °C for 15 min (51% product 3 and 33% bisbenzylamine by LCMS). After 15 min, the mixture was quenched with sat. aq. NaHCO3(50 ml) and stirred for 15 min. The mixture was combined with the same reaction performed on 200 mg scale and filtered over paper. The phases were separated, and the aqueous - 80 -25972-WO-PCT 12617.0005-00304 extracted with CH2Cl2(10 ml). The combined organic layers were dried over sodium sulfate, silica (20 g) was added, and the mixture was concentrated to dryness. The residue was purified by normal phase flash chromatography (100 g SiO2 cartridge, 0 to 20% EtOAc in heptanes over 15 CV) to afford racemic tert-butyl (1R,5S,6S)-6-(dibenzylamino)-5-fluoro-3- azabicyclo[4.1.0]heptane-3-carboxylate.1H NMR (400 MHz, DMSO-d6): δ 7.34 - 7.18 (m, 10H), 5.44 (d, J = 49.9 Hz, 1H), 3.86 (dd, J = 22.2, 11.2 Hz, 1H), 3.78 - 3.57 (m, 5H), 3.05 - 2.83 (m, 1H), 2.72 - 2.52 (m, 1H), 1.35 (s, 9H), 0.88 - 0.77 (m, 1H), 0.57 - 0.50 (m, 1H), 0.49 - 0.38 (m, 1H). Contains 5 wt% CH2Cl2.19F NMR (376 MHz, DMSO-d6): δ -165.97 (d, J = 338.9 Hz, 1F). LCMS (ESI) m / z: Calcd C25H32FN2O2+[M+H]+: 411.24 found 411.4. Step 3: tert-Butyl (1R,5S,6S)-6-amino-5-fluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate (relative stereochemistry)

[0166] A 50 ml round bottom flask was charged with tert-butyl 6-(dibenzylamino)-5-fluoro-3- azabicyclo[4.1.0]heptane-3-carboxylate 3 (620 mg, 1 eq, 1.51 mmol), MeOH (9.30 mL). N2 was bubbled into the mixture for 2 min, and palladium hydroxide (159 mg, 46.2 μL, 20 wt. % Pd / C, wet, 0.15 eq, 227 μmol) was added, degassed with N2 for 5 min. H2 was bubbled into the mixture from a fine needle for 5 min and then vigorously stirred under H2 for 19 h (full conversion by LCMS). The reaction mixture was purged with N2for 2 min and filtered through a syringe filter (large 0.45 um filter), rinsed with MeOH then EtOAc and concentrated to dryness to afford racemic rel-tert-butyl (1R,5S,6S)-6-amino-5-fluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate.1H NMR (400 MHz, DMSO-d6): δ 4.84 (dt, J = 51.4, 4.8 Hz, 1H), 3.47 (d, J = 13.0 Hz, 1H), 3.28 - 3.09 (m, 3H), 2.43 - 2.15 (m, 2H), 1.33 (s, 9H), 1.25 - 1.14 (m, 1H), 0.63 - 0.56 (m, 1H), 0.56 - 0.48 (m, 1H).19F NMR (376 MHz, DMSO-d6): δ -174.05 - -174.85 (m, 1F). Intermediate 30: tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0167] A 40 mL vial was charged with (1R,2R,5R)-tert-butyl 2-amino-8- azabicyclo[3.2.1]octane-8-carboxylate (0.7 g, 1.25 eq, 3 mmol), 7-chloro-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (1 g, 1 eq, 2 mmol), CsF (1 g, 4 eq, 9 mmol), and DMSO (6 mL). The vial was purged with N23 times, and reaction mixture was stirred at 110 - 81 -25972-WO-PCT 12617.0005-00304 °C for 2 h. The reaction mixture then was added dropwise to an beaker containing 20 mL of deionized water. The precipitate was filtered and dried overnight under vaccum to afford the desired product (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7- yl)amino)-8-azabicyclo[3.2.1] octane-8-carboxylate. MS (EI) calc'd for C20H24F3IN4O2Se [M+H]+, 616; found 616. Intermediate 31: N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0168] A 40 mL vial was charged with tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (150 mg, 1 eq, 244 μmol) was taken up in DCM (4.88 mL) and TFA (139 mg, 93.9 μL, 5 eq, 1.22 mmol) was added. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure to afford N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2- iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine as a TFA salt. MS (EI) calc'd for C15H16F3IN4Se[M+H]+, 516; found 516.

[0169] Each of the intermediates presented in Table 4 below were prepared in accordance with the synthetic route demonstrated for N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine, using procedures analogous to those described above.- 82 -25972-WO-PCT 12617.0005-00304Intermediate 35: N-(3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0170] A 40 mL vial was charged with ethane, 2-bromo-1,1-difluoro- (43.4 mg, 23.8 μL, 1.5 eq, 299 μmol), N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (100 mg, 1 eq, 200 μmol), potassium carbonate (110 mg, 4 eq, 798 μmol), MeCN (998 μL), and DIEA (38.7 mg, 52.1 μL, 1.5 eq, 299 μmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched by adding sat. ammonium chloride, and the desired product was extracted with DCM. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to afford the crude reaction mixture. The crude product was diluted to 4 mL in 1:1 MeOH DMSO and was subjected to mass directed reverse phase purification by HPLC, using acetonitrile / water gradient with base modifier linear gradient to afford N-(3-(2,2-difluoroethyl)-3- azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (Peak 1, MS (EI) calc'd for C16H16F5IN4Se [M+H]+, 516; found 516) and N-(3-(2,2- - 83 -25972-WO-PCT 12617.0005-00304 difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-amine (Peak 2, MS (EI) calc'd for C15H16F3IN4Se[M+H]+, 516; found 516. Intermediate 36: 2-iodo-N-(3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0171] A 40 mL vial was charged with oxetan-3-one (97.1 mg, 78.9 μL, 3 eq, 1.35 mmol), N- (3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7- amine (225 mg, 1 eq, 449 μmol), activated molecular sieves, and DCE (2.24 mL). Acetic acid (78.7 mg, 75.0 μL, 2.92 eq, 1.31 mmol) was added, and the reaction vial was purged with N23 times. The reaction mixture was stirred for 30 min at 50 °C. Sodium cyanoborohydride (113 mg, 4 eq, 1.80 mmol) was added, and the reaction mixture was stirred for an additional 3 h at 50 °C. The reaction mixture was quenched by adding sat. ammonium chloride, and the desired product was extracted with DCM. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to afford the crude reaction mixture. The crude product was diluted to 4 mL in 1:1 MeOH DMSO and was purified by mass directed reverse phase purification by HPLC, using acetonitrile / water gradient with base modifier linear gradient to afford 2-iodo-N-(3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (107.2 mg, 192.4 μmol, 42.9 %) as a mixture of isomers. Chiral SFC afforded 2-iodo-N-(3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (Peak 1) and 2-iodo-N-(3- (oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl) selanyl)pyrazolo[1,5- a]pyridin-7-amine (Peak 2). MS (EI) calc'd for Peak 1, C17H18F3IN4OSe [M+H]+, 559; found 559. MS (EI) calc'd for Peak 2, C17H18F3IN4OSe [M+H]+, 559; found 559. Intermediate 37: 3-(6-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)oxetane-3-carbonitrile- 84 -25972-WO-PCT 12617.0005-00304

[0172] A 40 mL vial was charged with N-(3-azabicyclo[4.1.0]heptan-6-yl)-7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (250 mg, 1 eq, 296 μmol). The vial was purged three times with argon. DCE (1.48 mL) was added under positive flow of N2 along with oxetan-3-one (53.4 mg, 47.5 μL, 2.5 Eq, 741 μmol). Acetic acid (21.4 mg, 20.4 μL, 1.2 eq, 356 μmol) was added, and the vial was stirred at 50 °C for 30 min after which trimethylsilyl cyanide (35.3 mg, 44.5 μL, 1.2 eq, 356 μmol) was added. The reaction vessel was stirred at 50 °C for another 2 h. The reaction mixture was extracted with DCM and 1M NaOH. The organic phases were combined, dried using magensium sulfate, and concentrated. The crude product was diluted to 4 mL in 1:1 MeOH DMSO and was purified by mass directed reverse phase purification by HPLC, using acetonitrile / water gradient with base modifier linear gradient to afford 3-(6-((7- iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-azabicyclo[4.1.0]heptan-3- yl)oxetane-3-carbonitrile (92.4 mg, 159 μmol, 53.5 %) as a mixture of isomers, which was subjected for chiral SFC purification, affording 3-(6-((7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-yl)amino)-3-azabicyclo[4.1.0]heptan-3- yl)oxetane-3-carbonitrile (Peak 1) and 3-(6-((7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-1-yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)oxetane-3-carbonitrile (Peak 2). MS (EI) calc'd for Peak 1, C18H17F3IN5OSe [M+H]+, 559; found 559. MS (EI) calc'd for Peak 2, C18H17F3IN5OSe [M+H]+, 584; found 584.

[0173] Each of the intermediates presented in Table 5 below were prepared in accordance with the synthetic route demonstrated for 3-(6-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)oxetane-3-carbonitrile, using procedures analogous to those described above.- 85 -25972-WO-PCT 12617.0005-00304- 86 -25972-WO-PCT 12617.0005-00304 EXAMPLES Example 1: N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamideStep 1: N-(3-(7-chloro-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn- 1-yl)cyclopropanecarboxamide

[0174] A stirred mixture of 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridine (50 mg, 0.118 mmol), Pd(PPh3)4(16.30 mg, 0.014 mmol), CuI (8.95 mg, 0.047 mmol), and DIPA (0.148 mL, 1.058 mmol) in DMSO (0.5 mL) was added a solution of N-(prop- 2-yn-1-yl)cyclopropanecarboxamide (14.47 mg, 0.118 mmol) in DMSO (0.5 mL) dropwise under N2, the mixture was stirred at 25°C for 10 min. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: ethyl acetate / petroleum ether = 1 / 0, v / v) to give N-(3-(7-chloro-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide. MS (ESI) m / z: calc’d for C15H12ClF3N3OSe+[M+H]+: 422.1 / 424.1, found: 422.0 / 424.0 [M+H]+, tR=0.719 min. Step 2: N-(3-(7-(( -3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide

[0175] A mixture of (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (25.1 mg, 0.190 mmol), Cs2CO3 (93 mg, 0.285 mmol), N-(3-(7-chloro-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide (40 mg, 0.095 mmol) and Pd PEPPSI- HeptCl (18.52 mg, 0.019 mmol) in dioxane (2 mL) was degassed and backfilled with N2(three - 87 -25972-WO-PCT 12617.0005-00304 times). The mixture was heated to 100°C for 1 h. After cooling to RT, the mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by Prep-HPLC to give N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide. MS (ESI) m / z: calc’d for C21H24F4N5OSe+[M+H]+: 518.1, found: 518.1 [M+H]+, tR=0.638 min.1H NMR (400 MHz, CDCl3) δ = 7.33 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.27 (br d, J = 9.1 Hz, 1H), 6.03 (d, J = 7.5 Hz, 1H), 5.90 (br s, 1H), 4.97 - 4.80 (m, 1H), 4.44 (d, J = 5.0 Hz, 2H), 3.71 - 3.54 (m, 1H), 3.30 - 3.19 (m, 1H), 3.01 - 2.90 (m, 1H), 2.42 - 2.26 (m, 5H), 2.26 - 2.18 (m, 1H), 2.17 - 2.06 (m, 1H), 2.03 (br dd, J = 3.0, 7.9 Hz, 1H), 1.06 - 1.00 (m, 2H), 0.83 - 0.74 (m, 2H). Example 2: 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamideStep 1: N-(3-(7-chloro-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn- 1-yl)-1-cyclopropyl-1H-pyrazole-4-carboxamide

[0176] To a mixture of 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (100 mg, 0.235 mmol), CuI (17.91 mg, 0.094 mmol), Pd(Ph3P)4(40.7 mg, 0.035 mmol), and DIPA (0.296 mL, 2.115 mmol) in DMSO (2 mL) was added 1-cyclopropyl-N-(prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (53.4 mg, 0.282 mmol) at 20°C. The resulting mixture was stirred at 40°C for 1 h under N2. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (eluent: ethyl acetate / petroleum ether = 1 / 0, v / v) to give N-(3-(7-chloro-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H- - 88 -25972-WO-PCT 12617.0005-00304 pyrazole-4-carboxamide. MS (ESI) m / z: calc’d for C18H14ClF3N5OSe+[M+H]+: 488.1 / 490.1, found: 488.0 / 490.0 [M+H]+, tR=0.754 min. Step 2: 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide

[0177] To a mixture of N-(3-(7-chloro-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4-carboxamide (30 mg, 0.062 mmol), (3S,4R)-3- fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine (15.08 mg, 0.080 mmol), and Cs2CO3 (60.2 mg, 0.185 mmol) in 1,4-dioxane (0.5 mL) was added PEPPSI-HeptCl-Pd (6.00 mg, 6.16 µmol) at 20°C under N2. The resulting mixture was stirred at 90°C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide. MS (ESI) m / z: calc’d for C27H30F4N7O2Se+[M+H]+: 640.1, found: 640.2 [M+H]+, tR= 0.721 min.1H NMR (400 MHz, CDCl3) δ = 7.95 (s, 1H), 7.76 (s, 1H), 7.33 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.27 (br d, J = 8.9 Hz, 1H), 6.04 (br d, J = 7.6 Hz, 2H), 4.97 - 4.81 (m, 1H), 4.64 (dd, J = 5.5, 12.3 Hz, 2H), 4.57 (d, J = 5.1 Hz, 2H), 4.24 (t, J = 6.0 Hz, 2H), 3.74 - 3.60 (m, 2H), 2.96 - 2.87 (m, 1H), 2.69 - 2.62 (m, 1H), 2.54 - 2.41 (m, 1H), 2.36 - 2.27 (m, 1H), 2.13 - 2.03 (m, 2H), 1.42 (s, 3H), 1.18 - 1.13 (m, 2H), 1.11 - 1.04 (m, 2H). Example 3: N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide

[0178] A mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine (30 mg, 0.058 mmol), N-(prop-2-yn-1-yl)acetamide - 89 -25972-WO-PCT 12617.0005-00304 (6.71 mg, 0.069 mmol), CuI (4.39 mg, 0.023 mmol), Pd(Ph3P)4(6.65 mg, 5.76 µmol), and DIPA (0.081 mL, 0.576 mmol) in DMSO (1 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 2 h. After cooling to RT, the mixture was filtered, and the filtrate was purified by Prep-HPLC to give N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide. MS (ESI) m / z: calc’d for C19H22F4N5OSe+[M+H]+: 490.1 / 492.1, found: 490.1 / 492.1, tR=1.309 min.1H NMR (MeOD, 400 MHz): δ (ppm) 7.43 (t, J = 8.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 4.99 (br s, 1H), 4.29 (s, 2H), 3.79-3.97 (m, 1H), 3.21-3.27 (m, 1H), 2.95 (br d, J = 11.3 Hz, 1H), 2.37-2.52 (m, 1H), 2.28-2.36 (m, 4H), 2.01-2.08 (m, 2H), 2.00 (s, 3H). Example 4: 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide

[0179] A mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine (30 mg, 0.058 mmol), 1-cyclopropyl-N-(prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (21.78 mg, 0.115 mmol), CuI (4.39 mg, 0.023 mmol), Pd(Ph3P)4(6.65 mg, 5.76 µmol), DIPA (0.081 mL, 0.576 mmol) in DMSO (1 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 2 h. After cooling to RT, the mixture was filtered, and the filtrate was purified by Prep-HPLC to give 1-cyclopropyl-N-(3- (7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc’d for C24H26F4N7OSe+[M+H]+: 582.1 / 584.1, found: 582.1 / 584.1, tR=1.381 min.1H NMR (MeOD, 400 MHz): δ (ppm) 8.17 (s, 1H), 7.90 (s, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 7.7 Hz, 1H), 4.90-5.01 (m, 1H), 4.44 (s, 2H), 3.80-3.95 (m, 1H), 3.68-3.75 (m, 1H), 3.20- 3.25 (m, 1H), 2.89-2.99 (m, 1H), 2.37-2.52 (m, 1H), 2.33 (s, 3H), 2.27-2.32 (m, 1H), 2.00-2.07 (m, 2H), 1.12 (t, J = 4.2 Hz, 2H), 1.04-1.10 (m, 2H). - 90 -25972-WO-PCT 12617.0005-00304 Example 5: 1-(tert-butyl)-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide

[0180] A mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine (30 mg, 0.058 mmol), 1-(tert-butyl)-N-(prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (14.18 mg, 0.069 mmol), CuI (4.39 mg, 0.023 mmol), Pd(Ph3P)4 (6.65 mg, 5.76 µmol), and DIPA (0.081 mL, 0.576 mmol) in DMSO (1 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 1-(tert-butyl)-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide. MS (ESI) m / z: calc’d for C25H30F4N7OSe+[M+H]+: 598.1 / 600.1, found: 598.1 / 600.1, tR=1.453 min.1H NMR (MeOD, 400 MHz): δ (ppm) 8.27 (s, 1H), 7.95 (s, 1H), 7.42 (t, J = 8.3 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.98 (br s, 1H), 4.45 (s, 2H), 3.80-3.95 (m, 1H), 3.20-3.27 (m, 1H), 2.94 (br d, J = 9.9 Hz, 1H), 2.36-2.51 (m, 1H), 2.27- 2.35 (m, 4H), 2.00-2.08 (m, 2H), 1.61 (s, 9H). Example 6: 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide

[0181] A mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine (30 mg, 0.058 mmol), 3-methoxy-N-methyl-4-(prop-2- yn-1-ylamino)benzamide (15.08 mg, 0.069 mmol), CuI (4.39 mg, 0.023 mmol), Pd(Ph3P)4(6.65 mg, 5.76 µmol), and DIPA (0.081 mL, 0.576 mmol) in DMSO (1 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 2 h. The mixture was filtered, and the filtrate was purified by Prep-HPLC to give 4-((3-(7-(((3S,4R)-3-fluoro-1- - 91 -25972-WO-PCT 12617.0005-00304 methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn- 1-yl)amino)-3-methoxy-N-methylbenzamide. MS (ESI) m / z: calc’d for C26H29F4N6O2Se+[M+H]+: 611.2 / 613.2, found: 611.1 / 613.2, tR=1.433 min.1H NMR (MeOD, 400 MHz): δ (ppm) 7.38-7.45 (m, 2H), 7.35 (s, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.26-6.33 (m, 1H), 4.91-4.99 (m, 1H), 4.36 (s, 2H), 3.92 (s, 3H), 3.78-3.89 (m, 1H), 3.20-3.25 (m, 1H), 2.90 (s, 4H), 2.35-2.50 (m, 1H), 2.25-2.35 (m, 4H), 1.98-2.06 (m, 2H). Example 7: N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0182] In a 25 mL flask containing N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (60 mg, 0.12 mmol) were added 1- methyl-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (21 mg, 0.13 mmol), CuI (8.8 mg, 46 μmol), and Pd(PPh3)4 (6.7 mg, 5.8 μmol), followed by DMSO (2 mL). After 3 min stirring, to the solution, was added DIPA (0.10 g, 0.15 mL, 1.0 mmol). The reaction was stirred at RT for 30 min. LCMS showed completion. The reaction mixture was directly purified by reverse-phase chromatography (40 g column, 5% to 100% MeCN in 10 mM ammonium bicarbonate, product came off with 60% MeCN). The corresponding fractions were combined, reduced under vacuum to remove most of the MeCN, and freeze-dried overnight to afford the pre-purified product contaminated with triphenylphosphine oxide. This fraction was submitted to Prep HPLC. The corresponding fractions were combined, reduced under vacuum to remove most of the MeCN, and freeze-dried overnight to afford N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide. LCMS (ESI) m / z: Calcd. C22H23F4N7OSe [M+H]+: 558.1; found: 558.3.1H NMR (400 MHz, DMSO-d6) δ 8.72 (t, J = 5.5 Hz, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.47 (t, J = 8.2 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 6.48 (brs, 1H), 4.88 (d, J = 49.7 Hz, 1H), 4.36 (d, J = 5.7 Hz, 2H), 3.95 – 3.80 (m, 1H), 3.86 (s, 3H), 3.05 (t, J = 11.0 Hz, 1H), 2.79 (d, J = 10.2 Hz, 1H), 2.28 (dd, J = 39.7, 14.2 Hz, 1H), 2.20 (s, 3H), 2.13 (t, J = 11.2 Hz, 1H), 2.04 – - 92 -25972-WO-PCT 12617.0005-00304 1.93 (m, 1H), 1.82 (d, J = 9.0 Hz, 1H). Isolated as HCOOH salt.19F NMR (376 MHz, DMSO- d6) δ -37.15 (s, 3F), -198.75 – -199.82 (m, 1F). Example 8: N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methylthiazole-5-carboxamide

[0183] In a microwave vial containing N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (25 mg, 48 μmol) were added 2- methyl-N-(prop-2-yn-1-yl)thiazole-5-carboxamide (9.5 mg, 53 μmol), CuI (3.7 mg, 19 μmol), and Pd(PPh3)4(2.8 mg, 2.4 μmol), followed by DMSO (1.0 mL). After 3 min stirring, to the solution, was added DIPA (44 mg, 61 μL, 0.43 mmol). The reaction was stirred at RT for 1 h. Additional Pd(PPh3)4 (55 mg, 48 μmol) and 2-methyl-N-(prop-2-yn-1-yl)thiazole-5-carboxamide (4.3 mg, 24 μmol) were added to the reaction mixture and stirred for an additional 1 h at RT. The reaction mixture was directly loaded to a C18 column and was purified by flash column chromatography (C18, 25 g, eluent of 5% to 100% MeCN / 10 mM AmB gradient @ 25 mL / min). The fractions containing the desired product were combined, and lyophilized overnight to afford N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2-methylthiazole-5- carboxamide. LCMS (ESI) m / z: Calcd. C22H23F4N6OSSe [M+H]+: 575.1; found: 575.3.1H NMR (400 MHz, DMSO-d6) δ 9.26 (t, J = 5.5 Hz, 1H), 8.25 (s, 1H), 7.48 (t, J = 8.2 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.55 – 6.42 (m, 2H), 4.88 (d, J = 49.1 Hz, 1H), 4.40 (d, J = 5.5 Hz, 2H), 3.97 – 3.78 (m, 1H), 3.06 (t, J = 11.2 Hz, 1H), 2.79 (d, J = 10.8 Hz, 1H), 2.68 (s, 3H), 2.28 (dd, J = 38.6, 13.3 Hz, 1H), 2.20 (s, 3H), 2.12 (t, J = 10.8 Hz, 1H), 1.98 (q, J = 12.1 Hz), 1.88 – 1.75 (m).19F NMR (376 MHz, DMSO-d6) δ -37.15 (s, 3F), -199.41 (s, 1F). - 93 -25972-WO-PCT 12617.0005-00304 Exampe 9: N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamideStep 1: N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide

[0184] A mixture of 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (60 mg, 0.141 mmol), N-(prop-2-yn-1-yl)acetamide (16.44 mg, 0.169 mmol), CuI (10.74 mg, 0.056 mmol), Pd(Ph3P)4 (16.30 mg, 0.014 mmol), and DIPA (0.198 mL, 1.410 mmol) in DMSO (1 mL) was degassed and backfilled with N2(three times). The mixture was heated to 25°C for 2 h. After cooling to RT, the reaction mixture was quenched with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep TLC (eluent: EtOAc = 100, v / v) to give N-(3-(7-chloro-3- ((trifluoromethyl)selanyl)pyrazolo [1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide. MS (ESI) m / z: calc'd for C13H10ClF3N3OSe+[M+H]+: 394.0 / 396.0 / 398.0, found: 393.9 / 395.9 / 397.9, tR=0.727 min. Step 2: N-(3-(7-chloro-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn- 1-yl)acetamide

[0185] A mixture of N-(3-(7-chloro-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)acetamide (16 mg, 0.041 mmol), (3S,4R)-3-fluoro-1-(3-methyloxetan-3- yl)piperidin-4-amine (11.45 mg, 0.061 mmol), PEPPSI-HeptCl-Pd (5.92 mg, 6.08 µmol), and Cs2CO3(39.6 mg, 0.122 mmol) in dioxane (1 mL) was degassed and backfilled with N2(three times). The mixture was heated to 100°C for 1 h. After cooling to RT, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC to give N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide. MS (ESI) m / z: calc'd for C22H26F4N5O2Se+[M+H]+: 548.0, found: 548.0, tR=1.407 min.1H NMR (MeOD, 400 MHz): δ (ppm) 7.42 (t, J = 8.2 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 7.4 Hz, 1H), 4.98 (br s, 1H), 4.64 (br d, J = 5.6 Hz, 1H), 4.58 (br d, J = 5.7 Hz, 1H), 4.30 (s, 2H), 4.26 (dd, J = 5.5, - 94 -25972-WO-PCT 12617.0005-00304 1.7 Hz, 2H), 3.80-3.95 (m, 1H), 2.88-3.00 (m, 1H), 2.63-2.70 (m, 1H), 2.47-2.61 (m, 1H), 2.33- 2.44 (m, 1H), 1.93-2.08 (m, 5H), 1.42 (s, 3H). Examples 10 (peak 1) and Example 11 (peak 2): 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)amino)benzamide (separated diastereomers)Step 1: 4-((3-(1-chloro-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn- 1-yl)amino)-3-methoxy-N-methylbenzamide

[0186] A mixture of diisopropylamine (0.889 mL, 6.35 mmol), 3-methoxy-N-methyl-4-(prop-2- yn-1-ylamino)benzamide (200 mg, 0.917 mmol), CuI (53.7 mg, 0.282 mmol), Pd(PPh3)4 (122 mg, 0.106 mmol), and 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine (300 mg, 0.705 mmol) in DMSO (2.5 mL) was stirred at 25°C for 1 h under N2atmosphere. The reaction was diluted with water (10 mL), extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography to afford 4-((3-(1- chloro-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy- N-methylbenzamide. MS (ESI) m / z: calc'd for C20H17ClF3N4O2Se+[M+H]+516.9 / 518.9, found [M+H]+516.9 / 518.9, tR= 0.956 min. Step 2: 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide

[0187] A mixture of 4-((3-(1-chloro-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (130 mg, 0.252 mmol), 3-methyl-3- azabicyclo [4.1.0]heptan-6-amine (50.9 mg, 0.403 mmol), N-ethyl-N-isopropylpropan-2-amine (0.660 mL, 3.78 mmol), and CsF (153 mg, 1.008 mmol) in DMSO (1 mL) was stirred at 60°C for 6 h. The reaction mixture was cooled to RT, diluted with water (6 mL), and extracted with EtOAc (6 mL x 3). The combined organic layers were washed with brine (10 mL x 2) and dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel - 95 -25972-WO-PCT 12617.0005-00304 chromatography (eluent: 20% MeOH gradient @ 30 mL / min) to afford 3-methoxy-N-methyl-4- ((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc'd for C27H29F3N6O2Se [M+H]+: 607.0, found: 607.0 [M+H]+. tR= 0.761 min. Step 3: 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide

[0188] The 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide (45 mg, 0.074 mmol) was separated by Prep-SFC to give peak 1, which was further purified by Prep- HPLC to give 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide (Isomer 1, tR = 1.291 min, ee =100%), and peak 2, which was further purified by Prep-HPLC to give 3- methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide (Isomer 2, tR = 1.949 min, ee =97.24%).

[0189] Isomer 1: MS (ESI) m / z: calc'd for C27H29F3N6O2Se [M+H]+: 607.1, found: 607.1 [M+H]+. tR= 1.307 min.1H NMR (400 MHz, MeOD) δ = 7.66 (d, J = 5.0 Hz, 1H), 7.41 (dd, J = 1.9, 8.2 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.21 (d, J = 5.0 Hz, 1H), 6.94 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.27 (s, 2H), 3.90 (s, 3H), 2.96 - 2.85 (m, 4H), 2.60 (d, J = 11.9 Hz, 1H), 2.41 (br d, J = 8.2 Hz, 2H), 2.31 - 2.16 (m, 4H), 2.09 - 1.99 (m, 1H), 1.48 - 1.28 (m, 1H), 1.00 (dd, J = 5.2, 9.5 Hz, 1H), 0.91 - 0.82 (m, 1H).

[0190] Isomer 2: MS (ESI) m / z: calc'd for C27H29F3N6O2Se [M+H]+: 607.1, found: 607.1 [M+H]+. tR = 1.307 min.1H NMR (400 MHz, MeOD) δ = 7.67 (d, J = 5.0 Hz, 1H), 7.41 (dd, J = 1.9, 8.2 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.95 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.28 (s, 2H), 3.90 (s, 3H), 2.96 - 2.85 (m, 4H), 2.61 (br d, J = 11.7 Hz, 1H), 2.49 - 2.37 (m, 2H), 2.30 - 2.20 (m, 4H), 2.12 - 2.00 (m, 1H), 1.40 - 1.28 (m, 1H), 1.00 (dd, J = 5.1, 9.9 Hz, 1H), 0.91 - 0.85 (m, 1H). Example 12: N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide- 96 -25972-WO-PCT 12617.0005-00304

[0191] A mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-1-amine (25 mg, 1.0 eq, 48 μmol), 1-methyl-N-(prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (8.6 mg, 1.1 eq, 53 μmol), and CuI (3.7 mg, 0.4 eq, 19 μmol) was degassed and purged with N2. Pd(PPh3)4(2.8 mg, 0.05 eq, 2.4 μmol) in DMSO (1.0 mL) was added, and the mixture was stirred for 3 min. DIPA (44 mg, 61 μL, 9 eq, 0.43 mmol) was added to this mixture, and the mixture was stirred at 23 °C for 20 h. The reaction mixture was directly purified by reverse-phase chromatography (40 g column, 5% to 90% MeCN in 10 mM ammonium bicarbonate) to obtain N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide.1H NMR (400 MHz, DMSO-d6): δ 8.65 (t, J = 5.6 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.45 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 4.9 Hz, 1H), 4.88 (d, J = 49.7 Hz, 1H), 4.29 (d, J = 5.7 Hz, 2H), 4.25 - 4.15 (m, 1H), 3.85 (s, 3H), 3.09 (s, 1H), 2.88 (s, 1H), 2.32 - 1.94 (m, 6H), 1.75 - 1.65 (m, 1H);19F NMR (376 MHz, DMSO-d6): δ - 36.29 (s, 3F), -198.02 - -198.99 (m, 1F). MS (ESI) m / z: Calcd. C22H24F4N7OSe+[M+H]+: 558.114; found: 558.3.

[0192] Each of the elaborated compounds presented in Table 6 below were prepared in accordance with the synthetic routes described for N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin- 4-yl)amino)-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-methyl- 1H-pyrazole-4-carboxamide, using procedures analogous to those described above.- 97 -25972-WO-PCT 12617.0005-00304 Example 15: 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide

[0193] A mixture of CuI (0.146 g, 0.768 mmol), DIPA (2.420 mL, 17.27 mmol), Pd(PPh3)4(0.333 g, 0.288 mmol), N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine (1 g, 1.919 mmol), and 3-methoxy-N- methyl-4-(prop-2-yn-1-ylamino)benzamide (0.419 g, 1.919 mmol) in DMSO (5 mL) was stirred at 25 °C for 1 h under N2atmosphere. LCMS showed desired mass. The reaction was diluted with water (10 mL), extracted with DCM (10 mL*3). The combined organic layers were washed with brine (20 mL*2) and dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 10% MeOH gradient @ 30 mL / min) to give give the crude product (1300 mg). The crude product (1300mg) was purified by Prep HPLC (Column WEPURE XP-C1810u 40*150mm Condition water (10mM-NH4HCO3)-ACN Begin B 35 End B 65 Gradient Time (min) 11100%B Hold Time 3 Flow Rate (mL / min) 50) to give the crude product (640 mg). The crude product (640 mg) was crystallized with MTBE (6 mL) and MeCN (1 mL). The mixture was stirred at RT for 24 h under 220 speed. The resulting product was filtered, rinsed with MTBE, and collected to give 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide. MS (ESI) m / z: calc'd for C26H29F4N6O2Se+[M+H]+613.1, found [M+H]+613.1.1H NMR (400 MHz, MeOD-d4) δ = 7.69 (d, J = 5.0 Hz, 1H), 7.43 (dd, J = 1.9, 8.3 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 4.94 (br s, 0.5H), 4.82 (br s, 0.5H), 4.30 (s, 2H), 4.27 - 4.13 (m, 1H), 3.92 (s, 3H), 3.25 - 3.16 (m, 1H), 2.97 (br dd, J = 2.3, 10.9 Hz, 1H), 2.90 (s, 3H), 2.44 - 2.33 (m, 1H), 2.31 (s, 3H), 2.29 - 2.12 (m, 2H), 1.87 - 1.80 (m, 1H). - 98 -25972-WO-PCT 12617.0005-00304 Example 16: 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide

[0194] A degassed mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (17 mg, 1 eq, 33 μmol), 4-methoxy-N- methyl-3-(prop-2-yn-1-ylamino)benzamide (11 mg, 1.5 eq, 49 μmol), CuI (3.1 mg, 0.55 μL, 0.5 eq, 16 μmol), and bis-(triphenylphosphino)-palladous chloride (1.1 mg, 0.05 eq, 1.6 μmol) in THF (0.5 mL) was stirred for 3 min. To the mixture was added DIPA (30 mg, 41 μL, 9 eq, 0.29 mmol). The reaction was stirred at 23 °C for 1 h. The reaction mixture was directly purified by reverse-phase chromatography (40 g column, 5% to 90% MeCN in 10 mM ammonium bicarbonate) to obtain 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide.1H NMR (400 MHz, DMSO-d6): δ 8.16 - 8.11 (m, 1H), 7.62 (d, J = 4.7 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 7.0 Hz, 1H), 7.25 - 7.23 (m, 2H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.52 (t, J = 6.3 Hz, 1H), 4.93 - 4.81 (m, 1H), 4.26 - 4.11 (m, 3H), 3.83 (s, 3H), 3.15 - 3.08 (m, 1H), 2.90 - 2.84 (m, 1H), 2.76 (d, J = 7.5 Hz, 3H), 2.34 - 1.90 (m, 6H), 1.68 - 3.08 (m, 1H).19F NMR (376 MHz, DMSO-d6): δ -35.78 - -37.52 (m, 3F), -197.73 - - 199.42 (m, 1F). LCMS (ESI) m / z: Calcd. C26H29F4N6O2Se+[M+H]+: 613.1; found: 613.4. Example 17: 1-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide

[0195] A flame dried 25 mL round bottom flask was charged with 7-iodo-N-((1R,2R,5R)-8- methyl-8-azabicyclo[3.2.1]octan-2-yl)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (30 mg, 1 eq, 57 μmol), and THF (1.00 mL) was added. The mixture was purged with N2for 10 - 99 -25972-WO-PCT 12617.0005-00304 min. Bis-(triphenylphosphino)-palladium chloride (2.0 mg, 0.05 eq, 2.8 μmol), CuI (2.2 mg, 0.2 eq, 11 μmol), and 1-methyl-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (11 mg, 1.2 eq, 68 μmol) were added and purging with N2 was continued for 3 more min. DIPA (52 mg, 72 μL, 9 eq, 0.51 mmol) was added, and the reaction was stir at 25 °C until full consumption of starting material. THF was removed in vacuo, and directly loaded on column. Reverse phase purification (C18 i-LOK 25 g cartridge, with 0-100% 10 mM AmB / MeCN as eluents) afforded the 1-methyl- N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide.1H NMR (400 MHz, CD3CN) δ 7.89 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 4.6 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.02 (d, J = 21.5 Hz, 1H), 7.00 (s, 1H), 5.58 (d, J = 6.9 Hz, 1H), 4.32 (d, J = 5.6 H, 3Hz), 3.86 (s, 3H), 3.36 (s, 1H), 3.15 (s, 1H), 2.19 (s, 2H, merging with water peak), 2.12 - 1.99 (m, 2H), 1.86 - 1.72 (m, 4H), 1.58 - 1.47 (m, 3H).19F NMR (376 MHz, CD3CN) δ -37.34 (s, 3F). MS (ESI) m / z: calc'd for C24H27F3IN7OSe+[M+H]+: 566.14 found: 566.4. Example 18: 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan- 2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide

[0196] To a dry 25 mL round bottom flask was charged with 7-iodo-N-((1R,2R,5R)-8-methyl- 8-azabicyclo[3.2.1]octan-2-yl)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (50 mg, 1 eq, 94 μmol) and THF (1.5 mL). The solution was purged with N2 for 10 min. Bis- (triphenylphosphino)-palladous chloride (3.3 mg, 0.05 eq, 4.7 μmol), CuI (3.6 mg, 0.2 eq, 19 μmol), and 4-methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (25 mg, 1.2 eq, 0.11 mmol) were added. The mixture was purged with N2 for 3 min, and DIPA (86 mg, 0.12 mL, 9 eq, 0.85 mmol) was added. The reaction was stirred at 23 °C until full consumption of starting material. The reaction mixture was then diluted by EtOAc (5 mL) and a saturated solution of NaHCO3(3 mL) and transferred to separating funnel. The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Reverse phase purification (C18 i- LOK, 25 g cartridge, with 0-100% 10 mM ammonium bicarbonate / MeCN as eluents) afforded 4- methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- - 100 -25972-WO-PCT 12617.0005-00304 ((trifluoromethyl)selanyl) pyrrolo [1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide.1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.6 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J = 4.7 Hz, 2H), 7.15 (dt, J = 8.0, 4.0 Hz, 1H), 6.87 (d, J = 8.2 Hz, 2H), 5.52 (t, J = 6.4 Hz, 1H), 4.24 (t, J = 13.2 Hz, 2H), 4.19 (s, 1H), 3.83 (s, 3H), 3.14 (d, J = 16.7 Hz, 1H), 3.01 (d, J = 5.9 Hz, 1H), 2.75 (d, J = 4.4 Hz, 3H), 2.15 (s, 3H), 2.04 - 1.86 (m, 1H), 1.83 - 1.19 (m, 7H).19F NMR (376 MHz, DMSO-d6) δ -36.44 (s, 3F). MS (ESI) m / z: calc'd for C28H32F3N6O2Se+[M+H]+: 621.17 found: 621.4. Example 19 and Example 20: 2-methyl-N-(3-(1-(((1R,6R or 1S,6S)-3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)thiazole-5-carboxamide (Peak 1) and 2-methyl-N-(3-(1-(((1R,6R or 1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5-carboxamide (Peak 2)Step 1: rac-2-methyl-N-(3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide

[0197] A solution of 7-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-1-amine (90 mg, 0.17 mmol), 2-methyl-N-(prop-2-yn-1- yl)thiazole-5-carboxamide (38 mg, 0.21 mmol), bis-(triphenylphosphino)-palladous chloride (6.1 mg, 8.7 μmol), and CuI (6.7 mg, 35 μmol) in THF (3 ml) was degassed (N2sparging) for 5 min, then DIPA (0.22 mL, 1.6 mmol) was added. The reaction mixture was stirred at RT for 3 h. The reaction mixture was reduced to dryness, and the crude product was suspended in CH2Cl2 (25 mL), washed with saturated NH4Cl (~20 mL), dried (Na2SO4), and reduced to afford the crude product. The crude product was purified by reverse-phase chromatography (40 g colum, 5% to 100% MeCN in 10 mM ammonium bicarbonate) to afford rac-2-methyl-N-(3-(1-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)thiazole-5-carboxamide. Step 2: SFC separation of isomers

[0198] rac-2-Methyl-N-(3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5-carboxamide (31 - 101 -25972-WO-PCT 12617.0005-00304 mg) was separated by SFC Prep 15 Auto-Purification System (Lux i‐Amylose‐1 LC, 5 μm, 10 x 250 mm, Stationary phase: Amylose tris(3,5‐dimethylphenylcarbamate); Mobile phase: 50% IPA + 0.1% NH4OH+50% supercritical CO2, 10 mL / min, 150 Bar, 40°C; run time = 13 min) to afford 2-methyl-N-(3-(1-(((1R,6R or 1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5-carboxamide (Peak 1) and 2-methyl-N-(3-(1-(((1R,6R or 1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide (peak 2).

[0199] Peak 1:1H NMR (400 MHz, DMSO-d6) δ 9.20 (t, J = 5.6 Hz, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 5.3 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 4.33 (d, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.66 - 2.52 (m, 2H), 2.29 - 2.13 (m, 3H), 2.12 (s, 3H), 2.00 - 1.89 (m, 1H), 1.26 - 1.19 (m, 1H), 0.85 (dd, J = 9.5, 4.4 Hz, 1H), 0.78 - 0.71 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -36.34 (s, 3F). MS (ESI) m / z: calc'd for C23H24F3N6OSSe+[M+H]+: 569.1 found: 569.2.

[0200] Peak 2:1H NMR (400 MHz, DMSO-d6) δ 9.20 (t, J = 5.6 Hz, 1H), 8.24 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 5.3 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 4.33 (d, J = 5.6 Hz, 2H), 2.67 (s, 3H), 2.66 - 2.52 (m, 2H), 2.29 - 2.13 (m, 3H), 2.12 (s, 3H), 2.00 - 1.89 (m, 1H), 1.26 - 1.19 (m, 1H), 0.85 (dd, J = 9.5, 4.4 Hz, 1H), 0.78 - 0.71 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -36.34 (s, 3F). MS (ESI) m / z: calc'd for C23H24F3N6OSSe+[M+H]+: 569.1 found: 569.2.

[0201] Each of the elaborated compounds presented in Table 7 below were prepared in accordance with the synthetic routes described for Examples 19 and 20, using procedures analogous to those described above.- 102 -25972-WO-PCT 12617.0005-00304Example 23: 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan- 2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamideStep 1: 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine

[0202] To a solution of 1-(trifluoromethyl)-4-(((trifluoromethyl)seleninyl)methyl)benzene (5 g, 1.5 eq, 0.02 mol) and 7-chloro-2-iodopyrazolo[1,5-a]pyridine (3 g, 1 eq, 0.01 mol) was added trifluoromethanesulfonic anhydride (2 mL, 1.2 eq, 0.01 mol) dropwise over 5 min. The solution was stirred at 23 °C for 1 h. The volatiles were removed under reduced pressure. The crude product was co-evaporated with pentane (50 mL x 2). To the resulting slurry was added pentane (35 mL), and the suspension was sonicated until complete dissolution. The flask was then cooled in an ice-bath (~15 min), and the resulting product was filtered over a fritted glass to afford 7- chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine. MS (ESI) m / z: Calcd. C8H4ClF3IN2Se+[M+H]+: 426.8; found: 427.0. Step 2: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0203] To a mixture of cesium fluoride (71.4 mg, 2.0 eq, 470 μmol) and (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (46.6 mg, 1.50 eq, 353 μmol) in DMSO (4 mL) was added 7-chloro-2- iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (100 mg, 1.00 eq, 235 μmol). The mixture was stirred at 110 °C for 18 h. The mixture was poured into sat aq NaHCO3, extracted with EtOAc (3 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc in hexane, 0-100%) to provide N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- - 103 -25972-WO-PCT 12617.0005-00304 ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine. MS (ESI) m / z: Calcd. C14H16F4IN4Se+[M+H]+: 523.0; found: 523.1. Step 3: 3-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide

[0204] A degassed mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (50 mg, 1 eq, 96 μmol), 4-methoxy-N- methyl-3-(prop-2-yn-1-ylamino)benzamide (31 mg, 1.5 eq, 0.14 mmol), CuI (9.1 mg, 1.6 μL, 0.5 eq, 48 μmol) and bis-(triphenylphosphino)-palladous chloride (3.4 mg, 0.05 eq, 4.8 μmol) in THF (1 mL) was stirred for 3 min. To the mixture was added DIPA (87 mg, 0.12 mL, 9 eq, 0.86 mmol). The reaction was stirred at 23 °C for 1 h. The mixture was concentrated under reduced pressure and then directly purified by reverse-phase chromatography (40 g column, 5% to 90% MeCN in 10 mM ammonium bicarbonate) to obtain 3-((3-(7-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn- 1-yl)amino)-4-methoxy-N-methylbenzamide.1H NMR (400 MHz, DMSO-d6): δ 8.14 (q, J = 4.4 Hz, 1H), 7.48 - 7.40 (m, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.3, 2.0 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.44 (dd, J = 12.1, 8.2 Hz, 2H), 5.61 (t, J = 6.5 Hz, 1H), 4.92 - 4.80 (m, 1H), 4.33 (d, J = 6.5 Hz, 2H), 3.93 - 3.77 (m, 4H), 3.05 (t, J = 11.0 Hz, 1H), 2.79 - 2.73 (m, 4H), 2.33 - 2.07 (m, 5H), 2.02 - 1.92 (m, 1H), 1.85 - 1.78 (m, 1H);19F NMR (376 MHz, DMSO-d6): δ -37.21 - -37.27 (m, 3F), -198.98 - -199.89 (m, 1F); MS (ESI) m / z: Calcd. C26H29F4N6O2Se+[M+H]+: 613.1; found: 613.4.

[0205] Each of the elaborated compounds presented in Table 8 below were prepared in accordance with the synthetic routes described for Examples 19, 20, and 23, using procedures analogous to those described above.- 104 -25972-WO-PCT 12617.0005-00304 Table 8Example 28: 2-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide

[0206] A 10 mL vial was charged with 2-iodo-N-((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (50 mg, 1.0 eq, 94 μmol), Pd(PPh3)4(5.5 mg, 0.05 eq, 4.7 μmol), 2-methyl-N-(prop-2-yn-1-yl)thiazole-5- carboxamide (26 mg, 1.5 eq, 0.14 mmol), CuI (7.2 mg, 0.4 eq, 38 μmol), and DMSO (2.0 mL). After 3 min of stirring, DIPA (86 mg, 0.12 mL, 9.0 eq, 0.85 mmol) was added, and the reaction was stirred at RT for 1 h. Purification by reverse phase column chromatography (C18, eluent: 5% to 100% MeCN / 10 mM ammonium bicarbonate gradient) afforded 2-methyl-N-(3-(7- (((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl) - 105 -25972-WO-PCT 12617.0005-00304 pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5-carboxamide.1H NMR (400 MHz, DMSO-d6): δ 9.28 (t, J = 5.6 Hz, 1H), 8.25 (s, 1H), 7.46 (t, J = 8.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.27 (d, J = 7.6 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 3.75 - 3.63 (m, 1H), 3.16 (d, J = 4.0 Hz, 1H), 3.04 (d, J = 6.4 Hz, 1H), 2.68 (s, 3H), 2.20 (s, 3H), 2.01 - 1.81 (m, 2H), 1.81 - 1.59 (m, 4H), 1.49 - 1.35 (m, 2H).19F NMR (376 MHz, DMSO-d6): δ -37.18 (s, 3F). MS (ESI) m / z: Calc'd for C24H26F3N6OSSe+[M+H]+: 583.09 found 583.4.

[0207] Each of the elaborated compounds presented in Table 9 below were prepared in accordance with the synthetic routes described for 2-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)thiazole-5-carboxamide, using procedures analogous to those described above.- 106 -25972-WO-PCT 12617.0005-00304 Example 31: 3-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamideStep 1: tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-5-(methylcarbamoyl)phenyl)amino) prop-1-yn-1-yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate

[0208] tert-butyl(1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (73 mg, 1 eq, 95 μmol), Pd(PPh3)4(22 mg, 0.2 eq, 19 μmol), 4-methoxy-N-methyl-3-(prop-2-yn-1ylamino)benzamide (37 mg, 85 wt%, 1.5 eq, 0.14 mmol), and CuI (3.6 mg, 0.64 μL, 0.2 eq, 19 μmol) were taken in a 10 mL round-bottom flask, and THF (3 mL) was added. The mixture was stirred for 3 min, and then DIPA (86 mg, 0.12 mL, 9.0 eq, 0.85 mmol) was added. The reaction was stirred for 3 h at 23 °C. Then the mixture was directly purified by reverse phase (25g C18 cartridge, 5% to 100% ACN in AmB over 15 CV) to give tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-5- (methylcarbamoyl)phenyl)amino)prop-1yn-1-yl)-3-trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z: calc'd for C32H38F3N6O4Se+[M+H]+: 707.2 found:707.5. Step 2: TFA salt of 3-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy- N-methylbenzamide

[0209] To a solution of tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-5- (methylcarbamoyl)phenyl) amino)prop-1-yn-1-yl)-3((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (15.0 mg, 0.08 eq, 21.3 μmol) in CH2Cl2 (1.5 mL) was added TFA (0.1 g, 0.2 mL, 10.0 eq, 2 mmol) at 23 °C, and the mixture was stirred for 2 h. The volatiles were removed under reduced pressure and azeotroped with CH2Cl2- 107 -25972-WO-PCT 12617.0005-00304 (4 x 3.0 mL) to give 3-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide trifluoroacetic acid salt. MS (ESI) m / z: calc'd for C27H30F3N6O2Se+[M+H]+: 607.15 found: 607.4. Step 3: 3-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide

[0210] 3-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn1-yl)amino)-4-methoxy-N-methylbenzamide (13 mg, 1 eq, 21 μmol) was dissolved in DMF (1.5 mL), and cesium carbonate (21 mg, 3 eq, 64 μmol) was added and stirred for 5 min at 23 °C. Then α-chloro-N,N-dimethylacetamide (2.6 mg, 2.2 μL, 1 eq, 21 μmol) was added and stirred for 8 h. Additional α-chloro-N,N-dimethylacetamide (2.6 mg, 2.2 μL, 1 eq, 21.0 μmol) was added and stirred overnight. After 12 h, α -chloro-N,N- dimethylacetamide (5.2 mg, 4.4 μL, 2.0 eq, 42.0 μmol) was added and stirred for another 16 h. The crude mixture was purified directly by reverse phase flash chromatography (12 g C18, 5% ACN in AmB to 100% AmB) to give 3-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide.1H NMR (400 MHz, DMSO-d6) δ 8.23 - 8.04 (m, 1H), 7.51 - 7.35 (m, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 6.89 (dd, J = 8.4, 3.5 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H), 6.24 (d, J = 7.7 Hz, 1H), 5.62 (t, J = 6.6 Hz, 1H), 4.33 (d, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.76 - 3.66 (m, 1H), 3.36 - 3.33 (m,1H), 3.26 - 3.13 (m, 3H), 3.08 (s, 3H), 2.84 (s, 3H), 2.74 (d, J = 4.5 Hz, 3H), 1.95 - 1.57 (m, 6H), 1.47 - 1.37 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -37.24 (s, 3F). MS (ESI) m / z: calc'd for C31H37F3N7O3Se+[M+H]+: 692.2 found: 692.5.

[0211] Each of the elaborated compounds presented in Table 10 below were prepared in accordance with the synthetic routes described for 3-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)- 2-oxoethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide, using procedures analogous to those described above. - 108 -25972-WO-PCT 12617.0005-00304Example 35: 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((S)-2- hydroxypropyl)-3-methoxybenzamideStep 1: tert-butyl (1R,2R,5R)-2-((2-(3-((tert-butoxycarbonyl)(4-(((S)-2-hydroxypropyl) carbamoyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0212] A microwave 2 -5 ml reaction vial was charged with tert-butyl (1R,2R,5R)-2-((2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (75 mg, 1 eq, 0.12 mmol), tert-butyl (S)-(4-((2-hydroxypropyl)carbamoyl)-2- methoxyphenyl)(prop-2-yn-1-yl)carbamate (70 mg, 95 wt%, 1.5 eq, 0.18 mmol), bis- (triphenylphosphino)-palladous chloride (4.3 mg, 0.05 eq, 6.1 μmol), and CuI (1.2 mg, 0.21 μL, - 109 -25972-WO-PCT 12617.0005-00304 0.05 eq, 6.1 μmol). The vial was flushed with N2, and THF (1.1 mL) was added. N2was bubbled into the mixture for 1 min, then DIPA (0.11 g, 0.15 mL, 9 eq, 1.1 mmol) was added. The reaction mixture was stirred at 22 °C for 2 h. The reaction mixture was diluted with EtOAc (25 ml) and water (10 mL). The aqueous and organic layers were separated. The organic layer was washed with water (25 ml), 3% NH4OH (25 ml), dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel chromatography (30 g, 0 to 30% CH3CN / CH2Cl2 over 10 CV) to afford tert-butyl (1R,2R,5R)-2-((2-(3-((tert-butoxycarbonyl)(4-(((S)-2- hydroxypropyl)carbamoyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) m / z: Calcd C39H50F3N6O7Se+[M+H]+: 851.3 found: 851.1. Step 2: 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((S)-2- hydroxypropyl)-3-methoxybenzamide

[0213] A 25 ml flask was charged with tert-butyl (1R,2R,5R)-2-((2-(3-((tert-butoxycarbonyl)(4- (((S)-2-hydroxypropyl)carbamoyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (75 mg, 1 eq, 88 μmol), and HCl in dioxane (0.39 g, 2.6 mL, 4.00 M, 120 eq, 11 mmol) was added at RT. The mixture was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc (25 ml) and sat aq NaHCO3 (25 ml) until pH = 8. This mixture was stirred at RT for 30 min. The aqueous and organic layers were separated. The organic layer was washed with sat aq NaHCO3(2 x 10 mL) and brine (15 ml), dried over sodium sulfate and concentrated to dryness. The residue was purified by reverse phase chromatography (30 g C18 cartridge, 10 to 70% CH3CN in 10 mM ammonium formate buffer) to afford 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N- ((S)-2-hydroxypropyl)-3-methoxybenzamide after lyophilization. Further purification by Prep HPLC (Column XSelect CSH Prep C18 OBD, 5 µm, 30 x 75 mm, Conditions: A-10 mM Ammonium Formate Buffer (pH 3.8); B- Acetonitrile. Begin: 15% B; End: 35% B Gradient Time: 12 min; Flow Rate: 49 L / min) afforded formate salt of 4-((3-(7-(((1R,2R,5S)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo [1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-N-((S)-2-hydroxypropyl)-3-methoxybenzamide formate.1H NMR (400 MHz, DMSO-d6) δ 8.13 (t, J = 5.6 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.37 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 7.7 Hz, 1H), 6.02 (t, J = 6.2 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 3.85 (s, 3H), 3.78 - 3.73 (m, 2H), 3.54 (d, J = 15.1 Hz, 3H), 3.23 - 3.11 (m, 2H), 2.09 - 1.85 (m, 2H), 1.82 - 1.66 (m, 3H), 1.60 - 1.46 (m, 3H), 1.04 (d, J - 110 -25972-WO-PCT 12617.0005-00304 = 6.2 Hz, 3H). Formic acid salt (1.24 eq at 8.38 ppm). MS (ESI) m / z: Calcd for free base C29H34F3N6O3Se+[M+H]+: 651.18 found: 651.1. Example 36: N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamideStep 1: N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide

[0214] In a 25 mL round bottom flask was added DIPEA (68.5 mg, 91.2 μL, 3 eq, 530 μmol) to a solution of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine 1 (70.0 mg, 1 eq, 177 μmol), cyclopropanecarboxylic acid (16.7 mg, 1.1 eq, 194 μmol), and HATU (80.6 mg, 1.2 eq, 212 μmol) in DMF (1.89 mL) at RT. The solution was stirred at RT for 1 h. Water (10 mL) and EtOAc (10 mL) were added. The aqueous and organic layers were separated. The aqueous layer was extracted by EtOAc (10 mL x 2). The combined organic layers were washed by water (20 mL x 2) and brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by normal phase column (12 g, with 0-40% EtOAc in Heptanes) to obtain N-(3-(8- bromo-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide.1H NMR (400 MHz, DMSO-d6): δ 8.64 (t, J = 5.5 Hz, 1H, NH), 8.48 (d, J = 7.1 Hz, 1H), 7.39 (dd, J = 7.2, 0.5 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.82 (d, J = 0.8 Hz, 1H), 4.20 (d, J = 5.6 Hz, 2H), 1.64 - 1.54 (m, 1H), 0.74 - 0.65 (m, 4H);19F NMR (376 MHz, DMSO-d6): δ -36.54 (s, 3F). MS (ESI) m / z: Calcd. C16H13BrF3N2OSe+[M+H]+: 464.93; found: 465.1 Step 2: N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide

[0215] In a 10 mL microwave vial was added cesium carbonate (98.3 mg, 24.1 μL, 2 eq, 302 μmol) to a solution of N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide (70.0 mg, 1 eq, 151 μmol), (3S,4R)-3-fluoro-1-methylpiperidin-4- amine (23.9 mg, 1.2 eq, 181 μmol), and PEPPSI-HeptCl-Pd (29.3 mg, 0.2 eq, 30.2 μmol) in dioxane (1.40 mL) at RT. After 10 min of N2 bubling, the vial was capped, and the suspension was heated at 100 °C for 4 h. Water (15 mL), aq NH4Cl (10 mL), and EtOAc (25 mL) were added. The aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (50 mL), dried over - 111 -25972-WO-PCT 12617.0005-00304 Na2SO4and concentrated. Purification by flash chromatography (iLOK SL 40 C1840 g, 5 to 50% of ACN in 10 mM ammonium formate) afforded formic acid salt of N-(3-(8-(((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide.1H NMR (400 MHz, DMSO-d6): δ 8.63 (t, J = 5.6 Hz, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.26 (s, 1H), 6.72 (t, J = 7.2 Hz, 1H), 6.09 (d, J = 7.6 Hz, 1H), 5.78 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 49.3 Hz, 1H), 4.18 (d, J = 5.6 Hz, 2H), 3.69 - 3.52 (m, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.82 (d, J = 10.3 Hz, 1H), 2.19 (s, 3H), 2.31 - 1.94 (m, 3H), 1.75 - 1.65 (m, 1H), 1.59 (tt, J = 7.6, 5.0 Hz, 1H), 0.74 - 0.64 (m, 4H). Contains 1 eq. of formic acid (8.20 ppm).19F NMR (376 MHz, DMSO-d6): δ -36.77 (s, 3F), -198.49 (s, 1F). MS (ESI) m / z: Calcd. C22H25F4N4OSe+[M+H]+: 517.11; found: 517.3. Example 37: N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamideStep 1: 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine

[0216] A mixture of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-ol (1.5 g, 3.78 mmol), and DBU (0.683 ml, 4.53 mmol) in THF (20 mL) was added DPPA (0.977 ml, 4.53 mmol). The mixture was stirred at 60 °C for 1 h. LCMS showed that desired target was observed and starting material was consumed. The reaction mixture was added aq. NaHCO3 to adjust pH~9 and extracted with EtOAc (20 mL*3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product 2- (3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine. The crude product was used directly without further work up and purification. MS (ESI) m / z: calc'd for C12H7BrF3N4Se+[M+H]+: 420.9 / 422.9 / 424.9, found [M+H]+: 420.7 / 422.7 / 424.7. Step 2: 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine

[0217] A mixture of 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine (1.5 g, 3.55 mmol) and triphenylphosphine (1.398 g, 5.33 mmol) in THF (20 mL) and water (10 mL) was stirred at 50 °C for 1 h . LCMS showed that desired target was observed and starting material was consumed. The reaction mixture was quenched with water (10 mL) and extracted - 112 -25972-WO-PCT 12617.0005-00304 with EtOAc (10 mL*3). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product 3-(8-bromo-3- ((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-amine. The crude product was used directly to the next step without further workup and purification. MS (ESI) m / z: calc'd for C12H9BrF3N2Se+[M+H]+: 394.9 / 396.9 / 398.9, found [M+H]+: 394.8 / 396.8 / 398.8. Step 3: N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1- methyl-1H-pyrazole-4-carboxamide

[0218] To a mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (0.323 g, 2.56 mmol) in DMF (20 mL) were added HATU (0.899 g, 2.363 mmol) and DIEA (0.688 mL, 3.94 mmol) at 20 °C, the mixture was stirred at 20 °C for 5 min, and then 3-(8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine (2 g, 1.969 mmol) was added. The resulting mixture was stirred at 20 °C for 1 h. LCMS showed desired mass peak was observed and the starting material was consumed. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (50 mL*3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 5% MeOH / DCM gradient @ 30 mL / min) to give N-(3-(8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc'd for C17H13BrF3N4OSe+[M+H]+: 502.9 / 504.9 / 506.9, found [M+H]+: 502.9 / 504.9 / 506.9. Step 4: N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

[0219] To a solution of N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)-1-methyl-1H-pyrazole-4-carboxamide (1 g, 1.983 mmol) in 1,4-dioxane (10 mL) were added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (0.341 g, 2.58 mmol), cesium carbonate (1.939 g, 5.95 mmol), and PEPPSI-IpentCl Pd (0.386 g, 0.397 mmol), and the resulting mixture was stirred at 100 °C for 50 min under N2. LCMS showed that desired target was observed and starting material was consumed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 7% MeOH / DCM gradient @ 30 mL / min) to give the crude product. The crude product was crystallized with MTBE (3 mL) and MeCN (0.2 mL). The mixture was stirred at RT for 24 h under 220 speed. The resulting product was filtered, rinsed with MTBE, and collected to give N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. - 113 -25972-WO-PCT 12617.0005-00304 MS (ESI) m / z: calc'd for C23H25F4N6OSe+[M+H]+: 555.1 / 557.1 / 558.1, found [M+H]+: 555.1 / 557.1 / 558.0.1H NMR (400 MHz, DMSO-d6) δ = 8.65 (t, J = 5.7 Hz, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.26 (s, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.08 (d, J = 7.6 Hz, 1H), 5.77 (br d, J = 8.3 Hz, 1H), 4.91 - 4.76 (m, 1H), 4.29 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 3.63 - 3.55 (m, 1H), 3.06 - 2.99 (m, 1H), 2.81 (br d, J = 9.7 Hz, 1H), 2.34 - 2.18 (m, 4H), 2.12 - 1.98 (m, 2H), 1.69 (br d, J = 10.8 Hz, 1H). Example 38: 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamideStep 1: N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1- cyclopropyl-1H-pyrazole-4-carboxamide

[0220] A flame dried pressure tube was charged with 1-cyclopropyl-1H-pyrazole-4-carboxylic acid (21 mg, 1.1 eq, 0.14 mmol) and HATU (58 mg, 1.2 eq, 0.15 mmol), and the tube was cooled on an ice bath. DMF (0.5 mL) was added, followed by a solution of 3-(8-bromo-3- ((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-amine (50 mg, 1 eq, 0.13 mmol) in DMF (0.5 mL) and DIPEA (49 mg, 65 μL, 3 eq, 0.38 mmol). This mixture was stirred at RT until full consumption of starting material. Then, the reaction mixture was directly loaded on a column for purification. Reverse phase purification was done on i-LOK SNAP C18, 25 gm column using 10 mm AmF / MeCN as eluents 0-100%. The desired product eluted in 40-50% 10 mm AmF / ACN. The corresponding pure fractions were combined, reduced under vacuum to afford N-(3-(8- bromo-3-((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4- carboxamide.1H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 7.1 Hz, 1H), 7.94 (s, 1H), 7.74 (s, 1H), 7.16 (dd, J = 7.2, 0.7 Hz, 1H), 6.88 (d, J = 0.8 Hz, 1H), 6.62 (t, J = 7.1 Hz, 1H), 5.94 (s, 1H), 4.50 (d, J = 5.2 Hz, 2H), 3.63 (ddd, J = 11.3, 7.3, 3.9 Hz, 2H), 1.18 - 1.11 (m, 2H), 1.10 - 1.02 (m, 2H).19F NMR (376 MHz, CDCl3): δ -35.93 (s, 3F). LCMS (ESI) m / z: Calcd. for C19H15F3BrN4OSe+[M+H]+: 531.3 found: 531.3. Step 2: 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide

[0221] A flame dried microwave vial was charged with N-(3-(8-bromo-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4- carboxamide (31 mg, 1 eq, 58 μmol), (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (8.5 mg, 1.1 - 114 -25972-WO-PCT 12617.0005-00304 eq, 64 μmol), cesium carbonate (38 mg, 2 eq, 0.12 mmol), PEPPSI-HeptCl-Pd (11 mg, 0.2 eq, 12 μmol), and dioxane (1.00 mL) were added. The solution was purged with N2 for 10 min at RT. The tube was sealed, and the reaction was transferred to a pre-heated oil bath at 100 °C. This mixture was stirred at 100 °C until full consumption of starting material. The reaction mixture was directly loaded on column for purification. Reverse phase purification was done on i-LOK SNAP C18, 25 g cartridge, using 10 mm AmF / MeCN as eluents. The pure fraction eluted in 30- 50% 10 mm AmF / MeCN. The corresponding pure fractions were combined, and reduced under vacuum to afford formate salt of 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide.1H NMR (400 MHz, CD3CN): δ 8.15 (s, Formic acid, 1H), 7.99 (d, J = 3.3 Hz, 1H), 7.89 (d, J = 7.0 Hz, 1H), 7.75 (t, J = 2.0 Hz, 1H), 7.05 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 0.7 Hz, 1H), 6.74 - 6.66 (m, 1H), 6.08 (d, J = 7.5 Hz, 1H), 4.96 - 4.75 (m, 1H), 4.74 - 4.53 (m, 1H), 4.32 (d, J = 5.7 Hz, 2H), 3.71 - 3.53 (m, 2H), 3.21 - 3.08 (m, 1H), 2.96 - 2.83 (m, 1H), 2.42 - 2.11 (m, 5H), 2.04 - 1.82 (m, 1H), 1.14 - 0.91 (m, 4H).19F NMR (376 MHz, CD3CN): δ -38.01 (m, 3F), -199.81 - -202.05 (m, 1F). LCMS (ESI) m / z: Calcd. for C25H27F4N6OSe+[M+H]+: 583.5 found: 583.5. Example 39: 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide

[0222] To a 5 mL microwave vial with stirring was added cesium carbonate (61 mg, 2.0 eq, 0.19 mmol), N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1- cyclopropyl-1H-pyrazole-4-carboxamide (50 mg, 1 eq, 94 μmol), (1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-amine (16 mg, 1.2 eq, 0.11 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1- propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine- kappaN)-palladium (18 mg, 0.2 eq, 19 μmol). To this mixture, dioxane (1.0 mL) was added at RT. After 10 min of N2bubbling, the solution was sealed and heated at 100 °C for 3 h. After 3 h reaction was cooled down to RT and diluted by NH4Cl solution in water (3 mL), and EtOAc (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted using EtOAc (5 mL X 2). combined organic layers were dried over Na2SO4 and concentrated under vacuum. Reverse phase column was done with i-LOK SNAP C1825 gm column using 10 mm AmB / MeCN. The - 115 -25972-WO-PCT 12617.0005-00304 desired product eluted in 50-60% of 10 mm AmB / MeCN. Purification was repeated again on reverse phase with i-LOK SNAP C1825 gm column using 10 mm AmF / MeCN. The pure fraction eluted in 20-28% 10 mm AmF / MeCN. The corresponding pure fractions were combined, reduced under vacuum to afford as formate salt of 1-cyclopropyl-N-(3-(8- (((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide.1H NMR (400 MHz, CD3CN): δ 8.46 (s, formic acid), 8.01 (s, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.77 (s, 1H), 7.22 (d, J = 4.9 Hz, 1H), 6.79 (s, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.31 (d, J = 7.5 Hz, 1H), 4.61 (d, J = 7.2 Hz, 1H), 4.32 (d, J = 5.7 Hz, 1H), 4.20 (d, J = 6.7 Hz, 1H), 3.77 - 3.54 (m, 3H), 3.25 (brs, s, 2H), 2.58 (s, 3H), 2.25 - 1.97 (m, 3H), 1.92 - 1.84 (m, 1H), 1.83 - 1.73 (m, 1H), 1.71 - 1.57 (m, 1H), 1.09 - 1.05 (m, 2H), 1.04 - 0.97 (m, 2H).19F NMR (376 MHz, CD3CN): δ -38.06 (s, 3F). LCMS (ESI) m / z: Calcd. for C27H30F3N6OSe+[M+H]+: 591.5 found: 591.5. Example 40: 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamideStep 1: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine

[0223] To a solution of 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine (150 mg, 0.353 mmol) in DMSO (1 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (65.2 mg, 0.494 mmol), N-ethyl-N-isopropylpropan-2-amine (182 mg, 1.410 mmol), and cesium fluoride (107 mg, 0.705 mmol). The mixture was stirred for 4 h at 80 °C. LCMS showed desired mass was formed. The reaction was diluted with water (8 mL), extracted with EtOAc (8 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 5% MeOH gradient @ 30 mL / min) to afford N- ((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-1-amine. MS (ESI) m / z: calc'd for C14H16F4IN4Se+[M+H]+522.9, found [M+H]+522.9. - 116 -25972-WO-PCT 12617.0005-00304 Step 2: 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid

[0224] A mixture of CuI (19.00 mg, 0.100 mmol), DIPA (0.315 mL, 2.245 mmol), Pd(PPh3)4 (43.2 mg, 0.037 mmol), N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-1-amine (130 mg, 0.249 mmol), and 3-methoxy- 4-(prop-2-yn-1-ylamino) benzoic acid (61.4 mg, 0.299 mmol) in DMSO (1 mL) was stirred at 25 °C for 1 h under N2atmosphere. LCMS showed desired MS. The reaction was quenched by slow addition of sat. NH4Cl (8 mL), extracted with DCM (8 mL*3). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 20% MeOH gradient @ 30 mL / min) to afford 4-((3-(1-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)-3-methoxybenzoic acid. MS (ESI) m / z: calc'd for C25H26F4N5O3Se+[M+H]+600.1, found [M+H]+600.0. Step 3: 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide

[0225] To 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (23 mg, 0.038 mmol) in DMF (0.5 mL) were added HATU (17.54 mg, 0.046 mmol) and DIEA (0.027 mL, 0.154 mmol) at 20 °C. The mixture was stirred at 20 °C for 5 min, and then 3- methyloxetan-3-amine (4.35 mg, 0.050 mmol) was added. The mixture was stirred at 20 °C for 1 h. LCMS showed desired mass peak was observed and the starting material was consumed. The reaction was filtered, and the residue was purified by Prep HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (10mM-NH4HCO3)-ACN Begin B37 End B 67 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25 ) to give 4-((3-(1-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-(3-methyloxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C29H33F4N6O3Se+[M+H]+669.2, found [M+H]+669.1.1H NMR (CDCl3, 400 MHz) δ 7.65 (d, 1H, J=4.9 Hz), 7.36 (d, 1H, J=1.5 Hz), 7.2-7.3 (m, 1H), 6.7-6.8 (m, 2H), 6.31 (s, 1H), 5.08 (br d, 1H, J=9.2 Hz), 4.9-5.0 (m, 2H), 4.87 (d, 2H, J=6.3 Hz), 4.79 (br s, 1H), 4.58 (d, 2H, J=6.3 Hz), 4.29 (d, 2H, J=6.1 Hz), 3.92 (s, 3H), 3.2-3.3 (m, 1H), 2.96 (br d, 1H, J=11.4 Hz), 2.2-2.4 (m, 5H), 1.9-2.0 (m, 2H), 1.77 (s, 3H). - 117 -25972-WO-PCT 12617.0005-00304 Example 41: (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanoneStep 1: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0226] To a mixture of 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (500 mg, 1.175 mmol) and (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (202 mg, 1.528 mmol) in DMSO (6 mL) were added N-ethyl-N-isopropylpropan-2-amine (0.614 mL, 3.53 mmol), and cesium fluoride (536 mg, 3.53 mmol) at 20 °C. The resulting mixture was stirred at 65 °C for 16 h. LCMS showed the reaction completed. The mixture was cooled, diluted with EtOAc (15 mL), washed with water (15 mL*3), dried (Na2SO4), and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of [0~30]% ethyl acetate / pet. ether gradient @ 40 mL / min) to give N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine. MS (ESI) m / z: calc'd for C14H15F4IN4Se+[M+H]+522.9, found 522.9 [M+H]+. Step 2: 4-((3-(7-(( -3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl) 2-yn-1-yl)amino)-3-methoxybenzoic acid

[0227] To a mixture of N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3- ((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine (220 mg, 0.422 mmol) and 3-methoxy- 4-(prop-2-yn-1-ylamino)benzoic acid (113 mg, 0.549 mmol) in DMSO (4 mL) was added CuI (40.2 mg, 0.211 mmol), PdCl2(dppf) (61.8 mg, 0.084 mmol) and N-ethyl-N-isopropylpropan-2- amine (0.221 mL, 1.266 mmol) at 20 °C under N2. The resulting mixture was stirred at 25 °C for 1 h. LCMS showed the reaction completed. The mixture was diluted with EtOAc (10 mL), washed with water (15 mL*3), dried (Na2SO4), and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 - 118 -25972-WO-PCT 12617.0005-00304 g SepaFlash® Silica Flash Column, eluent of [0~100]% ethyl acetate / pet. ether gradient @ 40 mL / min) to give 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid. MS (ESI) m / z: calc'd for C25H26F4N5O3Se+[M+H]+600.1, found 600.1 [M+H]+. Step 3: (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone

[0228] A mixture of 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (40 mg, 0.067 mmol), HATU (25.4 mg, 0.067 mmol), and N-ethyl-N-isopropylpropan-2- amine (0.035 mL, 0.201 mmol) in DMF (1 mL) was stirred for 5 min at 25 °C, then 3- methylazetidin-3-ol (5.82 mg, 0.067 mmol) was added and stirred at 25 °C for 20 min. LCMS showed the reaction completed. The residue was purified by Prep-HPLC (Column Boston Prime C18150*30mm*5um Condition Water (0.04% NH3H2O+10mM NH4HCO3)-ACN Begin B 45 End B 75 Gradient Time (min) 11100%B Hold Time 2 Flow Rate (mL / min) 25) to give (4-((3- (7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3-hydroxy-3-methylazetidin-1- yl)methanone. MS (ESI) m / z: calc'd for C29H33F4N6O3Se+[M+H]+: 669.2 found 669.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.32 - 7.27 (m, 1H), 7.25 (s, 1H), 7.17 (br d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.84 (br d, J = 7.9 Hz, 1H), 6.23 (br d, J = 8.9 Hz, 1H), 5.99 (d, J = 7.6 Hz, 1H), 4.95 (br t, J = 6.3 Hz, 1H), 4.93 - 4.77 (m, 1H), 4.35 (br d, J = 6.3 Hz, 2H), 4.30 - 4.03 (m, 4H), 3.88 (s, 3H), 3.68 - 3.51 (m, 1H), 3.25 (br t, J = 9.9 Hz, 1H), 2.97 (br d, J = 9.1 Hz, 1H), 2.34 (s, 3H), 2.26 (br d, J = 13.4 Hz, 1H), 2.23 - 2.14 (m, 1H), 2.10 - 1.96 (m, 2H), 1.53 (s, 3H).

[0229] Each of the elaborated compounds presented in Table 11 below were prepared in accordance with the synthetic routes and using procedures analogous to those described above for 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide and (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone. - 119 -25972-WO-PCT 12617.0005-00304- 120 -25972-WO-PCT 12617.0005-00304Example 50: N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2-methylpropyl)-1H- pyrazole-4-carboxamide

[0230] In a 40mL vial, 1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxylic acid (66 mg, 2 eq, 0.36 mmol), 7-(3-aminoprop-1-yn-1-yl)-N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (80 mg, 1 eq, 0.18 mmol), and HATU (0.14 g, 2 eq, 0.36 mmol) were dissolved in DMF (0.9 mL). After stirring until the contents were homogenous, DIPEA (0.12 g, 0.16 mL, 5 eq, 0.89 mmol) was added to the mixture. The reaction was allowed to stir at RT for 4 h. After stirring, LCMS showed formation of product. The reaction was quenched with LiCl solution and extracted with ethyl acetate. The organic layer was separated from the aqueous layer, dried over magnesium sulfate salts, filtered, and concentrated under reduced pressure. The concentrated material was dissolved in DMSO and submitted for TFA HPLC purification (C18, 19x150, 44-74% MPB). N-(3-(1-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide was obtained. NMR:1H NMR (500 MHz, DMSO) δ 8.70 (t, J = 5.6 Hz, 1H), 8.58 (s, 1H), 8.38 (d, J = 7.9 Hz, 2H), 8.16 (s, 1H), - 121 -25972-WO-PCT 12617.0005-00304 7.88 (s, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.27 (d, J = 4.9 Hz, 1H), 4.90 (d, J = 49.9 Hz, 2H), 4.76 (s, 1H), 4.30 (d, J = 5.5 Hz, 2H), 4.04 (s, 3H), 2.90 (s, 2H), 2.25 (s, 3H), 2.11 - 1.99 (m, 2H), 1.72 (s, 1H), 1.25 (s, 7H), 1.06 (s, 6H). MS (ESI) m / z [M+H]+: 614.1 / 616.1.

[0231] The compound listed below in Table 12 was accessed using the same methods described above for N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2- methylpropyl)-1H-pyrazole-4-carboxamide, above using commercially available carboxylic acids.Example 52: N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2-methylthiazole-4-carboxamide

[0232] In a 2 dram vial, N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-7-iodo-6- ((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-1-amine (40 mg, 1 eq, 77 μmol), 2-methyl-N- (prop-2-yn-1-yl)thiazole-4-carboxamide (28 mg, 2 eq, 0.15 mmol), CuI (2.9 mg, 0.2 eq, 15 μmol), and Pd(PPh3)4(18 mg, 0.2 eq, 15 μmol) were dissolved in DMSO (0.3 mL). The vial was purged and back filled with N2 three times. DIPEA (79 mg, 0.11 mL, 8 eq, 0.61 mmol) was added, and the reaction was allowed to stir at 50 °C for 2 h. After stirring, LCMS showed formation of product. Palladium scavenger was added to the reaction, and the reaction mixture was allowed to stir for 30 min at RT. After stirring, the reaction mixture was filtered. The filtered - 122 -25972-WO-PCT 12617.0005-00304 material was diluted further in DMSO and purified by NH4HPLC purification (C18, 19x150, 23- 53% MPB). N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2-methylthiazole-4- carboxamide was received back.

[0233] Compounds listed below in Table 13 were accessed using the same methods described above for N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2-methylthiazole-4-carboxamide.- 123 -25972-WO-PCT 12617.0005-00304Example 59: N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole-4- carboxamide, 2,2,2-trifluoroacetate salt

[0234] To N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-7-amine (40.00 mg, 1 eq, 76.75 μmol), and 1-(oxetan-3-yl)-N-(prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide (31.50 mg, 2.00 eq, 153.5 μmol) in a vial, CuI (7.309 mg, 0.5 eq, 38.38 μmol), Pd(PPh3)4 (8.87 mg, 0.1 eq, 7.675 μmol), DIEA (89.28 mg, 120 μL, 9.0 eq, 690.8 μmol), and 0.5ml DMSO were added, and the vial was thoroughly purged with N2and then stirred at 50°C for 2 h. The reaction was monitored using LC for completion. The reaction mix was diluted with 1mL DMSO, filtered, and purified on a reverse phase HPLC using gradient elution with 0-100% ACN-water using 0.1% TFA as a modifier. Appropriate fractions were pooled, and the sample lyophilized to give N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- - 124 -25972-WO-PCT 12617.0005-00304 yl)-1H-pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt. MS (ESI) m / z calc'd for C26H25F7N7O4Se [M+H]+: 600, found 599.81H NMR (500 MHz, DMSO) δ 8.51 (t, J = 5.5 Hz, 1H), 8.05 (s, 1H), 7.71 (s, 1H), 7.13 (s, 1H), 6.68 (d, J = 8.5 Hz, 3H), 6.14 (s, 1H), 5.26 (s, 1H), 4.56 (d, J = 44.6 Hz, 4H), 4.03 (s, 3H), 3.77 (s, 2H), 3.49 - 3.38 (m, 4H), 3.24 - 3.14 (m, 2H), 2.86 (s, 1H), 2.26 - 2.13 (m, 1H), 2.09 - 1.96 (m, 1H), 1.74 (d, J = 13.1 Hz, 1H). Example 60: 5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide, 2,2,2-trifluoroacetate salt

[0235] To N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-7-amine (35.00 mg, 1 eq, 67.16 μmol) and 4-methoxy-N-methyl-5-(prop- 2-yn-1-ylamino)picolinamide (29.45 mg, 2.00 eq, 134.3 μmol) in a vial, CuI (6.40 mg, 0.5 eq, 33.58 μmol), Pd(PPh3)4(7.761 mg, 0.1 eq, 6.72 μmol), DIEA (78.12 mg, 105 μL, 9.0 eq, 604.4 μmol), and 0.5ml DMSO were added, and the vial was thoroughly purged with N2 and then stirred at 50°C for 2 h. The reaction mixture was diluted with 1mL DMSO, filtered, and purified on a reverse phase HPLC using gradient elution with 0-100% ACN-water using 0.1% TFA as a modifier. Appropriate fractions were pooled and lyophilized to give 5-((3-(7-(((3S,4R)-3-fluoro- 1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylpicolinamide, 2,2,2-trifluoroacetate salt. MS (ESI) m / z calc'd for C26H25F7N7O4Se [M+H]+: 614, found 614.8.1H NMR (500 MHz, DMSO) δ 7.53 (s, 1H), 7.39 - 6.88 (m, 2H), 6.51 (s, 1H), 5.24 (d, J = 45.8 Hz, 1H), 4.30 - 4.08 (m, 5H), 4.13 - 3.96 (m, 6H), 3.90 - 3.82 (m, 2H), 3.55 (s, 2H), 3.36 - 3.11 (m, 1H), 2.86 (s, 4H), 2.46 - 2.29 (m, 1H), 2.22 - 2.02 (m, 1H). - 125 -25972-WO-PCT 12617.0005-00304 Example 61: N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4- (methylsulfonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-amine, 2,2,2-trifluoroacetate salt

[0236] To N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-7-amine (40.00 mg, 1 eq, 76.75 μmol) and 2-methoxy-4- (methylsulfonyl)-N-(prop-2-yn-1-yl)aniline (36.73 mg, 2.00 eq, 153.5 μmol) in a vial, CuI (5.85 mg, 0.4 eq, 30.70 μmol), Pd(PPh3)4(8.87 mg, 0.1 eq, 7.67 μmol), DIEA (89.28 mg, 120 μL, 9.0 eq, 690.8 μmol), and 0.5mL DMSO were added, and the vial was thoroughly purged with N2 and then stirred at 50°C for 2 h. The reaction mix was diluted with 1mL DMSO, filtered, and purified on a reverse phase HPLC using gradient elution with 0-100% ACN-water using 0.1% TFA as a modifier. Appropriate fractions were pooled and lyophilized to give N-((3S,4R)-3- fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl)phenyl)amino)prop-1-yn-1- yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine, 2,2,2-trifluoroacetate salt. MS (ESI) m / z calc'd for C27H27F7N5O5SSe [M+H]+: 634, found 633.7.1H NMR (500 MHz, DMSO) δ 7.49 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 5.21 (d, J = 47.3 Hz, 1H), 4.40 (s, 2H), 4.11 (d, J = 55.1 Hz, 1H), 3.99 - 3.82 (m, 4H), 3.26 - 3.13 (m, 1H), 3.10 (s, 3H), 2.84 (s, 3H), 2.41 - 2.27 (m, 1H), 2.08 (d, J = 12.4 Hz, 1H). Example 62: N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2- methylpropyl)-1H-pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt

[0237] To N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-iodo-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-7-amine (40.00 mg, 1 eq, 76.75 μmol) and 1-(2-hydroxy-2- - 126 -25972-WO-PCT 12617.0005-00304 methylpropyl)-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (33.96 mg, 2.00 eq, 153.5 μmol) in a vial, CuI (5.85 mg, 0.4 eq, 30.70 μmol), Pd(PPh3)4 (8.87 mg, 0.1 eq, 7.67 μmol), DIEA (89.28 mg, 120 μL, 9.0 eq, 690.8 μmol), and 0.5mL DMSO were added, and the vial was thoroughly purged with N2and then stirred at 50°C for 2 h. The reaction mix was diluted with 1mL DMSO, filtered, and purified on a reverse phase HPLC using gradient elution with 0-100% ACN-water using 0.1% TFA as a modifier. Appropriate fractions were pooled and lyophilized to give N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4- carboxamide, 2,2,2-trifluoroacetate salt. MS (ESI) m / z calc'd for C27H29F7N7O4Se [M+H]+: 616, found 615.8.1H NMR (500 MHz, DMSO) δ 8.95 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 7.18 (s, 2H), 6.63 (s, 1H), 5.37 (d, J = 47.4 Hz, 1H), 4.51 (s, 2H), 4.39 - 4.27 (m, 1H), 4.20 (s, 3H), 3.99 (s, 1H), 3.95 - 3.92 (m, 1H), 3.76 - 3.58 (m, 3H), 3.00 (s, 2H), 2.66 (s, 1H), 2.28 - 2.17 (m, 1H), 1.21 (s, 6H). Example 63: (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl- 8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)methanoneStep 1: methyl 4-((tert-butoxycarbonyl)amino)-3-methoxybenzoate

[0238] To a solution of methyl 4-amino-3-methoxybenzoate (500 mg, 2.76 mmol) in 1,4- dioxane (5 mL) was added di-tert-butyl dicarbonate (1807 mg, 8.28 mmol), and the mixture was stirred for 12 h at 110 °C. LCMS showed desired mass peak was observed. The mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0~10% ethyl acetate / pet. ether gradient @ 20 mL / min) to give methyl 4-((tert-butoxycarbonyl)amino)-3- methoxybenzoate. MS (ESI) m / z: calc'd for C14H20NO5+[M+H]+: 282.1, found: 226.2 [M+H- 56]+.1H NMR (400 MHz, CDCl3) δ = 8.17 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 1.7, 8.5 Hz, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.28 (br s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 1.54 (s, 9H). - 127 -25972-WO-PCT 12617.0005-00304 Step 2: 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl methanesulfonate

[0239] To a solution of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-ol (1500 mg, 3.78 mmol) in DCM (15 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.061 mL, 6.42 mmol) and methanesulfonic anhydride (987 mg, 5.67 mmol), the mixture was stirred for 1 h at 0 °C. The mixture was stirred for 12 h at 25 °C. LCMS showed desired mass peak was observed. The resulting mixture was quenched with 1 N HCl (40 mL), extracted with DCM (10 mL*3). The combined organic phases were washed with brine (20 mL *3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-(8-bromo-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl methanesulfonate. MS (ESI) m / z: calc'd for C13H10BrF3NO3SSe+[M+H]+: 475.9 / 477.9, found: 475.9 / 477.9 [M+H]+. Step 3: 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-ol

[0240] To a solution of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl methanesulfonate (200mg, 0.421 mmol) in DMF (2.5 mL) was added Cs2CO3(411 mg, 1.263 mmol), methyl 4-((tert-butoxycarbonyl)amino)-3-methoxybenzoate (130 mg, 0.463 mmol), and tetrabutylammonium bromide (54.3 mg, 0.168 mmol), and the mixture was stirred for 1 h at 25 °C under N2. LCMS showed desired mass peak was observed. The reaction mixture was quenched with H2O (25 mL) and extracted with EtOAc (10 mL *3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~15% ethyl acetate / pet. ether gradient @ 20 mL / min) to give methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)(tert-butoxycarbonyl)amino)-3-methoxybenzoate. MS (ESI) m / z: calc'd for C26H25BrF3N2O5Se+[M+H]+: 661.0 / 663.0 found: 661.0 / 663.0 [M+H]+. Step 4: methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzoate

[0241] To a solution of methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop- 2-yn-1-yl)(tert-butoxycarbonyl)amino)-3-methoxybenzoate (260 mg, 0.394 mmol) in DCM (5 mL) was added 2,6-dimethylpyridine (0.229 ml, 1.969 mmol) and trimethylsilyl trifluoromethane sulfonate (0.273 mL, 1.575 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C LCMS showed desired mass peak was observed. The reaction mixture was quenched with sat. NH4Cl aq. (15 mL) and extracted with DCM (10 mL *3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash - 128 -25972-WO-PCT 12617.0005-00304 Column, eluent of 0~20% ethyl acetate / pet. ether gradient @ 20 mL / min) to give methyl 4-((3- (8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate. MS (ESI) m / z: calc'd for C21H17BrF3N2O3Se+[M+H]+: 560.9 / 562.9, found: 560.9 / 562.9 [M+H]+. Step 5: 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)- 3-methoxybenzoic acid

[0242] To a solution of methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxybenzoate (200 mg, 0.357 mmol) in THF (3.00 mL), MeOH (3 mL), and water (1.00 mL) was added lithium hydroxide hydrate (59.9 mg, 1.428 mmol), and the mixture was stirred for 3 h at 50 °C. LCMS showed desired mass peak was observed. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (5 mL *3). The combined aqueous phases was acidified by 2N HCl to pH = 5 and then extracted with EtOAc (10 mL *3), the combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~40% ethyl acetate / pet. ether gradient @ 20 mL / min) to give 4-((3-(8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid. MS (ESI) m / z: calc'd for C20H15BrF3N2O3Se+[M+H]+: 546.9 / 548.9, found: 546.8 / 548.8 [M+H]+. Step 6: give (4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone

[0243] To a solution of 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzoic acid (160mg, 0.293 mmol) in DMF (1953 µL) was added HATU (167 mg, 0.439 mmol) and N-ethyl-N-isopropylpropan-2-amine (114 mg, 0.879 mmol), and the mixture was stirred for 15 min at 25 °C. Then 3-methylazetidin-3-ol (33.2 mg, 0.381 mmol) was added to the reaction mixture, and the reaction mixture was stirred for 12 h at 25 °C. LCMS showed desired mass peak was observed. The reaction mixture was quenched with H2O (20 mL) and extracted with EtOAc (10 mL *3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~60% ethyl acetate / pet. ether gradient @ 20 mL / min) to give (4-((3-(8- bromo-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3- hydroxy-3-methylazetidin-1-yl)methanone. MS (ESI) m / z: calc'd for C24H22BrF3N3O3Se+[M+H]+: 616.0 / 618.0, found: 615.9 / 617.9 [M+H]+. - 129 -25972-WO-PCT 12617.0005-00304 Step 7: (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn- 1-yl)amino)phenyl)methanone

[0244] To a solution of (4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone (100 mg, 0.163 mmol) in 1,4-dioxane (1083 µL) were added (1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- amine (34.2 mg, 0.244 mmol), cesium carbonate (159 mg, 0.488 mmol), and PEPPSI-IpentCl Pd (31.6 mg, 0.033 mmol), and the resulting mixture was stirred at 100 °C for 2 h under N2. LCMS showed that mass peak was observed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column Phenomenex Synergi C18150*30 mm*4um Condition water (0.1% TFA)-ACN Begin B 35 End B 55 Gradient Time (min) 10100% B Hold Time 2 Flow Rate (ml / min) 25 Injections 2) to give (3-hydroxy-3- methylazetidin-1-yl)(3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone. MS (ESI) m / z: calc'd for C32H37F3N5O3Se+[M+H]+: 676.2, found: 676.1[M+H]+.1H NMR (400 MHz, MeOD) δ = 7.90 (d, J = 7.2 Hz, 1H), 7.23 (dd, J = 1.7, 8.3 Hz, 1H), 7.18 (d, J = 1.8 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.11 (d, J = 7.4 Hz, 1H), 4.84 - 4.82 (m, 2H), 4.09 - 4.01 (m, 2H), 4.00 - 3.92 (m, 4H), 3.90 (s, 3H), 2.85 (s, 3H), 2.66 (s, 1H), 2.37 - 2.30 (m, 1H), 2.29 - 2.23 (m, 1H), 2.04 - 1.82 (m, 6H), 1.49 (s, 3H). Example 64: (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3- hydroxy-3-methylazetidin-1-yl)methanone

[0245] To a solution of (4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone (70 mg, 0.114 mmol) in 1,4-dioxane (758 µL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (19.55 mg, 0.148 mmol), cesium carbonate (222 mg, 0.683 mmol), and PEPPSI-IpentCl Pd (22.13 mg, 0.023 mmol), and the resulting mixture was stirred at 100 °C for 2 h under N2. LCMS showed that mass peak was observed. The mixture was filtered, and the filtrate was concentrated under - 130 -25972-WO-PCT 12617.0005-00304 reduced pressure. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (0.1%TFA) - ACN Begin B 28 End B 58 Gradient Time (min) 11 100% B Hold Time 3 Flow Rate (ml / min) 25 Injections 2) to give (4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone. MS (ESI) m / z: calc'd for C30H34F4N5O3Se+[M+H]+: 668.2, found: 668.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.93 (d, J = 6.8 Hz, 1H), 7.25 (dd, J = 1.8, 8.2 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 6.95 - 6.88 (m, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.14 (d, J = 7.5 Hz, 1H), 5.30 - 5.12 (m, 1H), 4.31 (s, 3H), 4.14 - 4.00 (m, 3H), 3.95 (br s, 1H), 3.92 (s, 3H), 3.91 - 3.86 (m, 1H), 3.67 - 3.58 (m, 1H), 3.57 - 3.44 (m, 1H), 3.30 - 3.22 (m, 1H), 2.96 (s, 3H), 2.38 - 2.27 (m, 1H), 2.25 - 2.17 (m, 1H), 1.51 (s, 3H).19F NMR (376 MHz, MeOD) δ = -38.82 (s, 3F), -204.52 (s, 1F). Example 65: 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)-3- methoxybenzamideStep 1: methyl 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate

[0246] To a solution of methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxybenzoate (340 mg, 0.607 mmol) in 1,4-dioxane (4.0 mL) was added (3S,4R)-3-fluoro-1-methylpiperidin-4-amine (160 mg, 1.214 mmol), cesium carbonate (1186 mg, 3.64 mmol), and PEPPSI-IpentCl Pd (118 mg, 0.121 mmol), and the resulting mixture was stirred at 100 °C for 2 h under N2. LCMS showed that mass peak was observed. The reaction mixture was quenched with H2O (15 mL) and extracted with EtOAc (10 mL *3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~10% MeOH / DCM gradient @ 25 mL / min) to give methyl 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate. MS (ESI) m / z: calc'd for C27H29F4N4O3Se+[M+H]+: 611.511, found: 613.0 [M+H]+. - 131 -25972-WO-PCT 12617.0005-00304 Step 2: 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid

[0247] To a solution of methyl 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate (270 mg, 0.442 mmol) in MeOH (1 mL), THF (1.0 mL), and water (1.0 mL) was added lithium hydroxide hydrate (111 mg, 2.65 mmol), and the mixture was stirred for 1 h at 60 °C. LCMS showed desired mass peak was observed. The resulting mixture was acified by 2N HCl to pH = 6, and the mixture was extracted with EtOAc (5 mL *3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 0~10% MeOH / DCM gradient @ 20 mL / min) to give 4-((3-(8-(((3S,4R)- 3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzoic acid. MS (ESI) m / z: calc'd for C26H27F4N4O3Se+[M+H]+: 597.484, found: 599.1 [M+H]+. Step 3: 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)-3- methoxybenzamide

[0248] To a solution of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (30 mg, 0.050 mmol) in DMF (0.5 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate(V) (24.82 mg, 0.065 mmol) and N-ethyl-N- isopropylpropan-2-amine (19.47 mg, 0.151 mmol), and the mixture was stirred for 0.5 h at 25 °C. Then (R)-1-aminopropan-2-ol (5.66 mg, 0.075 mmol) was added to the mixture, and the mixture was stirred for 1 h at 25 °C. LCMS showed desired mass peak was observed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column Boston Prime C18150 * 30 mm * 5 um Condition Water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN Begin B 45 End B 75 Gradient Time (min) 2.5100% B Hold Time 11 Flow Rate (ml / min) 25 Injections 1) to give 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2- hydroxypropyl)-3-methoxybenzamide. MS (ESI) m / z: calc'd for C29H34F4N5O3Se+[M+H]+: 656.2, found: 656.1 [M+H]+.1H NMR (MeOD, 400 MHz) δ 7.85 (d, J = 7.0 Hz, 1H), 7.46 (dd, J = 8.2, 1.9 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 6.84-6.94 (m, 2H), 6.65 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.4 Hz, 1H), 4.94 (br s, 1H), 4.29 (s, 2H), 3.94-4.00 (m, 1H), 3.92 (s, 3H), 3.55-3.71 (m, 1H), 3.36-3.45 (m, 1H), 3.33 (br s, 1H), 3.14-3.24 (m, 1H), 2.94 (br d, J = 11.0 Hz, 1H), 2.40 (d, J = - 132 -25972-WO-PCT 12617.0005-00304 13.2 Hz, 1H), 2.31 (s, 3H), 2.20-2.29 (m, 1H), 1.96-2.13 (m, 1H), 1.86-1.95 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H). Example 66: 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3-yl)benzamide

[0249] To a solution of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (30 mg, 0.050 mmol) in DMF (0.5 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate(V) (24.82 mg, 0.065 mmol) and N-ethyl-N- isopropylpropan-2-amine (19.47 mg, 0.151 mmol), and the mixture was stirred for 0.5 h at 25 °C. Then 3-methyloxetan-3-amine (6.56 mg, 0.075 mmol) was added to the mixture, and the mixture was stirred for 1 h at 25 °C. LCMS showed desired mass peak was observed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (10 mM - NH4HCO3) - ACN Begin B 40 End B 70 Gradient Time (min) 11100% B Hold Time 2.5 Flow Rate (ml / min) 25 Injections 1) to give 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C30H34F4N5O3Se+[M+H]+: 668.2, found: 668.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 6.9 Hz, 1H), 7.45 (dd, J = 8.3, 1.8 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 6.83-6.93 (m, 2H), 6.65 (t, J = 7.2 Hz, 1H), 6.04 (d, J = 7.4 Hz, 1H), 4.93 (br s, 1H), 4.86 (d, J = 6.6 Hz, 2H), 4.49 (d, J = 6.6 Hz, 2H), 4.29 (s, 2H), 3.91 (s, 3H), 3.55-3.70 (m, 1H), 3.14-3.25 (m, 1H), 2.93 (br d, J = 12.8 Hz, 1H), 2.39 (d, J = 13.0 Hz, 1H), 2.30 (s, 3H), 2.19-2.28 (m, 1H), 1.96-2.09 (m, 1H), 1.82-1.94 (m, 1H), 1.70 (s, 3H). - 133 -25972-WO-PCT 12617.0005-00304 Example 67: 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3-yl)benzamide

[0250] To a solution of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (30 mg, 0.050 mmol) in DMF (0.5 mL) were added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate(V) (24.82 mg, 0.065 mmol) and N-ethyl-N- isopropylpropan-2-amine (19.47 mg, 0.151 mmol), the mixture was stirred for 0.5 h at 25 °C. Then N-ethyl-N-isopropylpropan-2-amine (19.47 mg, 0.151 mmol) was added to the mixture, and the mixture was stirred for 1 h at 25 °C. LCMS showed desired mass peak was observed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (10 mM - NH4HCO3) - ACN Begin B 40 End B 70 Gradient Time (min) 11100% B Hold Time 2.5 Flow Rate (ml / min) 25 Injections 1) to give 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4- yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- (oxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C29H32F4N5O3Se+[M+H]+: 654.2, found: 654.1 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 6.9 Hz, 1H), 7.51 (dd, J = 8.3, 1.9 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 6.82-6.93 (m, 2H), 6.66 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.5 Hz, 1H), 5.07-5.18 (m, 1H), 4.92-4.95 (m, 2H), 4.80-4.86 (m, 1H), 4.72 (t, J = 6.6 Hz, 2H), 4.30 (s, 2H), 3.92 (s, 3H), 3.55-3.70 (m, 1H), 3.15-3.24 (m, 1H), 2.94 (br d, J = 12.9 Hz, 1H), 2.40 (d, J = 13.1 Hz, 1H), 2.31 (s, 3H), 2.20-2.29 (m, 1H), 1.98-2.09 (m, 1H), 1.87-1.95 (m, 1H). - 134 -25972-WO-PCT 12617.0005-00304 Example 68: 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3-yl)benzamide

[0251] To a solution of 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoic acid (30 mg, 0.050 mmol) in DMF (0.5 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate(V) (24.82 mg, 0.065 mmol) and N-ethyl-N- isopropylpropan-2-amine (19.47 mg, 0.151 mmol), and the mixture was stirred for 0.5 h at 25 °C. Then (R)-tetrahydrofuran-3-amine (6.56 mg, 0.075 mmol) was added to the mixture, and the mixture was stirred for 1 h at 25 °C. LCMS showed desired mass peak was observed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column Boston Prime C18150*30mm*5um Condition Water (0.05% NH3H2O + 10mM NH4HCO3) - ACN Begin B 45 End B 75 Gradient Time (min) 2.5100% B Hold Time 11 Flow Rate (ml / min) 25 Injections 1) to give 4-((3-(8-(((3S,4R)-3-fluoro-1- methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-((R)-tetrahydrofuran-3-yl)benzamide. MS (ESI) m / z: calc'd for C30H34F4N5O3Se+[M+H]+: 668.2, found: 668.1 [M+H]+.1H NMR (400 MHz, MeOD) δ = 7.85 (d, J = 6.9 Hz, 1H), 7.47 (dd, J = 1.8, 8.3 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 6.93 - 6.82 (m, 2H), 6.65 (t, J = 7.2 Hz, 1H), 6.05 (d, J = 7.4 Hz, 1H), 4.94 (br s, 1H), 4.62 - 4.54 (m, 1H), 4.29 (s, 2H), 4.02 - 3.94 (m, 2H), 3.92 (s, 3H), 3.83 (dt, J = 6.1, 8.2 Hz, 1H), 3.71 (dd, J = 4.2, 9.1 Hz, 1H), 3.68 - 3.56 (m, 1H), 3.26 - 3.13 (m, 1H), 3.01 - 2.90 (m, 1H), 2.44 - 2.32 (m, 1H), 2.31 (s, 3H), 2.29 - 2.19 (m, 2H), 2.07 - 1.96 (m, 2H), 1.94 - 1.87 (m, 1H). - 135 -25972-WO-PCT 12617.0005-00304 Example 69: 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamideStep 1: 4-methoxy-3-((3-(1 -8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid

[0252] A mixture of methyl 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- 2-yn-1-yl)amino)benzoate (136 mg, 0.219 mmol) and LiOH·H2O (36.8 mg, 0.877 mmol) in MeOH (1.5 mL) and water (0.5 mL) was stirred at 50 °C for 1 h. LCMS showed that desired target was observed and starting material was consumed. The solvent was concentrated under reduced pressure to give the crude 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- 2-yn-1-yl)amino)benzoic acid, which was not further purified. MS (ESI) m / z: calc'd for C27H29F3N5O3Se+[M+H]+: 608.1, found [M+H]+: 608.1. Step 2: 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(oxetan- 3-yl)benzamide

[0253] A mixture of 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid (20 mg, 0.033 mmol), DIEA (0.017 mL, 0.099 mmol), and 2-(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (16.30 mg, 0.043 mmol) in DMF (0.5 mL) was added oxetan-3-amine (2.89 mg, 0.040 mmol), and the mixture was stirred at 20 ºC for 1 h. LCMS showed desired mass. The reaction was filtered, and the residue was purified by Prep HPLC (Column Welch Xtimate C18150*25 mm*5 um Condition water (10mM-NH4HCO3)-ACN Begin B 45 End B 75 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- - 136 -25972-WO-PCT 12617.0005-00304 2-yn-1-yl)amino)-N-(oxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C30H34F3N6O3Se+[M+H]+663.1, found [M+H]+663.1.1H NMR (400 MHz, MeOD) δ = 7.63 (d, J = 4.9 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 2.1, 8.3 Hz, 1H), 7.19 (d, J = 4.9 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.11 (q, J = 6.8 Hz, 1H), 4.95 - 4.93 (m, 2H), 4.72 (t, J = 6.6 Hz, 2H), 4.35 - 4.28 (m, 3H), 3.92 (s, 3H), 3.42 (br d, J = 2.5 Hz, 1H), 3.17 - 3.12 (m, 1H), 2.31 (s, 3H), 2.17 - 2.01 (m, 1H), 1.91 - 1.71 (m, 4H), 1.67 - 1.56 (m, 2H), 1.55 - 1.46 (m, 1H). Example 70: 4-((3-(8-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide

[0254] A mixture containing 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn- 1-ol (200 mg, 0.50 mmol) in DCM (1 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (260 mg, 2.01 mmol) followed by methanesulfonyl chloride (90 mg, 0.79 mmol). The mixture was stirred 1 h, diluted with DCM, washed with water, dried (MgSO4), and concentrated. The concentrate was dissolved in 1,4-dioxane (1 mL) and treated with cesium carbonate (650 mg, 1.99 mmol) and 4-amino-3-methoxy-N-methylbenzamide (140 mg, 0.78 mmol). The mixture was stirred for 12 hours at 90 °C, filtered, and concentrated. The residue was purified by chromatography on SiO2(apply to SiO2in DCM, elute with 50% EtOAc / hexanes, 12 g silica gel) to provide 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide. MS (EI) calc'd for C21H18BrF3N3O2Se [M+H]+, 560; found, 560.

[0255] A mixture of 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl) amino)-3-methoxy-N-methylbenzamide (35 mg, 0.063 mmol), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (25 mg, 0.19 mmol), and cesium carbonate (75 mg, 0.23 mmol) in 1,4- - 137 -25972-WO-PCT 12617.0005-00304 dioxane (1 mL) was treated with Pd PEPPSI-HeptCl (15 mg, 0.015 mmol) and deoxygenated by bubbling Ar in the mixture for 3 min. The mixture was warmed to 100 °C and stirred for 6 hours. The reaction mixture was cooled, diluted with 1 mL of DMSO, and purified by reverse phase chromatography (gradient of 33-63% MeCN / water with 0.1% NH4OH) to provide 4-((3- (8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl) indolizin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide.1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1 H), 8.10 (s, 1 H), 7.83 (s, 1 H), 7.42 (s, 1 H), 7.35 (s, 1 H), 7.10-7.27 (m, 2 H), 7.03 (s, 1 H), 6.76 (m, 2 H), 6.06 (m, 2 H), 5.16 (m, 1 H), 4.27 (s, 2 H), 3.50 (s, 2 H), 3.41 (m, 1 H), 3.17 (s, 1 H), 2.83 (s, 3 H), 2.77 (s, 3 H), 2.21 (s, 1 H), 2.01 (s, 1 H). MS (EI) calc'd for C27H30F4N5O2Se [M+H]+, 612; found, 612. Example 71: 3-((3-(8-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide

[0256] A mixture of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-ol (50 mg, 0.13 mmol) in DCM (1 mL) was treated with Hunig's Base (0.10 mL, 0.57 mmol) and methanesulfonyl chloride (20 μL, 0.26 mmol). The mixture was stirred for 30 min, diluted with DCM, washed with water, dried over Na2SO4, and concentrated. The residue was dissolved in dioxane (1 mL) and treated with cesium carbonate (120 mg, 0.37 mmol) and 3-amino-4- methoxy-N-methylbenzamide (50 mg, 0.28 mmol). The mixture was stirred for 5 h at 100 °C, filtered, and concentrated. The concentrate was subjected to chromatography on SiO2 (0-50% EtOAc / hexanes) to produce 3-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn- 1-yl)amino)-4-methoxy-N-methylbenzamide. MS (EI) calc'd for C21H18BrF3N3O2Se [M+H]+, 560; found, 560. - 138 -25972-WO-PCT 12617.0005-00304

[0257] A mixture of 3-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide (13 mg, 0.023 mmol), (3S,4R)-3-fluoro-1- methylpiperidin-4-amine (20 mg, 0.15 mmol), and cesium carbonate (50 mg, 0.15 mmol) in 1,4- dioxane (1 mL) was treated with PEPPSI-HeptCl-Pd (10 mg, 0.010 mmol) and deoxygenated by bubbling Ar for 3 min. The mixture was warmed to 100 °C, stirred for 6 h, and filtered, and the filtrate purified by reverse phase chromatography (gradient of 16-80% MeCN / water) to provide 3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)selanyl)indolizin- 2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide.1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1 H), 8.14 (d, J = 4.5 Hz, 1 H), 7.82 (d, J = 6.7 Hz, 1 H), 7.26 (s, 1 H), 7.16 (d, J = 4.7 Hz, 2 H), 6.88 (d, J = 8.3 Hz, 1 H), 6.74 (t, J = 7.2 Hz, 1 H), 6.11 (d, J = 7.4 Hz, 1 H), 6.01 (d, J = 7.1 Hz, 1 H), 5.16 (m, 1 H), 4.27 (s, 2 H), 3.50 (m, 2 H), 3.42 (s, 1 H), 3.16 (s, 2 H), 2.83 (s, 3 H), 2.76 (s, 3 H), 2.19 (m, 2 H), 1.99 (m, 1 H). MS (EI) calc'd for C27H30F4N5O2Se [M+H]+, 612; found, 612. Example 72: 3-Methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan- 2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzamide

[0258] A mixture of 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide (20 mg, 0.036 mmol), (1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-amine (15 mg, 0.11 mmol), and cesium carbonate (40 mg, 0.12 mmol) in 1,4-dioxane (1 mL) was treated with PEPPSI-HeptCl-Pd (8 mg, 0.2 eq, 8 μmol) and deoxygenated by bubbling Ar for 3 min. The mixture was warmed to 100 °C, stirred for 18 h, filtered, and purified by reverse phase chromatography (9-49% MeCN / water with 0.1% NH4OH) gave desired product 3-methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide.1H NMR (500 MHz, DMSO-d6) δ 9.47 (s, 1 H), 8.10 (d, J = 4.3 Hz, 1 H), 7.82 (d, J = 6.9 Hz, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.35 (s, 1 H), 7.12 (d, J = 6.4 Hz, 1 H), 6.76 - 139 -25972-WO-PCT 12617.0005-00304 (m, 2 H), 6.12 (d, J = 7.5 Hz, 1 H), 5.94 (d, J = 7.5 Hz, 1 H), 4.27 (s, 2 H), 3.97 (m, 1 H), 3.88 (s, 1 H), 3.85 (s, 3 H), 3.81 (m, 1 H), 2.72-2.78 (m, 4 H), 2.10-2.30 (m, 2 H), 1.85-2.10 (m, 2 H), 1.70-1.85 (m, 4 H). MS (EI) calc'd for C29H33F3N5O2Se [M+H]+, 620; found, 620. Example 73: 4-Methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan- 2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzamide

[0259] A mixture of 3-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide (15 mg, 0.027 mmol), (1R,2R,5R)-8-methyl-8- azabicyclo [3.2.1]octan-2-amine (10 mg, 0.071 mmol), and cesium carbonate (40 mg, 0.12 mmol) in 1,4-dioxane (1 mL) was treated with PEPPSI-HeptCl-Pd (8 mg, 0.08 mmol) and deoxygenated by bubbling argon for 3 min. The mixture was warmed to 100 °C, stirred for 18 h, filtered, and purified by reverse phase chromatography (17-47% MeCN / water with 0.1% NH4OH) gave 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzamide.1H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1 H), 8.15 (s, 1 H), 7.81 (d, J = 6.8 Hz, 1 H), 7.25 (m, 1 H), 7.12-7.19 (m, 1 H), 7.11 (s, 1 H), 7.04 (s, 1 H), 6.88 (d, J = 8.2 Hz, 1 H), 6.75 (t, J = 7.0 Hz, 1 H), 6.12 (d, J = 7.3 Hz, 1 H), 5.94 (d, J = 7.5 Hz, 1 H), 4.27 (s, 2 H), 3.97 (m, 1 H), 3.88 (m, 1 H), 3.85 (s, 3 H), 3.82 (s, 1 H), 2.72-2.78 (m, 4 H), 2.10-2.25 (m, 2 H), 1.85-2.05 (m, 2 H), 1.70- 1.85 (m, 4 H). MS (EI) calc'd for C29H33F3N5O2Se [M+H]+, 620; found, 620. Example 74: N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)amino)benzamide- 140 -25972-WO-PCT 12617.0005-00304

[0260] A mixture of 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid (20 mg, 0.033 mmol), DIEA (0.017 mL, 0.099 mmol), and HATU (15.05 mg, 0.040 mmol) in DMF (0.5 mL) was added (R)-1-aminopropan-2-ol (3.22 mg, 0.043 mmol), and the mixture was stirred at 20 °C for 1 h. LCMS showed desired mass. The reaction was filtered, and the residue was purified by Prep HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (10 mM-NH4HCO3)-ACN Begin B 40 End B 70 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1- (((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino) benzamide. MS (ESI) m / z: calc'd for C30H36F3N6O3Se+[M+H]+665.0, found [M+H]+665.0.1H NMR (400 MHz, MeOD) δ = 7.63 (br d, J = 4.6 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.26 (br dd, J = 1.9, 8.3 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.13 (s, 1H), 6.90 (br d, J = 8.5 Hz, 1H), 4.37 - 4.28 (m, 3H), 3.99 - 3.94 (m, 1H), 3.91 (s, 3H), 3.41 (br dd, J = 4.4, 13.6 Hz, 3H), 3.16 (br d, J = 2.7 Hz, 1H), 2.39 - 2.28 (m, 3H), 2.17 - 2.01 (m, 1H), 1.92 - 1.80 (m, 3H), 1.79 - 1.71 (m, 1H), 1.67 - 1.57 (m, 2H), 1.55 - 1.47 (m, 1H), 1.18 (br d, J = 6.3 Hz, 3H). Example 75: 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamide

[0261] A mixture of 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl) amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid (26 mg, 0.043 mmol), DIEA (0.022 mL, 0.129 mmol), and 2-(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (21.19 mg, 0.056 mmol) in DMF (0.5 mL) was added oxetan-3-amine (6.27 mg, 0.086 mmol), and the mixture was stirred at 25 °C for 1 h. LCMS showed desired mass. The reaction was filtered, and the residue was purified by Prep HPLC (Column Welch Xtimate C4150*25 mm*10 um Condition water (10mM-NH4HCO3)-ACN Begin B 30 End B 60 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- - 141 -25972-WO-PCT 12617.0005-00304 2-yn-1-yl)amino)-N-(oxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C30H34F3N6O3Se+[M+H]+663.1, found [M+H]+663.1.1H NMR (400 MHz, MeOD) δ = 7.67 (d, J = 4.9 Hz, 1H), 7.53 (dd, J = 1.8, 8.3 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 7.15 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.20 - 5.09 (m, 1H), 4.97 - 4.93 (m, 2H), 4.74 (t, J = 6.6 Hz, 2H), 4.39 - 4.30 (m, 3H), 3.95 (s, 3H), 3.46 (br d, J = 2.9 Hz, 1H), 3.20 - 3.15 (m, 1H), 2.34 (s, 3H), 2.18 - 2.05 (m, 1H), 1.93 - 1.82 (m, 3H), 1.81 - 1.73 (m, 1H), 1.69 - 1.58 (m, 2H), 1.58 - 1.49 (m, 1H). Example 76: 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (3-methyloxetan-3-yl)benzamideStep 1: 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine

[0262] To a solution of 1-chloro-7-iodo-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazine (150 mg, 0.353 mmol) in DMSO (1 mL) was added (1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-amine (99 mg, 0.705 mmol), N-ethyl-N-isopropylpropan-2-amine (456 mg, 3.53 mmol), and cesium fluoride (214 mg, 1.410 mmol). The mixture was stirred for 12 h at 100 °C. LCMS showed desired mass. The reaction was diluted with water (8 mL) and extracted with EtOAc (8 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 10% MeOH gradient @ 30 mL / min) to afford 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine. MS (ESI) m / z: calc'd for C16H19F3IN4Se+[M+H]+530.8, found [M+H]+530.8. Step 2: 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid

[0263] A mixture of CuI (8.35 mg, 0.044 mmol), DIPA (0.138 mL, 0.986 mmol), Pd(PPh3)4(19.00 mg, 0.016 mmol), 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (58 mg, 0.110 mmol), and 4-methoxy-3- (prop-2-yn-1-ylamino)benzoic acid (33.7 mg, 0.164 mmol) in DMSO (0.5 mL) was stirred at 20 - 142 -25972-WO-PCT 12617.0005-00304 °C for 2 h under N2atmosphere. LCMS showed desired mass. The reaction was filtered, and the residue was purified by Prep HPLC (Column YMC-Actus Triart C18150*30 mm*5 um Condition water (0.1%TFA)-ACN Begin B 22 End B 42 Gradient Time (min) 11100%B Hold Time 1.1 Flow Rate (mL / min) 40) to give methyl 4-hydroxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo [3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- 2-yn-1-yl)amino)benzoate. MS (ESI) m / z: calc'd for C27H29F3N5O3Se+[M+H]+608.1, found [M+H]+608.1. Step 3: 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide

[0264] A mixture of 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid (17 mg, 0.028 mmol), DIEA (0.015 mL, 0.084 mmol), and 2-(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (13.85 mg, 0.036 mmol) in DMF (0.5 mL) was added 3-methyloxetan-3-amine (2.93 mg, 0.034 mmol), and the mixture was stirred at 20 °C for 1 h. LCMS showed desired mass. The reaction was filtered, and the residue was purified by Prep HPLC (Column Welch Xtimate C4150*25 mm*10 um Condition water (10 mM-NH4HCO3)-ACN Begin B 30 End B 60 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- 2-yn-1-yl)amino)-N-(3-methyloxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C31H36F3N6O3Se+[M+H]+677.1, found [M+H]+677.1.1H NMR (400 MHz, MeOD) δ = 7.67 - 7.61 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 2.0, 8.3 Hz, 1H), 7.19 (d, J = 4.9 Hz, 1H), 7.13 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.94 (br s, 2H), 4.51 (d, J = 6.7 Hz, 2H), 4.36 - 4.31 (m, 1H), 4.30 (s, 2H), 3.92 (s, 3H), 3.44 (br d, J = 2.7 Hz, 1H), 3.19 - 3.14 (m, 1H), 2.33 (s, 3H), 2.16 - 2.04 (m, 1H), 1.91 - 1.84 (m, 2H), 1.83 - 1.72 (m, 2H), 1.71 (s, 3H), 1.67 - 1.57 (m, 2H), 1.57 - 1.48 (m, 1H). - 143 -25972-WO-PCT 12617.0005-00304 Example 77: 4-((3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide

[0265] A mixture of 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide (37 mg, 0.066 mmol), 2-((1R,2R,5R)-2-amino-8- azabicyclo[3.2.1]octan-8-yl)ethan-1-ol (16.90 mg, 0.099 mmol), PEPPSI-IpentCl Pd (12.89 mg, 0.013 mmol), and Cs2CO3 (64.7 mg, 0.198 mmol) in dioxane (0.5 mL) and was stirred at 100 °C for 2 hours under N2 atmosphere. LCMS showed desired mass. The solvent was removed under reduced pressure, and the residue was purified by Prep HPLC (Column Phenomenex Synergi C18150*30MM*4um Condition water (0.1%TFA)-ACN Begin B 35 End B 55 Gradient Time (min) 10100%B Hold Time 2 Flow Rate (mL / min) 25) to give 4-((3-(8-(((1R,2R,5R)-8-(2- hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide. MS (ESI) m / z: calc'd for C30H35F3N5O3Se+[M+H]+650.2, found [M+H]+650.2.1H NMR (400 MHz, MeOD) δ = 7.90 (d, J = 7.0 Hz, 1H), 7.43 (dd, J = 1.9, 8.3 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 6.94 - 6.85 (m, 2H), 6.68 (t, J = 7.2 Hz, 1H), 6.09 (d, J = 7.6 Hz, 1H), 4.29 (s, 2H), 4.25 - 4.20 (m, 1H), 4.18 - 4.13 (m, 1H), 4.11 - 4.03 (m, 1H), 3.95 - 3.90 (m, 5H), 3.21 (t, J = 4.9 Hz, 2H), 2.90 (s, 3H), 2.37 - 2.23 (m, 2H), 2.14 - 2.05 (m, 2H), 2.03 - 1.95 (m, 2H), 1.94 - 1.84 (m, 2H). Example 78: 3-methoxy-N-methyl-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan- 2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide

[0266] A mixture of CuI (7.20 mg, 0.038 mmol), DIPA (0.119 mL, 0.850 mmol), Pd(PPh3)4 (16.38 mg, 0.014 mmol), 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-1-amine (50 mg, 0.094 mmol), and 3-methoxy- - 144 -25972-WO-PCT 12617.0005-00304 N-methyl-4-(prop-2-yn-1-ylamino)benzamide (20.62 mg, 0.094 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 h under N2 atmosphere. LCMS showed desired mass. The reaction was diluted with water (6 mL) and extracted with EtOAc (6 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep HPLC (Column Phenomenex Synergi C18150*30 mm *4 um Condition water (0.1%TFA)-ACN Begin B 28 End B 48 Gradient Time (min) 10100%B Hold Time 2 Flow Rate (mL / min) 25) to give 3-methoxy-N-methyl-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop- 2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc'd for C28H32F3N6O2Se+[M+H]+621.1, found [M+H]+621.1.1H NMR (400 MHz, MeOD) δ = 7.85 (d, J = 5.2 Hz, 1H), 7.43 (dd, J = 1.8, 8.3 Hz, 1H), 7.34 (d, J = 1.8 Hz, 2H), 7.26 (d, J = 5.2 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.31 (s, 2H), 4.09 (br d, J = 3.3 Hz, 1H), 3.94 (br d, J = 5.7 Hz, 1H), 3.92 - 3.90 (m, 3H), 2.90 (s, 3H), 2.84 (s, 3H), 2.44 - 2.31 (m, 1H), 2.25 - 2.14 (m, 2H), 2.10 - 1.88 (m, 5H). Example 79: 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamideStep 1: methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)(tert-butoxycarbonyl)amino)-3-methoxybenzoate

[0267] To a mixture of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl methanesulfonate (190 mg, 0.400 mmol), methyl 4-((tert-butoxycarbonyl)amino)-3- methoxybenzoate (124 mg, 0.440 mmol), and Cs2CO3 (391 mg, 1.200 mmol) in DMF (2.5 mL) was added tetrabutylammonium bromide (51.6 mg, 0.160 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (8 mL*3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of [0~5%] ethyl acetate / hexane gradient @ 35 mL / min) to give methyl 4-((3-(8-bromo-3- ((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)(tert-butoxycarbonyl)amino)-3- - 145 -25972-WO-PCT 12617.0005-00304 methoxybenzoate. MS (ESI) m / z: calc'd for C26H25BrF3N2O5Se+[M+H-C4H8]+: 605.1 / 607.1 found 604.9 / 606.9 [M+H-C4H8]+. Step 2: methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzoate

[0268] To a mixture of methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop- 2-yn-1-yl)(tert-butoxycarbonyl)amino)-3-methoxybenzoate (238 mg, 0.360 mmol) and 2,6- lutidine (0.210 mL, 1.802 mmol) in DCM (5 mL) was added trimethylsilyl trifluoromethanesulfonate (0.250 mL, 1.442 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with DCM (3 mL*3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH (1.5 mL), filtered, and rinsed with MeOH (1 mL). The filter cake was collected to give methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxybenzoate. MS (ESI) m / z: calc'd for C21H17BrF3N2O3Se+[M+H]+: 561.1 / 563.1 found 560.9 / 562.9 [M+H]+. Step 3: methyl 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoate

[0269] To a solution of methyl 4-((3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxybenzoate (54 mg, 0.096 mmol) in 1,4-dioxane (1.5 mL) was added (1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-amine (20.27 mg, 0.145 mmol), cesium carbonate (94 mg, 0.289 mmol), and PEPPSI-IpentCl Pd (18.75 mg, 0.019 mmol), and the resulting mixture was stirred at 100 °C for 1 h under N2. The reaction mixture was quenched with water (8 mL) and extracted with EtOAc (5 mL*3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica gel, MeOH / DCM = 1 / 6, v / v) to give methyl 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoate. MS (ESI) m / z: calc'd for C29H32F3N4O3Se+[M+H]+: 621.1 found 621.1 [M+H]+. Step 4: 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoic acid

[0270] To a mixture of methyl 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoate (44 mg, 0.071 mmol) in MeOH / water 4:1 (1.5 mL) was added lithium hydroxide hydrate (11.92 mg, 0.284 mmol) at 25 °C. The resulting mixture was stirred at 80 °C for 4 h. LCMS showed that the - 146 -25972-WO-PCT 12617.0005-00304 reaction completed. The reaction mixture was quenched with 2 M aq. HCl (0.15 mL) and concentrated under reduced pressure to give 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzoic acid. MS (ESI) m / z: calc'd for C28H30F3N4O3Se+[M+H]+: 607.1 found 607.1 [M+H]+. Step 5: 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan-3- yl)benzamide

[0271] To a mixture of 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoic acid (21 mg, 0.035 mmol), HATU (14.51 mg, 0.038 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.173 mmol) in DMF (1 mL) was stirred for 5 min at 25 °C, then 3-methyloxetan-3-amine (3.63 mg, 0.042 mmol) was added. The mixture was stirred at 25 °C for 20 min. LCMS showed the reaction completed. The reaction mixture was purified by Prep-HPLC (Column Welch Xtimate C18150*25 mm*5 um Condition water (10 mM-NH4HCO3)-ACN Begin B 40 End B 70 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give 3-methoxy-4- ((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan-3- yl)benzamide. MS (ESI) m / z: calc'd for C32H37F4N5O3Se+[M+H]+: 676.1 found 676.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.85 (d, J = 6.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.65 (t, J = 7.2 Hz, 1H), 6.55 (s, 1H), 6.36 (s, 1H), 6.11 (d, J = 7.4 Hz, 1H), 4.95 (t, J = 6.1 Hz, 1H), 4.87 (d, J = 6.3 Hz, 2H), 4.57 (d, J = 6.4 Hz, 2H), 4.29 (d, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.82 (br s, 1H), 3.74 (br d, J = 7.3 Hz, 1H), 3.36 (br d, J = 4.9 Hz, 1H), 3.24 - 3.18 (m, 1H), 2.36 (s, 3H), 2.07 (dt, J = 6.1, 12.0 Hz, 1H), 1.90 - 1.84 (m, 3H), 1.77 (s, 3H), 1.70 - 1.62 (m, 1H), 1.59 - 1.49 (m, 2H), 1.36 - 1.24 (m, 1H). - 147 -25972-WO-PCT 12617.0005-00304 Example 80: N-(3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamideStep 1: benzyl ((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate

[0272] A mixture of benzyl ((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)carbamate (1.6 g, 6.15 mmol), 2-bromoethan-1-ol (1.152 g, 9.22 mmol), and DIPEA (3.22 mL, 18.44 mmol) in MeCN (16 mL) was stirred at 80 °C for 1 h. LCMS showed that desired target was observed and starting material was consumed. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 30% ethyl acetate / ethanol gradient @ 30 mL / min) to give benzyl ((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate. MS (ESI) m / z: calc'd for C17H25N2O3+[M+H]+: 305.2, found [M+H]+: 305.0. Step 2: 2-((1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol

[0273] Benzyl N-[(1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl]carbamate,1.0 eq, 0.2 g in MeOH,10 mL and THF,10 mL . A 5mL fixed bed was packed with granular catalyst 5% Pd / Al2O3(WXC1035, 3.3 g) . The H2back pressure regulator was adjusted to 1.0 MPa, and the flow rate of H2was 30 mL / min. Then the solution was pumped to the fixed bed. Then the reaction mixture was collected. The solvent was removed under reduced pressure to give the crude product 2-((1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol. MS (ESI) m / z: calc'd for C9H19N2O+[M+H]+: 171.1, found [M+H]+: 171.1. Step 3: 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine

[0274] A mixture of 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-ol (200 mg, 0.504 mmol) and DBU (0.091 mL, 0.604 mmol) in THF (4 mL) was added DPPA (0.130 mL, 0.604 mmol). The mixture was stirred at 60 °C for 1 h. LCMS showed that desired target was observed and starting material was consumed. The reaction mixture was added aq. NaHCO3 to adjust pH~9 and extracted with EtOAc (10 mL*3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude - 148 -25972-WO-PCT 12617.0005-00304 product 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine. The crude product was used directly without further work up and purification. MS (ESI) m / z: calc'd for C12H7BrF3N4Se+[M+H]+: 420.9 / 422.9 / 424.9, found [M+H]+: 420.8 / 422.8 / 424.8. Step 4: 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine

[0275] A mixture of 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)selanyl)indolizine (200 mg, 0.474 mmol) and triphenylphosphine (249 mg, 0.948 mmol) in THF (2 mL) and water (1 mL) was stirred at 50 °C for 1 h. LCMS showed that desired target was observed and starting material was consumed. The reaction mixture was adjust to pH~4 by 2M HCl, and the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 50% ethyl acetate / pet. ether gradient @ 30 mL / min) to give 3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine. MS (ESI) m / z: calc'd for C12H9BrF3N2Se+[M+H]+: 394.9 / 396.9 / 398.9, found [M+H]+: 394.8 / 396.8 / 398.8. Step 5: N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1- methyl-1H-pyrazole-4-carboxamide

[0276] To a mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (20 mg, 0.159 mmol) in DMF (1 mL) were added HATU (72.4 mg, 0.190 mmol) and DIEA (0.055 mL, 0.317 mmol) at 20 °C, the mixture was stirred at 20 °C for 5 min, and then 3-(8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-amine (82 mg, 0.206 mmol) was added. The resulting mixture was stirred at 20 °C for 1 h. LCMS showed desired target was observed and the starting material was consumed. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (20 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (0.1%TFA)-ACN Begin B 43 End B 73 Gradient Time (min) 11100%B Hold Time 3 Flow Rate ( mL / min) 25 Injections 3) to give N-(3-(8-bromo-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc'd for C17H13BrF3N4OSe+[M+H]+: 502.9 / 504.9 / 506.9, found [M+H]+: 502.8 / 504.8 / 506.8. - 149 -25972-WO-PCT 12617.0005-00304 Step 6: N-(3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide

[0277] In a glove box, to a solution of N-(3-(8-bromo-3-((trifluoromethyl)selanyl)indolizin-2- yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (90 mg, 0.179 mmol) in 1,4-dioxane (1 mL) were added 2-((1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-ol (45.6 mg, 0.268 mmol), cesium carbonate (174 mg, 0.536 mmol), and PEPPSI-IpentCl Pd (34.7 mg, 0.036 mmol), and the resulting mixture was stirred at 100 °C for 15 min under N2. LCMS showed desired target was observed and the starting material was consumed. The mixture was filtered, and the filtrate was purified by Prep-HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (0.1%TFA)-ACN Begin B 20 End B 50 Gradient Time (min) 11100%B Hold Time 3 Flow Rate (ml / min) 25 Injections 1) to give N-(3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1- methyl-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc'd for C26H30F3N6O2Se+[M+H]+: 593.1 / 595.1 / 596.1, found [M+H]+: 593.1 / 595.1 / 596.1.1H NMR (400 MHz, MeOD) δ = 8.07 (s, 1H), 7.95 - 7.89 (m, 2H), 6.99 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H), 4.39 (s, 2H), 4.27 - 4.21 (m, 1H), 4.16 (br dd, J = 2.5, 6.2 Hz, 1H), 4.11 - 4.05 (m, 1H), 3.95 - 3.93 (m, 1H), 3.93 (s, 3H), 3.91 (br s, 1H), 3.22 (t, J = 5.1 Hz, 2H), 2.33 - 2.24 (m, 2H), 2.13 - 2.06 (m, 2H), 2.05 - 1.99 (m, 2H), 1.93 - 1.86 (m, 2H). Example 81: 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N- (3-methyloxetan-3-yl)benzamideStep 1: tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0278] A mixture of 7-chloro-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridine (250 mg, 0.588 mmol), tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (173 mg, 0.764 mmol), CsF (268 mg, 1.763 mmol), and DIEA (0.616 mL, 3.53 mmol) in DMSO (2 mL) was stirred at 80 °C for 16 h. LCMS showed that the reaction was completed. The reaction mixture was quenched with (20 mL) and extracted with EtOAc (15 mL*3). The combined - 150 -25972-WO-PCT 12617.0005-00304 organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, eluent of 5% ethyl acetate / pet. ether gradient @ 30 mL / min) to give tert-butyl (1R,2R,5R)-2-((2-iodo-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) m / z: calc'd for C20H24F3IN4O2Se+[M+H]+:615.0 / 617.0 found:615.0 / 617.0 [M+H]+. Step 2: N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0279] A mixture of tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.098 mmol) in DCM / TFA = 3:1 (1 mL) was stirred at 25 °C for 40 min. LCMS showed that the reaction was completed. The solvent was removed under vacuum to give the crude N-((1R,2R,5S)-8- azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine, which was used in next step without further purification. MS (ESI) m / z: calc'd for C15H17F3IN4Se+[M+H]+:515.0 / 517.0 found:515.0 / 517.0 [M+H]+. Step 3: 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine

[0280] To a solution of N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3- ((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-7-amine (50.2 mg, 0.097 mmol) and paraformaldehyde (7.31 mg, 0.244 mmol) in MeOH (1 mL) at 25 °C. After stirring for 0.5 h at 50 °C, NaBH3(CN) (18.37 mg, 0.292 mmol) was added to the mixture at 25 °C. The resulting mixture was stirred for another 2 h at 50 °C. LCMS showed the reaction was completed. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep TLC (silica gel, DCM / MeOH = 100 / 10, v / v) to give 2-iodo-N-((1R,2R,5R)-8- methyl-8-azabicyclo[3.2.1]octan-2-yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7- amine. MS (ESI) m / z: calc'd for C16H19F3IN4Se+[M+H]+:529.0 / 531.0 found:529.0 / 531.0 [M+H]+. Step 4: 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzoic acid

[0281] A mixture of 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-7-amine (50 mg, 0.094 mmol), 3-methoxy-4- (prop-2-yn-1-ylamino)benzoic acid (27.1 mg, 0.132 mmol), CuI (7.20 mg, 0.038 mmol), - 151 -25972-WO-PCT 12617.0005-00304 Pd(PPh3)4(16.38 mg, 0.014 mmol), and DIPA (0.132 mL, 0.945 mmol) in DMSO (2 mL), and the mixture was degassed and backfilled with N2 (three times). The mixture was stirred at 25 °C for 1.5 h. After cooling to r.t., LCMS showed that the reaction was completed. The mixture was filtered, and the filtrate was purified by Prep-HPLC (Column Boston Prime C18 150*30mm*5um Condition water (0.1%TFA)-ACN Begin B 42 End B 62 Gradient Time (min) 11100%B Hold Time 2 Flow Rate (ml / min) 25) to give 3-methoxy-4-((3-(7-(((1R,2R,5R)-8- methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)benzoic acid. MS (ESI) m / z: calc'd for C27H29F3N5O3Se+[M+H]+:606.0 / 608.0 found:606.1 / 608.1 [M+H]+. Step 5: 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide

[0282] To a solution of 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzoic acid (26 mg, 0.043 mmol) in DMF (1 mL) was added DIEA (0.030 mL, 0.171 mmol) and HATU (19.56 mg, 0.051 mmol) at 25 °C over 1 min. After stirring for 10 min at 25 °C, 3-methyloxetan- 3-amine (5.60 mg, 0.064 mmol) was added to the mixture at 25 °C. The resulting mixture was stirred for another 1 h. LCMS showed the reaction was completed. The mixture was filtered, and the filtrate was purified by Prep-HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (10mM-NH4HCO3)-ACN Begin B 50 End B 80 Gradient Time (min) 11100%B Hold Time 2.5 Flow Rate (ml / min) 25) to give 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan-3-yl)benzamide. MS (ESI) m / z: calc'd for C31H36F3N6O3Se+[M+H]+: 675.2 / 677.2 found: 675.1 / 677.1 [M+H]+.1H NMR (CDCl3, 400 MHz): δ (ppm) 7.37 (d, J = 1.8 Hz, 1H), 7.31-7.36 (m, 1H), 7.25 (dd, J = 8.3, 1.7 Hz, 1H), 6.97- 7.02 (m, 1H), 6.77-6.83 (m, 1H), 6.29-6.34 (m, 1H), 6.12-6.18 (m, 1H), 5.79-5.86 (m, 1H), 4.97- 5.03 (m, 1H), 4.87 (d, J = 6.3 Hz, 2H), 4.57 (d, J = 6.4 Hz, 2H), 4.37 (d, J = 6.2 Hz, 2H), 3.92 (s, 3H), 3.74-3.87 (m, 1H), 3.27-3.34 (m, 1H), 3.15-3.22 (m, 1H), 2.31-2.38 (m, 3H), 2.04-2.15 (m, 1H), 1.81-1.97 (m, 3H), 1.77 (s, 3H), 1.69-1.75 (m, 1H), 1.52 (br dd, J = 4.6, 3.9 Hz, 2H), 1.39- 1.50 (m, 1H). - 152 -25972-WO-PCT 12617.0005-00304 Example 82: 4-((3-(7-(((1S,2R,5R,7R)-7-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamideStep 1: ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate

[0283] To a solution of ethyl 5-formyl-1H-pyrrole-2-carboxylate (10 g, 59.8 mmol) in THF (200 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (13.41 g, 59.8 mmol), lithium chloride (2.66 g, 62.8 mmol), and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (9.56 g, 62.8 mmol), and the resulting mixture was stirred at 20 °C for 16 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was added water (200 mL) and extracted with EtOAc (100 mL * 3). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (120 g), Eluent of 0 ~ 20% ethyl acetate / petroleum ether gradient @ 50 mL / min) and triturated with pet. ether (100 mL) to give ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate. MS (ESI) m / z: calc'd for C12H16NO4+[M+H]+238.2, found [M+H]+238.1.1H NMR (400MHz, CDCl3-d) δ 9.27-9.48 (m, 1H), 7.52 (d, J = 16.0 Hz, 1H), 6.90 (dd, J = 4.0, 2.4 Hz, 1H), 6.52- 6.57 (m, 1H), 6.23 (d, J = 16.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.26 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H). Step 2: ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate

[0284] To a solution of ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate (10 g, 42.1 mmol) in AcOH (150 mL) was added rhodium / aluminum oxide (4.36 g, 21.07 mmol), and the resulting mixture was stirred at 50 °C for 48 h under H2. LCMS showed the starting material was consumed and desired compound was found. The reaction solution was filtered and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), and sat. aq. NaHCO3 (200 mL) was added. The mixture was extracted with EtOAc (50 mL * 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate, which used directly for the next step without additional purification. MS (ESI) m / z: calc'd for C12H22NO4+- 153 -25972-WO-PCT 12617.0005-00304 [M+H]+244.3, found [M+H]+244.0.1H NMR (400MHz, CDCl3-d) δ 4.09-4.23 (m, 4H), 3.71- 3.80 (m, 1H), 3.02-3.14 (m, 1H), 2.42 (td, J = 7.6, 4.1 Hz, 2H), 1.79-2.16 (m, 6H), 1.27 (dt, J = 8.0, 7.2 Hz, 6H). Step 3: ethyl 1-benzyl-5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate

[0285] To a solution of ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate (8 g, 32.9 mmol) in MeCN (120 mL) were added (bromomethyl)benzene (6.75 g, 39.5 mmol) and K2CO3 (9.09 g, 65.8 mmol), and the resulting mixture was stirred at 60 °C for 3 h. LCMS showed the starting material was consumed and desired compound was found. The reaction solution was filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (80 g), Eluent of 0 ~ 40% ethyl acetate / petroleum ether gradient @ 55 mL / min) to give ethyl 1-benzyl-5-(3-ethoxy-3-oxopropyl)pyrrolidine-2- carboxylate. MS (ESI) m / z: calc'd for C19H28NO4+[M+H]+334.4, found 334.3 [M+H]+.1H NMR (400MHz, CDCl3-d) δ 7.27-7.32 (m, 4H), 7.20-7.25 (m, 1H), 4.10-4.15 (m, 2H), 3.92-3.97 (m, 2H), 3.69 (d, J = 14.0 Hz, 1H), 3.31 (dd, J = 8.4, 6.0 Hz, 1H), 2.42-2.50 (m, 1H), 2.26-2.36 (m, 1H), 1.93-2.04 (m, 2H), 1.84-1.92 (m, 2H), 1.67-1.77 (m, 1H), 1.63 (dd, J = 8.0, 3.2 Hz, 1H), 1.24-1.28 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H). Step 4: ethyl 8-benzyl-2-oxo-8-azabicyclo[3.2.1]octane-3-carboxylate

[0286] To a solution of ethyl 1-benzyl-5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate (10 g, 30.0 mmol) in THF (150 mL) was added potassium 2-methylpropan-2-olate (45.0 mL, 45.0 mmol) slowly, and the resulting mixture was stirred at 60 °C for 4 h. LCMS showed the starting material was consumed and desired compound was found. The reaction solution was added HCl (40 mL, 2 M in H2O) and water (50 mL). The pH of aqueous phase was adjusted to around 9 by progressively adding K2CO3 and extracted with EtOAc (50 mL * 3). The combined organic fractions were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (80 g), Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 55 mL / min) to give ethyl (1R,5S)-8-benzyl-2-oxo-8-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) m / z: calc'd for C17H22NO3+[M+H]+288.3, found 288.1 [M+H]+.1H NMR (400MHz, CDCl3-d) δ 11.89 (br s, 1H), 7.29-7.39 (m, 4H), 7.23-7.27 (m, 1H), 4.18-4.28 (m, 2H), 3.67-3.78 (m, 2H), 3.30-3.46 (m, 2H), 2.64 (dd, J = 16.0, 4.9 Hz, 1H), 2.09-2.23 (m, 2H), 1.95-2.05 (m, 1H), 1.87 (d, J = 16.0 Hz, 1H), 1.51-1.56 (m, 1H), 1.29-1.35 (m, 3H). Step 5: ethyl (1R,5S)-8-benzyl-3-fluoro-2-oxo-8-azabicyclo[3.2.1]octane-3-carboxylate

[0287] To a solution of NaH (0.752 g, 18.79 mmol) in DMF (80 mL) was added ethyl (1R,5S)- 8-benzyl-2-oxo-8-azabicyclo[3.2.1]octane-3-carboxylate (4.5 g, 15.66 mmol) at 25 °C, and the - 154 -25972-WO-PCT 12617.0005-00304 resulting mixture was stirred at 25 °C for 1 h. Then 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (Selectfluor®, 6.10 g, 17.23 mmol) was added at 0 °C, and the resulting mixture was stirred at 0 °C for 4 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was quenched with water (100 mL) careful and extracted with EtOAc (50 mL * 5). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure for 16 h to afford ethyl (1R,5S)-8-benzyl-3-fluoro-2-oxo-8-azabicyclo[3.2.1]octane-3-carboxylate, which used directly for the next step without additional purification. MS (ESI) m / z: calc'd for C17H21FNO3+[M+H]+306.3, found 306.1 / 324.1 [M+H]+ / [M+H2O+H]+.1H NMR (400MHz, CDCl3-d) δ 7.24-7.46 (m, 5H), 4.06-4.30 (m, 4H), 3.71-3.94 (m, 2H), 2.89-3.16 (m, 1H), 1.92- 2.72 (m, 5H), 1.18-1.30 (m, 3H). Step 6: (1R,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-one

[0288] A solution of ethyl (1R,5S)-8-benzyl-3-fluoro-2-oxo-8-azabicyclo[3.2.1]octane-3- carboxylate (2 g, 6.55 mmol) in HCl (4 M in water) (30 mL) was stirred at 90 °C for 12 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was quenched with sat. aq. K2CO3 to adjusted the pH around 9 and extracted with EtOAc (30 mL * 5). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (1R,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-one, which used directly for the next step without additional purification. MS (ESI) m / z: calc'd for C14H17FNO+[M+H]+234.3, found 234.1 / 252.1 [M+H]+ / [M+H2O+H]+.1H NMR (400MHz, CDCl3-d) δ 7.31- 7.35 (m, 4H), 7.28 (d, J = 4.0 Hz, 1H), 4.98-5.19 (m, 1H), 3.71-3.75 (m, 2H), 3.43-3.56 (m, 2H), 2.34-2.54 (m, 2H), 2.15-2.30 (m, 2H), 1.71-1.85 (m, 2H).19F NMR (CDCl3-d, 376 MHz) δ - 196.03 (s, 1F). Step 7: (1R,3S,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-ol

[0289] To a solution of (1R,3S,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-one (1.5 g, 6.43 mmol) in MeOH (20 mL) was added NaBH4 (0.58 g, 15.33 mmol), and the resulting mixture was stirred at 20 °C for 1 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was quenched with HCl (1 mL, 2 M) and dried over Na2SO4. The residue was purified by silica gel chromatography (1 g, Eluent of 20% MeOH / EtOAc) to give (1R,3S,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-ol. MS (ESI) m / z: calc'd for C14H19FNO+[M+H]+236.3, found 236.1 [M+H]+. Step 8: (1R,3S,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-yl methanesulfonate

[0290] To a solution of (1R,3S,5S)-8-benzyl-3-fluoro-8-azabicyclo[3.2.1]octan-2-ol (1.5 g, 6.37 mmol) in DCM (20 mL) was added TEA (1.777 mL, 12.75 mmol) and methanesulfonic - 155 -25972-WO-PCT 12617.0005-00304 anhydride (1.666 g, 9.56 mmol), and the resulting mixture was stirred at 5 °C for 2 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was added water (40 mL) and extracted with EtOAc (20 mL * 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; Agela® Flash...

Claims

1. 25972-WO-PCT 12617.0005-00304 WHAT IS CLAIMED IS:

1. A compound of Formula I: or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Y1and Y2are independently N or C; X1, X2, X3, and X4are independently N, S, or CR, and each R is independently H, halogen, CH3, OCH3, CH3substitued by 1 to 3 halogen, or OCH3substitued by 1 to 3 halogen; R6is a) H; b) C1-C6alkyl; c) C1-C6 alkyl substituted by OH; d) C3-C6cycloalkyl; e) C3-C6cycloalkyl substituted by CH3, C(O)NHCH3, CN, or F; f) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; g) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; h) NH2, - 223 - 25972-WO-PCT 12617.0005-00304 i) NHCH3, or j) N(CH3)2; X7, X8, and X9are independently N, CH, or CF, and at least one of X7, X8, and X9is not N; wherein each R7is independently a) H; b) C1-C6alkyl; c) C1-C6 alkyl substituted by OH; d) C3-C6 cycloalkyl; e) C3-C6cycloalkyl substituted by CH3or OH; f) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P; g) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatom selected from N, S, O, and P, substituted by CH3; h) NH2; i) NHCH3; or j) N(CH3)2; R5is H, halogen, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl; R2is a) monocyclic C3-8cycloalkyl; b) bicyclic C4-8 cycloalkyl; c) C5-10 spiro-cycloalkyl; d) tricyclic C6-9cycloalkyl; e) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; or f) 4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; wherein said R2group is unsubstituted or substituted with 1 to 5 substituents independently selected from R8, and each R8is independently a) halogen; - 224 - 25972-WO-PCT 12617.0005-00304 b) C1-3alkyl; c) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; d) 4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; e) 5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P; f) NH2; g) NH-C1-3 alkyl; h) NH-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); i) NH-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); j) NH(5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); or k) N(C1-3 alkyl)2; wherein said R8group is unsubstituted or substituted with 1 to 5 substituents independently selected from halogen, OH, oxo, CN, CH3, CONH2, CONHCH3, CON(CH3)2, and OCH3.

2. The compound of claim 1, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein - 225 - 25972-WO-PCT 12617.0005-00304 , and wherein each R is independently H, halogen, CH3, OCH3, CH3substitued by 1 to 3 halogen, or OCH3substitued by 1 to 3 halogen.

3. The compound of claim 2, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein 4. The compound of claim 3, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein 5. The compound of any one of claims 1 to 4, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R1is C(=O)R3. - 226 - 25972-WO-PCT 12617.0005-00304 6. The compound of claim 5, or pharmaceutically acceptable salt, solvate, hydrate, or 7. The compound of any one of claims 1 to 4, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein .

8. The compound of claim 7, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein .

9. The compound of any one of claims 7 to 8, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein - 227 - 25972-WO-PCT 12617.0005-00304 10. The compound of any one of claims 7 to 9, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R5is OCH3.

11. The compound of any one of claims 7 to 10, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R1is , 12. The compound of any one of claims 1 to 11, or pharmaceutically acceptable salt, solvate, group is unsubstituted or substituted with 1 to 2 independently selected R8groups.

13. The compound of claim 12, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein each R8is independently H, F, CH3, NH2, NH(CH3), N(CH3)2, NH(CH2CH2F), NH(CH2CH2OH), NH(CH2CHF2), CH2CH2F, CH2CHF2, CH2CH2OH, - 228 - 25972-WO-PCT 12617.0005-00304 14. The compound of any one of claims 12 to 13, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R2is - 229 - 25972-WO-PCT 12617.0005-00304 15. The compound according to claim 1, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is selected from: (1) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (2) 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)-1H-pyrazole-4-carboxamide; (3) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (4) 1-cyclopropyl-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (5) 1-(tert-butyl)-N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (6) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (7) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl- 1H-pyrazole-4-carboxamide; (8) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; - 230 - 25972-WO-PCT 12617.0005-00304 (9) N-(3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (10) 3-methoxy-N-methyl-4-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (11) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (12) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (13) 1-cyclopropyl-N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (14) 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (15) 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (16) 1-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (17) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (18) 2-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (19) 2-methyl-N-(3-(1-((( 1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; - 231 - 25972-WO-PCT 12617.0005-00304 (20) 1-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (21) 1-methyl-N-(3-(1-((( 1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (22) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (23) 2-methyl-N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (24) 2-methyl-N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (25) 1-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (26) 1-methyl-N-(3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (27) 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (28) 4-methoxy-N-methyl-3-((3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (29) 2-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (30) 3-methoxy-N-methyl-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; - 232 - 25972-WO-PCT 12617.0005-00304 (31) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (32) 3-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (33) 3-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (34) 4-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (35) 4-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (36) 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((S)-2- hydroxypropyl)-3-methoxybenzamide; (37) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (38) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (39) 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (40) 1-cyclopropyl-N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (41) 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide; - 233 - 25972-WO-PCT 12617.0005-00304 (42) (4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3- hydroxy-3-methylazetidin-1-yl)methanone; (43) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-((R)- tetrahydrofuran-3-yl)benzamide; (44) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2- hydroxypropyl)-3-methoxybenzamide; (45) 4-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3- methyloxetan-3-yl)benzamide; (46) 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N- (3-methyloxetan-3-yl)benzamide; (47) 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-((R)-2- hydroxypropyl)-4-methoxybenzamide; (48) 3-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-((R)-2- hydroxypropyl)-4-methoxybenzamide; (49) 4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N- (3-methyloxetan-3-yl)benzamide; (50) 3-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-(3- methyloxetan-3-yl)benzamide; (51) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(2- hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide; (52) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; - 234 - 25972-WO-PCT 12617.0005-00304 (53) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-2- methylthiazole-4-carboxamide; (54) 4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzamide; (55) 1-(tert-butyl)-N-(3-(1-(((3R,4S)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (56) 1-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-3- methylurea; (57) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (58) 5-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; (59) N-(3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)selanyl) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)acetamide; (60) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan- 3-yl)-1H-pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt; (61) 5-((3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide, 2,2,2-trifluoroacetate salt; (62) N-((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)-2-(3-((2-methoxy-4-(methylsulfonyl) phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin- 7-amine, 2,2,2-trifluoroacetate salt; (63) N-(3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(2- hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt; - 235 - 25972-WO-PCT 12617.0005-00304 (64) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2- yl)prop-2-yn-1-yl)amino)phenyl)methanone; (65) (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3-hydroxy-3- methylazetidin-1-yl)methanone; (66) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)-3- methoxybenzamide; (67) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamide; (68) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamide; (69) 4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-(3-methyloxetan-3- yl)benzamide; (70) 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamide; (71) 4-((3-(8-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (72) 3-((3-(8-(((3S,4R)-3-Fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (73) 3-Methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (74) 4-Methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (75) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo [3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)amino)benzamide; - 236 - 25972-WO-PCT 12617.0005-00304 (76) 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamide; (77) 4-methoxy-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (3-methyloxetan-3-yl)benzamide; (78) 4-((3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (79) 3-methoxy-N-methyl-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (80) 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (81) N-(3-(8-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (82) 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N- (3-methyloxetan-3-yl)benzamide; (83) 4-((3-(7-(((1S,2R,5R,7R)-7-fluoro-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (84) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl) amino)-3-((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (85) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)selanyl)indolizin-2- yl)prop-2-yn-1-yl)amino)benzamide; (86) 1-(tert-butyl)-N-(3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; - 237 - 25972-WO-PCT 12617.0005-00304 (87) 1-(tert-butyl)-N-(3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (88) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide; (89) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(1-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide; (90) N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole- 4-carboxamide; (91) N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole- 4-carboxamide; (92) 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (93) 1-cyclopropyl-N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (94) 1-cyclopropyl-N-(3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (95) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (96) N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)acetamide; (97) 2-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)thiazole-5-carboxamide; (98) 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; - 238 - 25972-WO-PCT 12617.0005-00304 (99) N-(3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)selanyl) indolizin-2-yl)prop-2-yn-1-yl)-2-methylthiazole-5- carboxamide; (100) 1-methyl-N-(3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (101) 1-cyclopropyl-N-(3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (102) 1-methyl-N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (103) 1-methyl-N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (104) N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (105) N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (106) N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (107) 4-methoxy-N-methyl-3-((3-(1-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (108) 4-methoxy-N-methyl-3-((3-(1-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (109) 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide; - 239 - 25972-WO-PCT 12617.0005-00304 (110) (4-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (111) 1-methyl-3-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)indolizin-2-yl)prop-2-yn-1-yl)urea; (112) 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2- hydroxypropyl)-3-methoxybenzamide; (113) (3-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) selanyl)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxyphenyl)(3-hydroxy-3- methylazetidin-1-yl)methanone; (114) 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (115) 4-methoxy-N-methyl-5-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)picolinamide; (116) N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan- 3-yl)-1H-pyrazole-4-carboxamide; (117) N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (118) (4-((3-(7-(((1R,5S,6S)-5-fluoro-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone; (119) (4-((3-(7-(((1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone; (120) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl- 1H-pyrazole-4-carboxamide; - 240 - 25972-WO-PCT 12617.0005-00304 (121) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl- 1H-pyrazole-4-carboxamide; (122) 4-((3-(7-((3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (123) N-(3-(7-((3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl- 1H-pyrazole-4-carboxamide; (124) N-(3-(7-((3-(2,2-difluoroethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (125) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (126) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (127) 3-methoxy-N-methyl-4-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (128) 3-((3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (129) 4-((3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (130) 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (131) 3-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; - 241 - 25972-WO-PCT 12617.0005-00304 (132) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (133) 1-(tert-butyl)-N-(3-(1-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8-azabicyclo [3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (134) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide; (135) 1-(tert-butyl)-N-(3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (136) 1-(tert-butyl)-N-(3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (137) 3-((3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (138) 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (139) 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)selanyl) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide; (140) 3-((3-(1-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (141) 4-methoxy-N-methyl-3-((3-(1-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (142) 4-methoxy-N-methyl-3-((3-(1-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; - 242 - 25972-WO-PCT 12617.0005-00304 (143) N-(3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4- carboxamide; (144) 4-((3-(1-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl) selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3-methoxy-N,N- dimethylbenzamide; (145) 3-((3-(1-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (146) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (147) 1-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-3- methylurea; (148) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (149) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (150) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (151) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (152) 1-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-3- methylurea; (153) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (154) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; - 243 - 25972-WO-PCT 12617.0005-00304 (155) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (156) 3-methoxy-N-methyl-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)selanyl)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; and (157) 2-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)selanyl)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide.

16. The compound according to claim 1, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein the compound is selected from: - 244 - 25972-WO-PCT 12617.0005-00304 - 245 - 25972-WO-PCT 12617.0005-00304 - 246 - 25972-WO-PCT 12617.0005-00304 - 247 - 25972-WO-PCT 12617.0005-00304 - 248 - 25972-WO-PCT 12617.0005-00304 , - 249 - 25972-WO-PCT 12617.0005-00304 - 250 - 25972-WO-PCT 12617.0005-00304 , - 251 - 25972-WO-PCT 12617.0005-00304 17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, and a pharmaceutically acceptable carrier.

18. The use of a compound according to any one of claims 1 to 16, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, for the preparation of a medicament useful for the treatment of a disorder, condition, or disease that is responsive to retoration of wild type activity of the p53 mutant in a mammal in need thereof.

19. A compound according to any one of claims 1 to 16, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, for use in therapy.

20. A method of treating a disorder, condition or disease that is responsive to to retoration of wild type activity of the p53 mutant in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to any one of claims 1 to 16, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof. - 252 -

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