DNA polymerase theta inhibitors, compositions thereof, compositions further comprising a DNA dependent protein kinase, and uses of both in gene editing field

Abstract

The present disclosure is directed to compositions comprising POLQ inhibitor Compounds of Formula (I), methods of preparing the forgoing, combinations of the forgoing with DNA PK inhibitos as well as methods of use for said compositions.

Description

[0001] DNA POLYMERASE THETA INHIBITORS, COMPOSITIONS THEREOF, COMPOSITIONS FURTHER COMPRISING A DNA DEPENDENT PROTEIN KINASE, AND USES OF BOTH IN GENE EDITING FIELD

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to US Provisional Application No. 63 / 720,969, filed on November 15, 2024, the disclosure of which is incorporated herein by reference in its entirety for any purpose.

[0004] FIELD

[0005] The present disclosure relates generally to compounds, compositions, methods, and kits for increasing genome editing efficiency by administering an inhibitor of DNA polymerase theta (PolQ, Pol ) of general formula (I), and a genome editing system to a eukaryotic cell(s). The present disclosure further relates to compositions including the PolQ inhibitor of general formula (I), and DNA-PK inhibitors of general formulas SI and BI, methods of inserting a polynucleotide of interest into the genome of a eukaryotic cell, and kits for inserting a gene of interest into the genome of a eukaryotic cell. The methods and kits can improve the efficiency of CRISPR / Cas-mediated polynucleotide insertion in cells, in particular in CRISPR-engineered CAR-T cells.

[0006] INCORPORATION BY REFERENCE

[0007] This application contains subject matter related to applications PCT / US2024 / 043438 (WO 2025 / 049247), PCT / US2024 / 043441 (WO 2025 / 049250), and PCT / US2024 / 043446 (WO 2025 / 049253). These references are hereby incorporated by reference in their entirety.

[0008] INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0009] This application contains a Sequence Listing which has been submitted in XML format via Patent Center and is hereby incorporated by reference in its entirety. Said XML copy, created on January 24, 2024, is named 055920-626P01US_SeqList_ST26.xml and is 74 KB in size.

[0010] BACKGROUND

[0011] The development of cost-efficient and reliable methods for precise targeted alterations to the genome of living cells has been a long-standing goal. Genome editing has the potential to eliminate genes responsible for a particular disorder (i.e., a gene “knock-out”), or alternatively, provide a means for gene manipulation or insertion to correct a genetic deficiency or enhance a biological process via a gene “knock-in.” Genome editing can be applied for treatment of a multitude of disorders, including treatment of inherited disorders, hematological disorders and cancer, and in methods of immunotherapy. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) systems are prokaryotic immune systems (Ishino et al., Journal of Bacteriology 169:5429-5433 (1987)), which provide immunity against viruses and plasmids by targeting the nucleic acids of the viruses and plasmids in a sequence-specific manner (Soret et al., Nature Reviews Microbiology 6:181-186 (2008)). Since its original discovery, multiple groups have performed extensive research around potential applications of the CRISPR system in genetic engineering, including gene editing (Jinek et al., Science 337(6096): 816-821 (2012); Cong et al, Science 339(6121): 819-823 (2013); and Mali et al., Science 339(6121):823-826 (2013)). The CRISPR-Cas9 gene editing system has been used successfully in a wide range of organisms and cell lines.

[0012] The Cas9 endonuclease generates a double-stranded DNA break at the target sequence, upstream of a protospacer adjacent motif (PAM). The target sequence can then be removed, or a sequence of interest can be inserted into the target sequence using an endogenous repair pathway of the cell. Endogenous DNA repair pathways include the Nonhomology Mediated End-Joining (NHEJ) pathway, Microhomology Mediated End-Joining (MMEJ) pathway, and the Homology Directed Repair (HDR) pathway.

[0013] NHEJ, MMEJ, and HDR pathways repair double-stranded DNA breaks, but repair of such double-stranded DNA breaks may result in insertions or deletions at the double stranded break site. In NHEJ, a homologous template is not required for repairing breaks in the DNA. NHEJ repair can be error-prone, although errors are decreased when the DNA break includes compatible overhangs. NHEJ and MMEJ are mechanistically distinct DNA repair pathways with different subsets of DNA repair enzymes involved in each of them. Unlike NHEJ, which can be precise in some cases, or error-prone in some cases, MMEJ is always error-prone and results in both deletion and insertions at the site under repair. MMEJ-associated deletions are due to the micro-homologies (2-10 base pairs) at both sides of a double-strand break. In contrast, HDR requires a homologous template to direct repair, but HDR repairs are typically high-fidelity and less error prone. HDR-driven repair of double-stranded DNA breaks is therefore preferable to NHEJ- or MMEJ-mediated repair; however, in many cell types HDR is limited by the activity of NHEJ at all cell cycle stages, and HDR is primarily utilized in the S / G2 phase of cell growth (Mao et al., Cell Cycle, 7:2902-2906 (2008)).

[0014] The ability to modify the genome of any cell at a precise location has improved with the recent discovery and implementation of CRISPR / Cas9 editing technology. However, the capacity to introduce specific directed changes at given loci is hindered by the fact that the major cellular repair pathway that occurs following Cas9-mediated DNA cleavage is the erroneous non-homologous end joining (NHEJ) pathway. Homology-directed recombination (HDR) is less efficient than NHEJ, reducing editing efficiencies in eukaryotic cells. While the achievement of insertion or deletions (indels) from NHEJ is up to 70% effective in some reports, the efficiency of HDR remains challenging, with rates at less than 1%. Accordingly, there is a need for increasing genome editing efficiency, in particular, HDR efficiency.

[0015] Studies have shown that reduced NHEJ activity in vivo results in increases in HDR activity, and this phenomenon can be exploited to increase the efficiency of HDR-mediated CRISPR / Cas9 precision genome engineering (Pierce et al. Genes Dev., 15, 3237-3242 (2001); Ma et al. RNA Biol., 13, 605-612 (2016); Maruyama, et al. Nat. Biotechnol., 33, 538-542 (2015); Robert et al. Genome Med., 7, 93 (2015)).

[0016] DNA-dependent protein kinase (DNA-PK) is a nuclear serine / threonine kinase that has been shown to be essential in DNA double stranded break repair machinery. In mammals, the predominant pathway for repair of double stranded DNA breaks is the non-homologous end joining (NHEJ) pathway which is functional regardless of the phase of the cell cycle and acts by removing non-ligatable ends and ligating ends of double strand breaks. Although DNA-PKis result in increased HDR levels and reduction of NHEJ-associated InDeis, MH-dependent deletions are still present and occasionally elevated upon DNA-PK inhibition. Various reports have shown that knockout or knock-down of Pol 6 partially reduces MH-associated deletions and minimizes Cas9-related unwanted on-target effects, such as translocations and large deletions (Hussain et al. Nucleic Acids Res. 49, e74 (2021); Mateos-Gomez et al. Nature 518, 254-257 (2015); Kosicki et al. Nat. Commun. 13, 3422 (2022); Taheri-Ghahfarokhi et al. Nucleic Acids Res. 46, 8417-8434 (2018); Wyatt et al. Mol. Cell 63, 662-673 (2016); Schimmel et al. EMBO J. 36, 3634-3649 (2017)).

[0017] Therefore, these studies suggest that inhibition of Pol 6 might contribute to improved gene targeting efficiencies and mitigate undesired on- and off-target effects, especially when combined with inhibition of DNA-PK activity. The hypothesis has been supported by recent publications (Schimme et al. Cell Reports 42, 112019 (2023); Nature Commun. 14, 4761 (2023)).

[0018] DNA polymerase theta (Pol0, PolQ) is the primary mediator of MMEJ in most eukaryotic cells. Therefore, MMEJ through Pol0 is also referred to as Pol0-mediated end joining (TMEJ). The helicase domain of Pol0 promotes the annealing of resected 3' overhangs utilising microhomologies, while the polymerase domain extends annealed sequences. Resolution involves flap removal through endonucleases, such as Flap endonuclease 1 (FEN1), gap filling, and, finally, joining of ends by DNA ligase 1 (LIG1) or DNA ligase 3 (LIG3).

[0019] Human PolΘ (PolQ) is a unique, large (290 kDa) multifunctional A-family DNA polymerase that is required for DSB repair through the MMEJ pathway. Unique among eukaryotic polymerases, the N-terminal domain contains adenosinetriphosphatase (ATPase) activity that displaces RPA from single-stranded DNA. The C-terminal domain contains a DNA polymerase activity that is responsible for filling in the gap after annealing of resected DNA ends.

[0020] There is a need for potent and selective DNA-PK inhibitors in combination of DNA PolΘ (PolQ) inhibitors that transiently and simultaneously block the NHEJ and MMEJ pathways to promote DNA repair via the desirable HDR pathway, therefore, further improve the efficiency of CRISPR / Cas-mediated polynucleotide insertion in cells, such as CRISPR CAR-T cells compared with using either DNA-PKi or POLQi alone. SUMMARY

[0021] One aspect of the present disclosure relates to compositions comprising a PolO

[0022] B /

[0023] trrxXm

[0024] D

[0025] n

[0026] ,2$4^

[0027] (POLQ) inhibitor of Formula (I

[0028]

[0029] ):n(Formula I), or a pharmaceutically acceptable salt thereof, wherein: B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1; D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3; each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl; each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl; each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, -C(O)N(R4)2, C0-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(CI-4 alkyl); R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6; R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl; R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8;

[0030] R8is C1-C4 alkyl, or 5-membered heterocyclyl; X is N or CH; Y is O, NH, or S;

[0031] Z is O, S, NR5or CHR5; n is 2-3; m is 1-3; and wherein the compound is

[0032]

[0033] Another aspect of the present disclosure relates to compositions comprising a a Pol0

[0034]

[0035] (Formula I), or a pharmaceutically acceptable salt thereof, wherein: B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1; D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3; each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl; each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl; each R3is independently H, -OH, C1-C4 alkoxy, - C(O)C(R4)2, -C(O)N(R4)2, CO-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(Ci-4 alkyl); R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6; R6is H, (O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl; R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8; R8is C1-C4 alkyl, or 5-membered heterocyclyl; X is N or CH; Y is O, NH, or S; Z is O, S, NR5or CHR5; n is 2-3; m is 1-3; and wherein the compound is not

[0036]

[0037] and a DNAPK inhibitor of Formula (

[0038]

[0039] SI): or a pharmaceutically acceptable salt thereof, wherein: Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5; RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6; RS2is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2; RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylaryl, and aryl; each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; or two geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; each RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; and n is an integer from 1 to 3.

[0040] Another aspect of the present disclosure relates to compositions comprising a a PolO

[0041] ^rr / bJjTi

[0042] D

[0043] (POLQ) inhibitor of formula (

[0044]

[0045] I): (Formula I), or a pharmaceutically acceptable salt thereof, wherein: B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1; D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3; each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl; each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-Cs-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl; each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, -C(O)N(R4)2, C0-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(0)(NH)(Ci-4 alkyl); R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more - OH, halogen, 5- or 6-membered heterocycle, or 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6; R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl; R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8; R8is C1-C4 alkyl, or 5-membered heterocyclyl; X is N or CH; Y is O, NH, or S; Z is O, S, NR5or CHR5; n is 2-3; m is 1-3; and wherein the compound is not

[0046] and a DNAPK inhibitor of Formula (SI)I):

[0047]

[0048] (BI), or a pharmaceutically acceptable salt thereof, wherein: ASis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B; R1Sis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5S; R2Sis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C(O)NH2; R3Bis selected from the group consisting of H, F, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and C1-C4 alkyl; each R4Sis independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, C1-C4 alkoxy, CD3, CD2CD3, and Ci-Ce haloalkyl; or two geminal R4Stogether with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each R5Bis independently selected from the group consisting of halogen, NH2, OH, -CN, C(O)NH2, C(O)NHR7B, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6S; each R6Sis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; each R7Sis independently selected from H and C1-C4 alkyl; each nSis independently an integer from 0-4; rSis an integer from 0 to 2; sSis an integer from 0 to 2; and tSis an integer from 1 to 2.

[0049] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0050] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof., and the DNAPK inhibitor (SI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0051] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof., and the DNAPK inhibitor (BI) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0052] Another aspect of the present disclosure is directed to a composition comprising (a) POLQ inhibitor I, (b) a DNA protein kinase inhibitor (DNA-PKI) (SI) or (BI), (c) a DNA cutting agent. In some embodiments, the DNA-PKI is a compound of (SI) or a pharmaceutically acceptable salt thereof. In other embodiments, the DNA-PKI is a compound of (BI) or a pharmaceutically acceptable salt thereof.

[0053] Another aspect of the present disclosure is directed to a method for targeted genome editing in a cell, comprising contacting the cell with a DNA cutting agent, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of (SI) or (BI) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0054] Another aspect of the present disclosure is directed to a method for repairing a double stranded DNA break in the genome of a cell, comprising contacting the cell with a DNA cutting agent, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0055] Another aspect of the present disclosure is directed to a method for simultaneously inhibiting or suppressing repair of a DNA break in a cell via both nonhomologous end joining (NHEJ) pathway and Microhomology Mediated End-Joining (MMEJ) pathway, comprising contacting the cell with a DNA cutting agent, a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug, thereof, and POLQi Compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0056] Another aspect of the present disclosure is directed to a method for targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0057] Another aspect of the present disclosure relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for cell therapy in combination of POLQi Compound of Formula (I).

[0058] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, or pharmaceutical composition thereof, in the treatment of a cell in combination of DNAPK Inhibitor compound of Formula (SI) or (BI).

[0059] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

[0060] BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-246, Q-122, Q-242, or Q-126, respectively, on cell viability 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (1.25pM, 2.5pM or 5pM). Live cells are shown as a percentage of total cells.

[0061] FIG. 2 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-246, Q-122, Q-242, or Q-126, respectively, on T cell proliferation 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (1.25pM, 2.5pM or 5pM). Total live cell counts (xl0e6) are shown.

[0062] FIG. 3 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-246, Q-122, Q-242, or Q-126, respectively, on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (1.25pM, 2.5pM or 5pM). Frequency of CAR+ T cells is shown as a percentage of total live cells.

[0063] FIG. 4 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-246, Q-122, Q-242, or Q-126, respectively, on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (1.25pM, 2.5pM or 5pM). KI efficiency is shown as a fold change over the untreated control condition (calculated by dividing the %CAR+ of DNA-PK or DNA POLQ inhibitor treated by untreated).

[0064] FIG. 5 shows the effect of DNA-PK inhibitor B-l alone and in combination with DNA POLQ inhibitor Q-246, Q-122, Q-242, or Q-126, respectively, on total CARA cell yields 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor is as indicated (1.25pM, 2.5pM or 5pM). Relative CAR+ yield is shown as a fold change over the untreated control condition (calculated by dividing the total number of CAR+ cells in DNA-PK or DNA PolQ inhibitor treated conditions by untreated).

[0065] FIG. 6 shows the effect of DNA-PK inhibitor (S-35, B-66, or B-72) in combination of DNA POLQ inhibitor (Q-246, Q-122, Q-242, or Q-126) on cell viability 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Live cells are shown as a percentage of total cells.

[0066] FIG. 7 shows the effect of DNA-PK inhibitor (S-35, B-66, or B-72) in combination of DNA POLQ inhibitor (Q-246, Q-122, Q-242, or Q-126) on T cell proliferation 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Total live cell counts (xl0e6) are shown.

[0067] FIG. 8 shows the effect of DNA-PK inhibitor (S-35, B-66, or B-72) in combination of DNA POLQ inhibitor (Q-246, Q-122, Q-242, or Q-126) on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions.

[0068] Frequency of CAR+ T cells is shown as a percentage of total live cells.

[0069] FIG. 9 shows the effect of DNA-PK inhibitor (S-35, B-66, or B-72) in combination of DNA POLQ inhibitor on CAR insertion into the TRAC locus 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. KI efficiency is shown as a fold change over the untreated control condition (calculated by dividing the %CAR+ of inhibitor treated by untreated). FIG. 10 shows the effect of DNA-PK inhibitor (S-35, B-66, or B-72) in combination of DNA POLQ inhibitor (Q-246, Q-122, Q-242, or Q-126) on total CAR+ cell yields 5 days after electroporation. Concentration of DNA-PK inhibitor was 0.5pM for all conditions and the concentration of DNA POLQ inhibitor was 5pM for all conditions. Relative CAR+ yield is shown as a fold change over the untreated control condition (calculated by dividing the total number of CAR+ cells in inhibitor treated conditions by untreated).

[0070] DETAILED DESCRIPTION

[0071] Definitions

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed present disclosure. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0073] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0074] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0075] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(Ci-Ce) alkyl, (Ci-Ce) alkyl, (Ci-Ce) alkoxy, (Ci-Ce) haloalkyl, (Ci-Ce) haloalkoxy, -O-(C2-Ce) alkenyl, -O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6) alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(Ci-C6) alkyl, -NH2, -NH((CI-C6) alkyl), -N((CI-C6) alkyl)2, -NHC(O)(CI-C6) alkyl, -C(O)NH(CI-C6) alkyl, -S(O)2(Ci-C6) alkyl, -S(O)NH(Ci-Ce) alkyl, and S(O)N((Ci-Ce) alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0076] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a RM, and formulation into an efficacious therapeutic agent. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0077] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0078] As used herein, “Alkyl” refers to optionally substituted, straight and branched chain aliphatic groups having from 1 to 30 carbon atoms. “Cl, C2, C3, C4, C5 or C6 alkyl” or “Cl-C6 alkyl” is intended to include Cl, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intends to include Cl, C2, C3, C4, C5 and C6 alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. The term “heteroalkyl” as used herein contemplates an alkyl with one or more heteroatoms.

[0079] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0080] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0081] As used herein, the term “alkenyl” includes unsaturated or partially unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-6 for straight chain, C3-6 for branched chain). The term “C2-6” includes alkenyl groups containing two to six carbon atoms. The term “C3-6” includes alkenyl groups containing three to six carbon atoms. As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0082] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-6 for straight chain, C3-6 for branched chain). The term “C2-6” includes alkynyl groups containing two to six carbon atoms. The term “C3-6” includes alkynyl groups containing three to six carbon atoms.

[0083] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0084] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0085] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro) system having 3 to 30 carbon atoms (e.g., C3-12, C3-10, C3-8, or C3-6). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be nonaromatic.

[0086] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic or bicyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, l-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofurran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3,4]octanyl, 2-oxa-azaspiro[3,4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 1,3-dihydrobenzo[c]isoxazol-3-yl).

[0087] As used herein, the term “optionally substituted heterocycloalkyl” refers to unsubstituted heterocycloalkyl having designated substituents replacing one or more hydrogen atoms on one or more carbon or heteroatom. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0088] Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, — H, -halogen. — O — (Ci-e) alkyl, (Ci-e) alkyl, — O — (C2-6) alkenyl, — O — (C2-6) alkynyl, (C2-6) alkenyl, (C2-6) alkynyl, —OH, — OP(O)(OH)2, — OC(O)(Ci-6) alkyl, — C(O)(Ci-6) alkyl, — OC(O)O(Ci-6) alkyl, — NH2, NH((CI-6) alkyl), N((CI-6) alkyl)2, — S(O)2 — (Ci-e) alkyl, — S(O)NH(Ci-e) alkyl, and — S(O)N((Ci-e) alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,1 l-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like. Furthermore, when containing two or more fused rings, the aryl groups herein defined may have a saturated or partially unsaturated heterocyclic ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, benzo[d][l,3]dioxol-5-yl, 2,3-dihydrobenzo[b][l,4]dioxin-6-yl, benzo[d]isoxazol-3(2H)-on-6-yl, benzo[d]oxazol-2(3H)-on-6-yl, and benzo[d]oxazol-2(3H)-on-5-yl.

[0089] Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-112-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4] thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [l,2,3]triazolyl, imidazo[l,2-a]pyrimidinyl, [ 1,2,4]triazolo[4,3 -b]pyridazinyl, benzofc] [ 1,2, 5]thiadiazolyl, benzofc] [ 1,2, 5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [l,5-b][l,2]oxazinyl, 4, 5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof.

[0090] Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-l IH-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[l,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[l,2-a]indol- 1 (2H)-onyl, or benzofc] [ 1,2]oxaborol- 1 (3H)-olyl.

[0091] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[0092] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an — OH or — O—.

[0093] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo. The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0094] As used herein, the term “cyano” refers to a nitrile radical (e.g., — CN).

[0095] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0096] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moi eties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0097] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0098] As described herein, isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.” The compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0099] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.

[0100] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0101] The present disclosure also contemplates isotopically labelled compounds of Formula I (e.g., those labeled with D,2H, or14C). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0102] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

[0103] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0104] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0105] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton presents in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0106] It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0107] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.

[0108] An "effective amount" when used in connection with a compound is an amount effective for use in a cell therapy.

[0109] The term "carrier" as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject. The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0110] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0111] The term "prodrug" as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0112] The present disclosure relates to compounds and compositions that are capable of inhibiting DNA-dependent protein kinase (DNA-PK) in combination with POLQi compound of Formula I in a subject or in a biological sample.

[0113] In a first aspect of the present disclosure, the composition described herein comprises

[0114] B 7

[0115] D

[0116]

[0117] ,2:

[0118] a POLQi Compound of formula (I) A compound of Formula I,

[0119]

[0120] (Formula I), or a pharmaceutically acceptable salt thereof, wherein: B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1; D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3; each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl; each R2is independently H, halogen, Ci-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, C1-C3-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl; each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, -C(O)N(R4)2, Co-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(Ci-4 alkyl); R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6; R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl; R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8; R8is C1-C4 alkyl, or 5-membered heterocyclyl; X is N or CH; Y is O, NH, or S; Z is O, S, NR5or CHR5;

[0121] N

[0122] N' N

[0123] I] n is 2-3; m is 1-3; and wherein the compound is not

[0124]

[0125] 3

[0126] In another aspect, the invention is a compound of wherein B is selected from: phenyl, pyridinyl, C3-C8 cycloalkyl, pyrazolyl, azaindolyl, indolyl, thiazolyl, wherein the phenyl, cycloalkyl, heteroaryl is optionally substituted with one or more R1; each R1is independently H, halogen, CF3, CF2H, OCF2H, OCF3, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl.

[0127] In yet another aspect, the invention is a compound wherein D is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, imidazolyl, pyridonyl, indazolyl, bicyclo[4.2.0]octa-l, 3, 5-trienyl, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 68-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3In another aspect, the invention is a compound, wherein the compound is of Formula la-i -la-v:

[0128]

[0129] m is 0, 1, or 2, and n is 0, 1, or 2.

[0130] In one aspect, the invention is a compound wherein, D is selected from: 

[0131]

[0132]

[0133] e0 HN-Boc 0 HN- Z

[0134] \QI-I N-N N-N OH OH

[0135]

[0136] or a pharmaceutically acceptable salt thereof.

[0137] In another aspect, the invention is a compound wherein, wherein D is selected

[0138]

[0139]

[0140] r>i-i

[0141]

[0142]

[0143] HN, or a pharmaceutically acceptable salt thereof.

[0144] In yet another aspect, the invention is a compound, wherein the compound is of Formula Ic-i, Ic-ii, or Ic-iii:

[0145]

[0146] Ic-ii), or

[0147]

[0148] (Formula Ic-iii).

[0149] In one aspect, the invention is a compound, wherein the compound is of Formula Ild-i:

[0150]

[0151] , wherein m is 0, 1, or 2, or a pharmaceutically acceptable salt thereof.

[0152] In one aspect, the invention is a compound selected from the group consisting of: 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-3 -carboxamide; 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)pyridine-3-carboxamide; 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-3-carboxamide; 6-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]pyridine-3-carboxamide; 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide; 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide; 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide; 5-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]pyridine-2-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3- methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop- 1-yn-l-yl)-l,3-thiazole-4-carboxamide; 2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]-l,3-thiazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -oxazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide; 2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]-l,3-oxazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3-thiazole-5-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazole-5-carboxamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l,3,4-thiadiazol-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)-N-[3-(l,3,4-thiadiazol- 2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l -methyl- lH-imidazol-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[3-(pyridin-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridin-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3- yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyrimidin-5- yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridazin-3-yl)prop-2-yn-l-yl]acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-2-yl)prop-2-yn-l-yl]acetamide; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazol-2-yl]methyl } carbamate; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-1, 3 -thiazol-2-yl]methyl} carbamate; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazol-2-yl]methyl}carbamate; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l, 3 -thiazol-2-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l, 3 -thiazol-2-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-2-oxoacetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-2- oxoacetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn- 1 -yl } acetamide; N-[3 -(3 -amino- 1 -methyl- lH-pyrazol-5-yl)prop-2-yn- 1 -y 1 ] -2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3 -(3 -amino- 1 -methyl- lH-pyrazol-5-yl)prop-2-yn- 1 -y 1 ] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; N-[3-(3-amino-1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]-N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]acetamide; N-[3-(2-amino-l-methyl-lH-imidazol-4-yl)prop- 2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(2-amino-l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; methyl 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1 -methyl- lH-pyrazole-3 -carboxylate; methyl 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l-methyl-lH-pyrazole-3-carboxylate; methyl 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazole-4-carboxylate; methyl 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxylate; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- IH-pyrazol- 1 -yl]propanamide; 2- [4-(3 - {2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamido}prop- 1 -yn- l-yl)-lH-pyrazol- 1 -yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l -methyl- IH-imidazol -4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide; N-{3-[2-(aminomethyl)-l,3-thiazol-4-yl]prop-2-yn-l-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-{3-[2-(aminomethyl)-l,3-thiazol-4-yl]prop-2-yn-l-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-{3-[2-(aminomethyl)-l,3-thiazol-4-yl]prop-2-yn-l-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; ethyl (1 S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]cyclopropane-l-carboxylate; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[cz5-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]- N-(2-fluorophenyl)-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-fluorophenyl)-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3 -yl } -2- [3, 5 -bi s(trifluoromethyl)pyridin-2-yl] -N- { 3 - [cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-(2-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]-N-(2-phenylcyclopropyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-1-yl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyridazin-3-yl)prop-2-yn-1-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-N-{bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N- {bicyclo[3.1.0]hexan-6-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(6-m ethoxypyri din-3 -yl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(l-methyl-lH-pyrazol-4-yl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(thiophen-3-yl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[l-(4-methylbenzenesulfonyl)-6-oxo-l,6-dihydropyridin-2-yl]prop-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyrimidin-5-yl)prop-2-yn-1-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methoxypyridin-4-yl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-[3-(oxetan-3-yl)phenyl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(2-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(3-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn- 1 -yl]acetamide; N-[3 -(3 -amino- 1 -methyl- lH-pyrazol-5-yl)prop-2-yn- 1 -y 1] -2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyridazin-4-yl)prop-2-yn-1-yl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(2-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3,4-difluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]acetamide; N-[3- (6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-{1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl}acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2,3-difluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3,3-difluorocyclopentyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2-bromo-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-hydroxybut-2-yn-l-yl)-N-(3-methylphenyl)acetamide; N-(4-aminobut-2-yn-l-yl)-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-acetamidobut-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{4-[(5-methyl-l,3,4-oxadiazol-2-yl)formamido]but-2-yn-l-yl}-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-{4-[(pyridin-3-yl)formamido]but-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(6-oxo-l,6-dihydropyridin-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(l-hydroxycyclobutyl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-l,l-dioxo-1^6-thian-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l,3-dihydroxycyclobutyl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[4-(morpholin-4-yl)but-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[4-(l,l-dioxo-1^6-thiomorpholin-4-yl)but-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[4-(2-oxopyrrolidin-l-yl)but-2-yn-l-yl]acetamide; N-(4-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}but-2-yn-1-yl)prop-2-enamide; l-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-3-[2,6-dimethyl-4-(trifluoromethyl)phenyl]-l-(4-fluorophenyl)urea; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl] -2- [2-bromo-4-(trifluoromethyl)phenyl] -N-(4-fluorophenyl)acetamide; 2- [3, 5 -bis(trifluoromethyl)pyridin-2-yl]-N-[3-(l-hydroxycyclobutyl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxyoxetan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4- hydroxy-4-methylpent-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxyoxolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxyoxetan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-{4-[(pyridin-2-yl)formamido]but-2-yn-l-yl}acetamide; tert-butyl 4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-4-hydroxypiperidine-1 -carboxylate; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(6-m ethoxypyri din-3 -yl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(4-hydroxy-4-methylpent-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxyoxolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxythiolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn- l-yl}-N-(6-methoxypyri din-3 -yl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3 -(3 -hydroxy- 1, 1 -di oxo- 1 ^6-thiolan-3 -yl)prop-2-yn- 1 -yl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(6-methoxypyri din-3 -yl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-{l-methyl-lH-pyrrolo[2,3-b]pyridin-6-yl} acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)but-2-yn-1-yl]-N-(3-methylphenyl)acetamide; ethyl N-(4-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}but-2-yn-l-yl)carbamate; 2-[2-acetyl-4-(trifluoromethyl)phenyl]-N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide; 2-[2-acetyl-4-(trifluoromethyl)phenyl]-N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-methyl-4-(trifluoromethyl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn- 1 -yl]-N-(4-fluorophenyl)-2-[2-methyl-4-(trifluoromethyl)phenyl]acetamide; N- {bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[6-(dimethylphosphoryl)pyridin-3-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(3-hydroxycyclobut-l-en-l-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-l-methylpiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-l-methyl-l-oxo-l,5-phosphinan-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-1 -methyl- 1 -oxo- 1, 5-phosphinan-4-yl)prop-2-yn- 1 -yl]-N-(3 -methylphenyl)acetamide;

[0153] (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxylic acid;

[0154] (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(lS,2R)-2-(4-methyl-4-oxo- 1,4, 5-azaphosphinane- 1 -carbonyl)cyclopropyl]prop-2-yn- 1 -yl } acetamide; (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]-N-[2-(dimethylamino)ethyl]cyclopropane-1-carboxamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(1S,2R)-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}-N-(6-methoxypyridin-3-yl)acetamide; N-[3-(1-acetyl-4-hydroxypiperidin-4-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-[4-(morpholin-4-yl)but-2-yn-l-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-(2,4-dimethylphenyl)-N-(4-fluorophenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-{4-[(pyridin-3-yl)formamido]but-2-yn-l-yl}acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-{4-[(pyridin-2-yl)formamido]but-2-yn-l-yl}acetamide; N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1H-indazol-4-yl)prop-2-yn-1-yl]acetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(dimethylphosphoryl)pyrimidin-5-yl]prop-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N- (3-{4-[imino(methyl)oxo-^6-sulfanyl]phenyl}prop-2-yn-l-yl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-[4-(2-oxopyrrolidin- 1 -yl)but-2-yn- 1 -yl]acetamide; N-[3 -(6-aminopyridazin-3 -yl)prop-2-yn- 1 -yl]-2-[2-chloro-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-(4-bromo-2-methoxyphenyl)-N-(4-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-l-oxo-3H-1^6,2-benzothiazol-6-yl)prop-2-yn-l-yl]acetamide; N-(4-{2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamido}but-2-yn-l-yl)prop-2-enamide; tert-butyl 4-(3-{2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-4-hydroxypiperidine-1 -carboxylate; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxythiolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[4-bromo-2-(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(l-acetyl-4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(lS,2R)-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-{ l-methyl-lH-pyrrolo[2,3-b]pyridin-6-yl}acetamide; tert-butyl (2-((6-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn- 1-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate; N-(3-(6-(2-aminoacetamido)pyridazin-3-yl)prop-2-yn-l-yl)-N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamide; tert-butyl (2-((6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate; (1S,2R)-2-(3-(N-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop-1-yn-1-yl)cyclopropane-1-carboxylic acid; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dichlorophenyl)-N-(3-(4-hydroxy-1-methylpiperidin-4-yl)prop-2-yn-1-yl)acetamide; N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-((lR,2S)- 2-(4-(S-methylsulfonimidoyl)piperidine- 1 -carbonyl)cyclopropyl)prop-2-yn- 1 -yl)acetamide; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(4-bromophenyl)prop-2-yn-l-yl)-N-(6-m ethoxypyri din-3 -yl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-N-(4-fluorophenyl)-2-(4-(trifluoromethyl)-2-vinylphenyl)acetamide; 2-(3,5- bis(trifluoromethyl)pyridin-2-yl)-N-(3 -(4-hydroxy- 1 -methylpiperidin-4-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(4-methyl-2-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide; 2,6-dimethyl-4-(trifluoromethyl)phenyl (3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)(m-tolyl)carbamate; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(2-(dimethylphosphoryl)pyrimidin-5-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide l)acetamido)prop-l-yn-l-yl)cyclopropane-l -carboxylic acid; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(dimethylphosphoryl)pyridin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(S-methylsulfonimidoyl)pyridin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; 2,6-dimethyl-4-(trifluoromethyl)phenyl (3 -(4-(dimethylphosphoryl)phenyl)prop-2-yn- 1 -yl)(m-tolyl)carbamate; N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(but-3-yn-l-yl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(2-chloro-4-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide; (lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3 -yl)-2-(3, 5 -bi s(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)-N-((5-oxopyrrolidin-3-yl)methyl)cyclopropane-l -carboxamide; diethyl (3-((lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop-1 -yn- 1 -yl)cyclopropane- 1 -carboxamido)propyl)phosphonate; ( 1 S,2S)-2-(3 -(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1-yn-l-yl)-N-(((R)-morpholin-2-yl)methyl)cyclopropane-l -carboxamide; dimethyl (5-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)pyridin-2-yl)phosphonate; 2-(2-acetyl-4-(trifluoromethyl)phenyl)-N-(3-(6-aminopyridazin-3-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;

[0155] 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(3-(2-hydroxyacetamido)-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)- 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(6-(2-(4-methylpiperazin-l-yl)ethoxy)pyridin-3-yl)prop-2-yn-l-yl)acetamide; (lS,2S)-2-(4-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)but- 1 -yn- 1 -yl)cyclopropane- 1 -carboxylic acid; (lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop- 1 -yn- 1 -yl)-N-methylcyclopropane- 1 - carboxamide; (lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)-N-(2-methoxyethyl)-N-methylcyclopropane-1 -carboxamide; (lR,2S)-2-(4-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)but- 1 -yn- 1 -yl)cyclopropane-l -carboxylic acid; (lR,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop- 1 -yn- 1 -yl)-N-methylcyclopropane- 1 -carboxamide; (lR,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)-N-(2-methoxyethyl)-N-methylcyclopropane-1 -carboxamide; ethyl (6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)carbamate; N-(4-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)but-2-yn-l-yl)-5-methyl-l,3,4-oxadiazole-2-carboxamide; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(3-ethylureido)pyridazin-3-yl)prop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; diethyl (3-(3-(6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)ureido)propyl)phosphonate; N-(4-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)acetamido)but-2-yn-l-yl)-5-methyl-l,3,4-oxadiazole-2-carboxamide; ethyl 5-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop- 1 -yn- 1 -yl)picolinate; dimethyl (4-(3 -(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)phenyl)phosphonate; ethyl 5-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)pyrimidine-2-carboxylate; 2-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide; ethyl 5-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)picolinate; ethyl 5-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)acetamido)prop- 1 -yn- 1 -yl)pyrimidine-2-carboxylate; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3 -(6-oxo- 1,6-dihydropyridin-2-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide; dimethyl (6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)pyridazin-3-yl)phosphonate; N-(3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)-2-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide; N-(4-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)acetamido)but-2-yn-l-yl)-5-methyl-l,3,4-oxadiazole-2-carboxamide; methyl 6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m- tolyl)acetamido)prop- 1 -yn- 1 -yl)pyridazine-3 -carboxylate; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-((lS,2R)-2-(hydroxymethyl)cyclopropyl)but-3-yn-l-yl)-N-(m-tolyl)acetamide; 2-(2,4-bi s(trifluoromethyl)phenyl)-N-(4-(3 -hydroxy oxetan-3 -yl)but-3 -yn- 1 -yl)-N-(m-tolyl)acetamide; tert-butyl (2-((6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)amino)-2-oxoethyl)carbamate; ethyl (2-((6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop-l-yn-l-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(2-(2-hydroxyacetamido)pyrimidin-5-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(6-(2-hydroxyacetamido)pyridazin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-((lS,2R)-2-(hydroxymethyl)cyclopropyl)prop-2-yn-l-yl)acetamide; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-N-(3-(5-(2-hydroxyacetamido)pyrazin-2-yl)prop-2-yn-l-yl)acetamide; and (lR,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)-N-(((R)-morpholin-2-yl)methyl)cyclopropane- 1 -carboxamide, or a pharmaceutically acceptable salt thereof.

[0156] In another aspect, the invention is a compound selected from the group consisting of: 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-3 -carboxamide; 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)pyridine-3-carboxamide; 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-3-carboxamide; 6-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]pyridine-3-carboxamide 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide; 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide; 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide; 5-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]pyridine-2-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide; 2-(3-{2-[2,4- bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop- 1-yn-l-yl)-l,3-thiazole-4-carboxamide; 2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]-l,3-thiazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -oxazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide; 2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]-l,3-oxazole-4-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3-thiazole-5-carboxamide; 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazole-5-carboxamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l,3,4-thiadiazol-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)-N-[3-(l,3,4-thiadiazol- 2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l -methyl- lH-imidazol-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[3-(pyridin-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridin-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3- (6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-methylphenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)-N-[3- (pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridazin-3-yl)prop-2-yn-l-yl]acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-2-yl)prop-2-yn-l-yl]acetamide; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazol-2-yl]methyl } carbamate; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-1, 3 -thiazol-2-yl]methyl} carbamate; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazol-2-yl]methyl}carbamate; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l, 3 -thiazol-2-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l, 3 -thiazol-2-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-2-oxoacetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-2-oxoacetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol- 2-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn- 1 -yl } acetamide; N-[3 -(3 -amino- 1 -methyl- lH-pyrazol-5-yl)prop-2-yn- 1 -y 1 ] -2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3 -(3 -amino- 1 -methyl- lH-pyrazol-5-yl)prop-2-yn- 1 -y 1 ] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn- 1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; N-[3-(3-amino-1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]-N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]acetamide; N-[3-(2-amino-l-methyl-lH-imidazol-4-yl)prop- 2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-[3-(2-amino- l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; methyl 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1 -methyl- lH-pyrazole-3 -carboxylate; methyl 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l-methyl-lH-pyrazole-3-carboxylate; methyl 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazole-4-carboxylate; methyl 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxylate; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- IH-pyrazol- 1 -yl]propanamide; 2- [4-(3 - {2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamido}prop- 1 -yn- l-yl)-lH-pyrazol- 1 -yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamido}prop-l-yn-l-yl)-lH-pyrazol-l-yl]propanamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l -methyl- IH-imidazol -4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide; N-{3-[2-(aminomethyl)-l,3-thiazol-4-yl]prop-2-yn-l-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide; N-{3-[2-(aminomethyl)-l,3-thiazol-4-yl]prop-2-yn-l-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide; N-{3-[2-(aminomethyl)-l,3-thiazol-4-yl]prop-2-yn-l-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide; ethyl (1 S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]cyclopropane-l-carboxylate; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[cz5-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-[c7.s-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl [acetamide; 2- [2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-{3-[cz'5-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[cz -2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-fluorophenyl)-N-{3-[cz -2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3 -yl } -2- [3, 5 -bi s(trifluoromethyl)pyridin-2-yl] -N- { 3 - [cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl} acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-(2-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]-N-(2-phenylcyclopropyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide; N-[3-(5-aminopyrazin-2-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-1-yl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyridazin-3-yl)prop-2-yn-1-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-N-{bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-N-{bicyclo[3.1.0]hexan-6-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide; N-[3-(6- aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(6-m ethoxypyri din-3 -yl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-[3-(oxetan-3-yl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(l-methyl-lH-pyrazol-4-yl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(thiophen-3-yl)acetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[l-(4-methylbenzenesulfonyl)-6-oxo-l,6-dihydropyridin-2-yl]prop-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyrimidin-5-yl)prop-2-yn-1-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methoxypyridin-4-yl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-[3-(oxetan-3-yl)phenyl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(2-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(3-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn- 1 -yl]acetamide; N-[3 -(3 -amino- 1 -methyl- lH-pyrazol-5-yl)prop-2-yn- 1 -y 1] -2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyridazin-4-yl)prop-2-yn-1-yl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(2-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3,4-difluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide; N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]acetamide; N-[3-(6-aminopyridazin-3 -yl)prop-2-yn- 1 -yl] -2- [3, 5 -bi s(trifluoromethyl)pyridin-2-yl] -N- [3 - (difluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-{1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl}acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2,3-difluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3,3-difluorocyclopentyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2-bromo-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-hydroxybut-2-yn-l-yl)-N-(3-methylphenyl)acetamide; N-(4-aminobut-2-yn-l-yl)-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-acetamidobut-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{4-[(5-methyl-l,3,4-oxadiazol-2-yl)formamido]but-2-yn-l-yl}-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-{4-[(pyridin-3-yl)formamido]but-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(6-oxo-l,6-dihydropyridin-2-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(l-hydroxycyclobutyl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-l,l-dioxo-1^6-thian-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l,3-dihydroxycyclobutyl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[4-(morpholin-4-yl)but-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[4-(l,l-dioxo-1^6-thiomorpholin-4-yl)but-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[4-(2-oxopyrrolidin-l-yl)but-2-yn-l-yl]acetamide; N-(4-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}but-2-yn-1-yl)prop-2-enamide; l-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-3-[2,6-dimethyl-4-(trifluoromethyl)phenyl]-l-(4-fluorophenyl)urea; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl] -2- [2-bromo-4-(trifluoromethyl)phenyl] -N-(4-fluorophenyl)acetamide; 2- [3, 5 -bis(trifluoromethyl)pyridin-2-yl]-N-[3-(l-hydroxycyclobutyl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxyoxetan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-hydroxy-4-methylpent-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[2,4- bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxyoxolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxyoxetan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-{4-[(pyridin-2-yl)formamido]but-2-yn-l-yl}acetamide; tert-butyl 4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-4-hydroxypiperidine-1 -carboxylate; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(6-m ethoxypyri din-3 -yl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(4-hydroxy-4-methylpent-2-yn-l-yl)-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxyoxolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxythiolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn- l-yl}-N-(6-methoxypyri din-3 -yl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxy-1,1-dioxo-1λ6-thiolan-3-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(6-methoxypyri din-3 -yl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-{l-methyl-lH-pyrrolo[2,3-b]pyridin-6-yl} acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)but-2-yn-1-yl]-N-(3-methylphenyl)acetamide; ethyl N-(4-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}but-2-yn-l-yl)carbamate; 2-[2-acetyl-4-(trifluoromethyl)phenyl]-N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide; 2-[2-acetyl-4-(trifluoromethyl)phenyl]-N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-methyl-4-(trifluoromethyl)phenyl]acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn- 1 -yl]-N-(4-fluorophenyl)-2-[2-methyl-4-(trifluoromethyl)phenyl]acetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[6- (dimethylphosphoryl)pyridin-3-yl]prop-2-yn-l-yl} acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(3-hydroxycyclobut-l-en-l-yl)prop-2-yn-l-yl]acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-l-methylpiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-1-methyl-1-oxo-1λ5-phosphinan-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-1-methyl-1-oxo-1λ5-phosphinan-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide;

[0157] (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxylic acid;

[0158] (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(lS,2R)-2-(4-methyl-4-oxo- 1,4^ 5-azaphosphinane- 1 -carbonyl)cyclopropyl]prop-2-yn- 1 -yl } acetamide; (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]-N-[2-(dimethylamino)ethyl]cyclopropane-1-carboxamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(1S,2R)-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}-N-(6-methoxypyridin-3-yl)acetamide; N-[3-(1-acetyl-4-hydroxypiperidin-4-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-[4-(morpholin-4-yl)but-2-yn-l-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-(2,4-dimethylphenyl)-N-(4-fluorophenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-{4-[(pyridin-3-yl)formamido]but-2-yn-l-yl}acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]- N-(3-methylphenyl)-N-{4-[(pyridin-2-yl)formamido]but-2-yn-l-yl}acetamide; N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1H-indazol-4-yl)prop-2-yn-1-yl]acetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(dimethylphosphoryl)pyrimidin-5-yl]prop-2-yn-l-yljacetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-{4-[imino(methyl)oxo-^6-sulfanyl]phenyl}prop-2-yn-l-yl)acetamide; 2-[3,5- bis(trifluoromethyl)pyridin-2-yl]-N-[3-(4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-[4-(2-oxopyrrolidin- 1 -yl)but-2-yn- 1 -yl]acetamide; N-[3 -(6-aminopyridazin-3 -yl)prop-2-yn- 1 -yl]-2-[2-chloro-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-(4-bromo-2-methoxyphenyl)-N-(4-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-l-oxo-3H-1^6,2-benzothiazol-6-yl)prop-2-yn-l-yl]acetamide; N-(4-{2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamido}but-2-yn-l-yl)prop-2-enamide; tert-butyl 4-(3-{2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-4-hydroxypiperidine-1 -carboxylate; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxythiolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[4-bromo-2-(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide; N-[3-(l-acetyl-4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(lS,2R)-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-{ l-methyl-lH-pyrrolo[2,3-b]pyridin-6-yl}acetamide; tert-butyl (2-((6-(3-(N- (bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn- 1-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate; N-(3-(6-(2-aminoacetamido)pyridazin-3-yl)prop-2-yn-l-yl)-N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamide; tert-butyl (2-((6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate; (1S,2R)-2-(3-(N-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop-1-yn-1-yl)cyclopropane-1-carboxylic acid; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dichlorophenyl)-N-(3-(4-hydroxy-1-methylpiperidin-4-yl)prop-2-yn-1-yl)acetamide; N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-((lR,2S)- 2-(4-(S-methylsulfonimidoyl)piperidine- 1 -carbonyl)cyclopropyl)prop-2-yn- 1 -yl)acetamide; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(4-bromophenyl)prop-2-yn-l-yl)-N-(6-m ethoxypyri din-3 -yl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-N-(4-fluorophenyl)-2-(4-(trifluoromethyl)-2-vinylphenyl)acetamide; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3 -(4-hydroxy- 1 -methylpiperidin-4-yl)prop-2-yn- 1 -yl)- N-(m-tolyl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(4-methyl-2-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide; 2,6-dimethyl-4-(trifluoromethyl)phenyl (3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)(m-tolyl)carbamate; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(2-(dimethylphosphoryl)pyrimidin-5-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide l)acetamido)prop-l-yn-l-yl)cyclopropane-l -carboxylic acid; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(dimethylphosphoryl)pyridin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(S-methylsulfonimidoyl)pyridin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; 2,6-dimethyl-4-(trifluoromethyl)phenyl (3 -(4-(dimethylphosphoryl)phenyl)prop-2-yn- 1 -yl)(m-tolyl)carbamate; N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(but-3-yn-l-yl)acetamide; N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(2-chloro-4-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide; (lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3 -yl)-2-(3, 5 -bi s(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)-N-((5 -oxopyrrolidin-3-yl)methyl)cyclopropane-l -carboxamide; diethyl (3-((l S,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop-1 -yn- 1 -yl)cyclopropane- 1 -carboxamido)propyl)phosphonate; ( 1 S,2S)-2-(3 -(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop-l-yn-l-yl)-N-(((R)-morpholin-2-yl)methyl)cyclopropane-l -carboxamide; dimethyl (5-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)pyridin-2-yl)phosphonate; and 2-(2-acetyl-4-(trifluoromethyl)phenyl)-N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; or a pharmaceutically acceptable salt thereof.

[0159] In another aspect, the invention is a pharmaceutical composition comprising the compound of any one of of the preceding aspects, and a pharmaceutically acceptable excipient, diluent, or carrier. In one aspect, the invention is a composition comprising: a PolΘ (PolQ) inhibitor of

[0160]

[0161] (Formula I), or a pharmaceutically acceptable salt thereof, wherein: B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1; D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3; each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl; each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or Ci-C4 haloalkyl; each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, -C(O)N(R4)2, Co-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, C1-4 alkyl, S(O)(NH)(Ci-4 alkyl); R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6; R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl; R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8; R8is C1-C4 alkyl, or 5-membered heterocyclyl; X is N or CH; Y is O, NH, or S; Z is O, S, NR5or CHR5; n is 2-3; m is 1-3; and wherein the compound is not

[0162]

[0163] ; and a

[0164] :_RS3

[0165] 'RS4

[0166] DNAPK inhibitor of Formula (

[0167]

[0168] SI): (SI), or a pharmaceutically acceptable salt thereof, wherein: Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5; RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6; RS2is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2; RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylaryl, and aryl; each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; or two geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-C6alkoxy, Ci-C6haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; each RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; and n is an integer from 1 to 3 In another aspect, the invention is a composition of the preceding aspect, wherein a DNAPK inhibitor of Formula (SI) is selected from the group consisting of:

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] In another aspect, the invention is a a pharmaceutical composition comprising the compound of any one of preceding aspects, and a pharmaceutically acceptable excipient, diluent, or carrier.

[0180] In one aspect, the invention is a composition comprising: a PolΘ (PolQ) inhibitor of

[0181] B J

[0182] D

[0183]

[0184] ,2:

[0185] formula (I):n(Formula I), or a pharmaceutically acceptable salt thereof, wherein: B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1; D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3; each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl; each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or Ci-C4 haloalkyl; each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, -C(O)N(R4)2, Co-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(Ci-4 alkyl); R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6; R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl; R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8; R8is C1-C4 alkyl, or 5-membered heterocyclyl; X is N or CH; Y is O, NH, or S; Z is O, S, NR5or CHR5;

[0186] n is 2-3; m is 1-3; and wherein the compound is not

[0187]

[0188] and a R1B

[0189] HhT

[0190] DNAPK inhibitor of Formula (SI)

[0191]

[0192] (SI), (BI), or a pharmaceutically acceptable salt thereof, wherein: ASis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B; R1Sis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5S; R2Sis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4 alkyl, C1-C4 alkyl, Ci- C4 alkoxy, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, or C(0)NH2; R3Bis selected from the group consisting of H, F, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and C1-C4 alkyl; each R4Sis independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, C1-C4 alkoxy, CD3, CD2CD3, and Ci-Ce haloalkyl; or two geminal R4Stogether with the intervening geminal carbon atom, form a C3-C6 cycloalkyl; each R5Sis independently selected from the group consisting of halogen, NH2, OH, -CN, C(O)NH2, C(O)NHR7S, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6S; each R6Sis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; each R7Sis independently selected from H and C1-C4 alkyl; each nSis independently an integer from 0-4; rSis an integer from 0 to 2; sSis an integer from 0 to 2; and tSis an integer from 1 to 2.

[0193] In another aspect, the invention is the composition according to any of the preceding aspects, wherein a DNAPK inhibitor of Formula (SI)I) is selected from the group consisting

[0194]

[0195]

[0196] OH

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] acceptable salt thereof.

[0203] In one aspect, the invention is a pharmaceutical composition comprising the compound of any of the preceding aspects, and a pharmaceutically acceptable excipient, diluent, or carrier.

[0204] In one aspect, the invention is a composition according to any one of the preceding aspects further comprising a DNA cutting agent;

[0205] In one aspect, the invention is a composition according to any one of the preceding aspects, further comprising a cell.

[0206] In one aspect, the invention is a composition according to any one of the preceding aspects further comprising a donor DNA.

[0207] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the composition is about 10 pM or less and the concentration of the POLQi Compound II in the composition is about 15 pM or less.

[0208] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the composition is from about 0.05-10 pM and the concentration of the POLQi Compound II in the composition is about 15 pM or less.

[0209] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the composition is from about 0.05-5 pM and the concentration of the POLQi Compound II in the composition is about 15 pM or less.

[0210] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is a eukaryotic cell.

[0211] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is useful in adoptive cell therapy (ACT).

[0212] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is a stem cell.

[0213] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the stem cell is a hematopoietic stem cell (HSC) or an induced pluripotent stem cell (iPSC).

[0214] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is an immune cell.

[0215] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the immune cell is a leukocyte or a lymphocyte.

[0216] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the immune cell is a lymphocyte.

[0217] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is a T cell, a B cell, or an NK cell.

[0218] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is a T cell.

[0219] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein T cell is a primary T cell. In one aspect, the invention is a composition according to any one of the preceding aspects, wherein T cell is a regulatory T cell.

[0220] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is an activated T cell.

[0221] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the lymphocyte is a non-activated T cell.

[0222] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is a human cell.

[0223] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent comprises a CRISPR / Cas nuclease component and optionally a guide RNA component.

[0224] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent comprises a CRISPR / Cas nuclease that generates a double strand DNA break or single strand DNA break.

[0225] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof.

[0226] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the DNA cutting agent is a CRISPR / Cas nuclease component and a guide RNA component.

[0227] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease.

[0228] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises the Cas nuclease.

[0229] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type II Cas nuclease. In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Cas9 nuclease.

[0230] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a S. pyogenes Cas9 nuclease.

[0231] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type V Cas nuclease.

[0232] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Casl2a nuclease.

[0233] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease is a Acidaminococcus sp. Casl2a nuclease.

[0234] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the Cas nuclease generates a single strand DNA break.

[0235] In one aspect, the invention is a composition according to any one of the preceding aspects, comprising a modified RNA.

[0236] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA component is a guide RNA nucleic acid.

[0237] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA nucleic acid is a guide RNA (gRNA).

[0238] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA) composed of a crRNA and tracrRNA.

[0239] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a single-guide (sgRNA).

[0240] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the gRNA is a modified gRNA. In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cutting agent is Cas9 and the modified gRNA comprises a modification at one or more of the first five nucleotides at the 5’ end.

[0241] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cutting agent is Casl2a and the modified gRNA comprises a DNA / RNA hybrid molecule.

[0242] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.

[0243] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the composition comprises a guide RNA nucleic acid and a Class 2, Type II or Class 2, Type V Cas nuclease; and the molar ratio of the guide RNA to Cas nuclease is from about 4: 1 to 1:4.

[0244] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA.

[0245] In one aspect, the invention is a composition according to any one of the preceding aspects further comprising a vector.

[0246] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector encodes the donor DNA.

[0247] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector is a viral vector.

[0248] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector is a non- viral vector.

[0249] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the vector is an AAV.

[0250] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the cell is not a cancer cell. In another aspect, the invention is a method of targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi Compound I, and a DNA-PKI, wherein the POLQi and DNA-PKI is a compound according to any one of the preceding aspects.

[0251] In one aspect, the invention is a method according to any one of the preceding aspects, comprising growing the cell in a cell medium free of the DNA-PKI and POLQi Compound I, and adding the DNA-PKI POLQi Compound I, to the cell medium.

[0252] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA cutting agent before contacting the cell with the DNA-PKI and POLQi Compound I.

[0253] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA-PKI within about six hours of contacting the cell with the DNA cutting agent.

[0254] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA-PKI and POLQi Compound I within about three hours of contacting the cell with the DNA cutting agent.

[0255] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA cutting agent simultaneously with the DNA-PKI and POLQi Compound I.

[0256] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with the DNA cutting agent after contacting the cell with the DNA-PKI and POLQi Compound I.

[0257] In one aspect, the invention is a method according to any one of the preceding aspects, wherein contacting the cell with the DNA cutting agent comprises electroporation.

[0258] In one aspect, the invention is a method according to any one of the preceding aspect,, comprising contacting the cell with the DNA cutting agent within about three hours of contacting the cell with the DNA-PKI and POLQi Compound I. In one aspect, the invention is a method according to any one of the preceding aspects, comprising growing the cell in a cell medium comprising the DNA-PKI and POLQi Compound I.

[0259] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA cutting agent and the DNA-PKI and POLQi Compound I for at least about one day.

[0260] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA cutting agent and the DNA-PKI and POLQi Compound I for about one day to about two weeks.

[0261] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA cutting agent and the DNA-PKI and POLQi Compound I for about two weeks.

[0262] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA-PKI in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is about 10 pM or less and the concentration of the POLQi Compound I in the cell medium is about 15 pM or less.

[0263] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is contacted with the DNA-PKI in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is from about 0.05-10 pM and the concentration of the POLQi Compound I in the cell medium is about 15 pM or less.

[0264] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the concentration of the DNA-PKI in the cell medium is from about 0.025-5 pM and the concentration of the POLQi Compound I in the cell medium is about 15 pM or less.

[0265] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is a eukaryotic cell.

[0266] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is for use in adoptive cell therapy (ACT). In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is for use in autologous cell therapy.

[0267] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is for use in allogeneic cell therapy.

[0268] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is a stem cell.

[0269] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the stem cell is a hematopoietic stem cell (HSC).

[0270] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is an induced pluripotent stem cell (iPSC).

[0271] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is an immune cell.

[0272] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the immune cell is a leukocyte or a lymphocyte.

[0273] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the immune cell is a lymphocyte.

[0274] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is a T cell, a B cell, or an NK cell.

[0275] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is a T cell.

[0276] In one aspect, the invention is a method according to any one of the preceding aspects, wherein T cell is a primary T cell.

[0277] In one aspect, the invention is a method according to any one of the preceding aspects, wherein T cell is a regulatory T cell.

[0278] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is an activated T cell. In one aspect, the invention is a method according to any one of the preceding aspects, wherein the lymphocyte is a non-activated T cell.

[0279] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the cell is a human cell.

[0280] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof.

[0281] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent is a CRISPR / Cas nuclease component.

[0282] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease.

[0283] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the CRISPR / Cas nuclease component comprises an mRNA encoding the Cas nuclease.

[0284] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type II Cas nuclease.

[0285] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Class 2, Type V Cas nuclease.

[0286] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Cas9 nuclease.

[0287] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a S. pyogenes Cas9 nuclease.

[0288] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the Cas nuclease is a Casl2a nuclease. In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a modified RNA.

[0289] In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a guide RNA nucleic acid.

[0290] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the guide RNA nucleic acid is a gRNA.

[0291] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA).

[0292] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the guide RNA nucleic acid is or encodes a single-guide (sgRNA).

[0293] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the gRNA is a modified gRNA.

[0294] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the modified gRNA comprises a modification at one or more of the first five nucleotides at the 5’ end.

[0295] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.

[0296] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent is a Class 2, Type II Cas nuclease or Class 2, Type V Cas nuclease mRNA; and the ratio of the guide RNA nucleic acid to Cas nuclease is from about 4: 1 to 1:4 by molar ratio.

[0297] In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a donor DNA.

[0298] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with a vector comprising the donor DNA. In one aspect, the invention is a method according to any one of the preceding aspects, wherein the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA.

[0299] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the template sequence is integrated into the genome of the cell via homology directed repair (HDR).

[0300] In one aspect, the invention is a method according to any one of the preceding aspects, further comprising contacting the cell with a vector.

[0301] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector encodes the DNA cutting agent.

[0302] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector encodes a donor DNA.

[0303] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector is a viral vector.

[0304] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector is a non- viral vector.

[0305] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the vector is an AAV.

[0306] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent interacts with a target sequence within the genome of the cell, resulting in a double stranded DNA break (DSB).

[0307] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the method results in a gene knockout.

[0308] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the method results in a gene correction.

[0309] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the method results in a gene insertion. In one aspect, the invention is a method according to any one of the preceding aspects, wherein the donor DNA comprises a template comprising an exogenous nucleic acid encoding a protein.

[0310] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the protein is selected from the group consisting of a cytokine, an immunosuppressor, an antibody, a receptor, and an enzyme.

[0311] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the protein is a receptor.

[0312] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is selected from the group consisting of an immunological receptor, a T-cell receptor (TCR), and a chimeric antigen receptor.

[0313] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is an immunological receptor.

[0314] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is a TCR.

[0315] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the exogenous nucleic acid encodes a TCR alpha chain and / or a TCR beta chain.

[0316] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor a chimeric antigen receptor.

[0317] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent interacts with a target sequence within the TRAC gene of the T-cell.

[0318] In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with at least two different DNA cutting agents that target different loci. In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the template comprises a first homology arm and a second homology arm that are complementary to sequences located upstream and downstream.

[0319] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0320] Compounds of the present disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs thereof may exist in their tautomeric forms (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0321] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the protein is a receptor.

[0322] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is selected from the group consisting of an immunological receptor, a T-cell receptor (TCR), and a chimeric antigen receptor.

[0323] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is an immunological receptor.

[0324] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor is a TCR.

[0325] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the exogenous nucleic acid encodes a TCR alpha chain and / or a TCR beta chain.

[0326] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the receptor a chimeric antigen receptor.

[0327] In one aspect, the invention is a method according to any one of the preceding aspects, wherein the DNA cutting agent interacts with a target sequence within the TRAC gene of the T-cell. In one aspect, the invention is a method according to any one of the preceding aspects, comprising contacting the cell with at least two different DNA cutting agents that target different loci.

[0328] In one aspect, the invention is a composition according to any one of the preceding aspects, wherein the template comprises a first homology arm and a second homology arm that are complementary to sequences located upstream and downstream.

[0329] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0330] The compounds of the present disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0331] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this present disclosure. Enantiomers can also be separated by use of a chiral HPLC column.

[0332] It is also possible that the compounds of the present disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure.

[0333] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this present disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and transforms, as well as mixtures, are embraced within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present disclosure). Individual stereoisomers of the compounds of the present disclosure may, for example, be substantially free of other stereoisomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

[0334] The compounds of Formula I may form salts which are also within the scope of this present disclosure. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0335] The present disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0336] Method of Synthesizing the Compounds

[0337] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’ s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognised reference textbooks of organic synthesis known to those in the art.

[0338] During the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P. G M., Protective Groups in Organic Synthesis, 3rd edition. John Wiley & Sons. New York, 1999.

[0339] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0340] In the synthetic schemes described herein, compounds may be drawn with one

[0341] particular configuration for simplicity. Such particular configurations are not to be construed

[0342] as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer,

[0343] nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers, however,

[0344] it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a

[0345] higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0346] POLQ INHIBITORS

[0347] Methods include but are not limited to those methods described below. Compounds of the present disclosure can be synthesized by following the steps outlined in Schemes G1-G4, which comprise different sequences of assembling intermediates or compounds. Starting

[0348] materials are either commercially available or made by known procedures in the reported

[0349] literature or as illustrated below.

[0350] Scheme G1 for the syntheses of compounds of Formula la-1 — 6

[0351]

[0352] Formula I

[0353] The amine Gl-2 can be formed by displacement reactions of amine Gl-1 with 3-chloroprop-l-yne or 3 -bromoprop- 1-yne in the presence a base such as DIPEA, EtsN,

[0354] CS2CO3, or K2CO3 via nucleophilic substitution. The amide core Gl-4 can be formed by

[0355] amide formation from the acid Gl-2 and the amine Gl-2 with a coupling agent, e.g. HATU or T3P in the presence of a base such as DIEA or pyridine. Installation of the D portion of the molecule using either I-D or Br-D, can be performed under suitable C-C coupling conditions using a catalyst system such as bis(triphenylphosphine)palladium(II) dichloride and copper (I) iodide on the terminal alkyne core Gl-4 to synthesize the final product with general formula of Formula I (Scheme Gl).

[0356] Compositions Comprising Compounds of the Disclosure

[0357] Another aspect of the present disclosure relates to compositions comprising a (a) a DNA Polymerase theta (PolQ) inhibitor Compound I (b) a DNA protein kinase inhibitor (DNA-PKI) of formula (SI) or (BI) and (c) a DNA cutting agent, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. In some embodiments, the composition further comprises a cell. In some embodiments, the composition further comprises a donor DNA. In some embodiments, the composition further comprises a cell and a donor DNA.

[0358] In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is useful in adoptive cell therapy (ACT). In some embodiments, the cell is a stem cell. In some embodiments, the cell is a hematopoietic stem cell (HSC) or an induced pluripotent stem cell (iPSC). In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a leukocyte, or a lymphocyte (e.g., a T cell, a B cell, or an NK cell). In some embodiments, the immune cell is a lymphocyte. In some embodiments, the lymphocyte is a T cell. In some embedments, the lymphocyte is a primary T cell. In some embodiments, the lymphocyte is a regulatory T cell. In some embodiments, the lymphocyte is an activated T cell. In some embodiments, the lymphocyte is a non-activated T cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is not a cancer cell.

[0359] In some embodiments, the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA.

[0360] In some embodiments, the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof.

[0361] In some embodiments, the DNA cutting agent comprises a CRISPR / Cas nuclease component and optionally a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a double strand DNA break or single strand DNA break. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a single strand DNA break.

[0362] In some embodiments, the DNA cutting agent is a CRISPR / Cas nuclease component and a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the Cas nuclease is a Class 2, Type II Cas nuclease. In some embodiments, the Cas nuclease is a Cas9 nuclease (e.g., a S. pyogenes Cas9 nuclease). In some embodiments, the Cas nuclease is a Class 2, Type V Cas nuclease. In some embodiments, the Cas nuclease is a Casl2a nuclease (e.g., a Acidaminococcus sp. Casl2a nuclease).

[0363] In some embodiments, the composition comprises a modified RNA.

[0364] In some embodiments, the guide RNA component is a guide RNA nucleic acid. In some embodiments, the guide RNA component is a guide RNA (gRNA). In some embodiments, the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA). In some embodiments, the dual-guide RNA is composed of a crRNA and tracrRNA. In some embodiments, the guide RNA nucleic acid is or encodes a single-guide (sgRNA). In some embodiments, the gRNA is a modified gRNA.

[0365] In some embodiments, the DNA cutting agent is Cas9 or an mRNA encoding Cas9, and a modified gRNA comprising a modification at one or more of the first five nucleotides at the 5’ end. In some embodiments, the cutting agent is Casl2a or an mRNA encoding Casl2a, and a modified gRNA comprising a DNA / RNA hybrid molecule. In some embodiments, the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.

[0366] In some embodiments, the DNA cutting agent is a Class 2, Type II or Class 2, Type V Cas nuclease and a guide RNA nucleic acid; and the molar ratio of the guide RNA to Cas nuclease is from about 4:1 to 1:4.

[0367] In some embodiments, the composition further comprises a vector. In some embodiments, the vector encodes the donor DNA. In some embodiments, the vector is a viral vector (e.g., an AAV). In some embodiments, the vector is a non-viral vector. In some embodiments, the vector is a non-viral vector comprising donor DNA having a linear, close end, circular, single strand, double strand format. In some embodiments, the composition further comprises a vector. In some embodiments, the vector encodes the donor DNA. In some embodiments, the vector is a viral vector (e.g., an AAV). In some embodiments, the vector is a non-viral vector. In some embodiments, the vector is a non-viral vector comprising donor DNA having a linear, close end, circular, single strand, double strand format.

[0368] In some embodiments, the concentration of the DNA-PKI in the composition is about 10 μM or less and the concentration of the POLQi compound of Formula II is about 20 μM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.1 μM to about 10 μM and the concentration of the POLQi compound of Formula II is about 15 μM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.25 μM to about 5 μM and the concentration of the POLQi compound of Formula II is about 15 μM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.25 μM to about 10 μM and the concentration of the POLQi compound of Formula II is about 15 μM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.1 μM to about 5 μM and the concentration of the POLQi compound of Formula II is about 15 μM or less. In some embodiments, the concentration of the DNA-PKI in the composition is from about 0.1 μM to about 2.5 μM and the concentration of the POLQi compound of Formula II is about 15 μM or less.

[0369] Methods of Using the Disclosed Compounds

[0370] Another aspect of the present disclosure is directed to a method for targeted genome editing in a cell, comprising contacting the cell with a DNA cutting agent, a POLQi Compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0371] Another aspect of the present disclosure is directed to a method for repairing a double stranded DNA break in the genome of a cell, comprising contacting the cell with a DNA cutting agent, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the double stranded DNA break is a blunt end break. In some embodiments, the double stranded DNA break comprises paired single strand breaks (e.g., made by a combination of nickase nucleases).

[0372] Another aspect of the present disclosure is directed to a method for simultaneously inhibiting or suppressing repair of a DNA break in a cell via both nonhomologous end joining (NHEJ) pathway and Microhomology Mediated End-Joining (MMEJ) pathway, comprising contacting the cell with a DNA cutting agent, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof and POLQi compound of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0373] Another aspect of the present disclosure is directed to a method for targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi compound of Formula I, and a DNA-PKI, wherein the DNA-PKI is a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0374] In some embodiments of the methods disclosed herein, the method comprises growing the cell in a cell medium free of the DNA-PKI and a POLQi compound of Formula I, and adding the DNA-PKI and POLQi compound of Formula I to the cell medium.

[0375] In some embodiments of the methods disclosed herein, the method comprises contacting the cell with the DNA cutting agent before contacting the cell with the DNA-PKI and a POLQi compound of Formula I. In some embodiments, the method comprises contacting the cell with the DNA-PKI and a POLQi compound of Formula I within about six hours of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I within about three hours of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I within about two hours of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I between about 15 minutes and about 45 minutes of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA-PKI and a POLQi compound of Formula I about 30 minutes of contacting the cell with the DNA cutting agent. In some embodiments, the methods comprise contacting the cell with the DNA cutting agent simultaneously with the DNA-PKI and a POLQi compound of Formula I. In some embodiments of the methods disclosed herein, the method comprises growing the cell in a cell medium comprising the DNA-PKI and a POLQi compound of Formula I.

[0376] In some embodiments, the methods comprise contacting the cell with the DNA cutting agent after contacting the cell with the DNA-PKI and a POLQi compound of Formula I. In some embodiments, the methods comprise contacting the cell with the DNA cutting agent within about three hours of contacting the cell with the DNA-PKI and a POLQi compound of Formula I.

[0377] In some embodiments, contacting the cell with the DNA cutting agent comprises electroporating the cell to allow the DNA cutting agent to enter the cell. In some embodiments, contacting the cell with the DNA cutting agent comprises delivering the DNA cutting agent to the cell using other methods, e.g., microinjection or via a lipid nanoparticle, liposome, exosome, or gold nanoparticle. In some embodiments, the methods comprise contacting the cell with the DNA cutting agent and the donor DNA simultaneously.

[0378] In some embodiments of the methods disclosed herein, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for at least about one day. In some embodiments, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for about one day. In some embodiments, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for between about one day and about two weeks. In some embodiments, the method comprises contacting the cell with the DNA cutting agent and the DNA-PKI and a POLQi compound of Formula I for about two weeks.

[0379] In some embodiments of the methods disclosed herein, the method comprises contacting the cell with the DNA-PKI and POLQi compound of Formula I in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is about 10 pM or less and the concentration of the POLQi compound of Formula I in the cell medium is about 15 pM or less. In some embodiments, the method comprises contacting the cell with the DNA-PKI and POLQi compound of Formula I in a cell medium, wherein the concentration of the DNA-PKI and POLQi compound of Formula I in the cell medium is between about 0.1 pM and about 10 pM the concentration of the POLQi compound of Formula II in the cell medium is about 15 pM or less. In some embodiments, the method comprises contacting the cell with the DNA-PKI and POLQi compound of Formula I in a cell medium, wherein the concentration of the DNA-PKI in the cell medium is between about 0.25 pM and about 5 pM and the concentration of the POLQi compound of Formula I in the cell medium is about 15 pM or less.

[0380] In some embodiments of the methods disclosed herein, the cell is a eukaryotic cell. In some embodiments, the cell is for use in adoptive cell therapy (ACT). In some embodiments, the cell is for use in autologous cell therapy. In some embodiments, the cell is for use in allogenic cell therapy. In some embodiments, the cell is a stem cell. In some embodiments, the cell is a hematopoietic stem cell (HSC) or an induced pluripotent stem cell (iPSC). In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is a leukocyte, or a lymphocyte (e.g., a T cell, a B cell, or an NK cell). In some embodiments, the immune cell is a lymphocyte. In some embodiments, the lymphocyte is a T cell. In some embedments, the lymphocyte is a primary T cell. In some embodiments, the lymphocyte is a regulatory T cell. In some embodiments, the lymphocyte is an activated T cell. In some embodiments, the lymphocyte is a non-activated T cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is not a cancer cell.

[0381] In some embodiments of the methods disclosed herein, the DNA cutting agent is selected from a zinc finger nuclease, a TALE effector domain nuclease (TALEN), a CRISPR / Cas nuclease component, and combinations thereof.

[0382] In some embodiments of the methods disclosed herein, the DNA cutting agent comprises a CRISPR / Cas nuclease component and optionally a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a double strand DNA break or single strand DNA break. In some embodiments, the CRISPR / Cas nuclease component comprises or encodes a CRISPR / Cas nuclease that generates a single strand DNA break.

[0383] In some embodiments of the methods disclosed herein, the DNA cutting agent is a CRISPR / Cas nuclease component and a guide RNA component. In some embodiments, the CRISPR / Cas nuclease component comprises a Cas nuclease or an mRNA encoding the Cas nuclease. In some embodiments, the Cas nuclease is a Class 2, Type II Cas nuclease. In some embodiments, the Cas nuclease is a Cas9 nuclease (e.g., a S. pyogenes Cas9 nuclease). In some embodiments, the Cas nuclease is a Class 2, Type V Cas nuclease. In some embodiments, the Cas nuclease is a Casl2a nuclease (e.g., a Acidaminococcus sp. Casl2a nuclease).

[0384] In some embodiments of the methods disclosed herein, the methods further comprise contacting the cell with a modified RNA.

[0385] In some embodiments of the methods disclosed herein, the methods further comprise contacting the cell with a guide RNA component. In some embodiments, the guide RNA component is a guide RNA nucleic acid. In some embodiments, the guide RNA component is a guide RNA (gRNA). In some embodiments, the guide RNA nucleic acid is or encodes a dual-guide RNA (dgRNA). In some embodiments, the guide RNA nucleic acid is or encodes a single-guide (sgRNA). In some embodiments, the gRNA is a modified gRNA.

[0386] In some embodiments of the methods disclosed herein, the DNA cutting agent is Cas9 or an mRNA encoding Cas9, and a modified gRNA comprising a modification at one or more of the first five nucleotides at the 5’ end. In some embodiments, the cutting agent is Casl2a or an mRNA encoding Casl2a, and a modified gRNA comprising a DNA / RNA hybrid molecule. In some embodiments, the modified gRNA comprises a modification at one or more of the last five nucleotides at the 3’ end.

[0387] In some embodiments of the methods disclosed herein, the DNA cutting agent is a Class 2, Type II or Class 2, Type V Cas nuclease and a guide RNA nucleic acid; and the molar ratio of the guide RNA to Cas nuclease is from about 4: 1 to 1:4.

[0388] In some embodiments of the methods disclosed herein, the DNA cutting agent interacts with a target sequence within the TRAC gene of a T cell.

[0389] In some embodiments of the methods disclosed herein, the methods comprise contacting the cell with at least two different DNA cutting agents targeting different loci.

[0390] In some embodiments, the methods comprise contacting the cell with a vector encoding the DNA cutting agent. In some embodiments, the vector encodes the DNA cutting agent and the donor DNA. In some embodiments, the methods comprise contacting the cell with a vector encoding the DNA cutting agent, and a second vector encoding the donor DNA. In some embodiments, the vector is a viral vector (e.g., an AAV). In some embodiments, the vector is a non-viral vector. In some embodiments, the vector is a non-viral vector comprising donor DNA having a linear, close end, circular, single strand, double strand format.

[0391] In some embodiments of the methods disclosed herein, the DNA cutting agent interacts with a target sequence within the genome of the cell, resulting in a double stranded DNA break (DSB).

[0392] In some embodiments of the methods disclosed herein, the methods further comprise contacting the cell with a donor DNA. In some embodiments, the methods comprise contacting the cell with a vector comprising the donor DNA. In some embodiments, the vector encodes the donor DNA. In some embodiments, the donor DNA comprises a template comprising a sequence encoding a protein, a regulatory sequence, or a sequence encoding structural RNA. In some embodiments, the donor DNA comprises a template comprising an exogenous nucleic acid encoding a protein. In some embodiments, the protein is selected from a cytokine, an immunosuppressor, an antibody, a receptor, and an enzyme. In some embodiments, the protein is a receptor. In some embodiments, the receptor is selected from an immunological receptor, a T-cell receptor (TCR), and a chimeric antigen receptor. In some embodiments, the exogenous nucleic acid encodes a TCR chain of a TCR, e.g. a TCR alpha, beta, delta, or gamma chain, or any combination thereof. In some embodiments, the exogenous nucleic acid encodes a TCR alpha and / or TCR beta chain. In some embodiments, the template comprises a first homology arm and a second homology arm that are complementary to sequences located upstream and downstream of the cleavage site, respectively.

[0393] In some embodiments of the methods disclosed herein, the method results in a gene knockout. In some embodiments of the methods disclosed herein, the method results in a gene correction. In some embodiments of the methods disclosed herein, the method results in a gene insertion.

[0394] Another aspect of the present disclosure relates to the use of Compound I in combination with a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or pharmaceutical composition thereof, in the treatment of a cell.

[0395] In one embodiment, the subject is a mammal. In one embodiment, the mammal is a human.

[0396] Administration of the disclosed compounds may also be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0397] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[0398] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0399] The disclosed compounds may be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0400] The disclosed compounds may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U. S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.

[0401] Disclosed compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

[0402] Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of Formula (SI) of (BI), Compound I, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.

[0403] In one embodiment, the pharmaceutical acceptable carrier further comprises an excipient, diluent, surfactant, or any combination thereof.

[0404] In one embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent.

[0405] Another aspect of the present disclosure is directed to pharmaceutical compositions for use in cell therapy comprising Compound I and a compound of Formula (SI) or (BI), or a pharmaceutically acceptable salt thereof.

[0406] EXAMPLES

[0407] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0408] The compounds of the present disclosure may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds with specific details provided below in the experimental section to illustrate working examples.

[0409] All variable groups of these methods are as described in the generic description if they are not specifically defined below.

[0410] It is recognized that compounds of the disclosure with each claimed optional functional group may not be prepared by each of the below-listed methods. Within the scope of each method, optional substituents may appear on reagents or intermediates which may act as protecting or otherwise non-participating groups. Utilizing methods well known to those skilled in the art, these groups are introduced and / or removed during the course of the synthetic schemes which provide the compounds of the present disclosure.

[0411] Acronyms and Abbreviations

[0412] Table 1 provides a list of acronyms and abbreviations used in this specification, along with their meanings.

[0413] Table 1

[0414] ACRONYM OR MEANING OR DEFINITION ABBREVIATION

[0415] Ac Acetyl

[0416] ACN, MeCN Acetonitrile

[0417] Aq. Aqueous

[0418] Boc t-Butyloxycarbonyl

[0419] Brettphos Pd G3 [(2-Di-cyclohexylphosphino-3,6- dimethoxy-2',4',6'- triisopropyl- l,l'-biphenyl)-2- (2'-amino- 1,1' -biphenyl)]palladium(II) methanesulfonate methanesulfonate

[0420] DCM Dichloromethane

[0421] DIPEA, DIEA N, N-diisopropylethylamine, also known as Hunig’s base

[0422] DMA N,N-Dimethylacetamide

[0423] DMAP 4-(Dimethylamino)pyridine

[0424] DMF N,N-Dimethylformamide

[0425] DMSO Dimethyl sulfoxide

[0426] EA, EtOAc Ethyl acetate

[0427] h Hour

[0428] HC1 Hydrochloric acid

[0429] HPLC High pressure liquid chromatography Hunig’s base See DIPEA, DIEA

[0430] LCMS, LC-MS, LC / MS Liquid chromatography-mass spectrometry

[0431] min Minute

[0432]

[0433] MS Mass spectrometry

[0434] MTBE Methyl tert-butyl ether

[0435] NMR Nuclear magnetic resonance

[0436] PE Petroleum ether

[0437] Prep Preparative

[0438] RT (in context of liquid Retention time, in min chromatography)

[0439] rt or RT (in the context of Room (ambient) temperature, circa 25 °C reaction conditions)

[0440] Sat. Saturated

[0441] Soln Solution

[0442] TEA Triethylamine

[0443] TFA Trifluoroacetic acid

[0444] THF Tetrahydrofuran

[0445] TLC Thin layer chromatography

[0446]

[0447] Analytical Procedures

[0448] NMR

[0449] The following conditions were used for obtaining proton nuclear magnetic resonance (NMR) spectra: NMR spectra were taken in either 400 MHz or 500 MHz. Bruker instrument using either DMSO-de or CDCh as solvent and internal standard. The crude NMR data was analyzed by using either ACD Spectrus version 2015-01 by ADC Labs or MestReNova software.

[0450] Chemical shifts are reported in parts per million (ppm) downfield from internal tetramethylsilane (TMS) or from the position of TMS inferred by the deuterated NMR solvent. Apparent multiplicities are reported as: singlet-s, doublet-d, triplet-t, quartet-q, or multiplet-m. Peaks that exhibit broadening are further denoted as br. Integrations are approximate. It should be noted that integration intensities, peak shapes, chemical shifts and coupling constants can be dependent on solvent, concentration, temperature, pH, and other factors. Further, peaks that overlap with or exchange with water or solvent peaks in the NMR spectrum may not provide reliable integration intensities. In some cases, NMR spectra may be obtained using water peak suppression, which may result in overlapping peaks not being visible or having altered shape and / or integration.

[0451] Liquid chromatography

[0452] The following preparative and / or analytical (LC / MS) liquid chro tography methods were used.

[0453] Method A: Column: XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and MS (ESI + / -).

[0454] Method B: Column: XBridge Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: ACN / H2O (5:95) with 0.05 % TFA; Mobile Phase B: ACN / H2O (95:5) with 0.05 % TFA; Temperature: 50CC; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm) and M (ESI + / -).

[0455] Method C: Column: Aquity BEH Cl 8, 2.1 mm x 50 mm, 1.7 pm particles; Mobile Phase A: ACN / H2O (5:95) with 10 mM AA; Mobile Phase B: ACN / H2O (95:5) with 10 mM AA; Temperature: 50 °C; Gradient: 0-100 %B (0.0-3.0 min), 100 %B (3.0-3.5 min); Flow: 1.0 mL / min; Detection: UV (220 nm and 254 nm) and MS (ESI + / -).

[0456] Method D: Column: Kinetex XB- Cl 8 (75x3mm) 2.6 pm; Mobile phase A 0.1% TFA in H2O; Mobile phase B: 0.1% TFA in ACN; Flow Rate:1.0 mL / min; Time (min) / Grad (%B): 0 / 05, 2.5 / 95, 2.51 / 95, 4.5 / 95, 4.51 / 05, 5.5 / 05;

[0457] Method E: Column: Kinetex XB - C18 (75 x 3.0)mm, 2.6pm; Mobile Phase A: 5mm Ammonium formate pH 3.3: ACN (98:02); Mobile Phase B: ACN: Buffer (98:02); Flow: 1.0 mL / min; Time (min)ZGrad (%B): 0 / 20, 4.0 / 100, 4.1 / 100 (1.5 ml / min), 4,6 / 100 (1.5 ml / min), 4.7 / 20, 5.0 / 20

[0458] Analytical HPLC A: Column: Kinetex Biphenyl (100X4.6) mm, 2.6pm, Mobile phase: A: 0.05% TFA in WATER: ACN; Mobile phase: B: 0.05% TFA in ACN:water; Flow: 1.0 mL / min; Time / Gradient (%B): 0 / 10, 9 / 60, 11 / 100, 11.1 / 100 (1.5 mL / min), 12.5 / 100 (1.5 mL / min), 13 / 10, 15 / 10.

[0459] Analytical HPLC B: Column: Kinetex EVO C18 (100x4.6) mm, 2.6 pm, Mobile phase: A: 0.05% TFA in water: ACN (95:5), Mobile phase: B: ACN: 0.05%TFA in water (95:5); Flow: 1.0 mL / min; Time (min) / Grad (%B): 0 / 10, 1 / 30, 9 / 80, 11 / 100, 11.1 / 100 (1.5 mL / min), 12.5 / 100 (1.5 mL / min), 13 / 10, 15 / 10.

[0460]

[0461] Synthesis of 3-Methyl-N-(prop-2-yn-l-yl)aniline (intermediate 1):

[0462]

[0463] To a solution of m-toluidine (800 mg, 7.47 mmol) in DMF (3 mL), cesium carbonate (1216 mg, 3,73 mmol) and 3 -bromoprop- 1-yne (0.390 mL, 3.73 mmol) were added. The reaction mixture was then heated at 60 °C for 5 h. LC / MS shown formation of the mono- and di-alkylated products along with unreacted SM. The reaction mixture was then filtered, and the residue was purified by Prep. HPLC using CHsCN-ftO-ammonium acetate system.

[0464] Fractions of the mono-alkylated product were collected and concentrated with a rotavapor. It was then extracted with ethyl acetate (2 x 25 mL). The organic layers were then combined, dried with MgSCh, filtered and concentrated to give 3-methyl-N-(prop-2-yn-l-yl)aniline as a thick orange oil (377 mg, 2.60 mmol, 69.6 % yield). LCMS: RT:::1.60 min; m / z: 146.0 [M+Hf (Method C). 'HNMR (400 MHz, CHLOROFORM-d) 87.22 - 7.07 (m, 1H), 6.66 (d, J::::7.5 Hz, 1H), 6.61 - 6.48 (m, 2H) 3.97 (d,.7 2.4 Hz, 2H), 2.34 (s, 3H), 2.28 - 2.23 (m, 1H).

[0465] The following intermediates were prepared using the same procedure as that of intermediate 1:

[0466] 2-Methyl-N-(prop-2-yn-l-yl)aniline (intermediate 2):

[0467]

[0468] The titled compound was obtained as a thick orange oil (617 mg, 4.25 mmol, 91 % yield). LCMS: RT = 1.65 min; m / z: 145.9 [M+H]^ (Method C). 'HNMR (400 MHz, CHLOROFORM-d) 57.24 - 7.15 (m, 1H), 7.15 - 7.09 (m, 1H), 6.86 - 6.74 (m, 2H), 4.03 (d, <7=2.4 Hz, 2H), 2.30 - 2.25 (m, 1H), 2.21 (s, 3H).

[0469] 3-FIuoro-N-(prop-2-yn-l-yl)aniline (intermediate 3)

[0470]

[0471] The titled compound was obtained as a thick orange oil (156.9 mg, 1.052 mmol, 46.8 % yield). LCMS: RT = 1.65 min; m / z: 145.9 [M+H]+(Method C).!H NMR (400 MHz, CHLOROFORM-d) 87.21 - 7.13 (m, 1H), 6.54 - 6.46 (m, 2H), 6.46 - 6.39 (m, 1H), 3.95 (d, <7=2.5 Hz, 2H), 2.30 - 2.25 (m, 1H).

[0472] 2-FIuoro-N-(prop-2-yn-l-yI)aniline (intermediate 4)

[0473]

[0474] The titled compound was obtained as a thick orange oil (461 mg, 3.09 mmol, 86 % yield). LCMS: RT = 1.57 min; m / z: 149.9 [M+Hp (Method C).

[0475]

[0476] NMR (400 MHz, CHLOROFORM-d) 87.11 - 6.99 (m, 2H), 6.92 - 6.84 (m, 1H), 6.81 - 6.73 (m, 1H), 4.02 (s, 2H), 2.28 - 2.25 (m, 1H).

[0477] N-(Prop-2-yn-l-yI)bicyclo[4.2.0]octa-l(6),2,4-trien-3-amine (intermediate 5)

[0478] N

[0479]

[0480] The titled compound was obtained as a thick orange oil (125 mg, 0.795 mmol, 30.9 % yield). LCMS: RT = 1.71 min; m / z: 147.9 [M+Hp (Method C).]HNMR (400 MHz, CHLOROFORM-d) 86.91 (d, 7=7.9 Hz, 1H), 6.58 - 6.54 (m, 1H), 6.52 - 6.49 (m, IH), 3.94 (d,,7=2.4 Hz, 2H), 3.15 - 3.10 (m, 4H), 2.26 - 2.21 (m, IH).

[0481] 5-CycIopropyl-2-fluoro-N-(prop-2-yn-l-yl)aniline (intermediate 6)

[0482]

[0483] The titled compound was obtained as a thick orange oil (622 mg, 3.29 mmol, 99 % yield). LCMS: RT = 1.90 min; m / z: 190.0 [M+H];(Method C). 'HNMR (400 MHz, CHLOROFORM-d) 66.91 (dd, 7=11.2, 8.4 Hz, IH), 6.60 (dd, 7=8.2, 2.0 Hz, 1H), 6.52 - 6.44 (m, 1H), 4.01 (d, 7=2.4 Hz, 2H), 2.27 (t, 7=2.5 Hz, 1H), 1.96 - 1.73 (m, 1H), 1.02 - 0.85 (m, 2H), 0.76 - 0.60 (m, 2H).

[0484] 3-(Oxetan-3-yI)-N-(prop-2-yn-l-yl)aniIine (intermediate 7)

[0485] H

[0486]

[0487] The titled compound was obtained as a thick orange oil (118 mg, 0.630 mmol, 75 % yield). LCMS: RT = 1.29 min; m / z: 188.1[M+H] (Method C).rH NMR (400 MHz, CHLOROFORM-d) 87.25 (t,,7=7.8 Hz, IH), 6.88 (d,,7=7.6 Hz, 1H), 6.83 - 6.76 (m, 1H), 6.73 - 6.63 (m, IH), 5.07 (dd, 7 8.4. 6.0 Hz, 2H), 4.85 - 4.77 (m, 2H), 4.25 - 4.16 (m, I H) 4.00 (d, 7=2.4 Hz, 2H), 2.26 (t,,7=2.5 Hz, IH).

[0488] 2-(2,4-Bis(triflnoromethyI)phenyl)-N-(4-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide ( intermediate 8)

[0489]

[0490] To a solution of 4-fluoroaniline (1 g, 9.00 mmol) in DMF (8 mL), sodium hydride (0.378 g, 9.45 mmol) (60% in mineral oil) was added and the reaction mixture was stirred at rt for 30 min. Then the reaction mixture was cooled to 0 °C and 3 -bromoprop- 1 -yne (0.986 mL, 9.45 mmol) was added. It was then warmed to rt and stirred for 1 hr. LC / MS shown formation of the mono- and di-alkylated products. The reaction mixture was then quenched with sat. NaHCCh solution and suction filtered to give yellow solid. The filtrate was extracted with ethyl acetate (2X20mL). The combined organic layers were washed with brine, dried with MgSO4 and and concentrated to give a brownish thick oil as crude product (1.85 g) of 1ststep. LC / MS: contained both mono- and di-alkylated products, the desired mono-alkylated product was -60%.

[0491] To a solution of 2-(2,4-bis(trifluoroniethyl)phenyl)acetic acid (200 mg, 0.735 mmol), the crude product from the 1ststep (219 mg, 1.470 mmol) and pyridine (0.238 mL, 2.94 mmol) in ethyl acetate (2 mL), propylphosphonic anhydride solution (0.875 mL, 1.470 mmol) (50 wt.% in EtOAc) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then quenched by water and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine, dried with MgSO4 and concentrated to give the crude product as a think brownish oil. It was then purified by Prep. HPLC using CHaCN-IEO-ammonium acetate system. Fractions were collected and concentrated under speed-vac for overnight to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide as a light beige solid (230.5 mg, 0.572 mmol, 78 % yield). LCMS: RT = 1.71 min; m / z: 147.9 [M+H]+(Method C).rH NMR (400 MHz, CHLOROFORM-d) 6 7.87 (s, 1H), 7.79 (d,,7=8.1 Hz, 1H), 7.55 (d,,7=8.1 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.24 - 7.13 (m, 2H), 4.51 (d, J=2.4 Hz, 2H), 3.63 (s, 2H), 2.31 - 2.23 (m, 1H).

[0492] 2-(2,4-Bis(trifluoromethyI)phenyl)-N-(prop-2-yn-l-yI)-N-(m-toIyI)acetamide (intermediate 9):

[0493]

[0494] To a solution of 2-(2,4-bis(trifluoromethyl)phenyl)acetic acid (337 mg, 1.240 mmol), 3-methyl-N-(prop-2-yn-l-yl)aniline (180 mg, 1.240 mmol) and pyridine (0.401 mL, 4.96 mmol) in ethyl acetate (3 mL), propylphosphonic anhydride solution (1,476 mL, 2.479 mmol) (50 wt.% in EtOAc) was added and the reaction mixture was then warmed to RT and stirred overnight. The reaction mixture was quenched by water and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine, dried with MgSO-i and concentrated to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(prop-2-yn-l-yl)-N-(m-tolyl)acetamide as a light yellow solid (505 mg, 1.265 mmol, 102 % yield). LCMS: RT::::2.41 min; m / z: 400.0 [M+H]+(Method C). 'HNMR (400 MHz, CHLOROFORM-d) 57.86 (s, 1H), 7.78 (d, 7=8.1 Hz, 1H), 7.55 (d, 7=8.0 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.26 (d, 7=7.7 Hz, 1H), 7.18 - 7.11 (m, 2H), 4.50 (d, 7=2.4 Hz, 2H), 3.66 (s, 2H), 2.42 (s, 3H), 2.27 - 2.22 (m, 1H).

[0495] 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(prop-2-yn-l-yl)-N-(o-tolyl)acetamide (intermediate 10)

[0496]

[0497] The titled compound was obtained as a light orange solid (822 mg, 2.058 mmol, 100 % yield). LCMS: RT = 2.40 min; m / z: 399.9 [M+H]h(Method C). ’H NMR (400 MHz, CHLOROFORM-d) 67.87 (s, 1H), 7.78 (d, 7=8.0 Hz, 1H), 7.54 (d,,7=8.2 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.33 - 7.26 (m, 2H), 4.80 (dd, 7=17.2, 2.5 Hz, 1H), 4.16 (dd, 7=17.1, 2.5 Hz, 1H), 3.65 (d, 7=16.9 Hz, 1H), 3.45 (d, 7=16.8 Hz, 1H), 2.36 (s, 3H), 2.23 (t, 7=2.5 Hz, 1H).

[0498] 2-(2,4-Bis(trifluoromethyI)phenyl)-N-(3-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (intermediate 11)

[0499] F

[0500]

[0501] The titled compound was obtained as a light yellowish solid (298 mg, 0.739 mmol, 73.4 % yield). LCMS: RT = 2.31 min; m / z: 403.7[M+H]+(Method C). ’HNMR (400 MHz, CHLOROFORM-d) 67.88 (s, 1H), 7.80 (d, 7=8.2 Hz, 1H), 7.56 (d, 7=8.1 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.24 - 7.14 (m, 2H), 7.14 - 7.08 (m, 1H), 4.51 (d, 7=2.5 Hz, 2H), 3.67 (s, 2H), 2.33 - 2.23 (m, 1H).

[0502] 2-(2,4-Bis(trifluoromethyI)phenyl)-N-(2-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (intermediate 12)

[0503]

[0504] The titled compound was obtained as a beige solid (728 mg, 1.805 mmol, 100 % yield). LCMS: RT = 2.31 min; m / z: 403.7[M+H]+(Method C). 'HNMR (400 MHz, CHLOROFORM-d) 57.86 (s, 1H), 7.79 (d,.7=8,3 Hz, 1H), 7.56 (d,.7=8.1 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.32 - 7.23 (m, 2H), 4.86 (dd,.7=17,3, 2.5 Hz, 1H), 4.22 (dd, 7=17.3, 2.5 Hz, 1H), 3.75 (d,.7=16.6 Hz, 1H), 3.60 (d,.7=16.6 Hz, 1H), 2.23 (t,.7=2.5 Hz, 1H).

[0505] N-(Bicyclo[4.2.0]octa-l(6),2,4-trien-3-yI)-2-(2,4-bis(trifluoromethyI)phenyI)-N- (prop-2-yn-l-yI)acetamide (intermediate 13)

[0506]

[0507] The titled compound was obtained as a yellow solid (308 mg, 0.749 mmol, 96 % yield). LCMS: RT = 2.49 min; m / z: 411.8[M+H]+(Method A).5HNMR (400 MHz, CHLOROFORM-d) 57.86 (s, 1H), 7.78 (d,.7=8,1 Hz, 1H), 7.53 (d,.7=8.2 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.06 - 7.03 (m, 1H), 4.50 (d, 7=2.5 Hz, 2H), 3.65 (s, 2H), 3.27 - 3.21 (m, 4H), 2.25 (t,.7=2,5 Hz, 1H).

[0508] 2-(2,4-Bis(trifluoromethyI)phenyl)-N-(5-cyclopropyI-2-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (intermediate 14)

[0509]

[0510] The titled compound was obtained as an off-white solid (717 mg, 1.617 mmol, 96 % yield). LCMS: RT = 2.31 min; m / z: 444.1 [M+H]+(Method C). ^INMR (400 MHz, CHLOROFORM-d) 57.86 (s, 1H), 7.79 (d,.7=8.1 Hz, 1H), 7.56 (d,.7=8,1 Hz, 1H), 7.16 - 7.08 (m, 2H), 7.04 (dd,.7=7,3, 2.0 Hz, 1H), 4.83 (dd, 7=17.3, 2.5 Hz, 1H), 4.18 (dd, 7=17.3, 2.5 Hz, 1H), 3.74 (d, 7=16.7 Hz, 1H), 3.59 (d, 7=16.7 Hz, 1H), 2.23 (t,.7=2,5 Hz, 1H), 1.97 - 1.81 (m, 1H), 1.11 - 0.94 (m, 2H), 0.77 - 0.48 (m, 2H).

[0511] 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(3-(oxetan-3-yl)phenyl)-N-(prop-2-yn-l-yl)acetamide (intermediate 15)

[0512]

[0513] The titled compound was obtained as a beige solid (265 mg, 0.600 mmol, 99 % yield). LCMS: RT = 2.10 min; m / z: 442.1 [M+H]+(Method C). ’HNMR (400 MHz, CHLOROFORM-d) 87.86 (s, 1H), 7.80 (d, 7=8.1 Hz, 1H), 7.58 (d, 7=8.1 Hz, 1H), 7.52 -7.45 (m, 2H), 7.38 (s, 1H), 7.28 - 7.24 (m, 1H), 5.14 (dd,.7=8,3, 6.1 Hz, 2H), 4.74 (t,,7=6.3 Hz, 2H), 4.53 (d, 7=2.5 Hz, 2H), 4.36 - 4.20 (m, 1H), 3.65 (s, 2H) 2.27 (t, 7=2.5 Hz, 1H).

[0514] 2-(3,5-Bis(trifluoromethyl)pyridin-2-yl)-N-(3-fluorophenyI)-N-(prop-2-yn-l-yl)acetamide (intermediate 16)

[0515] F

[0516]

[0517] The titled compound was obtained as a yellowish thick oil (119 mg, 0.294 mmol, 78 % yield). LCMS: RT = 2.11 min; m / z: 405.0 [M+H]h(Method C).TH NMR (400 MHz, CHLOROFORM-d) 69.02 (s, 1H), 8.15 (s, 1H), 7.60 - 7.39 (m, 1H), 7.25 - 7.06 (m, 3H), 4.54 (d, 7 2 5 Hz, 211), 3.93 (s, 211), 2.35 - 2.17 (m, 1H).

[0518] 2-(3,5-Bis(trifluoromethyI)pyridin-2-yl)-N-(prop-2-yn-l-yl)-N-(o-tolyl)acetamide (intermediate 17)

[0519]

[0520] The titled compound was obtained as a yellowish thick oil (123 mg, 0.307 mmol, 81 % yield). LC S: RT - 2.19 min; m / z: 401.2 [M+H]h(Method C).TH NMR (400 MHz, CHLOROFORM-d) 69.01 (s, 1H), 8.14 (s, 1H), 7.41 - 7.30 (m, 4H), 4.79 (dd, 7=17.2, 2.5 Hz, 1H), 4.21 (dd, 7=17.2, 2.5 Hz, 1H), 3.89 (d, 7=16.5 Hz, 1H), 3.70 (d, 7=16.5 Hz, 1H), 2.41 (s, 3H), 2.21 (t, 7=2.5 Hz, 1H).

[0521] 2-(3,5-Bis(trifluoromethyl)pyridin-2-yl)-N-(2-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (intermediate 18)

[0522]

[0523] The titled compound was obtained as an orange oil (128 mg, 0.317 mmol, 85 % yield). LCMS: 100% pure, RT = 2.09 min; m / z: 405.1 [M+H]+(Method C). 'H NMR (400 MHz, CHLOROFORM-d) 88.99 (s, 1H), 8.19 - 8.02 (m, 1H), 7.53 - 7.38 (m, 2H), 7.33 -7.17 (m, 2H), 4.89 (dd, 7=17.3, 2.5 Hz, 1H), 4.23 (dd, 7=17.3, 2.4 Hz, 1H), 3.96 - 3.88 (m, 2H), 2.29 - 2.14 (m, 1H).

[0524] 2-(3,5-Bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-l-yl)-N-(m-tolyl)acetamide (intermediate 19)

[0525]

[0526] The titled compound was obtained as an orange oil (102 mg, 0.255 mmol, 68.2 % yield).

[0527] LCMS: 100% pure, RT = 2.21 min; m / z: 401.1 [M+H]+(Method C).1HNMR(400 MHz, CHLOROFORM-d) 69.01 (s, 1H), 8.12 (s, 1H), 7.40 - 7.33 (m, 1H), 7.27 - 7.22 (m, 1H), 7.21 - 7.15 (m, 2H), 4.53 (d, J=2.5 Hz, 2H), 3.92 (s, 2H), 2.43 (s, 3H), 2.26 - 2.22 (m, 1H).

[0528] N-(Bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-l-yl)acetamide (intermediate 20)

[0529]

[0530] 'HNMR (400 MHz, CHLOROFORM-d) 69.01 (s, 1H), 8.16 - 8.12 (m, 1H), 7.23 -7.18 (m, 1H), 7.17 - 7.12 (m, 1H), 7.11 - 7.08 (m, 1H), 4.52 (d, J=2.5 Hz, 2H), 3.91 (s, 2H), 3.23 (s, 4H), 2.25 - 2.22 (m, 1H).

[0531] 2-(2,4-Bis(trifluoromethyl)phenyl)-2-oxoacetic acid (intermediate 21)

[0532]

[0533] To a solution of ethyl 2-(2,4-bis(trifluoromethyl)phenyl)-2-oxoacetate (0.86 g, 2.74 mmol) in THF (5 mL) / MeOH (5 mL) / Water (5 mL), sodium hydroxide (0.328 g, 8.21 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was then concentrated and acidified with IN HC1 solution to pH~4. It was extracted with ethyl acetate (2 x 30 mL) and the organic layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated to give an off-white solid as the final product 2-(2,4-bis(trifluoromethyl)phenyl)-2-oxoacetic acid (721 mg, 2.52 mmol, 92 % yield). LC / MS: 284.7 [M-H]-(Method C);1HNMR(400 MHz, DMSO-d₆) δ8.28 - 8.17 (m, 2H), 8.05 (d, J=8.0 Hz, 1H).

[0534] 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-2-oxo-N-(prop-2-yn-l-yl)acetamide (intermediate 22)

[0535]

[0536] To a solution of 2-(2,4-bis(trifluoromethyl)phenyl)-2-oxoacetic acid (60 mg, 0.210 mmol) in CH2CI2 (2 mL), a drop of DMF and oxalyl chloride (0.022 mL, 0.252 mmol) were added. The reaction mixture was stirred at rt for 1.5 hr. Then it was cooled to 0 °C, 2-fluoro-N-(prop-2-yn-l-yl)aniline (46.9 mg, 0.315 mmol) and triethylamine (0.073 mL, 0.524 mmol) were added. The reaction mixture was then warmed to rt and stirred for 1.5 hr. The reaction mixture was then quenched with water and extracted with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with brine, dried over MgSO₄, filtered, and concentrated to give a thick yellowish oil. The crude product was purified by Prep. HPLC using CH3CN-H2O-ammonium acetate system. Fractions was collected and concentrated under speed-vac overnight. A yellowish thick oil was obtained as the final product 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-2-oxo-N-(prop-2-yn-l-yl)acetamide (55 mg, 0.132 mmol, 62.9 % yield). LC / MS: 418 [M+H]+(Method C). 'HNMR (400 MHz, CHLOROFORM-d) δ 8.05 - 7.97 (m, 2H), 7.97 - 7.91 (m, 1H), 7.46 - 7.34 (m, 2H), 7.24 -7.17 (m, 1H), 7.15 - 7.07 (m, 1H), 5.14 - 4.18 (m, 2H), 2.30 (t, J=2.5 Hz, 1H).

[0537] N-(Bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-2-oxo-N-(prop-2-yn-l-yl)acetamide (intermediate 23)

[0538]

[0539] The titled compound was obtained according to the same synthetic sequence as intermediate 22. 'HNMR (400 MHz, CHLOROFORM-d) 87.99 - 7.94 (m, 2H), 7.93 - 7.89 (m, 1H), 7.05 - 7.00 (m, 1H), 7.00 - 6.95 (m, 1H), 6.95 - 6.91 (m, 1H), 4.61 (d, J=2.5 Hz, 2H), 3.19 -3.10 (m, 4H), 2.33 (t, J=2.5 Hz, 1H).

[0540] EXAMPLE Q-l: 6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)nicotinamide (Example 1)

[0541]

[0542] In a reaction vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(prop-2-yn-l-yl)-N-(m-tolyl)acetamide (35 mg, 0.088 mmol), 6-bromonicotinamide (21.14 mg, 0.105 mmol), bis(triphenylphosphine)palladium(II) dichloride (12.30 mg, 0.018 mmol) and copper(I) iodide (5.01 mg, 0.026 mmol) were added. The vial was sealed, vacuumed, and flushed with nitrogen. DMF (1 mL) and DIPEA (0.046 mL, 0.263 mmol) were added, and the reaction mixture was heated at 100°C for 1.5 hr. LC / MS shown formation of the desired product. The reaction mixture was then added CH3CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 35-85% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give 6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)nicotinamide (15.3 mg, 0.029 mmol, 33.1 % yield). LCMS:100% pure, RT = 2.20 min, m / z:

[0543] 520.2[M+H]+(Method A). 'H NMR (500 MHz, DMSO-d6) 68.98 (br s, 1H), 8.19 (br s, 2H), 8.12 - 8.00 (m, 1H), 7.95 (br s, 1H), 7.82 - 7.70 (m, 1H), 7.66 (br s, 1H), 7.57 - 7.50 (m, 1H), 7.50 - 7.40 (m, 1H), 7.38 - 7.22 (m, 3H), 4.76 (br s, 2H), 3.74 (br s, 2H), 2.38 (br s, 3H).

[0544] Examples Q-2-23 below were obtained using procedure similar to example Q-l above. Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0545] m / z / RT

[0546] (min) / Purity

[0547] / (Method)

[0548] Q-2 / \ F 523.9 ‘HNMR C i [M+H]+ / 2.06 min / (400 MHz,

[0549] 97.4% / (Method C) CDCh) 68.99 (s,

[0550] 1H), 8.15 (dd, | ° N A NH,

[0551] F3C J. J=8.1, 1.9 Hz, M61H), 7.87 (s,

[0552] 1H), 7.80 (br d, CF3J=8.1 Hz, 1H),

[0553] 7.57 (d,. / =8,0 6-(3-(2-(2,4- Hz, 1H), 7.54 - bis(trifluoromethyl)phenyl)-N-(2- 7.41 (m, 3H), fluorophenyl)acetamido)prop- 1 -yn- 1 - 7.34 - 7.24 (m, yl)nicotinamide 2H), 6.57 - 5.61

[0554] (m, 2H), 5.07 (d, J=17.7 Hz, 1H), 4.55 (d, J=17.8 Hz, 1H), 3.77 (d, J=16.7 Hz, 1H), 3.64 (d, J=16.7 Hz, 1H)

[0555] Q-3 Tf 520.2 ‘HNMR [M+H]+ / 2.2 min / (500 MHz, 98.9% / (Method DMSO-d₆) δ

[0556] 8.98 (s, 1H), F3C 1 T. ° '^ YNH2 A)

[0557] 8.22 - 8.14 (m, IT62H), 8.04 (br d, CF3. / =8,2 Hz, 1H),

[0558] 7.95 (s, 1H), 6-(3-(2-(2,4- 7.77 (d,. / =8,0 bis(trifluoromethyl)phenyl)-N-(o- Hz, 1H), 7.65 (br tolyl)acetamido)prop- 1 -yn- 1 - s, 1H), 7.51 (d, yl)nicotinamide J=8.1 Hz, 1H),

[0559] 7.48 - 7.44 (m, 2H), 7.43 - 7.38 (m, 2H), 4.93 (d, J=17.8 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 3.73 (br

[0560]

[0561] d, J=17.0 Hz, Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0562] m / z / RT

[0563] (min) / Purity

[0564] / (Method)

[0565] 1H), 3.49 (d, J=17.0 Hz, 1H), 2.38 (s, 3H) Q-4 532.2[M+H] ‘HNMR+ / (500 MHz, DMSO-d6) 6 2.27

[0566] 8.98 (s, 1H), Min / 100% / 8.30 - 8.14 (m,31 ° N NH

[0567] F C 1.2

[0568] (Method A) 2H), 8.04 (br d,

[0569] . / =7,8 Hz, 1H), 7.95 (s, 1H), CF37.73 (br d, J=8.0

[0570] Hz, 1H), 7.67 (br 6-(3-(N-(bicyclo[4.2.0]octa- s, 1H), 7.54 (d, l(6),2,4-trien-3-yl)-2-(2,4- J=8.1 Hz, 1H), bis(trifluoromethyl)phenyl)acetamido)p

[0571] 7.36 - 7.21 (m, rop- 1 -yn- 1 -yl)nicotinamide

[0572] 3H), 4.74 (s, 2H), 3.73 (s, 2H), 3.19 (s, 4H) Q-5 520.1[M+H] ‘HNMR+ / 2.20 (500 MHz, DMSO-d6) 6 Min / 92.2%

[0573] 8.57 (br s, 1H), / (Method A)

[0574] F3C1NH2 8.15 (br s, 1H),

[0575] 8.08 - 7.99 (m, 2H), 7.95 (br s, CF32H), 7.78 - 7.68

[0576] (m, 2H), 7.50 - 5-(3-(2-(2,4- 7.41 (m, 1H), bis(trifluoromethyl)phenyl)-N-(m- 7.37 - 7.24 (m, tolyl)acetamido)prop- 1 -yn- 1 - 3H), 4.76 (br s, yl)picolinamide

[0577] 2H), 3.74 (br s, 2H), 2.38 (br s,

[0578]

[0579] 3H) Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0580] m / z / RT

[0581] (min) / Purity

[0582] / (Method)

[0583] Q-6 / \ F 524.1[M+H]

[0584] C ¥ ‘HNMR+ / 2.25 min / 95.9% / (500 MHz, (Method A) DMSO-d₆) δ

[0585] 8.53 (br s, 1H), F3C J.NrfNH2

[0586] 8.14 (br s, 1H), 8.08 - 7.89 (m, 4H), 7.78 - 7.66 ¥ (m, 3H), 7.61 - 5-(3-(2-(2,4- 7.54 (m, 1H), bis(trifluoromethyl)phenyl)-N-(2- 7.54 - 7.47 (m, fluorophenyl)acetamido)prop- 1 -yn- 1 - 1H), 7.47 - 7.37 yl)picolinamide (m, 1H), 4.89 (br d, J=17.8 Hz, 1H), 4.68 (br d, J=17.6 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.69 - 3.62 (m, 1H)

[0587] Q-7 520.1[M+H] ‘HNMR or+ / 2.36 min / 98.7% / (500 MHz, (Method A) DMSO-d₆) δ

[0588] 8.55 (d, J=1.4 Hz, 1H), 8.12 (br ■'-0 A "' s, 1H), 8.07 - CF38.00 (m, 2H),

[0589] 7.98 - 7.91 (m, 5-(3-(2-(2,4- 2H), 7.76 (d, bis(trifluoromethyl)phenyl)-N-(o- J=8.1 Hz, 1H), tolyl)acetamido)prop- 1 -yn- 1 - 7.72 (br s, 1H), yl)picolinamide

[0590] 7.52 - 7.45 (m, 2H), 7.45 - 7.37 (m, 2H), 4.95 (d, J=17.7 Hz, 1H), 4.52 (d, J=17.8 Hz, 1H), 3.73 (br d, J=17.1 Hz, 1H), 3.55 - 3.43 (m, 1H), 2.37 (s,

[0591]

[0592] 3H) Example # Structure and name Analytical 'H NMR LCMS ESI-MS(+)

[0593] m / z / RT

[0594] (min) / Purity

[0595] / (Method)

[0596] Q-8 532.2[M+H] 'H NMR+ / 2.34 min / 96.3% / (500 MHz, (Method B) DMSO-d6) 6 A 8.71 - 8.47 (m,

[0597] LX NH21H), 8.14 (br s, FsCykN

[0598] 1H), 8.07 - 8.00 (m, 2H), 7.99 - CF37.93 (m, 2H),

[0599] 7.77 - 7.69 (m, 5-(3-(N-(bicyclo[4.2.0]octa- 2H), 7.36 - 7.31 l(6),2,4-trien-3-yl)-2-(2,4- (m, 1H), 7.31 - bis(trifluoromethyl)phenyl)acetamido)p

[0600] 7.23 (m, 2H), rop- 1 -yn- 1 -yl)picolinamide

[0601] 4.75 (s, 2H), 3.73 (s, 2H), 3.20 (s, 4H) Q-9 526.1[M+H] ‘HNMR+ / 2.33 min / 96.1% / (500 MHz, Cl (Method A) DMSO-d6) 6 1s8.33 (s, 1H),

[0602] 8.05 (br d, J=8.0 A IJ Hz, 1H), 7.95 (s,F3CCX \

[0603] Tj 1H), 7.87 (br s,

[0604] < CNH21H), 7.73 (br d, CF3. / =7,9 Hz, 1H),

[0605] 7.64 (br s, 1H), 2-(3-(2-(2,4- 7.50 - 7.43 (m, bis(trifluoromethyl)phenyl)-N-(m- 1H), 7.34 - 7.25 tolyl)acetamido)prop- 1 -yn- 1 - (m, 3H), 4.80 (s, y 1 )thi azol e-4-carb oxami de 2H), 3.75 (br s,

[0606]

[0607] 2H), 2.38 (s, 3H) Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0608] m / z / RT

[0609] (min) / Purity

[0610] / (Method)

[0611] Q-10 / \ F 530.0[M+H] ‘HNMR CT+ / 2.22 min / 96.5% / (500 MHz, (Method A) DMSO-d₆) δ

[0612] 8.33 (s, 1H), 8.06 (br d, J=8.0 '■» A ° Hz, 1H), 7.97 (s, T J A >NH21H), 7.87 (br s,

[0613] 1H), 7.75 (br d, CF3. / =8,2 Hz, 1H), 2-(3-(2-(2,4- 7.69 - 7.62 (m, bis(trifluoromethyl)phenyl)-N-(2- 2H), 7.60 - 7.55 fluorophenyl)acetamido)prop- 1 -yn- 1 - (m, 1H), 7.54 - y 1 )thi azol e-4-carb oxami de 7.49 (m, 1H),

[0614] 7.46 - 7.39 (m, 1H), 4.89 (d, J=17.8 Hz, 1H), 4.74 (d, J=17.8 Hz, 1H), 3.93 - 3.75 (m, 1H), 3.73 - 3.59 (m, 1H)

[0615] Q-ll ccc 526.1[M+H] ‘HNMR 1s + / 2.32 min / 97.9% / (500 MHz, (Method A) DMSO-d₆) δ

[0616] 8.33 (s, 1H), A I? 8.05 (br d, J=8.0 Tj Hz, 1H), 7.96 (s,

[0617] CTNH21H), 7.85 (br s, CF31H), 7.77 (br d,

[0618] J=8.0 Hz, 1H), 2-(3-(2-(2,4- 7.65 - 7.61 (m, bis(trifluoromethyl)phenyl)-N-(o- 1H), 7.50 - 7.46 tolyl)acetamido)prop- 1 -yn- 1 - (m, 1H), 7.45 - y 1 )thi azol e-4-carb oxami de 7.37 (m, 3H),

[0619] 4.96 (d, J=18.0 Hz, 1H), 4.56 (d, J=18.0 Hz, 1H), 3.83 - 3.67 (m,

[0620]

[0621] 1H), 3.53 - 3.46 Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0622] m / z / RT

[0623] (min) / Purity

[0624] / (Method)

[0625] (m, 1H), 2.36 (s, 3H)

[0626] Q-12 538.0[M+H] ‘HNMR+ / 3.21 min / 98.7% / (500 MHz, (Method A) DMSO-d₆) δ

[0627] 8.33 (s, 1H), 8.05 (br d, J=8.0 P0

[0628] F3CX A \ Hz, 1H), 7.96 (s,

[0629] 1H), 7.91 - 7.81 T j < / NH2

[0630] (m, 1H), 7.72 (d, J=8.3 Hz, 1H), CF3

[0631] 7.67 - 7.53 (m, 2-(3-(N-(bicyclo[4.2.0]octa- 1H), 7.30 - 7.28 l(6),2,4-trien-3-yl)-2-(2,4- (m, 2H), 7.23 (s, bis(trifluoromethyl)phenyl)acetamido)p 1H), 4.78 (s, rop- 1 -yn- 1 -yl)thiazole-4-carboxamide 2H), 3.74 (s,

[0632] 2H), 3.20 (s, 4H) Q-13 510.1[M+H] ‘HNMR+ / 2.28 min / 95.1% / (500 MHz, dv (Method A) DMSO-d₆) δ

[0633] 8.64 (s, 1H), 8.05 (d,. / =8,2F CA A Hz, 1H), 7.95 (s, 3 _A \

[0634] TjNH21H), 7.78 (br s,

[0635] 1H), 7.73 (d, CF3. / =8,2 Hz, 1H),

[0636] 7.60 - 7.56 (m, 2-(3-(2-(2,4- 1H), 7.49 - 7.42 bis(trifluoromethyl)phenyl)-N-(m- (m, 1H), 7.34 - tolyl)acetamido)prop- 1 -yn- 1 - 7.24 (m, 3H), yl)oxazole-4-carboxamide 4.79 (s, 2H),

[0637] 3.75 (br s, 2H), 2.37 (s, 3H)

[0638]

[0639] Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0640] m / z / RT

[0641] (min) / Purity

[0642] / (Method)

[0643] Q-14 / \ F 514.1[M+H] ‘HNMR CT+ / 2.18 min / 99.2% / (500 MHz, (Method A) DMSO-d₆) δ

[0644] 8.65 - 8.60 (m, 1H), 8.06 (br d, '■» A ° A J=8.0 Hz, 1H), T J >NH27.96 (s, 1H),

[0645] 7.82 - 7.71 (m, CF32H), 7.68 - 7.61 2-(3-(2-(2,4- (m, 1H), 7.61 - bis(trifluoromethyl)phenyl)-N-(2- 7.54 (m, 2H), fluorophenyl)acetamido)prop- 1 -yn- 1 - 7.54 - 7.47 (m, yl)oxazole-4-carboxamide 1H), 7.46 - 7.38

[0646] (m, 1H), 4.88 (d, J=18.0 Hz, 1H), 4.75 (d, J=18.0 Hz, 1H), 3.93 - 3.73 (m, 1H), 3.70 - 3.57 (m, 1H)

[0647] Q-15 ccc 510.1[M+H] ‘HNMR+ / 2.27 min / 98.1% / (500 MHz, 1 0 (Method A) DMSO-d₆) δ

[0648] 8.63 (s, 1H), A IT 8.05 (br d,. / =7,6F3C^ TXj \

[0649] Hz, 1H), 7.96 (s, CTNH21H), 7.86 - 7.68 CF3(m, 2H), 7.56 (br s, 1H), 7.51 - 2-(3-(2-(2,4- 7.45 (m, 1H), bis(trifluoromethyl)phenyl)-N-(o- 7.45 - 7.35 (m, tolyl)acetamido)prop- 1 -yn- 1 - 3H), 4.95 (br d, yl)oxazole-4-carboxamide J=18.0 Hz, 1H),

[0650] 4.54 (br d, J=18.0 Hz, 1H), 3.73 (br d,

[0651]

[0652] J=17.4 Hz, 1H), Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0653] m / z / RT

[0654] (min) / Purity

[0655] / (Method)

[0656] 3.54 - 3.45 (m, 1H), 2.34 (s, 3H) Q-16 522.1[M+H] ‘HNMR Ul+ / 2.35 min / 100% / (500 MHz, (Method A) DMSO-d₆) δ

[0657] 8.84 - 8.53 (m, 1H), 8.04 (br d, A ic

[0658] F3C^ 1 "\ J=8.3 Hz, 1H), Tj CNH27.95 (s, 1H),

[0659] 7.77 (br s, 1H), CF37.72 (br d, J=8.2

[0660] Hz, 1H), 7.58 (br 2-(3-(N-(bicyclo[4.2.0]octa- s, 1H), 7.28 (s, l(6),2,4-trien-3-yl)-2-(2,4- 2H), 7.24 - 7.18 bis(trifluoromethyl)phenyl)acetamido)p (m, 1H), 4.78 (s, rop- 1 -yn- 1 -yl)oxazole-4-carboxamide 2H), 3.73 (s,

[0661] 2H), 3.19 (s, 4H) Q-17 526.1[M+H] ‘HNMR+ / 2.27 min / 99.3% / (500 MHz, Cl (Method A) DMSO-d6) 6 o 8.38 (s, 1H), r / /

[0662] 8.28 - 8.22 (m, | ^° blC^ NH

[0663] F31H), 8.05 (br d, C. A

[0664] J=8.1 Hz, 1H), CJ 7.95 (s, 1H),

[0665] 7.83 - 7.76 (m, CF3

[0666] 1H), 7.74 (br d, 2-(3-(2-(2,4-. / =7,9 Hz, 1H), bis(trifluoromethyl)phenyl)-N-(m- 7.50 - 7.42 (m, tolyl)acetamido)prop- 1 -yn- 1 - 1H), 7.34 - 7.24 y 1 )thi azol e- 5 -carb oxami de (m, 3H), 4.80 (s,

[0667] 2H), 3.75 (br s,

[0668]

[0669] 2H), 2.38 (s, 3H) Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0670] m / z / RT

[0671] (min) / Purity

[0672] / (Method)

[0673] Q-18 530.0[M+H] ‘HNMR C i + / 2.17 min / 100% / (500 MHz, (Method A) DMSO-d₆) δ

[0674] 8.37 (s, 1H), 8.25 (br s, 1H), F, C bNH8.05 (br d, J=8.1 " C Hz, 1H), 7.97 (s,

[0675] 1H), 7.82 - 7.77 CF3(m, 1H), 7.75 (br 2-(3-(2-(2,4- d,. / =8,0 Hz, bis(trifluoromethyl)phenyl)-N-(2- 1H), 7.68 - 7.62 fluorophenyl)acetamido)prop- 1 -yn- 1 - (m, 1H), 7.62 - y 1 )thi azol e- 5 -carb oxami de 7.55 (m, 1H),

[0676] 7.54 - 7.48 (m, 1H), 7.45 - 7.39 (m, 1H), 4.90 (d, J=18.2 Hz, 1H), 4.75 (d, J=18.0 Hz, 1H), 3.94 - 3.74 (m, 1H), 3.71 - 3.59 (m, 1H)

[0677] Q-19 526.1[M+H] ‘HNMR Of+ / 2.12 min / 93.3% / (400 MHz, CHLOROFORM 11 (Method C)

[0678] / ?

[0679] o

[0680] F, C fW^ / ') — \NH-d) 88.15 (br s,

[0681] 1H), 7.88 (s, 1H), 7.84 - 7.70 (m, 1H), 7.65 - M 7.47 (m, 1H), CF3

[0682] 7.45 - 7.30 (m, 2-(3-(2-(2,4- 4H), 6.09 (br s, bis(trifluoromethyl)phenyl)-N-(o- 2H), 5.05 (br d, tolyl)acetamido)prop- 1 -yn- 1 - J=17.5 Hz, 1H), y 1 )thi azol e- 5 -carb oxami de 4.50 (br d,

[0683] J=17.2 Hz, 1H), 3.69 (br d, J=17.0 Hz, 1H), 3.49 (br d,

[0684]

[0685] Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0686] m / z / RT

[0687] (min) / Purity

[0688] / (Method)

[0689] J=16.9 Hz, 1H), 2.40 (s, 3H) Q-20 / -\ F 488.1[M+H] ‘HNMR L I+ / 2.32 min / 93.1% / (500 MHz, r s (Method A) DMSO-d₆) δ

[0690] 9.71 - 9.67 (m,w(M ru1H), 8.11 - 8.02

[0691] (m, 1H), 7.97 (s, 1H), 7.80 - 7.73 (m, 1H), 7.70 - CF37.64 (m, 1H), N-(3-(l,3,4-thiadiazol-2- 7.61 - 7.55 (m, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.55 - 7.48 bis(trifluoromethyl)phenyl)-N-(2- (m, 1H), 7.47 - fluorophenyl)acetamide 7.38 (m, 1H),

[0692] 4.93 (d,.7=18.3 Hz, 1H), 4.79 (d, 7=18.4 Hz, 1H), 3.88 - 3.77 (m, 1H), 3.71 - 3.60 (m, 1H)

[0693] Q-21 Of 484.1[M+H] ‘HNMR+ / 2.4 (500 MHz, DMSO-d6) 6 min / 95.5% /

[0694] 9.69 (s, 1H), (Method A)

[0695] 8.05 (br d, 7=8.3 Hz, 1H), 7.96 (s, 1H), 7.77 (d, CF37=7.9 Hz, 1H),

[0696] 7.53 - 7.33 (m, N-(3-(l,3,4-thiadiazol-2- 4H), 5.00 (d, yl)prop-2-yn- 1 -yl)-2-(2,4- 7=18.1 Hz, 1H), bis(trifluoromethyl)phenyl)-N-(o- 4.62 (d, 7=18.0 tolyl)acetamide Hz, 1H), 3.83 - 3.68 (m, 1H),

[0697]

[0698] 2.36 (s, 3H) Example # Structure and name Analytical ‘HNMR LCMS ESI-MS(+)

[0699] m / z / RT

[0700] (min) / Purity

[0701] / (Method)

[0702] Q-22 480.2 ‘HNMR [M+H]+ / 2.32 min (400 MHz, CT

[0703] ^p^p / 95.4% / (Method CHLOROFORM T° w A) -d) 87.88 (s, F3C J. ** 1H), 7.78 (d, p J=8.0 Hz, 1H),

[0704] 7.50 (d,. / =8,0 CF3Hz, 1H), 7.46 - 7.20 (m, 6H), 2-(2,4- 5.18 (d, J=17.6 bis(trifluoromethyl)phenyl)-N-(3-(l- Hz, 1H), 4.59 (d, m ethyl- lH-imidazol-5-yl)prop-2-yn- 1 - J=17.6 Hz, 1H), yl)-N-(o-tolyl)acetamide 3.83 - 3.61 (m,

[0705] 4H), 3.45 (d, J=17.1 Hz, 1H), 2.37 (s, 3H) / \ F Q-23 484.1 ‘HNMR [M+H]+ / 2.22 min (400 MHz, n

[0706] / 100% / (Method CHLOROFORM ^p^p -d) 68.04 - 7.84 A)

[0707] (m, 2H), 7.80 (d, T° V F3C. I "

[0708] J=8.1 Hz, 1H), p 7.55 (d,.7=8.1 Hz, 1H), 7.52 - CF37.38 (m, 2H),

[0709] 7.35 - 7.26 (m, 2-(2,4- 3H), 4.98 (d, bis(trifluoromethyl)phenyl)-N-(2- 7=17.7 Hz, 1H), fluorophenyl)-N-(3 -(1 -methyl- 1 H- 4.63 (d, 7=17.7 imidazol-5-yl)prop-2-yn- 1 - Hz, 1H), 3.76 (d, yl)acetamide

[0710] 7=16.8 Hz, 1H), 3.67 - 3.54 (m, 4H)

[0711]

[0712] Example Q-24: 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(pyridin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide (Example 24)

[0713]

[0714] In a reaction vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(prop-2-yn-l-yl)-N-(m-tolyl)acetamide (35 mg, 0.088 mmol), 3 -bromopyridine (16.62 mg, 0.105 mmol), bis(triphenylphosphine)palladium(II) dichloride (12.30 mg, 0.018 mmol) and copper(I) iodide (5.01 mg, 0.026 mmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.046 mL, 0.263 mmol) were added and the reaction mixture was heated at 100°C for 2 hr. CH3CN was then added to the reaction mixture, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 37-67% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(pyridin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide (7 mg, 0.015 mmol, 16.76 % yield). LCMS: 100% pure, RT = 2.49 min; m / z: 477.1 [M+H]+(Method A). 'HNMR (500 MHz, DMSO-d6) 6 9.52-8.48 (m, 2H), 8.11 - 8.01 (m, 1H), 7.95 (br s, 1H), 7.88 - 7.78 (m, 1H), 7.78 - 7.69 (m, 1H), 7.64 - 7.41 (m, 2H), 7.39 - 7.25 (m, 3H), 4.74 (br s, 2H), 3.73 (br s, 2H), 2.38 (br s, 3H).

[0715] Examples Q-25-29 below were obtained using procedure similar to example Q-24 above. Example # Structure and name Analytical 'H NMR LCMS ESI- MS(+) m / z / RT

[0716] (min) / Purity

[0717] / (Method)

[0718] Q-25 481.1 'H NMR Ci [M+H]+ / 2.38 min (500 MHz, DMSO- / 100% / (Method d6) 69.17-8.43 ( m, A) 2H), 8.11 - 8.02 (m,

[0719] 1H), 7.96 (br s, F3C. I

[0720] 1H), 7.81 - 7.72 (m, 2H), 7.72 - 7.63 (m, 1H), 7.61 - 7.37 (m, CF34H), 4.87 (br d, J=17.8 Hz, 1H), 2-(2,4- 4.65 (br d, J=18.0 bis(trifluoromethyl)phenyl)-N-(2- Hz, 1H), 3.87 - 3.72 fluorophenyl)-N-(3 -(pyri din-3 - (m, 1H), 3.72 - 3.55 yl)prop-2-yn- 1 -yl)acetamide (m, 1H)

[0721] Q-26 / \ F 521.2[M+ 'H NMR L I H]+ / 2.47 min (500 MHz, DMSO- / 100% / (Method d6) 68.80 - 8.42 (m, 2H), 8.05 (br d,3C^° 1O A)

[0722] F C J. ^I\r J=8.5 Hz, 1H), 7.96

[0723] (s, 1H), 7.80 - 7.70 (m, 2H), 7.47 - 7.40 CF3

[0724] (m, 1H), 7.38 - 7.32 (m, 1H), 7.31 - 7.22 2-(2,4- (m, 2H), 4.84 (br d, bis(trifluoromethyl)phenyl)-N-(5- J=17.6 Hz, 1H), cyclopropyl-2-fluorophenyl)-N-(3- 4.63 (br d, J=17.7 (pyri din-3 -yl)prop-2-yn- 1 - Hz, 1H), 3.81 (br d, yl)acetamide J=16.4 Hz, 1H),

[0725] 3.64 (d, J=16.4 Hz, 1H), 2.05 - 1.92 (m, 1H), 1.06 - 0.89 (m, 2H), 0.74 - 0.55 (m,

[0726]

[0727] 2H) Example # Structure and name Analytical 'H NMR LCMS ESI- MS(+) m / z / RT

[0728] (min) / Purity

[0729] / (Method)

[0730] Q-27 477.1 'H NMR [M+H]+ / 2.49 min (500 MHz, DMSO-c / 99% / (Method de) 88.58 - 8.48 A Ao A) (m, 1H), 8.09 - 8.00

[0731] (m, 1H), 7.95 (br s, 1H), 7.85 - 7.70 (m, <k 2H), 7.50 - 7.26 (m,

[0732] 6H), 4.73 (br s, 2-(2,4- 2H), 3.74 (br s, bis(trifluoromethyl)phenyl)-N-(3- 2H), 2.37 (br s, 3H) (pyri din-2 -yl)prop-2-yn-l-yl)-N-(m- tolyl)acetamide, TFA

[0733] Q-28 / \ F

[0734] f T 481.1 'H NMR [M+H]+ / 2.39 min (500 MHz, DMSO- / 100% / (Method d6) 68.62 - 8.45 A) (m, 1H), 8.05 (br d, A AO J=8.0 Hz, 1H), 7.96

[0735] (s, 1H), 7.83 - 7.77 M (m, 1H), 7.75 (br d,

[0736] J=8.0 Hz, 1H), 7.70 CF3- 7.64 (m, 1H), 7.60

[0737] - 7.53 (m, 1H), 7.53 2-(2,4- - 7.47 (m, 1H), 7.45 bis(trifluoromethyl)phenyl)-N-(2- - 7.35 (m, 3H), 4.88 fluorophenyl)-N-(3-(pyridin-2- (d, J= 17.7 Hz, 1H), yl)prop-2-yn-l-yl)acetamide, TFA 4.63 (d, J=17.8 Hz,

[0738] 1H), 3.82 (br d, J=16.6 Hz, 1H), 3.64 (br d, J=16.8

[0739]

[0740] Hz, 1H) Example # Structure and name Analytical 'H NMR LCMS ESI- MS(+) m / z / RT

[0741] (min) / Purity

[0742] / (Method)

[0743] Q-29 480.2[M+ 'H NMR H]+ / 2.32 min (500 MHz, DMSO- Cl / 98.6% / (Method d6) 68.12 - 7.99 A) (m, IH), 7.94 (br s,

[0744] IH), 7.84 - 7.67 (m, C° Cl

[0745] F3C^ 1 N 2H), 7.51 - 7.39 (m,

[0746] IH), 7.36 - 7.20 (m, CJ

[0747] 4H), 4.75 (br s, 2H), 3.73 (br s, CF3

[0748] 2H), 3.44 (br s, 2-(2,4- 3H), 2.36 (br s, 3H) bi s(trifluoromethyl)phenyl)-N-(3 -( 1 - methyl- lH-imidazol-5-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide

[0749]

[0750] Example Q-30: N-(3-(6-Aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamide (Example 30)

[0751]

[0752] In a microwave vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (30 mg, 0.074 mmol), 6-bromopyridazin-3 -amine (15.53 mg, 0.089 mmol), Bis(triphenylphosphine)palladium(II) dichloride (10.44 mg, 0.015 mmol) and copper(I) iodide (4.25 mg, 0.022 mmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.039 mL, 0.223 mmol) were added and the reaction mixture was heated at 100 °C under microwave condition for Ih. The reaction mixture was added CH3CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 31-62% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C.

[0753] Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamide (6.8 mg, 0.013 mmol, 17.77 % yield). LCMS: 97.2% pure, RT = 2.11 min; m / z: 497.1 [M+H]+(Method A). 'H NMR (500 MHz, DMSO-d6) 68.09 - 8.01 (m, 1H), 7.95 (br s, 1H), 7.78 - 7.70 (m, 1H), 7.66 - 7.55 (m, 1H), 7.48 - 7.40 (m, 1H), 7.40 - 7.32 (m, 2H), 7.26 - 7.18 (m, 1H), 6.77 - 6.69 (m, 3H), 4.76 (br s, 2H), 3.77 (br s, 2H) Examples Q-31-41 below obtained using procedure similar to example Q-30 above.

[0754] Example Structure and name AnalyticalXH # LCMS NMR ESI- MS(+) m / z / RT

[0755] (min) / Purity /

[0756] (Method);

[0757] Q-31 497.1XH [M+H]+ / 2.10 min NMR (500 C i

[0758] / 98.6% / MHz, (Method A) DMSO-d6) A N J 88.09 - F3CXJ. N NH2

[0759] 8.02 (m, 1H), 7.96 (br s, 1H), CF37.80 - 7.72

[0760] (m, 1H), N-(3-(6-aminopyridazin-3-yl)prop- 7.69 - 7.62 2-yn-l-yl)-2-(2,4- (m, 1H), bis(trifluoromethyl)phenyl)-N-(2- 7.60 - 7.52 fluorophenyl)acetamide (m, 1H),

[0761] 7.52 - 7.45 (m, 1H), 7.44 - 7.36 (m, 1H), 7.23 - 7.14 (m, 1H),

[0762]

[0763] 6.78 - 6.71 Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0764] (min) / Purity /

[0765] (Method);

[0766] (m, 3H), 4.88 (br d, J=18.0 Hz, 1H), 4.60 (br d, J=17.7 Hz, 1H), 3.86 - 3.74 (m, 1H), 3.69 - 3.59 (m, 1H) Q-32 493.2XH [M+H]+ / 2.19 min NMR (500 / 99.3% / MHz, (Method A) DMSO-d6)

[0767] 88.03 (br F3C. I A T NX^NH2

[0768] d,. / =7,0 Hz, 1H), CF37.94 (br s,

[0769] 1H), 7.73 N-(3-(6-aminopyridazin-3-yl)prop- (br d,. / =7,9 2-yn-l-yl)-2-(2,4- Hz, 1H), bis(trifluoromethyl)phenyl)-N-(m- 7.50 - 7.38 tolyl)acetamide (m, 1H),

[0770] 7.38 - 7.18 (m, 4H), 6.89 - 6.66 (m, 3H), 4.71 (br s, 2H), 3.72 (br s, 2H), 2.36 (br s,

[0771]

[0772] 3H) Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0773] (min) / Purity /

[0774] (Method);

[0775] Q-33 493.2JH [M+H]+ / 2.22 min NMR (500 / 97.8% / (Method MHz, DMSO-d6)F CA A)

[0776] 3 \ / L N^NH2

[0777] 68.04 (br d,, / =8.3 CF3Hz, 1H),

[0778] 7.95 (s, N-(3-(6-aminopyridazin-3-yl)prop- 1H), 7.77 2-yn-l-yl)-2-(2,4- (d,. / =8,2 bis(trifluoromethyl)phenyl)-N-(o- Hz, 1H), tolyl)acetamide 7.49 - 7.32

[0779] (m, 4H), 7.21 (d, J=9.0 Hz, 1H), 6.76 - 6.67 (m, 3H), 4.89 (d, J=17.7 Hz, 1H), 4.48 (d, J=17.6 Hz, 1H), 3.71 (br d, J=17.2 Hz, 1H), 3.52 - 3.36 (m, 1H), 2.36

[0780]

[0781] (s, 3H) Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0782] (min) / Purity /

[0783] (Method);

[0784] Q-34 505.11H [M+H]+ / 2.28 min NMR (500 / 95.4% / (Method MHz, A); DMSO-d6)

[0785] δ 8.05 - F3C 7.99 (m,

[0786] 1H), 7.94 (s, 1H), CF37.76 - 7.68

[0787] (m, 1H), N-(3-(6-aminopyridazin-3-yl)prop- 7.31 - 7.18 2-yn-l-yl)-N-(bicyclo[4.2.0]octa-l(6),2,4- (m, 4H), trien-3-yl)-2-(2,4- 6.80 - 6.67 bis(trifluoromethyl)phenyl)acetamide (m, 3H),

[0788] 4.68 (s, 2H), 3.70 (br s, 2H), 3.18 (s, 4H) Q-35 537.21H [M+H]+ / 2.29 min NMR (500

[0789] / 100% / (Method MHz, A); DMSO-d6) A An 6 8.04 (br F3C d,. / =8,0 Hz, 1H), 7.95 (s, CF31H), 7.74

[0790] (br d,. / =8,2 N-(3-(6-aminopyridazin-3-yl)prop- Hz, 1H), 2-yn-l-yl)-2-(2,4- 7.36 - 7.30 bis(trifluoromethyl)phenyl)-N-(5- (m, 1H), cyclopropyl-2-fluorophenyl)acetamide 7.30 - 7.25

[0791] (m, 1H), 7.25 - 7.21 (m, 1H), 7.19 (d, J=9.1 Hz,

[0792]

[0793] 1H), 6.82 - Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0794] (min) / Purity /

[0795] (Method);

[0796] 6.66 (m, 3H), 4.86 (d, J=17.7 Hz, 1H), 4.56 (d, J=17.8 Hz, 1H), 3.80 (br d, J=16.3 Hz, 1H), 3.70 - 3.57 (m, 1H), 2.08 - 1.88 (m, 1H), 1.02 - 0.89 (m, 2H), 0.75 - 0.60 (m, 2H) Q-36 535.21H [M+H]+ / 1.85 min NMR (500 / 100% / (Method MHz, A); DMSO-d6) A

[0797] F3C^ J. N NH288.05 (br d, J=8.1 Hz, 1H), CF37.94 (br s,

[0798] 1H), 7.75 (br d,. / =7,9 N-(3-(6-aminopyridazin-3-yl)prop- Hz, 1H), 2-yn-l-yl)-2-(2,4- 7.63 - 7.50 bis(trifluoromethyl)phenyl)-N-(3-(oxetan-3- (m, 2H), yl)phenyl)acetamide

[0799] 7.49 - 7.43 (m, 1H), 7.43 - 7.35 (m, 1H), 7.28 - 7.18 (m, 1H),

[0800]

[0801] 6.84 - 6.65 Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0802] (min) / Purity /

[0803] (Method);

[0804] (m, 3H), 5.02 - 4.90 (m, 2H), 4.76 (br s, 2H), 4.67 - 4.57 (m, 2H), 4.39 - 4.25 (m, 1H), 3.74 (br s, 2H) Q-37 498.11H δ [M+H]+ / 1.79 min NMR (500

[0805] / 93.8% / MHz, (Method A); DMSO-d6) F3C δ 9.24 (s,

[0806] 1H), 8.52 N^NH2(s, 1H),

[0807] 7.59 - 7.21 (m, 5H), CF36.79 - 6.68

[0808] (m, 3H), N-(3-(6-aminopyridazin-3-yl)prop- 4.78 (s, 2-yn-l-yl)-2-(3,5- 2H), 3.95 bis(trifluoromethyl)pyridin-2-yl)-N-(3- (s, 2H) fluorophenyl)acetamide

[0809] Q-38 494.11H δ [M+H]+ / 1.88 min NMR (500

[0810] / 96.8% / MHz, F3C (Method A) DMSO-d6)

[0811] δ 9.23 (s,NH21H), 8.50

[0812] (s, 1H), 7.48 - 7.32 CF3(m, 1H),

[0813] 7.32 - 7.13 (m, 4H), N-(3-(6-aminopyridazin-3-yl)prop- 6.83 - 6.62

[0814]

[0815] 2-yn-l-yl)-2-(3,5- Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0816] (min) / Purity /

[0817] (Method); bis(trifluoromethyl)pyridin-2-yl)-N-(m- (m, 3H), tolyl)acetamide 4.73 (s,

[0818] 2H), 3.89 (s, 2H), 2.33 (s, 3H) Q-39 494.21H [M+H]+ / 1.86 min NMR (500

[0819] / 97.0% / MHz, (Method A) DMSO-d6) T° TT δ 9.22 (s,F3C'Y^NN NH2

[0820] 1H), 8.53 (s, 1H), CF37.60 - 7.31

[0821] (m, 5H), 7.30 - 6.90 N-(3-(6-aminopyridazin-3-yl)prop- (m, 3H), 2-yn-l-yl)-2-(3,5- 4.89 (d, bis(trifluoromethyl)pyridin-2-yl)-N-(o- J=17.9 Hz, tolyl)acetamide, TFA

[0822] 1H), 4.55 (d, J=17.8 Hz, 1H), 3.81 (br d, J=16.9 Hz, 1H), 3.68 - 3.63 (m, 1H), 2.37 (s, 3H) Q-40 506.41H [M+H]+ / 1.89 min NMR (500 n / 96.6% / MHz,

[0823] (Method A) DMSO-d6)

[0824] δ 9.22 (br s, F3C 1H), 8.51

[0825] (s, 1H), 7.35 - 7.16 CF3(m, 4H),

[0826] 6.85 - 6.58

[0827]

[0828] (m, 3H), Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0829] (min) / Purity /

[0830] (Method);

[0831] N-(3-(6-aminopyridazin-3-yl)prop- 4.71 (s, 2-yn-l-yl)-N-(bicyclo[4.2.0]octa-l(6),2,4- 2H), 3.87 trien-3-yl)-2-(3,5- (br s, 2H), bis(trifluoromethyl)pyridin-2-yl)acetamide 3.17 (s, 4H) Q-41 511.2 [M+H]+ / 1.93 min NMR (500 / 100% / (Method MHz, A) DMSO-d6) ° -0LQ. δ 8.37 - FjC^ / x N'^X'NH2

[0832] 8.28 (m, 1H), 8.28 - 8.15 (m, CF32H), 7.60 - 7.50 (m, N-(3-(6-aminopyridazin-3-yl)prop- 1H), 7.50 - 2-yn-l-yl)-2-(2,4- 7.41 (m, bis(trifluoromethyl)phenyl)-N-(2- 2H), 7.37 - fluorophenyl)-2-oxoacetamide, TFA 7.28 (m,

[0833] 1H), 7.28 - 7.17 (m, 1H), 7.06 (d,. / =9,4 Hz, 1H), 4.97 (s, 2H)

[0834]

[0835] Example Q-42. N-(3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamide (Example 42)

[0836]

[0837] In a microwave vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (30 mg, 0.074 mmol), 5-bromopyrimidin-2-amine (15.53 mg, 0.089 mmol), Bis(triphenylphosphine)palladium(II) dichloride (10.44 mg, 0.015 mmol) and copper(I) iodide (4.25 mg, 0.022 mmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.039 mL, 0.223 mmol) were added and the reaction mixture was heated at 100°C under microwave condition for 20 min. The reaction mixture was added CH3CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 33-66% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C.

[0838] Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give N-(3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamide (4.5 mg, 8.66 pmol, 11.64 % yield). LCMS: 95.5% pure, RT = 2.2 min; m / z: 497.1 [M+H]+(Method A). 'HNMR (500 MHz, DMSO-d6) δ 8.29 - 8.18 (m, 2H), 8.08 - 8.01 (m, 1H), 7.95 (br s, 1H), 7.73 (br d, J=7.2 Hz, 1H), 7.66 - 7.53 (m, 1H), 7.46 - 7.30 (m, 3H), 7.14 - 7.02 (m, 2H), 4.71 (br s, 2H), 3.75 (br s, 2H).

[0839] Examples Q-43-59 below were obtained using procedure similar to example Q-42 above. Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0840] (min) / Purity /

[0841] (Method);

[0842] Q-43 497.11H [M+H]+ / 2.19 min NMR (500

[0843] / 98.5% / (Method MHz, L AX

[0844] r ° I / A) DMSO-d6) F3C^ _1KI\Xi NH2δ 8.23 - 8.14 (m, " M 2H), 8.08 - CF38.01 (m,

[0845] 1H), 7.98 - N-(3-(2-aminopyrimidin-5- 7.92 (m, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.79 - bis(trifluoromethyl)phenyl)-N-(2- 7.69 (m, fluorophenyl)acetamide 1H), 7.69 - 7.60 (m, 1H), 7.59 - 7.52 (m, 1H), 7.52 - 7.45 (m, 1H), 7.44 - 7.36 (m, 1H), 7.11 - 7.05 (m, 2H), 4.90 - 4.77 (m, 1H), 4.62 - 4.48 (m, 1H), 3.85 - 3.73 (m, 1H), 3.68 - 3.57 (m,

[0846]

[0847] 1H) _ Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0848] (min) / Purity /

[0849] (Method);

[0850] Q-44 497.11H [M+H]+ / 2.10 min NMR (500 / 98.6% / MHz, (Method A) DMSO-d6) r

[0851] F3C^ J.0L

[0852] KN^NH2δ 8.27 - 8.18 (m, 2H), 8.07 - CF37.98 (m,

[0853] 1H), 7.93 N-(3-(2-aminopyrimidin-5- (s, 1H), yl)prop-2-yn- 1 -yl)-2-(2,4- 7.75 - 7.67 bis(trifluoromethyl)phenyl)-N-(4- (m, 1H), fluorophenyl)acetamide 7.58 - 7.48

[0854] (m, 2H), 7.43 - 7.34 (m, 2H), 7.05 (br s, 2H), 4.67 (s, 2H), 3.68 (br s, 2H) Q-45 493.21H [M+H]+ / 2.3 min / NMR (500 98.7% / (Method MHz, A) DMSO-d6)3r ° 1! J.

[0855] F C.1KN^NH2δ 8.31 - 8.14 (m, 2H), 8.03 CF3(br d,. / =7,0

[0856] Hz, 1H), N-(3-(2-aminopyrimidin-5- 7.94 (br s, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.79 - bis(trifluoromethyl)phenyl)-N-(m- 7.65 (m, tolyl)acetamide, TFA 1H), 7.52 - 7.38 (m, 1H), 7.34 - 7.24 (m, 3H), 4.66

[0857]

[0858] (br s, 2H), Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0859] (min) / Purity /

[0860] (Method);

[0861] 3.71 (br s, 2H), 2.36 (br s, 3H)

[0862] Q-46 493.2

[0863] TTJH

[0864] [M+H]+ / 2.31 min NMR (500 / 99.1% / MHz, f ° I / I (Method A) DMSO-d6)F3CX_J\ ^N^NH2δ 8.25 - TJ 8.17 (m,

[0865] 2H), 8.04 CF3

[0866] (br d, J=7.7 Hz, 1H), N-(3-(2-aminopyrimidin-5- 7.95 (s, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.75 bis(trifluoromethyl)phenyl)-N-(o- (br d,. / =7,9 tolyl)acetamide

[0867] Hz, 1H), 7.50 - 7.33 (m, 4H), 7.08 (s, 2H), 4.86 (br d, J=17.4 Hz, 1H), 4.43 (br d, J=17.6 Hz, 1H), 3.77 - 3.64 (m, 1H), 3.53 - 3.42 (m, 1H), 2.34

[0868]

[0869] (s, 3H) Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0870] (min) / Purity /

[0871] (Method);

[0872] Q-47 505.11H [M+H]+ / 2.38 min NMR (500 OL / 96.7% / MHz,

[0873] (Method A) DMSO-d6) r0I JL δ 8.23 (s, F3C. l ^N^NH22H), 8.04 (br d, J=7.8 Hz, 1H), CF37.95 (s,

[0874] 1H), 7.75 - N-(3-(2-aminopyrimidin-5- 7.68 (m, yl)prop-2-yn- 1 -yl)-N- 1H), 7.31 - (bicyclo[4.2.0]octa-l(6),2,4-trien-3- 7.24 (m, yl)-2-(2,4- 2H), 7.21 bis(trifluoromethyl)phenyl)acetamide (s, 1H),

[0875] 7.08 (s, 2H), 4.65 (s, 2H), 3.70 (br s, 2H), 3.19 (s, 4H) Q-48 537.21H [M+H]+ / 2.38 min NMR (500 / 96.9% / MHz, A> ifx (Method A); DMSO-d6) F3C J. ^N-^NH2

[0876] δ 8.19 (br s, 2H), 8.04 2 (br d, J=8.1

[0877] Hz, 1H), N-(3-(2-aminopyrimidin-5- 7.95 (s, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.73 bis(trifluoromethyl)phenyl)-N-(5- (br d,. / =8,0 cyclopropyl-2- Hz, 1H), fluorophenyl)acetamide 7.37 - 7.30

[0878] (m, 1H), 7.30 - 7.20 (m, 2H), 7.08 (br s,

[0879]

[0880] 2H), 4.82 Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0881] (min) / Purity /

[0882] (Method);

[0883] (d, J=17.7 Hz, 1H), 4.51 (d, J=17.7 Hz, 1H), 3.79 (br d, J=16.4 Hz, 1H), 3.67 - 3.58 (m, 1H), 2.03 - 1.93 (m, 1H), 1.02 - 0.92 (m, 2H), 0.72 - 0.59 (m, 2H)

[0884] Q-49 535.2JH [M+H]+ / 2.04 min NMR (500 / 95.5% / MHz, A iTX

[0885] F3C-^A ^NH2(Method A) DMSO-d6)

[0886] 68.23 (br s, 2H), 8.05 V (br d,. / =8,3

[0887] Hz, 1H), N-(3-(2-aminopyrimidin-5- 7.94 (s, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.74 bis(trifluoromethyl)phenyl)-N-(3- (br d,. / =7,9 (oxetan-3-yl)phenyl)acetamide Hz, 1H),

[0888] 7.62 - 7.51 (m, 2H), 7.50 - 7.42 (m, 1H), 7.42 - 7.32 (m, 1H), 7.08 (br s, 2H), 5.01 - 4.89 (m, 2H), 4.71

[0889]

[0890] (s, 2H), Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0891] (min) / Purity /

[0892] (Method);

[0893] 4.63 - 4.57 (m, 2H), 4.37 - 4.24 (m, 1H), 3.73 (br s, 2H) Q-50 498.2

[0894] [M+H]+ / 1.89 min NMR (500 ix / 92.9% / MHz, (Method A) DMSO-d6) r01 J. 89.23 (s,F3Cy4N1H), 8.53

[0895] (s, 1H), 8.23 (s, CF3

[0896] 2H), 7.65 - 7.49 (m, N-(3-(2-aminopyrimidin-5- 1H), 7.49 - yl)prop-2-yn- 1 -yl)-2-(3, 5 - 7.38 (m, bis(trifluoromethyl)pyridin-2-yl)-N- 1H), 7.38 - (3 -fluorophenyl)acetamide

[0897] 7.26 (m, 2H), 7.08 (s, 2H), 4.73 (s, 2H), 3.93 (s, 2H) Q-51 494.1XH [M+H]+ / 1.97 min NMR (500 / 90.4% / MHz, A- ^X^N (Method A) DMSO-d6) r0I J. 69.21 (s, F, C 1KI\XNH2

[0898] 1H), 8.50 (s, 1H), CF38.22 (s,

[0899] 2H), 7.43 - N-(3-(2-aminopyrimidin-5- 7.31 (m, yl)prop-2-yn- 1 -yl)-2-(3, 5 - 1H), 7.31 - 7.19 (m,

[0900]

[0901] 3H), 7.05 Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0902] (min) / Purity /

[0903] (Method); bis(trifluoromethyl)pyridin-2-yl)-N- (s, 2H), (m-tolyl)acetamide 4.68 (s,

[0904] 2H), 3.87 (s, 2H), 2.33 (s, 3H) Q-52 494.1XH [M+H]+ / 1.97 min NMR (500 / 90.4% / MHz, r ° I J. (Method A) DMSO-d6)F3Cy^NN NH2

[0905] δ 9.22 (s, 1H), 8.52 CF3(s, 1H),

[0906] 8.20 (s, N-(3-(2-aminopyrimidin-5- 2H), 7.50 - yl)prop-2-yn- 1 -yl)-2-(3, 5 - 7.30 (m, bis(trifluoromethyl)pyridin-2-yl)-N- 4H), 7.05 (o-tolyl)acetamide (s, 2H),

[0907] 4.84 (d, J=17.6 Hz, 1H), 4.46 (d, J=17.5 Hz, 1H), 3.83 - 3.76 (m, 1H), 3.66 - 3.60 (m, 1H), 2.35 (s, 3H) Q-53 511.1XH TT [M+H]+ / 2.02 min NMR (500

[0908] / 95.9% / MHz, (Method A)

[0909] °xk iTi DMSO-d6) F3C^ J\L'''I\T '''NH268.36 - 8.30 (m, 1H), 8.23 - CF38.17 (m,

[0910] 4H), 7.59 - 7.50 (m,

[0911]

[0912] 1H), 7.49 - Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0913] (min) / Purity /

[0914] (Method);

[0915] N-(3-(2-aminopyrimidin-5- 7.39 (m, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.36 - bis(trifluoromethyl)phenyl)-N-(2- 7.28 (m, fluorophenyl)-2-oxoacetamide 1H), 7.27 - 7.20 (m, 1H), 7.11 (s, 2H), 5.00 - 4.82 (m, 2H) Q-54 482.1

[0916] [M+H]+ / 2.32 min NMR (500 / 98.9% / MHz, (Method A) DMSO-d6) F3C. ^i\r 69.19 (br s,

[0917] 1H), 8.85 LJ

[0918] (br s, 2H), CF38.06 (br d,

[0919] , / =8.0 Hz, 2-(2,4- 1H), 7.96 bis(trifluoromethyl)phenyl)-N-(4- (br s, 1H), fluorophenyl)-N-(3-(pyrimidin-5- 7.73 (br d, yl)prop-2-yn- 1 -yl)acetamide, / =8.0 Hz,

[0920] 1H), 7.65 - 7.52 (m, 2H), 7.48 - 7.33 (m, 2H), 4.78 (br s, 2H), 3.72 (br s,

[0921]

[0922] 2H) Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0923] (min) / Purity /

[0924] (Method);

[0925] Q-55 / \,F482.1JH C i [M+H]+ / 2.18 min NMR (500

[0926] / 99.1% / MHz, (Method A) DMSO-d6) F ° I J 69.18 (s, F3C^ 1 ^I\r

[0927] 1H), 8.79 (s, 2H), 8.05 (br d, CF3. / =7,9 Hz,

[0928] 1H), 7.96 2-(2,4- (s, 1H), bis(trifluoromethyl)phenyl)-N-(2- 7.75 (br d, fluorophenyl)-N-(3-(pyrimidin-5-, / =8.2 Hz, yl)prop-2-yn- 1 -yl)acetamide 1H), 7.72 - 7.67 (m, 1H), 7.60 - 7.54 (m, 1H), 7.54 - 7.48 (m, 1H), 7.45 - 7.39 (m, 1H), 4.92 (d, J=18.0 Hz, 1H), 4.66 (d, J=17.9 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.71 - 3.58 (m,

[0929]

[0930] 1H) _ Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0931] (min) / Purity /

[0932] (Method);

[0933] Q-56 478.1JH Of [M+H]+ / 2.27 min NMR (500

[0934] / 95.7% / MHz, (Method A) DMSO-d6) r ° I j

[0935] F3c^k 89.18 (s,

[0936] 1H), 8.81 (s, 2H), 8.05 (br d, CF3

[0937] , / =7.5 Hz, 1H), 7.96 2-(2,4- (s, 1H), bis(trifluoromethyl)phenyl)-N-(3- 7.76 (br d, (pyrimidin-5-yl)prop-2-yn- 1 -yl)-N-(o-, / =8.2 Hz, tolyl)acetamide

[0938] 1H), 7.55 - 7.34 (m, 4H), 4.97 (d, J=17.9 Hz, 1H), 4.51 (d, J=17.8 Hz, 1H), 3.72 (br d, J=16.6 Hz, 1H), 3.49 (d,.7=16.8 Hz, 1H), 2.36 (s, 3H) Q-57 / \ F 522.2XH L k [M+H]+ / 2.49 min NMR (500

[0939] / 99.3% / MHz, (Method A) DMSO-d6) r ° I J 69.18 (s, F3C^ 1

[0940] 1H), 8.79 (s, 2H), 8.05 (br d, CF37=7.8 Hz,

[0941] 1H), 7.96 2-(2,4- (s, 1H), bis(trifluoromethyl)phenyl)-N-(5-

[0942]

[0943] 7.73 (d, Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0944] (min) / Purity /

[0945] (Method);

[0946] cyclopropyl-2-fluorophenyl)-N-(3-, / =8.0 Hz, (pyrimidin-5-yl)prop-2-yn- 1 - 1H), 7.35 yl)acetamide (t, J=9.2 Hz, 1H), 7.31 - 7.21 (m, 2H), 4.87 (d, J=17.9 Hz, 1H), 4.67 (d, J=17.9 Hz, 1H), 3.81 (br d, J=17.2 Hz, 1H), 3.65 (d, J=17.2 Hz, 1H), 2.05 - 1.94 (m, 1H), 1.03 - 0.93 (m, 2H), 0.73 - 0.59 (m, 2H) Q-58 520.2XH [M+H]+ / 2.03 min NMR (500 / 95% / (Method MHz, F3C 1 A o ^i\rNA) DMSO-d6)

[0947] 89.18 (s, v 1H), 8.83 CF3(s, 2H),

[0948] 8.06 (br d, 2-(2,4- J=8.4 Hz, bis(trifluoromethyl)phenyl)-N-(3- 1H), 7.95 (oxetan-3 -yl)phenyl)-N-(3 - (br s, 1H), (pyrimidin-5-yl)prop-2-yn- 1 - 7.75 (br d, yl)acetamide, / =8.2 Hz,

[0949] 1H), 7.65 - 7.52 (m,

[0950]

[0951] 2H), 7.52 - Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0952] (min) / Purity /

[0953] (Method);

[0954] 7.38 (m, 2H), 5.09 - 4.89 (m, 2H), 4.82 (br s, 2H), 4.67 - 4.53 (m, 2H), 4.42 - 4.22 (m, 1H), 3.76 (br s, 2H) Q-59 482.1XH [M+H]+ / 2.07 min NMR (500 L I

[0955] / 98.3% / MHz, (Method A) DMSO-d6)

[0956] 89.29 - 9.16 (m, 1H), 8.05 (br d,. / =8,3 CF3Hz, 1H),

[0957] 7.96 (s, 2-(2,4- 1H), 7.79 - bis(trifluoromethyl)phenyl)-N-(2- 7.66 (m, fluorophenyl)-N-(3 -(pyridazin-3 - 4H), 7.61 - yl)prop-2-yn- 1 -yl)acetamide 7.53 (m,

[0958] 1H), 7.54 - 7.47 (m, 1H), 7.46 - 7.37 (m, 1H), 4.95 (br d, J=17.9 Hz, 1H), 4.71 (br d, J=17.7 Hz, 1H), 3.87 - 3.77 (m,

[0959]

[0960] 1H), 3.72 - Example Structure and name Analytical1H # LCMS NMR ESI- MS(+) m / z / RT

[0961] (min) / Purity /

[0962] (Method);

[0963] 3.57 (m,

[0964]

[0965] 1H) _

[0966] Example Q- 60. N-(3-(5-Baminopyrazin-2-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)acetamide (Example 60

[0967]

[0968] In a microwave vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (35 mg, 0.087 mmol), 5-bromopyrazin-2-amine (18.12 mg, 0.104 mmol), Bis(triphenylphosphine)palladium(II) dichloride (12.18 mg, 0.017 mmol) and copper(I) iodide (4.96 mg, 0.026 mmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.045 mL, 0.260 mmol) were added and the reaction mixture was heated at 80°C under microwave condition for 1 hr. The reaction mixture was added CH3CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 33-63% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C.

[0969] Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give N-(3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)acetamide (8.1 mg, 0.015 mmol, 17.67 % yield). LCMS: 100% pure, RT = 2.17 min; m / z: 497.1 [M+H]+(Method A). HPLC purity: 97.72 %, RT = 4.15 min (HPLC Method B). ’H NMR (500 MHz, DMSO-d6) 58.08 - 8.01 (m, 1H), 7.95 (br s, 1H), 7.88 (br s, 1H), 7.81 (br s, 1H), 7.74 (br d, J=7.4 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.59 - 7.52 (m, 1H), 7.52 - 7.44 (m, 1H), 7.44 - 7.36 (m, 1H), 6.85 (br s, 2H), 4.85 (br d, J=18.1 Hz, 1H), 4.56 (br d, J=17.8 Hz, 1H), 3.86 - 3.73 (m, 1H), 3.68 - 3.56 (m, 1H).

[0970] Examples Q-61-84 below were obtained using procedure similar to example Q-60 above.

[0971] Example # Structure and name Ana ‘HNMR

[0972] lytical

[0973] LCMS ESI

[0974] -MS(+)

[0975] m / z / RT

[0976] (min)

[0977] / Purity /

[0978] (Method)

[0979] Q-61 497 ‘HNMR (500 MHz,

[0980] XN^N.1 DMSO-d6) 68.05 (br d,

[0981] [M+H]+ / 2., / =7.5 Hz, 1H), 7.99 - 7.89F3C. / L i ° X ^ 1NH219 min / (m, 2H), 7.82 (br s, 1H), 7.78

[0982] 100% / - 7.69 (m, 1H), 7.67 - 7.55 (Method (m, 1H), 7.48 - 7.29 (m, 3H), A) 4.73 (br s, 2H), 3.76 (br s, 2 2H)

[0983] N-(3 -(5 -aminopyrazin-2- yl)prop-2-yn- 1 -yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(3- fluorophenyl)acetamide, TFA

[0984] Q-62 497 ‘HNMR (500 MHz,

[0985] .0 DMSO-d6) 68.03 (br d, N [M+H]+ / 2. J=8.1 Hz, 1H), 7.97 - 7.87 09 min / (m, 2H), 7.81 (s, 1H), 7.72 F3C 1 i ° X ^NX^NH,

[0986] 100% / (br d, J=7.9 Hz, 1H), 7.59 - (Method 7.46 (m, 2H), 7.44 - 7.33 (m, V CF3A) 2H), 4.69 (s, 2H), 3.69 (br s,

[0987] 2H)

[0988] N-(3 -(5 -aminopyrazin-2- yl)prop-2-yn- 1 -yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(4-

[0989]

[0990] fluorophenyl)acetamide, TFA Example # Structure and name Ana 'HNMR

[0991] lytical

[0992] LCMS ESI

[0993] -MS(+)

[0994] m / z / RT

[0995] (min)

[0996] / Purity /

[0997] (Method)

[0998] Q-63 493 'HNMR (500 MHz,

[0999] ,2[M+H]+ / DMSO-d6) 68.05 - 7.75 (m, 2.29 min / 4H), 7.72 - 7.61 (m, 1H), 98.6% / 7.46 - 7.35 (m, 1H), 7.32 - F3C, 1 r ° 1 ^N 1^NH2

[1000] (Method 7.16 (m, 3H), 4.64 (br s, 2H), A) 3.87 (br s, 2H), 2.33 (br s, CF33H)

[1001] N-(3 -(5 -aminopyrazin-2- yl)prop-2-yn- 1 -yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(m- tolyl)acetamide, TFA

[1002] Q-64 493 'HNMR (500 MHz,

[1003] .2 DMSO-d6) 68.04 (br d, [M+H]+ / 2.. / =7,9 Hz, 1H), 7.95 (s, 1H), F3C JT° J^N^NH 29 min / 7.90 (s, 1H), 7.81 (s, 1H), u2

[1004] 100% / 7.76 (br d, J=7.8 Hz, 1H), (Method 7.49 - 7.32 (m, 4H), 6.84 (s, CF3A) 2H), 4.86 (d, J=17.7 Hz,

[1005] 1H), 4.45 (d, J=17.7 Hz, N-(3 -(5 -aminopyrazin-2- 1H), 3.70 (br d, J=16.6 Hz, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 3.51 - 3.41 (m, 1H), bis(trifluoromethyl)phenyl)-N-(o- 2.39 - 2.32 (m, 3H) tolyl)acetamide

[1006] Q-65 505 'HNMR (500 MHz,

[1007] .1 DMSO-d6) 68.05 - 7.99 (m, N [M+H]+ / 2. 1H), 7.96 - 7.89 (m, 2H), A ll 37 min / 7.82 (s, 1H), 7.70 (br d, F3CXN^NH296.1% / J=8.0 Hz, 1H), 7.29 - 7.21 (Method (m, 2H), 7.19 (s, 1H), 6.83 A) (s, 2H), 4.65 (s, 2H), 3.70 (br s, 2H), 3.18 (s, 4H)

[1008] N-(3 -(5 -aminopyrazin-2-

[1009]

[1010] yl)prop-2-yn- 1 -yl)-N- Example # Structure and name Ana 'HNMR

[1011] lytical

[1012] LCMS ESI

[1013] -MS(+)

[1014] m / z / RT

[1015] (min)

[1016] / Purity /

[1017] (Method)

[1018] (bicyclo[4.2.0]octa-l(6),2,4-trien- 3-yl)-2-(2,4- bis(trifluoromethyl)phenyl)acetam

[1019] ide

[1020] ^^ F

[1021] Q-66 Y Y 537.2 'HNMR (500

[1022] N [M+H]+ / 2.36 MHz, DMSO-d6) 68.04 min / 99% / (br d,. / =8,0 Hz, 1H), 7.95 F3C^^ rL ° L ^N X^NH2

[1023] (Method A) (s, 1H), 7.88 (s, 1H), 7.82

[1024] (s, 1H), 7.73 (d,. / =8,2 Hz, CF3

[1025] 1H), 7.37 - 7.30 (m, 1H), 7.30 - 7.25 (m, 1H), 7.23 - N-(3 -(5 -aminopyrazin-2- 7.19 (m, 1H), 6.84 (s, 2H), yl)prop-2-yn- 1 -yl)-2-(2,4- 4.85 (d, J=17.7Hz, 1H), bis(trifluoromethyl)phenyl)-N-(5- 4.51 (d, J=17.6 Hz, 1H), cyclopropyl-2- 3.80 (br d, <7=17.2 Hz, 1H), fluorophenyl)acetamide

[1026] 3.61 (br d, <7=16.5 Hz, 1H), 2.03 - 1.89 (m, 1H), 1.03 - 0.88 (m, 2H), 0.75 - 0.56 (m, 2H)

[1027] Q-67 / \ F 484 'HNMR (500 MHz,

[1028] TT

[1029] .1 DMSO-d6) 68.08 - 8.02 (m, [M+H]+ / 2. 1H), 7.96 (s, 1H), 7.74 (br d, 26 min / J=7.9 Hz, 1H), 7.69 - 7.61 98.1% / (m, 1H), 7.61 - 7.53 (m, 1H), (Method 7.53 - 7.46 (m, 1H), 7.45 - A) 7.35 (m, 1H), 7.29 - 7.22 (m, 2-(2,4- 1H), 7.01 - 6.87 (m, 1H), bis(trifluoromethyl)phenyl)-N-(2- 4.94 - 4.80 (m, 1H), 4.77 - fluorophenyl)-N-(3 -(1 -methyl- 1 H- 4.62 (m, 1H), 3.86 - 3.75 (m, imidazol-2-yl)prop-2-yn- 1 - 1H), 3.74 - 3.59 (m, 1H), yl)acetamide 3.54 (s, 3H)

[1030]

[1031] Example # Structure and name Ana 'HNMR

[1032] lytical

[1033] LCMS ESI

[1034] -MS(+)

[1035] m / z / RT

[1036] (min)

[1037] / Purity /

[1038] (Method)

[1039] Q-68 _ / \ F 616 'HNMR (500 MHz,

[1040] L I.0 DMSO-d6) 68.11 - 7.99 (m,

[1041] [M+H]+ / 2. 1H), 7.95 (br s, 1H), 7.84 -cA° 61 min / 7.68 (m, 3H), 7.68 - 7.34 (m,F3C^XL, A N HBoc 100% / 4H), 5.01 - 4.75 (m, 1H), (Method 4.58 (d, 7=17.8 Hz, 1H), 4.40 A A) - 4.27 (m, 2H), 3.85 - 3.71 (m, 1H), 3.68 - 3.57 (m, 1H), tert-butyl((4-(3 -(2-(2,4- 1.40 (br s, 9H) bis(trifluoromethyl)phenyl)-N-(2- fluorophenyl)acetamido)prop- 1 - yn-l-yl)thiazol-2- yl)methyl)carbamate

[1042] Q-69 612 'HNMR (500 MHz, or.2 DMSO-d6) 68.04 (br d,

[1043] [M+H]+ / 2. 7=7.5 Hz, 1H), 7.95 (s, 1H),F CA AQ 61 min / 7.81 - 7.72 (m, 3H), 7.48 -3\XA, VNHBOC

[1044] 100% / 7.44 (m, 1H), 7.43 - 7.34 (m, (Method 3H), 4.86 (d, 7=17.6 Hz, A A) 1H), 4.46 (d, 7=17.7 Hz,

[1045] 1H), 4.34 (br d, 7=6.1 Hz, tert-butyl((4-(3 -(2-(2,4- 2H), 3.70 (br d, 7=16.6 Hz, bis(trifluoromethyl)phenyl)-N-(o- 1H), 3.51 - 3.44 (m, 1H), tolyl)acetamido)prop- 1 -yn- 1 - 2.35 (s, 3H), 1.41 (s, 9H) yl)thiazol-2-yl)methyl)carbamate

[1046] Q-70 _ / \ F 656 'HNMR (500 MHz,

[1047] £T.3 DMSO-d6) 68.05 (br d,

[1048] [M+H]+ / 2. 7=8.0 Hz, 1H), 7.95 (s, 1H), [ N= / 69 min / 7.83 - 7.70 (m, 3H), 7.38 - A NHBOC

[1049] 100% / 7.30 (m, 1H), 7.30 - 7.24 (m, (Method 1H), 7.24 - 7.16 (m, 1H), CF3

[1050] A) 4.83 (d, 7=17.8 Hz, 1H), 4.56

[1051] (br d, 7=18.0 Hz, 1H), 4.34 tert-butyl ((4-(3-(2-(2,4- (br d, 7=6.0 Hz, 2H), 3.80 (br

[1052]

[1053] bis(trifluoromethyl)phenyl)-N-(5- Example # Structure and name Ana ‘HNMR

[1054] lytical

[1055] LCMS ESI

[1056] -MS(+)

[1057] m / z / RT

[1058] (min)

[1059] / Purity /

[1060] (Method)

[1061] cyclopropyl-2- d, J=16.6 Hz, 1H), 3.62 (br fluorophenyl)acetamido)prop- 1 - d, J=16.6 Hz, 1H), 2.02 - yn-l-yl)thiazol-2- 1.90 (m, 1H), 1.41 (s, 9H), yl)methyl)carbamate 1.05 - 0.91 (m, 2H), 0.78 - 0.62 (m, 2H)

[1062] Q-71 517 ‘HNMR (500 MHz,

[1063] L I.1 DMSO-d6) 68.12 - 8.01 (m,

[1064] [M+H]+ / 2. 1H), 7.96 (s, 1H), 7.75 (br d, 22 min / , / =7.9 Hz, 1H), 7.67 - 7.60F3C>A 'VOH 100% / (m, 1H), 7.60 - 7.54 (m, 1H),

[1065] (Method 7.54 - 7.47 (m, 2H), 7.45 - V A) 7.38 (m, 1H), 4.87 (d, J=18.1

[1066] Hz, 1H), 4.71 (d, J=17.9 Hz, 2-(2,4- 1H), 4.54 (s, 2H), 3.87 - 3.75 bis(trifluoromethyl)phenyl)-N-(2- (m, 1H), 3.70 - 3.57 (m, 1H) fluorophenyl)-N-(3-(4- (hydroxymethyl)thiazol-2-yl)prop- 2-yn- 1 -yl)acetamide

[1067] Q-72 513 ‘HNMR (500 MHz,

[1068] .1 DMSO-d6) 68.04 (br d, [M+H]+ / 2. J=7.8 Hz, 1H), 7.95 (s, 1H), 29 min / 7.77 (d, J=8.0 Hz, 1H), 7.53F’C\A V, OH 100% / (s, 1H), 7.50 - 7.44 (m, 1H),

[1069] (Method 7.44 - 7.35 (m, 3H), 5.41 (t, 2 A) J=5.8 Hz, 1H), 4.93 (d, J=17.9 Hz, 1H), 4.60 - 4.49 2-(2,4- (m, 3H), 3.73 (br d, J=17.1 bis(trifluoromethyl)phenyl)-N-(3- Hz, 1H), 3.53 - 3.45 (m, 1H), (4-(hydroxymethyl)thiazol-2- 2.36 (s, 3H) yl)prop-2-yn- 1 -yl)-N-(o- tolyl)acetamide

[1070]

[1071] Example # Structure and name Ana ‘HNMR

[1072] lytical

[1073] LCMS ESI

[1074] -MS(+)

[1075] m / z / RT

[1076] (min)

[1077] / Purity /

[1078] (Method)

[1079] Q-73 557 ‘HNMR (500 MHz,

[1080] .2 DMSO-d6) 68.05 (br d, [M+H]+ / 2. J=7.8 Hz, 1H), 7.96 (s, 1H), 39 min / 7.74 (d,. / =8,2 Hz, 1H), 7.71F3C> A ~ VOH 96.3% / - 7.71 (m, 1H), 7.54 (s, 1H),

[1081] (Method 7.38 - 7.32 (m, 1H), 7.31 - V A) 7.26 (m, 1H), 7.25 - 7.21 (m,

[1082] 1H), 5.42 (t, J=5.6 Hz, 1H), 2-(2,4- 4.87 (d, J=17.9 Hz, 1H), 4.63 bis(trifluoromethyl)phenyl)-N-(5- - 4.63 (m, 1H), 4.67 (d, cyclopropyl-2-fluorophenyl)-N-(3- J=18.0 Hz, 1H), 4.55 (d, (4-(hydroxymethyl)thiazol-2-. / =5,6 Hz, 2H), 3.82 (br d, yl)prop-2-yn- 1 -yl)acetamide J=16.6 Hz, 1H), 3.63 (br d,

[1083] J=16.8 Hz, 1H), 2.06 - 1.86 (m, 1H), 1.06 - 0.90 (m, 2H), 0.78 - 0.60 (m, 2H)

[1084] Q-74 525 ‘HNMR (500 MHz,

[1085] .2 DMSO-d6) 68.03 (br d, [M+H]+ / 2.. / =8,2 Hz, 1H), 7.95 (s, 1H), £ s 29 min / 7.72 (br d, J=7.9 Hz, 1H),

[1086] 96.2% / 7.59 - 7.46 (m, 1H), 7.30 -F3C'VA5IVOH (Method 7.24 (m, 2H), 7.21 (s, 1H), T J

[1087] A) 4.75 (s, 2H), 4.55 (br s, 2H), CF33.73 (br s, 2H), 3.19 (s, 4H)

[1088] N-(bicyclo[4.2.0]octa- l(6),2,4-trien-3-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(3- (4-(hydroxymethyl)thiazol-2- yl)prop-2-yn- 1 -yl)acetamide

[1089]

[1090] Example # Structure and name Ana 'HNMR

[1091] lytical

[1092] LCMS ESI

[1093] -MS(+)

[1094] m / z / RT

[1095] (min)

[1096] / Purity /

[1097] (Method)

[1098] Q-75 531 'HNMR (500 MHz,

[1099] [ Y.1 DMSO-d6) 68.31 (br d,

[1100] [M+H]+ / 2. J=8.0Hz, 1H), 8.26 - 8.12 °Y^ Y> 05 min / (m, 2H), 7.58 - 7.42 (m, 3H),F3C\<AX \__0H 98.8% / 7.38 - 7.29 (m, 1H), 7.27 - (Method 7.15 (m, 1H), 5.00 (br s, 2H),

[1101] 4.55 (d, J=5.6 Hz, 2H), 3.17 CF3A)

[1102] (d, J=5.1 Hz, 1H)

[1103] 2-(2,4- bis(trifluoromethyl)phenyl)-N-(2- fluorophenyl)-N-(3-(4- (hydroxymethyl)thiazol-2-yl)prop- 2-yn- 1 -yl)-2-oxoacetamide

[1104] Q-76 539 'HNMR (500 MHz,

[1105] .2 DMSO-d6) 68.32 - 8.23 (m, [M+H]+ / 2. 1H), 8.23 - 8.14 (m, 2H), 16 min / 7.55 (s, 1H), 7.18 - 7.11 (m, Y^° I? 100% / 1H), 7.10 - 7.02 (m, 2H),F3C\AX ' VOH

[1106] (Method 4.96 (s, 2H), 4.55 (d, J=5.6 A) Hz, 2H), 3.17 (br d, J=5.0 CF3Hz, 1H), 3.10 - 3.02 (m, 4H) N-(bicyclo[4.2.0]octa- l(6),2,4-trien-3-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(3- (4-(hydroxymethyl)thiazol-2- yl)prop-2-yn- 1 -yl)-2- oxoacetamide

[1107]

[1108] Example # Structure and name Ana 'HNMR

[1109] lytical

[1110] LCMS ESI

[1111] -MS(+)

[1112] m / z / RT

[1113] (min)

[1114] / Purity /

[1115] (Method)

[1116] Q-77 514 'HNMR (500 MHz,

[1117] .1 DMSO-d6) δ 9.23 (s, 1H), £ 'A\.s [M+H]+ / 2. 8.53 (s, 1H), 7.53 (s, 1H), r^° TJ 01 min / 7.48 - 7.44 (m, 1H), 7.43 -F’cy4NVOH 97.4% / 7.33 (m, 3H), 4.90 (d, J=17.9

[1118] (Method Hz, 1H), 4.64 - 4.51 (m, 3H), CF3A) 3.86 - 3.78 (m, 1H), 3.70 - 3.62 (m, 1H), 2.37 (s, 3H) 2-(3,5- bis(trifluoromethyl)pyridin-2-yl)- N-(3-(4-(hydroxymethyl)thiazol-2- yl)prop-2-yn- 1 -yl)-N-(o- tolyl)acetamide, TFA

[1119] Q-78 _ / \ F

[1120] Ci 512 'HNMR (500 MHz,

[1121] .2 DMSO-d6) 68.76 (br s, 2H), [M+H]+ / 2. 8.05 (br d, J=8.5 Hz, 1H), 02 min / 7.96 (s, 1H), 7.74 (br d, 98.2% / J=8.4 Hz, 1H), 7.69 (brt, (Method. / =7,4 Hz, 1H), 7.61 - 7.54 CF3A) (m, 1H), 7.54 - 7.46 (m, 1H),

[1122] 7.45 - 7.38 (m, 1H), 4.96 - 2-(2,4- 4.88 (m, 1H), 4.75 - 4.54 (m, bis(trifluoromethyl)phenyl)-N-(2- 3H), 3.81 (br d, J=16.4 Hz, fluorophenyl)-N-(3-(2- 1H), 3.71 - 3.60 (m, 1H) (hydroxymethyl)pyrimidin-5- yl)prop-2-yn- 1 -yl)acetamide

[1123] Q-79 508 'HNMR (500 MHz,

[1124] .2 DMSO-d6) 68.77 (br s, 2H), [M+H]+ / 2. 8.05 (br d, J=7.8 Hz, 1H),... A 1 min / 7.96 (s, 1H), 7.76 (br d,

[1125] 100% / J=7.9 Hz, 1H), 7.51 - 7.44 (Method (m, 2H), 7.43 - 7.37 (m, 2H), CF3A) 5.48 - 5.32 (m, 1H), 4.95 (br

[1126]

[1127] d, J=17.8 Hz, 1H), 4.70 - Example # Structure and name Ana 'HNMR

[1128] lytical

[1129] LCMS ESI

[1130] -MS(+)

[1131] m / z / RT

[1132] (min)

[1133] / Purity /

[1134] (Method)

[1135] 2-(2,4- 4.56 (m, 2H), 4.50 (br d, bis(trifluoromethyl)phenyl)-N-(3- J=17.7Hz, 1H), 3.72 (brd, (2-(hydroxymethyl)pyrimidin-5- J=16.9Hz, 1H), 3.56 - 3.43 yl)prop-2-yn- 1 -yl)-N-(o- (m, 1H), 2.36 (s, 3H) tolyl)acetamide

[1136] Q-80 / \,F552 'HNMR (500 MHz,

[1137] £ ¥.2 DMSO-d6) 68.75 (br s, 2H),

[1138] [M+H]+ / 2. 8.05 (br d, J=7.6 Hz, 1H), ¥° £ X-X / - °H24 min / 7.96 (s, 1H), 7.73 (br d,

[1139] 99.2% / J=8.2Hz, 1H), 7.39 - 7.31 " Q (Method (m, 1H), 7.31 - 7.24 (m, 2H), CF3A) 4.87 (brd, J=18.0Hz, 1H),

[1140] 4.70 - 4.58 (m, 3H), 3.81 (br 2-(2,4- d, J=16.6Hz, 1H), 3.64 (br bis(trifluoromethyl)phenyl)-N-(5- d, J=16.5 Hz, 1H), 2.05 - cyclopropyl-2-fluorophenyl)-N-(3- 1.93 (m, 1H), 1.04 - 0.91 (m, (2-(hydroxymethyl)pyrimidin-5- 2H), 0.72 - 0.59 (m, 2H) yl)prop-2-yn- 1 -yl)acetamide

[1141] Q-81 520 'HNMR (500 MHz,

[1142] £1.1 DMSO-d6) 68.81 (br s, 2H),

[1143] [M+H]+ / 2. 8.03 (br d, J=8.0 Hz, 1H), 20 min / 7.95 (s, 1H), 7.77 - 7.67 (m,F.e^ ° ¥vV0H 97.4% / 1H), 7.37 - 7.19 (m, 3H), (Method 4.96 - 4.46 (m, 4H), 3.72 (br CF3A) s, 2H), 3.19 (s, 4H)

[1144] N-(bicyclo[4.2.0]octa- l(6),2,4-trien-3-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(3- (2-(hydroxymethyl)pyrimidin-5- yl)prop-2-yn- 1 -yl)acetamide

[1145]

[1146] Example # Structure and name Ana 'HNMR

[1147] lytical

[1148] LCMS ESI

[1149] -MS(+)

[1150] m / z / RT

[1151] (min)

[1152] / Purity /

[1153] (Method)

[1154] Q-82 501 'HNMR (500 MHz,

[1155] L I.1 DMSO-d6) 68.05 (br d, £ 0 [M+H]+ / 2. J=8.0 Hz, 1H), 8.01 - 7.97 06 min / (m, 1H), 7.96 (s, 1H), 7.75 O° X?

[1156] F3C\<^L. \_,0H 100% / (br d,. / =7,9 Hz, 1H), 7.67 - (Method 7.53 (m, 2H), 7.53 - 7.46 (m, M A) 1H), 7.44 - 7.38 (m, 1H), CF35.30 - 5.23 (m, 1H), 4.90 - 4.83 (m, 1H), 4.75 - 4.68 (m, 2-(2,4- 1H), 4.35 (br d, J=5.7 Hz, bis(trifluoromethyl)phenyl)-N-(2- 2H), 3.87 - 3.76 (m, 1H), fluorophenyl)-N-(3-(4- 3.70 - 3.60 (m, 1H) (hydroxymethyl)oxazol-2-yl)prop- 2-yn- 1 -yl)acetamide

[1157] Q-83 497 'HNMR (500 MHz,

[1158] or.1 DMSO-d6) 68.04 (br d,

[1159] [M+H]+ / 2., / =7.5 Hz, 1H), 7.99 (s, 1H),fA rQ 14 min / 7.95 (s, 1H), 7.76 (d, J=8.1F3C\rA^1\^OH

[1160] 97.6% / Hz, 1H), 7.51 - 7.44 (m, 1H), (Method 7.44. 7.36 (m, 3H), 4.93 (d, 2

[1161] A) J=18.0 Hz, 1H), 4.53 (d, J=18.0 Hz, 1H), 4.36 (s, 2H), 2-(2,4- 3.73 (br d, J=17.1 Hz, 1H), bis(trifluoromethyl)phenyl)-N-(3- 3.54 - 3.43 (m, 1H), 2.34 (s, (4-(hydroxymethyl)oxazol-2- 3H)

[1162] yl)prop-2-yn- 1 -yl)-N-(o- tolyl)acetamide

[1163]

[1164] Example # Structure and name Ana 'HNMR

[1165] lytical

[1166] LCMS ESI

[1167] -MS(+)

[1168] m / z / RT

[1169] (min)

[1170] / Purity /

[1171] (Method)

[1172] Q-84 509 'HNMR (500 MHz,

[1173] .2 DMSO-d6) 68.04 (br d, [M+H]+ / 2.. / =7,7 Hz, 1H), 8.00 (s, 1H), r o 23 min / 7.95 (s, 1H), 7.72 (br d,

[1174] 99.4% / J=7.8 Hz, 1H), 7.33 - 7.24 ~ VOH (Method (m, 2H), 7.21 (s, 1H), 4.75 j j

[1175] A) (s, 2H), 4.36 (br s, 2H), 3.73 CF3(br s, 2H), 3.20 (s, 4H)

[1176] N-(bicyclo[4.2.0]octa- l(6),2,4-trien-3-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-(3- (4-(hydroxymethyl)oxazol-2- yl)prop-2-yn- 1 -yl)acetamide

[1177]

[1178] Example Q-85: N-(3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamide (Example 85)

[1179]

[1180] In a microwave vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)-N-(prop- 2-yn-l-yl)acetamide (35 mg, 0.087 mmol), 5-bromo-l-methyl-lH-pyrazol-3-amine (18.33 mg, 0.104 mmol), XPhos Pd G3 (7.35 mg, 8.68 pmol) and copper(I) iodide (1.653 mg, 8.68 pmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.045 mL, 0.260 mmol) were added and the reaction mixture was heated at 80 °C under microwave condition for Ih. The reaction mixture was then added CH3CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 33-68% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give N-(3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamide (5.7 mg, 0.011 mmol, 12.91 % yield). LCMS: 100% pure, RT = 2.19 min; m / z: 499.2 [M+H]+(Method A). HPLC purity: 97.72 %, RT - 4.15 min (HPLC Method B).JH NMR (500 MHz, DMSO-d6) 5 8.13 - 8.00 (m, IH), 7.96 (s, IH), 7.77 - 7.66 (m, IH), 7.66 - 7.54 (m, IH), 7.50 - 7.28 (m, 3H), 5.55 (s, IH), 4.79 (s, 2H), 3.84 - 3.65 (m, 2H), other peaks overlapping with solvent peak which was minimized.

[1181] Examples Q-86-102 below were obtained using procedure similar to example Q-85 above.

[1182] Structure and name Analytic 'HNMR Example al LCMS

[1183] #

[1184] ESI- MS(+) m / z / RT

[1185] (min) / Purity /

[1186] (Method)

[1187] Q-86 / \ F 499.1XH NMR (500 MHz,

[1188] [M+H]+ / 2.18 DMSO-d6) 88.08 - 8.03 (m, min / 98.7% / IH), 7.96 (s, IH), 7.77 - 7.70 (Method A) (m, IH), 7.67 - 7.60 (m, IH),

[1189] 7.59 - 7.53 (m, IH), 7.52 -FiciS 7.45 (m, IH), 7.44 - 7.37 (m, CF3IH), 5.53 (s, IH), 4.88 - 4.79

[1190] (m, IH), 4.75 - 4.61 (m, 3H), N-(3-(3-amino-l- 3.89 - 3.72 (m, IH), 3.70 - methyl-lH-pyrazol-5-yl)prop-2- 3.58 (m, IH), 3.45 (s, 3H) yn-l-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N-

[1191]

[1192] (2-fluorophenyl)acetamide Structure and name Analytic 'HNMR Example al LCMS

[1193] #

[1194] ESI- MS(+) m / z / RT

[1195] (min) / Purity /

[1196] (Method)

[1197] Q-87 499 'HNMR (500 MHz,

[1198] [M+H]+ / 2.12 DMSO-d6) 68.03 (br d, min / 97.9% / . / =7,6 Hz, 1H), 7.94 (s, 1H), (Method A) 7.71 (br d, J=7.9 Hz, 1H),

[1199] 7.58 - 7.49 (m, 2H), 7.46 - 7.33 (m, 2H), 5.57 (s, 1H), CF34.74 (s, 2H), 3.71 (br s, 2H),

[1200] 3.49(s, 3H)

[1201] N-(3-(3-amino-l- methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N- (4-fluorophenyl)acetamide

[1202] Q-88 495.1[M 'HNMR (500 MHz,

[1203] +H]+ / 2.27 min / DMSO-d6) 68.09 - 8.00 (m, 98.9% / 1H), 7.95 (br s, 1H), 7.78 - 1 N

[1204] X (Method A) 7.68 (m, 1H), 7.50 - 7.39 (m,; N 1H), 7.36 - 7.22 (m, 3H), F3C 1 \ 5.55 (br s, 1H), 4.84 - 4.61 (m, 4H), 3.73 (br s, 2H), 3.44 (br s, 3H), 2.36 (s, 3H).

[1205] N-(3-(3-amino-l- methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N- (m-tolyl)acetamide

[1206] Q-89 495.2 'HNMR (500 MHz, or [M+H]+ / 2.26 DMSO-d6) 68.01 (br d, i N min / 93.9% / J=8.9 Hz, 1H), 7.94 (s, 1H), O L / / N(Method A) 7.72 (d, J=8.1 Hz, 1H), 7.47

[1207] - 7.43 (m, 1H), 7.42 - 7.35 I J (m, 3H), 5.56 (s, 1H), 4.88 (d, J=17.7 Hz, 1H), 4.46 (d, CF3

[1208] J=17.8 Hz, 1H), 3.46 (s, 3H),

[1209]

[1210] 2.32 (s, 3H) Structure and name Analytic 'HNMR Example al LCMS

[1211] #

[1212] ESI- MS(+) m / z / RT

[1213] (min) / Purity /

[1214] (Method)

[1215] N-(3-(3-amino-l- Other peaks methyl-lH-pyrazol-5-yl)prop-2- overlapping with solvent yn-l-yl)-2-(2,4- peak which was minimized. bis(trifluoromethyl)phenyl)-N- (o-tolyl)acetamide

[1216] Q-90 507.1 'HNMR (500 MHz,

[1217] [M+H]+ / 2.36 DMSO-d6) 68.03 (br d, min / 99.5% / . / =8,2 Hz, 1H), 7.95 (s, 1H), N V* (Method A) 7.71 (br d, J=7.5 Hz, 1H),

[1218] 7.32 - 7.23 (m, 2H), 7.23 -F, CIS 7.17 (m, 1H), 5.55 (s, 1H), CF34.72 (s, 2H), 3.72 (s, 2H),

[1219] 3.48 (s, 3H), 3.19 (s, 4H) N-(3-(3-amino-l- methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-N-(bicyclo[4.2.0]octa- l(6),2,4-trien-3-yl)-2-(2,4- bis(trifluoromethyl)phenyl)acet

[1220] amide

[1221] Q-91 539.2 'HNMR (500 MHz,

[1222] XT [M+H]+ / 2.37 DMSO-d6) 67.81 (br d, min / 98.7% / J=7.7Hz, 1H), 7.71 (s, 1H), F, C JL \ (Method A) 7.49 (br d, J=8.1 Hz, 1H), "H27.14 - 7.05 (m, 1H), 7.05 - CF36.96 (m, 2H), 5.30 (s, 1H),

[1223] 4.64 - 4.52 (m, 1H), 4.51 - N-(3-(3-amino-l- 4.34 (m, 1H), 3.57 (brd, methyl-lH-pyrazol-5-yl)prop-2- J=16.8 Hz, 1H), 3.46 - 3.35 yn-l-yl)-2-(2,4- (m, 1H), 3.22 (s, 3H), 1.78 - bis(trifluoromethyl)phenyl)-N- 1.68 (m, 1H), 0.81 - 0.69 (m, (5-cyclopropyl-2- 2H), 0.50 - 0.34 (m, 2H). fluorophenyl)acetamide

[1224]

[1225] Structure and name Analytic 'HNMR Example al LCMS

[1226] #

[1227] ESI- MS(+) m / z / RT

[1228] (min) / Purity /

[1229] (Method)

[1230] Q-92 537.0 'HNMR (500 MHz,

[1231] [M+H]+ / 2.00 DMSO-d6) 68.10 - 8.00 (m, min / 94.4% / 1H), 7.94 (s, 1H), 7.73 (br d, (Method B) J=8.2 Hz, 1H), 7.61 - 7.43 (m, 3H), 7.43 - 7.29 (m, 1H), X4h:5.54 (s, 1H), 5.03 - 4.89 (m, CF32H), 4.78 (s, 2H), 4.65 - 4.53

[1232] (m, 2H), 4.41 - 4.23 (m, 1H), N-(3-(3-amino-l- 3.75 (br s, 2H), 3.46 (s, 3H) methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N- (3-(oxetan-3- yl)phenyl)acetamide

[1233] Q-93 F 513.2 N / A [M+H]+ / 2.01

[1234] min / 98.4% /

[1235] (Method A)

[1236] F3C X \

[1237] M "H2

[1238] CF3

[1239] N-(3-(3-amino-l- methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-2-(2,4- bis(trifluoromethyl)phenyl)-N- (2-fluorophenyl)-2- oxoacetamide

[1240] Q-94 500.2 'HNMR (500 MHz,

[1241] [M+H]+ / 1.88 DMSO-d6) δ 9.22 (br s, 1H), min / 94.3% / 8.51 (br s, 1H), 7.72 - 7.50 i N (Method A) (m, 1H), 7.50 - 7.38 (m, 1H), A 7.38 - 7.25 (m, 2H), 5.77 (s, F3C Y / ^LUN \ NH21H), 4.81 (br s, 2H), 3.96 (br s, 2H)

[1242] CF3

[1243]

[1244] Structure and name Analytic 'HNMR Example al LCMS

[1245] #

[1246] ESI- MS(+) m / z / RT

[1247] (min) / Purity /

[1248] (Method)

[1249] N-(3-(3-amino-l- Other peaks methyl-lH-pyrazol-5-yl)prop-2- overlapping with solvent yn-l-yl)-2-(3,5- peak which was minimized. bis(trifluoromethyl)pyridin-2- yl)-N-(3- fluorophenyl)acetamide, TFA

[1250] Q-95 496.2 'HNMR (500 MHz,

[1251] [M+H]+ / 1.96 DMSO-d6) δ 9.22 (br s, 1H), min / 99.0% / 8.50 (br s, 1H), 7.49 - 7.34 (Method A) (m, 1H), 7.30 - 7.17 (m, 3H), A0L?

[1252] F3C 1K1\ 5.56 (s, 1H), 4.75 (s, 2H), V j NH2

[1253] 3.90 (br s, 2H), 2.33 (s, 3H) Other peaks CF3

[1254] overlapping with solvent peak which was minimized. N-(3-(3-amino-l- methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-2-(3,5- bis(trifluoromethyl)pyridin-2- yl)-N-(m-tolyl)acetamide

[1255] Q-96 508.5 'HNMR (500 MHz,

[1256] [M+H]+ / 2.05 DMSO-d6) δ 9.22 (br s, 1H), min / 100% / 8.52 (br s, 1H), 7.35 - 7.10 (Method A) (m, 3H), 5.56 (br s, 1H), 4.73

[1257] (s, 2H), 3.88 (br s, 2H), 3.49 (s, 3H), 3.17 (s, 4H) Other peaks overlapping with solvent N-(3-(3-amino-l- peak which was minimized. methyl-lH-pyrazol-5-yl)prop-2- yn-l-yl)-N-(bicyclo[4.2.0]octa- l(6),2,4-trien-3-yl)-2-(3,5- bis(trifluoromethyl)pyridin-2- yl)acetamide

[1258]

[1259] Structure and name Analytic 'HNMR Example al LCMS

[1260] #

[1261] ESI- MS(+) m / z / RT

[1262] (min) / Purity /

[1263] (Method)

[1264] Q-97 / \ F 499.1[M 'HNMR (500 MHz, f ¥ +H]+ / 2.09 min / DMSO-d6) 68.06 - 8.02 (m,

[1265] 100% / (Method 1H), 7.95 (s, 1H), 7.76 - 7.72 A) (m, 1H), 7.67 - 7.31 (m, 4H), -A A 5.58 (br s, 1H), 4.96 - 4.69 (m, 1H), 4.56 - 4.30 (m, 1H), CF33.84 - 3.68 (m, 1H), 3.67 - 3.52 (m, 1H)

[1266] N-(3-(2-amino-l- Other peaks methyl-lH-imidazol-4-yl)prop- overlapping with solvent 2-yn-l-yl)-2-(2,4- peak which was minimized. bis(trifluoromethyl)phenyl)-N- (2-fluorophenyl)acetamide

[1267] Q-98 or 495.2 'HNMR (500 MHz,

[1268] [M+H]+ / 2.16 DMSO-d6) 68.06 - 8.01 (m, 0° rO min / 94.4% / 1H), 7.95 (s, 1H), 7.79 - 7.73

[1269] (Method A) (m, 1H), 7.52 - 7.29 (m, 4H),F,cn 5.53 (br s, 1H), 4.96 - 4.65 (m, 1H), 4.54 - 4.28 (m, 1H), CF33.77 - 3.57 (m, 1H), 2.34 (br s, 3H)

[1270] N-(3-(2-amino-l- Other peaks methyl-lH-imidazol-4-yl)prop- overlapping with solvent 2-yn-l-yl)-2-(2,4- peak which was minimized bis(trifluoromethyl)phenyl)-N- (o-tolyl)acetamide

[1271] Q-99 n 542.1 'HNMR (400 MHz,

[1272] [M+H]+ / 2.43 CHLOROFORM-d) 87.88 r0L / / Nmin / 99.1% / (s, 1H), 7.80 (d,. / =8,0 Hz, Il 1 (Method A) 1H), 7.55 (d,.7=8.1 Hz, 1H),

[1273] zk~OMe

[1274] 7.53 - 7.40 (m, 2H), 7.36 - CF37.27 (m, 2H), 6.87 (s, 1H),

[1275] 4.98 (d, 7=17.7 Hz, 1H), 4.66 Methyl 5-(3-(2-(2,4- (d, 7=17.8 Hz, 1H), 3.94 (s, bis(trifluoromethyl)phenyl)-N- 3H), 3.88 (s, 3H), 3.77 (d, (2- 7=16.7 Hz, 1H), 3.62 (d,

[1276]

[1277] fluorophenyl)acetamido)prop- 1 - 7=16.7 Hz, 1H) Structure and name Analytic 'HNMR Example al LCMS

[1278] #

[1279] ESI- MS(+) m / z / RT

[1280] (min) / Purity /

[1281] (Method)

[1282] yn- 1 -yl)- 1 -methyl- IH-pyrazole- 3- carboxylatefluorophenyl)aceta

[1283] mide

[1284] Q-100 538.21HNMR (400 MHz,

[1285] or

[1286] [M+H]+ / 2.52 CHLOROFORM-d) 87.89 min / 100% / (s, 1H), 7.79 (d, J=8.1 Hz, O V

[1287] F3C^X \ (Method A) 1H), 7.52 (d, J=8.1 Hz, 1H), Il 1 z^~OMe 7.44 - 7.32 (m, 3H), 7.32 - CF37.26 (m, 1H), 6.88 (br s, 1H),

[1288] 5.05 (d, J=17.5 Hz, 1H), 4.48 methyl 5-(3-(2-(2,4- (d, J=17.5 Hz, 1H), 3.94 (s, bis(trifluoromethyl)phenyl)-N- 3H), 3.86 (s, 3H), 3.69 (d, (o-tolyl)acetamido)prop- 1 -yn- 1 - J=17.1 Hz, 1H), 3.47 (d, yl)-l-methyl-lH-pyrazole-3- J=17.0 Hz, 1H), 2.39 (s, 3H). carboxylate

[1289] Q-101F545.11HNMR (400 MHz,

[1290] L I [M+H]+ / 2.47 CHLOROFORM-d) 68.21 min / 100% / (br s, 1H), 7.87 (s, 1H), 7.81 r^° L? (Method A) (br d, J=8.0 Hz, 1H), 7.57 (brF3C^, \ d, J=8.0 Hz, 1H), 7.52 - 7.43 T Jo^OMe (m, 2H), 7.36 - 7.24 (m, 2H),

[1291] 5.10 (br d, J=17.7 Hz, 1H),F3

[1292] 4.48 (br d, J=17.5 Hz, 1H), 3.99 (s, 3H), 3.75 (d, J=16.6 methyl 2-(3-(2-(2,4- Hz, 2H), 3.63 (d, J=16.7 Hz, bis(trifluoromethyl)phenyl)-N- 1H)

[1293] (2- fluorophenyl)acetamido)prop- 1 - yn- 1 -yl)thiazole-4-carboxylate

[1294]

[1295] Structure and name Analytic 'H NMR Example al LCMS

[1296] #

[1297] ESL MS(+) m / z / RT

[1298] (min) / Purity /

[1299] (Method)

[1300] Q-102 or 541.11HNMR (400 MHz,

[1301] [M+H]+ / 2.55 CHLOROFORM-d) 88.18 min / 100% / (s, 1H), 7.88 (s, 1H), 7.80 (d, ^0% (Method A) J=8.2 Hz, 1H), 7.55 (d, J=8.1 T? ^OMe

[1302] Hz, 1H), 7.42 - 7.34 (m, 2H), CF37.34 - 7.31 (m, 2H), 5.07 (d,

[1303] J=17.5 Hz, 1H), 4.42 (d, methyl 2-(3-(2-(2,4- J=17.5 Hz, 1H), 3.98 (s, 3H), bis(trifluoromethyl)phenyl)-N- 3.67 (d, J=17.0 Hz, 1H), 3.48 (o-tolyl)acetamido)prop- 1 -yn- 1 - (d, J=17.1 Hz, 1H), 2.38 (s, yl)thiazole-4-carboxylate 3H)

[1304]

[1305] Example Q-103: 2-(4-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamido)prop-l-yn-l-yl)-lH-pyrazol-l-yl)propanamide (Example 103)

[1306]

[1307] In a reaction vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide (35 mg, 0.087 mmol), 2-(4-Iodo-lh-pyrazol-l-yl)propanamide (27.6 mg, 0.104 mmol), XPhos Pd G3 (7.35 mg, 8.68 pmol) and copper(I) iodide (1.653 mg, 8.68 pmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.045 mL, 0.260 mmol) were added and the reaction mixture was heated at 60 °C for 2 hr. The reaction mixture was then added CH3CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 33-66% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give 2-(4-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-fluorophenyl)acetamido)prop-l-yn-l-yl)-lH-pyrazol-l-yl)propanamide (8.5 mg, 0.016 mmol, 18.12 % yield). LCMS: 100% pure, RT = 2.17 min; m / z: 541.2 [M+H]+(Method A). 'H NMR (500 MHz, DMSO-d6) 68.05 (br d, J=7.5 Hz, 1H), 8.00 (br s, 1H), 7.95 (br s, 1H), 7.73 (br d, J=7.9 Hz, 1H), 7.66 - 7.46 (m, 3H), 7.46 - 7.29 (m, 3H), 7.25 (br s, 1H), 5.04 -4.87 (m, 1H), 4.69 (br s, 2H), 3.75 (br s, 2H), 1.58 (br d, J=5.6 Hz, 3H).

[1308] Examples Q-104-108 below were obtained using procedure similar to example Q-103 above.

[1309] Structure and name Analytical ‘HNMR Exampl LCMS

[1310] e #

[1311] ESI-MS(+)

[1312] m / z / RT (min)

[1313] / Purity / (Method)

[1314] Q-104 541.2[M+H]+‘HNMR L I / 2.2 min / 100% / (500 MHz,

[1315] (Method A) DMSO-d6) 6 Ao

[1316] 8.09 - 8.02 (m, A

[1317] 1H), 7.99 - 7.93 (m, 2H), 7.74 (d, CF3J=8.1 Hz, 1H),

[1318] 7.62 (t,. / =7,7 2-(4-(3-(2-(2,4- Hz, 1H), 7.58 - bis(trifluoromethyl)phenyl)-N-(2- 7.45 (m, 4H), fluorophenyl)acetamido)prop- 1 -yn- 7.44 - 7.37 (m, 1 -yl)- IH-pyrazol- 1 -yl)propanamide 1H), 7.24 (br s,

[1319] 1H), 4.97 - 4.92 (m, 1H), 4.82 (br d, J=17.9 Hz, 1H), 4.51 (d, J=17.7 Hz, 1H), 3.79 (br d, J=16.6 Hz, 1H), 3.62 (br d,

[1320]

[1321] J=16.8 Hz, 1H), Structure and name Analytical ‘HNMR Exampl LCMS

[1322] e #

[1323] ESI-MS(+)

[1324] m / z / RT (min)

[1325] / Purity / (Method)

[1326] 1.57 (d, J=7.2 Hz, 3H)

[1327] Q-105 541.0 ‘HNMR XI [M+H]+ / 2.09 min / (400 MHz, Ao)pN 100% / (Method A) CHL0R0F0R F3C J. \NH2 M-d) 87.87 (s,

[1328] 1H), 7.79 (br d, " Q O)

[1329] J=8.0 Hz, 1H), CF37.66 (br s, 2H),

[1330] 7.55 (d, J=8.1 2-(4-(3-(2-(2,4- Hz, 1H), 7.41 - bis(trifluoromethyl)phenyl)-N-(4- 7.31 (m, 2H), fluorophenyl)acetamido)prop- 1 -yn- 7.25 - 7.15 (m, 1 -yl)- IH-pyrazol- 1 -yl)propanamide 2H), 6.34 (br s,

[1331] 1H), 5.51 (br s, 1H), 4.87-5.01 (m, 1H), 4.69 (s, 2H), 3.64 (s, 2H), 1.92 - 1.72 (m, 3H)

[1332] Q-106 537.2 ‘HNMR [M+H]+ / 2.26 min / (500 MHz, 100% / (Method A) DMSO-d6) 6 Ao 8.04 (br d,. / =7,9 F3C J. \NH2 Hz, 1H), 7.99 (br s, 1H), 7.94 CF3(br s, 1H), 7.72

[1333] (br d,. / =7,4 Hz, 2-(4-(3-(2-(2,4- 1H), 7.53 (br s, bis(trifluoromethyl)phenyl)-N-(m- 2H), 7.48 - 7.40 tolyl)acetamido)prop- 1 -yn- 1 -yl)- 1H- (m, 1H), 7.35 - pyrazol- 1 -yl)propanamide 7.20 (m, 4H),

[1334] 5.09 - 4.85 (m, 1H), 4.64 (br s, 2H), 3.70 (br s, 2H), 2.37 (br s, 3H), 1.58 (br d,

[1335]

[1336] , / =6.4 Hz, 3H) Structure and name Analytical ‘HNMR Exampl LCMS

[1337] e #

[1338] ESI-MS(+)

[1339] m / z / RT (min)

[1340] / Purity / (Method)

[1341] Q-107 ^?\ F 581.2 ‘HNMR [M+H]+ / 2.34 min / (500 MHz, 100% / (Method A) DMSO-d₆) δ

[1342] 7.81 (br d, J=8.1 F3C Hz, 1H), 7.76 - 7.68 (m, 2H), CF37.50 (br d, J=8.0

[1343] Hz, 1H), 7.26 (s, 2-(4-(3-(2-(2,4- 2H), 7.14 - 7.05 bis(trifluoromethyl)phenyl)-N-(5- (m, 1H), 7.05 - cyclopropyl-2- 6.93 (m, 3H), fluorophenyl)acetamido)prop- 1 -yn- 4.72 (q,, / =7.3 1 -yl)- IH-pyrazol- 1 -yl)propanamide Hz, 1H), 4.55 (d,

[1344] J=17.6 Hz, 1H), 4.26 (d, J=17.6 Hz, 1H), 3.55 (br d, J=16.8 Hz, 1H), 3.37 (br d, J=17.0 Hz, 1H), 1.81 - 1.68 (m, 1H), 1.34 (d, J=7.2 Hz, 3H), 0.82 - 0.67 (m, 2H), 0.50 - 0.35 (m, 2H)

[1345] Q-108 579.2 ‘HNMR [M+H]+ / 1.92 min / (500 MHz, Ao jpN 95.9% / (Method A) DMSO-d₆) δ

[1346] 8.04 (br d, J=7.7 Hz, 1H), 7.98 AS A

[1347] (br s, 1H), 7.94 CF3(br s, 1H), 7.73

[1348] (br d,. / =8,0 Hz, 2-(4-(3-(2-(2,4- 1H), 7.59 - 7.48 bis(trifluoromethyl)phenyl)-N-(3- (m, 4H), 7.48 - (oxetan-3-yl)phenyl)acetamido)prop- 7.43 (m, 1H), 1 -yn- 1 -yl)- 1 H-pyrazol- 1 - 7.41 - 7.32 (m, yl)propanamide 1H), 7.24 (br s,

[1349]

[1350] 1H), 5.02 - 4.90 Structure and name Analytical ‘HNMR Exampl LCMS

[1351] e #

[1352] ESI-MS(+)

[1353] m / z / RT (min)

[1354] / Purity / (Method)

[1355] (m, 3H), 4.68 (br s, 2H), 4.64 - 4.57 (m, 2H), 4.36 - 4.26 (m, 1H), 3.72 (br s, 2H), 1.57 (br d,

[1356]

[1357] J=7.1 Hz, 3H)

[1358] Example Q-109.2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-N-(3-(l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl)acetamide (Example 109)

[1359]

[1360] In a microwave vial, 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-N-(prop- 2-yn-l-yl)acetamide (35 mg, 0.087 mmol), 4-bromo-l-methyl-lH-imidazole (16.77 mg, 0.104 mmol), Methanesulfonato(2-(di-t-butylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-l,r-biphenyl)(2'-amino-l,r-biphenyl-2-yl)palladium(II), dichloromethane adduct, min. 98%[t-BuBrettPhos Palladacycle Gen. 3] (14.83 mg, 0.017 mmol) and copper(I) iodide (1.653 mg, 8.68 pmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. DMF (1 mL) and DIPEA (0.045 mL, 0.260 mmol) were added and the reaction mixture was heated at 80 °C under microwave condition for 1h. The reaction mixture was added CH₃CN, filtered and the filtrate was purified via preparative LC / MS with the following conditions: Column: XBridge C18, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 32-62% B over 25 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-N-(3-(l-methyl-lH-imidazol-4-yl)prop-2-yn-l-yl)acetamide (4.7 mg, 9.52 pmol, 10.97 % yield). LCMS: 97.9% pure, RT = 2.19 min; m / z: 484.1 [M+H]+(Method A).

[1361] 1H NMR (500 MHz, DMSO-d6) 68.05 (br d, J=7.6 Hz, 1H), 7.95 (s, 1H), 7.75 (br d, J=8.0 Hz, 1H), 7.67 - 7.34 (m, 6H), 4.83 (br d, J=17.2 Hz, 1H), 4.51 (br d, J=17.2 Hz, 1H), 3.79 (br d, J=16.4 Hz, 1H), 3.70 - 3.52 (m, 4H).

[1362] Examples 110-112 below obtained using procedure similar to example Q-109 above.

[1363] Example Structure and name AnalyticalJH # LCMS NMR

[1364] ESI-MS(+)

[1365] m / z / RT (min)

[1366] / Purity / (Method);

[1367] Q-110 484.1XH [M+H]+ / 2.21 min / NMR (500 97.9% / (Method A) MHz, DMSO- < %> — de) 58.05 (br I N=s /

[1368] F3C^A d,. / =7,7 Hz,

[1369] 1H), 7.95 (br s, 1H), 7.73 (br CF3

[1370] d, J=7.6 Hz, 2-(2,4- 1H), 7.66 - 7.50 (m, 2H), bis(trifluoromethyl)phenyl)-N- (3 -fluorophenyl)-N-(3 -( 1 - 7.45 - 7.26 (m,

[1371] 4H), 4.70 (br s, methyl- lH-imidazol-4-yl)prop- 2H), 3.74 (br s, 2-yn- 1 -yl)acetamide

[1372] 2H), 3.62 (br s, 3H)

[1373] Q-lll 484.1JH [M+H]+ / 2.21 min / NMR (500 100% / (Method A) MHz, DMSO- r ° de) 68.10 - 8.02 (m, 1H), 7.95 (s, 1H), CF37.80 - 7.70 (m,

[1374] 1H), 7.65 - 7.27 (m, 6H), 2-(2,4- 4.69 (s, 2H), bis(trifluoromethyl)phenyl)-N- 3.72 (s, 2H), (4-fluorophenyl)-N-(3 -( 1 -

[1375]

[1376] 3.62 (s, 3H) Example Structure and name AnalyticalJH # LCMS NMR

[1377] ESI-MS(+)

[1378] m / z / RT (min)

[1379] / Purity / (Method);

[1380] methyl- lH-imidazol-4-yl)prop- 2-yn- 1 -yl)acetamide

[1381] Q-112 480.2XH [M+H]+ / 2.29 min / NMR (500 96.6% / (Method A) MHz, DMSO- d6) 68.08 - r °

[1382] F3C^X 8.00 (m, 1H),

[1383] 7.94 (br s, 1H), 7.77 - 7.68 (m, CF3

[1384] 1H), 7.60 - 7.53 (m, 1H), 2-(2,4- 7.47 - 7.39 (m, bis(trifluoromethyl)phenyl)-N- 1H), 7.35 (br s, (3-(l -methyl- IH-imidazol -4- 1H), 7.32 - yl)prop-2-yn- 1 -yl)-N-(m- 7.20 (m, 3H), tolyl)acetamide

[1385] 4.64 (br s, 2H), 3.71 (br s, 2H), 3.62 (br s, 3H),

[1386]

[1387] 2.36 (s, 3H) Example Q-113. N-(3-(2-(aminomethyl)thiazol-4-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)acetamide (Example 113)

[1388]

[1389] To a solution of tert-butyl ((4-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)acetamido)prop-l-yn-l-yl)thiazol-2-yl)methyl)carbamate (11 mg, 0.018 mmol) in Dichloromethane (1 mL), TFA (0.069 mL, 0.893 mmol) was added. The reaction mixture was stirred at RT for 4 hr. The reaction mixture was then concentrated and the residue was purified via preparative LC / MS with the following conditions: Column: XBridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 40-100% B over 10 minutes, then a 2-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give N-(3-(2-(aminomethyl)thiazol-4-yl)prop-2-yn-l-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)acetamide (4.1 mg, 7.83 pmol, 43.8 % yield). LCMS: RT = 98.4% pure, 2.22 min; m / z: 516.1 [M+H]+(Method A). 'H NMR (500 MHz, DMSO-d6) 68.05 (br d, J=8.3 Hz, 1H), 7.96 (s, 1H), 7.79 - 7.71 (m, 2H), 7.67 - 7.60 (m, 1H), 7.59 - 7.52 (m, 1H), 7.52 - 7.46 (m, 1H), 7.44 - 7.37 (m, 1H), 4.85 (br d, J=17.7 Hz, 1H), 4.59 (d, J=17.7 Hz, 1H), 4.10 - 3.97 (m, 2H), 3.85 - 3.74 (m, 1H), 3.69 - 3.57 (m, 1H).

[1390] Examples Q-114-115 below were obtained using procedure similar to example Q-113 above.

[1391] Example Structure and name Analytical ‘HNMR # LCMS

[1392] ESI-MS(+)

[1393] m / z / RT (min)

[1394] / Purity / (Method)

[1395] Q-114 512.1 ‘HNMR or

[1396] [M+H]+ / 2.22 min / (500 MHz, 96.9% / (Method DMSO-d6) 6 1 N= /

[1397] A A) 8.04 (br d, J=8.3

[1398] Hz, 1H), 7.95 (s, < J: F31H), 7.76 (d, J=8.0 Hz, 1H), N-(3-(2- 7.73 (s, 1H), (aminomethyl)thiazol-4- 7.52 - 7.33 (m, yl)prop-2-yn- 1 -yl)-2-(2,4- 4H), 4.85 (d, bis(trifluoromethyl)phenyl)-N- J=17.8 Hz, 1H), (o-tolyl)acetamide 4.46 (d, J=17.6 Hz, 1H), 4.02 - 3.89 (m, 2H), 3.76 - 3.62 (m, 1H), 3.52 - 3.40 (m, 1H), 2.35 (s,

[1399]

[1400] 3H) Example Structure and name Analytical ‘HNMR # LCMS

[1401] ESI-MS(+)

[1402] m / z / RT (min)

[1403] / Purity / (Method)

[1404] Q-115 556.1 ‘HNMR [M+H]+ / 2.27 min / (500 MHz, 100% / (Method DMSO-d6) 6 Ao TO5

[1405] ~ VNH2A) 8.05 (d,. / =7,9 Hz, 1H), 7.95 (s, CF31H), 7.78 - 7.68

[1406] (m, 2H), 7.37 - N-(3-(2- 7.30 (m, 1H), (aminomethyl)thiazol-4- 7.30 - 7.24 (m, yl)prop-2-yn- 1 -yl)-2-(2,4- 1H), 7.24 - 7.17 bis(trifluoromethyl)phenyl)-N- (m, 1H), 4.83 (5-cyclopropyl-2- (d, J=17.6 Hz, fluorophenyl)acetamide 1H), 4.55 (d, J=17.8 Hz, 1H), 3.97 (s, 1H), 3.80 (br d, J=17.0 Hz, 1H), 3.62 (br d, J=17.0 Hz, 1H), 2.03 - 1.93 (m, 1H), 1.91 (s, 2H), 1.03 - 0.91 (m, 2H), 0.76 - 0.58 (m, 2H)

[1407]

[1408] Example Q-116: Ethyl c / s-2-(3-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)cyclopropane-l-carboxylate (Example 116) Pd(CN)2Cl2

[1409] X-phos, Cs2CO3Toluene, 100°C

[1410]

[1411] In a reaction vial, N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(prop-2-yn-l-yl)acetamide (30 mg, 0.073 mmol), ethyl cis-2-iodocyclopropane- 1 -carboxylate (17.51 mg, 0.073 mmol), Bis(acetonitrile)palladium(II) chloride (1.892 mg, 7.29 pmol), X-Phos (10.43 mg, 0.022 mmol) and cesium carbonate (59.4 mg, 0.182 mmol) were added. The vial was sealed, vacuumed and flushed with nitrogen. Toluene (1.5 mL) was added and the reaction mixture was heated at 100°C for 3 hrs. The reaction mixture was then concentrated and the residue was purified via preparative LC / MS with the following conditions: Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 51-84% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give ethyl cis-2-(3-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)cyclopropane-l-carboxylate (2.6 mg, 4.97 pmol, 6.81 % yield). LCMS: m / z: 100% pure, 524.2[M+H]+, RT = 2.59 min (Method A). 'H NMR (500 MHz, DMSO-d6) 68.04 - 8.00 (m, 1H), 7.93 (br s, 1H), 7.68 (br d, J=7.6 Hz, 1H), 7.31 - 7.18 (m, 2H), 7.15 (s, 1H), 4.39 (d, J=17.2 Hz, 1H), 4.30 (d, J=17.2 Hz, 1H), 4.14 - 3.99 (m, 2H), 3.64 (br s, 2H), 3.18 (s, 4H), 2.02 - 1.82 (m, 2H), 1.30 - 1.01 (m, 5H).

[1412] Example Q-117: N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(c / s-2-(hydroxymethyl)cyclopropyl)prop-2-yn-l-yl)acetamide (Example 117)

[1413] Pd(CN)2Cl2

[1414] X-phos, Cs2CO3THF, 60°C

[1415]

[1416] In a reaction vial, N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(prop-2-yn-l-yl)acetamide (30 mg, 0.073 mmol), (cis-2-iodocyclopropyl)methanol (14.44 mg, 0.073 mmol), Bis(acetonitrile)palladium(II) chloride (1.892 mg, 7.29 pmol), X-Phos (10.43 mg, 0.022 mmol) and cesium carbonate (59.4 mg, 0.182 mmol) were added. The vial was sealed, vacuumed, and flushed with nitrogen. THF (1.5 mL) was added, and the reaction mixture was heated at 60°C for 1.5 hrs. The reaction mixture was then concentrated and the residue was purified via preparative LC / MS with the following conditions: Column: XB ridge Cl 8, 19 mm x 200 mm, 5 pm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 41-73% B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C.

[1417] Fraction collection was triggered by UV (220 nm) and MS (ESI +). Fractions containing the desired products were combined and dried via centrifugal evaporation to give N- (bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(cA-2-(hydroxymethyl)cyclopropyl)prop-2-yn-l-yl)acetamide (6.9 mg, 0.014 mmol, 19.65 % yield). LCMS:m / z: 100% pure, 482.1 [M+H]+, RT = 2.29 min (Method A). 'H NMR (500 MHz, DMSO-d6) 68.01 (br d, J=8.0 Hz, 1H), 7.93 (s, 1H), 7.68 (br d, J=7.9 Hz, 1H), 7.30 - 7.16 (m, 2H), 7.13 (s, 1H), 4.63 - 4.50 (m, 1H), 4.45 - 4.25 (m, 2H), 3.64 (s, 2H), 3.56 - 3.23 (m, 2H), 3.18 (s, 4H), 1.54 - 1.34 (m, 1H), 1.22 - 1.04 (m, 1H), 0.97 - 0.82 (m, 1H), 0.37 - 0.21 (m, 1H).

[1418] Examples Q-118-122 below obtained using procedure similar to example Q-119 above. Example # Structure and name / Analytical i LCMS HNMR ESI- MS(+) m / z / RT

[1419] (min) / Purity /

[1420] (Method)

[1421]

[1422] Q-118 474.2[M+ H]+ / 2.11 min / 1H NMR 97.1% / (Method (500 A) MHz, DMSO- d6) δ 8.00 (br d,. / =7,9 Hz, 1H), 7.92 (s, 1H), bis(trifluoromethyl)phenyl)-N-(2- 7.68 (br fluorophenyl)-N-(3-(czs-2- d,. / =7,9 (hydroxymethyl)cyclopropyl)prop-2- Hz, 1H), yn-l-yl)acetamide 7.58 - 7.48 (m, 2H), 7.46 - 7.39 (m, 1H), 7.39 - 7.30 (m, 1H), 4.62 - 4.49 (m, 2H), 4.24 (br d, J=17.3 Hz, 1H), 3.71 (br d, J=16.7 Hz, 1H), 3.55 - 3.51 (m, 1H), 3.40 - 3.28 (m, 1H), 3.23 - 3.13 (m, 1H), 1.43 - 1.30 (m, 1H), 1.17 - 1.06 (m, 1H), 0.92 - 0.82 (m, 1H),

[1423]

[1424] 0.28 - 0.18 (m,

[1425] 1H) Q-119 F 474.2[M+ i H]+ / 2.13 min / 1H NMR 98.1% / (Method (500 A) MHz,OHDMSO- A M d6) δ 8.04 sO-^^-Lx^ (br d, J=8.3 Hz, M 1H), 7.95 CF3(br s,

[1426] 1H), 7.71 2-(2,4- (br d, bis(trifluoromethyl)phenyl)-N-(3- J=8.0 Hz, fluorophenyl)-N-(3-(czs-2- 1H), 7.64 (hydroxymethyl)cyclopropyl)prop-2- - 7.51 yn-l-yl)acetamide (m, 1H),

[1427] 7.44 - 7.15 (m, 3H), 4.61 - 4.51 (m, 1H), 4.44 (br s, 2H), 3.71 (br s, 2H), 3.52 - 3.20 (m, 2H), 1.51 - 1.34 (m, 1H), 1.23 - 1.01 (m, 1H), 0.99 - 0.79 (m, 1H), 0.36 - 0.09 (m, 1H)

[1428]

[1429] Q-120 470.2[M+ H]+ / 2.20 min / 1H NMR 98.9% / (Method (500 A) MHz, DMSO- d6) δ 7.77 (br d, J=8.5 Hz, 1H), 7.70 (s, 1H), bis(trifluoromethyl)phenyl)-N-(3-(cis- 7.47 (br 2-(hydroxymethyl)cyclopropyl)prop-2- d, J=8.1 yn- 1 -yl)-N-(o-tolyl)acetamide Hz, 1H),

[1430] 7.26 - 7.06 (m, 4H), 4.46 - 4.27 (m, 1H), 3.95 - 3.77 (m, 1H), 3.42 - 3.36 (m, 1H), 3.29 - 3.26 (m, 1H), 3.20 - 3.10 (m, 1H), 3.08 - 2.97 (m, 1H), 2.05 (s, 3H), 1.23 - 1.09 (m, 1H), 0.96 - 0.81 (m, 1H), 0.70 - 0.52 (m, 1H), 0.09 - 0.05

[1431]

[1432] (m, 1H) Q-121 475.2[M+ H]+ / 1.91 min / 1H NMR 97.9% / (Method (500 A) MHz, DMSO- d6) δ 9.19 (s, 1H), 8.50 (s, 1H), 7.57 - 7.46 bis(trifluoromethyl)pyridin-2-yl)-N-(2- (m, 2H), fluorophenyl)-N-(3-(czs-2- 7.45 - (hydroxymethyl)cyclopropyl)prop-2- 7.37 (m, yn-l-yl)acetamide 1H), 7.35

[1433] - 7.27 (m, 1H), 4.61 - 4.49 (m, 2H), 4.28 (br d, J=17.7 Hz, 1H), 3.88 - 3.73 (m, 2H), 3.41 - 3.28 (m, 1H), 3.26 - 3.12 (m, 1H), 1.45 - 1.30 (m, 1H), 1.17 - 1.05 (m, 1H), 0.92 - 0.72 (m, 1H), 0.28 - 0.09 (m, 1H)

[1434]

[1435] Q-122 483.2[M+ H]+ / 2.09 min / 1H NMR 95.7% / (Method (500 A) MHz, DMSO- d6) δ 9.21 (s, 1H), 8.50 (s, 1H), 7.33 - 7.16 N-(bicyclo[4.2.0]octa-l(6),2,4- (m, 2H), trien-3-yl)-2-(3,5- 7.12 (s, bis(trifluoromethyl)pyridin-2-yl)-N-(3- 1H), 4.59 (czs-2- - 4.48 (hydroxymethyl)cyclopropyl)prop-2- (m, 1H), yn-l-yl)acetamide 4.46 - 4.27 (m, 2H), 3.81 (s, 2H), 3.47 - 3.35 (m, 1H), 3.34 - 3.24 (m, 1H), 3.16 (s, 4H), 1.55 - 1.33 (m, 1H), 1.22 - 1.05 (m, 1H), 1.00 - 0.80 (m, 1H), 0.40 - 0.16 (m, 1H)

[1436]

[1437] Q-123 471.3

[1438] [M+H]+ / 2.03 min1H NMR / 98.6% / (Method (500 A) MHz, DMSO- d6) δ 8.96 (s, 1H), 8.37 - 8.08 (m, 2-[3,5- 1H), 7.08 bis(trifluoromethyl)pyridin-2-yl]-N-{3- (br s, [(c / .s-2- 4H), 4.53 (hydroxymethyl)cyclopropyl]prop-2- - 4.26 yn-l-yl}-N-(2-methylphenyl)acetamide (m, 1H),

[1439] 3.99 - 3.77 (m, 1H), 3.55 - 3.38 (m, 1H), 3.26 - 2.83 (m, 3H), 1.29 - 1.09 (m, 1H), 0.99 - 0.83 (m, 1H), 0.74 - 0.55 (m, 1H), 0.19 - - 0.18 (m, 1H)

[1440]

[1441] Examples Q-124-126 below were obtained using procedure similar to Example Q-42 above. Example # Structure and name Analytical1H LCMS NMR ESI- MS(+) m / z / RT

[1442] (min) / Purity /

[1443] (Method);

[1444] Q-124 564.61H [M+H]+ / 2.24 min NMR (500 / 93.6% / MHz, (Method A) DMSO-d6) δ

[1445] 8.07 - 7.99 (m, 1H), 7.95 (s, 1H), 7.80 - 7.70 (m, 3H),

[1446] 7.52 - 7.44 N-(bicyclo[4.2.0]octa-l(6),2,4- (m, 2H), 7.32 trien-3-yl)-2-(2,4- - 7.25 (m, bis(trifluoromethyl)phenyl)-N-(3-(4- 2H), 7.23 (...

Claims

1. CLAIMS1. A compound of Formula I,4.

5. (Formula I), or a pharmaceutically acceptable salt thereof,6.wherein:7.B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1;8.D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3;9.each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl;10.each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2- C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl;11.each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, - C(O)N(R4)2, C0-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4; each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(CI-4alkyl);12.R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6- membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6;13.R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl;14.R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8;15.R8is C1-C4 alkyl, or 5-membered heterocyclyl;16.X is N or CH;17.Y is O, NH, or S;18.Z is O, S, NR5or CHR5;19.n is 2-3;20.m is 1-3; and21.wherein the compound is not22.

2. The compound of claim 1, wherein B is selected from: phenyl, pyridinyl, C3- Cs cycloalkyl, pyrazolyl, azaindolyl, indolyl, thiazolyl, wherein the phenyl, cycloalkyl, heteroaryl is optionally substituted with one or more R1;each R1is independently H, halogen, CF3, CF2H, OCF2H, OCF3, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl;3. The compound of claim 1, wherein D is selected from: phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, imidazolyl, pyridonyl, indazolyl, bicyclo[4.2.0]octa-l, 3, 5-trienyl, C1-C4 alkyl, C3-C6 cycloalkyl, 4- to 68-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3.

4. The compound of claim 1, wherein the compound is of Formula la-i -la-v:

28.

30.

31. m is 0, 1, or 2, and n is 0, 1, or 2.32.The compound of claim 4, wherein D is selected from:

33.

36.

38.

39. 0 < / =\ 0 HN- / ' N-N 0 J / =N ’O V HJ ■ K / ^°v KbNH240.I41.0,m0 HN-Boc 0 HN— / 42.XQI-I N-N N-N44.

45. , or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is of Formula Ic-i, Ic-ii, or Ic-iii:

47. 49.(Formula Ic-ii), or51.

52. (Formula Ic-iii).

7. The compound of claim 1, wherein the compound is of Formula Ild-i:

55. 57.wherein m is 0, 1, or 2.

8. A compound selected from the group consisting of:59.6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-3 -carboxamide;60.6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)pyridine-3 -carboxamide; 6-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-3 -carboxamide;61.6-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]pyridine-3-carboxamide;62.5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide;63.5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide;64.5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)pyridine-2-carboxamide;65.5-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]pyridine-2-carboxamide;66.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide;67.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide;68.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxamide;69.2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]-l,3-thiazole-4-carboxamide;70.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide;71.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide;72.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-oxazole-4-carboxamide; 2-[3-(N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-l-yn-l-yl]-l,3-oxazole-4-carboxamide;73.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-5-carboxamide;74.2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-5-carboxamide;75.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l,3,4-thiadiazol-2-yl)prop-2-yn- 1 -yl]acetamide;76.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)-N-[3-(l,3,4-thiadiazol-2-yl)prop-2-yn- 1 -yl]acetamide;77.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]-N-(2-methylphenyl)acetamide;78.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-5 -yl)prop-2-yn- 1 -yl] acetamide;79.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide;80.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridin-3-yl)prop-2-yn-l-yl]acetamide;81.2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-[3-(pyridin-3 -yl)prop-2-yn- 1 -yl] acetamide;82.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[3-(pyridin-2-yl)prop-2-yn-l-yl]acetamide;83.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridin-2-yl)prop-2-yn-l-yl]acetamide;84.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-methyl-lH-imidazol-5-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3 -fluorophenyl)acetamide;85.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide;86.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;87.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide;88.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide;89.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide;90.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide;91.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide;92.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide;93.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-methylphenyl)acetamide;94.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]acetamide;95.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide;96.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3 -fluorophenyl)acetamide; N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide;97.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;98.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;99.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide;100.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide;101.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide;102.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide;103.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide;104.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide;105.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-methylphenyl)acetamide;106.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide;107.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn- 1 -yl] acetamide;108.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn- 1 -yl] acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn- 1 -yl] acetamide;109.2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-[3-(pyrimidin-5-yl)prop-2-yn-l-yl]acetamide;110.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]-N-[3-(pyrimidin-5-yl)prop-2-yn- 1 -yl]acetamide;111.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(pyridazin-3-yl)prop-2-yn- 1 -yl] acetamide;112.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide;113.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide;114.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;115.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;116.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide;117.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide;118.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide;119.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(l-methyl-lH-imidazol-2-yl)prop-2-yn- 1 -yl]acetamide;120.tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazol-2-yl]methyl } carbamate; tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazol-2-yl]methyl } carbamate;121.tert-butyl N-{[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamido}prop- 1 -yn- 1 -yl)- 1,3 -thiazol-2-yl]methyl } carbamate;122.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-thi azol -2-y 1 ] prop-2-y n- 1 -y 1 } acetamide;123.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn- 1 -yl } -N-(2-methylphenyl)acetamide;124.2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l, 3 -thiazol-2-yl]prop-2-yn-l-yl} acetamide;125.N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxym ethyl)- 1, 3 -thiazol-2-yl]prop-2-yn-l-yl} acetamide;126.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-2-oxoacetamide;127.N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn-l-yl}-2-oxoacetamide;128.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[4-(hydroxymethyl)-l,3-thiazol-2-yl]prop-2-yn- 1 -yl } -N-(2-methylphenyl)acetamide;129.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn- 1 -yl } acetamide;130.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn- 1 -yl } -N-(2-methylphenyl)acetamide;131.2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn- 1 -yl } acetamide;132.N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(hydroxymethyl)pyrimidin-5-yl]prop-2-yn- 1 -yl } acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn-l-yl} acetamide;133.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxymethyl)-l,3-oxazol-2-yl]prop-2-yn- 1 -yl } -N-(2-methylphenyl)acetamide;134.N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(hydroxym ethyl)- 1, 3 -oxazol-2-yl]prop-2-yn-l-yl} acetamide;135.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamide;136.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide;137.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;138.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;139.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide;140.N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide;141.N-[3-(3-amino-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide;142.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamide;143.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-2-oxoacetamide;144.N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [3, 5 -bis(trifluoromethyl)pyridin-2-yl]-N-(3-fluorophenyl)acetamide; N- [3 -(3 -amino- 1 -methyl- 1 H-pyrazol-5 -yl)prop-2-yn- 1 -yl] -2- [3, 5 -bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide;145.N-[3-(3-amino-1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]-N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]acetamide;146.N-[3-(2-amino-1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide;147.N-[3-(2-amino-1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide;148.methyl 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-1-yn-1-yl)-1-methyl-1H-pyrazole-3-carboxylate;149.methyl 5-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-1-yn-1-yl)-1-methyl-1H-pyrazole-3-carboxylate;150.methyl 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxylate;151.methyl 2-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamido}prop-l-yn-l-yl)-l,3-thiazole-4-carboxylate;152.2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)acetamido}prop-1-yn-1-yl)-1H-pyrazol-1-yl]propanamide;153.2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamido}prop-1-yn-1-yl)-1H-pyrazol-1-yl]propanamide;154.2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamido}prop-1-yn-1-yl)-1H-pyrazol-1-yl]propanamide;155.2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}prop-1-yn-1-yl)-1H-pyrazol-1-yl]propanamide;156.2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamido}prop-1-yn-1-yl)-1H-pyrazol-1-yl]propanamide; 2-[4-(3-{2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(oxetan-3-yl)phenyl]acetamido}prop-1-yn-1-yl)-1H-pyrazol-1-yl]propanamide;157.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-[3-(1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]acetamide;158.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-[3-(1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]acetamide;159.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]acetamide;160.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide;161.N-{3-[2-(aminomethyl)-1,3-thiazol-4-yl]prop-2-yn-1-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)acetamide;162.N-{3-[2-(aminomethyl)-1,3-thiazol-4-yl]prop-2-yn-1-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methylphenyl)acetamide;163.N-{3-[2-(aminomethyl)-1,3-thiazol-4-yl]prop-2-yn-1-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(5-cyclopropyl-2-fluorophenyl)acetamide;164.ethyl (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxylate;165.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}acetamide;166.2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-fluorophenyl)-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}acetamide;167.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}acetamide;168.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}-N-(2-methylphenyl)acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(2-fluorophenyl)-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}acetamide;169.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}acetamide;170.2- [3, 5 -bi s(trifluoromethyl)pyridin-2-yl] -N- { 3 - [cis-2-(hydroxymethyl)cyclopropyl]prop-2-yn-l-yl}-N-(2-methylphenyl)acetamide;171.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-1-yl}acetamide;172.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-(2-fluorophenyl)acetamide;173.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-1-yl}acetamide;174.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]acetamide;175.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide;176.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide;177.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]-N-(2-phenylcyclopropyl)acetamide;178.N-[3-(3-amino-1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide;179.N-[3-(5-aminopyrazin-2-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-phenylcyclopropyl)acetamide;180.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-1-yl)acetamide;181.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]acetamide;182.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyridazin-3-yl)prop-2-yn-1-yl]acetamide;183.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-N-{bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide;184.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-N-{bicyclo[3.1.0]hexan-6-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamide;185.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(6-methoxypyridin-3-yl)acetamide;186.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-[3-(oxetan-3-yl)phenyl]acetamide;187.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(1-methyl-1H-pyrazol-4-yl)acetamide;188.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(thiophen-3-yl)acetamide;189.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[1-(4-methylbenzenesulfonyl)-6-oxo-1,6-dihydropyridin-2-yl]prop-2-yn-1-yl}acetamide;190.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyrimidin-5-yl)prop-2-yn-1-yl]acetamide;191.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2-methoxypyridin-4-yl)acetamide;192.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-[3-(oxetan-3-yl)phenyl]acetamide; 2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(2-methylphenyl)acetamide;193.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(3-methylphenyl)acetamide;194.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(3-fluorophenyl)acetamide;195.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]acetamide;196.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]acetamide;197.N-[3-(3-amino-1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(difluoromethyl)phenyl]acetamide;198.N-{bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(pyridazin-4-yl)prop-2-yn-1-yl]acetamide;199.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-cyclopropylprop-2-yn-l-yl)-N-(2-fluorophenyl)acetamide;200.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)acetamide;201.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3,4-difluorophenyl)acetamide;202.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluoro-3-methylphenyl)acetamide;203.N-[3-(3-amino-1-methyl-1H-pyrazol-5-yl)prop-2-yn-1-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]acetamide;204.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]-N-[3-(1-methyl-1H-imidazol-5-yl)prop-2-yn-1-yl]acetamide; N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(difluoromethyl)phenyl]acetamide;205.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-{1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl}acetamide;206.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(2,3-difluorophenyl)acetamide;207.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3,3-difluorocyclopentyl)acetamide;208.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2-bromo-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;209.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-hydroxybut-2-yn-l-yl)-N-(3-methylphenyl)acetamide;210.N-(4-aminobut-2-yn-l-yl)-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;211.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-acetamidobut-2-yn-l-yl)-N-(3-methylphenyl)acetamide;212.2-[2,4-bis(trifluoromethyl)phenyl]-N-{4-[(5-methyl-l,3,4-oxadiazol-2-yl)formamido]but-2-yn-l-yl}-N-(3-methylphenyl)acetamide;213.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-{4-[(pyridin-3-yl)formamido]but-2-yn- 1 -yl } acetamide;214.N-{bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(6-oxo- 1,6-dihydropyridin-2-yl)prop-2-yn- 1 -yl]acetamide;215.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(l-hydroxycyclobutyl)prop-2-yn- 1 -yl]acetamide;216.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-l,l-dioxo-l,6-thian-4-yl)prop-2-yn- 1 -yl]-N-(3 -methylphenyl)acetamide;217.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l,3-dihydroxycyclobutyl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide;218.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[4-(morpholin-4-yl)but-2-yn- 1 -yl] acetamide;219.2-[2,4-bis(trifluoromethyl)phenyl]-N-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)but-2-yn-1-yl]-N-(3-methylphenyl)acetamide;220.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-[4-(2-oxopyrrolidin-l-yl)but-2-yn-l-yl]acetamide;221.N-(4-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}but-2-yn-1-yl)prop-2-enamide;222.1-[3-(2-aminopyrimidin-5-yl)prop-2-yn-1-yl]-3-[2,6-dimethyl-4-(trifluoromethyl)phenyl]-1-(4-fluorophenyl)urea;223.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-1-yl]-2-[2-bromo-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;224.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(l-hydroxycyclobutyl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;225.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxyoxetan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;226.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-hydroxy-4-methylpent-2-yn-l-yl)-N-(3-methylphenyl)acetamide;227.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxyoxolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;228.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxyoxetan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide; 2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)-N-{4-[(pyridin-2-yl)formamido]but-2-yn- 1 -yl } acetamide;229.tert-butyl 4-(3 - { 2 - [2, 4 -b i s(trifluoromethyl)phenyl] -N-(3 -methylphenyl)acetamido}prop- 1 -yn- 1 -yl)-4-hydroxypiperidine- 1 -carboxylate;230.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn- 1 -yl]acetamide;231.2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-fluorophenyl)-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn- 1 -yl]acetamide;232.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(6-m ethoxypyri din-3 -yl)acetamide;233.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(4-hydroxy-4-methylpent-2-yn-l-yl)-N-(3-methylphenyl)acetamide;234.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxyoxolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;235.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxythiolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;236.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-(6-methoxypyri din-3 -yl)acetamide;237.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(3-hydroxy-1,1-dioxo-1λ6-thiolan-3-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide;238.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(4-hydroxyoxan-4-yl)prop-2-yn-l-yl]-N-(6-methoxypyridin-3-yl)acetamide;239.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[4-(dimethylphosphoryl)phenyl]prop-2-yn-l-yl}-N-{l-methyl-lH-pyrrolo[2,3-b]pyridin-6-yl}acetamide;240.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)but-2-yn-1-yl]-N-(3-methylphenyl)acetamide; ethyl N-(4-{2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamido}but-2-yn- 1 -yl)carbamate;241.2-[2-acetyl-4-(trifluoromethyl)phenyl]-N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide;242.2-[2-acetyl-4-(trifluoromethyl)phenyl]-N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)acetamide;243.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl]acetamide;244.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-(2-hydroxypropan-2-yl)-4-(trifluoromethyl)phenyl]acetamide;245.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-methyl-4-(trifluoromethyl)phenyl]acetamide;246.N-[3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl]-N-(4-fluorophenyl)-2-[2-methyl-4-(trifluoromethyl)phenyl]acetamide;247.N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[6-(dimethylphosphoryl)pyridin-3-yl]prop-2-yn-1-yl}acetamide;248.2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[3-(3-hydroxycyclobut-l-en- 1 -yl)prop-2-yn- 1 -yl]acetamide;249.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;250.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-1-methylpiperidin-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide;251.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-1-methyl-1-oxo-1λ5-phosphinan-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide;252.2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(4-hydroxy-1-methyl-1-oxo-1λ5-phosphinan-4-yl)prop-2-yn-1-yl]-N-(3-methylphenyl)acetamide; (1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxylic acid;253.(1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]cyclopropane-1-carboxamide;254.N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(1S,2R)-2-(4-methyl-4-oxo-1,4λ5-azaphosphinane-1-carbonyl)cyclopropyl]prop-2-yn-1-yl}acetamide;255.(1S,2R)-2-[3-(N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]acetamido)prop-1-yn-1-yl]-N-[2-(dimethylamino)ethyl]cyclopropane-1-carboxamide;256.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-[2-fluoro-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;257.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(1S,2R)-2-(hydroxymethyl)cyclopropyl]prop-2-yn-1-yl}-N-(6-methoxypyridin-3-yl)acetamide;258.N-[3-(1-acetyl-4-hydroxypiperidin-4-yl)prop-2-yn-1-yl]-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;259.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-[4-(morpholin-4-yl)but-2-yn-l-yl]acetamide;260.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl]-2-(2,4-dimethylphenyl)-N-(4-fluorophenyl)acetamide;261.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-{4-[(pyridin-3-yl)formamido]but-2-yn-1-yl}acetamide;262.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-{4-[(pyridin-2-yl)formamido]but-2-yn-1-yl}acetamide;263.N-{bicyclo[4.2.0]octa-1,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(1H-indazol-4-yl)prop-2-yn-1-yl]acetamide; N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[2-(dimethylphosphoryl)pyrimidin-5-yl]prop-2-yn- 1 -yl } acetamide;264.N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(3-{4-[imino(methyl)oxo-^6-sulfanyl]phenyl}prop-2-yn-l-yl)acetamide;265.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;266.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)-N-[4-(2-oxopyrrolidin-1 -yl)but-2-yn- 1 -yl]acetamide;267.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[2-chloro-4-(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide;268.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-(4-bromo-2-methoxyphenyl)-N-(4-fluorophenyl)acetamide;269.N-{bicyclo[4.2.0]octa-l,3,5-trien-3-yl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-[3-(l-m ethyl- 1 -oxo-3H- 1 ^6,2-benzothiazol-6-yl)prop-2-yn- 1 -yl]acetamide;270.N-(4-{2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamido}but-2-yn- 1 -yl)prop-2-enamide;271.tert-butyl 4-(3-{2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamido}prop- 1 -yn- 1 -yl)-4-hydroxypiperidine- 1 -carboxylate;272.2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-[3-(3-hydroxythiolan-3-yl)prop-2-yn-l-yl]-N-(3-methylphenyl)acetamide;273.N-[3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl]-2-[4-bromo-2-(trifluoromethyl)phenyl]-N-(3-methylphenyl)acetamide;274.N-[3-(l-acetyl-4-hydroxypiperidin-4-yl)prop-2-yn-l-yl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(3-methylphenyl)acetamide;275.2-[2,4-bis(trifluoromethyl)phenyl]-N-{3-[(lS,2R)-2-(hydroxymethyl)cyclopropyl]prop-2-yn- 1 -yl }-N- { 1 -methyl- lH-pyrrolo[2, 3 -b]pyridin-6-yl} acetamide; tert-butyl (2-((6-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate;276.N-(3-(6-(2-aminoacetamido)pyridazin-3-yl)prop-2-yn-l-yl)-N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamide;277.tert-butyl (2-((6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)amino)-2-oxoethyl)carbamate;278.f75,27? -2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-y2-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dichlorophenyl)-N-(3-(4-hydroxy-l-methylpiperidin-4-yl)prop-2-yn-l-yl)acetamide;279.N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-((lR,2S)-2-(4-(S-methylsulfonimidoyl)piperidine-l-carbonyl)cyclopropyl)prop-2-yn-l-yl)acetamide;280.2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(4-bromophenyl)prop-2-yn-l-yl)-N-(6-m ethoxypyri din-3 -yl)acetamide;281.N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-N-(4-fluorophenyl)-2-(4-(trifluoromethyl)-2-vinylphenyl)acetamide;282.2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(4-hydroxy-l-methylpiperidin-4-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;283.N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(4-methyl-2-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide;284.N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide;285.2,6-dimethyl-4-(trifluoromethyl)phenyl (3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)(m-tolyl)carbamate; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(2-(dimethylphosphoryl)pyrimidin-5-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide l)acetamido)prop- 1 -yn- 1 -yl)cyclopropane- 1 -carboxylic acid;286.2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(dimethylphosphoryl)pyridin-3-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;287.2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(S-methylsulfonimidoyl)pyridin-3-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;288.2,6-dimethyl-4-(trifluoromethyl)phenyl (3-(4-(dimethylphosphoryl)phenyl)prop-2-yn-1 -yl)(m-tolyl)carbamate;289.N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(but-3-yn- 1 -yl)acetamide;290.N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-2-(2-chloro-4-(trifluoromethyl)phenyl)-N-(m-tolyl)acetamide;291.(lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)-N-((5-oxopyrrolidin-3-yl)methyl)cyclopropane- 1 -carboxamide;292.diethyl (3-((lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)cyclopropane- 1 -carboxamido)propyl)phosphonate;293.(lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)-N-(((R)-morpholin-2-yl)methyl)cyclopropane- 1 -carboxamide;294.dimethyl (5-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-1 -yl)pyridin-2-yl)phosphonate;295.2-(2-acetyl-4-(trifluoromethyl)phenyl)-N-(3-(6-aminopyridazin-3-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(3-(2-hydroxyacetamido)-l-methyl-lH-pyrazol-5-yl)prop-2-yn-l-yl)-N-(m-tolyl)acetamide;296.N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(6-(2-(4-methylpiperazin- 1 -yl)ethoxy)pyri din-3 -yl)prop-2-yn- 1 -yl)acetamide;297.(15.25)-2-(4-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)but- 1 -yn- 1 -yl)cyclopropane- 1 -carboxylic acid;298.(15.25)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop- 1 -yn- 1 -yl)-N-methylcyclopropane- 1 -carboxamide;299.(lS,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)-N-(2 -methoxy ethyl)-N-m ethylcyclopropane- 1 -carboxamide;300.(lR,2S)-2-(4-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)but- 1 -yn- 1 -yl)cyclopropane- 1 -carboxylic acid;301.(lR,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop- 1 -yn- 1 -yl)-N-methylcyclopropane- 1 -carboxamide;302.(lR,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l,3,5-trien-3-yl)-2-(2,4-bis(trifluoromethyl)phenyl)acetamido)prop-l-yn-l-yl)-N-(2 -methoxy ethyl)-N-m ethylcyclopropane- 1 -carboxamide;303.ethyl (6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)carbamate;304.N-(4-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)but-2-yn-l-yl)-5-methyl-l,3,4-oxadiazole-2-carboxamide;305.2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-(3-ethylureido)pyridazin-3-yl)prop-2-yn-l-yl)-N-(4-fluorophenyl)acetamide; diethyl (3-(3-(6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)ureido)propyl)phosphonate;306.N-(4-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)acetamido)but-2-yn-l-yl)-5-methyl-l,3,4-oxadiazole-2-carboxamide;307.ethyl 5-(3 -(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop- 1 -yn- 1 -yl)picolinate;308.dimethyl (4-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-1 -yl)phenyl)phosphonate;309.ethyl 5-(3 -(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop- 1 -yn- 1 -yl)pyrimidine-2-carboxylate;310.2-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-(prop-2-yn-l-yl)acetamide;311.ethyl 5-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)picolinate;312.ethyl 5-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)acetamido)prop-l-yn-1 -yl)pyrimidine-2-carboxylate;313.2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(6-oxo-l,6-dihydropyridin-2-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;314.dimethyl (6-(3-(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop-l-yn-l-yl)pyridazin-3-yl)phosphonate;315.N-(3-(2-aminopyrimidin-5-yl)prop-2-yn-l-yl)-2-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide;316.N-(4-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(2-(difluoromethyl)-4-(trifluoromethyl)phenyl)acetamido)but-2-yn-l-yl)-5-methyl-l,3,4-oxadiazole-2-carboxamide;317.methyl 6-(3 -(2-(2,4-bis(trifluoromethyl)phenyl)-N-(m-tolyl)acetamido)prop- 1 -yn- 1 -yl)pyridazine-3 -carboxylate; 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-((lS,2R)-2-(hydroxymethyl)cyclopropyl)but-3-yn-l-yl)-N-(m-tolyl)acetamide;318.2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-(3-hydroxyoxetan-3-yl)but-3-yn-l-yl)-N-(m-tolyl)acetamide;319.tert-butyl (2-((6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)amino)-2-oxoethyl)carbamate;320.ethyl (2-((6-(3-(2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)acetamido)prop- 1 -yn- 1 -yl)pyridazin-3 -yl)amino)-2-oxoethyl)carbamate;321.2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(2-(2-hydroxyacetamido)pyrimidin-5-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;322.2-(2,4-bis(trifluoromethyl)phenyl)-N-(3-(6-(2-hydroxyacetamido)pyridazin-3-yl)prop-2-yn- 1 -yl)-N-(m-tolyl)acetamide;323.N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(3-((lS,2R)-2-(hydroxymethyl)cyclopropyl)prop-2-yn-l-yl)acetamide;324.2-(2,4-bis(trifluoromethyl)phenyl)-N-(2-fluorophenyl)-N-(3-(5-(2-hydroxyacetamido)pyrazin-2-yl)prop-2-yn-l-yl)acetamide; and325.(lR,2S)-2-(3-(N-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)-2-(3,5-bis(trifluoromethyl)pyridin-2-yl)acetamido)prop- 1 -yn- 1 -yl)-N-(((R)-morpholin-2-yl)methyl)cyclopropane-l -carboxamide, or a pharmaceutically acepptable salt thereof.

9. A pharmaceutical composition comprising the compound of any one of claims 1-8, and a pharmaceutically acceptable excipient, diluent, or carrier.

10. A composition comprising:328.a Pole (PolQ) inhibitor of formula (I):

329.

330. (Formula I), or a pharmaceutically acceptable salt thereof,331.wherein:332.B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1;333.D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4-to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3;334.each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl;335.each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl;336.each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, - C(O)N(R4)2, C0-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1-C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4;337.each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(CI-4alkyl);338.R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6- membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6;339.R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl;340.R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8;341.R8is C1-C4 alkyl, or 5-membered heterocyclyl;342.X is N or CH;343.Y is O, NH, or S;344.Z is O, S, NR5or CHR5;345.n is 2-3;346.m is 1-3; and347.N348.N" NH2349.wherein the compound is not350. 352.and353.a DNAPK inhibitor of Formula (SI):RS1354.HN356.

357. (SI),358.or a pharmaceutically acceptable salt thereof,359.wherein:360.Asis a 5-membered or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more RS5;361.RS1is an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more RS6;362.RS2is H, Ci-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CN, OH, CH2OH, NH2, or CH2NH2;363.RS3and RS4are each independently selected from the group consisting of -OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylaryl, and aryl;364.each RS5is independently selected from the group consisting of halogen, oxo, thioxo, C1-C4 alkyl, CD3, CD2CD3, C1-C4 alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; or two geminal RS5, together with the intervening geminal carbon atom, form a C3-C6 cycloalkyl;365.each RS6is independently selected from the group consisting of halogen, oxo, NH2, OH, -CN, C(O)NHRS7, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more RS7; each RS7is independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy; and366.n is an integer from 1 to 3.

11. A composition comprising:368.a P0I6 (POLQ) inhibitor of formula (I):369.D370., u2$^372.

373. (Formula I), or a pharmaceutically acceptable salt thereof,374.wherein:375.B is C3-C8 cycloalkyl, aryl, or 5- or 6-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R1;376.D is H, C1-C4 alkyl, C3-C8 cycloalkyl, 5- to 10- membered heteroaryl, or 4- to 8-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R3;377.each R1is independently H, halogen, C1-C3 fluoroalkyl, or C1-C3 fluoroalkoxy, C3-C8 cycloalkyl, 4-to 8-membered heterocyclyl, aryl, Ci-Ce alkyl, or C1-C4 alkoxy, or wherein two R1on adjacent carbons are taken together to form a C4-C6 cycloalkyl, or aryl;378.each R2is independently H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkylsilane, C(O)alkyl, Ci-C3-alkoxyalkyl, C2-C4 alkenyl, C2- C4 alkynyl, nitrile, nitro, or C1-C4 haloalkyl;379.each R3is independently H, -OH, C1-C4 alkoxy, -C(O)C(R4)2, - C(O)N(R4)2, CO-C3-N(R4)2, -C(O)R4, C(O)N(R4)2, NHC(O)R4, NHC(O)R4, NHS(O)2R4, -C(O)OR4, P(O)(R4)2, P(O)(OR4)2, SO2R4, SO(R4)(=N-R4), C1- C3 hydroxyalkyl, C3-C8 cycloalkyl, Co-C3-4-to 8-membered heterocyclyl, OP(O)(OR4)2,or C1-C4 alkyl, wherein the C1-C4 alkoxy, C1-C3 hydroxyalkyl, Co-C3-4-to 8-membered heterocyclyl, C3-C8 cycloalkyl, and C1-C4 alkyl is optionally substituted with one or more R4;380.each R4is independently H, -OH, C1-C4 alkyl, C1-C4 alkyl(R6), C1-C3 hydroxyalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -N(R6)2, -NHC(O)R7, NHC(O)OR7, -C(O)R7or wherein two R4on can come together to form a 5-7 membered heterocycle, optionally substituted with an oxo, Ci-4 alkyl, S(O)(NH)(CI-4alkyl);381.R5is H, -OH, C1-C4 alkoxy, C3-C6 cycloalkyl, C1-C4 alkyl, or C2-C4 alkynyl, wherein the cycloalkyl, alkyl and alkynyl is optionally substituted with one or more -OH, halogen, 5- or 6-membered heterocycle, or 5- or 6- membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more R6;382.R6is H, P(O)(O C1-C4 alkyl)2, N(R7)2, Co-C3-4-to 8-membered heterocyclyl, or C1-C4 alkyl;383.R7is H, C1-C4 alkyl, C1-C4 alkoxy, NH2, or C(O)R8;384.R8is C1-C4 alkyl, or 5-membered heterocyclyl;385.X is N or CH;386.Y is O, NH, or S;387.Z is O, S, NR5or CHR5;388.n is 2-3;389.m is 1-3; and wherein the compound is not390.

391. and a DNAPK inhibitor of Formula (SI)I):

393. 395.or a pharmaceutically acceptable salt thereof,396.wherein:397.ASis a 5- or 6-membered heteroaryl or heterocycloalkyl group containing at least one heteroatom selected from the group consisting of N, O, and S, wherein the heteroaryl or heterocycloalkyl is optionally substituted with one or more R4B;398.R1Sis an aryl or heteroaryl containing at least one heteroatom selected from the group consisting of N, O, S, and Se, wherein the aryl or heteroaryl is optionally substituted with one or more R5B;399.R2Bis H, halogen, -(CH2)nB-CN, -OH, -(CH2)nB-O-Ci-C4alkyl, Ci-C4alkyl, Ci-C4alkoxy, Ci-C4haloalkyl, C2-C4alkenyl, C2-C4alkynyl, or C(O)NH2;400.R3Bis selected from the group consisting of H, F, C2-C4alkenyl, C2-C4alkynyl, CN, OH, CH2OH, NH2, CH2NH2, and Ci-C4alkyl;401.each R4Bis independently selected from the group consisting of halogen, oxo, thioxo, Ci-C4alkyl, Ci-C4alkoxy, CDs, CD2CDs, and Ci-Ce haloalkyl; or402.two geminal R4Btogether with the intervening geminal carbon atom, form a Cs-Ce cycloalkyl; each R5Bis independently selected from the group consisting of halogen, NH2, OH, -CN, C(O)NH2, C(O)NHR7B, C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CD3, CD2CD3, Ci-Ce alkoxy, Ci-Ce haloalkyl, C3-C6 cycloalkyl, heterocycloalkyl, heteroaryl, and aryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl is optionally substituted with one or more R6B;403.each R6Bis independently selected from the group consisting of halogen, OH, oxo, NH2, CHO, C1-C4 alkyl, and Ci-Ce alkoxy;404.each R7Bis independently selected from H and C1-C4 alkyl;405.each nB is independently an integer from 0-4;406.rBis an integer from 0 to 2;407.sBis an integer from 0 to 2; and408.tBis an integer from 1 to 2.

12. A composition according to any one of the preceding claims further comprising a DNA cutting agent.

13. A method of targeted insertion of a donor DNA into the genome of a cell, comprising contacting the cell with a DNA cutting agent, the donor DNA, POLQi Compound I, and a DNA-PKI, wherein the DNA-PKI is a compound according to any one of claims 10 or 11.

14. The method of claim 13, comprising growing the cell in a cell medium comprising a DNA-PKI compound and a POLQi Compound I.

15. The composition of any one of the preceding claims, wherein the composition comprises a guide RNA nucleic acid and a Class 2, Type II or Class 2, Type V Cas nuclease; and the molar ratio of the guide RNA to Cas nuclease is from about 4: 1 to 1:4.

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