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, stabilize, and restore the level of correctly folded p53 by stabilizing an active p53 conformation and restoring wild type-like transcriptional function of mutant p53.

Description

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 / 674,687, filed July 23, 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 25961-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 tumor 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.

[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 stabilized 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.These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilize 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 stabilizing 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 destabilized 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:and pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof.

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

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

[0017] The disclosure also provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, or 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, or 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 compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof, to a subject.

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

[0021] Also provided are pharmaceutical compositions comprising compounds of Formula I, and 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.DETAILED DESCRIPTION

[0024] The present disclosure is directed to compounds of Formula I:and pharmaceutically acceptable salts, solvates, hydrates, or tautomers thereof, wherein Y1and Y2are independently N or C; X1, X2, X3, and X4are independently N, S, or CR, and each R is independently H, halogens, CH3, OCH3, CH3 substituted by 1 to 3 halogen, or OCH3 substituted by 1 to 3 halogen;R6is a) H; b) C1-C6 alkyl; c) C1-C6alkyl substituted by OH; d) C3-C6 cycloalkyl; 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) OCH3;i) NH2; j) NHCH3; or k) 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-C6alkyl 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 C3-8 cycloalkyl; b) bicyclic C4-8cycloalkyl; 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; 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(C1-3 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.

[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, whereinhalo, CH3, OCH3, CH3 substituted by 1 to 3 halo, or OCH3 substituted by 1 to 3 halo. In aspectstembodiment,articular aspect of the embodiment,

[0027] In a second embodiment, R

[0028] In a first aspect of the second embodiment, R1is C(=O)R3, wherein R3is R6,, or ; wherein R6is H; C1-C6 alkyl; C1-C6 alkyl substituted by OH; C3- C6cycloalkyl; C3-C6cycloalkyl 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; OCH3; NH2; NHCH3; or N(CH3)2. In instances of this first aspect, R, wherein: each R7is H; C1-C6alkyl; C1-C6alkyl substituted by OH; C3-C6cycloalkyl; C3-C6 cycloalkyl substituted by CH3; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatoms selected from N, S, O, and P; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatoms selected from N, S, O, and P, substituted by CH3; NH2; NHCH3; or N(CH3)2; R5is H, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl. In instances of this second aspect, R

[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; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatoms selected from N, S, O, and P; 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatoms selected from N, S, O, and P, substituted by CH3; NH2; NHCH3; or N(CH3)2. In specific instances, R4isor.

[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 C3-8 cycloalkyl; bicyclic C4-8 cycloalkyl; C5-10 spiro-cycloalkyl; tricyclic C6-9cycloalkyl; 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; C1-3alkyl; 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 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- C1-3alkyl; 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, and OCH3. In aspects of this third embodiment, Rwhereinsaid R2group is unsubstituted or substituted with 1 to 2 R8groups. In instances of aspects of the third embodiment, each R8is independently F, CH3, NH2, NH(CH3), N(CH3)2, NH(CH3CH2CH2F), NH(CH3CH2CH2OH), NH(CH3CH2CHF2), CH2CH2F, CH2CHF2, ffirst instances of further aspects of the third embodiment, each R2is unsubstituted. In second instances of further aspects of the third embodiment, each R2is substituted with 1 to 2 R8groups. In third instances of further aspects of the third embodiment, each R2is substituted with 1 R8group. In fourth instances of further aspects of the third embodiment, each R2is substituted with2 R8groups. In first instances of the third embodiment, R2seth

[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.

[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 Y220C mutant of p53 are compounds of the following structures:,and pharmaceutically acceptable salts, solvates, hydrates, and tautomers thereof.

[0039] 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, or tautomers thereof: (1) (3-methoxy-4-((3-(7-(((1S, 6S or 1R, 6R)-3-methyl-3-azabicyclo[4.1.0] heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (2) (3-methoxy-4-((3-(7-(((1S,6S or 1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (3) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N-[5-(2- oxa-6-azaspiro[3.3] heptan-6-yl)bicyclo[3.1.1]heptan-1-yl]-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-amine; (4) 1-cyclopropyl-N-[3-(7-{[5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[3.1.1] heptan-1-yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2- yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide; (5) N~5~-{2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)- 3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-yl}-N~1~,N~1~- dimethylbicyclo[3.1.1]heptane-1,5-diamine; (6) 1-cyclopropyl-N-[3-(7-{[trans-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl] amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]-1H-pyrazole-4-carboxamide; (7) N-(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide;(8) N-(3-{7-[(4-aminobicyclo[2.1.1]hexan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide; (9) 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (10) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-amine; (11) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-(2- hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide; (12) 5-{[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}- 4-methoxy-N-methylpyridine-2-carboxamide; (13) 4-{[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}- 3-methoxy-N-methylbenzamide; (14) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]cyclopropanecarboxamide; (15) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]acetamide; (16) 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (17) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1- methyl-1H-pyrazole-4-carboxamide; (18) N-methyl-N’-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)urea; (19) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide;(20) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)cyclopropanecarboxamide; (21) 1-cyclopropyl-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (22) 1-(2-hydroxy-2-methylpropyl)-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide; (23) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide; (24) 1-cyclopropyl-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (25) 1-(2-hydroxy-2-methylpropyl)-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide; (26) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)cyclopropanecarboxamide; (27) N-methyl-N’-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)urea; (28) 1-methyl-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (29) 2-(3-{[2-methoxy-4-(methylsulfonyl)phenyl]amino} prop-1-yn-1-yl)-N-[1-(3- methyloxetan-3-yl)piperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-7-amine; (30) 3-[4-({2-(3-{[2-methoxy-4-(methylsulfonyl)phenyl]amino} prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-yl}amino)piperidin-1- yl]oxetane-3-carbonitrile; (31) 5-{[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylpyridine-2-carboxamide;(32) 4-{[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; (33) 1-tert-butyl-N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (34) 2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-amine; (35) N-[3-(7-{[(3S,4R)-1-(3-cyanooxetan-3-yl)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]acetamide; (36) 3-[(3S,4R)-4-({2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3- yl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine- 7-yl}amino)-3-fluoropiperidin-1-yl]oxetane-3-carbonitrile; (37) N~1~-{2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)- 3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-yl}-N~4~-(oxetan-3- yl)bicyclo[2.1.1]hexane-1,4-diamine; (38) N-[3-(7-{[4-(dimethylamino)bicyclo[2.1.1]hexan-1-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-(2- hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide; (39) N~4~-{2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}prop-1-yn- 1-yl)-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-yl}-N~1~,N~1~- dimethylbicyclo[2.1.1]hexane-1,4-diamine; (40) N-[3-(7-{[4-(dimethylamino)bicyclo[2.1.1]hexan-1-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-methyl- 1H-pyrazole-4-carboxamide; (41) 4-[(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide; (42) N-(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)cyclopropanecarboxamide;(43) N-(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1-cyclopropyl-1H- pyrazole-4-carboxamide; (44) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyrazin-8-amine; (45) 1-cyclopropyl-N-[3-(8-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl]-1H-pyrazole-4-carboxamide; (46) 3-[(3S,4R)-3-fluoro-4-({2-(3-{[2-methoxy-4-(methylsulfonyl) phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-7-yl}amino)piperidin-1-yl]-1λ~6~-thietane-1,1-dione; (47) 3-[(3S,4R)-4-({2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1- yn-1-yl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-yl}amino)-3- fluoropiperidin-1-yl]-1λ~6~-thietane-1,1-dione; (48) 5-{[3-(7-{[(3S,4R)-1-(1,1-dioxo-1λ~6~-thietan-3-yl)-3-fluoropiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]amino}-4-methoxy-N-methylpyridine-2-carboxamide; (49) 1-cyclopropyl-N-[3-(7-{[(3S,4R)-1-(1,1-dioxo-1λ~6~-thietan-3-yl)-3- fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide; (50) N-[3-(7-{[(3S,4R)-1-(1,1-dioxo-1λ~6~-thietan-3-yl)-3-fluoropiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]acetamide; (51) N-[3-(7-{[(1R,2R,4R,6S)-9-methyl-9-azatricyclo [4.2.1.0~2,4~]nonan-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]acetamide; (52) 3-[4-({2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)- 3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-yl}amino)piperidin-1- yl]oxetane-3-carbonitrile; (53) N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]acetamide;(54) 1-cyclopropyl-N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (55) N-methyl-N’-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]urea; (56) 2-methyl-N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino}- 3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1,3- thiazole-5-carboxamide; (57) 1-methyl-N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino}- 3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (58) 1-(2-hydroxy-2-methylpropyl)-N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (59) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N-[1-(3- methyloxetan-3-yl)piperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-7-amine; (60) N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]acetamide; (61) 1-cyclopropyl-N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (62) N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]cyclopropanecarboxamide; (63) 1-methyl-N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (64) N-methyl-N’-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]urea; (65) N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]acetamide;(66) N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-cyclopropyl-1H- pyrazole-4-carboxamide; (67) N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]cyclopropanecarboxamide; (68) 1-methyl-N-(3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carboxamide; (69) 1-methyl-N-(3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carboxamide; (70) 3-methoxy-N-methyl-4-((3-(7-((3-(3-methyloxetan-3-yl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2- yn-1-yl)amino)benzamide; (71) 1-methyl-N-(3-(7-((3-(3-methyloxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (72) 1-methyl-N-(3-(1-((3-(3-methyloxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (73) methyl (3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)carbamate; (74) (4-((3-(7-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (75) (4-((3-(7-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (76) (4-((3-(7-((5-aminobicyclo [3.1.1]heptan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide; (77) (4-((3-(7-((4-aminobicyclo [2.1.1]hexan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide;(78) (3-methoxy-4-((3-(7-(((1r,4r)-4-(3-methoxyazetidin-1-yl)cyclohexyl) amino)-3- ((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide; (79) N-(3-(7-(((3S,4R)-1-(1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (80) 3-((3S,4R)-4-((2-(3-((6-(dimethylphosphoryl)-2-methoxypyridin-3-yl)amino)prop- 1-yn-1-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-yl)amino)-3- fluoropiperidin-1-yl)thietane 1,1-dioxide; (81) 1-(tert-butyl)-N-(3-(7-(((3S,4R)-1-(1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)- 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)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (83) (3-methoxy-4-((3-(7-(((1R,2R,5R)-8-(3-methyloxetan-3-yl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)phenyl)dimethylphosphine oxide; (84) 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; (85) 1-(tert-butyl)-N-(3-(8-(((3S,4R)-1-(3-cyanooxetan-3-yl)-3-fluoropiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (86) 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (87) 6-(4-(4-fluoro-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)-7-methylisoquinolin- 3-amine; (88) 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide;(89) 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (90) 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (91) 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide (diastereomer); (92) 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide (diastereomer); (93) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide; (94) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (95) : 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)-N-(oxetan-3-yl)benzamide; (96) 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (97) (4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (98) (3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide; (99) 4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide;(100) (4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide; (101) 3-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (102) 4-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (103) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8-azabicyclo [3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (104) rac-N-(3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (105) N-(3-(7-(((1R,2R,5R)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (106) N-(3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (107) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-(2-(methylsulfonyl)ethyl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)-1H-pyrazole-4-carboxamide; (108) N-(3-(7-(((1R,2R,5R)-8-(dimethylglycyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (109) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-(3-(methylamino)-3-oxopropyl)-8-azabicyclo [3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (110) 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide;(111) 3-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (112) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4- carboxamide; (113) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (114) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (115) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2-methylpropyl)- 1H-pyrazole-4-carboxamide; (116) 1-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-3-methylurea; (117) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)t hio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (119) N-(3-(7-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt; (120) (3-methoxy-4-((3-(8-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (121) (3-methoxy-4-((3-(8-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (122) 4-methoxy-N-methyl-3-((3-(8-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (123) 4-methoxy-N-methyl-3-((3-(8-(((1R,6R)-3-methyl-3-azabic yclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide;(124) N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (125) N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (126) (3-methoxy-4-((3-(7-(((1S,6S)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino) phenyl)dimethylphosphine oxide; (127) (3-methoxy-4-((3-(7-(((1R,6R)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (128) N-(3-(7-(((1S,6S)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (129) N-(3-(7-(((1R,6R)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (130) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (131) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4- carboxamide; (132) 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (133) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carboxamide; (134) 1-cyclopropyl-N-(3-(7-(((1S,2R,4R,6S)-9-methyl-9-azatricyclo[4.2.1.02,4]nonan- 4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide;(135) 2-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (136) 3-methoxy-N-methyl-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (137) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)benzamide; (138) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)benzamide; (139) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (140) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (141) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (142) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (143) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-((R)-2-hydroxypropyl)-3-methoxybenzamide; (144) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-((R)-2-hydroxypropyl)-3-methoxybenzamide; (145) 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide;(146) 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; (147) 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (148) N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (149) 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (150) (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane- 1,2-dicarboxamide; (151) (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane- 1,2-dicarboxamide; (152) (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)thio)indolizin-2-yl)prop- 2-yn-1-yl)amino)phenyl)methanone; (153) 1-cyclopropyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (154) 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan- 3-yl)benzamide; (155) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop- 2-yn-1-yl)amino)benzamide; (156) 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide (diastereomer); (157) 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide (diastereomer);(158) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (159) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (160) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (161) 3-methoxy-N,N-dimethyl-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)benzamide; (162) 4-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (163) 2-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (164) (4-((3-(7-(((1R,2R,5S)-8-Azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide; (165) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (166) 4-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (167) 3-methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide; (168) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide;(169) 2-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (170) 3-methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (171) 4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (172) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (173) 3-methoxy-N-methyl-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (174) 3-methoxy-N-methyl-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (175) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (176) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (177) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (178) 4-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (179) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide;(180) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (181) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (182) 4-methoxy-N-methyl-3-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (183) 4-methoxy-N-methyl-3-((3-(8-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide; (184) 4-methoxy-N-methyl-3-((3-(8-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide; (185) 4-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (186) and 4-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (187) abs-3-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (188) abs-3-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (189) 1-(tert-butyl)-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (190) 3-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide;(191) 4-methoxy-N-methyl-3-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; and (192) 4-methoxy-N-methyl-3-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide.

[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.

[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 valuesdisclosed 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.

[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 asr bridged (in which one or more atoms spans or bridges another ring of atoms, such asricyclic carbocyclic rings similarly feature three fused or bridged rings. Spirocyclic rings, in which a single carbon atom is shared by either two rings (such asre 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). Theheterocycloalkyl 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 as) or 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.

[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 as oepresents the point of attachment.

[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 C1-5alkylcarbonylamino C1-6 alkyl substituent is equivalent to: O -6alkyl) -(C1-5alkyl) N H.

[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 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). Protiumis 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, 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, 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 comprisesadministration 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, 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, about0.1, 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.

[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; (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; 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 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 novelmethods 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 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

[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. General Schemes Scheme 1

[0101] In Scheme 1, commercially available anilines were reacted with 3-bromoprop-1-yne to afford functionalized 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] In Scheme 3, a fused heterocycle heteroaromatic intermediate prepared as described herein can be subjected to base-catalyzed nucleophilic aromatic substitution (SnAr) chemistry with commercially available amines followed by BOC-deprotection when monoprotected diamines are coupled. X1, X4, Y1, and Y2are independently either N, C, or CH. Leaving group LG can be a halide or other suitable leaving group. The intermediates obtained therein were either used directly into the next step or functionalized further. Representative preparative examples from each sequence are described in more detail below.Scheme 4

[0104] In Scheme 4, Intermediate 18, Intermediate 20, Intermediate 22, or Intermediate 25 were subjected to acid catalyzed Strecker reaction to afford the corresponding aminonitriles which were then reacted with organozinc or Grignard reagents (Bruylants reaction) to afford corresponding methyl substituted amines. Representative preparative examples from each sequence are described in more detail below. Scheme 5

[0105] In Scheme 5, one of Intermediates 18, 20, or 22-26 was subjected to reductive amination chemistry with commercially available aldehydes or ketones. Representative preparative examples from each sequence are described in more detail below. Scheme 6

[0106] In Scheme 6, intermediates prepared as described in Scheme 3 were transformed under Pd-catalyzed C-C coupling conditions with either commercially available or syntheticallyprepared propargyl amides, anilines, carbamates, or ureas to afford final compounds of form Gen 1 or Gen 2. X1, X4, Y1, and Y2are independently either N, C, or CH. Leaving group LG can be a halide or other suitable leaving group. The representative compounds are described in more detail below. Scheme 7

[0107] In Scheme 7, heteroaryl halide intermediates, such as the one shown, can be transformed under palladium-catalyzed C-N coupling conditions or base catalyzed SnAr conditions with either commercially available or synthetically amines to afford final compounds of the form Gen 3. The representative compounds are described in more detail below. Scheme 8

[0108] In Scheme 8, heteroaryl halide intermediates, such as the iodide shown, were first transformed under palladium-catalyzed C-C coupling conditions. In the second step, the product obtained from the first step were transformed under reductive amination conditions or Strecker- Bruylants chemistry described in Scheme 4 to afford final compounds of the form Gen 4. The representative compounds are described in more detail below. SYNTHESIS OF INTERMEDIATES Intermediate 1: 7-chloro-2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridineStep 1: 2-iodopyrazolo[1,5-a]pyridine

[0109] A 1000 mL round-bottom flask was charged with pyrazolo[1,5-a]pyridine (25 g, 211.61 mmol) and 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 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; then, 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 flash silica gel column chromatography (eluent: 100% CyHex to 95:5 CyHex:EtOAc) 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

[0110] 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 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 purified via flash silica gel chromatography (0-5% ethyl acetate in cyclohexane) to obtain 7-chloro-2-iodo-pyrazolo[1,5- a]pyridine. MS (ESI) m / z = 278.9 - 281.0 [M+H]+. Step 3: 7-chloro-2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5-a]pyridine

[0111] A 250 mL round-bottom flask was charged with 7-chloro-2-iodo-pyrazolo[1,5- a]pyridine (5.0 g, 17.95 mmol) and 1,1-dioxo-2-(trifluoromethylsulfanyl)-1,2-benzothiazol-3-one (7.6 g, 26.93 mmol). The reaction vessel was purged with N2three times. Under positive flow of N2, MeCN (90 mL) was added, and the reaction mixture was stirred at RT for 5 min. Chloro (trimethyl)silane (3.42 mL, 26.93 mmol) was added dropwise, and the resulting mixture was heated to 60°C and stirred for 30 min. At 30 min, the reaction mixture was concentrated in vacuo.The residue was re-dissolved in DCM (50 mL), and 1 M NaOH (50 mL) was added. The reaction mixture was stirred for 5 min, and the organic phase were combined, dried (Na2SO4) and concentrated in vacuo to obtain 7-chloro-2-iodo-3-(trifluoromethylsulfanyl)pyrazolo[1,5- a]pyridine (Intermediate 2). MS (m / z) 379.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.71 (dd, J = 8.9, 1.2 Hz, 1H), 7.37 (dd, J = 8.8, 7.4 Hz, 1H), 7.04 (dd, J = 7.4, 1.2 Hz, 1H). Intermediate 2: 8-bromo-2-iodo-3-(trifluoromethylsulfanyl)imidazo[1,2-a]pyridineStep 1: 2-amino-3-bromo-1-(2-ethoxy-2-oxoethyl)pyridin-1-ium (1:1 Bromide)

[0112] 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 N2atmosphere. At 16 h, the reaction mixture became a suspension and was diluted with Et2O and filtered. The resulting product 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, 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: 8-bromo-2-chloro-imidazo[1,2-a]pyridine

[0113] 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 N2atmosphere. 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 NH4OH 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: 8-bromo-2-iodo-imidazo[1,2-a]pyridine

[0114] 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. HI (3.0 mL, 39.87 mmol) was added under positive flow of N2, and the reaction vesselwas 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. Na2S2O3 was 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). Step 4: 8-bromo-2-iodo-3-(trifluoromethylsulfanyl)imidazo[1,2-a]pyridine

[0115] A 40 mL vial was charged with 8-bromo-2-iodo-imidazo[1,2-a]pyridine (400.0 mg, 1.24 mmol) and 1,1-dioxo-2-(trifluoromethylsulfanyl)-1,2-benzothiazol-3-one (456.11 mg, 1.61 mmol). The reaction mixture was purged with N2three times, and, under positive flow of N2, MeCN (6 mL) was added. Chloro(trimethyl)silane (205.44 mg, 1.89 mmol) was added, and the resulting mixture was stirred at RT overnight. At 16 h, the reaction mixture was diluted with water and DCM. The aqueous phase was extracted with DCM (three times). The organic phases were combined, dried with sodium sulfate, filtered on a phase separator, and evaporated under reduced pressure. The resulting crude material was purified by flash silica gel chromatography (gradient: cyclohexane / EtOAc from 100:0 to 89:11), affording 8-bromo-2-iodo-3- (trifluoromethylsulfanyl)imidazo[1,2-a]pyridine. (ESI) m / z = 422.93 / 424.94 [M+H]+(Bromine pattern).1H NMR (400 MHz, DMSO) δ 7.12 (dd, J = 7.5, 6.8 Hz, 1H), 7.89 (dd, J = 7.5, 1.0 Hz, 1H), 8.71 (dd, J = 6.7, 1.0 Hz, 1H). Intermediate 3: 2-bromo-8-chloro-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazineStep 1: ethyl 4-bromo-1-(2,2-dimethoxyethyl)-1H-imidazole-2-carboxylate

[0116] A mixture of Cs2CO3 (4.46 g, 13.70 mmol), ethyl 4-bromo-1H-imidazole-2-carboxylate (3 g, 13.70 mmol) and 2-bromo-1,1-dimethoxyethane (2.428 mL, 20.54 mmol) in DMF (20 mL) was stirred at 80°C for 4 h. LCMS showed that desired product was formed. The mixture was filtered, and the solvent was evaporated under reduced pressure. The solvent was removed under reduced pressure, and the residue was dissolved in water (50 mL) and EtOAc (30 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (30 mL x 3), and the combined organic layers 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: 30% ethyl acetate / petroleum ether gradient) to give ethyl 4-bromo-1- (2,2-dimethoxyethyl)-1H-imidazole-2-carboxylate. MS (ESI) m / z: calc’d for C10H16BrN2O4[M+H]+: 307.0 / 309.0, found: 307.0 / 309.0 [M+H]+. Step 2: 4-bromo-1-(2,2-dimethoxyethyl)-1H-imidazole-2-carboxamide

[0117] A mixture of ethyl 4-bromo-1-(2,2-dimethoxyethyl)-1H-imidazole-2-carboxylate (1 g, 3.26 mmol) and ammonia solution (0.465 mL, 3.26 mmol) was stirred at 40°C for 1 h. LCMS showed that desired product was formed. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in water (60 mL) and EtOAc (50 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: DCM: MeOH=10:1) to give 4-bromo-1-(2,2-dimethoxyethyl)- 1H-imidazole-2-carboxamide. MS (ESI) m / z: calc’d for C8H12BrN3O3[M+H]+: 278.0 / 280.0, found: 278.1 / 280.1 [M+H]+. Step 3: 2-bromoimidazo[1,2-a]pyrazin-8(7H)-one

[0118] 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 product was concentrated in vacuum to give 2-bromoimidazo[1,2-a]pyrazin-8(7H)-one. LCMS (ESI) m / z: calc’d for C6H4BrN3O [M+H]+: 214.0 / 216.0, found: 214.0 / 216.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 11.25 - 11.39 (m, 1 H), 7.97 (s, 1 H), 7.45 (d, J = 5.60 Hz, 1 H), 6.91 (d, J = 5.48 Hz, 1 H). Step 4: 2-bromo-8-chloroimidazo[1,2-a]pyrazine

[0119] To a mixture of 2-bromoimidazo[1,2-a]pyrazin-8(7H)-one (300 mg, 1.402 mmol) and POCl3(0.653 mL, 7.01 mmol) in toluene (2 mL) was added DIEA (0.490 mL, 2.80 mmol) at 20°C. The resulting mixture was stirred at 100°C for 12 h. The reaction mixture was concentrated in vacuum. The reaction mixture was neutralized with sat. NaHCO3(30 mL) until pH~8. The reaction mixture was filtered and concentrated in vacuum to give 2-bromo-8-chloroimidazo[1,2- a]pyrazine that was used in the next step without further workup. LCMS (ESI) m / z: calc’d for C6H4BrClN3 [M+H]+: 231.9 / 233.9, found: 231.9 / 233.9 [M+H]+. Step 5: 2-bromo-8-chloro-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazine

[0120] A mixture of 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine (190 mg, 0.817 mmol), 2- ((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (569 mg, 2.011 mmol), diphenylsilane (38.1 mg, 0.163 mmol) and iron(III) chloride (26.5 mg, 0.163 mmol) in DCM (2mL) was degassed and backfilled with N2(three times). The mixture was heated to 40°C for 10 h to give a mixture. After cooling to RT, the mixture was filtered, and the solvent was evaporated under reduced pressure. The solvent was removed under reduced pressure, and the residue was dissolved in water (30 mL) and EtOAc (20 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (20 mL x 3), and the combined organic layers 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 (eluent: 30% ethyl acetate / petroleum ether gradient) to give 2-bromo-7-chloro-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyrimidine. MS (ESI) m / z: calc'd for C7H3BrClF3N3S [M+H]+: 331.9 / 333.9, found: 331.9 / 333.9 [M+H]+. tR=0.724 min.1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (d, J = 4.53 Hz, 1 H), 8.06 (d, J = 4.53 Hz, 1 H). Intermediate 4: 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiopheneStep 1: 7-bromo-2-iodobenzo[b]thiophene

[0121] To a solution of 7-bromobenzo[b]thiophene (4.5 g, 21.12 mmol) in THF (50 mL) was added LDA (12.67 mL, 25.3 mmol) at -78°C over 5 min. After stirring for 30 min at 0°C, a solution of 1,2-diiodoethane (7.14 g, 25.3 mmol) in THF (20 mL) was added to the mixture at - 78°C. The resulting mixture was stirred for another 2 h. The reaction mixture was quenched with sat. NH4Cl (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 reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 100% petroleum ether) to give 7-bromo-2-iodobenzo[b]thiophene.1H NMR (CDCl3, 400 MHz): δ (ppm) 7.66 (dd, J = 7.9, 0.6 Hz, 1H), 7.64 (s, 1H), 7.43 (dd, J = 7.7, 0.8 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H). Step 2: 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene

[0122] To a solution of 7-bromo-2-iodobenzo[b]thiophene (1.2 g, 3.54 mmol), 9,10-[1,2] benzenoanthracen-9(10H)-yl(methyl)sulfane (0.053 g, 0.177 mmol) and 2-((trifluoromethyl)thio) benzo[d]isothiazol-3(2H)-one 1,1-dioxide (2 g, 7.06 mmol) in DCE (15 mL) was added TfOH (0.314 mL, 3.54 mmol) at 25°C over 3 min. After stirring for 1 h at 25°C, the reaction mixture was quenched with sat. NaHCO3(30 mL) and extracted with EtOAc (20 mL x 3). The combinedorganic 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 (eluent: 100% petroleum ether) to give 7-bromo-2-iodo-3-((trifluoromethyl) thio)benzo[b]thiophene.1H NMR (CDCl3, 400 MHz): δ (ppm) 7.95 (d, J = 8.0 Hz, 1H), 7.52- 7.56 (m, 1H), 7.35 (t, J = 7.9 Hz, 1H). Intermediate 5: N-(prop-2-yn-1-yl)acetamide

[0123] 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: (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amineStep 1: tert-butyl ( 4-(dibenzylamino)-3-fluoropiperidine-1-carboxylate

[0124] 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), KI (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) 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]+. Step 2: (3S,4R)-N,N-dibenzyl-3-fluoropiperidin-4-amine

[0125] 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. Themixture was concentrated and dissolved in water (20 mL), adjusted pH=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 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]+. Step 3: 3-((3S,4R)-4-(dibenzylamino)-3-fluoropiperidin-1-yl)oxetane-3-carbonitrile

[0126] 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, trimethylsilane carbonitrile (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]+. Step 4: (3S,4R)-N,N-dibenzyl-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine

[0127] 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 x 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. Step 5: (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine

[0128] To a solution of (3S,4R)-N,N-dibenzyl-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- amine (250 mg, 0.678 mmol) in MeOH (25 mL) and THF (25 mL) was stirred at RT until clear and transparent, The solution was pumped at 0.3 mL / min through a ½” fixed bed column reactor packed with granular catalyst (5% Pd(OH)2 / Al2O3(64.1 mg.0.457 mmol)) at 35°C. The H2back pressure regulator was adjusted to 1.0 MPa. The flow rate of H2 was 30 mL / min. The reaction mixture was collected after running 10 min. Collection of the reaction mixture was stopped after 1 h. The fixed bed was washed by MeOH. The filtrate was concentrated under reduced pressureto give (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine that was used in next step directly. MS (ESI) m / z: calc’d for C9H18FN2O [M+H]+: 189.1, found: 189.1 [M+H]+.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 7: 4-dimethylphosphoryl-2-methoxy-N-prop-2-ynyl-aniline

[0129] 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 (three times) and then DCM:MeOH 9:1 (three times). The combined organic factions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified through by Prep-HPLC to afford 4-dimethylphosphoryl-2-methoxy-N-prop-2-ynyl-aniline. MS (ESI) m / z = 238.45 [M+H]+.

[0130] 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 11: 1-(tert-butyl)-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide

[0131] 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]+.

[0132] 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 17: N-(2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a] yridine-7- yl)bicyclo[3.1.1]heptane-1,5-diamine

[0133] A 40 mL vial was charged with 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridine (380 mg, 1.00 mmol), tert-butyl (5-aminobicyclo[3.1.1]heptan-1-yl)carbamate (250 mg, 1.10 mmol). DMSO (4.0 mL) was added, and the reaction mixture was stirred at RT for 5 min. Cesium fluoride (750 mg, 4.94 mmol) was added, and the reaction mixture stirred for 1 h at 110°C. The mixture was poured into DCM and washed with sat. NH4Cl. The organic layer was dried over Na2SO4, concentrated, and purified by flash silica gel chromatography (eluent: 0-50% EtOAc / DCM) gave the desired product, tert-butyl (5-((2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridine-7-yl)amino)bicyclo[3.1.1]heptan-1-yl)carbamate (495 mg, 0.871 mmol). This product was then dissolved in DCM (1.0 mL) and treated with a 4 M dioxane solution of HCl (0.87 mL, 3.5 mmol). The mixture was aged for 2 h and concentrated to provide N-(2-iodo-3- ((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-7-yl)bicyclo[3.1.1]heptane-1,5-diamine. MS (EI) calc’d for C15H17F3IN4S [M+H]+, 469; found 469. Intermediates 21, 21A, and 21B: 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (mixture of diastereomers and separated diastereomers)Step 1: 2-iodo-N -((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (Intermediate 21)

[0134] To a solution of N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine (590mg, 1.299 mmol) in MeOH (4 mL) was added formaldehyde (117 mg, 3.90 mmol) and AcOH (0.015 mL, 0.260 mmol), the mixture was stirred for 0.5 h at 50°C, then NaBH3(CN) (163 mg, 2.60 mmol) was added to the mixture, and it was stirred for 2 h at 50°C. LCMS showed desired mass peak was observed. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 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®; 12 g SepaFlash® Silica Flash Column, eluent of 0~10% MeOH / DCM gradient @ 20 mL / min) to give 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine. MS (ESI) m / z: calc’d for C15H17F3IN4S+[M+H]+:469.0 found: 468.9 [M+H]+.1δ 7.37 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.48 (s, 1H), 6.31 (dd, J = 1.0, 7.7 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.75 - 2.67 (m, 1H), 2.37 - 2.29 (m, 2H), 2.28 (s, 3H), 2.20 - 2.10 (m, 2H), 1.51 - 1.43 (m, 1H), 1.10 (dd, J = 5.1, 9.7 Hz, 1H), 0.98 - 0.93 (m, 1H). Step 2: 2-iodo-N-(( 3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine and 2-iodo-N-((1S,6R)-3-methyl- 3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0135] The 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine (220 mg, 0.470 mmol) was resolved by Chiral-SFC (Column Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 um) Condition CO2 MeOH (0.1% NH3H2O) Begin B 40 End B 40 Gradient Time (min) 1100%B Hold Time 1 Flow Rate (mL / min) 60 ) to give 2-iodo-N-((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine, and 2-iodo-N-((1S,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine. SFC method: Column: Cellulose-2 100×4.6mm I.D., 3um; Mobile phase: A: CO2 B: methanol (0.2% MNH3); Isocratic: 40% B; Flow rate: 2.8mL / min; Column temp.: 35°C; ABPR: 1500psi. Peak 1 (21A): MS (ESI) m / z: calc’d for C15H17F3IN4S+[M+H]+: 469.0 found 469.0. Peak 2 (21B): MS (ESI) m / z: calc’d for C15H17F3IN4S+[M+H]+: 469.0 found 469.0.Intermediate 22: N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-7-amineStep 1: tert-butyl 6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)- 3-azabicyclo[4.1.0]heptane-3-carboxylate

[0136] To a solution of 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine (400 mg, 1.057 mmol) in DMSO (4 mL) was added cesium fluoride (642 mg, 4.23 mmol), N-ethyl-N- isopropylpropan-2-amine (1093 mg, 8.45 mmol) and tert-butyl 6-amino-3-azabicyclo[4.1.0] heptane-3-carboxylate (269 mg, 1.268 mmol); the mixture was stirred for 2 h at 100°C under N2. LCMS showed desired mass peak was observed. The reaction mixture was quenched with H2O (40 mL) and extracted with EtOAc (10 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 0~20% ethyl acetate / pet. ether gradient @ 30 mL / min) to give tert-butyl 6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0] heptane-3-carboxylate. MS (ESI) m / z: calc’d for C19H23F3IN4O2S+[M+H-t-Bu]+: 498.0 found: 498.2. Step 2: N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine

[0137] To a solution of tert-butyl 6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7- yl)amino)-3-azabicyclo[4.1.0]heptane-3-carboxylate (480 mg, 0.866 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (0.6 mL, 0.866 mmol); the mixture was stirred for 2 h at 25°C. LCMS showed desired mass peak was observed. The mixture was concentrated under reduced pressure to give N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-7-amine, TFA salt. MS (ESI) m / z: calc’d for C14H15F3IN4S+[M+H]+: 455.0 found: 455.0 [M+H]+.

[0138] Each of the intermediates presented in Table 4 below was prepared in accordance with the synthetic route demonstrated in Scheme 3, using procedures analogous to those describedabove for Intermediates 17, 21, and 22 using intermediates prepared as described above or further below.Intermediate 27: 3-(4-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7- yl)amino)piperidin-1-yl)oxetane-3-carbonitrile

[0139] A 40 mL vial was charged with 2-iodo-N-(piperidin-4-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a],yridine-7-amine (750 mg, 1 eq, 1.70 mmol) and purged three times with Ar. DCE (8.00 mL) and oxetan-3-one (350 mg, 2.86 eq, 4.86 mmol) were added under positive flow of N2 and followed by addition of AcOH (105 mg, 100 μL, 1.03 eq, 1.75 mmol). The vial was stirred at 50°C for 30 min, after which trimethylsilylnitrile (202 mg, 0.27 mL, 1.2 eq, 2.04 mmol) was added dropwise. The reaction vessel was stirred at 65°C for 16 h; then, the reaction mixture was extracted with DCM and 1 M NaOH. The organic phases were combined, dried using MgSO4, and filtered. The filtered organic mixture was concentrated under reduced pressure. The crude product was dissolved in DMSO and purified by reverse phase HPLC to afford 3-(4-((2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile. MS (ESI) m / z calc’d for C17H17F3IN5OS [M+H]+: 524, found 524.Intermediate 28: 2-iodo-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-7-amine

[0140] A 40mL vial was charged with 3-(4-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridine-7-yl)amino)piperidin-1-yl)oxetane-3-carbonitrile (293 mg, 1 eq, 560 μmol) and neodymium(III) trifluoromethanesulfonate (82.8 mg, 0.25 eq, 140 μmol).1,4-Dioxane (5.60 mL) was added, and the resulting suspension was stirred for 5 min. The vial was purged with N2three times and cooled to 0°C before dimethyl zinc (267 mg, 1.40 mL, 2.00 molar, 5 eq, 2.80 mmol) was added dropwise under N2over 5 min. The reaction was gradually warmed to 50°C overnight. At 16 h, the reaction mixture was quenched with sat. NH4Cl and extracted with DCM. The organic layers were separated, dried, and concentrated. The crude reaction mixture was diluted in DCM and purified by flash silica gel column chromatography (eluent: 0-100% hexanes in 3:1 ethyl acetate ethanol) to afford 2-iodo-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)-3- ((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-7-amine. MS (ESI) m / z calc’d for C17H20F3IN4OS [M+H]+: 513, found 513.

[0141] Each of the intermediates presented in Table 5 below was prepared in accordance with the synthetic route demonstrated in Scheme 4, using procedures analogous to those described above.Intermediate 32: (rac-1R,2R,4R,6S)-N-(2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridine-7-yl)-9-methyl-9-azatricyclo[4.2.1.02,4]nonan-4-amine

[0142] A vial was charged with (rac-1R,2R,4R,6S)-N-(2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridine-7-yl)-9-azatricyclo[4.2.1.02,4]nonan-4-amine (0.120 g, 0.250 mmol), paraformaldehyde (0.009 g, 0.300 mmol), 4Å molecular sieves, acetic acid (0.029 mL, 0.500 mmol), and DCE (0.833 mL). The reaction was stirred at 50°C for 30 min, then sodium cyanoborohydride (0.047 g, 0.750 mmol) was added to the reaction. The reaction was continued to be stirred at 50°C for 16 h. The reaction was cooled down, quenched with sat NaHCO3(10 mL), and extracted with DCM (5 mL x 3). The combined organic phases were dried over Na2SO4, and the solvent removed under reduced pressure. The resultant crude residue was subjected to purification by flash silica gel chromatography (eluent: Hexanes in 3:1 EtOAc / EtOH, 0-100%) to afford (rac-1R,2R,4R, 6S)-N-(2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridine-7-yl)-9-methyl-9-azatricyclo [4.2.1.02,4]nonan-4-amine. MS (ESI) m / z calc’d for C19H25FN4O [M+H]+: 495, found 495.

[0143] Each of the intermediates presented in Table 6 below were prepared in accordance with the synthetic route demonstrated in Scheme 5, using procedures analogous to those described above.Intermediate 39: N-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[3.1.1]heptan-1-yl)-2-iodo- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine

[0144] A 40 mL vial was charged with N1-(2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridine-7-yl)bicyclo[3.1.1]heptane-1,5-diamine (100.00 mg, 1 eq, 213.55 µmol) and DMF (2000.00 µL). To the reaction vessel was added, KI (8.8622 mg, 0.25 eq, 53.387 µmol), potassium carbonate (118.05 mg, 4.0 eq, 854.19 µmol), KOH (11.98 mg, 1.0 eq, 213.55 µmol) and 3,3-bis(chloromethyl)oxetane (132.42 mg, 4.0 eq, 854.19 µmol). The resulting solution was heated to 100°C overnight. At 16 h, the mixture was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash silica gel column chromatography (eluent: DCM / MeOH) to give N-(5-(2-oxa-6-azaspiro[3.3]heptan-6- yl)bicyclo[3.1.1]heptan-1-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridine-7-amine. MS (ESI) m / z calc’d for C20H22F3IN4OS [M+H]+: 551, found 551.Intermediate 40: N-((1r,4r)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine

[0145] A 40 mL vial was charged with (1r,4r)-N1-(2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridine-7-yl)cyclohexane-1,4-diamine (450.00 mg, 1 eq, 986.26 µmol) and DMF (4000.00 µL). KI (40.930 mg, 0.25 eq, 246.56 µmol), potassium carbonate (545.20 mg, 4.0 eq, 3.9450 mmol), KOH (55.34 mg, 1.0 eq, 986.26 µmol) and 3,3-bis(chloromethyl)oxetane (305.78 mg, 2.0 eq, 1.9725 mmol) were added, and the resulting solution was heated to 100°C overnight. At 16 h, the mixture was diluted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel column chromatography (eluent: MeOH / DCM) to give N-((1r,4r)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl)-2- iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridine-7-amine. MS (ESI) m / z calc’d for C19H22F3IN4OS [M+H]+: 539, found 539. Intermediate 41A: (4-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2- yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide

[0146] A 100 mL round-bottom flask was charged with 7-chloro-2-iodo-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridine (5.00 g, 13.2 mmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl) dimethylphosphine oxide (4.00 g, 16.9 mmol) and DMSO (30 mL). The solvent was deoxygenated by bubbling Ar gas for 5 min. To this mixture, Pd(PPh3)4 (760 mg, 658 μmol) and CuI (750 mg, 3.94 mmol) were added. The flask was purged and backfilled three times with Ar. Finally, DIPEA (11.5 mL, 66.0 mmol) was added, and the reaction was stirred at 50°C for 1 h. The mixture was diluted with 5:1 DCM / MeOH, washed with sat. NH4Cl and water. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash silica gel columnchromatography (eluent: 9:1 DCM / MeOH). The product was triturated with diethyl ether overnight, filtered, and dried in vacuum to obtain (4-((3-(7-chloro-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. MS (EI) calc’d for C20H19ClF3N3O2PS [M+H]+, 488; found 488.

[0147] The following intermediates in Table 7 were prepared in an analogous fashion to that described for Intermediate 41A, (4-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridine-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide.Intermediate 42: 5-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-yl)prop- 2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide

[0148] A 30 mL vial was charged with DIPEA (0.331 mL, 2.364 mmol), 8-bromo-2-iodo-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridine (100 mg, 0.236 mmol), Pd(PPh3)4 (27.3 mg, 0.024mmol), CuI (22.51 mg, 0.118 mmol) and 4-methoxy-N-methyl-5-(prop-2-yn-1-ylamino) picolinamide (104 mg, 0.473 mmol) and DMSO (1 mL). The solvent was degassed and backfilled with N2three times. The mixture was heated to 25°C for 1 h. At 1 h, the reaction mixture was quenched with water (30 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 reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 50% petroleum ether / ethyl acetate gradient) to give 5-((3-(8-bromo-3- ((trifluoromethyl)thio) imidazo[1,2-a]pyridine-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide. Intermediate 43: N-(3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridine-2-yl)prop- 2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide

[0149] A 40 mL vial was charged with 8-bromo-2-iodo-3-((trifluoromethyl)thio)imidazo [1,2- a]pyridine (200 mg, 0.473 mmol), Pd(PPh3)4(65.6 mg, 0.057 mmol), CuI (36.0 mg, 0.189 mmol), DIPEA (0.596 mL, 4.26 mmol), DMSO (2.5 mL) and 1-(tert-butyl)-N-(prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (102 mg, 0.496 mmol). The reaction vessel was purged with N2three times, and the mixture was stirred at RT for 1 h. At 1 h, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 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 flash silica gel chromatography (eluent: 0~30% ethyl acetate / petroleum ether gradient) to give N-(3-(8-bromo-3-((trifluoromethyl)thio)imidazo [1,2-a]pyridine-2-yl)prop-2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide. LCMS (ESI) m / z: 500.0 / 502.0 [M+H]+, tR=0.714 min. Intermediate 44: 8-bromo-2-iodo-3-((trifluoromethyl)thio)indolizineStep 1: methyl 2-((3-bromopyridin-2-yl)(hydroxy)methyl)acrylate

[0150] To a mixture of 3-bromopicolinaldehyde (5 g, 26.9 mmol) in 1,4-dioxane (37.5 ml) and water (12.5 ml) was added methyl acrylate (2.53 g, 29.4 mmol) and DABCO (0.302 g, 2.69 mmol) at 20°C. The resulting mixture was stirred at 20°C for 16 h. LCMS showed that the reaction completed. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (30 mL*3). The combined organic phases were washed with water (60 mL) and brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give methyl 2-((3-bromopyridin-2-yl)(hydroxy)methyl)acrylate. MS (ESI) m / z: calc’d for C10H11BrNO3+[M+H]+272.1, found [M+H]+271.7 / 273.7. Step 2: methyl 8-bromoindolizine-2-carboxylate

[0151] A mixture of methyl 2-((3-bromopyridin-2-yl)(hydroxy)methyl)acrylate (7 g, 25.7 mmol) in Ac2O (100 mL) was stirred at 120°C under N2for 16 h. LCMS showed the starting material was consumed, and the desired compound was found. The mixture was added sat. aq. NaHCO3(200 mL) and 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. 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) and the product was triturated with pet. ether (50 mL) and filtered to afford methyl 8- bromoindolizine-2-carboxylate. MS (ESI) m / z: calc’d for C10H9BrNO2+[M+H]+254.08, found [M+H]+253.7 / 255.7.1H NMR (400MHz, CDCl3-d) δ 7.83-7.90 (m, 2H), 7.02 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.44 (t, J = 7.2 Hz, 1H), 3.91 (s, 3H). Step 3: methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylate

[0152] To a mixture of methyl 8-bromoindolizine-2-carboxylate (4.2 g, 16.53 mmol) in MeCN (80 mL) was added 2-((trifluoromethyl)thio)-3a,7a-dihydrobenzo[d]isothiazol-3(2H)-one 1,1- dioxide (4.95 g, 17.36 mmol) and chlorotrimethylsilane (0.359 g, 3.31 mmol), and the resulting mixture was stirred at 20°C for 2 h. LCMS showed the starting material was consumed, and the desired compound was found. The reaction solution was filtered and concentrated in vacuo. The residue was added water (50 mL) and extracted with EtOAc (30 mL * 3). The combined organic fractions were washed with brine (10 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 ~ 10% ethyl acetate / petroleum ether gradient @ 55 mL / min) to give methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylate. MS (ESI) m / z: calc’d for C11H8BrF3NO2S+[M+H]+354.14, found [M+H]+353.7 / 355.7.1H NMR (400MHz, CDCl3-d) δ 8.54 (d, J = 7.2 Hz, 1H), 7.27-7.28 (m, 1H), 7.25 (d, J = 7.2 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 3.97 (s, 3H). Step 4: 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylic acid

[0153] To a mixture of methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylate (4.5 g, 12.71 mmol) in THF (20 mL) was added water (10 mL), MeOH (20 mL), and lithium hydroxide hydrate (2.67 g, 63.5 mmol) at 20°C. The resulting mixture was stirred at 40°C for 3 h. LCMS showed that the starting material was consumed, and desired compound was found. The reaction solution was concentrated in vacuo. Then the product was diluted with water (100 mL), and the pH was adjusted to around 4 by progressively adding HCl (2 M in water). The mixture was extracted with EtOAc (30 mL * 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8- bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylic acid. MS (ESI) m / z: calc’d for C10H6BrF3NO2S+[M+H]+340.11, found [M+H]+339.7 / 341.7.1H NMR (400MHz, MeOD-d4) δ 8.68 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 0.8 Hz, 1H), 6.88 (t, J = 7.2 Hz, 1H).Step 5: tert-butyl (8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)carbamate

[0154] To a solution of 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylic acid (2 g, 5.88 mmol) in toluene (30 mL) was added 2-methylpropan-2-ol (1.125 mL, 11.76 mmol), DIEA (1.024 mL, 5.88 mmol), diphenyl phosphorazidate (1.264 mL, 5.88 mmol), and the resulting mixture was stirred at 80°C for 1 h. LCMS showed the starting material was consumed, and the 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 (10 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 (20 g), eluent of 0 ~ 20% ethyl acetate / petroleum ether gradient @ 40 mL / min) to give tert-butyl (8-bromo-3- ((trifluoromethyl)thio)indolizin-2-yl)carbamate. MS (ESI) m / z: calc’d for C14H15BrF3N2O2S+[M+H]+411.24, found [M+H]+410.7 / 412.7.1H NMR (400MHz, CDCl3-d) δ 8.32 (d, J = 6.8 Hz, 1H), 7.20 (dd, J = 7.2, 0.8 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.59 (t, J = 7.2 Hz, 1H), 1.58 (s, 9H). Step 6: 8-bromo-3-((trifluoromethyl)thio)indolizin-2-amine

[0155] To a solution of tert-butyl (8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)carbamate (1.5 g, 3.65 mmol) in MeOH (10 mL) was added HCl / dioxane (2M) (10.00 mL), and the resulting mixture was stirred at 40°C for 3 h. LCMS showed the starting material was consumed, and the desired compound was found. The reaction solution was concentrated in vacuo. Aq. NaHCO3 (50 mL) was added, and the solution was extracted with EtOAc (20 mL * 3). The combined organic fractions were washed with brine (10 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 (20 g), eluent of 0 ~ 30% ethyl acetate / petroleum ether gradient @ 55 mL / min) to give 8-bromo-3-((trifluoromethyl)thio) indolizin-2-amine. MS (ESI) m / z: calc’d for C9H7BrF3N2S+[M+H]+311.12, found [M+H]+310.7 / 312.7.1H NMR (400MHz, CDCl3-d) δ 8.24 (d, J = 6.8 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.47 (t, J = 7.2 Hz, 1H), 6.17 (s, 1H). Step 7: 8-bromo-2-iodo-3-((trifluoromethyl)thio)indolizine

[0156] To a solution of 8-bromo-3-((trifluoromethyl)thio)indolizin-2-amine (1 g, 3.21 mmol) in MeCN (20 mL) was added copper(I) iodide (1.224 g, 6.43 mmol), tert-butyl nitrite (0.663 g, 6.43 mmol), and the resulting mixture was stirred at 60°C for 6 h. LCMS showed the starting material was consumed, and new peaks formed. After the addition of water (30 mL), the mixture was extracted with EtOAc (10 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 Column Silica-CS (20 g), eluent of 0 ~ 10% ethyl acetate / petroleum ether gradient @ 35 mL / min) to give 8-bromo-2-iodo- 3-((trifluoromethyl)thio)indolizine. MS (ESI) m / z: calc’d for C9H5BrF3INS+[M+H]+422.0.1H NMR (400MHz, CDCl3-d) δ 8.43 (d, J = 6.8 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.61 (t, J = 7.2 Hz, 1H). Intermediate 45A: (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)dimethylphosphine oxide

[0157] To a solution of 8-bromo-2-iodo-3-((trifluoromethyl)thio)indolizine (50 mg, 0.118 mmol) in DMSO (1 mL) was added CuI (9.03 mg, 0.047 mmol), Pd(Ph3P)4 (16.43 mg, 0.014 mmol), DIIPA (0.149 mL, 1.066 mmol) and (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl) dimethylphosphine oxide (28.1 mg, 0.118 mmol) in DMSO (0.5 mL) under N2. Then the mixture was stirred at 20°C for 1 h. LCMS showed the starting material was consumed, and the desired compound was found. To the mixture was added water (5 mL), and the mixture was extracted with 10% MeOH in EtOAc (3 mL * 3). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by Prep-TLC (DCM: MeOH=10:1) to afford (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. MS (ESI) m / z: calc’d for C21H20BrF3N2O2PS+[M+H]+531.33, found [M+H]+530.9 / 532.9.

[0158] The Intermediates in Table 8 were prepared in an analogous fashion to that described for the synthesis of (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)dimethylphosphine oxide, using propyne intermediates prepared as described above.Intermediate 46: (4-((3-(1-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxideStep 1: methyl 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxylate

[0159] To a solution of methyl 4-iodo-1H-pyrrole-2-carboxylate (1.9 g, 7.57 mmol) in DMF (20 mL) were added Cs2CO3(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. LCMS showed the desired product was found. 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]. Step 2: 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxylic acid

[0160] A mixture of lithium hydroxide (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. LCMS showed that the product was found. 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 was re-extracted with EtOAc (5 mL*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 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]. Step 3: 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxamide

[0161] 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. LCMS showed the desired product was found, and the reaction was completed. The reaction mixture was quenched with water (5 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®; 20 g SepaFlash® Silica Flash Column, eluent of 50% ethyl acetate / pet. ether gradient @ 30 mL / min) 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].Step 4: 7-iodopyrrolo[1,2-a]pyrazin-1(2H)-one

[0162] A mixture of 1-(2,2-dimethoxyethyl)-4-iodo-1H-pyrrole-2-carboxamide (20 mg, 0.062 mmol) in acetic acid (0.5 mL, 0.062 mmol) was stirred at 100°C for 2 h. LCMS showed that the desired compound was formed. The solvent was removed under reduced pressure to give the residue 7-iodopyrrolo[1,2-a]pyrazin-1(2H)-one. LCMS (ESI) m / z: calc’d for C7H6IN2O+[M+H]+: 260.9 found: 260.9 [M+H]+. Step 5: 1-chloro-7-iodopyrrolo[1,2-a]pyrazine

[0163] 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. LCMS showed that the desired compound was formed. The reaction mixture was concentrated in vacuum. Sat NaHCO3(30 mL) was added until the pH reached ~8. The mixture was extracted with EtOAc (20 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-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]+. Step 6: 1-chloro-7-iodo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine

[0164] A mixture of 1-chloro-7-iodopyrrolo[1,2-a]pyrazine (300 mg, 1.077 mmol), 2- ((trifluoromethyl)thio)-3a,7a-dihydrobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (615 mg, 2.155 mmol), iron(III) chloride (34.9 mg, 0.215 mmol) and diphenyl selenide (50.2 mg, 0.215 mmol) in DCM (8 mL) was stirred at 50°C for 12 h. LCMS showed that the product was found. The solvent was removed under reduced pressure. The residue was purified by Pre-HPLC (Column Boston Green ODS 150*30mm*5um Condition water (0.1%TFA)-ACN Begin B 75 End B 100Gradient Time (min) 10100%B Hold Time 2 Flow Rate (ml / min) 25) to give 1-chloro-7-iodo-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine. LCMS (ESI) m / z: calc’d for C8H4ClF3IN2S+[M+H]+:378.9 found:378.9 [M+H]+. Intermediate 47: (R)-N-(2-hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamideStep 1: methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate

[0165] To a solution of methyl 4-amino-3-methoxybenzoate (20 g, 110 mmol) in DMF (200 mL) were 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 purified by reversed phase column to give methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate. MS (ESI) m / z: calc’d for C12H14NO3+[M+H]+: 220.0 found:220.0. Step 2: 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid

[0166] 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 (60.0 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 the desired mass peak was observed. The resulting mixture was concentrated under reduced pressure to removed MeOH. Then the mixture 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. MS (ESI) m / z: calc’d for C11H11NO3+[M+H]+: 206.1 found:206.2. Step 3: ( (2-hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide

[0167] To a mixture of 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (200 mg, 0.975 mmol) in DMF (3 ml) were added HATU (445 mg, 1.170 mmol) and DIEA (0.340 ml, 1.949 mmol) at 20°C; the mixture was stirred at 20°C for 5 min, and then (R)-1-aminopropan-2-ol (73.2 mg, 0.975 mmol) was added. The resulting mixture was stirred at 20°C for 12 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 (10 mL*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 flash silica gel chromatography (ISCO®; 4g SepaFlash® Silica Flash Column, eluent of 0~70% ethyl acetate / pet. ether gradient @ 40 mL / min) to (R)-N-(2-hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide. MS (ESI) m / z: calc’d for C14H19N2O3+[M+H]+:263.2 found:263.0. Intermediate 48: 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amineStep 1: tert-butyl (1R,2R,5R)-2-((7-iodo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0168] To a solution of 1-chloro-7-iodo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazine (400 mg, 1.057 mmol) in DMSO (4 ml) was added tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo [3.2.1]octane-8-carboxylate (287 mg, 1.268 mmol), N-ethyl-N-isopropylpropan-2-amine (1093 mg, 8.45 mmol) and cesium fluoride (642 mg, 4.23 mmol). The mixture was stirred for 2 h at 100°C under N2. LCMS showed the desired mass peak was observed. The reaction mixture was quenched with H2O (40 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®; 12 g SepaFlash® Silica Flash Column, eluent of 0~30% ethyl acetate / pet. ether gradient @ 30 mL / min) to give tert-butyl (1R,2R,5R)-2-((7-iodo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin- 1-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z: calc’d for C20H25F3IN4O2S+[M+H]+: 569.1 found 569.1 [M+H]+. Step 2: N-(( -azabicyclo[3.2.1]octan-2-yl)-7-iodo-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amine

[0169] To a solution of tert-butyl (1R,2R,5R)-2-((7-iodo-6-((trifluoromethyl)thio)pyrrolo[1,2- a]pyrazin-1-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (370 mg, 0.651 mmol) in DCM (4 mL) was added TFA (0.4 mL, 5.19 mmol), the mixture was stirred for 0.5 h at 40°C. LCMS showed desired mass peak was observed. The resulting mixture was concentrated under reduced pressure to give N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-7-iodo-6-((trifluoromethyl)thio) pyrrolo[1,2-a]pyrazin-1-amine. MS (ESI) m / z: calc’d for C15H17F3IN4S+[M+H]+: 469.1 found 469.1 [M+H]+.Step 3: 7-iodo-N-(( 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amine

[0170] To a solution of N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-7-iodo-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amine (200 mg, 0.427 mmol) in MeOH (0.5 mL) was added AcOH (5.13 mg, 0.085 mmol), formaldehyde (12.82 mg, 0.427 mmol) and sodium cyanotrihydroborate (26.8 mg, 0.427 mmol), the mixture was stirred for 1 h at 60°C. LCMS showed the starting material was consumed, and the desired mass peak was observed. The resulting mixture was 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 7-iodo-N-((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-. MS (ESI) m / z: calc’d for C16H19F3IN4S+[M+H]+: 482.9 found 482.9 [M+H]+. Intermediate 49: (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1- ylamino)phenyl)methanone

[0171] To a mixture of 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (200 mg, 0.975 mmol) in DMF (3 mL) were added HATU (445 mg, 1.170 mmol) and DIEA (0.340 mL, 1.949 mmol) at 20°C. The mixture was stirred at 20°C for 5 min, and then 3-methylazetidin-3-ol (85 mg, 0.975 mmol) was added. The resulting mixture was stirred at 20°C for 12 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 (10 mL*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 flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent of 0~80% ethyl acetate / pet. ether gradient @ 40 mL / min) to give (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl) methanone. MS (ESI) m / z: calc’d for C15H19N2O3+[M+H]+: 275.1, found: 275.0 [M+H]+.Intermediate 50: 2-iodo-N-(3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0172] To N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine (160.00 mg, 1 Eq, 352.23 μmol) and 2-methoxyethyl 4-methylbenzene sulfonate (137.89 mg, 1.7 Eq, 598.79 μmol) in a vial, DIEA (166.17 mg, 224 μL, 3.65 Eq, 1.2856 mmol) and ACN (0.80 mL) were added, and the reaction was stirred at 70°C overnight. Excess solvent was removed under reduced pressure, and the product obtained was co-evaporated a couple of times with dry acetonitrile and then vacuum dried to give to give 2-iodo-N-(3-(2- methoxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin- 7-amine. MS (ESI) m / z calc’d for C17H20F3IN4OS [M+H]+: 513, found 513.0. Intermediate 51: 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acidStep 1: methyl 3-methoxy-4-(prop-2-yn-1-ylamino)benzoate

[0173] 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 purified 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-(prop-2-yn-1-ylamino)benzoic acid

[0174] 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 the desired mass peak was observed. The resulting mixture was concentrated under reduced pressure to removed MeOH. Then the mixture was acidified to pH = 6 by 2 NHCl, and then the mixture was 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 52: 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-olStep 1: methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylate

[0175] Ethyl 8-bromoindolizine-2-carboxylate (100 g, 394 mmol, 1.00 eq) and 2- ((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (123 g, 433 mmol, 1.10 eq) were combined in MeCN (1.00 L). TMSCl (8.55 g, 78.7 mmol, 0.20 eq) was added into the reaction at 0°C. The mixture was stirred at 20°C for 1 h. The reaction mixture was poured into water (2.00 L). The mixture was extracted with DCM (1.00 L, 800 mL). The organic layer was washed with brine (1.00 L then dried over Na2SO4, filtered, and the filtrate was concentrated to give the residue. The crude product was purified by silica gel chromatography followed by re- crystallization from n-hexane (2.60 L) at 80°C to afford methyl 8-bromo-3-((trifluoromethyl) thio)indolizine-2-carboxylate.1H NMR: (400 MHz, CDCl3) δ 8.53 (d, J = 7.2 Hz, 1 H), 7.25 (m, 2 H), 6.74 (t, J = 7.2 Hz, 1 H), 3.96 (s, 3 H). Step 2: (8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)methanol

[0176] A solution of methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carboxylate (170 g, 480 mmol, 1.00 eq) in DCM (1.70 L) was prepared and reacted with DIBALH (1.00 M, 1.44 L, 3.00 eq) in a flow reactor. The solution of methyl 8-bromo-3-((trifluoromethyl)thio)indolizine-2- carboxylate was pumped (flow rate = 3.61 mL / min) into a mixer, where it was mixed with DIBAL-H (1.00 M, 1.44 L, 3.00 eq), which was being delivered by a separate pump (flow rate = 2.80 mL / min) into the mixer. Both streams were precooled and mixed at -20°C. Upon mixing, the reaction mixture was passed through a PFA (perfluoroalkoxy alkane) tubular reactor (3.17 mm I.D., 64.1 mL volume) at -20°C, with a residence time of 10 minutes. Upon exiting the cooled reactor, the reaction mixture was collected and analyzed by TLC until methyl 8-bromo-3- ((trifluoromethyl)thio) indolizine-2-carboxylate was completely consumed. The reaction mixture was then poured into 1 N aq HCl (5.00 L) and extracted with DCM (3.00 L). The reaction mixture was extracted again with DCM (2.00 L), and then the combined organic layers were washed with brine (3.00 L) and dried over sodium sulfate. The mixture was then filtered to remove sodium sulfate, and the filtrate was concentrated to give the desired product.Step 3: 8-bromo-3-((trifluoromethyl)thio)indolizine-2-carbaldehyde

[0177] (8-Bromo-3-((trifluoromethyl)thio)indolizin-2-yl)methanol (78.0 g, 239 mmol, 1.00 eq) was charged into EtOAc (936 mL).2-Iodoxybenzoic acid (167 g, 598 mmol, 2.50 eq) was then charged into the solution. The reaction mixture was stirred at 80°C for 6 h at which point the reaction was complete by TLC. The mixture was filtered, washing the filtrate with H2O (5.00 L), then dried over Na2SO4and concentrated to give 8-bromo-3-((trifluoromethyl)thio)indolizine-2- carbaldehyde.1H-NMR: 1 (400 MHz, DMSO-d6) δ 10.3 (s, 1 H), 8.75 (d, J = 7.2 Hz, 1 H), 7.55 (d, J = 6.8 Hz, 1 H), 7.11 (s, 1 H), 7.02 (t, J = 7.2 Hz, 1 H). Step 4: 8-bromo-2-ethynyl-3-((trifluoromethyl)thio)indolizine

[0178] 8-Bromo-3-((trifluoromethyl)thio)indolizine-2-carbaldehyde (75.0 g, 231 mmol, 1.00 eq) was dissolved in MeOH (1.13 L). K2CO3 (95.9 g, 694 mmol, 3.00 eq) and dimethyl (1-diazo- 2-oxopropyl)phosphonate (88.9 g, 463 mmol, 2.00 eq) were added. The reaction mixture was stirred at 20°C for 1 h at which point the reaction was complete by TLC analysis. The reaction mixture was concentrated under vacuum, and the residue was poured into ice-water (2.00 L). The mixture was extracted with EtOAc (800 mL, 500 mL). The combined organic layers were washed with Na2CO3solution (1.00 L) and brine (1.00 L), dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography to afford 8-bromo-2- ethynyl-3-((trifluoromethyl)thio)indolizine.1H-NMR: (400 MHz, CDCl3) δ 8.39 (d, J = 7.2 Hz, 1 H), 7.21 (d, J = 6.8 Hz, 1 H), 6.91 (s, 1 H), 6.68 (t, J = 7.2 Hz, 1 H), 3.35 (s, 1 H). Step 5: 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol

[0179] Zn(OTf)2 (112 g, 309 mmol, 2.20 eq) was added to toluene (450 mL). Then TEA (31.3 g, 309 mmol, 2.20 eq) and TMEDA (35.9 g, 309 mmol, 2.20 eq) were added, and the solution was stirred at 25°C for 1 h.8-Bromo-2-ethynyl-3-((trifluoromethyl)thio)indolizine (45.0 g, 141 mmol, 1.00 eq) was added into toluene. (45.0 mL), and the resulting mixture was charged into the reaction. The reaction mixture was stirred at 60°C for 1 h. CH2O (13.9 g, 464 mmol, 3.30 eq) was added into the reaction mixture, and the resulting mixture was stirred at 60°C for 1 h. The mixture was poured into 2 N HCl (1.50 L) and extracted with DCM (1.50 L, 1.00 L). The organic layer was washed with brine (1.00 L, 1.00 L, 1.00 L), dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 0 / 1) to afford the title compound1H-NMR: (400 MHz, CDCl3) δ 8.38 (d, J = 6.8 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 6.86 (s, 1 H), 6.66 (t, J = 7.2 Hz, 1 H), 4.58 (d, J = 5.2 Hz, 2 H), 1.73 (t, J = 5.6 Hz, 1 H).Intermediate 53: 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-amineStep 1: 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)thio)indolizine

[0180] A solution of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol (200 mg, 1 eq, 571 μmol) in THF (3.0 mL) was cooled to 0°C and treated with diphenylphosphoryl diphenylphosphoryl azide (157 mg, 123 μL, 1 eq, 571 μmol), DBU (87.0 mg, 85.4 μL, 1 eq, 571 μmol), and the mixture was stirred at 25°C for 2 h. Water was added to the reaction mixture then repeatedly extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution, and the organic extract was dried over sodium sulphate. The residue was purified on a silica gel column using gradient elution with 0-15% DCM-MeOH to give 2-(3-azidoprop-1-yn-1-yl)-8-bromo-3-((trifluoromethyl)thio)indolizinel. MS (ESI) m / z calc’d for C12H6BrF3N4S [M+H]+: 375, found 375. Step 2: 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-amine

[0181] A polymer based diphenyl(4-vinylphenyl)phosphine-divinylbenzene-styrene copolymer (391.98 mg, 2.5 eq, 666.36 μmol) was added to a solution of 2-(3-azidoprop-1-yn-1-yl)-8-bromo- 3-((trifluoromethyl)thio)indolizine (100.00 mg, 1 eq, 266.55 μmol) in THF (3.0 mL) and water (3.0 mL). The reaction mixture was stirred at 65°C for 1.5 h. The reaction mixture was cooled to RT. EtOAc was added, and the mixture was stirred for 5 min, filtered, and concentrated under reduced pressure. The residue was purified directly on a silica gel chromatography 0 - 40% MeOH / DCM) to give 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-amine. MS (ESI) m / z calc'd for C12H8BrF3N2S [M+H]+: 349, found 349. Intermediate 54: 2-bromo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio) imidazo[1,2-a]pyrazin-8-amineStep 1: tert-butyl (1R,2R,5R)-2-((2-bromo-3-((trifluoromethyl)thio)imidazo[1,2- a]pyrazin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0182] 2-bromo-8-chloro-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazine (500 mg, 1.50 mmol), tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (425 mg, 1.88 mmol), cesium fluoride (914 mg, 6.0 mmol), and DMSO (7.5 mL) were combined. The reaction mixture was stirred at 110°C for 2 h. The crude reaction mixture was diluted with EtOAc (50 mL) The organic mixture was washed with saturated NH4Cl (aq, 50 mL) and brine (aq, 50 mL). The organic solution was then dried (Na2SO4) and concentrated. Column chromatography (silica gel, MeOH in DCM, gradient 0 to 15%) yielded the desired product. MS: 522 [M+1]+, 524 [M+3]+. Step 2: N-(( ]octan-2-yl)-2-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-8-amine

[0183] Tert-butyl (1R,2R,5R)-2-((2-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-8- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.57 mmol) and DCM (2.9 mL) were combined. Trifluoroacetic acid (0.9 mL, 11.5 mmol) was added. The reaction mixture was stirred at 25°C for 2 h. Volatiles were removed to yield the desired product, which was used in the next step without further purification. MS: 422 [M+1]+, 424 [M+3]+. Step 3: 2-bromo-N-(( 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3-((trifluoromethyl)thio) imidazo[1,2-a]pyrazin-8-amine

[0184] N-((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-bromo-3-((trifluoromethyl)thio)imidazo [1,2-a]pyrazin-8-amine (240 mg, 0.57 mmol), paraformaldehyde (51.2 mg, 1.7 mmol), DCE (2.8 mL), and AcOH (0.16 mL, 2.8 mmol) were combined. The reaction mixture was stirred at 50°C for 1 h. Sodium triacetoxyborohydride (361 mg, 1.7 mmol) was then added. The reaction mixture was stirred at 50°C for 1 h. The reaction mixture was diluted with DCM (50 mL) The organic mixture was washed with sat NH4Cl (aq, 50 mL) and brine (aq, 50 mL). The organic solution was then dried (Na2SO4) and concentrated. Purification by mass-directed reverse phase HPLC (MeCN / water with 0.1% NH4OH modifier) afforded the desired product. MS: 436 [M+1]+, 438 [M+3]+.Intermediate 55: rel-tert-Butyl (1R,5S,6S)-6-amino-5-fluoro-3-azabicyclo[4.1.0]heptane-3- carboxylateStep 1: tert-Butyl 4-(dibenzylamino)-3-fluoro-3,6-dihydropyridine-1(2H)-carboxylate

[0185] A 50 ml round bottom flask equipped with a 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), and dibenzylamine (1.82 g, 1.77 mL, 1 eq, 9.21 mmol) and heated to a strong reflux for 24 h. 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. 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 ( 6-(dibenzylamino)-5-fluoro-3-azabicyclo[4.1.0]heptane-3-carboxylate

[0186] A flame dried 250 ml round bottom flask equipped with an internal temperature probe under nitrogen was charged with CH2Cl2(60.0 mL), cooled to 0 °C using an ice bath and diethylzinc (1.00 M in hexanes) (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 (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 ((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 (1.1 to 3.5 °C), and the mixture was stirred at 0 °C for 15 min. After 15 min, the mixture was quenched with saturated aqueous 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 extracted with CH2Cl2(10 ml). The combined organic layers were dried over sodium sulfate; silica (20 g) was added and concentrated to dryness. The residue was purified by normal phase flash chromatography (100 g SiO2 cartridge, 0to 20% EtOAc in heptanes over 15 CV, product eluted at 8%) to afford racemic rel-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: rel-tert-Butyl (1R,5S,6S)-6-amino-5-fluoro-3-azabicyclo[4.1.0]heptane-3- carboxylate

[0187] 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 minutes 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 minutes. H2 was bubbled into the mixture for 5 minutes and then vigorously stirred under H2for 19 h (full conversion by LCMS). The reaction mixture was purged with N2 for 2 min and filtered, 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). EXAMPLES Example 1 and Example 2: (3-methoxy-4-((3-(7-(((1S, 6S or 1R, 6R)-3-methyl-3- azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2- yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide (Peak 1) and (3-methoxy-4-((3- (7-(((1S,6S or 1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide (Peak 2)Step 1: 2-iodo-N-((1S,6S or 1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine (Peak 1, Intermediate 20.1) and 2- iodo-N-((1S, 6S or 1R, 6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine (Peak 2, Intermediate 20.2)

[0188] 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-7-amine was resolved to its component enantiomers by chiral Prep SFC (Column & dimensions: Lux-2, 21 x 250mm, 5μm; Mobile phase A: CO2; Mobile phase B: MeOH with 0.1% NH4OH) to afford 2-iodo-N-((1S,6S or 1R,6R)-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine (Peak 1, Intermediate 20.1) (tR = 3.6) MS (ESI) m / z calc’d for C15H16F3IN4S [M+H]+: 469 and 2-iodo-N-((1S,6S or 1R,6R)-3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine (Peak 2, Intermediate 20.2) (tR= 4.3). MS (ESI) m / z calc’d for C15H16F3IN4S [M+H]+: 469. Step 2: (3-methoxy-4-((3-(7-(((1S, 6S or 1R, 6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide and (3-methoxy-4-((3-(7-(((1S,6S or 1R,6R)- 3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridine-2-yl)prop-2-yn-1-yl)amino)phenyl)dimethylphosphine oxide

[0189] A 30 mL vial was charged with 2-iodo-N-((1S,6S or 1R,6R)-3-methyl-3-azabicyclo [4.1.0]heptan-6-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-7-amine (Peak 1, Intermediate 20.1) (15.0 mg, 1 eq, 32.0 μmol), (3-methoxy-4-(prop-2-yn-1-ylamino)phenyl) dimethylphosphine oxide (15.2 mg, 2 eq, 64.1 μmol), Pd(PPh3)4 (5.55 mg, 0.15 eq, 4.80 μmol), Hunig’s base (33.1 mg, 44.6 μL, 8 eq, 256 μmol), CuI (2.44 mg, 0.4 eq, 12.8 μmol), and DMSO(641 μL). Reaction mixture was purged with N2three times and stirred at 50°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 submitted for mass-directed reverse phase purification by HPLC, using acetonitrile / water gradient with 0.1% base linear gradient to afford (3-methoxy-4-((3-(7-(((1S, 6S or 1R, 6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide (Example 1). [M+H]+: 578.

[0190] A similar procedure was followed to obtain Example 2. [M+H]+: 578.

[0191] Each of the elaborated compounds presented in Table 9 below was prepared in accordance with the synthetic routes in Scheme 6 and Scheme 3, using procedures analogous to those described above.Table 9Table 9Table 9Table 9Table 9Table 9Table 9Table 9Table 9Table 9Table 9Table 9Example 74: (4-((3-(7-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide

[0192] A mixture of tert-butyl (4-aminobicyclo[2.2.1]heptan-1-yl)carbamate (21 mg, 0.092 mmol), (4-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (15 mg, 0.031 mmol), cesium carbonate (40 mg, 0.12 mmol), and rac-BINAP-Pd-G4 (6.2 mg, 0.006 mmol) in dioxane (1 mL) was deoxygenated by bubbling Ar for 5 min. The mixture was warmed to 100°C and stirred for 2 h. Silica gel-support Pd scavenger (100 mg) was added, and the mixture stirred for 30 min, filtered, and concentrated. The mixture pyridines dissolved in 1 mL of 1:1 DCM / TFA and aged for 1 h. The mixture was then concentrated to dryness. The dried mixture was dissolved the residue in 1 mL of DMSO and purified by reverse phase chromatography (eluent: MeCN / water with 0.1% TFA) to provide the desired compound (4-((3-(7-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide.1H NMR (500 MHz, DMSO-d6) δ: 8.26 (s, 3 H), 7.47 (m, 1 H), 7.29 (m, 1 H), 7.23 (m, 1 H), 7.14 (m, 1 H), 7.00 (m, 1 H), 6.42 (m, 1 H), 4.35 (m, 2 H), 3.86 (s, 3 H), 2.25 (m, 2 H), 2.11 (m, 2 H), 1.93 (m, 4 H), 1.80 (m, 2 H), 1.59 (s, 3 H), 1.57 (s, 3 H); MS (EI) calc’d for C27H32F3N5O2PS [M+H]+, 578; found 578. Example 75: (4-((3-(7-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxideStep 1: benzyl (4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-yl)carbamate

[0193] A mixture of benzyl (4-aminobicyclo[2.1.1]hexan-1-yl)carbamate (500 mg, 1.768 mmol), 3,3-bis(bromomethyl)oxetane (1.29 g, 5.30 mmol) and DIEA (1.85 mL, 10.61 mmol) in MeCN (5 mL) was stirred at 60°C for 8 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0~5% MeOH / CH2Cl2gradient) to give benzyl (4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1- yl)carbamate. MS (ESI) m / z: calc’d for C19H24N2O3 [M+H]+: 329.1 found 329.2 [M+H]+. Step 2: 4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-ami

[0194] A solution of benzyl N-[4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-bicyclo[2.1.1]hexanyl] carbamate (150 mg, 0.457 mmol) in MeOH (19.95 mL) was stirred at 20°C until clear. The solution was pumped at 0.3 mL / min through a ½” fixed bed column reactor packed with granular catalyst (5% Pd(OH)2 / Al2O3 (64.1 mg.0.457 mmol)) at 30°C. The H2 back pressure regulator was adjusted to 1 MPa. The flow rate of H2was 30 mL / min. The reaction mixture was collected after running 10 min. The reaction mixture was concentrated under reduced pressure to give 4-(2-oxa-6-azaspiro [3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-amine, which was used directly in the next step without further purification. MS (ESI) m / z: calc’d for C11H18N2O [M+H]+: 195.1, found: 195.2 [M+H]+. Step 3: (4-((3-(7-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide

[0195] A mixture of (4-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (20 mg, 0.041 mmol), 4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-amine (10.3 mg, 0.053 mmol), DIEA (0.043 mL, 0.246 mmol) and CsF (24.9 mg, 0.164 mmol) in DMSO (1 mL) was stirred at 100°C for 2 h. The reaction mixture was filtered and purified by Prep-HPLC to give (4-((3-(7-((4-(2-oxa-6- azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. MS (ESI) m / z: calc’d for C31H35F3N5O3PS [M+H]+: 646.2, found: 646.2 [M+H]+.1H NMR (400 MHz, MeOD) δ =7.43 - 7.37 (m, 1 H), 7.32 - 7.23 (m, 1 H), 7.20 - 7.15 (m, 1 H), 7.01 - 6.92 (m, 2 H), 6.28 - 6.24 (m, 1 H), 4.75 (s, 4 H), 4.37 (s, 2 H), 3.94 (s, 3 H), 3.50 - 3.48 (m, 4 H), 2.01 - 1.98 (m, 2 H), 1.83 - 1.80 (m, 4 H), 1.75 (s, 3 H), 1.72 (s, 3 H), 1.67 - 1.64 (m, 2 H).

[0196] Each of the elaborated compounds presented in Table 10 below was prepared in accordance with the synthetic routes in Scheme 7 and Scheme 1, using procedures analogous to those described above.Example 79: N-(3-(7-(((3S,4R)-1-(1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamideStep 1: N-(3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide

[0197] A vial was charged with N-((3S,4R)-3-fluoropiperidin-4-yl)-2-iodo-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-7-amine(0.300 g, 0.652 mmol), 1-(tert-butyl)-N-(prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (0.080 g, 0.652 mmol), Pd(PPh3)4 (0.075 g, 0.065 mmol), and CuI (0.050 g, 0.261 mmol). The vial was sealed, and its contents were placed under an inert atmosphere by performing three vacuum / N2 cycles. To the vial, DIPEA (0.908 mL, 5.21 mmol) and DMSO (2.17 mL) were added. The reaction was stirred at 23°C for 1.5 h. The reaction was diluted with sat. ammonium chloride (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure. The crude residue was subject to purification by reversed phase HPLC, eluting with water (0.1% NH4OH)-ACN to afford N-(3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide. MS (ESI) m / z calc’d for C18H22ClFN4O [M+H]+: 456, found 456.Step 2: N-(3-(7-(((3S,4R)-1-(1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide

[0198] A vial was charged with N-(3-(7-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide (0.035 g, 0.077 mmol), thietane-3-one 1,1-dioxide (0.023 g, 0.192 mmol), 4Å molecular sieves, DCE (0.384 mL), and a drop of acetic acid. The reaction was stirred at 50°C for 1 h, then sodium cyanoborohydride (0.019 g, 0.307 mmol) was added to the reaction. The reaction was continued to be stirred at 50°C for 14 h. The reaction was cooled to RT, quenched with sat. NaHCO3 (5 mL) and extracted with DCM (5 mL x 3). The combined organic phases were dried over Na2SO4, and the solvent removed under reduced pressure. The crude residue was subject to purification by reversed phase HPLC, eluting with water (0.1% NH4OH)-ACN to afford N-(3-(7-(((3S,4R)-1- (1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide. MS (ESI) m / z calc’d for C18H22ClFN4O [M+H]+: 560, found 560.1H NMR (400 MHz, d-DMSO, 25°C) δ: 8.71 (s, 1H), 7.54 (t, J = 8.2 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 48.7 Hz, 1H), 4.26 (d, J = 5.6 Hz, 4H), 4.18 (dd, J = 14.3, 6.2 Hz, 1H), 4.13 – 4.04 (m, 1H), 4.03 – 3.86 (m, 2H), 3.15 (s, 1H), 3.19 – 3.06 (m, 2H), 2.91 (s, 1H), 2.89 (d, 1H), 2.67 – 2.55 (m, 1H), 2.41 (dd, J = 37.6, 12.9 Hz, 1H), 2.23 (t, J = 11.2 Hz, 1H), 2.10 – 1.98 (m, 1H), 1.89 (s, 1H), 1.61 (s, 1H), 0.72 (t, J = 6.1 Hz, 4H).

[0199] Each of the elaborated compounds presented in Table 11 below was prepared in accordance with the synthetic routes in Scheme 8 and Scheme 4, using procedures analogous to those described above.Example 84: 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide

[0200] To a solution of 5-((3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylpicolinamide (40 mg, 0.078 mmol), (3S,4R)-3- fluoro-1-methylpiperidin-4-amine (20.56 mg, 0.156 mmol), cesium carbonate (127 mg, 0.389 mmol) in 1,4-dioxane (1 mL) was added BINAP (19.37 mg, 0.031 mmol) and Pd(OAc)2 (3.49 mg, 0.016 mmol) under N2. The resulting mixture was stirred at 90°C for another 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to give 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo [1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide. MS (ESI) m / z: calc’d for C28H31F4N7O3S [M+H]+: 622.1, found: 622.3 [M+H]+.1H NMR (400 MHz, MeOD) δ = 8.08 (br s, 1H), 7.95 (br d, J = 6.6 Hz, 1H), 7.82 (br s, 1H), 7.06 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.27 - 5.12 (m, 1H), 4.82 (br d, J = 7.7 Hz, 1H), 4.53 - 4.45 (m, 4H), 4.15 (br s, 3H), 4.11 - 4.05 (m, 1H), 3.67 - 3.58 (m, 1H), 3.54 - 3.44 (m, 1H), 3.42 - 3.34 (m, 2H), 3.26 - 3.18 (m, 1H), 2.99 (s, 3H), 2.33 - 2.26 (m, 1H), 2.25 - 2.12 (m, 1H), 1.76 (s, 3H). Example 85 and Example 86: 1-(tert-butyl)-N-(3-(8-(((3S,4R)-1-(3-cyanooxetan-3-yl)-3- fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide (Example 85) and 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3- fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2- a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (Example 86)Step 1: 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide

[0201] To a mixture of N-(3-(8-bromo-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2- yl)prop-2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide (928 mg, 1.855 mmol), tert-butyl (3S,4R)-4-amino-3-fluoropiperidine-1-carboxylate (1215 mg, 5.56 mmol) and cesium carbonate (1813 mg, 5.56 mmol) in 1,4-dioxane (28 ml) was added (R)-(+)-BINAP (577 mg, 0.927 mmol) and palladium(II) acetate (104 mg, 0.464 mmol) at 25°C. The resulting mixture was stirred at 100°C for 1 h under N2. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue waspurified by flash silica gel chromatography (eluent: 0~30% ethyl acetate / petroleum ether gradient) to give tert-butyl (3S,4R)-4-((2-(3-(1-(tert-butyl)-1H-pyrazole-4-carboxamido)prop-1- yn-1-yl)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyridin-8-yl)amino)-3-fluoropiperidine-1- carboxylate.

[0202] A mixture of tert-butyl (3S,4R)-4-((2-(3-(1-(tert-butyl)-1H-pyrazole-4- carboxamido)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-8-yl)amino)-3- fluoropiperidine-1-carboxylate (800 mg, 1.255 mmol) and 2,2,2-trifluoroacetic acid (1.5 ml, 20.19 mmol) in DCM (10 ml) was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure to give 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide, which was used in next step directly. LCMS (ESI) m / z: 538.2 [M+H]+. Step 2: 1-(tert-butyl)-N-(3-(8-((( -(3-cyanooxetan-3-yl)-3-fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide (Example 85)

[0203] To a mixture of 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (30 mg, 0.056 mmol) and oxetan-3-one (6.03 mg, 0.084 mmol) in DCE (1 mL) was added TMS- CN (0.014 mL, 0.101 mmol) at 25°C. The mixture was stirred at 60°C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give 1-(tert- butyl)-N-(3-(8-(((3S,4R)-1-(3-cyanooxetan-3-yl)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (4.52 mg, 6.73 µmol) and 1-(tert-butyl)-N-(3-(8-(((3S,4R)-1-(3-cyanooxetan-3-yl)-3- fluoropiperidin-4-yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide (Example 85), which is used for the next step. MS (ESI) m / z: calc’d for C28H30F4N8O2S [M+H]+: 619.1, found 619.2 [M(s, 1H), 7.83 - 7.78 (m, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 6.09 (br s, 1H), 5.49 (d, J = 9.4 Hz, 1H), 5.01 - 4.86 (m, 1H), 4.83 - 4.78 (m, 2H), 4.73 (dd, J = 6.4, 14.6 Hz, 2H), 4.56 (d, J = 5.1 Hz, 2H), 3.72 - 3.55 (m, 1H), 3.06 - 2.97 (m, 1H), 2.77 (br dd, J = 1.8, 10.8 Hz, 1H), 2.52 - 2.39 (m, 1H), 2.34 (dt, J = 3.9, 10.8 Hz, 1H), 2.12 - 1.99 (m, 2H), 1.61 (s, 9H). Step 3: 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide (Example 86)

[0204] The compound of Example 86 was prepared using conditions highlighted in Scheme 4. MS (ESI) m / z: calc’d for C28H33F4N7O2S [M+H]+: 608.1, found 608.3 [M+H]+.1H NMR (400MHz, MeOH-d4) δ = 8.26 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 6.7 Hz, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 5.54 (d, J = 9.1 Hz, 1H), 4.96 - 4.88 (m, 1H), 4.63 (d, J = 5.6 Hz, 1H), 4.57 (d, J = 5.7 Hz, 1H), 4.45 (s, 2H), 4.24 (dd, J = 2.5, 5.5 Hz, 2H), 3.88 - 3.71 (m, 1H), 2.94 - 2.84 (m, 1H), 2.67 - 2.60 (m, 1H), 2.58 - 2.44 (m, 1H), 2.36 (br t, J = 10.5 Hz, 1H), 2.03 - 1.87 (m, 2H), 1.60 (s, 9H), 1.41 (s, 3H). Example 87: 6-(4-(4-fluoro-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)-7- methylisoquinolin-3-amineStep 1: tert-butyl (3-(7-bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn- 1-yl)carbamate

[0205] A mixture of 7-bromo-2-iodo-3-((trifluoromethyl)thio)benzo[b]thiophene (540 mg, 1.230 mmol), tert-butyl prop-2-yn-1-ylcarbamate (229 mg, 1.476 mmol), Pd(PPh3)4 (142 mg, 0.123 mmol), CuI (94 mg, 0.492 mmol), and DIPA (1.724 mL, 12.30 mmol) in DMSO (5 mL) was degassed and backfilled with N2 (three times). The mixture was stirred at 25°C for 1 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 x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 10% ethyl acetate / petroleum ether gradient) to give tert-butyl (3-(7- bromo-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate. MS (ESI) m / z: calc’d for C17H15BrF3NO2S2 [M+H]+: 466.0 / 468.0 [M+H-C4H8]+, found: 409.9 / 413.9. Step 2: tert-butyl (3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)- 3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate

[0206] A mixture of PEPPSI-HeptCl (62.6 mg, 0.064 mmol), tert-butyl (3-(7-bromo-3- ((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (200 mg, 0.429 mmol), (3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine (121 mg, 0.643 mmol) and Cs2CO3(419 mg, 1.287 mmol) in 1,4-dioxane (3 mL), and the mixture was degassed and backfilled with N2 (three times). The mixture was heated to 100°C for 1 h. The mixture was cooled and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 50% ethyl acetate / petroleum ether gradient) to give tert-butyl (3-(7- (((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio) benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate. MS (ESI) m / z: calc’d for C26H31F4N3O3S2[M+H]+: 574.2, found: 574.2 [M+H]+. Step 3: (3S,4R)-N-(2-(3-aminoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)benzo[b] thiophen-7-yl)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine

[0207] A mixture of tert-butyl (3-(7-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)carbamate (100 mg, 0.174 mmol) in DCM (0.5 mL) and TFA (0.167 mL) was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to give the crude (3S,4R)-N-(2-(3-aminoprop-1-yn-1- yl)-3-((trifluoromethyl)thio)benzo[b]thiophen-7-yl)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- amine (80 mg), which was used in next step directly. MS (ESI) m / z: calc’d for C21H23F4N3OS2 [M+H]+: 474.1, found: 474.1 [M+H]+. Step 4: N-(3-(7-((( 3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn-1-yl)acetamide

[0208] A mixture of (3S,4R)-N-(2-(3-aminoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)benzo[b] thiophen-7-yl)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-amine (25 mg, 0.053 mmol), TEA (0.022 mL, 0.158 mmol), and acetyl chloride (4.13 µl, 0.058 mmol) in DCM (0.5 mL) was stirred at 25°C for 1 h. 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-(3-methyloxetan-3- yl)piperidin-4-yl)amino)-3-((trifluoromethyl)thio)benzo[b]thiophen-2-yl)prop-2-yn-1- yl)acetamide. MS (ESI) m / z: calc’d for C23H25F4N3O2S2[M+H]+:516.1, found: 516.1 [M+H]+.1400 MHz) δ 7.3-7.4 (m, 2H), 6.8-6.9 (m, 1H), 4.80 (br s, 1H), 4.6-4.7 (m, 2H), 4.57 (d, 1H, J = 5.6 Hz), 4.33 (s, 2H), 4.2-4.3 (m, 2H), 3.7-3.8 (m, 1H), 2.8-3.0 (m, 1H), 2.6-2.7 (m, 1H), 2.4-2.6 (m, 1H), 2.3-2.4 (m, 1H), 2.00 (s, 3H), 1.97 (br d, 1H, J = 3.6 Hz), 1.41 (s, 3H).Example 88: 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan- 2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide

[0209] A mixture of CuI (7.11 mg, 0.037 mmol), DIPA (0.118 mL, 0.840 mmol), Pd(PPh3)4(16.17 mg, 0.014 mmol) 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (45 mg, 0.093 mmol), 4-methoxy-N- methyl-3-(prop-2-yn-1-ylamino)benzamide (28.5 mg, 0.131 mmol) in DMSO (0.5 mL) was stirred at 25°C for 1 h under N2atmosphere. LCMS showed the mass of the desired product. The reaction was diluted with water (5 mL), extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (10 mL * 2) and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (10 mM-NH4HCO3)-MeCN Begin B 47 End B 77 Gradient Time(min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give 4-methoxy-N-methyl-3- ((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc'd for C28H32F3N6O2S+[M+H]+573.3, found [M+H]+573.3.1H NMR (400 MHz, MeOD) δ 7.47 - 7.39 (m, 2H), 7.35 (d, J = 1.9 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 7.7 Hz, 1H), 4.76 - 4.48 (m, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.81 - 3.75 (m, 1H), 3.22 - 3.17 (m, 1H), 2.90 (s, 3H), 2.32 (s, 3H), 2.19 - 2.06 (m, 1H), 1.98 - 1.75 (m, 4H), 1.69 - 1.51 (m, 3H). Example 89 and Example 90: 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide and 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamideStep 1: 1-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3- azabicyclo[4.1.0]heptan-3-yl)-2-methylpropan-2-ol

[0210] A mixture of N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.220 mmol), 2,2-dimethyloxirane (23.81 mg, 0.330 mmol), N-ethyl-N-isopropylpropan-2-amine (0.154 mL, 0.881 mmol) in EtOH (1 mL) was stirred at 140 °C for 2 h by microwave reactor. LCMS showed the desired mass was found. The solvent was removed under reduced pressure to give 1-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)-2-methylpropan-2-ol. The product was used for the next step without purification. MS (ESI) m / z: calc'd for C18H23F3IN4OS+[M+H]+527.0, found [M+H]+527.0. Step 2: 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy- N-methylbenzamide

[0211] A mixture of CuI (7.24 mg, 0.038 mmol), DIPA (0.120 mL, 0.855 mmol), Pd(PPh3)4 (16.47 mg, 0.014 mmol), 1-(6-((2-iodo-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)-2-methylpropan-2-ol (50 mg, 0.095 mmol), 4- methoxy-N-methyl-3-(prop-2-yn-1-ylamino)benzamide (29.0 mg, 0.133 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 h under N2. LCMS showed the mass of the desired product. The reaction was diluted with water (5 mL), extracted with EtOAc (4 mL*3). The combined organic layers were washed with brine (10 mL*2) and dried over anhydrous Na2SO4, filtered, and concentrated. The concentrate was purified by Prep-TLC (SiO2, CH2Cl2 / MeOH = 10:1) to give 3- ((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide. MS (ESI) m / z: calc'd for C30H36F3N6O3S+[M+H]+617.2, found [M+H]+617.1.Step 3: 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy- N-methylbenzamide

[0212] The 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide (36 mg, 0.058 mmol) was separated by Prep-SFC (Column DAICEL CHIRALPAK IE (250mm*30mm,10um) Condition n-Heptane-(i-PrOH / ACN=2:1) (0.1%NH3H2O) Begin B 60 End B 60 Gradient Time(min) 8100%B Hold Time 1 Flow Rate(mL / min) 100) to give 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan- 6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide as two separated diastereomers.

[0213] Peak 1: MS (ESI) m / z: calc'd for C30H36F3N6O3S+[M+H]+617.2, found [M+H]+617.2, tR=1.567 min.1H NMR (400 MHz, MeOD) δ = 7.43 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 2.1, 8.3 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 4.36 (s, 2H), 3.92 (s, 3H), 3.16 - 3.03 (m, 1H), 2.90 (s, 3H), 2.83 (br d, J = 11.2 Hz, 1H), 2.59 - 2.44 (m, 2H), 2.38 - 2.24 (m, 3H), 2.12 - 2.00 (m, 1H), 1.20 (d, J = 3.0 Hz, 6H), 1.05 - 0.99 (m, 2H).

[0214] Peak 2: MS (ESI) m / z: calc'd for C30H36F3N6O3S+[M+H]+617.2, found [M+H]+617.2, tR=1.567 min;1H NMR (400 MHz, MeOD) δ = 7.45 - 7.39 (m, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.23 (dd, J = 2.0, 8.3 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 1.0, 7.7 Hz, 1H), 4.36 (s, 2H), 3.91 (s, 3H), 3.07 (br dd, J = 4.6, 11.5 Hz, 1H), 2.90 (s, 3H), 2.82 (br d, J = 11.6 Hz, 1H), 2.55 - 2.42 (m, 2H), 2.35 - 2.25 (m, 3H), 2.07 (td, J = 5.7, 13.5 Hz, 1H), 1.42 - 1.38 (m, 1H), 1.19 (d, J = 3.2 Hz, 6H), 1.05 - 0.99 (m, 2H).

[0215] SFC method: Column: Chiralpak IE 100*4.6mm 3um Mobile phase: A: Hexane(0.1%DEA) B:IPA / MeCN=2 / 1 Isocratic: A / B=40 / 60 Flow Rate:1mL / min Column Temp.: 35°C Example 91 and Example 92: 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide (separated diastereomers)Step 1: 3-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide

[0216] To a solution of 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine (500 mg, 1.321 mmol) in DMSO (3 mL) were added 4-methoxy-N-methyl-3-(prop-2-yn-1- ylamino)benzamide (346 mg, 1.585 mmol), copper(I) iodide (101 mg, 0.528 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (97 mg, 0.132 mmol), and DIPEA (2.076 mL, 11.89 mmol) under N2. The mixture was stirred for 1 h at 40 °C under N2. LCMS showed that desired target was observed and starting material was consumed. The reaction mixture was quenched with H2O (30 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®; 12 g SepaFlash® Silica Flash Column, eluent of 0~85% ethyl acetate / pet. ether gradient @ 30 mL / min) to give 3-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn- 1-yl)amino)-4-methoxy-N-methylbenzamide. MS (ESI) m / z: calc’d for C20H17ClF3N4O2S+[M+H]+: 469.1, found: 469.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 0.7, 8.8 Hz, 1H), 7.37 (dd, J = 7.4, 8.8 Hz, 1H), 7.21 (dd, J = 2.0, 8.2 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.80 (d, J = 8.3 Hz, 1H), 6.14 (br s, 1H), 5.42 (br s, 1H), 4.36 (s, 2H), 3.90 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H). Step 2: tert-butyl 6-((2-(3-((2-methoxy-5-(methylcarbamoyl)phenyl)amino)prop-1-yn-1- yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3- azabicyclo[4.1.0]heptane-3-carboxylate

[0217] To a solution of 3-((3-(7-chloro-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (100 mg, 0.213 mmol) in DMSO (3 mL) were added cesium fluoride (130 mg, 0.853 mmol), N-ethyl-N-isopropylpropan-2-amine (221 mg, 1.706 mmol) and tert-butyl 6-amino-3-azabicyclo[4.1.0]heptane-3-carboxylate (54.3 mg, 0.256 mmol). The mixture was stirred for 2 h at 100 °C under N2. LCMS showed desired mass peak was observed. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM:MeOH = 10:1 (10 mL * 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 (silica gel, ethyl acetate / pet. ether = 1 / 0, v / v) to give tert-butyl 6-((2-(3-((2-methoxy-5-(methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0]heptane-3-carboxylate. MS (ESI) m / z: calc’d for C31H36F3N6O4S+[M+H]+: 645.2, found: 645.1 [M+H]+.Step 3: 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide

[0218] To a solution of tert-butyl 6-((2-(3-((2-methoxy-5-(methylcarbamoyl)phenyl)amino) prop-1-yn-1-yl)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0] heptane-3-carboxylate (75 mg, 0.116 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (0.3 ml, 0.116 mmol). The mixture was stirred for 0.5 h at 40 °C. LCMS showed the desired mass peak was observed, and the starting material was consumed. The resulting mixture was concentrated under reduced pressure to give 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide. MS (ESI) m / z: calc’d for C26H28F3N6O2S+[M+H]+:545.2, found: 545.2 [M+H]+. Step 4: 4-methoxy-N ethyl-3-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide

[0219] To a solution of 3-((3-(7-((3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (50 mg, 0.092 mmol) in MeOH (0.5 mL) was added AcOH (1.051 µl, 0.018 mmol), formaldehyde (2.76 mg, 0.092 mmol), and NaBH3(CN) (5.77 mg, 0.092 mmol), the mixture was stirred for 1 h at 60 °C. LCMS showed the starting material was consumed and the desired mass peak was observed. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (silica gel, DCM / MeOH= 10 / 1, v / v) to give 4-methoxy-N-methyl-3-((3-(7-((3-methyl- 3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc’d for C27H30F3N6O2S+[M+H]+: 559.2 found: 559.2. Step 5: 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide

[0220] The 4-methoxy-N-methyl-3-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide (25 mg, 0.045 mmol) was resolved by Chiral-SFC (Column: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 um) Condition: CO2- MEOH (0.1% NH3H2O), Begin B 30% End B 30% Gradient Time (min) 20100%B Hold Time: 20 Flow Rate (ml / min): 80) to give 4-methoxy-N-methyl-3-((3-(7- (((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide as two separated diastereomers.

[0221] Peak 1: LCMS (ESI) m / z: calc’d for C27H30F3N6O2S [M+H]+: 559.2, found: 559.2 [M+H]+.1H NMR (MeOD, 400 MHz) δ 7.41 - 7.29 (m, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 2.0, 8.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.33 (dd, J = 0.9, 7.7 Hz, 1H), 4.26 (s, 2H), 3.81 (s, 3H), 2.88 (dd, J = 6.1, 12.1 Hz, 1H), 2.80 (s, 3H), 2.56 (br d, J = 11.7 Hz, 1H), 2.37 - 2.19 (m, 3H), 2.18 (s, 3H), 2.06 - 1.97 (m, 1H), 1.43 - 1.34 (m, 1H), 0.98 (dd, J = 4.8, 9.8 Hz, 1H), 0.83 (t, J = 5.7 Hz, 1H).

[0222] Peak 2: LCMS (ESI) m / z: calc’d for C27H30F3N6O2S [M+H]+: 559.2, found: 559.2 [M+H]+.1H NMR (MeOD, 400 MHz) δ 7.38 - 7.29 (m, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 2.0, 8.3 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.33 (dd, J = 0.8, 7.7 Hz, 1H), 4.26 (s, 2H), 3.81 (s, 3H), 2.89 (br dd, J = 6.3, 12.0 Hz, 1H), 2.80 (s, 3H), 2.56 (br d, J = 12.0 Hz, 1H), 2.37 - 2.20 (m, 3H), 2.19 (s, 3H), 2.07 - 1.97 (m, 1H), 1.43 - 1.32 (m, 1H), 0.98 (dd, J = 4.9, 9.8 Hz, 1H), 0.83 (t, J = 5.7 Hz, 1H).

[0223] SFC Method: Column: Chiralcel OD-350×4.6mm I.D., 3um, Mobile phase: A: CO2 B: Methanol (0.2% MNH3) Gradient: from 5% to 40% of B in 1.5 min and hold 40% for 1.0 min, then 5% of B for 0.5 min, Flow rate: 4mL / min, Column temp.: 35℃, ABPR: 1500 psi. Example 93: N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)amino)benzamide

[0224] To a solution of 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amine (40mg, 0.083 mmol) in DMSO (0.5 mL) were added (R)-N-(2-hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (21.75 mg, 0.083 mmol), CuI (6.32 mg, 0.033 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ii) (6.07 mg, 8.29 µmol), and DIEA (0.130 ml, 0.746 mmol) under N2. The mixture was stirred for 1 h at 40 °C under N2. LCMS showed that desired mass peak was observed. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (Column Phenomenex Synergi C18150*30MM*4um Condition water (0.1%TFA)-ACN Begin B 20 End B 40 Gradient Time (min) 10100%B Hold Time 2 Flow Rate (ml / min) 25) to give N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo [1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc’d for C30H36F3N6O3S+[M+H]+: 616.7, found: 617.2 [M+H]+.1H NMR (400 MHz, MeOD) δ = 7.85 (d, J = 5.1 Hz, 1H), 7.46 (dd, J = 1.8, 8.3 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 5.1 Hz, 1H), 7.25 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.32 (s, 2H), 4.13 - 4.05 (m, 1H), 3.99 - 3.91 (m, 5H), 3.45 - 3.37 (m, 1H), 2.84 (s, 3H), 2.66 (s, 1H), 2.36 (dt, J = 6.1, 12.5 Hz, 1H), 2.29 - 2.12 (m, 2H), 2.09 - 1.86 (m, 5H), 1.37 (dd, J = 3.6, 6.6 Hz, 1H), 1.20 (d, J = 6.3 Hz, 3H). Example 94: (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl- 8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7- yl)prop-2-yn-1-yl)amino)phenyl)methanone

[0225] To a solution of 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amine (40mg, 0.083 mmol) in DMSO (0.5 mL) were added (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl) methanone (22.75 mg, 0.083 mmol), CuI (6.32 mg, 0.033 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (6.07 mg, 8.29 µmol), and DIEA (0.130 mL, 0.746 mmol) under N2. The mixture was stirred for 1 h at 40 °C under N2. LCMS showed that desired mass peak was observed. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by Pre-HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (0.1%TFA) - ACN Begin B 10 End B 40 Gradient Time (min) 11100%B Hold Time 3 Flow Rate (ml / min) 25) to give (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(1- (((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo [1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)phenyl)methanone. MS (ESI) m / z: calc’d for C31H36F3N6O3S+[M+H]+: 628.7, found: 629.2[M+H]+.1H NMR (400 MHz, MeOD) δ = 7.87 (d, J = 5.1 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.23 (dd, J = 1.8, 8.2 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.36 - 4.21 (m, 4H), 4.15 - 3.99 (m, 3H), 3.97 - 3.84 (m, 4H), 2.84 (s, 3H), 2.44 - 2.30 (m, 1H), 2.26 - 2.14 (m, 2H), 2.11 - 1.86 (m, 5H), 1.49 (s, 3H).Example 95: 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N- (oxetan-3-yl)benzamideStep 1: 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid

[0226] To a solution of 7-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-1-amine (90 mg, 0.187 mmol) in DMSO (0.5 mL) were added 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (38.3 mg, 0.187 mmol), CuI (14.22 mg, 0.075 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (13.65 mg, 0.019 mmol), and DIEA (0.293 mL, 1.679 mmol) under N2. The mixture was stirred for 1 h at 40 °C under N2. LCMS showed that desired mass peak was observed. The reaction mixture was quenched with H2O (5 mL) and extracted with EtOAc (3 mL*3). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica gel, DCM / MeOH = 10 / 1, v / v) to give 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid. MS (ESI) m / z: calc’d for C27H29F3N5O3S+[M+H]+: 559.6, found: 560.1 [M+H]+. Step 2: 3-methoxy-4-((3-(1-((( 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(oxetan-3- yl)benzamide

[0227] To a mixture of 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid (30 mg, 0.054 mmol) in DMF (1 mL) were added HATU (30.6 mg, 0.080 mmol) and DIEA (0.037 mL, 0.214 mmol) at 20°C. The mixture was stirred at 20°C for 5 min, and then oxetan-3- amine (3.92 mg, 0.054 mmol) was added. The resulting mixture was stirred at 20°C for 2 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 (10 mL*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 Pre-HPLC (Welch Xtimate C18150*25 mm*5 um Condition water (10 mM-NH4HCO3)-ACN Begin B 20 End B 70 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)thio) pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(oxetan-3-yl)benzamide. MS (ESI) m / z: calc’d for C30H34F3N6O3S+[M+H]+:614.7, found:615.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.67 (d, J = 4.9 Hz, 1H), 7.51 (dd, J = 1.8, 8.3 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 4.9 Hz, 1H), 7.12 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.15 - 5.09 (m, 1H), 4.72 (br t, J = 6.5 Hz, 4H), 4.35 - 4.26 (m, 3H), 3.92 (s, 3H), 3.43 (br d, J = 2.6 Hz, 1H), 3.20 - 3.12 (m, 1H), 2.32 (s, 3H), 2.16 - 2.01 (m, 1H), 1.90 - 1.68 (m, 4H), 1.67 - 1.47 (m, 3H). Example 96: 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide

[0228] To a mixture of 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzoic acid (30mg, 0.054 mmol) in DMF (1 mL) were added HATU (30.6 mg, 0.080 mmol) and DIEA (0.037 ml, 0.214 mmol) at 20°C. The mixture was stirred at 20°C for 5 min, and then 3- methyloxetan-3-amine (4.67 mg, 0.054 mmol) was added. The resulting mixture was stirred at 20°C for 2 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 (10 mL*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 Pre- HPLC (Welch Xtimate C18150*25mm*5um Condition water (10mM-NH4HCO3)-ACN Begin B 20 End B 70 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)thio)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 C31H36F3N6O3S+[M+H]+: 628.715, found: 629.2 [M+H]+.1H NMR (400 MHz, MeOD) δ = 7.68 (d, J = 4.9 Hz, 1H), 7.45 (dd, J = 1.9, 8.3 Hz,1H), 7.35 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 5.0 Hz, 1H), 7.11 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.85 (br s, 2H), 4.50 (d, J = 6.7 Hz, 2H), 4.34 (br dd, J = 3.0, 5.3 Hz, 1H), 4.31 (s, 2H), 3.92 (s, 3H), 3.44 (br d, J = 2.3 Hz, 1H), 3.20 - 3.14 (m, 1H), 2.33 (s, 3H), 2.09 (br dd, J = 8.5, 12.6 Hz, 1H), 1.92 - 1.80 (m, 3H), 1.79 - 1.73 (m, 1H), 1.71 (s, 3H), 1.65 - 1.49 (m, 3H). Example 97: (4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxideStep 1: 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine

[0229] To a vial, 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol (141 mg, 1 eq, 403 μmol) in DCM (5.0 mL) was added triphenylphosphine dibromide (219 mg, 1.29 eq, 519 μmol), and the solution was stirred for an hour at RT. The resulting mixture was concentrated under reduced pressure and purified on a silica gel column eluting with 0-15% DCM-MeOH to give 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine. MS (ESI) m / z calc’d for C12H6Br2F3NS [M+H]+: 412, found 412. Step 2: (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide

[0230] To a vial containing 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio) indolizine (300.00 mg, 1 eq, 726.30 μmol) in DMF (5.00 mL) were added potassium carbonate (301.13 mg, 3.00 eq, 2.1789 mmol) and (4-amino-3-methoxyphenyl)dimethylphosphine oxide (144.67 mg, 1 eq, 726.30 μmol), and the solution was stirred for an hour at 70°C. The resulting mixture was concentrated under reduced pressure and purified on a silica gel column using gradient elution 0-15% DCM-MeOH to give (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin- 2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide. MS (ESI) m / z calc’d for C21H19BrF3N2O2PS [M+H]+: 531, found 531.Step 3: tert-butyl (1R,2R,5R)-2-((2-(3-((4-(dimethylphosphoryl)-2- methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate

[0231] In a 20mL vial, (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxyphenyl)dimethylphosphine oxide (300.00 mg, 1 eq, 564.62 μmol). tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (140.56 mg, 1.1 eq, 621.08 μmol), cesium carbonate (919.82 mg, 5.00 eq, 2.8231 mmol) and rac-BINAP Pd G4 (56.826 mg, 0.10 eq, 56.462 μmol) were added. The vial was purged and backfilled with N23 times.1,4-Dioxane (5.00 mL) was added, and the reaction was heated to 100°C for 4 h. The reaction mixture was filtered and concentrated then partitioned between sat aq NaHCO3and DCM. The organic layer was washed with brine, dried over (Na2SO4), concentrated, and purified by silica gel column chromatography (0-50% EtOAc / DCM) to give tert-butyl (1R,2R,5R)-2-((2-(3-((4- (dimethylphosphoryl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio) indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z calc’d for C33H40F3N4O4PS [M+H]+: 677, found 677. Step 4: (4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide

[0232] To a solution of tert-butyl (1R,2R,5R)-2-((2-(3-((4-(dimethylphosphoryl)-2- methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (286.00 mg, 1 eq, 422.61 μmol) in MeOH (5.00 mL) was added 4N HCl in dioxane (5.00 mL), and the resulting mixture was stirred at 20°C for 12 h. The reaction solution was concentrated in vacuo, added aq. NaHCO3, and extracted with EtOAc (* 3). The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO® Flash Column Silica (12 g), Eluent of 0 ~ 30% ethyl acetate / Hex gradient @ 55 mL / min). The fractions containing product were combined and evaporated under reduced pressure and further purified by Prep HPLC Reverse phase (C-18), eluting with acetonitrile / water + 0.1% NH4, to give to give (4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide. MS (ESI) m / z calc’d for C28H32F3N4O2PS [M+H]+: 577, found 577.1H NMR (499 MHz, DMSO-d6) δ 7.80 (d, J = 6.8 Hz, 1H), 7.28 – 7.07 (m, 4H), 6.89 – 6.67 (m, 2H), 6.07 – 5.92 (m, 2H), 5.71 (d, J = 7.9 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 1.89 – 1.62 (m, 3H), 1.59 (s, 3H), 1.57 (s, 3H), 1.51 – 1.32 (m, 8H).Example 98: (3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide

[0233] A suspension of (4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethyl phosphine oxide (50.00 mg, 1 eq, 86.71 μmol) in 1,4-dioxane (3.00 mL) was treated with TEA (10.53 mg, 14.5 μL, 1.2 eq, 104.1 μmol) to aid solubility, then formaldehyde (7.038 mg, 6.457 μL, 37% wt, 1 eq, 86.71 μmol) and sodium triacetoxyborohydride (36.76 mg, 2 eq, 173.4 μmol) were added. The reaction mixture was stirred for 12 h at 20°C. The mixture was quenched with sat NaHCO3and stirred for 1 h to consume reagent. The mixture was extracted with DCM, washed with DCM and water, and separated the organic layer, dried over (Na2SO4) and concentrated. The concentrated material was dissolved in a small amount of DCM and loaded onto a solid phase flash column. The material was then purified on a silica gel column using 0- 50% MeOH / DCM. The fractions containing product were combined and evaporated under reduced pressure and further purified by Prep HPLC reverse phase (C-18), eluting with acetonitrile / water + 0.1% NH4, to give (3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo [3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide. MS (ESI) m / z calc’d for C29H34F3N4O2PS [M+H]+: 591, found 591.1H NMR (499 MHz, DMSO-d6) δ 7.81 (d, J = 6.8 Hz, 1H), 7.29 – 7.09 (m, 3H), 6.92 – 6.72 (m, 2H), 6.00 (dd, J = 6.8, 3.5 Hz, 2H), 5.69 (d, J = 7.9 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.86 (s, 3H), 2.18 (s, 3H), 2.00 – 1.62 (m, 8H), 1.60 (s, 3H), 1.57 (s, 3H), 1.55 – 1.36 (m, 3H). Example 99: 4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamideStep 1: 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide

[0234] To a vial, 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (500.00 mg, 1 eq, 1.2105 mmol) and potassium carbonate (501.88 mg, 3.00 eq, 3.6315 mmol) in DMF (10.00 mL) was added 4-amino-3-methoxy-N-methylbenzamide (218.15 mg, 1 eq, 1.2105 mmol), and the solution was stirred for an hour at 70°C. The resulting mixture was concentrated under reduced pressure and purified on a silica gel column using gradient eluting with 0-15% DCM-MeOH to give 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide. MS (ESI) m / z calc’d for C21H17BrF3N3O2S [M+H]+: 512, found 512. Step 2: tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-4- (methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0235] In a 20mL vial, 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide (276.00 mg, 1 eq, 538.69 μmol). tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (134.11 mg, 1.1 eq, 592.56 μmol), cesium carbonate (877.59 mg, 5.00 Eq, 2.6935 mmol) and rac-BINAP Pd G4 (54.217 mg, 0.10 eq, 53.869 μmol) were added. The vial was purged and backfilled with N23 times.1,4-Dioxane (5.00 mL) was added, and the reaction was heated to 100°C for 4 h. The reaction mixture was filtered and concentrated, then partitioned between sat aq NaHCO3and DCM. The organic layer was washed with brine, dried over (Na2SO4), concentrated and purified on a silica gel column chromatography (0-50% EtOAc / DCM) to give tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-4- (methylcarbamoyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)- 8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z calc’d for C33H38F3N5O4S [M+H]+: 658, found 658. Step 3: 4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide

[0236] To a solution of tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-4-(methylcarbamoyl) phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo [3.2.1]octane-8-carboxylate (200.00 mg, 1 eq, 304.07 μmol) in MeOH (5.00 mL) was added 4 N HCl in dioxane (2.00 mL), and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated. The crude was purified by Prep HPLC Reverse phase (C-18), eluting with acetonitrile / water + 0.1% NH4to give 4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1] octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide. MS (ESI) m / z calc’d for C28H30F3N5O2S [M+H]+: 558, found 558.1H NMR (499 MHz, DMSO-d6) δ 8.10 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.50 – 7.29 (m, 2H), 7.17 (s, 1H), 6.76 (t, J = 7.6 Hz, 2H), 6.11 – 5.88 (m, 2H), 5.71 (d, J = 7.8 Hz, 1H), 4.28 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 2.76 (d, J = 4.5 Hz, 3H), 1.88 – 1.76 (m, 3H), 1.72 – 1.40 (m, 8H). Example 100: (4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxideStep 1: tert-butyl (1R,2R,5R)-2-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1]octane- 8-carboxylate

[0237] To a solution of tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (4000.00 mg, 1 eq, 17.674 mmol) in anhydrous DCM (10.00 mL) was added Et3N (6.4384 g, 8.87 mL, 3.6 eq, 63.627 mmol) and benzyl chloroformate (10.553 g, 8.831 mL, 3.5 eq, 61.859 mmol) at 0°C. The mixture was warmed to RT and stirred for 2 h. The mixture was treated with water and separated. The organic phase was washed with water and brine, dried over anhydrous Na2SO4and concentrated. The residue was purified on a silica gel chromatography (MeOH / DCM) to obtain tert-butyl (1R,2R,5R)-2-(((benzyloxy)carbonyl)amino)-8-azabicyclo[3.2.1] octane-8-carboxylate. MS (ESI) m / z calc’d for C20H28N2O4[M+H]+: 361, found 361. Step 2: benzyl (( 8-azabicyclo[3.2.1]octan-2-yl)carbamate

[0238] To a solution of tert-butyl (1R,2R,5R)-2-(((benzyloxy)carbonyl)amino)-8-azabicyclo [3.2.1]octane-8-carboxylate (330.00 mg, 1 eq, 915.52 μmol) in DCM (5.00 mL) was added TFA (7.40 g, 5.00 mL, 70.9 eq, 64.9 mmol), and the resulting mixture was stirred at 20 °C for 12 h. The reaction solution was concentrated in vacuo. Then, aq. NaHCO3 was added, and the solution was extracted with EtOAc (* 3). The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by a flash silica gel chromatography (ISCO®; Agela® Flash Column Silica-CS (12 g), eluting with 0 ~ 30% MeOH / DCM gradient @ 55 mL / min) to give benzyl ((1R,2R,5S)-8-azabicyclo[3.2.1] octan-2-yl)carbamate. MS (ESI) m / z calc’d for C15H20N2O2[M+H]+: 261, found 261.Step 3: benzyl (( 8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate

[0239] To benzyl ((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)carbamate (170.00 mg, 1 eq, 652.99 μmol) in DMF (5.00 mL) were added 1-bromo-2-fluoroethane (82.904 mg, 1 eq, 652.99 μmol) and potassium carbonate (90.244 mg, 1 eq, 652.99 μmol), and the reaction mixture was heated to 90 °C for 20 h. The reaction mixture was concentrated in vacuo and partitioned between sat aq NaHCO3and DCM. The organic layer was washed with brine, dried (Na2SO4), concentrated, and purified on a silica gel column chromatography (0-50% EtOAc / DCM) to give benzyl ((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)carbamate. MS (ESI) m / z calc’d for C17H23FN2O2 [M+H]+: 307, found 307. Step 4: (1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-amine

[0240] To a solution of the benzyl ((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2- yl)carbamate (100 mg, 1 eq, 326 μmol) in 1:1 EtOH / EtOAc (6.00 mL) was added Pd / C (3.47 mg, 0.1 eq, 32.6 μmol). The resulting mixture was stirred under an atmosphere of H2 for 24 h, after which time the mixture was filtered through a pad of diatomaceous earth (CELITE®). The pad was washed with EtOAc, and the filtrate was concentrated in vacuo to give (1R,2R,5R)-8-(2- fluoroethyl)-8-azabicyclo[3.2.1]octan-2-amine. MS (ESI) m / z calc’d for C9H17FN2[M+H]+: 173, found 173. The product was taken to next step without purification. Step 5: (4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide

[0241] (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide (35.00 mg, 1 eq, 65.87 μmol). (1R,2R,5R)-8-(2- fluoroethyl)-8-azabicyclo[3.2.1]octan-2-amine (11.35 mg, 1 eq, 65.87 μmol), cesium carbonate (107.3 mg, 5.00 eq, 329.4 μmol), and rac-BINAP Pd G4 (6.630 mg, 0.10 eq, 6.587 μmol) were added to a 20 mL vial. The vial was purged and backfilled with N23 times.1,4-Dioxane (3.00 mL) was added, and the reaction was heated to 100°C for 4 h. The mixture was concentrated in vacuo and partitioned between sat aq NaHCO3and DCM. The organic layer was washed with brine, dried (Na2SO4), concentrated, and purified on a silica gel column chromatography (0-50% EtOAc / DCM). The purified material was further purified by reverse phase chromatography to give (4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide. MS (ESI) m / z calc’d for C30H35F4N4O2PS [M+H]+: 623, found 623.1H NMR (499 MHz, DMSO-d6) δ 7.81 (d, J = 6.8 Hz, 1H), 7.33 – 7.07 (m, 3H), 6.91 – 6.68 (m, 2H), 6.07 – 5.92 (m, 2H), 5.72 (d, J = 7.8 Hz, 1H), 4.50 (dt, J = 47.8, 4.9 Hz, 2H), 4.28 (d, J =6.2 Hz, 2H), 3.86 (s, 3H), 2.62 (dd, J = 27.1, 6.0 Hz, 2H), 2.05 – 1.74 (m, 3H), 1.59 (s, 3H), 1.57 (s, 3H), 1.55 – 1.36 (m, 8H).

[0242] Each of the elaborated compounds presented in Table 12 below were prepared in accordance with the synthetic routes and procedures described for Examples 99 and 100 above starting from the appropriate pyrazolopyridine intermediates prepared as described above.Example 119: N-(3-(7-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole- 4-carboxamide, 2,2,2-trifluoroacetate saltStep 1: N-((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)-3-((trifluorom ethyl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0243] To 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine (200.00 mg, 1 eq, 528.35 μmol) and tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (179.36 mg, 1.5 eq, 792.52 μmol) in DMSO (0.75 mL), cesium fluoride (401.28 mg, 5.00 eq, 2.64 mmol) was added. The reaction was monitored using LC-MS. The reaction mixture was filtered and partitioned into EtOAc and sat. NaHCO3. The aqueous layer was extracted twice; the organic layers were combined, dried over anhydrous MgSO4, and filtered. The excess solvent was removed under reduced pressure. The product obtained was purified on a silica gel column using gradient elution with 0-15% DCM-MeOH. Appropriate fractions were pooled, and excess solvent was removed under reduced pressure. The product obtained was vacuum dried to give tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z calc’d for C20H24F3IN4O2S [M+ tbutyl, found 513.0. Step 2: )-2-iodo-3-((trifluorometh yl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0244] To tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate, 1ml DCM and 0.2mL TFA were added, and the reaction stirred at RT for 2 h. Excess solvent was removed under pressure, and the product obtained was vacuum dried. The reaction was stirred at RT for 3 h. Excess solvent was removed under reduced pressure, and the product obtained was co-evaporated with ethyl ether and vacuum dried to give N-((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluorometh yl)thio) pyrazolo[1,5-a]pyridin-7-amine. MS (ESI) m / z calc’d for C15H16F3IN4S [M+H]+: 469 found 469.0 Step 3: N-(( 8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0245] To a solution of N-((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (20.00 mg, 1 eq, 42.71 μmol) and DIPEA (19.87 mg, 26.8 μL, 3.6 eq, 153.8 μmol) in MeCN (0.50 mL) was added 2-fluoroethyl 4- methylbenzenesulfonate (10.25 mg, 59.0 μL, 1.10 eq, 46.98 μmol). The resulting solution was stirred at 70°C overnight. LC showed a single peak. Excess solvent was removed under reduced pressure, and the product obtained was directly used for the next step. N-((1R,2R,5R)-8-(2- fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-amine was obtained. MS (ESI) m / z calc’d for C17H19F4IN4S [M+H]+: 515, found 515 Step 4: N-(3-(7-((( 8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt

[0246] To N-((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (30.00 mg, 1 eq, 58.33 μmol) and 1- methyl-N-(prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (19.04 mg, 2.00 eq, 116.7 μmol) in a vial, DMSO (0.50 mL), CuI (5.554 mg, 0.5 eq, 29.16 μmol), Pd(PPh3)4(6.74 mg, 0.10 eq, 5.83 μmol), and DIEA (67.85 mg, 91.4 μL, 9.0 eq, 525.0 μmol) were added. The reaction was thoroughly purged with N2and then stirred at 50°C for 2 h. The reaction mix was diluted with excess 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-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt. MS (ESI) m / z calc’d for C27H27F7N7O3S [M+H]+: 550, found 550.2.1H NMR (499 MHz, DMSO) δ 9.74 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.57 (d, J = 16.4 Hz, 1H), 7.48 (s, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.39 (d, J = 7.9 Hz, 1H), 4.89 (d, J = 47.2 Hz, 2H), 4.37 (s, 2H), 4.26 (s, 1H), 4.06 (d, J = 45.1 Hz, 2H), 3.87 (s, 3H), 2.47 – 2.39 (m, 1H), 2.27 – 2.18 (m, 1H), 2.18 – 2.05 (m, 1H), 2.05 – 1.91 (m, 2H), 1.86 – 1.73 (m, 3H). Example 120 and Example 121 (3-methoxy-4-((3-(8-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide and (3-methoxy-4-((3-(8-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide

[0247] To (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide (19.00 mg, 1 eq, 35.76 μmol) and 3-methyl-3- azabicyclo[4.1.0]heptan-6-amine (6.769 mg, 1.50 eq, 53.64 μmol) in 1,4-dioxane (0.40 mL), rac BINAP (3.59 mg, 0.10 eq, 3.576 μmol) and cesium carbonate (58.26 mg, 5.00 eq, 178.8 μmol) were added, and the reaction was thoroughly purged with N2 and then stirred at 100°C for 5 h. The reaction mixture was filtered and purified on a silica gel column using gradient elution 0- 15% DCM-MeOH. Appropriate fractions were pooled; excess solvent was removed under reduced pressure. The product obtained was vacuum dried. The racemic product was resolved on SFC to give two peaks using Column & Dimensions: CCO F4, 21X250mm, 5um UV Wavelength: 215nm Flow Rate: 70ml / min Modifier: 25% MeOH w / 0.1% NH4OH. Stereochemistry was arbitrarily assigned; absolute stereochemistry was not determined for both peaks.

[0248] Peak 1: MS (ESI) m / z calc’d for C28H32F3N4O2PS [M+H]+: 577, found 57(499 MHz, DMSO) δ 7.84 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 6.93 (s, 1H), 6.90 – 6.75 (m, 2H), 6.70 (s, 1H), 6.23 (s, 1H), 5.97 (s, 1H), 4.27 (s, 2H), 3.85 (s, 3H), 2.75 (s, 1H), 2.36 – 2.10 (m, 6H), 2.05 – 1.88 (m, 2H), 1.58 (d, J = 13.1 Hz, 7H), 1.31 – 1.22 (m, 3H), 0.92 – 0.80 (m, 2H).

[0249] Peak 2 MS (ESI) m / z calc’d for C28H32F3N4O2PS [M+H]+: 577, found 577.2.1H NMR (499 MHz, DMSO) δ 7.82 (d, J = 6.8 Hz, 1H), 7.21 (d, J = 10.6 Hz, 1H), 7.13 (d, J = 11.0 Hz, 1H), 6.93 (s, 1H), 6.86 (s, 2H), 6.71 (s, 1H), 6.23 (d, J = 7.5 Hz, 1H), 6.00 (s, 1H), 4.27 (s, 2H), 3.85 (s, 3H), 2.74 – 2.66 (m, 1H), 2.61 – 2.54 (m, 1H), 2.19 – 2.10 (m, 6H), 1.58 (d, J = 13.2 Hz, 7H), 1.29 – 1.20 (m, 3H), 0.89 – 0.78 (m, 2H).

[0250] The compounds in Table 13 below were synthesized in an analogous manner from the corresponding bromide intermediates prepared as described above and the racemic mixtures were resolved via Chiral SFC to give the corresponding peaks.Example 124 and Example 125: N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide and N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan- 3-yl)-1H-pyrazole-4-carboxamide

[0251] To 2-iodo-N-(3-methyl-3-azabicyclo[4.1.0]heptan-1-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine (50.00 mg, 1 eq, 106.8 μmol) and 1-(oxetan-3-yl)-N-(prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide (43.82 mg, 2.00 eq, 213.5 μmol), copper(I) iodide (10.17 mg, 0.5 eq, 53.39 μmol), tetrakis(triphenylphosphine)palladium(0) (12.34 mg, 0.10 eq, 10.68 μmol), DIEA (124.2 mg, 167 μL, 9.00 eq, 961.0 μmol), and DMSO (0.50 mL) were added, and the vial was thoroughly purged with N2and then stirred at 50°C for 2 h. The reaction was monitored using LCMS. 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 racemic N-(3-(7-(((1S,6S)- 3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin- 2-yl)prop-2-yn-1-yl)-1-(oxetan-3-yl)-1H-pyrazole-4-carboxamide. The racemic compound was resolved on chiral SFC to give Peak 1 and Peak 2 Column & Dimensions: IG, 21X250mm, 5um UV Wavelength: 215nm Flow Rate: 70ml / min Modifier: 45% MeOH w / 0.1% NH4OH.

[0252] Example 124: Peak 1 – MS (ESI) m / z calc’d for C25H26F3N7O2S [M+H]+: 546, found 546.9.1H NMR (500 MHz, DMSO) δ 8.80 (s, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.55 (s, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.45 (s, 1H), 5.67 – 5.56 (m, 1H), 4.97 – 4.92 (m, 2H), 4.92 – 4.82 (m, 3H), 4.38 (s, 2H), 2.74 – 2.66 (m, 1H), 2.16 (s, 6H), 1.97 (s, 1H), 1.46 – 1.29 (m, 1H), 1.07 – 0.98 (m, 1H), 0.86 – 0.76 (m, 1H).

[0253] Example 125: Peak 2 – MS (ESI) m / z calc’d for C25H26F3N7O2S [M+H]+: 546, found 546.2.1H NMR (500 MHz, DMSO) δ 8.80 (d, J = 5.7 Hz, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.62 – 7.47 (m, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.45 (s, 1H), 5.71 – 5.58 (m, 1H), 4.98 – 4.81 (m, 4H), 4.37 (s, 2H), 2.76 – 2.68 (m, 1H), 2.53 (s, 1H), 2.15 (d, J = 15.5 Hz, 6H), 2.03 – 1.92 (m, 1H), 1.46 – 1.29 (m, 1H), 1.11 – 0.96 (m, 1H), 0.89 – 0.74 (m, 1H).

[0254] The compounds in Table 14 were synthesized using Intermediate 50 and the corresponding alkyne, following general Songashira conditions detailed in Examples 1 and 2. The stereochemistry has been arbitrarily assigned; absolute stereochemistry is unknown.Table 14

[0255] Each of the elaborated compounds presented in Table 15 below was prepared in accordance with the synthetic routes in Scheme 6 and Scheme 1, using procedures analogous to those described above for Examples 1 and 2.Example 137 and Example 138: N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide and N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3- methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide

[0256] A mixture of (R)-N-(2-hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (16.80 mg, 0.064 mmol), Intermediate 21A (1 eq), CuI (3.25 mg, 0.017 mmol), Pd(PPh3)4(7.40 mg, 6.41 µmol), and DIPA (5.39 mL, 38.4 mmol) in DMSO (1 mL) was degassed and backfilled with N2(three times). The mixture was heated to 25°C for 40 min. LCMS showed that desired product was formed. The mixture was filtered, and the residue was purified by Pre-HPLC (Column Boston Prime C18150 * 30 mm * 5 um Condition Water (0.05% NH3H2O + 10 mM NH4HCO3) - ACN Begin B 50 End B 80 Gradient Time(min) 2.5100%B Hold Time 11 FlowRate (ml / min) 25 Injections 1) to give N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3-methyl- 3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc’d for C29H34F3N6O3S+[M+H]+: 603.2 found 603.2, tR=1.524 min.1H NMR (400 MHz, MeOD) δ 7.48 - 7.41 (m, 2H), 7.38 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 7.0 Hz, 1H), 4.36 (s, 2H), 3.98 - 3.94 (m, 1H), 3.93 (s, 3H), 3.44 - 3.38 (m, 1H), 3.35 - 3.33 (m, 1H), 2.94 (dd, J = 6.1, 11.9 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.42 - 2.30 (m, 2H), 2.29 - 2.26 (m, 1H), 2.26 (s, 3H), 2.17 - 2.05 (m, 1H), 1.54 - 1.40 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H), 1.07 (dd, J = 5.1, 9.9 Hz, 1H), 0.92 (t, J = 5.7 Hz, 1H)

[0257] Similarly, a mixture of (R)-N-(2-hydroxypropyl)-3-methoxy-4-(prop-2-yn-1- ylamino)benzamide (16.80 mg, 0.064 mmol), Intermediate 21B, CuI (3.25 mg, 0.017 mmol), Pd(PPh3)4(7.40 mg, 6.41 µmol), and DIPA (5.39 mL, 38.4 mmol) in DMSO (1 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 40 min. LCMS showed that desired product was formed. The mixture was filtered, and the residue was purified by Pre-HPLC (Column Boston Prime C18150 * 30 mm * 5um Condition water (0.04% NH3H2O + 10mM NH4HCO3) - ACN Begin B 52 End B 82 Gradient Time (min) 10100%B Hold Time 2 Flow Rate (ml / min) 25 Injections 1) to give N-((R)-2-hydroxypropyl)-3-methoxy-4- ((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc’d for C29H34F3N6O3S+[M+H]+: 603.2 found 603.2, tR=1.522 min.1H NMR (400 MHz, MeOD) δ 7.49 - 7.40 (m, 2H), 7.38 (d, J = 1.3 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 4.35 (s, 2H), 4.00 - 3.93 (m, 1H), 3.92 (s, 3H), 3.45 - 3.36 (m, 1H), 3.33 (br s, 1H), 2.92 (br dd, J = 5.9, 11.7 Hz, 1H), 2.68 - 2.56 (m, 1H), 2.34 (br d, J = 7.9 Hz, 2H), 2.24 (s, 4H), 2.16 - 2.00 (m, 1H), 1.53 - 1.39 (m, 1H), 1.19 (d, J = 6.3 Hz, 3H), 1.05 (br dd, J = 5.1, 9.9 Hz, 1H), 0.90 (t, J = 5.5 Hz, 1H). Example 139 and Example 140: (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-((3- methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone and (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone

[0258] A mixture of (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1-ylamino) phenyl)methanone (11.72 mg, 0.043 mmol), Intermediate 21A (1 eq), CuI (3.25 mg, 0.017 mmol), Pd(PPh3)4(7.40 mg, 6.41 µmol), and DIPA (5.39 mL, 38.4 mmol) in DMSO (0.5 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 40 min. LCMS showed that desired product was formed. The mixture was filtered, and the residue was purified by Pre-HPLC (Column Boston Prime C18150 * 30 mm * 5 um Condition Water (0.05% NH3H2O + 10 mM NH4HCO3) - ACN Begin B 50 End B 80 Gradient Time(min) 2.5100% B Hold Time 11 Flow Rate (ml / min) 25 Injections 1) to give (3-hydroxy-3-methylazetidin-1-yl)(3- methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone. MS (ESI) m / z: calc’d for C30H34F3N6O3S+ [M+H]+: 615.2, found: 615.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 7.44 (t, J = 8.2 Hz, 1H), 7.26 - 7.16 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.47 - 6.41 (m, 1H), 4.35 (s, 2H), 4.29 (br s, 2H), 4.10 - 3.98 (m, 2H), 3.90 (s, 3H), 2.94 (br dd, J = 6.1, 11.7 Hz, 1H), 2.68 - 2.59 (m, 1H), 2.41 - 2.31 (m, 2H), 2.30 - 2.26 (m, 1H), 2.26 (s, 3H), 2.15 - 2.07 (m, 1H), 1.49 (s, 3H), 1.48 - 1.43 (m, 1H), 1.07 (dd, J = 4.9, 9.8 Hz, 1H), 0.92 (t, J = 5.5 Hz, 1H).

[0259] Similarly, a mixture of (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1- ylamino)phenyl)methanone (11.72 mg, 0.043 mmol), Intermediate 21B (1 eq), CuI (3.25 mg, 0.017 mmol), Pd(PPh3)4(7.40 mg, 6.41 µmol), and DIPA (5.39 mL, 38.4 mmol) in DMSO (0.5 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 25°C for 40 min. LCMS showed that desired product was formed. The mixture was filtered, and the residue was purified by Pre-HPLC (Column Boston Prime C18150 * 30 mm * 5um Condition water (0.04% NH3H2O + 10 mM NH4HCO3) - ACN Begin B 52 End B 82 Gradient Time (min) 10 100% B Hold Time 2 Flow Rate (ml / min) 25 Injections 1) to give (3-hydroxy-3-methylazetidin- 1-yl)(3-methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone. MS (ESI) m / z: calc’d for C30H34F3N6O3S+[M+H]+: 615.2, found: 615.2 [M+H]+.1H NMR (400 MHz, MeOD) δ = 7.43 (br t, J = 8.1 Hz, 1H), 7.25 - 7.17 (m, 2H), 6.97 (br d, J = 8.6 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H),6.43 (d, J = 7.7 Hz, 1H), 4.35 (s, 2H), 4.28 (br s, 2H), 4.04 (br s, 2H), 3.90 (s, 3H), 2.91 (br dd, J = 5.9, 11.7 Hz, 1H), 2.73 - 2.58 (m, 1H), 2.33 (br d, J = 8.0 Hz, 2H), 2.24 (s, 4H), 2.15 - 2.05 (m, 1H), 1.48 (s, 3H), 1.47 - 1.39 (m, 1H), 1.05 (br dd, J = 4.7, 9.5 Hz, 1H), 0.90 (br t, J = 5.5 Hz, 1H). Example 141 and Example 142: 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo [4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide (Peak 1) and 4-((3-(7-(((cis)-3-(1,1- dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (Peak 2)Step 1: 1,1-dioxidothietan-3-yl methanesulfonate

[0260] To a mixture of 3-hydroxythietane 1,1-dioxide (16.5 mg, 0.135 mmol) and TEA (0.056 mL, 0.405 mmol) in DCM (1 mL) was added methanesulfonic anhydride (35.3 mg, 0.203 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction solution was used to next step without work up. MS (ESI) m / z: calc’d for C4H9O5S2+[M+H]+201.1, found no MS [M+H]+. Step 2: 3-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3- azabicyclo[4.1.0]heptan-3-yl)thietane 1,1-dioxide

[0261] To a mixture of 1,1-dioxidothietan-3-yl methanesulfonate (27 mg, 0.135 mmol) and TEA (13.65 mg, 0.135 mmol) in DCM (1.5 mL) was added N-(3-azabicyclo[4.1.0]heptan-6-yl)- 2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (55.1 mg, 0.121 mmol) at 25°C. The resulting mixture was stirred at 25°C for 1 h. LCMS showed that the reaction completed. The mixture was diluted with MeOH (0.5 mL), washed with water (3 mL*2), dried (Na2SO4), and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by Pre-TLC (silica gel, ethyl acetate / pet. ether = 1 / 3, v / v) to give 3-(6-((2-iodo-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)thietane 1,1-dioxide. MS (ESI) m / z: calc’d for C17H19F3IN4O2S2+[M+H]+559.0, found 559.0 [M+H]+. Step 3: 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide (Peak 1) and 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide (peak2)

[0262] To a mixture of 3-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl) amino)-3-azabicyclo[4.1.0]heptan-3-yl)thietane 1,1-dioxide (40 mg, 0.072 mmol), 3-methoxy-N- methyl-4-(prop-2-yn-1-ylamino)benzamide (31.3 mg, 0.143 mmol), CuI (6.82 mg, 0.036 mmol) and (PPh3)4Pd (83 mg, 0.072 mmol) in DMSO (1.5 mL) was added DIPA (0.090 mL, 0.645 mmol) at 25°C. The resulting mixture was stirred at 25°C for 1 h under N2. LCMS showed that the reaction completed. The mixture was diluted with EtOAc (5 mL), washed with water (5 mL*2), dried (Na2SO4), and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by Pre-TLC (silica gel, ethyl acetate / pet. ether = 1 / 0, v / v) to give an isomer mixture. SFC_Method:Column: Chiralpak AD-350×4.6mm I.D., 3um, Mobile phase: A: CO2 B:ethanol (0.2% MNH3), Isocratic: 40% B, Flow rate: 3.5mL / min, Column temp.: 35 ℃, ABPR: 1500 psi. The crude product was resolved by Chiral-SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um), Condition CO2-EtOH (0.1%NH3H2O) Begin B 50% End B 50% Gradient Time(min) 50, 100%B Hold Time 1 Flow Rate(mL / min) 150) to give:

[0263] Example 141 (Peak 1): 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide, 1st Peak on SFC method. MS (ESI) m / z: calc’d for C29H32F3N6O4S2+[M+H]+: 649.1, found: 649.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.35 (m, 2H), 7.23 (dd, J = 1.5, 8.2 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.45 (s, 1H), 6.31 (d, J = 6.9 Hz, 1H), 6.09 (br d, J = 4.5 Hz, 1H), 4.93 (br t, J = 5.9 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H), 4.18 - 4.10 (m, 2H), 4.08 - 3.98 (m, 2H), 3.91 (s, 3H), 3.19 (t, J = 7.5 Hz, 1H), 2.99 (d, J = 4.8 Hz, 3H), 2.83 - 2.78 (m, 1H), 2.74 - 2.68 (m, 1H), 2.34 - 2.23 (m, 3H), 2.18 - 2.12 (m, 1H), 1.52 - 1.44 (m, 1H), 1.10 (dd, J = 4.7, 9.7 Hz, 1H), 0.96 (t, J = 5.5 Hz, 1H).

[0264] Example 142 (Peak 2): 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)- 3-methoxy-N-methylbenzamide, 2nd Peak on SFC method. MS (ESI) m / z: calc’d for C29H32F3N6O4S2+[M+H]+: 649.1, found: 649.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.35 (m, 2H), 7.24 (dd, J = 1.8, 8.2 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.45 (s, 1H), 6.31 (dd, J = 0.8, 7.7 Hz, 1H), 6.11 (br d, J = 4.3 Hz, 1H), 4.93 (br t, J = 6.0 Hz, 1H), 4.34 (d, J = 6.1 Hz, 2H), 4.18 - 4.10 (m, 2H), 4.08 - 3.98 (m, 2H), 3.91 (s, 3H), 3.18 (quin, J = 7.6 Hz, 1H), 2.99 (d, J = 4.8 Hz, 3H), 2.84 - 2.77 (m, 1H), 2.74 - 2.68 (m, 1H), 2.33 - 2.26 (m,3H), 2.18 - 2.14 (m, 1H), 1.48 (td, J = 5.0, 9.8 Hz, 1H), 1.10 (dd, J = 4.8, 9.7 Hz, 1H), 0.95 (t, J = 5.5 Hz, 1H). Example 143 and Example 144: 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo [4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-((R)-2-hydroxypropyl)-3-methoxybenzamide (Peak 1) and 4-((3-(7-(((cis)-3- (1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-((R)-2-hydroxypropyl)-3- methoxybenzamide (Peak 2)

[0265] To a mixture of 3-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)thietane 1,1-dioxide (60 mg, 0.107 mmol), (R)-N-(2- hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (56.4 mg, 0.215 mmol), CuI (10.23 mg, 0.054 mmol) and (PPh3)4Pd (124 mg, 0.107 mmol) in DMSO (1.5 mL) was added DIPA (0.136 mL, 0.967 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h under N2. LCMS showed that the reaction completed. The mixture was diluted with EtOAc (5 mL), washed with water (5 mL*2), dried (Na2SO4), and filtered. The solvent was evaporated under reduced pressure. The residue was purified by Pre-TLC (silica gel, ethyl acetate / pet. ether = 1 / 0, v / v) to give a isomer mixture. SFC Method: Column: Chiralpak AD-350×4.6mm I.D., 3um, Mobile phase: A: CO2 B: ethanol (0.2% MNH3), Isocratic: 40% B, Flow rate: 4mL / min, Column temp.: 35 °C, ABPR: 1500 psi. The crude product was resolved by Chiral-SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um), Condition CO2-EtOH (0.1%NH3H2O) Begin B 50% End B 50% Gradient Time (min) 50, 100%B Hold Time 1 Flow Rate (mL / min) 150) to give:

[0266] Example 143 (Peak 1): 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)- N-((R)-2-hydroxypropyl)-3-methoxybenzamide 1st Peak on SFC method. MS (ESI) m / z: calc’d for C31H36F3N6O5S2+[M+H]+: 693.1, found: 693.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.41 - 7.33 (m, 2H), 7.31 - 7.27 (m, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.70 (br t, J = 5.7 Hz, 1H), 6.47 (s, 1H), 6.32 - 6.28 (m, 1H), 4.34 (s, 2H), 4.17 - 4.10 (m, 2H), 4.07 -3.98 (m, 3H), 3.88 (s, 3H), 3.59 (ddd, J = 2.8, 6.4, 13.9 Hz, 1H), 3.33 - 3.25 (m, 1H), 3.17 (quin, J = 7.6 Hz, 1H), 2.82 - 2.77 (m, 1H), 2.71 - 2.66 (m, 1H), 2.30 - 2.23 (m, 3H), 2.12 (br dd, J = 4.0, 8.6 Hz, 1H), 1.49 - 1.42 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.07 (dd, J = 4.7, 9.8 Hz, 1H), 0.93 (t, J = 5.5 Hz, 1H)

[0267] Example 144 (Peak 2): 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)- N-((R)-2-hydroxypropyl)-3-methoxybenzamide 2nd Peak on SFC method. MS (ESI) m / z: calc’d for C31H36F3N6O5S2+[M+H]+: 693.1, found: 693.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.40 - 7.35 (m, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.29 (dd, J = 1.7, 8.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.77 - 6.71 (m, 2H), 6.47 (s, 1H), 6.30 (d, J = 7.6 Hz, 1H), 4.97 (br s, 1H), 4.34 (br d, J = 3.6 Hz, 2H), 4.17 - 4.09 (m, 2H), 4.06 - 3.97 (m, 3H), 3.88 (s, 3H), 3.58 (ddd, J = 2.7, 6.4, 14.0 Hz, 1H), 3.33 - 3.25 (m, 1H), 3.16 (quin, J = 7.6 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.70 - 2.65 (m, 1H), 2.32 - 2.22 (m, 3H), 2.17 - 2.08 (m, 1H), 1.45 (td, J = 4.9, 9.6 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.07 (dd, J = 4.8, 9.8 Hz, 1H), 0.96 - 0.90 (m, 1H) Example 145 and Example 146: 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo [4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide (Peak 1) and 3-((3-(7-(((cis)-3-(1,1- dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide (Peak 2)

[0268] To a mixture of 3-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)thietane 1,1-dioxide (40 mg, 0.072 mmol), 4-methoxy- N-methyl-3-(prop-2-yn-1-ylamino)benzamide (31.3 mg, 0.143 mmol), CuI (6.82 mg, 0.036 mmol), and (PPh3)4Pd (83 mg, 0.072 mmol) in DMSO (1.5 mL) was added DIPA (0.090 mL, 0.645 mmol) at 25 °C. The resulting mixture was stirred at 25 °C for 1 h under N2. LCMS showed that the reaction completed. The mixture was diluted with EtOAc (5 mL), washed with water (5 mL*2), dried (Na2SO4), and filtered. The solvent was evaporated under reduced pressure. The residue was purified by Pre-TLC (silica gel, ethyl acetate / pet. ether = 1 / 0, v / v) to give an isomer mixture. SFC Method: Column: Chiralpak AD-350×4.6mm I.D., 3um, Mobilephase: A: CO2B: ethanol (0.2% MNH3) Isocratic: 40% B, Flow rate: 4mL / min Column temp.: 35 °C ABPR: 1500 psi. The crude product was resolved by Chiral-SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um), Condition CO2-EtOH (0.1%NH3H2O) Begin B 50% End B 50% Gradient Time (min) 50, 100%B Hold Time 1 Flow Rate (mL / min) 150) to give:

[0269] Example 145 (Peak 1): 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide 1st Peak on SFC method. MS (ESI) m / z: calc’d for C29H32F3N6O4S2+ [M+H]+: 649.1, found: 649.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.38 (t, J = 8.2 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.05 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.47 (s, 1H), 6.31 (d, J = 7.0 Hz, 1H), 6.11 (br d, J = 4.4 Hz, 1H), 4.78 - 4.57 (m, 1H), 4.35 (s, 2H), 4.19 - 4.11 (m, 2H), 4.09 - 3.98 (m, 2H), 3.90 (s, 3H), 3.19 (quin, J = 7.5 Hz, 1H), 3.00 (d, J = 4.8 Hz, 3H), 2.85 - 2.78 (m, 1H), 2.75 - 2.69 (m, 1H), 2.35 - 2.24 (m, 3H), 2.19 - 2.12 (m, 1H), 1.49 (td, J = 4.9, 9.8 Hz, 1H), 1.11 (dd, J = 4.8, 9.5 Hz, 1H), 0.96 (t, J = 5.5 Hz, 1H).

[0270] Example 146 (Peak 2): 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop- 2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide 2nd Peak on SFC method. MS (ESI) m / z: calc’d for C29H32F3N6O4S2+[M+H]+: 649.1, found: 649.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.38 (t, J = 8.2 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.05 (d, J = 8.7 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.47 (s, 1H), 6.31 (dd, J = 0.8, 7.6 Hz, 1H), 6.11 (br d, J = 4.3 Hz, 1H), 4.80 - 4.58 (m, 1H), 4.35 (s, 2H), 4.19 - 4.11 (m, 2H), 4.08 - 3.99 (m, 2H), 3.90 (s, 3H), 3.24 - 3.15 (m, 1H), 3.00 (d, J = 4.8 Hz, 3H), 2.84 - 2.78 (m, 1H), 2.75 - 2.70 (m, 1H), 2.35 - 2.24 (m, 3H), 2.20 - 2.12 (m, 1H), 1.50 (td, J = 5.0, 9.7 Hz, 1H), 1.11 (dd, J = 4.8, 9.6 Hz, 1H), 0.97 (t, J = 5.5 Hz, 1H). Example 147 and Example 148: 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide and N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamideStep 1: tert-butyl (1R,2R,5R)-2-((2-(3-(1-methyl-1H-pyrazole-4-carboxamido)prop-1-yn- 1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate

[0271] To a solution of N-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)- 1-methyl-1H-pyrazole-4-carboxamide (29 mg, 0.063 mmol) in 1,4-dioxane (1 mL) were added tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (17.22 mg, 0.076 mmol), Cs2CO3 (62.0 mg, 0.190 mmol) and PEPPSI IpentCl Pd (12.34 mg, 0.013 mmol), the resulting mixture was stirred at 100°C for 1 h. LCMS showed the starting material was consumed and the desired compound was found. The mixture was added water (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Pre-TLC (silica gel, ethyl acetate / pet. ether = 1 / 1, v / v) to give tert-butyl (1R,2R,5R)-2-((2-(3-(1-methyl-1H-pyrazole-4-carboxamido)prop-1- yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z: calc'd for C29H34F3N6O3S+[M+H]+603.2, found [M+H]+603.2. Step 2: N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide (Example 147)

[0272] A mixture of tert-butyl (1R,2R,5R)-2-((2-(3-(1-methyl-1H-pyrazole-4-carboxamido) prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (20 mg, 0.033 mmol) in DCM (0.5 mL) was added TFA (0.1 mL, 1.298 mmol) and stirred at 20°C for 1 h. LCMS showed that the desired target was observed and that the starting material was consumed. The mixture was added aq. NaHCO3to adjust pH~8. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL*3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (15 mg, 0.027 mmol), which was no further purified.

[0273] The compound N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (5 mg) was purified by pre-HPLC (Column Welch Xtimate C18150*25 mm*5 um Condition water(0.1%TFA)-ACN Begin B 23 End B 43 Gradient Time (min) 11100%B Hold Time 3 Flow Rate (mL / min) 25 Injections 1) to give N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide. MS (ESI) m / z: calc’d for C24H26F3N6OS+[M+H]+: 503.2, found [M+H]+: 503.1.1H NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.97 - 7.92 (m, 1H), 7.90 (s, 1H), 6.98 (s, 1H), 6.79 - 6.72 (m, 1H), 6.19 - 6.12 (m, 1H), 4.42 - 4.38 (m, 2H), 4.07 (br t, J = 6.4 Hz, 2H), 3.93 (s, 4H), 2.30 - 2.21 (m, 1H), 2.20 - 2.10 (m, 1H), 2.05 - 1.80 (m, 6H). Step 3: 1-methyl-N-(3-(8-((( 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide (Example 148)

[0274] To a solution of N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (10 mg, 0.020 mmol) in MeOH (0.5 mL) were added formaldehyde (2.390 mg, 0.080 mmol) and AcOH (0.228 µl, 3.98 µmol), the resulting mixture was stirred at 40°C for 0.5 h. Then NaBH3CN (3.75 mg, 0.060 mmol) was added, and the resulting mixture was stirred at 40°C for 1 h. LCMS showed the starting material was consumed and desired compound was found. The residue was purified by Pre-HPLC (Column Welch Xtimate C18150*25 mm*5 um Condition water (0.1%TFA)-ACN Begin B 23 End B 43 Gradient Time(min) 11100%B Hold Time 3 Flow Rate (mL / min) 25) to give 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoro methyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc’d for C25H28F3N6OS+[M+H]+: 517.2, found [M+H]+: 517.1.1H NMR (400 MHz, MeOD) δ 8.07 (s, 1H), 7.93 - 7.85 (m, 2H), 6.95 (s, 1H), 6.75 - 6.69 (m, 1H), 6.09 (d, J = 7.5 Hz, 1H), 4.40 (s, 2H), 3.93 (s, 3H), 3.79 - 3.68 (m, 1H), 3.37 (br s, 1H), 2.36 (s, 3H), 2.18 - 2.08 (m, 1H), 1.94 - 1.85 (m, 2H), 1.84 - 1.75 (m, 2H), 1.67 - 1.54 (m, 3H), 1.35 - 1.24 (m, 1H).Example 149: 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamideStep 1: 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzoic acid

[0275] To a solution of 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (27 mg, 0.056 mmol) in DMSO (0.5 mL) were added 3-methoxy-4-(prop-2-yn-1-ylamino)benzoic acid (11.49 mg, 0.056 mmol), CuI (4.26 mg, 0.022 mmol), DIPA (0.072 mL, 0.504 mmol), and Pd(PPh3)4(6.47 mg, 5.60 µmol) under N2. The resulting mixture was stirred at 20°C for 1 h. LCMS showed the starting material was consumed and the desired compound was found. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic phases were washed with brine (10 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Pre-HPLC (Column Welch Xtimate C18150*25 mm*5 um Condition water (0.1%TFA)-ACN Begin B 28 End B 58 Gradient Time (min) 11100%B Hold Time 3 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)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzoic acid. MS (ESI) m / z: calc’d for C18H16BrF3N3O2S+[M+H]+: 560.2, found [M+H]+: 560.1. Step 2: 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide

[0276] To a mixture of 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzoic acid (10 mg, 0.018 mmol) in DMF (0.5 mL) were added 3-methyloxetan-3-amine (2.024 mg, 0.023 mmol) and DIEA (6.24 µl, 0.036 mmol) at 20°C, the mixture was stirred at 20°C for 5 min, and then HATU (8.15 mg, 0.021 mmol) was added. The resulting mixture was stirred at 20°C for 0.5 h. LCMS showed desired mass peak was observed, and the starting material was consumed. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL*3).The combined organic phases were washed with brine (10 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Pre-HPLC (Column Welch Xtimate C18150*25 mm*5 um 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 Injections 1) to give 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)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 C31H36F3N6O3S+[M+H]+: 629.2, found [M+H]+: 629.2.1H NMR (400MHz, MeOD) δ = 7.48 - 7.41 (m, 2H), 7.36 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 7.6 Hz, 1H), 4.85 - 4.83 (m, 3H), 4.49 (d, J = 6.4 Hz, 2H), 4.38 (s, 2H), 3.93 (s, 3H), 3.82 - 3.76 (m, 1H), 3.25 - 3.19 (m, 1H), 2.34 (s, 3H), 2.18 - 2.07 (m, 1H), 1.92 - 1.77 (m, 4H), 1.71 (s, 3H), 1.67 - 1.52 (m, 3H). Example 150 and Example 151: (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)cyclopropane-1,2-dicarboxamide (Peak 1) and (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)- 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop- 2-yn-1-yl)cyclopropane-1,2-dicarboxamide (Peak 2)Step 1: (1R,2R)-2-(methylcarbamoyl)cyclopropane-1-carboxylic acid

[0277] A mixture of methyl (1R,2R)-2-(methylcarbamoyl)cyclopropane-1-carboxylate (260 mg, 1.654 mmol) and LiOH^H2O (139 mg, 3.31 mmol) in MeOH (1.8 mL) and water (0.6 mL) was stirred at 50°C for 1 h. TLC (pet. ether:EtOAc=0:1) showed the starting material was consumed. The mixture was added HCl (2M) to adjust pH~5. The aqueous phase was dried by freeze drying machine. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude (1R,2R)-2-(methylcarbamoyl)cyclopropane-1-carboxylic acid, which was not further purified.1H NMR (400 MHz, MeOD) δ = 2.72 (s, 3H), 1.95 - 1.84 (m, 2H), 1.20 - 1.11 (m, 2H)Step 2: ( N1-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-N2-methylcyclopropane-1,2-dicarboxamide

[0278] To a mixture of (1R,2R)-2-(methylcarbamoyl)cyclopropane-1-carboxylic acid (200 mg, 0.419 mmol) and 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-amine (190 mg, 0.545 mmol) in DMF (3 mL) was added DIEA (0.5 mL, 2.86 mmol) at 20 °C. The mixture was stirred at 20°C for 5 min, and then HATU (191 mg, 0.503 mmol) was added. The resulting mixture was stirred at 20°C for 1 h. LCMS showed the reaction was completed. 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 Pre-TLC (silica gel, pet. ether / ethyl acetate = 0 / 1, v / v) to give (1R,2R)-N1-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin- 2-yl)prop-2-yn-1-yl)-N2-methylcyclopropane-1,2-dicarboxamide. MS (ESI) m / z: calc’d for C18H16BrF3N3O2S+[M+H]+: 474.0 / 476.0, found [M+H]+: 473.9 / 475.9. Step 3: tert-butyl ( 2-((2-(3-((1R,2R)-2-(methylcarbamoyl)cyclopropane-1-carboxamido)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate

[0279] To a solution of (1R,2R)-N1-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop- 2-yn-1-yl)-N2-methylcyclopropane-1,2-dicarboxamide (100 mg, 0.211 mmol) in 1,4-dioxane (2 mL) were added tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (57.3 mg, 0.253 mmol), Cs2CO3(206 mg, 0.633 mmol) and PEPPSI IpentCl Pd (41.0 mg, 0.042 mmol), the resulting mixture was stirred at 100°C for 2 h. LCMS showed the reaction was completed. The mixture was added water (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC (silica gel, pet. ether / ethyl acetate = 0 / 1, v / v) to give tert-butyl (1R,2R,5R)-2-((2-(3-((1R,2R)-2-(methylcarbamoyl)cyclopropane-1-carboxamido) prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate. MS (ESI) m / z: calc'd for C30H37F3N5O4S+[M+H]+620.2 found [M+H]+620.2. Step 4: (1R,2R)-N1-(3-(8-(((1R,2R,5S)-8-a )amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-N2-methylcyclopropane-1,2- dicarboxamide

[0280] A mixture of tert-butyl (1R,2R,5R)-2-((2-(3-((1R,2R)-2-(methylcarbamoyl) cyclopropane-1-carboxamido)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.097 mmol) in DCM (1 mL) was added TFA (0.2 mL, 2.60 mmol) and stirred at 20°C for 1 h. LCMS showed that desired target was observedand starting material was consumed. The mixture was added aq. NaHCO3to adjust pH~8. The reaction 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 crude (1R,2R)-N1-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-N2-methylcyclopropane-1,2- dicarboxamide, which was not further purified. MS (ESI) m / z: calc’d for C25H29F3N5O2S+[M+H]+: 520.2 found [M+H]+: 520.1. Step 5: (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane-1,2- dicarboxamide

[0281] To a solution of (1R,2R)-N1-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-N2-methylcyclopropane-1,2- dicarboxamide (60 mg, 0.115 mmol) in MeOH (0.5 mL) were added formaldehyde (13.87 mg, 0.462 mmol) and AcOH (1.322 µL, 0.023 mmol). The mixture was stirred at 40°C for 0.5 h. Then NaBH3CN (21.77 mg, 0.346 mmol) was added, and the resulting mixture was stirred at 40°C for 3 h. LCMS showed the starting material was consumed and desired compound was found. The residue was purified by Pre-HPLC (Column Welch Xtimate C18150*25 mm*5 um Condition water (0.1%TFA)-ACN Begin B 20 End B 40 Gradient Time (min) 12100%B Hold Time 3 Flow Rate ( mL / min) 25 Injections 1) to give (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)- 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2- yn-1-yl)cyclopropane-1,2-dicarboxamide. MS (ESI) m / z: calc’d for C26H31F3N5O2S+[M+H]+: 534.2, found [M+H]+: 534.4. Step 6: (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane-1,2- dicarboxamide and (1R,2R)-N1-m 8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)cyclopropane-1,2-dicarboxamide

[0282] The (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane-1,2- dicarboxamide (20 mg, 0.037 mmol) was resolved by Chiral-SFC (Column DAICEL CHIRALPAK IG (250 mm*30 mm,10 um) Condition CO2-MeOH (0.1%NH3H2O) Begin B 60 End B 60 Gradient Time (min) 20100%B Hold Time 20 Flow Rate ( mL / min) 80 Injections 70) to give (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane-1,2-dicarboxamide (tR= 0.739 min) as the first eluting peak, and (1R,2R)-N1-methyl-N2-(3-(8- (((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin- 2-yl)prop-2-yn-1-yl)cyclopropane-1,2-dicarboxamide (tR= 1.473 min) as the second eluting peak.

[0283] Example 150 (Peak 1): MS (ESI) m / z: calc’d for C26H31F3N5O2S+[M+H]+:534.2 found:534.2.1H NMR (MeOD, 400 MHz): δ 7.88 (d, J = 6.9 Hz, 1H), 6.95 (s, 1H), 6.76 - 6.69 (m, 1H), 6.09 (d, J = 7.5 Hz, 1H), 4.69 - 4.51 (m, 1H), 4.26 (s, 2H), 3.73 (br dd, J = 3.0, 6.2 Hz, 1H), 3.39 (br s, 1H), 3.26 (br d, J = 6.3 Hz, 1H), 2.73 (s, 3H), 2.37 (s, 3H), 2.13 (td, J = 6.0, 12.0 Hz, 1H), 2.08 - 2.02 (m, 2H), 1.91 (br t, J = 6.0 Hz, 2H), 1.81 (br dd, J = 4.6, 12.0 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.30 - 1.27 (m, 2H).

[0284] Example 151 (Peak 2): MS (ESI) m / z: calc’d for C26H31F3N5O2S+[M+H]+:534.2 found:534.2.1H NMR (MeOD, 400 MHz): δ = 7.87 (d, J = 6.9 Hz, 1H), 6.95 (s, 1H), 6.75 - 6.70 (m, 1H), 6.08 (d, J = 7.5 Hz, 1H), 4.68 - 4.53 (m, 1H), 4.26 (s, 2H), 3.71 (br dd, J = 3.1, 6.2 Hz, 1H), 3.36 (br s, 1H), 3.23 (br d, J = 6.0 Hz, 1H), 2.73 (s, 3H), 2.35 (s, 3H), 2.15 - 2.01 (m, 3H), 1.91 - 1.77 (m, 4H), 1.68 - 1.60 (m, 2H), 1.30 - 1.27 (m, 2H).

[0285] SFC Method: Column: Chiralpak IG-350×4.6mm I.D., 3um, Mobile phase: A: CO2B: Methanol (0.2% MNH3), Isocratic:40%B, Flow rate: 4 mL / min, Column temp.: 35℃, ABPR: 1500psi Example 152: (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)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)methanoneStep 1: (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone

[0286] A mixture of 8-bromo-2-iodo-3-((trifluoromethyl)thio)indolizine (70 mg, 0.166 mmol), (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone (68.3 mg, 0.249 mmol), Pd(Ph3P)4 (28.8 mg, 0.025 mmol), and DIPA (0.209 mL, 1.493 mmol) in DMSO (1 mL) was degassed and backfilled with N2(three times). The mixture was stirred at 25°C for 1 h. LCMS showed that desired product was formed. The reaction mixture wasquenched with water (20 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 flash silica gel chromatography (ISCO®; 2 g SepaFlash® Silica Flash Column, eluent of 0~50% ethyl acetate / pet. ether gradient @ 30 mL / min) to give (4-((3-(8-bromo-3-((trifluoromethyl)thio)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 C24H22BrF3N3O3S+[M+H]+:568.0 / 570.0, found: 568.0 / 570.0 [M+H]+. Step 2: tert-butyl (1R,2R,5R)-2-((2-(3-((4-(3-hydroxy-3-methylazetidine-1-carbonyl)-2- methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate

[0287] A mixture of PEPPSI-HeptCl (19.79 mg, 0.020 mmol), Cs2CO3 (132 mg, 0.406 mmol), (4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone (77 mg, 0.135 mmol), and tert- butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (46.0 mg, 0.203 mmol) in dioxane (2 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 100°C for 2 h. After cooling to RT, LCMS showed that desired product was formed. The mixture was cooled and filtered, and the residue was purified by Pre-TLC (silica gel, ethyl acetate / pet. ether = 50 / 50, v / v) to give tert-butyl (1R,2R,5R)-2-((2-(3-((4-(3-hydroxy-3-methylazetidine-1- carbonyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z: calc’d for C36H45F3N7O3+[M+H]+:714.2, found: 714.2 [M+H]+. Step 3: (4-((3-(8-((( 8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3-hydroxy-3- methylazetidin-1-yl)methanone

[0288] A mixture of tert-butyl (1R,2R,5R)-2-((2-(3-((4-(3-hydroxy-3-methylazetidine-1- carbonyl)-2-methoxyphenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (40 mg, 0.056 mmol) in DCM (1.2 mL) and TFA (0.40 mL) was stirred at 25°C for 1 h. LCMS showed that the starting material was consumed, and the mixture was concentrated under reduced pressure to give (4-((3-(8- (((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop- 2-yn-1-yl)amino)-3-methoxyphenyl)(3-hydroxy-3-methylazetidin-1-yl)methanone, which was used in next step directly. MS (ESI) m / z: calc’d for C31H35F3N5O3S+[M+H]+:614.2, found: 614.2 [M+H]+.Step 4: (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)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)methanone

[0289] To a solution of (4-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)(3-hydroxy-3- methylazetidin-1-yl)methanone (30 mg, 0.049 mmol) in MeOH (1 mL) was added acetic acid (0.280 µl, 4.89 µmol) and paraformaldehyde (2.94 mg, 0.098 mmol) at 25°C over 2 min. After stirring for 30 min at 50°C, NaBH3(CN) (6.14 mg, 0.098 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 purified by Pre-HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (0.1%TFA)-ACN Begin B 28 End B 48 Gradient Time (min) 12100%B Hold Time 3 Flow Rate (ml / min) 25) 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)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone. MS (ESI) m / z: calc’d for C32H37F3N5O3S+[M+H]+:628.2 found:628.2 [M+H]+.1H NMR (MeOD, 400 MHz): δ 7.91-7.96 (m, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.17-7.19 (m, 1H), 6.91 (s, 1H), 6.86-6.90 (m, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.13-6.18 (m, 1H), 4.31 (s, 2H), 4.25-4.29 (m, 1H), 4.08 (br d, J = 1.8 Hz, 1H), 3.92-4.01 (m, 4H), 3.91 (s, 3H), 2.84-2.89 (m, 3H), 2.22-2.40 (m, 2H), 1.74-2.18 (m, 7H), 1.49 (s, 3H). Example 153: 1-cyclopropyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamideStep 1: N-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1- cyclopropyl-1H-pyrazole-4-carboxamide

[0290] To a solution of 8-bromo-2-iodo-3-((trifluoromethyl)thio)indolizine (55 mg, 0.130 mmol) in DMSO (1 mL) was added CuI (9.93 mg, 0.052 mmol), Pd(PPh3)4 (18.07 mg, 0.016 mmol), DIPA (0.164 mL, 1.173 mmol), and 1-cyclopropyl-N-(prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide (27.1 mg, 0.143 mmol) in DMSO (0.5 mL) under N2. Then the mixture was stirredat 20°C for 2 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was added water (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by Prep-TLC (Pet. ether : EtOAc=1:2) to afford N-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1- cyclopropyl-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc’d for C19H15BrF3N4OS+[M+H]+483.3, found [M+H]+482.8 / 484.8. Step 2: tert-butyl (1R,2R,5R)-2-((2-(3-(1-cyclopropyl-1H-pyrazole-4-carboxamido)prop- 1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate

[0291] To a solution of N-(3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)- 1-cyclopropyl-1H-pyrazole-4-carboxamide (35 mg, 0.072 mmol) in 1,4-dioxane (1.5 mL) was added tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.133 mmol), Cs2CO3(70.8 mg, 0.217 mmol), and PEPPSI IpentCl Pd (14.09 mg, 0.014 mmol). The resulting mixture was stirred at 100°C for 2 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was added water (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by Prep-TLC (100% EtOAc) to afford tert-butyl (1R,2R,5R)-2-((2-(3-(1-cyclopropyl-1H-pyrazole-4- carboxamido)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1] octane-8-carboxylate. MS (ESI) m / z: calc’d for C31H36F3N6O3S+[M+H]+628.7, found 629.3 [M+H]+. Step 3: N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4-carboxamide

[0292] To a solution of tert-butyl (1R,2R,5R)-2-((2-(3-(1-cyclopropyl-1H-pyrazole-4- carboxamido)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1] octane-8-carboxylate (25 mg, 0.040 mmol) in DCM (1 mL) was added TFA (0.2 mL), and the resulting mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was added aq. sat. NaHCO3(10 mL) and extracted with 10% MeOH in DCM (3 mL * 3). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by Prep-TLC (DCM:MeOH=10:1) to afford N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4-carboxamide. MS (ESI) m / z: calc’d for C26H28F3N6OS+[M+H]+528.6, found 529.2 [M+H]+.Step 4: 1-cyclopropyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide

[0293] A mixture of N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4-carboxamide (12 mg, 0.023 mmol), polyoxymethylene (2.045 mg, 0.068 mmol), and AcOH (0.130 µl, 2.270 µmol) in MeOH (0.5 mL) was stirred at 50°C for 20 min. After cooled to RT, NaBH3(CN) (4.28 mg, 0.068 mmol) was added to the mixture, the resulting mixture was stirred at 50 °C for another 1 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (0.01% TFA)-MeCN Begin B 22 End B 52 Gradient Time (min) 11100%B Hold Time 3 Flow Rate (mL / min) 25) to give 1-cyclopropyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide. MS (ESI) m / z: calc'd for C27H30F3N6OS+[M+H]+542.6, found 543.1 [M+H]+.1H NMR (400MHz, MeOD-d4) δ 8.15 (s, 1H), 7.95 (d, J = 6.8 Hz, 1H), 7.89 (s, 1H), 6.97 (s, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H), 4.36-4.43 (m, 2H), 3.97 (d, J = 5.6 Hz, 3H), 3.68-3.74 (m, 1H), 2.86 (s, 3H), 2.31-2.41 (m, 1H), 2.22-2.30 (m, 1H), 2.10-2.18 (m, 1H), 1.94-2.06 (m, 3H), 1.85-1.91 (m, 1H), 1.06-1.13 (m, 4H). Example 154: 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan- 3-yl)benzamideStep 1: 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine

[0294] A mixture of 3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-ol (7.5 g, 21.42 mmol) and triphenylphosphine dibromide (11.75 g, 27.8 mmol) in DCM (100 mL) was stirred at 25 °C for 1.5 h under N2. LCMS showed the desired compound was found. Water (100mL) was added to the mixture, and the mixture was extracted with DCM (50 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 gelchromatography (ISCO®; Agela® Flash Column Silica-CS (80 g), Eluent of 0 ~ 20% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to give 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3- ((trifluoromethyl)thio)indolizine. MS (ESI) m / z: calc’d for C12H7Br2F3NS+[M+H]+414.1, found 413.7 / 415.7 [M+H+2]+ / [M+H]+.1H NMR (400MHz, CDCl3-d) δ 8.38 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.88 (s, 1H), 6.67 (t, J = 7.2 Hz, 1H), 4.23 (s, 2H). Step 2: methyl 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)-3-methoxybenzoate

[0295] To a solution of 8-bromo-2-(3-bromoprop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizine (500 mg, 1.211 mmol) in DMF (6 mL) was added methyl 4-amino-3-methoxybenzoate (230 mg, 1.271 mmol), K2CO3(502 mg, 3.63 mmol), and the resulting mixture was stirred at 60 °C for 3 h. LCMS showed the starting material was consumed. Water (30mL) was added to the mixture, and the mixture was extracted EtOAc (10 mL * 3). The combined organic fractions were washed with brine (10 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 (12g), Eluent of 0 ~ 30% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to give methyl 4-((3-(8- bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate. MS (ESI) m / z: calc’d for C21H17BrF3N2O3S+[M+H]+514.3, found 513.0 / 515.0 [M]+ / [M+2]+.1H NMR (400MHz, CDCl3-d) δ 8.32-8.38 (m, 1H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 6.77-6.82 (m, 2H), 6.62-6.67 (m, 1H), 4.98-5.14 (m, 1H), 4.33 (s, 2H), 3.92-3.94 (m, 3H), 3.87-3.90 (m, 3H). Step 3: tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-4-(methoxycarbonyl)phenyl)amino) prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate

[0296] To a solution of methyl 4-((3-(8-bromo-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2- yn-1-yl)amino)-3-methoxybenzoate (320 mg, 0.623 mmol) in 1,4-dioxane (6 mL) was added tert- butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (155 mg, 0.686 mmol), cesium carbonate (609 mg, 1.870 mmol), PEPPSI-IpentCl Pd (60.6 mg, 0.062 mmol), and the resulting mixture was stirred at 100 °C for 2 h under N2. LCMS showed the starting material was consumed and desired compound was found. The mixture was added water (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic fractions were washed with brine (10 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 (4 g), Eluent of 0 ~ 80% Ethyl acetate / Petroleum ether gradient @ 35 mL / min) to give tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-4-(methoxycarbonyl)phenyl)amino)prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. MS (ESI) m / z: calc’d for C33H38F3N4O5S+[M+H]+659.7, found 681.4 [M+H+Na]+.1H NMR (400MHz, CDCl3-d) δ 7.90 (br d, J = 6.8 Hz, 1H), 7.70 (dd, J = 8.2, 1.7 Hz, 1H), 7.45 (d, J = 1.6 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.59-6.76 (m, 1H), 6.52 (s, 1H), 6.29-6.48 (m, 1H), 4.99-5.08 (m, 1H), 4.35-4.50 (m, 1H), 4.31 (s, 2H), 4.16-4.29 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.61-3.82 (m, 2H), 1.86-2.04 (m, 3H), 1.75-1.84 (m, 2H), 1.60-1.66 (m, 3H), 1.52 (s, 9H). Step 4: methyl 4-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate

[0297] To a solution of tert-butyl (1R,2R,5R)-2-((2-(3-((2-methoxy-4-(methoxycarbonyl) phenyl)amino) prop-1-yn-1-yl)-3-((trifluoromethyl)thio)indolizin-8-yl)amino)-8-azabicyclo [3.2.1]octane-8-carboxylate (150 mg, 0.228 mmol) in DCM (5 mL) was added TFA (1 mL), and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed. The mixture was quenched with sat. aq. NaHCO3 (15 mL), the pH was over 7 and extracted with 10% MeOH in DCM (6 mL * 3). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product methyl 4-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate, which used directly for the next step without additional purification. MS (ESI) m / z: calc’d for C28H30F3N4O3S+[M+H]+559.6, found 559.1 [M+H]+. Step 5: methyl 3-methoxy-4-((3-(8-(((1 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoate

[0298] To a solution of methyl 4-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxybenzoate (80 mg, 0.143 mmol) in MeOH (2 mL) was added formalin (12.90 mg, 0.430 mmol), AcOH (8.20 µl, 0.143 mmol), and the resulting mixture was stirred at 25 °C for 20 min. Then sodium cyanoborohydride (27.0 mg, 0.430 mmol) was added, and the resulting mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed and desired compound was found. The mixture was quenched with sat. aq. NaHCO3 (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by Prep-TLC (EtOAc) to afford methyl 3- methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoate. MS (ESI) m / z: calc’d for C29H32F3N4O3S+[M+H]+573.6, found 573.2 [M+H]+.Step 6: 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoic acid

[0299] To a solution of methyl 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoate (50 mg, 0.087 mmol) in THF (1.000 mL) was added MeOH (1 mL), water (0.5 mL), lithium hydroxide monohydrate (18.32 mg, 0.437 mmol), and the resulting mixture was stirred at 40 °C for 16 h. LCMS showed the desired compound was found. The pH of the mixture was adjusted to around 7 by progressively adding HCl (1 M) and filtered and concentrated in vacuo. The crude was purified by Prep-TLC (DCM: MeOH=5:1) to afford 3-methoxy-4-((3-(8-(((1R,2R,5R)-8- methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn- 1-yl)amino)benzoic acid. MS (ESI) m / z: calc’d for C28H30F3N4O3S+[M+H]+559.6, found 559.1 [M+H]+.1H NMR (400MHz, MeOD-d4) δ 7.75 (d, J = 6.8 Hz, 1H), 7.64 (dd, J = 8.4, 1.7 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 6.88 (t, J = 4.0 Hz, 2H), 6.64 (t, J = 7.2 Hz, 1H), 6.10 (d, J = 7.6 Hz, 1H), 4.30 (s, 2H), 3.93-3.98 (m, 1H), 3.91 (s, 3H), 3.78-3.83 (m, 2H), 2.78 (s, 3H), 2.25-2.36 (m, 1H), 2.18 (td, J = 9.6, 4.8 Hz, 1H), 2.03-2.11 (m, 2H), 1.87-1.93 (m, 2H), 1.76-1.85 (m, 2H). Step 7: 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan-3- yl)benzamide

[0300] To a solution of 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoic acid (15 mg, 0.027 mmol) in DMF (1 mL) was added 3-methyloxetan-3-amine (3.51 mg, 0.040 mmol), DIPEA (0.023 mL, 0.134 mmol), HATU (15.32 mg, 0.040 mmol), and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and desired compound was found. The reaction solution was filtered and purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (10 mM-NH4HCO3)-MeCN Begin B 45 End B 75 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)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan-3-yl)benzamide. MS (ESI) m / z: calc’d for C32H37F3N5O3S+[M+H]+628.7, found 628.2 [M+H]+.1H NMR (400MHz, CDCl3-d) δ 7.88 (d, J = 6.8 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.24-7.26 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 7.2 Hz, 1H), 6.51 (s, 1H), 6.30 (s, 1H), 6.14 (d, J = 7.2 Hz, 1H), 4.96 (t, J = 6.0 Hz, 1H), 4.87 (d, J = 6.4 Hz, 2H), 4.58 (d, J = 6.4 Hz, 2H), 4.31 (d, J = 6.0 Hz, 2H), 3.93 (s, 3H), 3.70-3.74 (m, 1H), 3.34 (d, J = 1.2 Hz, 1H), 3.19 (dt, J = 4.8, 2.4 Hz, 1H), 2.35(s, 3H), 2.01-2.13 (m, 1H), 1.80-1.92 (m, 3H), 1.77 (s, 3H), 1.48-1.56 (m, 3H), 1.25-1.32 (m, 1H). Example 155: N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide

[0301] To a solution of 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzoic acid (15 mg, 0.027 mmol) in DMF (1 mL) was added (R)-1-aminopropan-2-ol (3.03 mg, 0.040 mmol), DIPEA (0.023 mL, 0.134 mmol), HATU (15.32 mg, 0.040 mmol), and the resulting mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and the desired compound was found. The reaction solution was filtered and purified by Prep-HPLC (Column Welch Xtimate C18150 * 25 mm * 5 um Condition water (0.01% TFA)-MeCN Begin B 35 End B 55 Gradient Time (min) 11100%B Hold Time 3 Flow Rate (mL / min) 25) to give N-((R)-2- hydroxypropyl)-3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc’d for C31H37F3N5O3S+[M+H]+616.7, found 616.2 [M+H]+.1H NMR (400MHz, MeOD-d4) δ 7.93 (d, J = 6.8 Hz, 1H), 7.46 (dd, J = 8.4, 1.9 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 6.91 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.16 (d, J = 7.2 Hz, 1H), 4.31 (s, 2H), 3.95 (d, J = 6.4 Hz, 4H), 3.93 (s, 3H), 3.39-3.45 (m, 1H), 3.33 (s, 1H), 2.86 (s, 3H), 2.34 (dd, J = 12.4, 6.8 Hz, 1H), 2.22-2.29 (m, 1H), 2.09-2.16 (m, 1H), 1.95-2.04 (m, 3H), 1.82-1.93 (m, 2H), 1.20 (d, J = 6.3 Hz, 3H).19F NMR (MeOD-d4, 376 MHz) δ -45.93 (s, 3F).Example 156 and Example 157: 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide (separated diastereomers)Step 1: 2-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3- azabicyclo[4.1.0]heptan-3-yl)ethan-1-ol

[0302] A mixture of N-(3-azabicyclo[4.1.0]heptan-6-yl)-2-iodo-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine (130 mg, 0.286 mmol), K2CO3 (158 mg, 1.145 mmol), DIEA (0.150 mL, 0.859 mmol), and 2-bromoethan-1-ol (0.051 mL, 0.715 mmol) in MeCN (1 mL) was stirred at 80 °C for 2 h. LCMS showed that desired product was formed. The reaction was diluted with water (4 mL), extracted with EtOAc (4 mL*3). The combined organic layers were washed with brine (10 mL*2) and dried over anhydrous Na2SO4, filtered, and concentrated to give 2-(6- ((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-3-azabicyclo[4.1.0]heptan- 3-yl)ethan-1-ol. The product was used for the next step without purification. MS (ESI) m / z: calc'd for C16H19F3IN4OS+[M+H]+498.9, found [M+H]+498.9. Step 2: 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide

[0303] A mixture of CuI (18.35 mg, 0.096 mmol), DIPA (0.304 mL, 2.167 mmol), Pd(PPh3)4 (41.7 mg, 0.036 mmol), 2-(6-((2-iodo-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-7- yl)amino)-3-azabicyclo[4.1.0]heptan-3-yl)ethan-1-ol (120 mg, 0.241 mmol), 4-methoxy-N- methyl-3-(prop-2-yn-1-ylamino)benzamide (73.6 mg, 0.337 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 h under N2. LCMS showed the mass of the desired product. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (4 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 Prep-TLC (SiO2, CH2Cl2 / MeOH=10:1) to give 3- ((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide. MS (ESI) m / z: calc'd for C28H32F3N6O3S+[M+H]+589.2, found [M+H]+589.2. Step 3: 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide (separated diastereomers)

[0304] The 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide (60 mg, 0.102 mmol) was separated by Prep-SFC (Column DAICEL CHIRALPAK AD (250mm*30mm,10um) Condition CO2-i-PrOH (0.1%NH3H2O) Begin B 50 End B 50 Gradient Time (min) 50100% B Hold Time 1 Flow Rate (mL / min) 150) to give Example 156 (Peak 1): 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide and Example 157 (Peak 2): 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)- 4-methoxy-N-methylbenzamide.

[0305] Example 156 (Peak 1): MS (ESI) m / z: calc'd for C28H32F3N6O3S+[M+H]+589.2, found [M+H]+589.2.17.43 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 2.0, 8.3 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.46 (d, J = 7.6 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.07 - 2.99 (m, 1H), 2.90 (s, 3H), 2.71 (br d, J = 11.9 Hz, 1H), 2.52 (br t, J = 5.9 Hz, 2H), 2.49 - 2.42 (m, 1H), 2.39 - 2.29 (m, 2H), 2.15 - 2.02 (m, 1H), 1.51 - 1.42 (m, 1H), 1.04 (br dd, J = 4.4, 9.9 Hz, 1H), 1.00 - 0.95 (m, 1H)

[0306] Example 157 (Peak 2): MS (ESI) m / z: calc'd for C28H32F3N6O3S+[M+H]+589.2, found [M+H]+589.2.1H NMR (400 MHz, MeOD-d4) δ = 7.43 (dd, J = 7.9, 8.5 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 2.1, 8.3 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.46 (dd, J = 0.9, 7.8 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.09 - 3.00 (m, 1H), 2.90 (s, 3H), 2.75 - 2.68 (m, 1H), 2.53 (t, J = 6.0 Hz, 2H), 2.47 (br dd, J = 4.6, 9.1 Hz, 1H), 2.38 - 2.29 (m, 2H), 2.14 - 2.02 (m, 1H), 1.50 - 1.41 (m, 1H), 1.05 (dd, J = 4.8, 9.7 Hz, 1H), 1.00 - 0.94 (m, 1H)

[0307] SFC method: Column: Chiralpak AD-350×4.6mm I.D., 3um; Mobile phase: A: CO2B:iso-propanol (0.2% MNH3); Isocratic: 40% B; Flow rate: 3.5mL / min; Column temp.: 35℃Example 158: N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide

[0308] A mixture of CuI (6.32 mg, 0.033 mmol), DIPA (0.105 mL, 0.746 mmol), Pd(PPh3)4(14.38 mg, 0.012 mmol), 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (40 mg, 0.083 mmol), (S)-N-(2- hydroxypropyl)-3-methoxy-4-(prop-2-yn-1-ylamino)benzamide (32.6 mg, 0.124 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 hours under N2. LCMS showed the mass of the desired product. The reaction was diluted with water (4 mL), extracted with EtOAc (3 mL*3). The combined organic layers were washed with brine (8 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (Column Welch Xtimate C18 150*25mm*5um Condition water (10mM-NH4HCO3)-ACN Begin B 44 End B 74 Gradient Time (min)11100% B Hold Time 2.5 Flow Rate (mL / min) 25) to give N-((R)-2-hydroxypropyl)-3- methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide. MS (ESI) m / z: calc'd for C30H36F3N6O3S+[M+H]+617.3, found [M+H]+617.3.1HMeOD-d4) δ = 7.49 - 7.37 (m, 3H), 6.98 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.23 (d, J = 7.7 Hz, 1H), 4.80 - 4.54 (m, 1H), 4.38 (s, 2H), 3.99 - 3.94 (m, 1H), 3.93 (s, 3H), 3.83 - 3.74 (m, 1H), 3.51 - 3.33 (m, 2H), 3.20 (br d, J = 4.8 Hz, 1H), 2.33 (s, 3H), 2.18 - 2.06 (m, 1H), 1.93 - 1.74 (m, 4H), 1.68 - 1.52 (m, 3H), 1.19 (d, J = 6.3 Hz, 3H). Example 159: (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl- 8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)phenyl)methanone

[0309] A mixture of CuI (6.32 mg, 0.033 mmol), DIPA (0.105 mL, 0.746 mmol), Pd(PPh3)4(14.38 mg, 0.012 mmol), 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (40 mg, 0.083 mmol), (3-hydroxy-3- methylazetidin-1-yl)(3-methoxy-4-(prop-2-yn-1-ylamino)phenyl)methanone (34.1 mg, 0.124 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 h under N2. The reaction was diluted with water (4 mL), extracted with EtOAc (4 mL*3). The combined organic layers were washed with brine (10 mL*2) and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150*25mm*5um Condition water (10mM- NH4HCO3)-ACN Begin B 44 End B 74 Gradient Time(min) 11100%B Hold Time 2.5 Flow Rate (mL / min) 25) to give (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-(((1R,2R,5R)- 8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin- 2-yl)prop-2-yn-1-yl)amino)phenyl)methanone. MS (ESI) m / z: calc'd for C31H36F3N6O3S+[M+H]+629.2, found [M+H]+629.2.1H NMR (400 MHz, MeOD-d4) δ = 7.43 (t, J = 8.2 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.97 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 4.71 - 4.49 (m, 1H), 4.37 (s, 2H), 4.32 - 4.22 (m, 2H), 4.13 - 3.97 (m, 2H), 3.96 - 3.87 (m, 3H), 3.83 - 3.72 (m, 1H), 3.24 - 3.15 (m, 1H), 2.33 (s, 3H), 2.19 - 2.05 (m, 1H), 1.94 - 1.77 (m, 4H), 1.71 - 1.52 (m, 3H), 1.48 (s, 3H). Example 160: N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamideStep 1: (R)-N-(2-hydroxypropyl)-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide

[0310] To a mixture of 4-methoxy-3-(prop-2-yn-1-ylamino)benzoic acid, prepared in a similar fashion as described for Intermediate 51, (150 mg, 0.731 mmol) in DMF (2 mL) were added HATU (334 mg, 0.877 mmol) and DIEA (0.511 mL, 2.92 mmol) at 20 °C; the mixture was stirred at 20 °C for 5 min and then (R)-1-aminopropan-2-ol (60.4 mg, 0.804 mmol) was added. The resulting mixture was stirred at 20 °C for 12 h. LCMS showed the desired mass and the starting material was consumed. The reaction mixture was quenched with H2O (6 mL) and extracted with EtOAc (7 mL*3). The combined organic phases were washed with brine (20mL*2), 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 0~70% ethyl acetate / pet. ether gradient @ 40 mL / min) to give (R)-N-(2- hydroxypropyl)-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide. MS (ESI) m / z: calc'd for C14H19N2O3+[M+H]+263.0, found [M+H]+263.0. Step 2: N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamide

[0311] A mixture of CuI (4.74 mg, 0.025 mmol), DIPA (0.078 mL, 0.560 mmol), Pd(PPh3)4 (10.78 mg, 9.33 µmol), 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (30 mg, 0.062 mmol), and (R)-N-(2- hydroxypropyl)-4-methoxy-3-(prop-2-yn-1-ylamino)benzamide (32.6 mg, 0.124 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 hours under N2 atmosphere. LCMS showed the mass of the desired product. The reaction was diluted with water (5 mL), extracted with EtOAc (4 mL*3). The combined organic layers were washed with brine (10 mL*2) and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150*25mm*5um 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 N-((R)-2- hydroxypropyl)-4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide. MS (ESI) m / z: calc'd for C30H36F3N6O3S+[M+H]+617.3, found [M+H]+617.3.1H NMR (400 MHz, MeOD-d4) δ = 7.43 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.27 (dd, J = 2.0, 8.4 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 4.72 - 4.53 (m, 1H), 4.39 (s, 2H), 4.00 - 3.90 (m, 4H), 3.83 - 3.74 (m, 1H), 3.45 - 3.34 (m, 2H), 3.20 (br d, J = 5.0 Hz, 1H), 2.33 (s, 3H), 2.11 (br dd, J = 6.1, 11.2 Hz, 1H), 1.96 - 1.77 (m, 4H), 1.68 - 1.52 (m, 3H), 1.18 (d, J = 6.3 Hz, 3H).Example 161: 3-methoxy-N,N-dimethyl-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)amino)benzamideStep 1: tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin- 7-yl)amino)-8-azabicyclo[3.2.1] octane-8-carboxylate

[0312] A mixture of tert-butyl (1R,2R,5R)-2-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (430 mg, 1.900 mmol), 7-chloro-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine (350 mg, 0.925 mmol), N-ethyl-N-isopropylpropan-2-amine (0.646 mL, 3.70 mmol) and cesium fluoride (281 mg, 1.849 mmol) in DMSO (3 mL) was stirred at 80°C for 12 h. LCMS showed the desired mass was found. The reaction was cooled to RT and diluted with water (10 mL), extracted with EtOAc (8 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®; 4 g SepaFlash® Silica Flash Column, eluent of 10% EtOAc / Pet. ether gradient @ 30 mL / min) to afford tert-butyl (1R,2R,5R)-2-((2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1] octane-8- carboxylate. MS (ESI) m / z: calc’d for C20H25F3IN4O2S+[M+H]+: 569.0, found: 569.0 [M+H]+. Step 2: N-((1R,2R,5S)-8-azabicyclo[3.2.1] octan-2-yl)-2-iodo-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0313] A mixture of tert-butyl (1R,2R,5R)-2-((2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-7-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (450 mg, 0.792 mmol) in TFA:DCM=1:3 (3 mL) was stirred at 25°C for 1 h. LCMS showed the desired mass was found. The solvent was removed under reduced pressure to give N-((1R,2R,5S)-8-azabicyclo[3.2.1] octan-2-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine. The product was used for the next step without purification. MS (ESI) m / z: calc’d for C15H17F3IN4S+[M+H]+: 468.9, found: 468.9 [M+H]+.Step 3: 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine

[0314] A mixture of formalin (14.11 mg, 0.470 mmol), AcOH (2.445 µl, 0.043 mmol), N- ((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)-2-iodo-3-((trifluoromethyl)thio)pyrazolo[1,5-a] pyridin-7-amine (200 mg, 0.427 mmol), and NaBH3CN (42.9 mg, 0.683 mmol) in MeOH (2 mL) was stirred at 40 °C for 2 h. LCMS showed the mass of the desired product. The reaction was diluted with water (8 mL), extracted with EtOAc (7 mL * 3). The combined organic layers were washed with brine (10 mL * 2) and dried over anhydrous Na2SO4, filtered, and concentrated to give 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-amine. MS (ESI) m / z: calc'd for C16H19F3IN4S+[M+H]+482.9, found [M+H]+482.9. Step 4: 3-methoxy-N,N-dimethyl-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide

[0315] A mixture of CuI (5.53 mg, 0.029 mmol), DIPA (0.092 mL, 0.653 mmol), Pd(PPh3)4 (12.58 mg, 10.89 µmol), 2-iodo-N-((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-7-amine (35 mg, 0.073 mmol), 3-methoxy-N,N- dimethyl-4-(prop-2-yn-1-ylamino)benzamide (30.3 mg, 0.131 mmol) in DMSO (0.5 mL) was stirred at 25 °C for 1 hours under N2 atmosphere. LCMS showed the mass of the desired product. The reaction was diluted with water (5 mL), extracted with EtOAc (4 mL * 3). The combined organic layers were washed with brine (8 mL * 2) and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (Column Welch Xtimate C18150 *25 mm * 5 um Condition water (10 mM-NH4HCO3)-MeCN Begin B 52 End B 82 Gradient Time (min) 11100%B Hold Time 2.5 Flow...

Claims

1. 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, halo, CH3, OCH3, CH3 substituted by 1 to 3 halo, or OCH3 substituted by 1 to 3 halo; a) H; b) C1-C6alkyl; c) C1-C6 alkyl substituted by OH; d) C3-C6cycloalkyl; e) C3-C6 cycloalkyl 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) OCH3; i) NH2; j) NHCH3; or k) 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-C6alkyl substituted by OH; d) C3-C6 cycloalkyl; e) C3-C6cycloalkyl substituted by CH3or OH; f) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatoms selected from N, S, O, and P; g) 4-membered monocyclic heterocycloalkyl containing 1 ring heteroatoms selected from N, S, O, and P, substituted by CH3; h) NH2; i) NHCH3; or j) N(CH3)2; R5is H, OH, CH3, OCH3, OCHF2, OCF3, or O-cyclopropyl; R2is a) monocyclic C3-8 cycloalkyl; b) bicyclic C4-8cycloalkyl; 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; 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; l) NH-C1-3 alkyl; m) NH-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); n) NH-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); g) NH-(5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P); or h) 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.

2. The compound of claim 1, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein wherein each R is independently H, halogen, CH3, OCH3, CH3 substituted by 1 to 3 halogen, or OCH3substituted 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 any one of claims 1 to 3, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R1is C(=O)R3.

5. The compound of claim 4, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R1is:.

6. The compound of any one of claims 1 to 3, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R7. The compound of claim 6, or pharmaceutically acceptable salt, solvate, hydrate, ortautomer thereof, wherein R8. The compound of any one of claims 6 to 7, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R9. The compound of any one of claims 6 to 8, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R5is OCH3.

10. The compound of any one of claims 6 to 9, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R1is: ,11. The compound of any one of claims 1 to 10, or pharmaceutically acceptable salt, solvate,group is unsubstituted or substituted with 1 to 2 independently selected R8groups.

12. The compound of claim 11, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein Rwherein said R2group is substituted with 1 to 2 independently selected R8groups.

13. The compound of claim 11, or pharmaceutically acceptable salt, solvate, hydrate, or t14. The compound of any one of claims 11 to 12, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein each R8is independently F, CH3, NH2, NH(CH3), N(CH3)2, NH(CH3CH2CH2F), NH(CH3CH2CH2OH), NH(CH3CH2CHF2), CH2CH2F, CH2CHF2,15. The compound of claim 11, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R2is16. The compound of claim 11, or pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein R2is17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:,a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (1) (3-methoxy-4-((3-(7-(((1S, 6S or 1R, 6R)-3-methyl-3-azabicyclo[4.1.0] heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (2) (3-methoxy-4-((3-(7-(((1S,6S or 1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (3) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N-[5-(2- oxa-6-azaspiro[3.3] heptan-6-yl)bicyclo[3.1.1]heptan-1-yl]-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-amine; (4) 1-cyclopropyl-N-[3-(7-{[5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[3.1.1] heptan-1-yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2- yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide; (5) N~5~-{2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)- 3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-yl}-N~1~,N~1~- dimethylbicyclo[3.1.1]heptane-1,5-diamine; (6) 1-cyclopropyl-N-[3-(7-{[trans-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cyclohexyl] amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]-1H-pyrazole-4-carboxamide; (7) N-(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide;(8) N-(3-{7-[(4-aminobicyclo[2.1.1]hexan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide; (9) 1-cyclopropyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (10) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-amine; (11) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-(2- hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide; (12) 5-{[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}- 4-methoxy-N-methylpyridine-2-carboxamide; (13) 4-{[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}- 3-methoxy-N-methylbenzamide; (14) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]cyclopropanecarboxamide; (15) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]acetamide; (16) 1-tert-butyl-N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (17) N-[3-(7-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1- methyl-1H-pyrazole-4-carboxamide; (18) N-methyl-N’-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)urea; (19) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide;(20) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)cyclopropanecarboxamide; (21) 1-cyclopropyl-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (22) 1-(2-hydroxy-2-methylpropyl)-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide; (23) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)acetamide; (24) 1-cyclopropyl-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (25) 1-(2-hydroxy-2-methylpropyl)-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn- 1-yl)-1H-pyrazole-4-carboxamide; (26) N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)cyclopropanecarboxamide; (27) N-methyl-N’-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)urea; (28) 1-methyl-N-(3-{7-[(3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino]-3- [(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1H- pyrazole-4-carboxamide; (29) 2-(3-{[2-methoxy-4-(methylsulfonyl)phenyl]amino} prop-1-yn-1-yl)-N-[1-(3- methyloxetan-3-yl)piperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-7-amine; (30) 3-[4-({2-(3-{[2-methoxy-4-(methylsulfonyl)phenyl]amino} prop-1-yn-1-yl)-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-yl}amino)piperidin-1- yl]oxetane-3-carbonitrile; (31) 5-{[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-4-methoxy-N- methylpyridine-2-carboxamide;(32) 4-{[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]amino}-3-methoxy-N- methylbenzamide; (33) 1-tert-butyl-N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (34) 2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-amine; (35) N-[3-(7-{[(3S,4R)-1-(3-cyanooxetan-3-yl)-3-fluoropiperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]acetamide; (36) 3-[(3S,4R)-4-({2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3- yl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine- 7-yl}amino)-3-fluoropiperidin-1-yl]oxetane-3-carbonitrile; (37) N~1~-{2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)- 3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-yl}-N~4~-(oxetan-3- yl)bicyclo[2.1.1]hexane-1,4-diamine; (38) N-[3-(7-{[4-(dimethylamino)bicyclo[2.1.1]hexan-1-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-(2- hydroxy-2-methylpropyl)-1H-pyrazole-4-carboxamide; (39) N~4~-{2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}prop-1-yn- 1-yl)-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-7-yl}-N~1~,N~1~- dimethylbicyclo[2.1.1]hexane-1,4-diamine; (40) N-[3-(7-{[4-(dimethylamino)bicyclo[2.1.1]hexan-1-yl]amino}-3- [(trifluoromethyl)sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-methyl- 1H-pyrazole-4-carboxamide; (41) 4-[(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)amino]-3-methoxy-N- methylbenzamide; (42) N-(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)cyclopropanecarboxamide;(43) N-(3-{7-[(5-aminobicyclo[3.1.1]heptan-1-yl)amino]-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl}prop-2-yn-1-yl)-1-cyclopropyl-1H- pyrazole-4-carboxamide; (44) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N- [(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4-yl]-3- [(trifluoromethyl)sulfanyl] imidazo[1,2-a]pyrazin-8-amine; (45) 1-cyclopropyl-N-[3-(8-{[(3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl]imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl]-1H-pyrazole-4-carboxamide; (46) 3-[(3S,4R)-3-fluoro-4-({2-(3-{[2-methoxy-4-(methylsulfonyl) phenyl]amino}prop-1-yn-1-yl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-7-yl}amino)piperidin-1-yl]-1λ~6~-thietane-1,1-dione; (47) 3-[(3S,4R)-4-({2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1- yn-1-yl)-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-yl}amino)-3- fluoropiperidin-1-yl]-1λ~6~-thietane-1,1-dione; (48) 5-{[3-(7-{[(3S,4R)-1-(1,1-dioxo-1λ~6~-thietan-3-yl)-3-fluoropiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]amino}-4-methoxy-N-methylpyridine-2-carboxamide; (49) 1-cyclopropyl-N-[3-(7-{[(3S,4R)-1-(1,1-dioxo-1λ~6~-thietan-3-yl)-3- fluoropiperidin-4-yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-2-yl)prop-2-yn-1-yl]-1H-pyrazole-4-carboxamide; (50) N-[3-(7-{[(3S,4R)-1-(1,1-dioxo-1λ~6~-thietan-3-yl)-3-fluoropiperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]acetamide; (51) N-[3-(7-{[(1R,2R,4R,6S)-9-methyl-9-azatricyclo [4.2.1.0~2,4~]nonan-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]acetamide; (52) 3-[4-({2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)- 3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-7-yl}amino)piperidin-1- yl]oxetane-3-carbonitrile; (53) N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1- yl]acetamide;(54) 1-cyclopropyl-N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (55) N-methyl-N’-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]urea; (56) 2-methyl-N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino}- 3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1,3- thiazole-5-carboxamide; (57) 1-methyl-N-[3-(7-{[(1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl]amino}- 3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (58) 1-(2-hydroxy-2-methylpropyl)-N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4- yl]amino}-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn- 1-yl]-1H-pyrazole-4-carboxamide; (59) 2-(3-{[4-(dimethylphosphoryl)-2-methoxyphenyl]amino}prop-1-yn-1-yl)-N-[1-(3- methyloxetan-3-yl)piperidin-4-yl]-3-[(trifluoromethyl)sulfanyl] pyrazolo[1,5- a]pyridine-7-amine; (60) N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]acetamide; (61) 1-cyclopropyl-N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (62) N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl]pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]cyclopropanecarboxamide; (63) 1-methyl-N-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1H- pyrazole-4-carboxamide; (64) N-methyl-N’-[3-(7-{[1-(3-methyloxetan-3-yl)piperidin-4-yl]amino}-3- [(trifluoromethyl)sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]urea; (65) N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]acetamide;(66) N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]-1-cyclopropyl-1H- pyrazole-4-carboxamide; (67) N-[3-(7-{[1-(3-cyanooxetan-3-yl)piperidin-4-yl]amino}-3-[(trifluoromethyl) sulfanyl] pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl]cyclopropanecarboxamide; (68) 1-methyl-N-(3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carboxamide; (69) 1-methyl-N-(3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carboxamide; (70) 3-methoxy-N-methyl-4-((3-(7-((3-(3-methyloxetan-3-yl)-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2- yn-1-yl)amino)benzamide; (71) 1-methyl-N-(3-(7-((3-(3-methyloxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (72) 1-methyl-N-(3-(1-((3-(3-methyloxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (73) methyl (3-(7-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)carbamate; (74) (4-((3-(7-((4-aminobicyclo[2.2.1]heptan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridine-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (75) (4-((3-(7-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)bicyclo[2.1.1]hexan-1-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxyphenyl)dimethylphosphine oxide; (76) (4-((3-(7-((5-aminobicyclo [3.1.1]heptan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide; (77) (4-((3-(7-((4-aminobicyclo [2.1.1]hexan-1-yl)amino)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide;(78) (3-methoxy-4-((3-(7-(((1r,4r)-4-(3-methoxyazetidin-1-yl)cyclohexyl) amino)-3- ((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide; (79) N-(3-(7-(((3S,4R)-1-(1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)cyclopropanecarboxamide; (80) 3-((3S,4R)-4-((2-(3-((6-(dimethylphosphoryl)-2-methoxypyridin-3-yl)amino)prop- 1-yn-1-yl)-3-((trifluoromethyl)thio) pyrazolo[1,5-a]pyridin-7-yl)amino)-3- fluoropiperidin-1-yl)thietane 1,1-dioxide; (81) 1-(tert-butyl)-N-(3-(7-(((3S,4R)-1-(1,1-dioxidothietan-3-yl)-3-fluoropiperidin-4- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)- 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)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (83) (3-methoxy-4-((3-(7-(((1R,2R,5R)-8-(3-methyloxetan-3-yl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo [1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)phenyl)dimethylphosphine oxide; (84) 5-((3-(8-(((3S,4R)-3-fluoro-1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylpicolinamide; (85) 1-(tert-butyl)-N-(3-(8-(((3S,4R)-1-(3-cyanooxetan-3-yl)-3-fluoropiperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (86) 1-(tert-butyl)-N-(3-(8-(((3S,4R)-3-fluoro-1-(3-methyloxetan-3-yl)piperidin-4- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (87) 6-(4-(4-fluoro-3-methyltetrahydrofuran-3-yl)piperazin-1-yl)-7-methylisoquinolin- 3-amine; (88) 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide;(89) 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (90) 3-((3-(7-((3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (91) 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide (diastereomer); (92) 4-methoxy-N-methyl-3-((3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide (diastereomer); (93) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)benzamide; (94) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2- a]pyrazin-7-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (95) : 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)-N-(oxetan-3-yl)benzamide; (96) 3-methoxy-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (97) (4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl)dimethylphosphine oxide; (98) (3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)phenyl) dimethylphosphine oxide; (99) 4-((3-(8-(((1R,2R,5R)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N-methylbenzamide;(100) (4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide; (101) 3-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (102) 4-((3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (103) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8-azabicyclo [3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (104) rac-N-(3-(7-(((1R,2R,5R)-8-(2-(dimethylamino)-2-oxoethyl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (105) N-(3-(7-(((1R,2R,5R)-8-(2-cyanoethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (106) N-(3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (107) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-(2-(methylsulfonyl)ethyl)-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)-1H-pyrazole-4-carboxamide; (108) N-(3-(7-(((1R,2R,5R)-8-(dimethylglycyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (109) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-(3-(methylamino)-3-oxopropyl)-8-azabicyclo [3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2- yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (110) 4-methoxy-N-methyl-3-((3-(7-(((1R,2R,5R)-8-(2-(methylamino)-2-oxoethyl)-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide;(111) 3-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (112) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(tert-butyl)-1H-pyrazole-4- carboxamide; (113) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4- carboxamide; (114) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (115) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(2-hydroxy-2-methylpropyl)- 1H-pyrazole-4-carboxamide; (116) 1-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-3-methylurea; (117) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)t hio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)cyclopropanecarboxamide; (119) N-(3-(7-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide, 2,2,2-trifluoroacetate salt; (120) (3-methoxy-4-((3-(8-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (121) (3-methoxy-4-((3-(8-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (122) 4-methoxy-N-methyl-3-((3-(8-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (123) 4-methoxy-N-methyl-3-((3-(8-(((1R,6R)-3-methyl-3-azabic yclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide;(124) N-(3-(7-(((1S,6S)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (125) N-(3-(7-(((1R,6R)-3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-(oxetan-3- yl)-1H-pyrazole-4-carboxamide; (126) (3-methoxy-4-((3-(7-(((1S,6S)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino) phenyl)dimethylphosphine oxide; (127) (3-methoxy-4-((3-(7-(((1R,6R)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)phenyl)dimethylphosphine oxide; (128) N-(3-(7-(((1S,6S)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (129) N-(3-(7-(((1R,6R)-3-(2-methoxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide; (130) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)acetamide; (131) N-(3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-cyclopropyl-1H-pyrazole-4- carboxamide; (132) 4-((3-(7-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (133) 1-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1H-pyrazole- 4-carboxamide; (134) 1-cyclopropyl-N-(3-(7-(((1S,2R,4R,6S)-9-methyl-9-azatricyclo[4.2.1.02,4]nonan- 4-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide;(135) 2-methyl-N-(3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-6- ((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (136) 3-methoxy-N-methyl-4-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (137) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)benzamide; (138) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)benzamide; (139) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (140) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-((3-methyl-3- azabicyclo[4.1.0]heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (141) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (142) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (143) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-((R)-2-hydroxypropyl)-3-methoxybenzamide; (144) 4-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-N-((R)-2-hydroxypropyl)-3-methoxybenzamide; (145) 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide;(146) 3-((3-(7-(((cis)-3-(1,1-dioxidothietan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-4-methoxy-N-methylbenzamide; (147) 1-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4-carboxamide; (148) N-(3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (149) 3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-N-(3- methyloxetan-3-yl)benzamide; (150) (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane- 1,2-dicarboxamide; (151) (1R,2R)-N1-methyl-N2-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl) thio)indolizin-2-yl)prop-2-yn-1-yl)cyclopropane- 1,2-dicarboxamide; (152) (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)thio)indolizin-2-yl)prop- 2-yn-1-yl)amino)phenyl)methanone; (153) 1-cyclopropyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)-1H-pyrazole-4- carboxamide; (154) 3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-N-(3-methyloxetan- 3-yl)benzamide; (155) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(8-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop- 2-yn-1-yl)amino)benzamide; (156) 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide (diastereomer); (157) 3-((3-(7-((3-(2-hydroxyethyl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide (diastereomer);(158) N-((R)-2-hydroxypropyl)-3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (159) (3-hydroxy-3-methylazetidin-1-yl)(3-methoxy-4-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)phenyl)methanone; (160) N-((R)-2-hydroxypropyl)-4-methoxy-3-((3-(7-(((1R,2R,5R)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5- a]pyridin-2-yl)prop-2-yn-1-yl)amino)benzamide; (161) 3-methoxy-N,N-dimethyl-4-((3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1] octan-2-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)benzamide; (162) 4-((3-(7-(((1R,2R,5R)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (163) 2-methyl-N-(3-(7-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (164) (4-((3-(7-(((1R,2R,5S)-8-Azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3-methoxyphenyl) dimethylphosphine oxide; (165) 4-methoxy-N-methyl-3-((3-(1-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (166) 4-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (167) 3-methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide; (168) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide;(169) 2-methyl-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)thiazole-5- carboxamide; (170) 3-methoxy-N-methyl-4-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (171) 4-((3-(8-(((1R,2R,5R)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3- ((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1-yl)amino)-3-methoxy-N- methylbenzamide; (172) 4-methoxy-N-methyl-3-((3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)indolizin-2-yl)prop-2-yn-1- yl)amino)benzamide; (173) 3-methoxy-N-methyl-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (174) 3-methoxy-N-methyl-4-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (175) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (176) 4-methoxy-N-methyl-3-((3-(7-((3-(oxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; (177) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-2- methylthiazole-5-carboxamide; (178) 4-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-3- methoxy-N-methylbenzamide; (179) N-(3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)-1-methyl-1H- pyrazole-4-carboxamide;(180) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (181) 3-((3-(7-((3-(3-cyanooxetan-3-yl)-3-azabicyclo[4.1.0]heptan-6-yl)amino)-3- ((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1-yl)amino)-4- methoxy-N-methylbenzamide; (182) 4-methoxy-N-methyl-3-((3-(1-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 6-((trifluoromethyl)thio)pyrrolo[1,2-a]pyrazin-7-yl)prop-2-yn-1- yl)amino)benzamide; (183) 4-methoxy-N-methyl-3-((3-(8-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide; (184) 4-methoxy-N-methyl-3-((3-(8-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1- yl)amino)benzamide; (185) 4-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0]heptan-6- yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)-3-methoxy-N-methylbenzamide; (186) and 4-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-3-methoxy-N-methylbenzamide; (187) abs-3-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (188) abs-3-((3-(7-(((1R,5S,6S or 1S,5R,6R)-5-fluoro-3-methyl-3-azabicyclo[4.1.0] heptan-6-yl)amino)-3-((trifluoromethyl) thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2- yn-1-yl)amino)-4-methoxy-N-methylbenzamide; (189) 1-(tert-butyl)-N-(3-(8-(((1R,2R,5R)-8-methyl-8-azabicyclo[3.2.1]octan-2- yl)amino)-3-((trifluoromethyl)thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)- 1H-pyrazole-4-carboxamide; (190) 3-((3-(8-(((1R,2R,5S)-8-azabicyclo[3.2.1]octan-2-yl)amino)-3-((trifluoromethyl) thio)imidazo[1,2-a]pyrazin-2-yl)prop-2-yn-1-yl)amino)-4-methoxy-N- methylbenzamide;(191) 4-methoxy-N-methyl-3-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide; and (192) 4-methoxy-N-methyl-3-((3-(7-((3-methyl-3-azabicyclo[4.1.0]heptan-6-yl)amino)- 3-((trifluoromethyl)thio)pyrazolo[1,5-a]pyridin-2-yl)prop-2-yn-1- yl)amino)benzamide.

19. A pharmaceutical composition comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

21. A compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in therapy.

22. A method of treating a disorder, condition or disease that is responsive to restoration 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 18, or a pharmaceutically acceptable salt thereof.

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