Substituted imidazoarenes and methods of their use

Abstract

Disclosed are substituted imidazoarenes of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof; a method for manufacturing the compounds disclosed herein, and their therapeutic uses.

Description

[0001] SUBSTITUTED IMIDAZOARENES AND METHODS OF THEIR USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of US Provisional Application No. 63 / 601,402, filed November 21, 2023, the contents of which are hereby incorporated herein in their entirety and for all purposes. FIELD The disclosure relates to the use of a splicing modulator for a treatment slowing progression of Huntington’s disease. BACKGROUND Huntington’s disease (HD) is a hereditary, neurodegenerative and progressive disorder, which has a prevalence of about 5 in 100,000 worldwide. It is caused by CAG repeat expansions in the huntingtin gene (i.e., gene encoding the protein huntingtin) and it is characterized by motor, cognitive, psychiatric and functional capacity decline. The CAG trinucleotide repeat expansion results in a mutant huntingtin protein (mHTT), which is associated with neural dysfunction and ultimately death. The number of CAG repeats in the HTT gene ranges from 6 to 35 in healthy individuals. Disease penetrance is seen to be reduced for individuals carrying 36 to 39 CGA repeats, however those with 40 or more CAG repeats are almost certain to develop the disease. As described in European Journal of Neurology, 2017, 24- 34, clinical diagnosis of HD is based on: - confirmed family history or positive genetic test (i.e., confirmation of CAG repeat expansion ≥36); and - onset of motor disturbance as defined by the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score (TMS) diagnostic confidence score (DCS), which ranges from 0 (no motor abnormalities suggestive of HD) to 4 (motor abnormalities ≥ 99% likely to be due to HD), wherein a score of 4 defines “motor onset” or “manifest” HD. Typically, age of onset (i.e., once the DCS reaches 4) ranges between 30 to 50 years and average duration of survival after clinical diagnosis is 15 to 20 years. Currently, after onset, it is “function” (i.e., assessment of functional capacities), rather than motor signs, which determines disease stage (e.g., in Neurology, 1979, 29, 1-3 or in Neurology, 1981, 31, 1333-1335). The Total Functional Capacity (TFC) scale (e.g., in Movement Disorders, 1996, 11, 136-142) is a component of the UHDRS and ranges from 0 (fully dependent for all care) to 13 (fully independent) the level of independence of a person with HD. This scale assesses functional status of a HD patient in terms of ability to work, handle household finances, manage domestic chores, perform activities of daily living, and level of care needed. Based on the UHDRS total functional capacity (TFC), HD is divided into stages 1 to 5 of disease progression. The categorization of HD, based on TFC score (also referred to as Shoulson and Fahn stages), are also described as early stage of HD (corresponding to stages 1 or 2, based on TFC score), moderate stage or mid stage HD (corresponding to stage 3, based on TFC score) and advanced stage or late-stage HD (corresponding to stage 4 or 5, based on TFC score). At present, only symptomatic treatments are available. Thus, to date, there is no therapy available to slow the progression of HD. Accordingly, there is a need to find disease-modifying therapies for HD, such as therapeutic options that can slow disease progression. SUMMARY In one aspect, disclosed is a compound of Formula (I): , or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein X1is CR2or N; X2is CR6or N; each of X3and X4is independently CH, CR8, or N, wherein R8is halogen (e.g., fluoro); W is O or NRN, wherein RNis hydrogen or C1-6alkyl; R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, halogen, and -N(RN1)2; C1-6alkyl substituted with -N(RN1)2or heterocyclyl; C2-6alkenyl substituted with -N(RN1)2or heterocyclyl; C3-8cycloalkyl substituted with -N(RN1)2; or -CH=C(RN2)2, wherein each RN1is independently H or C1-6alkyl, and both RN2, together with the atom to which they are attached, combine to form a heterocyclyl comprising at least one endocyclic nitrogen atom; R2is hydrogen, halogen, C1-6alkyl, or C1-6haloalkyl; each of R3and R6is independently hydrogen, hydroxyl, C1-6alkoxy, or halogen; R4is halogen, cyano, or heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C1-6alkoxy, hydroxyl, oxo, and halogen, and each R5, when present, is independently halogen or C1-6alkoxy; or R4and one R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen; R7is hydrogen, C1-6alkyl, C1-6haloalkyl, or -OR9, wherein R9is C1-6alkyl or C1-6haloalkyl; n is 0 or 1; and m is 0, 1, or 2. In some embodiments, the compound is a compound of Formula (I): , or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein X1is CR2or N; X2is CR6or N; each of X3and X4is independently CH, CR8, or N, wherein R8is halogen (e.g., fluoro); W is O or NRN, wherein RNis hydrogen or C1-6alkyl; R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen; R2is hydrogen, halogen, C1-6alkyl, or C1-6haloalkyl; each of R3and R6is independently hydrogen, hydroxyl, C1-6alkoxy, or halogen; R4is halogen, cyano, or heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C1-6alkoxy, hydroxyl, oxo, and halogen, and each R5, when present, is independently halogen or C1-6alkoxy; or R4and one R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen; R7is hydrogen, C1-6alkyl, C1-6haloalkyl, or -OR9, wherein R9is C1-6alkyl or C1-6haloalkyl; n is 0 or 1; and m is 0, 1, or 2. In some embodiments, X3is N. In some embodiments, X3is CH. In some embodiments, X3is CR8. In some embodiments, R8is fluoro. In some embodiments, X4is CH. In some embodiments, X4is N. In some embodiments, the compound is of Formula (I’): . In some embodiments, the compound is of Formula (I-A): . In some embodiments, X1is N. In some embodiments, X1is CR2. In some embodiments, X2is N. In some embodiments, X2is CR6. In some embodiments, the compound is of Formula (I-B): . In some embodiments, R6is hydrogen. In some embodiments, R6is fluorine. In some embodiments, the compound is of Formula (I-C): . In some embodiments, R3is hydroxyl. In some embodiments, R3is fluorine. In some embodiments, R3is C1-6alkoxy. In some embodiments, R4is a 5-membered monocyclic heteroaryl comprising 1, 2, 3, or 4 nitrogen atoms in the ring and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen. In some embodiments, R4is selected from the group consisting of:

[0002] . In some embodiments, R4is selected from the group consisting of: In some embodiments, R4is selected from the group consisting of: In some embodiments, R4is a 6-membered monocyclic heteroaryl comprising 1, 2, or 3 nitrogen atoms in the ring and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen. In some embodiments, R4is selected from the group consisting of: In some embodiments, R4is selected from the group consisting of: In some embodiments, R4is selected from the group consisting of: .In some embodiments, R4is cyano. In some embodiments, R4is chloro. In some embodiments, R4is an N-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen. In some embodiments, R4is a bicyclic N-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen. In some embodiments, R4is . In some embodiments, R4and R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen or C1-6alkoxy, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen. In some embodiments, R4is selected from the group consisting of: . In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, n is 0, and m is 0. In some embodiments, R5is fluorine. In some embodiments, W is O. In some embodiments, W is NRN. In some embodiments, RNis methyl. In some embodiments, R1is a heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen. In some embodiments, R1is a 6-membered monocyclic heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen. In some embodiments, R1is a 7-membered monocyclic heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen. In some embodiments, R1is a bicyclic heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen. In some embodiments, R1is bonded to the core through the endocyclic carbon atom of R1. In some embodiments, R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl and hydroxyl. In some embodiments, R1is a spirocyclic heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen. In some embodiments, R1is C1-6alkyl substituted with -N(RN1)2or heterocyclyl. In some embodiments, R1is C2-6alkenyl substituted with -N(RN1)2or heterocyclyl. In some embodiments, R1is C3-8cycloalkyl substituted with -N(RN1)2. In some embodiments, R1is -CH=C(RN2)2, wherein each RN1is independently H or C1-6alkyl, and both RN2, together with the atom to which they are attached, combine to form a heterocyclyl comprising at least one endocyclic nitrogen atom. In some embodiments, R1is selected from the group consisting of: In some embodiments, R1is selected from the group consisting of: In some embodiments, R1is selected from the group consisting of: In some embodiments, R1is selected from the group consisting of: In some embodiments, R1is . In some embodiments, R1is selected from the group consisting of: In some embodiments, R1is selected from the group consisting of: . In some embodiments, R1is selected from the group consisting of: In some embodiments, R1is selected from the group consisting of: . In some embodiments, R7is hydrogen. In another aspect, disclosed is a compound selected from the group consisting of: 53 60 61 62 133 134 135 136 137 138 139 140

[0003] and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-151, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-73, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-33, 64, 65, 69, 73, 83, 86, 88, 89, 93-95, 99, 110-113, 115, 117, 118, 134, 135, 139, 144-147, 149, 150, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-33, 64, 65, 69, 73, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-20, 64, 65, 69, 83, 86, 88, 89, 93-95, 99, 110-113, 115, 117, 118, 134, 135, 139, 144-147, 149, 150, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is selected from the group consisting of compounds 1-20, 64, 65, 69, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. In some embodiments, the compound is compound 1 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof. In some embodiments, the compound is compound 2 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 7 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof. In some embodiments, the compound is compound 10 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer salt thereof. In some embodiments, the compound is compound 11 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof. In yet another aspect, disclosed is a pharmaceutical composition comprising an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof and one or more pharmaceutically acceptable carriers. In a further aspect, disclosed is a method of treating Huntington’s disease, spinal muscular atrophy, or familial dysautonomia, the method comprising administering to a subject in need thereof an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, or the pharmaceutical composition disclosed herein. In some embodiments, the method is of treating Huntington’s disease. In some embodiments, the method is of treating spinal muscular atrophy. In some embodiments, the method is of treating familial dysautonomia. In some embodiments, the method further comprises administering an effective amount of an MSH3 inhibitor. In yet further aspect, disclosed is the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, or the pharmaceutical composition disclosed herein, for use in the treatment of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia. In some embodiments, the use is in the treatment of Huntington’s disease. In some embodiments, the use is in the treatment of treating spinal muscular atrophy. In some embodiments, the use is in the treatment of treating familial dysautonomia. In some embodiments, the use is in combination with an MSH3 inhibitor. In still further aspect, disclosed is the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition disclosed herein, for treating of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia. In some embodiments, the compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition, is for treating Huntington’s disease. In some embodiments, the compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition, is for treating spinal muscular atrophy. In some embodiments, the compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition, is for treating familial dysautonomia. In some embodiments, the treating is in combination with an MSH3 inhibitor. In another aspect, disclosed is use of a compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof in the manufacture of a medicament for the treatment of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia. In some embodiments, the medicament is for the treatment of Huntington’s disease. In some embodiments, the medicament is for the treatment of treating spinal muscular atrophy. In some embodiments, the medicament is for the treatment of treating familial dysautonomia. In some embodiments, the use is in combination with an MSH3 inhibitor. In yet another aspect, disclosed is a method of forming a complex comprising a component of a spliceosome, a nucleic acid, and the compound disclosed herein: comprising contacting the nucleic acid with the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof. In some embodiments, the component of a spliceosome is a major spliceosome component or a minor spliceosome component. In some embodiments, the nucleic acid is a DNA or RNA. In some embodiments, the nucleic acid is a pre-mRNA transcript. In still another aspect, disclosed is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an intronic exon, the method comprising contacting the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof with a cell comprising a pre-mRNA transcript comprising at least two exons and at least one intron, wherein at least one of the exons is upstream of the intron and at least one of the exons is downstream of the intron. In some embodiments, the intron comprises in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site, an intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3' splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide. In some embodiments, the intron further comprises in 5′ to 3′ order: a 5′ splice site, a branch point, and a 3′ splice site, wherein the 5′ splice site, the branch point, and the 3′ splice site are upstream of the iREMS. In some embodiments, the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25; and HTT, SMN2, ELP1, FOXM1, and MAPT. In some embodiments, the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: C12orf4, CDH18, CHEK1, DHFR, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, POMT2, TAF2, TRIM65, and WDR27; ADAMTS19, BECN1, CACNB4, CADM2, CHEK1, CHRM2, CMAHP, DENND4A, DHFR, EVC, GXYLT1, MEMO1, MYCBP2, NUPL1, PDXDC1, SENP6, SPIDR, TNRC6A, TRIM65, URGCP-MRPS24, WDR90, ZFP82, ZNF618, and ZNF680; and AGPS, AKT1, ANXA11, ARHGAP5, ARL15, ATF6, BIN3, C11orf30, C11orf73, CDH18, CENPI, DCAF17, DENND4A, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777. In some embodiments, the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: HTT; ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHRM2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AGPS, AKT1, ANXA11, ARHGAP5, ATF6, ASAP1, BHMT2, BIN3, C11orf30, C11orf73, C1orf27, CENP1, DCAF17, ENAH, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1524, KIAA1715, KIDINS220, LYRM1, MFN2, MORF4L1, NGF, RERE, SF3B3, SLC25A17, SNX24, SNX7, STRADB, STXBP6, TA5P1, TBCA, TCF4, TMEM214, UBE2D3, UBE2L3, VDAC2, WNK1, XRN2, ZNF138, ZNF350, and ZNF777; and DIAPH3, NIPA1, RAF1, DCAF172a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H. In some embodiments, the pre-mRNA transcript is a pre-mRNA transcript of the HTT, SMN2, ELP1, FOXM1, or MAPT gene. In some embodiments, the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene. DETAILED DESCRIPTION The disclosure relates to compounds of formula (I), including (I’), (I-A), (I-B), (I-C), exemplified compounds, salts thereof, particularly pharmaceutically acceptable salts thereof, hydrates, solvates, prodrugs, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties. For purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. As used herein, the term “alkyl” refers to a fully saturated branched or unbranched hydrocarbon substituent. A C1-10alkyl is an alkyl having 1 to 10 carbon atoms. The terms “C1-6alkyl” and “C1-4alkyl” are to be construed accordingly. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl. As used herein, the term “alkenyl” refers to a branched or unbranched hydrocarbon substituent having one or two carbon-carbon double bonds. A C2-10alkenyl is an alkenyl having 2 to 10 carbon atoms. The terms “C2-6alkyl” and “C2-4alkyl” are to be construed accordingly. Representative examples of alkenyl include, but are not limited to, ethenyl, prop-2-en-1-yl, prop- 1-en-1-yl, i-propenyl, 2-methylprop-1-en-1yl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, but-1-en- 2-yl, but-2-en-2-yl, but-3-en-2-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, pent-1-en-2-yl, pent-2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, 2-methylbut-1-en-1-yl, 3- methylbut-1-en-1-yl, 2-methylbut-2-en-1-yl, prenyl, 3-methylbut-1-en-2-yl, 3-methylbut-2-en-2-yl, hexenyl, hepenyl, octenyl, nonenyl and decenyl, and their constitutional isomers. As used herein, the term “alkoxy” refers to -O-alkyl, wherein alkyl is defined herein above. The term “C1-6alkoxy” is to be construed accordingly. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy- and decyloxy-. The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms and includes one or more aromatic rings optionally fused to one or more non-aromatic hydrocarbon rings. The term “C6-10aryl” is to be construed accordingly. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl. The term “aryl alkyl” referts to a group -L-R, wherein L is an alkyl group substituted by R, which is an aryl group. As used herein, the term “cycloalkyl” refers to saturated or non-aromatic, unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups. A C3-12cycloalkyl is a cycloalkyl of 3-12 carbon atoms. The term “C3-8cycloalkyl” refers to a fully saturated or non-aromatic, unsaturated monocyclic hydrocarbon group of 3-8 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6- trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include, for example, adamantyl. As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halogen atom. The haloalkyl group can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl has one iodo, bromo, chloro or fluoro substituent on the alkyl group. Dihaloalkyl and polyhaloalkyl groups have two or more of the same halo substituents or a combination of different halo substituents on the alkyl. The term “C1-6haloalkyl” is to be construed accordingly. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl group refers to an alkyl group having all hydrogen atoms replaced with halo substituents. As used herein, the term “halogen” or “halo” refers to fluoro, chloro, bromo, and iodo. As used herein, the term "heteroaryl" refers to a 5-, 6-, or 7-membered monocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N, an 8-, 9-, or 10- membered fused bicyclic ring system containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N, or an 11-, 12-, 13-, or 14-membered fused tricyclic ring system containing 1, 2, 3, 4, 5 or 6 heteroatoms selected from O, S and N, wherein at least one of the rings of the bicyclic or tricyclic ring systems is fully aromatic. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3- furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2, 3- triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4- , 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6- , 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3- , 5-, 6-, 7-, or 8- quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1- , 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2- , 3-, 4-, 6-, 7- , 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or l-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 -, or 11-7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6-, or 7-2H- furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5- 1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d] thiazolyl, 3-, 5-, or 8-pyrazino[2,3- d]pyridazinyl, 2-, 3-, 5-, or 6- imidazo[2,1-b] thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2- b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9- benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2- b][2]benzazapinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. As used herein, the term “heterocyclyl” or “heterocyclo” refers to a saturated or unsaturated non-aromatic ring or ring system, which is a 4-, 5-, 6-, or 7-membered monocyclic ring containing 1, 2 or 3 heteroatoms selected from O, S and N, a 7-, 8-, 9-, 10-, 11-, or 12- membered bicyclic ring system containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N, or a 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and containing 1, 2, 3, 4, 5, 6 or 7 heteroatoms selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. The heterocyclic group can be attached via a heteroatom or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane and thiomorpholine. As used herein, the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term “an optical isomer” or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound disclosed herein and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the present disclosure includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- lngold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) by which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. 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. As used herein, the term “oxo” refers to group =O. As used herein, the term “optionally substituted” refers to a group that is either unsubstituted or substituted. As used herein, the term “protecting group” refers to those groups intended to protect a functional group (e.g., -OH or -NH2) against undesirable reactions during synthetic procedures. Commonly used protecting groups are disclosed in Greene, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary protecting groups suitable for protecting -OH (with the oxygen atom to which they are attached) include, e.g., esters, carbonates, carbamates, sulfonates, and ethers. As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound disclosed herein. “Salts” include in particular “pharmaceutically acceptable salts.” The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds disclosed herein and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. The term "a therapeutically effective amount" or “an effective amount” of a compound disclosed herein refers to an amount of the compound disclosed herein that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one embodiment, the term “a therapeutically effective amount” refers to the amount of the compound disclosed herein that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and / or ameliorate a condition, or a disorder or a disease (i) mediated by HTT, SMN2, ELP1, or (ii) associated with [receptor] activity, or (iii) characterized by activity (normal or abnormal) of [receptor]; or (2) reduce or inhibit the activity of [receptor]; or (3) reduce or inhibit the expression of [receptor]. In another embodiment, the term “a therapeutically effective amount” refers to the amount of the compound disclosed herein that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of [receptor]; or at least partially reducing or inhibiting the expression of [receptor]. The meaning of the term “a therapeutically effective amount” as illustrated in the above embodiment for [receptor] also applies by the same means to any other relevant proteins / peptides / enzymes, such as [receptorYZ], or other [receptorAB], and the like. As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female). In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human. As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, the term “MSH3 inhibitor” refers to a compound (e.g., an inhibitory oligonucleotide, such as siRNA or antisense oligonucleotide (ASO), or a small molecule) that, upon contacting a cell containing MSH3, reduces or suppresses the activity of MSH3 in a cell, e.g., by reducing or suppressing the activity or production of the MSH3 protein. Non-limiting examples of MSH3 inhibitors are known in the art, e.g., MSH3 inhibitors disclosed in in US 20210355491, US 20220072028, US 20230313185, US 20240263179, WO 2021247020, and WO 2023168304, the disclosures of which are hereby incorporated by reference. As used herein, the term “treat”, “treating" or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or arresting the development of the disease or at least one of the clinical symptoms thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those which may not be discernible to the patient. As used herein, a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. As used herein, the term “a,” “an,” “the” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. Any asymmetric atom (e.g., carbon or the like) of the compound(s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form. Accordingly, as used herein a compound disclosed herein can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization. Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds disclosed herein into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. Compounds disclosed herein are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof. When both a basic group and an acid group are present in the same molecule, the compounds disclosed herein may also form internal salts, e.g., zwitterionic molecules. Furthermore, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the disclosure embrace both solvated and unsolvated forms. The term “solvate” refers to a molecular complex of a compound disclosed herein (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term “hydrate” refers to the complex where the solvent molecule is water. The compounds disclosed herein, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs. The disclosure further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material. Compounds disclosed herein and intermediates can also be converted into each other according to methods generally known to those skilled in the art. In general, the present disclosure provides compounds that may be useful in the treatment of Huntington’s disease. Without wishing to be bound by theory, compounds disclosed herein may promote Huntingtin mRNA decay by promoting pseudoexon inclusion during splicing of Huntingtin pre-mRNA. The compounds disclosed herein are those of Formula ( , or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein X1is CR2or N; X2is CR6or N; each of X3and X4is independently CH, CR8, or N, wherein R8is halogen; W is O or NRN, wherein RNis hydrogen or C1-6alkyl; R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, halogen, and -N(RN1)2; C1-6alkyl substituted with -N(RN1)2or heterocyclyl; C2-6alkenyl substituted with -N(RN1)2or heterocyclyl; C3-8cycloalkyl substituted with -N(RN1)2; or -CH=C(RN2)2, wherein each RN1is independently H or C1-6alkyl, and both RN2, together with the atom to which they are attached, combine to form a heterocyclyl comprising at least one endocyclic nitrogen atom; R2is hydrogen, halogen, C1-6alkyl, or C1-6haloalkyl; each of R3and R6is independently hydrogen, hydroxyl, C1-6alkoxy, or halogen; R4is halogen, cyano, or heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C1-6alkoxy, hydroxyl, oxo, and halogen, and each R5, when present, is independently halogen or C1-6alkoxy; or R4and one R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen; R7is hydrogen, C1-6alkyl, C1-6haloalkyl, or -OR9, wherein R9is C1-6alkyl or C1-6haloalkyl; n is 0 or 1; and m is 0, 1, or 2. In some embodiments, the compound is a compound of Formula (I): , or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein X1is CR2or N; X2is CR6or N; each of X3and X4is independently CH, CR8, or N, wherein R8is halogen (e.g., fluoro); W is O or NRN, wherein RNis hydrogen or C1-6alkyl; R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen; R2is hydrogen, halogen, C1-6alkyl, or C1-6haloalkyl; each of R3and R6is independently hydrogen, hydroxyl, C1-6alkoxy, or halogen; R4is halogen, cyano, or heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C1-6alkoxy, hydroxyl, oxo, and halogen, and each R5, when present, is independently halogen or C1-6alkoxy; or R4and one R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen; R7is hydrogen, C1-6alkyl, C1-6haloalkyl, or -OR9, wherein R9is C1-6alkyl or C1-6haloalkyl; n is 0 or 1; and m is 0, 1, or 2. Non-limiting examples of the compounds disclosed herein include the following: 98 99 100 101 102 103 104 105 106 107

[0004] and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof. Pharmaceutically Acceptable Salts Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfornate, chloride / hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. The pharmaceutically acceptable salts disclosed herein can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Isotopically Enriched Compounds Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as 2H,3H,11C,13C,14C,15N,18F,31P,32P,35S,36Cl,125I respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes, such as3H,13C, and14C, are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds disclosed herein and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Further, substitution with heavier isotopes, particularly deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound disclosed herein is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically labeled reagents in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, d6- DMSO. Co-crystals Compounds disclosed herein, i.e., compounds of formula (I) that contain groups capable of acting as donors and / or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co- crystal formers include those described in WO 2004 / 078163. Hence the disclosure further provides co-crystals comprising a compound of formula (I). Tautomeric Forms The compounds disclosed herein may also exist in their tautomeric forms. Such forms although not explicitly indicated in the present application are intended to be included within the scope of the present disclosure. Pharmaceutical Compositions The present disclosure also provides a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions disclosed herein can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc. Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art. Suitable compositions for oral administration include an effective amount of a compound disclosed herein in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient. Suitable compositions for transdermal application include an effective amount of a compound disclosed herein with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant. The present disclosure further provides anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds disclosed herein as active ingredient(s), since water may facilitate the degradation of certain compounds. Anhydrous pharmaceutical compositions and dosage forms disclosed herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs. The disclosure further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound disclosed herein as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc. Methods of Use The compounds of formula I in free form or in salt form, exhibit valuable pharmacological properties, e.g., full length protein (e.g., HTT) production modulating properties. Thus, as a further embodiment, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof in therapy. In a further embodiment, the therapy is selected from a disease which may be treated by modulating full length protein (e.g., HTT) production. In another embodiment, the present disclosure provides a method of treating a disease which is treated by modulating full length protein (e.g., HTT) production comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof to a patient in need of such therapy. Thus, as a further embodiment, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof for the manufacture of a medicament. In a further embodiment, the medicament is for treatment of a disease which may be treated by modulation of protein (e.g., HTT) production. In one embodiment, the methods and uses described above described above pertain to modulation of protein production, where the protein (e.g., a full length protein) is selected from the group consisting of: ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25; and HTT, SMN2, ELP1, FOXM1, and MAPT. In one embodiment, the protein is HTT and the disease is Huntington’s disease. In one embodiment, the protein is SMN2 and the disease is spinal muscular atrophy (SMA). In one embodiment, the protein is ELP1 and the disease is familial dysautonomia. Modulation of the protein production may involve modulation of the gene transcript (e.g., pre-mRNA) splicing. Thus, in one embodiment, the present disclosure provides a method for modifying RNA splicing in order to produce a mature mRNA transcript having an intronic exon, the method comprising contacting the compound described herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof with a cell comprising a pre-mRNA transcript comprising at least two exons and at least one intron, wherein at least one of the exons is upstream of the intron and at least one of the exons is downstream of the intron. In one embodiment, the intron comprises in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site, an intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3' splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide. The intron may further comprise in 5′ to 3′ order: a 5′ splice site, a branch point, and a 3′ splice site, wherein the 5′ splice site, the branch point, and the 3′ splice site are upstream of the iREMS. Without wishing to be bound by theory, it is believed that RNA splicing modulation proceeds through the formation of a complex comprising a component of a spliceosome, a nucleic acid, and the compound disclosed herein. Accordingly, the present disclosure also provides a method of forming a complex comprising a component of a spliceosome, a nucleic acid, and the compound disclosed herein. The nucleic acid may be RNA (e.g., in the context of RNA splicing modulation), e.g., a pre-mRNA. In one embodiment, the pre-mRNA is a pre-mRNA transcript of a gene selected from the group consisting of: ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25; and HTT, SMN2, ELP1, FOXM1, and MAPT In one embodiment, the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene and the disease is Huntington’s disease. In one embodiment, the pre-mRNA transcript is a pre- mRNA transcript of the SMN2 gene and the disease is spinal muscular atrophy (SMA). In one embodiment, the pre-mRNA transcript is a pre-mRNA transcript of the ELP1 gene and the disease is familial dysautonomia. In one embodiment, the present disclosure provides a method of treating Huntington’s disease, spinal muscular atrophy, or familial dysautonomia, the method comprising administering to a subject in need thereof an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, or the pharmaceutical composition disclosed herein. In one embodiment, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, or the pharmaceutical composition disclosed herein, for use in the treatment of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia. In one embodiment, the present disclosure provides a use of the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof in the manufacture of a medicament for the treatment of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia. The compound, pharmaceutical composition, or combination of the present disclosure can be in unit dosage of about 0.01-1000 mg of active ingredient(s) for a subject of about .05-70 kg or about 1-20 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 0.01-1 mg or about 0.01-0.1 mg or about 1-50 mg of active ingredients. The effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. The above-cited dosage properties are demonstrable in in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds disclosed herein can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10-3molar and 10-9molar concentrations. An effective amount in vivo may range depending on the route of administration, between about 0.1-500 mg / kg, or between about 1-100 mg / kg. The compound disclosed herein may be administered either simultaneously with, or before or after, one or more other therapeutic agent. The compound disclosed herein may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. In one embodiment, the present disclosure provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of Huntington’s disease. Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g., in the form of a kit. In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above. In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I). In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. The kit disclosed herein may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit disclosed herein typically comprises directions for administration. In the combination therapies disclosed herein, the compound disclosed herein and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Moreover, the compound disclosed herein and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g., in the case of a kit comprising the compound disclosed herein and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g., during sequential administration of the compound disclosed herein and the other therapeutic agent. Preparations of Compounds It is understood that in the following description, combinations of substituents and / or variables of the depicted formulae are permissible only if such contributions result in stable compounds. The compounds of the 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. Generally, compounds of formula (I) can be prepared, e.g., according to the Schemes provided infra. As shown above, a compound of formula (I) may be prepared from intermediate I4 or I5, e.g., by deprotection of -O-(protecting group) in R3to provide -OH as R3. A protecting group Intermediate I3 may be prepared from intermediates I1 and I2, e.g., through an annulation reaction between I1 and I2. Reaction conditions appropriate for the annulation reactions are known in the art. Such reactions typically involve the use of a polar solvent (e.g., an alcoholic solvent, such as 2-propanol) at elevated temperatures (e.g., under solvent reflux, such as at 80-100 deg. C). The following examples are intended to illustrate the disclosure and are not to be construed as being limitations thereon. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods. Abbreviations used are those conventional in the art, unless otherwise noted. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds disclosed herein are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed.1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds disclosed herein can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. It will also be appreciated by those skilled in the art that in the processes described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t- butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. The protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds disclosed herein may not possess pharmacological activity as such, they may be administered to a subject and thereafter metabolized in the body to form compounds disclosed herein which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds disclosed herein are included within the scope of the disclosure. The following examples are meant to illustrate the disclosure. They are not meant to limit the disclosure in any way. EXAMPLES General methods Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Avance spectrometer or Varian Oxford 400 MHz spectrometer unless otherwise noted. NMR spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26) or other solvent as indicated in NMR spectral data. A small amount of dry sample (2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. The chemical names were generated using ChemDraw Professional v22 from Perkin Elmer Informatics. Temperatures are given in degrees Celsius. As used herein, unless specified otherwise, the term "room temperature" or "ambient temperature" means a temperature of from 15 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 30 degrees centigrade, such as of from 20 degrees centigrade to 25 degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized in the synthesis of the compounds of the present disclosure are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Abbreviations The following LC-MS methods were used for characterization of the examples and intermediates: LC / MS method 1 Pump: Waters AcQuity UPLC Column: AcQuity UPLC BEH C181.7 μM, 2.1x30 mm Column temperature: 50 °C Gradient (Time (min.) / %B): 0.0 / 2, 0.1 / 2, 1.5 / 98, 1.8 / 98, 1.9 / 2, 2.0 / 2 Eluent A: 0.1% Formic acid in water Eluent B: 0.1% Formic acid in acetonitrile Flow: 1.0 mL / min ELSD: SofTA 1100 ELSD Mass Spec: Waters QDa LC / MS method 2 Pump: Waters AcQuity UPLC Column: AcQuity UPLC BEH C181.7 μM, 2.1x30 mm Column temperature: 50 °C Gradient (Time (min.) / %B): 0.0 / 2, 0.1 / 2, 1.5 / 98, 1.8 / 98, 1.9 / 2, 2.0 / 2 Eluent A: 5 mM Ammonium hydroxide in water Eluent B: 5 mM Ammonium hydroxide in acetonitrile Flow: 1.0 mL / min ELSD: SofTA 1100 ELSD Mass Spec: Waters QDa LC / MS method 3 Pump: Waters AcQuity UPLC Column: AcQuity UPLC BEH C181.7 μM, 2.1x50 mm Column temperature: 50 °C Gradient (Time (min.) / %B): 0.0 / 2, 4.4 / 98, 5.15 / 98, 5.19 / 2 Eluent A: 0.1% Formic acid in water Eluent B: 0.1% Formic acid in acetonitrile Flow: 1.0 mL / min ELSD: SofTA 1100 ELSD Mass Spec: Waters QDa LC / MS method 4 Pump: Waters AcQuity UPLC Column: AcQuity UPLC BEH C181.7 μM, 2.1x50 mm Column temperature: 50 °C Gradient (Time (min.) / %B): 0.0 / 2, 4.4 / 98, 5.15 / 98, 5.19 / 2 Eluent A: 5 mM Ammonium hydroxide in water Eluent B: 5 mM Ammonium hydroxide in acetonitrile Flow: 1.0 mL / min ELSD: SofTA 1100 ELSD Mass Spec: Waters QDa LC / MS method 5 System: Shimadzu –LCMS 2020 (single quad) Column: ACQUITY UPLC BEH C181.7 μm, 2.1*50 mm Column temperature: 40 °C Gradient (Time (min.) / %B): 0.01 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5 Eluent A: 0.1% HCOOH in water Eluent B: 0.1% HCOOH in CH3CN Flow: 0.8 mL / min Ion Source: DUIS –ESI & APCI Nebulizing Gas Flow: 1.5 L / min DL Temperature: 250 °C Heat Block Temperature: 300 °C LC / MS method 6 System: Shimadzu –LCMS 2020 (single quad) Column: ACQUITY UPLC BEH C181.7 μm, 2.1*50 mm Column temperature: 40 °C Gradient (Time (min.) / %B): 0.01 / 5, 1.20 / 50, 2.10 / 75, 2.80 / 95, 3.20 / 5, 4.0 / 5 Eluent A: 0.1% HCOOH in water Eluent B: 0.1% HCOOH in CH3CN Flow: 0.8 mL / min Ion Source: DUIS –ESI & APCI Nebulizing Gas Flow : 1.5 L / min DL Temperature: 250 °C Heat Block Temperature: 300 °C LC / MS method 7 System: Shimadzu –LCMS 2020 (single quad) Column: Synergi 2.5 μ MAX-RP 100 A Mercury Column temperature: 40 °C Gradient (Time (min.) / %B): 0.01 / 5, 1.20 / 50, 2.10 / 75, 2.80 / 95, 3.20 / 5, 4.0 / 5 Eluent A: 0.1% HCOOH in water Eluent B: 0.1% HCOOH in CH3CN Flow: 0.8 mL / min Ion Source: DUIS –ESI & APCI Nebulizing Gas Flow : 1.5 L / min DL Temperature: 250 °C Heat Block Temperature: 300 °C LC-MS method 8 System: Shimadzu –LCMS 2020 (single quad) Column: ACQUITY UPLC BEH C181.7 μm,2.1*50mm Column temperature: 40 °C Gradient (Time / %B ) : 0.01 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5 Eluent A: 0.1% HCOOH in water Eluent B: 0.1% HCOOH CH3CN Flow: 0.8 mL / min Ion Source : DUIS –ESI & APCI Nebulizing Gas Flow :1.5 L / min DL Temperature : 250° C Heat Block Temperature :300° C LC-MS method 9 System: Shimadzu –LCMS 2020 (single quad) Column: ACQUITY UPLC BEH C181.7 μm,2.1*50mm Column temperature: 40 °C Gradient(Time / %B ) : 0.01 / 5, 1.20 / 50, 2.10 / 75, 2.80 / 95, 3.20 / 5, 4.0 / 5 Eluent A: 0.1% HCOOH in water Eluent B: 0.1% HCOOH CH3CN Flow: 0.8 mL / min Ion Source : DUIS –ESI & APCI Nebulizing Gas Flow :1.5 L / min DL Temperature : 250° C Heat Block Temperature :300° C LC-MS method 10 System: Shimadzu –LCMS 2020 (single quad) Column: ACQUITY UPLC BEH C181.7 μm,2.1*50mm Column temperature: 40 °C Gradient (Time / %B) : 0.01 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5 Eluent A: 0.1% HCOOH in water Eluent B: 0.1% HCOOH CH3CN Flow: 0.8 mL / min Ion Source: DUIS –ESI & APCI Nebulizing Gas Flow : 1.5 L / min DL Temperature: 250° C Heat Block Temperature :300° C LC-MS method 11 System: Shimadzu Nexera LCMS-2020 with Single Quad. Column: ACQUITY UPLC BEH C181.7 μm,2.1*50mm. Gradient: A- 0.1% formic acid in water, B- 0.1% formic acid in acetonitrile. Time / %B: 0.01 / 5, 0.30 / 5, 0.50 / 100,1.80 / 100,2.0 / 5,3.0 / 5; Flow: 0.8 mL / min. UV detection array 200 – 400. Mass detection 100 – 1000 (Multimode -electrospray ionization / Atmospheric Pressure Chemical Ionization); Column temperature: 40 °C Nebulizing Gas Flow: 1.5 L / min DL Temperature: 250 °C Heat Block Temperature: 300 °C Synthesis of amino-pyrimidine intermediates Key amino-pyrimidine intermediates Synthesis of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (Intermediate A1) 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6- tetrahydropyridine- hydrochloride (3.0 g, 1.3 equiv, 9.9 mmol), 4-chloropyrimidin-2-amine (1.0 g, 1.0 equiv, 7.7 mmol), THF (5.0 mL), 2 wt% aqueous TPGS-750-M surfactant solution (20.0 mL) and triethylamine (4.7 g, 6.5 mL, 6.0 equiv, 46 mmol) were added to a 250 mL round-bottom flask. To this was added PdCl2(dppf)CH2Cl2(315 mg, 0.050 equiv, 386.0 μmol) and the resulting mixture was degassed with nitrogen for 30 min. The resulting mixture was magnetically stirred at 50 °C for 1 day at which time LCMS showed conversion to the target product. The reaction was allowed to cool to ambient temperature, diluted with EtOAc, and filtered through a pad of celite, rinsing with EtOAc. The solution was washed with brine. The brine layer was extracted with EtOAc. All the organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified via automated flash chromatography (80 gram Redisep Silver silica gel column, dry load, 0-20% (10% 7N NH4OH in MeOH) / DCM). The product-containing fractions were combined, concentrated under reduced pressure and further dried under high vacuum to provide the desired product 4-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)pyrimidin-2-amine (1.4 g, 6.1 mmol, 78% yield). ESI-MS m / z 233.3, [M+H]+, Rt = 0.66 min., LC / MS method 2. 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 5.4 Hz, 1H), 6.80 (d, J = 5.4 Hz, 1H), 6.75 (t, J = 1.7 Hz, 1H), 2.34 (d, J = 1.7 Hz, 2H), 1.31 (s, 6H), 1.23 (s, 6H). Synthesis of 4-(2,2,6,6-tetramethylpiperidin-4-yl) pyrimidin-2-amine (intermediate B1) To a mixture of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrimidin-2-amine (A1) (0.5 g, 2.2 mmol, 1 equiv) in ethanol (5 mL) was added palladium hydroxide on carbon (302 mg, 1 equiv, 2.2 mmol) at RT under argon atmosphere. The reaction mixture was stirred at RT under H2balloon pressure for 5 h. The progress of the reaction was monitored by TLC & LCMS. Upon completion of the reaction, the reaction mixture was diluted with ethanol and filtered through a pad of Celite, rinsing with ethanol. The combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on a C18column (eluent: water / CH3CN (using 0.1% formic acid) = 100:0 to 60:40; 13 g RediSep Rf reversed-phase C18column using a 5 g solid cartridge for dry-loading) to give 4-(2,2,6,6- tetramethylpiperidin-4-yl) pyrimidin-2- amine (0.5 g, 1.9 mmol, 90% yield) as an off white solid. ESI-MS m / z 235.25, [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 5.0 Hz, 1H), 6.48 – 6.39 (m, 3H), 2.94 – 2.79 (m, 1H), 1.68 – 1.52 (m, 2H), 1.33 – 1.22 (m, 2H), 1.18 (s, 6H), 1.06 (s, 6H). Synthesis of 5-fluoro-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2- amine (Intermediate A2) To a 100 mL round-bottom flask were added 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (2.07 g, 7.79 mmol, 1.15 equiv), 4-chloro-5- fluoropyrimidin-2-amine (1.0 g, 6.8 mmol, 1.0 equiv), THF (4.0 mL), 2 wt% aqueous TPGS- 750-M surfactant solution (16.0 mL), and triethylamine (2.74 g, 3.78 mL, 27.1 mmol, 4.0 equiv). To this mixture was added PdCl2(dppf).CH2Cl2(277 mg, 339 μmol, 0.05 equiv), and the resulting mixture was degassed with nitrogen for 30 min. Then, the magnetically stirred mixture was heated at 50 °C for 1 day. Heating was discontinued and the mixture was allowed to come to RT. The mixture was diluted with EtOAc and filtered through a pad of Celite, rinsing with EtOAc. The filtrate was washed with brine, and the brine layer was back extracted with EtOAc twice. The Organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. Purification of the resulting residue via automated flash chromatography (40 g Redisep Silver column, dry loading, 0-30% (10% 7N NH4OH in MeOH) / DCM). The product containing fractions were combined, concentrated and further dried under high vacuum to furnish 5-fluoro-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)pyrimidin-2-amine (1.23 g, 4.89 mmol, 72% yield). ESI-MS m / z 251.0, Rt = 0.76 min., LC / MS method 2. 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J = 4.1 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 2.39 (t, J = 1.4 Hz, 2H), 1.33 (s, 6H), 1.24 (s, 6H). Synthesis of 5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-2-amine (Intermediate 5-fluoro-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (A2) (1.22 g, 4.87 mmol, 1.0 equiv) and 10% palladium hydroxide on carbon (684 mg, 0.10 equiv, 487 μmol) were combined in methanol (42 mL) under nitrogen. The reaction vessel was evacuated and the atmosphere replaced with hydrogen from a balloon. This was repeated three times. Then, the reaction mixture was stirred under hydrogen atmosphere from a balloon for 7 hours. The mixture was filtered through a pad of Celite with the aid of DCM and methanol, and the filtrate was concentrated under reduced pressure to furnish 5-fluoro-4-(2,2,6,6- tetramethylpiperidin-4-yl)pyrimidin-2-amine (1.20 g, 4.76 mmol, 97% yield). ESI-MS m / z 253.5, [M+H]+; Rt = 0.70 min, LC / MS method 2. 1H NMR (400 MHz, methanol-d4) δ 8.06 (d, J = 2.5 Hz, 1H), 3.46 (tdt, J = 12.5, 3.4, 1.6 Hz, 1H), 1.73 – 1.67 (m, 2H), 1.56 (t, J = 12.9 Hz, 2H), 1.33 (s, 6H), 1.22 (s, 6H). Synthetic scheme for Intermediates A3 and B3 Synthesis of 5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrimidin-2- amine (intermediate A3) To a stirred solution of 4-chloro-5-methylpyrimidin-2-amine (2.0 g, 13.9 mmol) in dioxane (20 mL) and water (4 mL) were added 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (3.67 g, 13.9 mmol) and K2CO3(5.67 g, 41.7 mmol). The reaction mixture was purged with argon for 15 min. Then, Pd(dppf)Cl2.DCM (1.14 g, 1.39 mmol) was added and again the reaction mixture was sparged with argon for 5min. The reaction mixture was stirred at 90 °C for 12 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to RT and filtered through a pad of Celite, rinsing with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The residue thus obtained was purified by reversed phase flash chromatography (CombiFlash, 24 g C18 column, gradient elution, 0-50% acetonitrile in water) to afford 5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrimidin-2-amine (A3) (0.6 g, 2.43 mmol, 17% yield) as pale-yellow thick mass. ESI-MS m / z 247.15, [M+H]+. Synthesis of 5-methyl-4-(2,2,6,6-tetramethylpiperidin-4-yl) pyrimidin-2-amine (B3) To a stirred solution of 5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrimidin-2-amine (A3) (0.6 g, 2.43 mmol) in EtOH (6.0 mL) was added 10% Pd(OH)2on carbon (500 mg) under argon. The reaction mixture was stirred at rt under H2balloon pressure for 6 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite, rinsing with ethyl acetate twice. The combined organic layers were concentrated under reduced pressure. Purification by reverse phase HPLC (CombiFlash, 12 g C18 column, gradient elution, 0-50% acetonitrile in water) afforded 5-methyl-4-(2,2,6,6-tetramethylpiperidin-4-yl) pyrimidin-2-amine (B3) (550 mg, 2.21 mmol, 91% yield) as a pale-yellow, thick oil. ESI-MS m / z 249.10, [M+H]+. Synthetic scheme for Intermediates A4 and B4 Synthesis of 2-chloro-5-(trifluoromethyl) pyrimidin-4-amine (2a) and 4-chloro-5- (trifluoromethyl) pyrimidin-2-amine (2b) To a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (6.0 g, 27.65 mmol, 1 equiv) in THF (60 mL) at 0 °C was added 28% aq. NH3(5.0 mL) via syringe. Upon complete addition, the reaction mixture was slowly warmed to RT and stirred at RT for 16 h. Progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into ice water and extracted with EtOAc (150 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue thus obtained was purified 3 times by MPLC (CombiFlash, 12 g RediSep Silver column, Gradient Elution, 30-40% EtOAc in hexane) to afford 2-chloro-5-(trifluoromethyl) pyrimidin-4-amine (2a) (1.5 g, 27% yield) as a white solid, ESI-MS m / z 197.95, [M+H]+, and 4-chloro-5-(trifluoromethyl) pyrimidin-2-amine (2b) (1.8 g, 33% yield, 9.11 mmol) as a white solid, ESI-MS m / z 199.8, [M+H+2]+. Synthesis of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine (intermediate A4) To a stirred solution of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (2b) (1.0 g, 5.06 mmol) in 1,4-dioxane (50 mL) and water (4 mL) was added 2,2,6,6-tetramethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.34 g, 5.06 mmol) followed by Na2CO3(1.61 g, 15.186 mmol). The mixture was sparged with argon for 5 min. Then, Pd(dppf)Cl2.DCM (0.41 g, 0.51 mmol) was added, and the mixture was sparged with argon for another 5 min before heating to 80 °C for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite, rinsing with EtOAc (50 mL). The filtrate was evaporated under reduced pressure to obtain a residue that was poured into water and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by MPLC (CombiFlash, C18, 40 g column, gradient elution, 20- 30% CH3CN in H2O) afforded 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5- (trifluoromethyl) pyrimidin-2-amine (A4) (0.65 g, 43%, 2.16 mmol) as a brown solid. ESI-MS m / z 301.1, [M+H]+. Synthesis of 4-(2,2,6,6-tetramethylpiperidin-4-yl)-5-(trifluoromethyl) pyrimidin-2-amine (Intermediate B4) To a stirred solution of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (A4) (0.6 g, 2.0 mmol) in EtOH (30 mL) at RT was added 10% Pd(OH)2on carbon (0.6 g). The reaction mixture was stirred under H2balloon pressure at RT for 16 h. Progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered through a pad of Celite, rinsing with EtOH (50 mL). The filtrate was concentrated under reduced pressure to afford 4-(2,2,6,6-tetramethylpiperidin-4-yl)-5- (trifluoromethyl)pyrimidin-2-amine (0.49 g, 1.62 mmol, 81% yield) as a pale brown, thick oil. ESI-MS m / z 303.05, [M+H]+. Synthesis of α-bromo-ketone intermediates 1-(2-(benzyloxy)-4-bromophenyl)-2-bromoethan-1-one (intermediate D) To a stirred solution of 1-(2-(benzyloxy)-4-bromophenyl)ethan-1-one (5.0 g, 16.4 mmol, 1 equiv) in 1,4-dioxane (50 mL) at RT was added dropwise bromine (0.76 mL, 14.7 mmol, 0.9 equiv) dissolved in 1,4-dioxane (50 mL) via syringe over a period of 10 min. After addition was complete, the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting residue was poured into ice water and extracted with DCM three times. The combined organic layers were washed with sodium thiosulphate solution (1x), water (1x) and brine (1x), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 1-(2-(benzyloxy)-4-bromophenyl)-2-bromoethan-1-one (4.6 g, 11.97 mmol, 73% yield) as a pale yellow solid. ESI-MS m / z 384.8, [M+H]+. The synthesis of intermediate D is reported in WO 2007037187. 2-bromo-1-(5-bromo-3-methoxypyridin-2-yl)ethan-1-one (intermediate E) 1-(5-bromo-3-methoxypyridin-2-yl)ethan-1-one (1.1 g, 1.0 equiv, 4.9 mmol) was dissolved in 1,4-dioxane (44 mL) and diethyl ether (22 mL) in a 500 mL round-bottom flask at room temperature under nitrogen. Bromine (2.4 g, 759 μL, 3.0 equiv, 14.7 mmol) was slowly added to the solution. The reaction mixture was allowed to stir for 2 days at which time LCMS showed 75% conversion to the target product. A lot of solid formed upon diluting with a small amount of EtOAc (10 mL). The solid was filtered off and dried under high vacuum. The solid thus isolated (1.6 g) was dissolved in DCM (350 mL) and the solution was washed with water (3 x 30 mL), brine (1 x 30 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and further dried under high vacuum to provide the desired product, 2- bromo-1-(5-bromo-3-methoxypyridin-2-yl)ethan-1-one (1.06 g, 3.44 mmol, 70% yield) as an off- white solid. ESI-MS m / z 307.9, [M+H]+; Rt = 0.89 min., LC / MS method 2. 1H NMR (400 MHz, methanol-d4) δ 8.35 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 4.75 (s, 2H), 3.98 (s, 3H). 1-(3-(benzyloxy)-5-bromopyridin-2-yl)-2-bromoethan-1-one (intermediate F) Synthesis of 3-(benzyloxy)-5-bromopicolinonitrile (2) To a stirred solution of NaH (2.11 g, 87.9 mmol, 1.2 equiv) in THF (20 mL) was added 5- bromo-3-nitropicolinonitrile (10.0 g, 44.1 mmol, 1 equiv) in THF (40 mL) via syringe over a period of 10 min at 0 °C. Upon complete addition, the reaction was stirred for 10 min. Then, benzyl alcohol (4.72 g, 43.6 mmol, 1 equiv) in THF (20 mL) was added and the reaction mixture was stirred at rt for 2 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was quenched with ice water and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was triturated with n-pentane to afford 3- (benzyloxy)-5-bromopicolinonitrile (10.0 g, 31.1 mmol, 70% yield) as a brown solid. ESI-MS m / z 289.9, [M+H]+. Synthesis of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)ethan-1-one (3) To a stirred solution of 3-(benzyloxy)-5-bromopicolinonitrile (2) (5.0 g, 17.3 mmol, 1 equiv) in THF (70 mL), methylmagnesium bromide 3.0 M in diethyl ether (16.5 mL) was added dropwise via syringe over a period of 10 min at 0°C. Upon complete addition, the reaction was stirred at RT for 1 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was quenched with ice water, the pH was adjusted to acidic with 10% H2SO4solution, and the mixture was stirred at RT for 30 min. The aqueous layer was poured into saturated aqueous sodium bicarbonate solution (40 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by MPLC (CombiFlash, 24 g RediSep Silver column, gradient elution, 15% EtOAc in hexanes to afford 3 1-(3-(benzyloxy)-5-bromopyridin-2-yl)ethan-1-one (2.6 g, 8.5 mmol, 49% yield) as a pale yellow solid. ESI-MS m / z 307.75, [M+H]+. Synthesis of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)-2-bromoethan-1-one (4) (intermediate F) To a stirred solution of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)ethan-1-one (3) (1.0 g, 3.3 mmol, 1 equiv.) in acetic acid (8.0 mL), hydrogen bromide-acetic acid solution (230 mg, 164 μL, 0.5 equiv, 1.63 mmol) was added and cooled to 0 °C. Bromine (365 mg, 118 μL, 0.7 equiv, 2.29 mmol) was added and the mixture was stirred at 55 °C for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was quenched with water and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by MPLC (CombiFlash, 24 g RediSep Silver column, gradient elution, 10% EtOAc in hexanes to afford 1-(3-(benzyloxy)-5-bromopyridin-2-yl)-2-bromoethan-1-one (550 mg, 1.32 mmol, 40% yield, 92% purity) as an off-white solid. ESI-MS m / z 385.80, [M+H]+. Synthesis of intermediate G Synthesis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethan-1-one (2) To a mixture of 1-(4-bromo-2-fluoro-6-hydroxyphenyl)ethan-1-one (5.0 g, 21.5 mmol, 1.0 equiv) and K2CO3(8.9 g, 64.4 mmol, 3.0 equiv) in acetonitrile (50 mL) was added iodomethane (9.14 g, 64.4 mmol, 3.0 equiv). The reaction vessel was sealed and the reaction mixture was stirred at 50 °C for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100:0 to 80:20; 24 g RediSep Silver column using a 5 g solid cartridge) furnished 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethan-1-one (4.0 g, 16.2 mmol, 75% yield) as a colorless liquid. ESI-MS m / z 247.0, [M+H]+. Synthesis of 2-bromo-1-(4-bromo-2-fluoro-6-methoxyphenyl)ethan-1-one (3) (Intermediate G) To a stirred solution of 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethan-1-one (2) (4.0 g, 16.2 mmol, 1.0 equiv) in 1,4-dioxane (30 mL) was added dropwise a solution of bromine (2.85 g, 1.1 equiv, 17.8 mmol) in dioxane (20 mL) at RT. Upon complete addition, the reaction mixture was stirred at RT for 4 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 10% sodium thiosulfate solution. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluent: hexane / DCM = 95:5 to 90:10; 12 g RediSep Silver column using a 5 g solid cartridge) furnished 2-bromo-1-(4- bromo-2-fluoro-6-methoxyphenyl)ethan-1-one (2.0 g, 6.1 mmol, 38% yield) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 6.98 – 6.91 (m, 2H), 4.32 (s, 2H), 3.88 (s, 3H). Synthetic scheme for Intermediate H Synthesis of 3-bromo-2-fluorophenyl acetate (2) To a stirred solution of 3-bromo-2-fluorophenol (5.0 g, 26.2 mmol) in dichloromethane (50 mL) was added triethylamine (7.15 mL, 52.4 mmol). After 5 min, acetyl chloride (2.8 mL, 39.3 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by automated flash chromatography using a CombiFlash system, eluting with 0-10% of ethyl acetate in hexanes to afford 3-bromo-2-fluorophenyl acetate (5.8 g, 24.9 mmol, 95% yield) as a pale yellow, thick mass. ESI-MS m / z No ionization. 1H NMR (CDCl3) δ 7.44-7.40 (m, 1H), 7.09-7-02 (m, 2H), 2.34 (s, 3H). Synthesis of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (3) Aluminum trichloride (5.14 g, 38.6 mmol) was added in portions to a round-bottom flask containing 3-bromo-2-fluorophenyl acetate (3.0 g, 12.9 mmol) at RT. After addition of the aluminum trichloride, the reaction mixture was stirred at 140 °C for 3 h. Then, the reaction mixture was cooled to 80 °C and ice was added, followed by 10% hydrochloric acid. Upon completion of the reaction as judged by TLC, the reaction mixture was extracted with ethyl acetate (2x). The combined organic phases were washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by automated flash chromatography using a CombiFlash system, eluting with 0-10% of ethyl acetate in hexanes to afford 1-(4-bromo-3-fluoro-2- hydroxyphenyl)ethan-1-one (2.8 g, 12 mmol, 93% yield) as an off-white solid. ESI-MS m / z 234.80 [M+H]+. Synthesis of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (4) To a stirred solution of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (2.80 g, 12.0 mmol) in ACN (30 mL) was added potassium carbonate (8.30 g, 60.1 mmol) followed by methyl iodide (3.74 mL, 60.1 mmol) at RT. Then, the reaction mixture was heated at 60 °C for 4 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was quenched with ice-water and partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(4-bromo-3- fluoro-2-hydroxyphenyl)ethan-1-one (2.6 g, 10.5 mmol, 87% yield) as an off-white solid. ESI-MS m / z 248.80 [M+H]+. Synthesis of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (5) (intermediate H) To a stirred solution of 1-(4-bromo-3-fluoro-2-methoxyphenyl)ethan-1-one (1.0 g, 4.1 mmol) in 1,4-dioxane (5 mL) was added a solution of bromine (0.26 mL, 5.3 mmol) in 1,4- dioxane (5 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC & LCMS. Upon completion of the reaction, the reaction was quenched with ice-water and partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue thus obtained was purified by by automated flash chromatography using a CombiFlash system, eluting with 0- 10% of ethyl acetate in hexanes to afford 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethan-1-one (0.8 g, 2.5 mmol, 60% yield) as a pale brown solid. ESI-MS m / z 326.8 [M+H+2]+. General scheme for synthesis of imidazo-pyrimidine core Synthesis of final compounds through functionalization of imidazo-pyrimidine core Compound 4: Synthetic scheme for 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6- tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol Synthesis of 2-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-7-(2,2,6,6- tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidine and 2-(2-(benzyloxy)-4-(2- methyl-2H-tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2- a]pyrimidine (2a and 2b) A mixture of 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-2-bromoethan-1-one and 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethan-1-one (0.50 g, 1.3 mmol) and 4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-2-amine (A1) (0.23 g, 0.98 mmol) in diphenyl ether (5 mL) was heated at 120 °C in a microwave reactor for 3 hours. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with 10% MeOH in DCM and concentrated under reduced pressure. The residue thus obtained was purified by automated reverse phase flash chromatography (CombiFlash, 12 g Redisep Silver column, gradient elution, 30% acetonitrile in water) to obtain 2-(2-(benzyloxy)-4- (1-methyl-1H-tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidine and 2-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4- yl)imidazo[1,2-a]pyrimidine as a brick-red solid (0.30 g, 0.57 mmol, 44% yield). ESI-MS m / z 523.65, [M+H]+; Rt = 1.49 min., LC / MS method 5. Synthesis of 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol (3b, compound 4) To a stirred solution of 2-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-7-(2,2,6,6- tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidine and 2-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol- 5-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidine (0.50 g, 0.95 mmol) in TFA (5 mL) cooled to 0 °C was added triflic acid (0.5 mL). The resulting mixture was stirred at 70 °C for 1 h. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in 10% MeOH in DCM and basified to pH = ~8-9 by treatment with Amberlyte-A21 resin for 20 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by reversed-phase HPLC with mobile phases A= 0.1% HCOOH in water and B= acetonitrile, column: X SELECT (250mm x 20.0mm), 5.0 μ. The product-containing fractions were combined and lyophilized to obtain 5-(2-methyl-2H- tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formic acid salt (formic acid salt of compound 4) as an off-white solid (0.10 g, 0.23 mmol, 24% yield). ESI-MS m / z 433.15, [M+H]+; Rt = 1.78 min., LC / MS method 7. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.97 (d, J = 6.9 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.64 – 7.58 (m, 1H), 7.14 (d, J = 6.9 Hz, 1H), 4.43 (s, 3H), 1.90 – 1.82 (m, 2H), 1.68 – 1.56 (m, 2H), 1.37 (s, 6H), 1.27 (s, 6H).

[0005] Compound 7: 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- Step 1: 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (A1) (350 mg, 1.0 equiv, 1.50 mmol) and 2-bromo-1-(4-chloro-2-methoxyphenyl)ethan-1-one (C) (596 mg, 1.5 equiv, 2.26 mmol) were combined in Isopropanol (14.00 mL). The resulting mixture was heated at 85 °C for 2 days, at which time LCMS showed conversion to the target product. Lots of solid was formed from a clear reaction mixture to begin with. To the mixture was added saturated aqueous sodium bicarbonate solution as well as EtOAc and water. The phases were separated, and the aqueous phase was extracted with EtOAc (3x). All the organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified via automated flash chromatography (40 gram Redisep Silver silica gel column, dry load, 0-30% (10% 7N NH4OH in MeOH) / DCM). The product containing fractions were combined, concentrated under reduced pressure and further dried under high vacuum to provide the desired product 2-(4-chloro-2-methoxyphenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin- 4-yl)imidazo[1,2-a]pyrimidine (207 mg, 520 μmol, 35% yield). ESI-MS m / z 397.3, [M+H]+; Rt = 1.17 min., LC / MS method 2. Step 2: Pd2(dba)3(95 mg, 0.20 equiv, 104 μmol) and 2-(di-tert-butylphosphino)-3,4,5,6- tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (100 mg, 0.40 equiv, 208 μmol) were combined in a screw-cap glass vial under nitrogen followed by addition of anhydrous toluene (4.0 mL) and 1,4- dioxane (1.0 mL). The mixture was degassed by sparging with nitrogen for 5 minutes. Then, the magnetically stirred mixture was heated at 120 °C in a heating block for 5 minutes. Following that, the vial was left to cool down to ambient temperature. Separately, 2-(4-chloro-2- methoxyphenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (207 mg, 1.0 equiv, 520 μmol), triazacyclopentadiene (54 mg, 45 μL, 1.5 equiv, 780 μmol), and potassium phosphate (221 mg, 86 μL, 2 equiv, 1.04 mmol) were combined in anhydrous toluene (4.0 mL) and 1,4-dioxane (1.0 mL) in a microwave vial. The mixture was degassed by sparging with nitrogen for 10 minutes. Then, the solution of the palladium complex was transferred from the screw-cap vial to the microwave vial via syringe and the combined mixture was degassed with nitrogen for another 5 min. The resulting mixture was irradiated at 120 °C for 4 hours in the microwave at which time LCMS showed conversion to the target product. The reaction was left to cool to ambient temperature, diluted with EtOAc, water, and brine, and filtered through a pad of celite, rinsing with EtOAc. The aqueous layer was extracted with EtOAc. All the organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified via flash chromatography (24 gram Redisep Silver silica gel column, dry load, 0-30% (10% 7N NH4OH in MeOH) / DCM). The product- containing fractions were combined, concentrated under reduced pressure and further dried under high vacuum to provide the desired product 2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)- 7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (123 mg, 286 μmol, 55 % yield). ESI-MS m / z 430.4, [M+H]+; Rt = 1.06 min., LC / MS method 2. Step 3: BBr3(1M in DCM) (717 mg, 2.86 mL, 10 equiv, 2.86 mmol) was added dropwise to a cold (0 °C), magnetically stirred solution of 2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7- (2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (123 mg, 1.0 equiv, 286 μmol) in DCM (4.0 mL) in a glass vial. The ice bath was removed, and the resulting suspension was left to stir at room temperature for 2 hours at which time LCMS showed conversion to the target product. Then, the vial was placed in an ice bath (0 °C) and the reaction was slowly quenched with MeOH (2 mL) followed by slow addition of ammonium hydroxide (30% solution) (5 mL); a lot of gas evolution was observed. The reaction mixture was allowed to come to ambient temperature, stirred for another 45 min., and then concentrated under reduced pressure. The mixture was then directly purified via C18 Basic Reverse Phase silica gel column (50 gram column, 0.1% Formic Acid modifier, 0-100% ACN / H2O). The product-containing fractions were lyophilized to provide the desired product, 2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (Compound 7) (23 mg, 39 μmol, 19% yield). HRMS calculated for the desired product, C23H26N7O [M+H]+= 416.2199, found = 416.2182. ESI-MS m / z 416.4, [M+H]+; Rt = 0.67 min., LC / MS method 1.1H NMR (400 MHz, methanol-d4) δ 8.62 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.79 (s, 2H), 7.57 - 7.48 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 6.74 – 6.69 (m, 1H), 2.51 (s, 2H), 1.28 (s, 6H), 1.19 (s, 6H). Compound 10: 3-fluoro-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl) imidazo[1,2-a] pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl) phenol Synthesis of 2-(4-bromo-2-fluoro-6-methoxyphenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl) imidazo[1,2-a] pyrimidine (1) A mixture of 2-bromo-1-(4-bromo-2-fluoro-6-methoxyphenyl) ethan-1-one (Intermediate G) (2.0 g, 2 equiv, 6.14 mmol) and 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrimidin-2- amine (Intermediate A1) (713 mg, 1 equiv, 3.07 mmol) in isopropanol (20 mL) was stirred at 90 °C for 16 h. The progress of the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was concentrated under reduced pressure and the residue thus obtained was purified by preparative HPLC: Column: Gemini NX (250 mm x 21.2mm), 5.0 μ, Flow: 18mL / min, Mobile Phase: A= 0.1% HCOOH in water, B = acetonitrile. The product-containing fractions were concentrated under reduced pressure to afford 2-(4- bromo-2-fluoro-6-methoxyphenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl) imidazo[1,2-a] pyrimidine (1) (0.80 g, 1.1 mmol, 37% yield, 65% purity) as a white solid. ESI-MS m / z 460.95, [M+H]+. Synthesis of 2-(2-fluoro-6-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6- tetramethyl- 1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (2) Pd2(dba)3(60 mg, 0.20 equiv, 65 μmol) and 2-(di-tert-butylphosphino)-3,4,5,6- tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (63 mg, 0.40 equiv, 0.13 mmol) were combined in anhydrous toluene (3.0 mL) and anhydrous 1,4-dioxane (1.0 mL) under an atmosphere of nitrogen. The mixture was degassed by sparging with nitrogen for 10 minutes. The magnetically stirred mixture was heated at 120 °C for 10 minutes. Then, the mixture was left to cool down to ambient temperature. Separately, 2-(4-bromo-2-fluoro-6-methoxyphenyl)-7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a] pyrimidine (150 mg, 1.0 equiv, 0.33 mmol), 1,2,3-triazole (68 mg, 3.0 equiv, 0.98 mmol) and potassium phosphate (139 mg, 2.0 equiv, 0.65 mmol) were combined in toluene (3.0 mL) and 1,4-dioxane (1.0 mL). The mixture was degassed by sparging with nitrogen for 10 min. Then, the solution of the palladium complex was transferred to the vessel containing the reactants via syringe. The resulting mixture was stirred at 120 °C for 16 h. The progress of the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the crude was purified by reverse phase column chromatography, eluting with 50% acetonitrile in water using a 23 g C18column to afford 2-(2-fluoro-6-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6- tetramethyl- 1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (2) (100 mg, 0.223 mmol, 68% yield) as a yellow solid. ESI-MS m / z 448.10, [M+H]+. Synthesis of 3-fluoro-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl) imidazo[1,2-a] pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl) phenol (3, Compound 10 formic acid salt) To a solution of 2-(2-fluoro-6-methoxy-4-(2H-1,2,3-triazol-2-yl) phenyl)-7-(2,2,6,6- tetramethyl-1,2,3,6- tetrahydropyridin-4-yl) imidazo[1,2-a] pyrimidine (2) (50 mg, 1.0 equiv, 0.11 mmol), in 1,2-dichloroethane (2.0 mL) at 0 °C was added boron tribromide (280 mg, 10.0 equiv, 1.11 mmol) and the reaction mixture was stirred at RT for 16 h. The progress of the reaction was monitored by LCMS. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. Purification by preparative HPLC: Column: X-bridge (C18, 19 mm X 150 mm), Flow: 18 mL / min, Mobile Phase: A= 0.1% HCOOH in water, B = acetonitrile. The product-containing fractions were pooled and concentrated under reduced pressure to afford 3-fluoro-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl) imidazo[1,2- a] pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl) phenol formic acid salt (3, formic acid salt of compound 10) (40 mg, 0.082 mmol, 73% yield) as a yellow solid. ESI-MS m / z 434.05, [M+H]+, Rt = 2.14 min., LC / MS method 6. 1H NMR (400 MHz, methanol-d4) δ 8.90 – 8.81 (m, 1H), 8.53 (s, 1H), 8.27 – 8.20 (m, 1H), 7.96 (s, 2H), 7.55 – 7.41 (m, 3H), 6.89 (s, 1H), 2.92 (s, 2H), 1.63 (s, 6H), 1.54 (s, 6H). Compound 11: 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)pyridin-3-ol Step 1: 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (A1) (120 mg, 1 equiv, 516 μmol) and 2-bromo-1-(5-bromo-3-methoxypyridin-2-yl)ethan-1-one (E) (239 mg, 1.5 equiv, 775 μmol) were combined in isopropanol (5.5 mL) in a microwave vial. The resulting mixture was heated at 50 °C for 2 days at which time LCMS showed conversion to the target product. Lots of solid was formed from a clear reaction mixture to begin with. To the mixture was added saturated aqueous sodium bicarbonate solution as well as ethyl acetate and water. The phases were separated, and the aqueous phase was extracted with EtOAc (3x). All the organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified via automated flash chromatography (24 g Redisep Silver silica gel column, dry load, 0-30% (10% 7N NH4OH in MeOH) / DCM). The product-containing fractions were combined, concentrated under reduced pressure, and further dried under high vacuum to provide the desired product 2-(5-bromo-3-methoxypyridin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (170 mg, 384 μmol, 74% yield). ESI-MS m / z 444.3, [M+H]; Rt = 0.85 min, LC / MS method 2. Step 2: Pd2(dba)3(70.4 mg, 0.20 equiv, 76.9 μmol) and 2-(di-tert-butylphosphino)-3,4,5,6- tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (73.9 mg, 0.40 equiv, 154 μmol) were combined in a screw-cap glass vial under nitrogen, followed by addition of anhydrous toluene (3.0 mL) and anhydrous 1,4-dioxane (0.75 mL). The mixture was degassed by sparging with nitrogen for 5 minutes. The magnetically stirred mixture was heated at 120 °C in a heating block for 5 minutes. Then, the vial was left to cool down to ambient temperature. Separately, 2-(5-bromo-3- methoxypyridin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidine (170 mg, 1 equiv, 384 μmol), triazacyclopentadiene (39.8 mg, 33.4 μL, 1.5 equiv, 577 μmol), and potassium phosphate (163 mg, 63.6 μL, 2 equiv, 769 μmol) were combined in anhydrous toluene (3.0 mL) and anhydrous 1,4-dioxane (0.75 mL) in a microwave vial. The mixture was degassed by sparging with nitrogen for 10 minutes. Then, the solution of the palladium complex was transferred from the screw-cap glass vial to the microwave vial via syringe, and the combined mixture was degassed with nitrogen for another 5 min. The resulting mixture was irradiated at 120 °C for 4 hours in the microwave at which time LCMS showed conversion to the target product. The reaction was cooled to ambient temperature, diluted with EtOAc, water, brine, and filtered through a pad of celite, rinsing with EtOAc. The aqueous layer was extracted with EtOAc. All the organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified via flash chromatography (24 g Redisep Silver silica gel column, dry load, 0-30% (10% 7N NH4OH in MeOH) / DCM). The product-containing fractions were combined, concentrated under reduced pressure, and further dried under high vacuum to provide the desired product 2-(3-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (121 mg, 281 μmol, 73% yield). ESI-MS m / z 431.4, [M+H]+; Rt = 0.82 min., LC / MS method 2. Step 3: BBr3(1M in DCM) (704 mg, 2.8 mL, 1.0 molar, 10 equiv, 2.8 mmol) was added dropwise to a cold (0 °C), magnetically stirred solution of 2-(3-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-2- yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (121 mg, 1 equiv, 281 μmol) in DCM (4.0 mL) in a glass vial. The ice bath was removed, and the resulting suspension was left to stir at room temperature for 2 hours, at which time LCMS showed conversion to the target product. Then, the vial was placed in an ice bath (0 °C) and the reaction was slowly quenched with MeOH (1.5 mL), followed by slow addition of ammonium hydroxide (30% solution) (3 mL). A lot of gas evolution was observed. The reaction mixture was slowly allowed to come to RT, stirred for another 45 min., and then concentrated under reduced pressure. It was then directly purified via C18Basic Reverse Phase silica gel column chromatography (50 g reverse phase column, 0.1% formic acid modifier, 0-100% ACN / H2O). The product-containing fractions were lyophilized to provide the desired product, 2-(7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)pyridin-3-ol formic acid salt (formic acid salt of Compound 11) (18.8 mg, 39 μmol, 14% yield). HRMS calculated for the desired product, C22H25N8O [M+H]+= 417.2151, found = 417.2142 ESI-MS m / z 417.3 [M+H]+; Rt = 0.64 min, LC / MS method 1.1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.93 (d, J = 7.3 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.41 (s, 1H), 8.18 – 8.11 (m, 2H), 7.82 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 6.94 – 6.89 (m, 1H), 2.41 – 2.38 (m, 2H), 1.23 (s, 6H), 1.12 (s, 6H). Compound 28: 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol Synthesis of 4-acetyl-3-(benzyloxy)benzonitrile (2) To a magnetically stirred solution of 1-(2-(benzyloxy)-4-bromophenyl)ethan-1-one (5.0 g, 16.4 mmol, 1.0 equiv) in DMF (50 mL) at RT was added cuprous cyanide (8.8 g, 98.3 mmol, 6.0 equiv). The reaction mixture was stirred at 150 °C for 7 hours. Upon completion of the reaction, the reaction mixture was quenched with sodium hypochlorite solution. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 0:100 to 20:80; 40 g Redisep Silver column using a 25 g solid cartridge) to give 4-acetyl-3-(benzyloxy)benzonitrile (1.1 g, 4.3 mmol, 26% yield) as a white solid. ESI-MS m / z 250.10 Synthesis of 1-(2-(benzyloxy)-4-(1H-tetrazol-5-yl)phenyl)ethan-1-one (3) To a stirred solution of 4-acetyl-3-(benzyloxy)benzonitrile (1.1 g, 4.4 mmol, 1.0 equiv) in DMF (20 mL) at RT were added triethylamine hydrochloride (1.81 g, 13.1 mmol, 3.0 equiv) and sodium azide (854 mg, 13.1 mmol, 3.0 equiv). The reaction mixture was stirred at 110 °C for 16 h. The reaction was quenched with ice water and acidified with 6 M HCl, and then back- extracted twice with 10% MeOH in DCM. The obtained organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue thus obtained was purified by flash column chromatography on silica gel (eluent: DCM / MeOH = 0:100 to 10:90; 40 g Redisep Silver column using a 25 g solid cartridge) to give 1-(2-(benzyloxy)-4-(1H-tetrazol-5- yl)phenyl)ethan-1-one (1.1 g, 2.7 mmol, 62% yield) as a colorless liquid. ESI-MS m / z 295.05, [M+H]+. Synthesis of 1-(2-(benzyloxy)-4-(2-methyl-1H-tetrazol-5-yl)phenyl)ethan-1-one and 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)ethan-1-one (4a & 4b) To a stirred solution of 1-(2-(benzyloxy)-4-(1H-tetrazol-5-yl)phenyl)ethan-1-one (1.1 g, 3.74 mmol, 1.0 equiv) in DMF (10 mL) at RT was added potassium carbonate (1.55 g, 11.2 mmol, 3.0 equiv). The mixture was cooled to 0 °C and methyl iodide (1.6 g, 0.70 mL, 11.2 mmol, 3.0 equiv) was added. The resulting mixture was stirred at RT for 1 hour. The reaction was quenched by addition of ice water and extracted once with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a mixture of both isomers 1-(2-(benzyloxy)-4-(2-methyl-1H-tetrazol-5-yl)phenyl)ethan-1-one and 1-(2- (benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)ethan-1-one (1.0 g, 2.6 mmol, 69% yield). This mixture was directly used in the next step. ESI-MS m / z 309.05, [M+H]+. Synthesis of 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethan-1- one and 1-(2-(benzyloxy)-4-(1-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethan-1-one (5a & 5b) To a stirred solution of 1-(2-(benzyloxy)-4-(2-methyl-1H-tetrazol-5-yl)phenyl)ethan-1-one and 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)ethan-1-one (0.40 g, 1.3 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) at 0 °C was added dropwise and slowly a solution of bromine (166 mg, 54.0 μL, 1.04 mmol, 0.8 equiv) in 1,4-dioxane (8.0 mL). The reaction mixture was stirred at RT for 4 h. Then, the reaction was quenched by addition of ice water. The mixture wasextracted twice with EtOAc, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5- yl)phenyl)-2-bromoethan-1-one and 1-(2-(benzyloxy)-4-(1-methyl-2H-tetrazol-5-yl)phenyl)-2- bromoethan-1-one (0.50 g, 1.29 mmol) as a mixture. This mixture was directly used in the next step without further purification. ESI-MS m / z 386.95, [M+H]+. Synthesis of 2-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine and 2-(2- methoxy-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (7a & 7b) A mixture of 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethan-1-one and 1-(2-(benzyloxy)-4-(1-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethan-1-one (0.50 g, 1.29 mmol, 1.0 equiv) from the preceding step and 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)pyrimidin-2-amine (240 mg, 1.03 mmol, 0.80 equiv) in isopropanol (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on a C18 column (eluent: water / CH3CN = 0:100 to 50:50; 13 g Redisep Rf, Reversed-phase C18 column using a 25 g solid cartridge ) to give a mixture of 2-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethyl- 1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine and 2-(2-methoxy-4-(2-methyl-2H- tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidine (130 mg, 0.15 mmol, 61% purity, 12% yield). ESI-MS m / z 521.25 [M+H]+. Synthesis of 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol and 5-(1-methyl-1H- tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)phenol (8a & 8b) To a stirred solution of 2-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine and 2-(2-methoxy-4-(2- methyl-2H-tetrazol-5-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidine (200 mg, 384 μmol, 1.0 equiv) in TFA (3 mL) at 0 °C was added triflic acid (0.50 g, 0.30 mL, 1.78 mmol, 4.6 equiv). The reaction mixture was stirred at 70 °C for 40 min. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in 10% MeOH in DCM and basified to pH = ~8-9 by treatment with Amberlyte-A21 resin. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (H2O / CH3CN (containing 0.1% formic acid), Column (X-SELECT (250 mm X 20 mm), 5.0 micron, A = 1% Formic acid in water, B = acetonitrile, Flow 15 mL / min. The product-containing fractions were combined and lyophilized to give 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formic acid salt (8b, formic acid salt of compound 28) (41 mg, 90 μmol, 23% yield) as a pale yellow solid. ESI-MS m / z 431.10, [M+H]+; Rt = 1.51 min., LC / MS method 5. 1H NMR (400 MHz, methanol-d4) δ 8.83 (d, J = 7.1 Hz, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.48 (d, J = 7.1 Hz, 1H), 6.86 (s, 1H), 4.43 (s, 3H), 2.91 (s, 2H), 1.62 (s, 6H), 1.52 (s, 6H). Compound 39: The N1-isomer isolated during the preparation of compound 28 was re-purified using reversed-phase HPLC (H2O / CH3CN (containing 0.1% formic acid)). The product-containing fractions were combined and lyophilized to give 5-(1-methyl-1H-tetrazol-5-yl)-2-(7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formic acid salt (8a, formic acid salt of compound 39): ESI-MS m / z 431.05, [M+H]+; Rt = 1.49 min., LC / MS method 5. 1H NMR (400 MHz, methanol-d4) δ 8.75 (d, J = 7.3 Hz, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.33 – 7.27 (m, 2H), 6.78 (s, 1H), 4.15 (s, 3H), 2.80 (s, 2H), 1.51 (s, 6H), 1.41 (s, 6H). Compound 40: Synthetic scheme for 4-(2-(2-hydroxy-4-(2H-1,2,3-triazol-2- yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl)-2,2,6,6-tetramethylpiperidin-4-ol Step 1: 2-(2-(benzyloxy)-4- (2H-1,2,3-triazol-2-yl) phenyl)imidazo[1,2-a]pyrimidin-7- ol A mixture of 1-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl) phenyl)-2-bromoethan-1-one (1.0 g, 2.7 mmol), 2-aminopyrimidin-4-ol (298 mg, 2.69 mmol), NaHCO3(226 mg, 2.69 mmol), EtOH (12.0 mL), and water (4.0 mL) was heated to 120 °C in a microwave for 30 minutes. Then, the reaction mixture was left to cool to RT and filtered. The solid was washed with diethyl ether and water to give 2-(2-(benzyloxy)-4- (2H-1,2,3-triazol-2-yl) phenyl)imidazo[1,2-a]pyrimidin-7-ol (673 mg, 33% yield, 50% purity) as a yellow solid. ESI-MS m / z 385.1, [M+H]+. Step 2: 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2- yl)phenyl)imidazo[1,2-a]pyrimidin-7- yl trifluoromethanesulfonate To crude 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl) phenyl)imidazo[1,2-a] pyrimidin-7-ol from the preceding step (283 mg, 0.375 mmol, 50% purity) in DCM (10.0 mL) was added DIPEA (146 mg, 1.13 mmol, 3.0 equiv). The solution was cooled to 0 °C and trifluoromethanesulfonic anhydride (1.0 M in DCM, 751 μL, 0.751 mmol, 2.0 equiv) was added dropwise. The reaction mixture was stirred at 0 °C for 1 hour. Then, DCM (2 mL) was added. The reaction was quenched with 10% aqueous HCl (1.03 mL, 4.14 mmol) and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over MgSO4, and the solvent was evaporated under reduced pressure to give 2-(2-(benzyloxy)-4- (2H-1,2,3-triazol-2- yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl trifluoromethanesulfonate (484 mg, ~60% purity by UV DAD). The material was taken on to the next step without purification. ESI-MS m / z 517.0, [M+H]+. Step 3: 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6- tetramethyl- 1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine Crude 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl trifluoromethanesulfonate from the preceding step (484 mg, 0.590 mmol), 2,2,6,6-tetramethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (188 mg, 0.708 mmol), K2CO3(245 mg, 1.77 mmol), Pd(dppf)2Cl2(21.6 mg, 0.0295 mmol), 1,4-dioxane (1.0 mL), and water (0.20 mL) were added sequentially to a vial equipped with a stir bar. The reaction mixture was degassed with nitrogen and then heated at 80 °C for 3 hours. Then, the reaction mixture was concentrated under reduced pressure, and the residue was directly purified by automated flash chromatography with a silica gel column, eluting with ethyl acetate / heptane first and then with 10% MeOH in EA (with 1volume % of 7N NH3in MeOH) to afford 2-(2-(benzyloxy)-4-(2H- 1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidine (109 mg, 30% yield). ESI-MS m / z 506.2, [M+H]+. Step 4: 4-(2- (2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin- 7-yl)-2,2,6,6- tetramethylpiperidin-4-ol 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidine (109 mg, 0.215 mmol) was dissolved in a mixture of DCM (4.0 mL) and isopropanol (20.0 mL). The solution was cooled to 0 °C. After stirring for 20 min, Mn(TMHD)3(26.1 mg, 0.043 mmol) was added at 0 °C and the mixture was stirred for 5 min. Then, phenylsilane (140 mg, 1.29 mmol) was added. The reaction mixture was stirred at room temperature, open to air, for 1 hour. Then, the mixture was concentrated under reduced pressure and the residue was dry loaded onto a silica gel column. Purification by automated flash chromatography, eluting with ethyl acetate to wash out impurities first, and then eluting with 10% - 50% MeOH in ethyl acetate (with 1 volume% 7N NH3in MeOH) yielded 4-(2- (2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl)-2,2,6,6- tetramethylpiperidin-4-ol (25.0 mg, 22% yield). ESI-MS m / z 524.3, [M+H]+. Step 5: 4-(2-(2-hydroxy-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7- yl)-2,2,6,6- tetramethylpiperidin-4-ol To a mixture of 4-(2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2- a]pyrimidin-7-yl)- 2,2,6,6-tetramethylpiperidin-4-ol (25.0 mg, 0.048 mmol) and Pd / C (5 mg, 10% wt., 0.005 mmol) was added EtOH (10 mL) under N2gas. The reaction mixture was stirred at room temperature under balloon pressure of H2gas (1 atm) for 4 hours. Then, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated and purified by automated flash chromatography using a silica gel column, eluting with 10-30% of MeOH in DCM (with 1% of 7N NH3as basic modifier in MeOH) to afford 4-(2-(2-hydroxy-4-(2H-1,2,3- triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl)-2,2,6,6-tetramethylpiperidin-4-ol (7 mg, 32% yield). ESI-MS m / z 434.3, [M+H]+; Rt = 1.94 min., LC / MS method 4. 1H NMR (400 MHz, methanol-d4) δ 8.90 (d, J = 7.1 Hz, 1H), 8.38 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.94 (s, 2H), 7.80 – 7.62 (m, 2H), 7.50 (d, J = 6.9 Hz, 1H), 2.18 (d, J = 14.7 Hz, 2H), 1.97 (d, J = 14.3 Hz, 2H), 1.68 (s, 6H), 1.37 (s, 6H). Further Exemplary Compounds Compounds below were prepared according to modified versions of the procedures described above. 4-(3-fluoro-5-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- n-2(1H)-one ESI-MS m / z 474.30, [M+H]+, compound 1;1H NMR (400 MHz, methanol-d4) δ 8.85 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 8.26 (d, J = 4.3 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 12.3, 1.8 Hz, 1H), 6.92 – 6.87 (m, 1H), 6.83 – 6.79 (m, 1H), 6.73 (dd, J = 7.1, 2.1 Hz, 1H), 3.61 (s, 3H), 2.80 (s, 2H), 1.54 (s, 6H), 1.44 (s, 6H). 3-fluoro-5-(1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formate ESI-MS m / z: 415.3 [M+H]+; compound 3:1H NMR (400 MHz, methanol-d4) δ 9.19 (d, J = 7.2 Hz, 1H), 8.68 (m, 3H), 8.09 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 8.2, 1.7 Hz, 1H), 7.37 (m, 1H), 7.28 (m, 1H), 3.02 (s, 2H), 1.76 (s, 6H), 1.63 (s, 6H). 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)phenol formate ESI-MS m / z: 433.15 [M+H]+, compound 4, formate salt;1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.97 (d, J = 6.9 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 8.1 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.64 – 7.58 (m, 1H), 7.14 (d, J = 6.9 Hz, 1H), 4.43 (s, 3H), 1.90 – 1.82 (m, 2H), 1.68 – 1.56 (m, 2H), 1.37 (s, 6H), 1.27 (s, 6H). 5-(1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)phenol formate ESI-MS m / z: 417.1 [M+H]+; compound 5, formate salt:1H NMR (400 MHz, DMSO-d6) δ 11.39 (broad s, 1H), 9.05 (m, 1H), 8.70 (m, 1H), 8.45 (m, 1H), 8.01 (s, 2H), 7.83 (m, 2H), 7.35 (m, 1H), 7.17 (m, 2H), 3.65 – 3.54 (m, 1H), 1.98 (m, 2H), 1.76 (t, J = 13.2 Hz, 2H), 1.45 (s, 6H) 1.39 (s, 6H). 4-(3-fluoro-5-hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)phenyl)-1-methylpyridin-2(1H)-one formate ESI-MS m / z: 476.25 [M+H]+, compound 6;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.03 (d, J = 7.0 Hz, 1H), 8.34 (d, J = 4.5 Hz, 1H), 8.28 (s, 1H), 7.79 (d, J = 7.0 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.19 – 7.15 (m, 1H), 6.79 – 6.73 (m, 1H), 6.67 – 6.61 (m, 1H), 3.46 (s, 3H), 1.87 – 1.80 (m, 2H), 1.58 – 1.48 (m, 2H), 1.31 (s, 6H), 1.19 (s, 6H). 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H- 1,2,3-triazol-2-yl)phenol HRMS calculated for the desired product, C23H26N7O [M+H]+= 416.2199, found = 416.2182 ESI-MS m / z: 416.4 [M+H]+, compound 7;1H NMR (400 MHz, methanol-d4) δ 8.62 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.79 (s, 2H), 7.57 - 7.48 (m, 2H), 7.30 (d, J = 7.2 Hz, 1H), 6.74 – 6.69 (m, 1H), 2.51 (s, 2H), 1.28 (s, 6H), 1.19 (s, 6H). 4-(3-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.30 – 7.22 (m, 2H), 6.87 (d, J = 1.6 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 7.1, 2.1 Hz, 1H), 3.62 (s, 3H), 2.92 (s, 2H), 1.62 (s, 6H), 1.53 (s, 6H). 5-(4-methoxy-1,3,5-triazin-2-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)phenol ESI-MS m / z: 460.2 [M+H]+; compound 9;1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 9.07 (s, 1H), 8.95 (d, J = 7.0 Hz, 1H), 8.50 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H), 8.01 (dd, J = 8.2, 1.7 Hz, 1H), 7.12 (d, J = 6.9 Hz, 1H), 4.09 (s, 3H), 3.30 – 3.27 (m, 1H), 1.74 (dd, J = 12.8, 3.2 Hz, 2H), 1.40 (t, J = 12.6 Hz, 2H), 1.24 (s, 6H), 1.09 (s, 6H). 3-fluoro-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-(2H-1,2,3-triazol-2-yl)phenol formate ESI-MS m / z 434.05, [M+H]+, compound 10, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.90 – 8.81 (m, 1H), 8.53 (s, 1H), 8.27 – 8.20 (m, 1H), 7.96 (s, 2H), 7.55 – 7.41 (m, 3H), 6.89 (s, 1H), 2.92 (s, 2H), 1.63 (s, 6H), 1.54 (s, 6H). 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H- 1,2,3-triazol-2-yl)pyridin-3-ol HRMS calculated for the desired product, C22H25N8O [M+H]+= 417.2151, found = 417.2142 ESI-MS m / z: 417.3 [M+H]+, compound 11;1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.93 (d, J = 7.3 Hz, 1H), 8.81 (t, J = 2.3 Hz, 1H), 8.41 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 6.92 (d, J = 1.7 Hz, 1H), 2.40 (s, 2H), 1.23 (s, 6H), 1.12 (s, 6H). 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H-1,2,3-triazol-1- ESI-MS m / z: 418.1 [M+H]+; compound 12, formate salt:1H NMR (400 MHz, methanol-d4) δ 8.72 (d, J = 6.9 Hz, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.83 (s, 2H), 7.55 (m, 2H), 7.00 (d, J = 7.0 Hz, 1H), 3.45 (tt, J = 12.3, 3.3 Hz, 1H), 2.06 (dd, J = 14.3, 3.3 Hz, 2H), 1.86 ESI-MS m / z: 458.25 [M+H]+, compound 13, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.84 (d, J = 6.8 Hz, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.29 – 7.22 (m, 2H), 7.13 (d, J = 6.4 Hz, 1H), 6.84 – 6.78 (m, 1H), 6.74 (dd, J = 7.1, 2.0 Hz, 1H), 3.61 (s, 3H), 3.59 – 3.47 (m, 1H), 2.18 – 2.10 (m, 2H), 2.00 – 1.88 (m, 2H), 1.60 (s, 6H), 1.50 (s, 6H). 3-fluoro-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol formate ESI-MS m / z: 436.1 [M+H]+, compound 14, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.91 (d, J = 7.0 Hz, 1H), 8.53 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.96 (s, 2H), 7.53 – 7.50 (m, 1H), 7.48 (dd, J = 12.3, 2.1 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 3.65 – 3.54 (m, 1H), 2.18 (dd, J = 14.4, 3.3 Hz, 2H), 2.02 – 1.90 (m, 2H), 1.62 (s, 6H), 1.52 (s, 6H). 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z: 418.4 [M+H]+; compound 15:1H NMR (400 MHz, methanol-d4) δ 8.89 – 8.68 (m, 1H), 8.28 (s, 1H), 8.07 – 7.97 (m, 1H), 7.94 (s, 2H), 7.71 – 7.57 (m, 2H), 7.12 – 6.95 (m, 1H), 3.44 – 3.37 (m, 1H), 1.99 – 1.90 (m, 2H), 1.63 (t, J = 12.9 Hz, 2H), 1.40 (s, 6H), 1.28 (s, 6H). 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H- 1,2,3-triazol-1-yl)phenol ESI-MS m / z: 416.0 [M+H]+; compound 16:1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 7.2 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.94 (s, 2H), 7.76 – 7.60 (m, 2H), 7.46 (d, J = 7.0 Hz, 1H), 6.87 (s, 1H), 2.66 (s, 2H), 1.43 (s, 6H), 1.34 (s, 6H). 2-(6-fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-(2H-1,2,3-triazol-2-yl)phenol HRMS calculated for the desired product C23H25FN7O [M+H]+= 434.2105, found = 434.2095 ESI-MS m / z: 434.1 [M+H]+, compound 17;1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 6.8 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.77 (s, 2H), 7.44 (s, 1H), 7.30 – 7.20 (m, 1H), 6.68 – 6.62 (m, 1H), 2.49 – 2.44 (m, 2H), 1.25 (s, 6H), 1.17 (s, 6H). 5-(1H-pyrazol-1-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)phenol formate ESI-MS m / z: 417.20 [M+H]+, compound 18, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 6.9 Hz, 1H), 8.55 (s, 1H), 8.29 (s, 1H), 8.24 (d, J = 2.5 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.5, 2.2 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H), 6.60 – 6.50 (m, 1H), 3.57 – 3.46 (m, 1H), 2.14 – 2.06 (m, 2H), 1.92 – 1.82 (m, 2H), 1.56 (s, 6H), 1.46 (s, 6H). 2-(7-(8-azabicyclo[3.2.1]oct-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- ESI-MS m / z: 459.2 [M+H]+; compound 21:1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.94 (d, J = 7.0 Hz, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.2, 1.8 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 0.9 Hz, 1H), 3.44 (s, 3H), 1.77 (d, J = 12.7 Hz, 2H), 1.44 (t, J = 12.7 Hz, 2H), 1.26 (s, 6H), 1.12 (s, 6H). 5-(pyridin-4-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z: 428.5 [M+H]+; compound 22:1H NMR (400 MHz, DMSO-d6) δ 11.84 (broad s, 1H), 8.90 (d, J = 6.8 Hz, 1H), 8.59 (s, 2H), 8.39 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 5.0 Hz, 2H), 7.32 (m, 2H), 7.09 (d, J = 6.9 Hz, 1H), 3.39 – 3.28 (m, 1H), 1.78 (m, 2H), 1.50 (m, 2H), 1.27 (s, 6H), 1.16 (s, 6H). 5-hydroxy-1'-methyl-6-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)- [3,4'-bipyridin]-2'(1'H)-one formate ESI-MS m / z: 459.05 [M+H]+, compound 23, formate salt;1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.03 (d, J = 6.9 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 7.1, 2.1 Hz, 1H), 3.47 (s, 3H), 1.88 – 1.79 (m, 2H), 1.58 – 1.48 (m, 2H), 1.32 (s, 6H), 1.19 (s, 6H). 6-(6-fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-hydroxy-1'-methyl-[3,4'-bipyridin]-2'(1'H)-one ESI-MS m / z: 475.2 [M+H]+; compound 24:1H NMR (400 MHz, DMSO) δ 9.28 (d, J = 7.1 Hz, 1H), 8.51 (s, 2H), 7.81 (d, J = 7.1 Hz, 1H), 7.66 (s, 1H), 6.85 – 6.73 (m, 2H), 6.70 – 6.63 (m, 1H), 3.47 (s, 3H), 2.41 – 2.38 (m, 2H), 1.25 (s, 6H), 1.16 (s, 6H).19F NMR (377 MHz, methanol-d4) δ -151.85. 2-(6-fluoro-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)pyridin-3-ol HRMS calculated for the desired product C22H26FN8O [M+H]+= 437.2214, found = 437.2208 ESI-MS m / z: 437.4 [M+H]+, compound 25;1H NMR (400 MHz, methanol-d4) δ 8.96 (d, J = 5.1 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 2H), 7.86 (d, J = 2.2 Hz, 1H), 3.72 – 3.63 (m, 1H), 1.92 – 1.87 (m, 2H), 1.76 – 1.66 (m, 2H), 1.38 (s, 6H), 1.27 (s, 6H). 2-(6-fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-(2H-1,2,3-triazol-2-yl)pyridin-3-ol HRMS calculated for the desired product C22H27N8O [M+H]+= 419.2308, found = 419.2296 ESI-MS m / z: 419.3 [M+H]+, compound 27;1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 7.0 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.31 (s, 1H), 7.89 (s, 2H), 7.84 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 3.38 – 3.28 (m, 1H), 1.89 – 1.81 (m, 2H), 1.60 – 1.50 (m, 2H), 1.31 (s, 6H), 1.19 (s, 6H). 5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formate ESI-MS m / z: 431.1 [M+H]+, compound 28, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.83 (d, J = 7.1 Hz, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.48 (d, J = 7.1 Hz, 1H), 6.86 (s, 1H), 4.43 (s, 3H), 2.91 (s, 2H), 1.62 (s, 6H), 1.52 (s, 6H). 2-(3-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-7-(2,2,6,6-tetramethylpiperidin-4- yl)imidazo[1,2-a]pyrimidine HRMS calculated for the desired product C23H29N8O [M+H]+= 433.2462, found = 433.2509 ESI-MS m / z: 433.2 [M+H]+, compound 29;1H NMR (400 MHz, methanol-d4) δ 8.98 (d, J = 2.0 Hz, 1H), 8.71 (d, J = 7.0 Hz, 1H), 8.36 (s, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.93 (s, 2H), 6.97 (d, J = 7.0 Hz, 1H), 4.08 (s, 3H), 3.38 – 3.32 (m, -1H), 1.93 – 1.84 (m, 2H), 1.64 – 1.52 (m, 2H), 1.33 (s, 6H), 1.22 (s, 6H). 2-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2- a]pyrimidine formate ESI-MS m / z: 376.10 [M+H]+, compound 31, formate salt;1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, = 7.0 Hz, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.21 (d, = 7.9 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.14 (d, J = 7.0 Hz, 1H), 3.42 – 3.33 (m, 1H), 1.88 – 1.78 (m, 2H), 1.65 – 1.49 (m, 2H), 1.34 (s, 6H), 1.22 (s, 6H). 2-(3-fluoro-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-7-(2,2,6,6-tetramethylpiperidin-4- yl)imidazo[1,2-a]pyrimidine ESI-MS m / z 421.3 [M+H]+, compound 32;1H NMR (400 MHz, methanol-d4) δ 9.25 – 9.17 (m, 1H), 8.75 (d, J = 7.0 Hz, 1H), 8.33 – 8.25 (m, 2H), 7.96 (s, 2H), 7.03 (d, J = 7.0 Hz, 1H), 3.40 (t, J = 12.7 Hz, 1H), 2.00 – 1.90 (m, 2H), 1.69 (t, J = 13.1 Hz, 2H), 1.39 (s, 6H), 1.28 (s, 6H). 5-chloro-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formate ESI-MS m / z: 385.5 [M+H]+; compound 33, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.72 (d, J = 7.0 Hz, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.93 – 6.77 (m, 2H), 3.46 (tt, J = 12.6, 3.2 Hz, 1H), 2.06 (dd, J = 14.3, 3.3 Hz, 2H), 1.85 (t, J = 13.4 Hz, 2H), 1.51 (s, 6H), 1.42 (s, 6H). 4-(3-hydroxy-4-(6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)phenyl)-1-methylpyridin -2(1H)-one formate ESI-MS m / z: 472.1 [M+H]+, compound 34, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.0 Hz, 1H), 7.27 – 7.21 (m, 2H), 6.82 – 6.78 (m, 1H), 6.74 (dd, J = 7.0, 2.1 Hz, 1H), 3.68 – 3.60 (m, 1H), 3.61 (s, 3H), 2.45 (s, 3H), 2.06 – 1.93 (m, 4H), 1.60 (s, 6H), 1.49 (s, 6H). 4-(2-fluoro-3-hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)phenyl)-1-methylpyridin-2(1H)-one ESI-MS m / z: 476.2 [M+H]+, compound 35;1H NMR (400 MHz, MeOD) δ 8.84 (d, J = 6.9 Hz, 1H), 8.40 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.13 (d, J = 6.8 Hz, 1H), 7.07 – 7.01 (m, 1H), 6.79 (s, 1H), 6.67 (d, J = 6.9 Hz, 1H), 3.63 (s, 3H), 3.57 – 3.50 (m, 1H), 2.12 – 2.04 (m, 2H), 1.87 – 1.80 (m, 2H), 1.53 (s, 6H), 1.43 (s, 6H). 2-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin- 4-yl)imidazo[1,2-a]pyrimidine formate ESI-MS m / z 435.15 [M+H]+, compound 36, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.83 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 8.25 (d, J = 3.8 Hz, 1H), 8.10 (s, 2H), 7.98 (dd, J = 11.8, 6.3 Hz, 1H), 7.63 (dd, J = 12.0, 6.2 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 6.88 (s, 1H), 2.97 – 2.84 (m, 2H), 1.63 (s, 6H), 1.53 (s, 6H).19F NMR (282 MHz, methanol-d4) δ -120.45, -121.67. 2-(6-methyl-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol formate ESI-MS m / z: 432.1 [M+H]+, compound 37, formate salt;1H NMR (400 MHz, DMSO-d6) δ 12.11 (br s, 1H), 8.85 – 8.75 (m, 1H), 8.35 (s, 1H), 8.34 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.13 (s, 2H), 7.64 – 7.57 (m, 2H), 3.52 – 3.43 (m, 1H), 2.38 (s, 3H), 1.82 – 1.74 (m, 2H), 1.71 – 1.61 (m, 2H), 1.39 (s, 6H), 1.27 (s, 6H). 5-(1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)phenol HRMS calculated for the desired product C24H31N6O [M+H]+= 431.2559, found = 431.2546 ESI-MS m / z: 431.4 [M+H]+, compound 38;1H NMR (400 MHz, methanol-d4) δ 8.69 (d, J = 6.9 Hz, 1H), 8.13 (s, 1H), 7.87 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.73 – 7.71 (m, 1H), 7.05 – 6.97 (m, 3H), 3.84 (s, 3H), 3.42 – 3.32 (m, 1H), 1.98 – 1.90 (m, 2H), 1.75 – 1.63 (m, 2H), 1.40 (s, 6H), 1.29 (s, 6H). 5-(1-methyl-1H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol formate ESI-MS m / z 434.3, [M+H]+, compound 40;1H NMR (400 MHz, methanol-d4) δ 8.90 (d, J = 7.1 Hz, 1H), 8.38 (s, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.94 (s, 2H), 7.80 – 7.62 (m, 2H), 7.50 (d, J = 6.9 Hz, 1H), 2.18 (d, J = 14.7 Hz, 2H), 1.97 (d, J = 14.3 Hz, 2H), 1.68 (s, 6H), 1.37 (s, 6H). 2-(7-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)imidazo[1,2-a]pyrimidin-2-yl)-5- (2H-1,2,3-triazol-2-yl)phenol formate ESI-MS m / z: 389.10 [M+H]+, compound 41, formate salt;1H NMR (400 MHz, DMSO) δ 8.65 – 8.54 (m, 1H), 8.32 (s, 2H), 8.11 (s, 2H), 8.02 (s, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.57 – 7.50 (m, 2H), 6.55 (d, J = 7.0 Hz, 1H), 3.80 – 3.70 (m, 2H), 3.58 – 3.48 (m, 2H), 3.37 – 3.23 (m, 2H), 3.12 – 2.94 (m, 4H). 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl)-5- (2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z: 477.3 [M+H]+; compound 43:1H NMR (400 MHz, DMSO) δ 9.28 (d, J = 5.2 Hz, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 7.81 (d, J = 7.1 Hz, 1H), 7.68 (s, 1H), 6.82 (s, 1H), 6.71 – 6.64 (m, 1H), 3.47 (s, 3H), 1.77 – 1.69 (m, 2H), 1.51 – 1.43 (m, 2H), 1.24 (s, 6H), 1.10 (s, 6H).19F NMR (377 MHz, methanol-d4) δ -155.57. 2-fluoro-6-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-3-(2H-1,2,3- triazol-2-yl)phenol formate ESI-MS m / z: 436.1 [M+H]+, compound 44, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.87 – 8.81 (m, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 8.00 (s, 2H), 7.89 – 7.82 (m, 1H), 7.30 (dd, J = 8.6, 6.7 Hz, 1H), 7.13 (d, J = 6.5 Hz, 1H), 3.60 – 3.51 (m, 1H), 2.19 – 2.10 (m, 2H), 2.00 – 1.87 (m, 2H), 1.59 (s, 6H), 1.49 (s, 6H). 4-(3-hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrimidin-2-yl)phenyl)-1-methylpyridin-2(1H)-one formate ESI-MS m / z: 526.6 [M+H]+, compound 45, formate salt;1H NMR (400 MHz, DMSO-d6) δ 11.23 (br s, 1H), 9.61 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.31 (dd, J = 8.1, 1.8 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 6.64 (d, J = 2.0 Hz, 1H), 6.55 (dd, J = 7.1, 2.1 Hz, 1H), 3.46 (s, 3H), 1.89 – 1.73 (m, 4H), 1.34 (s, 6H), 1.28 (s, 6H). 2-(6-fluoro-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol HRMS calculated for the desired product, C23H27FN7O [M+H]+= 436.2261, found = 436.2246 ESI-MS m / z: 436.1 [M+H]+, compound 46;1H NMR (400 MHz, methanol-d4) δ 8.40 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.78 (s, 2H), 7.46 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.5, 2.2 Hz, 1H), 3.61 – 3.52 (m, 1H), 1.79 – 1.73 (m, 2H), 1.59 – 1.49 (m, 2H), 1.25 (s, 6H), 1.13 (s, 6H). 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2- a]pyrimidine formate ESI-MS m / z: 402.15 [M+H]+, compound 47, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 7.0 Hz, 1H), 8.55 (s, 1H), 8.24 (s, 1H), 8.20 – 8.16 (m, 2H), 8.15 – 8.10 (m, 2H), 7.96 (s, 2H), 7.11 (d, J = 7.0 Hz, 1H), 3.62 – 3.51 (m, 1H), 2.20 – 2.11 (m, 2H), 2.02 – 1.90 (m, 2H), 1.61 (s, 6H), 1.50 (s, 6H). 5-(1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z: 433.1 [M+H]+, compound 49, formate salt;1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.99 (d, J = 6.9 Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.43 (dd, J = 8.1, 1.8 Hz, 1H), 7.16 (d, J = 6.9 Hz, 1H), 4.22 (s, 3H), 1.92 – 1.81 (m, 2H), 1.67 – 1.55 (m, 2H), 1.36 (s, 6H), 1.25 (s, 6H). 6-fluoro-2-(3-fluoro-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-7-(2,2,6,6-tetramethylpiperidin-4- yl)imidazo[1,2-a]pyrimidine ESI-MS m / z 439.3 [M+H]+, compound 50;1H NMR (400 MHz, methanol-d4) δ 9.22 (dd, J = 2.1, 0.9 Hz, 1H), 8.90 (d, J = 5.0 Hz, 1H), 8.32 – 8.27 (m, 2H), 7.96 (s, 2H), 3.76 – 3.60 (m, 1H), 1.92 (dd, J = 14.1, 2.8 Hz, 2H), 1.73 (t, J = 13.1 Hz, 2H), 1.39 (s, 6H), 1.28 (s, 6H). 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H-tetrazol-5- yl)phenol ESI-MS m / z: 419.10 [M+H]+, compound 51;1H NMR (400 MHz, DMSO) δ 11.48 (br s, 1H), 8.96 (d, J = 6.9 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.59 – 7.51 (m, 2H), 7.12 (d, J = 6.9 Hz, 1H), 1.95 – 1.86 (m, 2H), 1.73 – 1.61 (m, 2H), 1.40 (s, 6H), 1.30 (s, 6H). 6-fluoro-2-(3-fluoro-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine ESI-MS m / z 515.4 [M+H]+, compound 54;1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 9.27 (d, J = 7.1 Hz, 1H), 8.56 (d, J = 2.8 Hz, 1H), 8.46 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H), 7.43 (dd, J = 13.2, 1.4 Hz, 1H), 7.37 – 7.29 (m, 2H), 6.74 (d, J = 1.7 Hz, 1H), 4.25 (s, 3H), 2.44 (s, 2H), 1.28 (s, 6H), 1.20 (s, 6H). 2-(7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol formate ESI-MS m / z 376.85 [M+H]+, compound 55;1H NMR (400 MHz, methanol-d4) δ 8.52 – 8.37 (m, 3H), 8.0 -7.93 (br s, 1H), 7.92 (s, 2H), 7.90 – 7.80 (m, 1H), 7.68 – 7.59 (m, 2H), 6.85 (d, 1H), 3.92 – 3.82 (m, 4H), 2.75 – 2.68 (m, 4H), 2.48 (s, 3H). 2-(7-(4-ethyl-3,3-dimethylpiperazin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 419.4 [M+H]+, compound 56;1H NMR (400 MHz, methanol-d4) δ 8.28 (d, J = 7.6 Hz, 1H), 7.82 – 7.75 (m, 4H), 7.52 – 7.46 (m, 2H), 6.67 (d, J = 7.7 Hz, 1H), 3.75 (t, J = 5.4 Hz, 2H), 3.47 (s, 2H), 2.62 (t, J = 5.4 Hz, 2H), 2.42 (q, J = 7.1 Hz, 2H), 1.05 – 1.00 (m, 9H). 2-(7-(3,3,5,5-tetramethyl-1,4-diazepan-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H-1,2,3-triazol- 1-yl)phenol ESI-MS m / z 433.4 [M+H]+, compound 57;1H NMR (400 MHz, methanol-d4) δ 8.42 (d, J = 1.2 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.4, 2.2 Hz, 1H), 6.66 (d, J= 7.7 Hz, 1H), 3.97 – 3.74 (m, 2H), 3.70 – 3.62 (m, 2H), 2.01 – 1.95 (m, 2H), 1.16 (s, 6H), 1.14 (s, 6H). 2-(7-(3,3,5,5-tetramethyl-1,4-diazepan-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol- 2-yl)phenol ESI-MS m / z 433.3 [M+H]+, compound 58;1H NMR (400 MHz, methanol-d4) δ 8.39 (d, J = 7.6 Hz, 1H), 7.92 (s, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.64 – 7.57 (m, 2H), 6.73 (d, J = 7.5 Hz, 1H), 4.00 – 3.83 (m, 2H), 3.80 – 3.70 (m, 2H), 2.12 – 2.04 (m, 2H), 1.26 (s, 6H), 1.25 (s, 6H). 2-(7-(3,5-dimethylpiperazin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 391.1 [M+H]+, compound 59;1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 8.12 (s, 2H), 7.99 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.56 – 7.51 (m, 2H), 6.91 (d, J = 7.7 Hz, 1H), 4.49 – 4.25 (m, 2H), 2.78 – 2.68 (m, 2H), 2.48 – 2.31 (m, 2H), 1.06 (s, 3H), 1.05 (s, 3H). 5-(1H-pyrazol-4-yl)-2-(7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ( ( ( 7.44 (m, 1H), 6.83 – 6.76 (m, 1H), 2.44 (s, 2H), 1.28 (s, 6H), 1.20 (s, 6H). 2-(7-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H- 1,2,3-triazol-2-yl)phenol ESI-MS m / z 416.4 [M+H]+, compound 64;1H NMR (400 MHz, methanol-d4) δ 9.02 (s, 1H), 8.67 (d, J = 7.3 Hz, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.38 – 7.27 (m, 3H), 6.78 – 6.73 (m, 1H), 2.55 (m, 2H), 1.33 (s, 6H), 1.23 (s, 6H). 5-(1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 416.2 [M+H]+, compound 65;1H NMR (400 MHz, methanol-d4) δ 9.14 (d, J = 7.3 Hz, 1H), 8.74 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.15 (s, 2H), 7.97 (d, J = 7.3 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.23 – 7.17 (m, 1H), 2.99 (d, J = 1.6 Hz, 2H), 1.71 (s, 6H), 1.60 (s, 6H). 3-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)naphthalen-2-ol formate N,3-dimethoxy-N-methyl-2-naphthamide (Intermediate 2) To a stirred solution of 3-methoxy-2-naphthoic acid (2 g, 1 equiv., 9.89 mmol) in N,N- dimethylformamide (20 mL) were added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimideHydrochloride (EDCI) (3.79 g, 2 equiv., 19.8 mmol) and HOBt (1.81 g, 1.2 Eq, 11.9 mmol) at 0 °C. After addition the reaction mixture was stirred for 2 h at 0°C. Then was added N,O-dimethyl hydroxylamine hydrochloride (1.43 g, 1.5 equiv., 14.8 mmol) , followed by DIPEA (10.3 mL, 6.0 equiv., 59.3 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to get crude product, whichwas purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100 : 0 to 50 : 50; on 24 g Redisep Silver column) to give N,3-dimethoxy-N-methyl-2-naphthamide as a white solid (1.6 g, 6.13 mmol, 62% yield, 94% purity). ESI-MS m / z [M+H]+; 246.1 LC / MS method 8. 1-(3-methoxynaphthalen-2-yl)ethan-1-one (Intermediate 3) To a stirred solution of N,3-dimethoxy-N-methyl-2-naphthamide (1.5 g, 1 equiv., 6.1 mmol) in tetrahydrofuran (30 mL) was added MeMgBr (2.18 g, 6.11 mL, 3.0 molar in THF, 3 equiv., 18.4 mmol) at 0 °C over a period of 5 minutes. The resulting reaction mixture was stirred at RT for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by a saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to get crude product, whichwas purified by flash column chromatography on silica gel (eluent: Hexane / EtOAc = 100 : 0 to 80 : 20; on 24 g Redisep column via liquid injection) to give 1-(3-methoxynaphthalen-2-yl)ethan-1-one as a white solid (800 mg, 3.84 mmol, 62% yield, 96% purity). ESI-MS m / z [M+H]+; 201 LC / MS method 8. 2-bromo-1-(3-methoxynaphthalen-2-yl)ethan-1-one (Intermediate 4) To a stirred solution of 1-(3-methoxynaphthalen-2-yl) ethan-1-one (750 mg, 1 equiv., 3.75 mmol) in tetrahydrofuran (10 mL) was added phenyltrimethylammonium tribromide (1.41 g, 1.0 equiv., 3.75 mmol) in tetrahydrofuran (10 mL) at 0°C over the period of 5 min. Then, the resulting reaction mixture was stirred at RT for 16 h. Reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure to yield crude compound which was purified by flash column chromatography on silica gel (eluent: Hexane / EtOAc = 100 : 0 to 90 : 10; on 24 g Redisep column via liquid injection) to give 2-bromo-1-(3-methoxynaphthalen-2-yl)ethan-1-one (700 mg, 2.37 mmol, 63% yield, 94.4% purity) as a white solid. ESI-MS m / z [M+H]+; 280.90 LC / MS method 10. 2-(3-methoxynaphthalen-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidine (Intermediate To a stirred solution of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2- amine (100 mg, 1.0 equiv., 430 μmol) in Isopropanol (5 mL) was added 2-bromo-1-(3- methoxynaphthalen-2-yl) ethan-1-one (180 mg, 1.5 equiv., 646 μmol). The reaction mixture was gradually heated to 100 °C for 16 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude compound, whichwas dissolved in DCM and was loaded onto silica gel (~1g). The silica gel was placed in a sample-load cartridge to be purified by column chromatography (12 g RediSep, CombiFlash, gradient elution 0 - 10% MeOH to give the desired product 2-(3-methoxynaphthalen- 2-yl)-7- (2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (120 mg, 205 μmol, 47% yield, 70% purity). ESI-MS m / z [M+H]+; 413.05 LC / MS method 9. 3-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)naphthalen-2-ol To a stirred solution of -(3-methoxynaphthalen-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (100 mg, 1.0 equiv., 242. μmol) in 1,2- dichloroethane (2 mL) was added boron tribromide (0.200 mL, 8.73 equiv., 2.12 mmol) at 0°C. After addition the reaction mixture was stirred at 25 °C for 16 h. After 16 h, LCMS showed starting material was remaining, therefore reaction mixture was heated to 60 °C for 2 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude product, which was purified by prep HPLC (mobile Phase: A = 0.1% HCOOH in water, B = ACN, column: X SELECT C18 (250mm ×19 mm) 5.0μ, flow: 15 mL / min)The fractions containing the desired product were lyophilized to give 3-(7-(2,2,6,6- tetramethyl1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)naphthalen-2-ol as a pale yellow solid (compound 66, formate salt, 40 mg, 86.4 μmol, 35% yield, 96% purity). ESI-MS m / z 399.05 [M+H]+, LC / MS method 8. HPLC: Rt 6.80 min, 96%. 1H NMR (400 MHz, methanol-d4) δ 8.80 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.47 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.41 – 7.36 (m, 1H), 7.32 – 7.27 (m, 1H), 7.26 (s, 1H), 6.86 (s, 1H), 2.81 (s, 2H), 1.54 (s, 6H), 1.44 (s, 6H). 5-(1H-pyrazol-4-yl)-2-(7-(1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)phenol ESI-MS m / z: 441.2 [M+H]+; compound 67:1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 11.87 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.38 (s, 1H), 8.22 (s, 1H), 8.04 – 7.84 (m, 2H), 7.47 (d, J = 7.3 Hz, 1H), 7.20 (dt, J = 4.7, 2.4 Hz, 2H), 6.94 (t, J = 3.6 Hz, 1H), 3.48 (q, J = 2.9 Hz, 2H), 2.92 (t, J = 5.7 Hz, 2H), 2.69 (m, 2H).19F NMR (376 MHz, DMSO) δ -68.06 (t, J = 10.2 Hz). 3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 449.2, [M+H]+, compound 68;1H NMR (400 MHz, methanol-d4+CDCl3) δ 8.82 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 4.2 Hz, 1H), 7.77 (s, 2H), 7.56 – 7.51 (m, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.43 (dd, J = 11.9, 1.6 Hz, 1H), 6.89 – 6.81 (m, 1H), 4.43 (s, 3H), 2.79 (s, 2H), 1.53 (s, 6H), 1.44 (s, 6H). 6-hydroxy-3-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)quinazolin-4(3H)-one formate methyl 4-bromo-5-methoxy-2-nitrobenzoate [Intermediate 2] To a stirred solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (10 g, 1.0 equiv, 36 mmol) in methanol (100 mL) was added potassium tert-butoxide (8.1 g, 2.0 equiv, 72 mmol) at RT. The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate and concentrated to obtain a crude residue which was triturated with n-pentane. The resulting solid was collected by filtration, washed with n-pentane, and dried under reduced pressure to afford methyl 4-bromo-5-methoxy-2-nitrobenzoate (7.5 g, 21 mmol, 58% yield, 81% purity) as a pale yellow solid. ESI-MS m / z 291.85 [M+H]+; LC / MS method 10 4-bromo-5-methoxy-2-nitrobenzoic acid [Intermediate 3] To a stirred solution of methyl 4-bromo-5-methoxy-2-nitrobenzoate (7.5 g, 1.0 equiv, 25.86 mmol) in THF (60 mL) and water (10 mL) was added lithium hydroxide monohydrate (5.4 g, 3.6 mL, 5.0 equiv, 129 mmol). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted to pH = 7 with with 1M HCl. EtOAc was added. The layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue which was triturated with Et2O. The resulting solid was collected by filtration, washed with Et2O, and dried under reduced pressure to afford 4-bromo-5-methoxy-2-nitrobenzoic acid (7.0 g, 24.6 mmol, 95% yield, 97% purity) as a pale yellow solid. ESI-MS m / z 275.9 [ method 8 4-bromo-5-methoxy-N-methyl-2-nitrobenzamide [Intermediate 4] To a stirred solution of 4-bromo-5-methoxy-2-nitrobenzoic acid (7.0 g, 1.0 equiv, 25.4 mmol) in N,N-Dimethylformamide (70 mL) were added DIPEA (22.1 mL, 5.0 equiv, 127 mmol) and HATU (11.6 g, 1.2 equiv, 30.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. After 15 minutes, Methylamine hydrochloride (3.4 g, 2.0 equiv, 50.7 mmol) was added. The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to a crude residue, which was diluted with water. The solid that separated was filtered through a buchner funnel and washed with excess water and dried under vacuum to obtain a crude residue. The crude residue was triturated with Et2O and dried under reduced pressure to afford 4-bromo-5- methoxy-N-methyl-2-nitrobenzamide (5.7 g, 19.05 mmol, 75% yield, 97% purity) as a pale yellow solid. ESI-MS m / z 288.9 [M+H]+; LC / MS method 8 2-amino-4-bromo-5-methoxy-N-methylbenzamide [Intermediate 5] To a stirred solution of 4-bromo-5-methoxy-N-methyl-2-nitrobenzamide (5.7 g, 1.0 equiv, 19.7 mmol) in tetrahydrofuran (60 mL) and water (15 mL) was added ammonium chloride (10.55 g, 10 equiv, 197.2 mmol) at 0 °C. After stirring for 15 mins at 0 °C, zinc (12.89 g, 10 equiv, 197.2 mmol) was added in portions at 0 °C. The reaction mixture was stirred at RT for 16 h. Then, the reaction mixture was filtered through a celite bed, washing with excess ethyl acetate. The combined filtrate was dried over sodium sulphate and concentrated to obtain the crude product. Purification: The crude product was dissolved in DCM and was loaded onto silica gel (~10 g). The silica gel was placed in a sample-load cartridge to be purified by column chromatography (40 g Redisep, CombiFlash, Gradient Elution 0-10% Methanol in DCM) to obtain 2-amino-4-bromo-5- methoxy-N-methylbenzamide (3.6 g, 13.66 mmol, 69% yield, 98% purity) as a white solid. ESI-MS m / z 260.9 [M+H]+; LC / MS method 9 7-bromo-6-methoxy-3-methylquinazolin-4(3H)-one [Intermediate 6] To a stirred solution of 2-amino-4-bromo-5-methoxy-N-methyl benzamide (3.6 g, 1.0 equiv, 13.89 mmol) in ethanol (40 mL) was added triethyl orthoformate (6.2 g, 6.9 mL, 3.0 equiv, 41.7 mmol). The reaction mixture was heated to 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (eluent: Hexane / EtOAc = 100:0 to 0:100; a 24 g Redisep Silver column using a 5 g solid cartridge) to give 7-bromo-6-methoxy-3-methylquinazolin-4(3H)-one (2.2 g, 7.9 mmol, 56% yield, 96% purity) as a white solid. ESI-MS m / z 270.85 [M+H]+; LC / MS method 9 7-acetyl-6-methoxy-3-methylquinazolin-4(3H)-one [Intermediate 8] To a stirred solution of 7-bromo-6-methoxy-3-methylquinazolin-4(3H)-one (2.1 g, 1.0 equiv, 7.8 mmol) in toluene (20 mL) were added (1-ethoxyvinyl) tributylstannane (3.4 g, 3.2 mL, 1.2 equiv, 9.36 mmol) and potassium carbonate (3.23 g, 3 equiv, 23.41 mmol). The reaction mixture was purged with argon for 15 min. After 15 minutes, Pd(PPh3)4(1.8 g, 0.2 equiv, 1.56 mmol) was added and the reaction mixture was purged with argon for another 10 min. The reaction mixture was heated to 90 °C for 16 h. Then, the reaction mixture was filtered through a celite bed, washing with with excess ethyl acetate. The combined filtrate was dried over sodium sulphate and concentrated under reduced pressure to obtain a residue (3 g) which was dissolved in tetrahydrofuran (30 mL). Hydrochloric acid (23 mL, 1 molar) was added at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with 10% NaHCO3and EtOAc. The layers were separated. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: Hexane / EtOAc = 100:0 to 0:100; a 40 g Redisep Silver column using a 25 g solid cartridge) to give 7-acetyl-6-methoxy- 3-methylquinazolin-4(3H)-one (0.9 g, 3.15 mmol, 27% yield, 81% purity) as a pale yellow solid. ESI-MS m / z 233.0 [M+H]+; LC / MS method 8 7-(2-bromoacetyl)-6-methoxy-3-methylquinazolin-4(3H)-one [Intermediate 10] To a stirred solution of 7-acetyl-6-methoxy-3-methylquinazolin-4(3H)-one (500 mg, 1.0 equiv, 2.15 mmol) in tetrahydrofuran (10 mL) was added phenyltrimethylammonium tribromide (Jacques Reagent) (809 mg, 1.0 equiv, 2.15 mmol) in tetrahydrofuran (10 mL) at 0 °C. The resulting reaction mixture was heated to 60 °C for 4 h. The reaction mixture was filtered through a celite bed and the filtrate was concentrated to yield the crude product, which was purified by flash column chromatography on silica gel (eluent: Hexane / EtOAc = 100:0 to 0:100; a 12 g Redisep column via injection of compound solution) to give 7-(2-bromoacetyl)-6-methoxy-3- methylquinazolin-4(3H)-one (270 mg, 608 μmol, 28% yield, 70% purity) as a pale yellow solid. ESI-MS m / z 312.9 [M+H]+; LC / MS method 10 6-methoxy-3-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- To a stirred solution of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2- amine (150 mg, 1.0 equiv, 646 μmol) in isopropanol (3 mL) was added 7-(2-bromoacetyl)-6- methoxy-3-methylquinazolin-4(3H)-one (241 mg, 1.2 equiv, 775 μmol) and the reaction mixture was heated to 80 °C for 16 h. The reaction mixture was diluted with 10% aqueous NaHCO3solution and DCM. The layers were separated. The aqueous layer was extracted three times with DCM, and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (eluent: DCM / [MeOH / (28% NH3aq) (9:1)] = 100:0 to 90:10; a 12 g Redisep Silver column via injection of a solution of the compound) to afford 6-methoxy-3-methyl-7-(7-(2,2,6,6-tetramethyl- 1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinazolin-4(3H)-one (170 mg, 316 μmol, 48% yield, 82% Purity) as a pale yellow solid. ESI-MS m / z 445.10 [M+H]+; LC / MS method 9 6-hydroxy-3-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)quinazolin-4(3H)-one To a stirred solution of 6-methoxy-3-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinazolin-4(3H)-one (160 mg, 1.0 equiv, 360 μmol) in 1,2-dichloroethane (2 mL) was added boron tribromide (1 mL, 29.4 equiv, 10.6 mmol) at 0 °C. The reaction mixture was heated to 60 °C for 3 h. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reversed phase HPLC (Prep conditions: Mobile Phase: A= 0.1% HCOOH IN WATER, B= ACN, Column: Gemini NX (250 mm x 21.2 mm), 5.0 μm , Flow: 18 mL / min). The product-containing fractions were pooled and lyophilized to give 6-hydroxy-3-methyl-7-(7- (2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl) imidazo[1,2-a]pyrimidin-2-yl)quinazolin-4(3H)-one as the formic acid salt (compound 69, formate salt; 30 mg, 61 μmol, 16% yield, 97% purity) as a pale yellow solid. ESI-MS m / z [M+H]+; 431.05 LC / MS method 8 HPLC: Rt 5.13 min, 97% pure. 1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 7.2 Hz, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.51 (d, J = 7.3 Hz, 1H), 6.89 (br s, 1H), 3.60 (s, 3H), 2.93 (s, 2H), 1.62 (s, 6H), 1.53 (s, 6H). 2-(7-(8-azabicyclo[3.2.1]oct-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- ( (d, J = 7.3 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 3.84 – 3.75 (m, 2H), 2.83 (d, J = 16.4 Hz, 1H), 2.41 (d, J = 17.4 Hz, 1H), 1.94 (dt, J = 20.1, 10.6 Hz, 2H), 1.85 – 1.74 (m, 1H), 1.59 – 1.47 (m, 1H). First eluting peak using the following column and conditions for enantiomer separation: Column: Chiralcel OX-H 21x250mm 5um - (CPC117) Flow Rate: 80g per minute Cosolvent: 50% 4:1 MeOH:ACN w / 10mM NH3 in CO2 Detection: 272nm BPR Set Point: 125bar Injection Size: 3 mg (2.0mg / mL in MeOH) System: Thar80 Acronyms: MeOH = Methanol, ACN = Acetonitrile, NH3 = Ammonia 2-(7-(8-azabicyclo[3.2.1]oct-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 386.2 [M+H]+, compound 71;1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.41 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.14 (s, 2H), 7.67 – 7.57 (m, 2H), 7.40 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 3.86 – 3.77 (m, 2H), 2.87 – 2.79 (m, 1H), 2.42 (d, J = 17.5 Hz, 1H), 2.01 – 1.88 (m, 2H), 1.86 – 1.76 (m, 1H), 1.59 – 1.49 (m, 1H). Second eluting peak using the following column and conditions for enantiomer separation: Column: Chiralcel OX-H 21x250mm 5um - (CPC117) Flow Rate: 80g per minute Cosolvent: 50% 4:1 MeOH:ACN w / 10mM NH3in CO2Detection: 272nm BPR Set Point: 125bar Injection Size: 3 mg (2.0mg / mL in MeOH) System: Thar80 Acronyms: MeOH = Methanol, ACN = Acetonitrile, NH3 = Ammonia

[0006] 2-(3-fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-(2H-1,2,3-triazol-2-yl)phenol formate 1-(4-Bromo-2-methoxyphenyl)ethan-1-one To a mixture of 1-(4-bromo-2-hydroxyphenyl)ethan-1-one (10 g, 1 equiv, 46.501 mmol), potassium carbonate (19.27 g, 3 equiv, 139.5 mmol) in acetonitrile (100 mL) was added methyl iodide (5.81 mL, 2 equiv, 93.0 mmol) and reaction was stirred at 50°C for 16 h. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to get crude product. The crude residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100 / 0 to 80 / 20; 24 g Redisep Silver column using a 25 g solid cartridge) to give 1-(4-bromo-2-methoxyphenyl)ethan-1-one (10 g, 43.65 mmol, 93.88%) as a white solid. ESI-MS m / z [M+H]+; 229.0 LC / MS method 10 1-(2-Methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethan-1-one The stirred mixture of Pd2(dba)3(3.198 g, 0.2 equiv, 3.49 mmol) and 2-(di-tert- butylphosphino)-3,4,5,6-tetramethyl-2',4',6'- triisopropyl-1,1'-biphenyl (3.35 g, 0.4 equiv, 6.98 mmol) in toluene (15 mL) and 1,4-dioxane (7.5 mL) was purged with argon and stirred at 120 °C for 15 min. In another sealed tube 1-(4-bromo-2-methoxyphenyl) ethan-1-one (4 g, 1 equiv, 17.46 mmol), 2H-1,2,3-triazole (6.03 g, 5 Eq, 87.31 mmol) and potassium phosphate (11.12 g, 4.337 mL, 3 equiv., 52.39 mmol) in toluene (15 mL) and 1,4-dioxane (7.5 mL) was purged with argon for 5 min. To this mixture, preheated catalyst was added and the mixture was purged with argon for 5 min. The reaction mixture was heated to 120 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4,filtered and the filtrate was concentrated under reduced pressure to get crude product. The crude residue was purified by flash column chromatography on silica gel (eluent: hexane / EtOAc(10- 15%), 24 g Redisep Silver column using a 25 g solid cartridge) to give 1-(2-methoxy-4-(2H-1,2,3- triazol-2-yl) phenyl)ethan-1-one (2.8 g, 13 mmol, 72% yield, 98% purity) as a white solid. ESI-MS m / z [M+H]+; 218.10 LC / MS method 10 2-Bromo-1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethan-1-one To a mixture of 1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethan-1-one (2.8 g, 1 equiv, 12.89 mmol) in 1,4-dioxane (40 mL) was added bromine (2.06 g, 664.0 μL, 1 equiv, 12.89 mmol) in 1,4-dioxane (10 mL) dropwise at rt. After addition the reaction mixture was stirred at 27°C for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction it was quenched with water and the product was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to get crude product. The crude residue was purified by flash column chromatography on silica gel (eluent: hexane / DCM (30-35%), 24 g Redisep Silver column via liquid injection) to give 2-bromo-1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethan-1-one (2.3 g, 7.6 mmol, 59% yield, 98% purity) as a white solid. ESI-MS m / z [M+H]+; 297.85 LC / MS method 8 2-(2-Methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine To a stirred solution of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) pyrimidin-2- amine (300 mg, 1 equiv, 1.291 mmol) in isopropanol (5 mL) was added 2-bromo-1-(2-methoxy-4- (2H-1,2,3-triazol-2-yl)phenyl)ethan-1-one (458.8 mg, 1.2 equiv, 1.550 mmol) at rt. The reaction mixture was gradually heated to 80°C for 16 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with saturated NaHCO3and extracted with chloroform thrice. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get crude product which was triturated with Et2O. The resulting solids were collected by filtration, washed with Et2O, and dried under reduced pressure to afford 2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (400 mg, 838.0 μmol, 64% yield, 89.9% purity) as a pale yellow solid. ESI-MS m / z [M+H]+; 430.25 LC / MS method 8 3-Fluoro-2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine To a stirred solution of -(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidine (400 mg, 1 equiv, 931.3 μmol) in acetonitrile (5 mL) was added selectfluor (329.9 mg, 1 equiv, 931.3 μmol) at 0 °C. Then, the reaction mixture was stirred at 25 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product. The crude product was purified by column chromatography (12 g Redisep Silver column, solvent gradient 0-10% MeOH in DCM) to obtain the product. The product was repurified by preparative RP-HPLC. The pure fractions were concentrated to obtain 3-fluoro-2-(2-methoxy-4- (2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidine (70 mg, 95 μmol, 10% yield, 61% purity) as a yellow solid. ESI-MS m / z [M+H]+; 448.10 LC / MS method 8 2-(3-Fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol [S0-EE-NBFI] To a stirred solution of 3-fluoro-2-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (70.00 mg, 1 eq, 156.4 μmol) in 1,2-dichloroethane (2 mL) was added boron tribromide (0.5 mL, 33.8 equiv, 5.29 mmol) at 0 °C. The reaction mixture was gradually heated to 60°C for 3 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get crude product as brown solid. The crude product was purified by RP-HPLC. The pure fractions containing product were lyophilized to afford the desired product 2-(3- fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl) imidazo[1,2-a] pyrimidin-2-yl)-5-(2H- 1,2,3-triazol-2-yl)phenol (compound 72, 16 mg, 35.53 μmol, 22% yield, 96.25% purity) as a yellow solid. ESI-MS m / z [M+H]+; 434.05 LC / MS method 8 HPLC: Rt 5.67 min; 96% purity 1H NMR (400 MHz, methanol-d4) δ 8.68 (d, J = 7.3 Hz, 1H), 8.53 (s, 1H), 7.94 (s, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 – 7.67 (m, 2H), 7.61 (d, J = 7.4 Hz, 1H), 6.90 (s, 1H), 2.86 (s, 2H), 1.59 (s, 6H), 1.49 (s, 6H).19F NMR (282 MHz, methanol-d4) δ –136.93 (m). ESI-MS m / z 434.1 [M+H]+, compound 72, formate salt;1H NMR (400 MHz, methanol- d4) δ 8.68 (d, J = 7.3 Hz, 1H), 8.53 (s, 1H), 7.94 (s, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 – 7.67 (m, 2H), 7.61 (d, J = 7.4 Hz, 1H), 6.90 (s, 1H), 2.86 (s, 2H), 1.59 (s, 6H), 1.49 (s, 6H).19F NMR (282 MHz, methanol-d4) δ –136.93 (m). 5-(1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 430.5 [M+H]+, compound 73;1H NMR (400 MHz, DMSO) δ 12.43 (s, 1H), 8.97 (d, J = 7.1 Hz, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 1.8 Hz, 1H), 3.90 (s, 3H), 2.42 (s, 2H), 1.26 (s, 6H), 1.16 (s, 6H). 2-(7-(2-amino-2-methylpropoxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 366.05 [M+H]+, compound 74, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.73 (d, J = 7.2 Hz, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.92 (s, 2H), 7.68 – 7.61 (m, 2H), 6.71 (d, J = 7.2 Hz, 1H), 4.52 (s, 2H), 1.51 (s, 6H). 3-chloro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)quinolin-7-ol (Compound 75) (E)-3-((4-bromo-3-methoxyphenyl)imino)-2-chloropropanal [Intermediate 2] To a stirred mixture of 4-bromo-3-methoxyaniline (5.0 g, 1 equiv., 24.75 mmol) in ethanol (50 mL) was added 2-chloromalonaldehyde (3.16 g, 1.2 equiv, 29.7 mmol) at 0oC. After addition the reaction mixture was stirred at RT for 16 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated under reduced pressure to get crude product which was triturated with diethyl ether to afford product (E)-3-((4-bromo-3- methoxyphenyl)imino)-2-chloropropanal (6.0 g, 20.79 mmol, 84% yield) as a yellow solid. ESI-MS m / z 291.10, [M+H]+; LC / MS method 8 6-bromo-3-chloro-7-methoxyquinoline [Intermediate 3] A mixture of (E)-3-((4-bromo-3-methoxyphenyl)imino)-2-chloropropanal (6.0 g, 1 equiv., 20.6 mmol) in PPA (50 g, 24.27 mL, 13.60 eq., 280.9 mmol) was stirred at 140 °C for 4 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO3solution and extracted twice with EtOAc. The combined organic layers were washed with water followed by brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to get the crude reaction product. The crude product was purified by flash column chromatography on silica gel (eluent: hexanes / ethyl acetate = 0:100 to 80:20; 40 g Redisep Silver column using a 5 g solid cartridge) to give 6-bromo-3-chloro-7-methoxyquinoline (1.2 g, 5.92 mmol, 21% yield, 97.2% purity) as a yellow solid. ESI-MS m / z 273.8, [M+H]+; Rt = 1.82 min (LC / MS method 8) 1-(3-chloro-7-methoxyquinolin-6-yl)ethan-1-one [Intermediate 4] To a mixture of 6-bromo-3-chloro-7-methoxyquinoline (1.2 g, 1 equiv., 4.4 mmol) in toluene (3.0 mL) was added tributyl(1-ethoxyvinyl)stannane (1.59 g, 1 equiv., 4.4 mmol). The reaction mixture was purged with argon for 10 min, then Pd (PPh3)4(1.02 g, 0.2 equiv., 880.6 μmol) was added and the reaction mixture was stirred at 90 °C for 16 h. After completion of reaction, the reaction mixture was diluted with ethyl acetate and filtered through a Celite bed. The Celite bed was washed twice with ethyl acetate. The combined filtrate was concentrated under reduced pressure to get crude 3-chloro-6-(1-ethoxyvinyl)-7-methoxyquinoline (1.7 g) as a brown solid, which was used directly for the next step. To a mixture of 3-chloro-6-(1-ethoxyvinyl)-7-methoxyquinoline (1.7 g, 1 equiv., 6.446 mmol) in tetrahydrofuran (15 mL) were added 2M HCl (3.2 mL, 2 molar, 1 eq., 6.446 mmol) at 0 °C and stirred at RT for 4 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to get crude product. The crude prodcut was purified by flash column chromatography on silica gel (eluent: hexane / ethyl acetate = 100:0 to 90:10; 40 g Redisep Silver column using a 5 g solid cartridge) to give 1-(3-chloro-7- methoxyquinolin-6-yl)ethan-1-one (600 mg, 2.448 mmol, 37.98% yield, 96.16% purity) as a yellow solid. ESI-MS m / z 235.9, [M+H]+; LC / MS method 8 2-bromo-1-(3-chloro-7-methoxyquinolin-6-yl)ethan-1-one [Intermediate 5] To a mixture of 1-(3-chloro-7-methoxyquinolin-6-yl)ethan-1-one (200 mg, 1 equiv, 848.64 μmol), in THF (5.0 mL) was added mono(N,N,N-trimethylbenzenaminium)tribromide, 98% (319 mg, 1 eq, 848.64 μmol) in portions at 0 °C and stirred for 5 min. After 16 h at RT, the reaction mixture was heated at 80 °C for 36 h. Afterwards, the reaction mixture was concentrated under reduced pressure to get the crude product which was purified by flash chromatography using a 24 g Silicycle silica gel cartridge eluting with 30-100% DCM in hexane. Pure fractions were collected and concentrated under reduced pressure to afford product 2-bromo-1-(3-chloro-7- methoxyquinolin-6-yl)ethan-1-one (200.0 mg, 582 μmol, 68.6% yield, 91.5% purity) as an off white solid. ESI-MS m / z 315.8, [M+H]+; LC / MS method 8 3-chloro-7-methoxy-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)quinoline [Intermediate 6] To a stirred mixture of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2- amine (110 mg, 1 eq., 473.5 μmol) in IPA (4.0 mL) was added 2-bromo-1-(3-chloro-7- methoxyquinolin-6-yl)ethan-1-one (193.6 mg, 1.3 eq., 615.5 μmol) at RT and subsequently the reaction mixture was heated at 80 °C for 48 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was cooled to rt and quenched with ice followed by sat. aq. NaHCO3solution (2 ml) and extracted with 10% methanol in DCM twice. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get crude product which was triturated with diethyl ether to get product 3- chloro-7-methoxy-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)quinoline (100 mg, 0.21 mmol, 43% yield, 92% purity) as a pale brown solid. ESI-MS m / z 448.10, [M+H]+; LC / MS method 8 3-chloro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- To the stirred solution of 3-chloro-7-methoxy-6-(7- (2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinoline (60.00 mg, 1 eq., 133.9 μmol) in DCM (3 mL) was added boron trichloride (608 mg, 0.6 mL, 1.0 molar, 4.48 eq., 600 μmol) dropwise at 0 °C. After addition the temperature was gradually increased to RT and the reaction mixture was stirred for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with ice, and basified with sat. aq. NaHCO3solution (1-2 drops) and extracted twice with ethyl acetate, followed by 10% methanol in DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield crude product as a pale brown solid. The crude product was purified by prep. HPLC (mobile phase: A= 0.1% HCOOH in water, CAN; column: LUNA (C18, 20mm x 250mm); flow: 15 ml / min; gradient program (time / %B) 0min / 40, 2min / 50, 8min / 65. Pure fractions were combined and lyophilized to afford product 3-chloro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinolin-7-ol formate (compound 75, formate salt, 18.00 mg, 36.70 μmol, 27.40% yield, 97.87% purity) as yellow solid. ESI-MS m / z 434.04 [M+H]+; LC / MS method 8 HPLC: 97.87%, 4.885 min 1H NMR (400 MHz, methanol-d4) δ = 8.84 (d, J = 7.2 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.57 - 8.53 (m, 3H), 8.40 (d, J = 2.0 Hz, 1H), 7.51 - 7.46 (m, 2H), 6.91 – 6.88 (m, 1H), 2.89 (s, 2H), 1.63 (s, 6H), 1.50 (s, 6H). 2-(5-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2- yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 417.10 [M+H]+, compound 76;1H NMR (400 MHz, methanol-d4) δ = 9.22 (d, J = 7.2 Hz, 1H), 8.34 (dd, J = 8.0, 1.0 Hz, 1H), 7.97 (s, 2H), 7.78 - 7.75 (m, 3H), 7.05 (s, 1H), 3.01 – 2.98 (m, 2H), 1.69 (s, 6H), 1.59 (s, 6H). 2-(7-(1-ethyl-2,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5- ESI-MS m / z 416.20 [M+H]+, compound 77;1H NMR (400 MHz, methanol-d4) δ = 8.75 (d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.92 (s, 2H), 7.70 – 7.63 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H), 6.95 – 6.91 (m, 1H), 3.51 – 3.44 (m, 2H), 2.81 – 2.63 (m, 4H), 1.32 – 1.26 (m, 3H), 1.22 , (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). (R)-2-(7-(3-aminopyrrolidin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 363.02 [M+H]+, compound 78, formate salt;1H NMR (400 MHz, DMSO-d6) δ = 12.68 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 8.24 (s, 1H), 8.11 (d, J = 5.6 Hz, 2H), 8.00 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.53 (td, J = 8.3, 2.2 Hz, 2H), 6.55 (d, J = 7.6 Hz, 1H), 3.73 – 3.66 (m, 4H), 3.58 (m, 1H), 2.20 – 2.10 (m, 1H), 1.92 – 1.78 (m, 1H). 2-(7-(3-(ethylamino)-3-methylbutyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 392.10 [M+H]+, compound 79, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.82 (d, J = 6.8 Hz, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.92 (s, 2H), 7.67 (s, 1H), 7.66 – 7.63 (m, 1H), 7.06 (d, J = 6.8 Hz, 1H), 3.15 (q, J = 7.3 Hz, 2H), 3.08 – 3.00 (m, 2H), 2.26 - 2.18 (m, 2H), 1.46 (s, 6H), 1.38 (t, J = 7.3 Hz, 3H). 2-(7-(3-methyl-3-(methylamino)butyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 378.15 [M+H]+,compound 80, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.81 (d, J = 6.8 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.93 (s, 2H), 7.67 - 7.65 (m, 2H), 7.06 (d, J = 6.8 Hz, 1H), 3.04 - 3.00 (m, 2H), 2.72 (s, 3H), 2.22 - 2.18 (m, 2H), 1.45 (s, 6H). 2-(7-(4-methyl-4-azaspiro[2.5]oct-6-en-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)pyridin-3-ol ESI-MS m / z 401.20 [M+H]+,compound 81, formate salt;1H NMR (400 MHz, DMSO-d6) δ = 12.90 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.31 (s, 1H), 8.23 (s, 2H), 7.87 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.10 (dt, J = 5.4, 2.4 Hz, 1H), 3.48 - 3.46 (m, 2H), 2.54 – 2.50 (m, 2H), 2.30 (s, 3H), 0.60 – 0.58 (m, 2H), 0.50 – 0.46 (m, 2H). 2-(7-(4-ethyl-4-azaspiro[2.5]oct-6-en-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol- 2-yl)pyridin-3-ol ESI-MS m / z 415.15 [M+H]+,compound 82, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.88 (d, J = 2.2 Hz, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.02 (s, 2H), 7.96 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.01 - 6.99 (m, 1H), 3.65 (d, J = 2.8 Hz, 2H), 2.81 (q, J = 7.3 Hz, 2H), 2.61 (s, 2H), 1.16 (t, J = 7.2 Hz, 3H), 0.79 - 0.76 (m, 2H), 0.63 - 0.60 (m, 2H). 4-(3-fluoro-4-(6-fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)-5-hydroxyphenyl)-1-methylpyridin-2(1H)-one ESI-MS m / z 492.50 [M+H]+,compound 83, formate salt;1H NMR (400 MHz, methanol-d4) δ = 9.07 (d, J = 6.4 Hz, 1H), 8.53 (s, 1H), 8.31 (d, J = 4.4 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.15 – 7.13 (m, 1H), 7.09 (dd, J = 12.3, 1.8 Hz, 1H), 6.83 – 6.81 (m, 2H), 6.73 (dd, J = 7.1, 2.0 Hz, 1H), 3.61 (s, 3H), 2.86 (s, 2H), 1.59 (s, 6H), 1.50 (s, 6H).19F NMR (376 MHz, methanol-d4) δ -112.24, -147.95. 2-(7-(4-azaspiro[2.5]oct-6-en-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 386.05 [M+H]+, compound 84;1H NMR (400 MHz, methanol-d4) δ = 8.74 (d, J = 7.2 Hz, 1H), 8.30 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.90 (s, 2H), 7.68 – 7.62 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.05 – 7.01 (m, 1H), 3.66 – 3.60 (m, 2H), 2.72 – 2.66 (m, 2H), 0.78 – 0.73 (m, 2H), 0.65 – 0.60 (m, 2H). 2-(7-(4-azaspiro[2.5]octan-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 388.10 [M+H]+,compound 85, enantiomer 1;1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 6.9 Hz, 1H), 8.29 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.92 (s, 2H), 7.69 – 7.63 (m, 2H), 7.07 (d, J = 6.9 Hz, 1H), 3.23 – 3.15 (m, 2H), 3.01 – 2.91 (m, 1H), 2.37 – 2.26 (m, 1H), 2.13 – 2.05 (m, 1H), 1.95 – 1.83 (m, 1H), 1.48 – 1.38 (m, 1H), 0.78 – 0.69 (m, 2H), 0.66 – 0.57 (m, 2H). Second eluting peak using the following column and conditions for enantiomer separation by chiral SFC: Rt = 11.09 min. Column: LUX-AMYLOSE-2, 4.6 mm x 150 mm x 5 μM Flow Rate: 3 mL / min Outlet pressure: 100 bar Temperature: 40 °C Cosolvent: 40% 1:1:1 IPA:EtOH:MeOH with 10 mM ammonia in CO2Acronyms: MeOH = Methanol, IPA = isopropanol, EtOH = ethanol 2-(7-(4-azaspiro[2.5]octan-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 388.10 [M+H]+, compound 85, enantiomer 2;1H NMR (400 MHz, methanol-d4) δ 8.78 (d, J = 7.0 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.92 (s, 2H), 7.69 – 7.62 (m, 2H), 7.06 (d, J = 6.9 Hz, 1H), 3.22 – 3.10 (m, 2H), 2.97 – 2.87 (m, 1H), 2.33 – 2.24 (m, 1H), 2.11 – 2.02 (m, 1H), 1.93 – 1.81 (m, 1H), 1.44 – 1.36 (m, 1H), 0.75 – 0.63 (m, 2H), 0.62 – 0.51 (m, 2H). First eluting peak using the following column and conditions for enantiomer separation by chiral SFC: Rt = 8.42 min. Column: LUX-AMYLOSE-2, 4.6 mm x 150 mm x 5 μM Flow Rate: 3 mL / min Outlet pressure: 100 bar Temperature: 40 °C Cosolvent: 40% 1:1:1 IPA:EtOH:MeOH with 10 mM ammonia in CO2Acronyms: MeOH = Methanol, IPA = isopropanol, EtOH = ethanol 5-(1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- l ESI-MS m / z 429.20 [M+H]+, compound 86;1H NMR (400 MHz, methanol-d4) δ = 9.14 (d, J = 7.2 Hz, 1H), 8.62 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H) 7.86 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.2, 1.6 Hz, 1H), 7.23 – 7.20 (m, 2H), 3.95 (s, 3H), 3.00 – 2.96 (m, 2H), 1.71 (s, 6H), 1.60 (s, 6H). 2-(7-(4-azaspiro[2.5]oct-6-en-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- ESI-MS m / z 387.10 [M+H]+, compound 87, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.92 – 8.85 (m, 2H), 8.43 (s, 1H), 8.38 (s, 1H), 8.01 (s, 2H), 7.98 – 7.94 (m, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.08 – 7.01 (m, 1H), 3.90 – 3.82 (m, 2H), 2.90 – 2.82 (m, 2H), 0.99 – 0.94 (m, 2H), 0.86 – 0.82 (m, 2H). 5-hydroxy-1'-methyl-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- ESI-MS m / z 457.20 [M+H]+, compound 88, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.90 (d, J = 7.3 Hz, 1H), 8.54 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 6.90 (s, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 7.1, 2.1 Hz, 1H), 3.62 (s, 3H), 2.81 (s, 2H), 1.55 (s, 6H), 1.43 (s, 6H). 2-(7-(9-azabicyclo[3.3.1]non-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)pyridin-3-ol Single enantiomer. ESI-MS m / z 401.05 [M+H]+, compound 89, enantiomer 1, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.93 (d, J = 7.3 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 8.01 (s, 2H), 7.99 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 5.7 Hz, 1H), 4.29 – 4.17 (m, 1H), 4.00 – 3.89 (m, 1H), 3.26 – 3.19 (m, 2H), 2.07 – 1.84 (m, 4H), 1.81 – 1.59 (m, 2H). In order to obtain compound 89 as a single enantiomer, chiral separation of the intermediate shown below was performed. The enantiomerically pure intermediate was then converted into compound 89, enantiomer 1, through demethylation followed by Boc- deprotection. Column Name : REGIS(S,S) WHELK-01, 4.6 mm x150 mm x 5 μm Mobile phase: CO2and co-solvent Co-solvent: 50% Co-solvent name: 10 mM ammonia in CAN:MeOH:isopropanol (2:1:1) Flow rate: 3 mL / min. Outlet pressure: 100 bar Temperature: 40 °C Rt = 13.38 min. (second-eluting enantiomer) 2-(7-(9-azabicyclo[3.3.1]non-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- Single enantiomer. ESI-MS m / z 401.05 [M+H]+, compound 89, enantiomer 2, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.94 (d, J = 7.2 Hz, 1H), 8.91 (d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.01 (s, 2H), 7.99 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.03 – 6.97 (m, 1H), 4.38 – 4.29 (m, 1H), 4.06 – 3.98 (m, 1H), 3.30 - 3.26 (m, 1H), 3.05 – 2.94 (m, 1H), 2.14 – 1.89 (m, 4H), 1.83 – 1.63 (m, 2H). In order to obtain compound 89 as a single enantiomer, chiral separation of the intermediate shown below was performed. The enantiomerically pure intermediate was then converted into compound 89, enantiomer 2, through demethylation followed by Boc- deprotection. Column Name : REGIS(S,S) WHELK-01, 4.6 mm x150 mm x 5 μm Mobile phase: CO2and co-solvent Co-solvent: 50% Co-solvent name: 10 mM ammonia in CAN:MeOH:isopropanol (2:1:1) Flow rate: 3 mL / min. Outlet pressure: 100 bar Temperature: 40 °C Rt = 9.44 min. (first-eluting enantiomer) 2-(7-(4-azaspiro[2.5]octan-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- ESI-MS m / z 432.05 [M+H]+, compound 91;1H NMR (400 MHz, methanol-d4) δ = 10.42 (d, J = 7.2 Hz, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 8.15 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.93 – 6.88 (m, 1H), 4.15 (s, 3H), 2.84 (s, 2H), 1.56 (s, 6H), 1.46 (s, 6H). 5-(oxazol-2-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)pyridin-3-ol 8.20 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.47 (s, 1H), 6.99 (d, J = 1.7 Hz, 1H), 2.46 (s, 2H), 1.29 (s, 6H), 1.18 (s, 6H). 5-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z: 448.3 [M+H]+; compound 93, formate salt:1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 12.51 (s, 1H), 8.97 (d, J = 7.3 Hz, 1H), 8.40 (d, J = 2.0 Hz, 2H), 8.27 (s, 1H), 8.03 (d, J = 3.1 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.50 (s, 1H), 6.97 (s, 1H), 3.78 (s, 3H), 2.42 (s, 2H), 1.26 (s, 6H), 1.15 (s, 6H).19F NMR (376 MHz, dimethyl sulfoxide-d6) δ -134.66. 5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z: 448.2 [M+H]+; compound 94, formate salt:1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 12.78 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.00 (s, 1H), 2.69 (s, 3H), 2.44 (s, 2H), 1.27 (s, 6H), 1.16 (s, 6H). 6-(3-fluoro-5-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- idin-4(3H)-one ESI-MS m / z 475.3, [M+H]+, compound 95;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.35 (d, J = 4.5 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.57 – 7.51 (m, 2H), 7.07 (d, J = 0.9 Hz, 1H), 6.99 (d, J = 1.5 Hz, 1H), 3.44 (s, 3H), 2.41 (s, 2H), 1.26 (s, 6H), 1.15 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ –111.0. 6-(3-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)phenyl)-3-methylpyrimidin-4(3H)-one ESI-MS m / z 457.5, [M+H]+, compound 96;1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.2, 1.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 6.96 – 6.89 (m, 2H), 3.44 (s, 3H), 2.41 (s, 2H), 1.25 (s, 6H), 1.15 (s, 6H). 5-(4-methoxy-1,3,5-triazin-2-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 458.4, [M+H]+, compound 97;1H NMR (400 MHz, methylene chloride-d2) δ 12.49 (s, 1H), 8.92 (s, 1H), 8.42 (d, = 7.2 Hz, 1H), 8.14 (d, J = 1.7 Hz, 1H), 8.05 (dd, J = 8.2, 1.7 Hz, 1H), 7.93 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 6.77 (d, = 1.7 Hz, 1H), 4.14 (s, 3H), 2.52 (d, J = 1.6 Hz, 2H), 1.31 (s, 6H), 1.22 (s, 6H). 5-(6-ethoxypyrimidin-4-yl)-3-fluoro-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 489.3, [M+H]+, compound 98;1H NMR (400 MHz, dichloromethane-d2) δ 13.31 (s, 1H), 8.79 (d, J = 1.1 Hz, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 4.2 Hz, 1H), 7.46 (d, J = 11.5 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 1.1 Hz, 1H), 6.77 (t, J = 1.6 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.52 (d, J = 1.6 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H), 1.26 (s, 6H), 1.23 (s, 6H).19F NMR (377 MHz, methylene chloride-d2) δ –111.4. 5-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 444.3 [M+H]+, compound 99;1H NMR (400 MHz, methylene chloride-d2) δ 12.20 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.84 – 6.75 (m, 1H), 3.90 (s, 3H), 2.59 – 2.53 (m, 2H), 2.45 (s, 3H), 1.35 (s, 6H), 1.26 (s, 6H). 5-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 431.4 [M+H]+, compound 100, formate salt;1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.3 Hz, 1H), 8.78 (d, J = 1.9 Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 6.99 (s, 1H), 3.97 (s, 3H), 2.57 (s, 2H), 1.38 (s, 6H), 1.27 (s, 6H) 3'-fluoro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- ESI-MS m / z 445.5 [M+H]+, compound 101;1H NMR (400 MHz, methanol-d4) δ 8.91 (d, J = 7.3 Hz, 1H), 8.62 (d, J = 2.8 Hz, 1H), 8.53 (d, J = 5.0 Hz, 1H), 8.48 – 8.46 (m, 1H), 8.45 (s, 1H), 7.75 (dd, J = 6.8, 5.1 Hz, 1H), 7.72 – 7.69 (m, 1H), 7.56 (d, J = 7.3 Hz, 1H), 6.95 – 6.89 (m, 1H), 2.77 (s, 2H), 1.52 (d, J = 2.3 Hz, 6H), 1.43 (s, 6H). 5-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 481.6 [M+H]+, compound 102,1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.43 – 9.32 (m, 1H), 9.01 (d, J = 7.3 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.10 (dd, J = 9.4, 1.9 Hz, 1H), 7.89 – 7.79 (m, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.07 – 6.94 (m, 1H), 2.52 (s, 3H), 2.46 (s, 2H), 1.29 (s, 6H), 1.19 (s, 6H). 5-fluoro-6'-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- ESI-MS m / z 445.0 [M+H]+, compound 103;1H NMR (400 MHz, DMSO-d6) δ 10.24 (d, J = 7.5 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.72 (d, J = 2.9 Hz, 1H), 8.63 (s, 1H), 8.16 (dd, J = 8.9, 4.3 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.89 (td, J = 8.7, 3.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.97 – 6.91 (m, 1H), 1.31 (s, 6H), 1.20 (s, 6H). CH2resonance eclipsed by solvent peak. 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1- (trifluoromethyl)-1H-pyrazol-4-yl)pyridin-3-ol ESI-MS m / z 484.4 [M+H]+, compound 104, formate salt;1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.15 (s, 1H), 8.98 (d, J = 7.3 Hz, 1H), 8.61 (d, J = 2.4 Hz, 2H), 8.44 (s, 1H), 8.20 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 6.99 – 6.95 (m, 1H), 2.45 (s, 2H), 1.28 (s, 6H), 1.17 (s, 6H). 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 444.4 [M+H]+, compound 105;1H NMR (400 MHz, methylene chloride-d2) δ 12.10 (s, 1H), 8.35 (d, J = 7.0 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 7.1 Hz, 1H), 6.75 – 6.64 (m, 1H), 3.75 (s, 3H), 2.44 (s, 2H), 2.35 (s, 3H), 1.24 (s, 6H), 1.15 (s, 6H). 5'-fluoro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- ESI-MS m / z 445.5 [M+H]+, compound 106;1H NMR (400 MHz, methylene chloride-d2) δ 12.43 (s, 1H), 8.77 (t, J = 1.7 Hz, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.45 (d, J = 2.1 Hz, 1H), 8.24 (s, 1H), 7.75 – 7.70 (m, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 6.84 – 6.77 (m, 1H), 2.58 (s, 2H), 1.37 (s, 6H), 1.27 (s, 6H). 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H- 1,2,4-triazol-1-yl)pyridin-3-ol ESI-MS m / z 417.5 [M+H]+, compound 107;1H NMR (400 MHz, methanol-d4) δ 9.24 (s, 1H), 8.85 (d, J = 7.3 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.93 – 6.88 (m, 1H), 2.64 – 2.58 (m, 2H), 1.40 (s, 6H), 1.31 (s, 6H). 5-(4-methyl-1H-pyrazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 430.0 [M+H]+, compound 108;1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.98 (d, J = 7.3 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.44 – 8.40 (m, 2H), 7.76 (d, J = 2.3 Hz, 1H), 7.66 (s, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.01 – 6.95 (m, 1H), 2.42 (s, 2H), 2.13 (s, 3H), 1.26 (s, 6H), 1.15 (s, 6H). 5-(4-methyl-1H-1,2,3-triazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- n-3-ol ESI-MS m / z 431.5 [M+H]+, compound 109;1H NMR (400 MHz, methylene chloride-d2) δ 12.41 (s, 1H), 8.76 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 7.1 Hz, 1H), 8.08 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 6.72 – 6.65 (m, 1H), 2.44 (s, 2H), 2.34 (s, 3H), 1.23 (s, 6H), 1.14 (s, 6H). 5-(3-methyl-1H-1,2,4-triazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 431.4 [M+H]+, compound 110;1H NMR (400 MHz, methylene chloride-d2) δ 12.49 (s, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.68 – 6.62 (m, 1H), 2.54 (br s, 2H), 2.39 (s, 3H), 1.35 (br s, 6H), 1.26 (br s, 6H). 5-(4-methyl-2H-1,2,3-triazol-2-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 431.5 [M+H]+,1H NMR (400 MHz, methylene chloride-d2) δ 12.54 (br s, 1H), 8.88 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 7.3 Hz, 1H), 8.19 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J = 7.0 Hz, 1H), 6.83 – 6.77 (m, 1H), 2.56 (mj, 2H), 2.46 (s, 3H), 1.35 (s, 6H), 1.26 (s, 6H). 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- n-3-ol ESI-MS m / z 431.4 [M+H]+, compound 112;1H NMR (400 MHz, methanol-d4) δ 8.64 (d, J = 7.3 Hz, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 6.75 – 6.70 (m, 1H), 4.13 (s, 3H), 2.50 – 2.46 (m, 2H), 1.26 (s, 6H), 1.17 (s, 6H). 5-(2-methyloxazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 431.3 [M+H]+, compound 113;1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 7.3 Hz, 1H), 8.48 (s, 1H), 8.37 (s, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 6.90 (s, 1H), 2.62 (s, 2H), 2.59 (s, 3H), 1.41 (s, 6H), 1.31 (s, 6H). 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5- (thiazol-2-yl)pyridin-3-ol ESI-MS m / z 433.3 [M+H]+, compound 114;1H NMR (400 MHz, methylene chloride-d2) δ 8.68 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.11 (s, 1H), 7.84 (d, J = 3.2 Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 6.70 – 6.66 (m, 1H), 2.45 – 2.42 (m, 2H), 1.23 (s, 6H), 1.14 (s, 6H). 5-(2-methylthiazol-5-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z: 447.4 [M+H]+, compound 115, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.95 (d, J = 7.2 Hz, 1H), 8.50 (br s, 1H), 8.44 – 8.30 (m, 2H), 8.07 (s, 1H), 7.66 – 7.48 (m, 2H), 6.94 – 6.90 (m, 1H), 3.00 – 2.96 (m, 2H), 2.78 (s, 3H), 1.67 (s, 6H), 1.58 (s, 6H). 2-(3-methoxy-5-(1H-1,2,4-triazol-1-yl)pyridin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine ESI-MS m / z 431.4 [M+H]+, compound 116;1H NMR (400 MHz, methylene chloride-d2) δ 8.35 (d, J = 7.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 6.68 – 6.64 (m, 1H), 3.34 (s, 3H), 2.45 (s, 2H), 1.26 (s, 6H), 1.16 (s, 6H).

[0007] 6-hydroxy-2-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)isoquinolin-1(2H)-one 7-bromo-6-methoxyisoquinoline 2-oxide2-bromo-1-(5-bromo-3-methoxypyridin-2- yl)ethan-1-one (intermediate 2) To a mixture of 7-bromo-6-methoxyisoquinoline (4.0 g, 1.0 equiv, 16.8 mmol) in DCM (80 mL) at 0 °C was added m-CPBA (5.8 g, 2.0 equiv, 33.6 mmol) in portions. After stirring for 15 min, the reaction mixture was stirred at 25 °C for 16 h. Then, the reaction mixture was diluted with ice- cooled water and diluted with MeOH:DCM [10:90]. The layers were separated. The aqueous layer was extracted three times with MeOH:DCM [10:90], and the combined organic extracts were washed with 10% NaOH solution (40 mL), followed by washing with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure and further dried under high vacuum to provide the desired product, 7-bromo-6-methoxyisoquinoline 2-oxide (3.2 g, 10.9 mmol, 64%, 86% purity) as an off-white solid. ESI-MS m / z 255.85, [M+H]+; LC / MS method 8. 7-bromo-6-methoxyisoquinolin-1(2H)-one (Intermediate 3) To a mixture of 7-bromo-6-methoxyisoquinoline 2-oxide (3.2 g, 1.0 equiv, 12.6 mmol) in water (20 mL) and 1,2-dichloroethane (40 mL) at 25 °C was added sodium acetate (3.1 g, 3.0 equiv, 37.8 mmol) and bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (11.74 g, 2.0 equiv, 25.2 mmol). After stirring for 10 min, the reaction mixture was heated to 85 °C for 16 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with water and MeOH:DCM [10:90]. The layers were separated. The aqueous layer was extracted twice with MeOH:DCM [10:90], and the combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered, and concentrated to obtain a crude residue. The residue was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 70:30 to 60:40; a 12 g Redisep Silver column using a 5 g solid cartridge) to give the product, 7-bromo-6-methoxyisoquinolin-1(2H)-one (2 g, 7.73 mmol, 61% yield, 98.7% purity) as a brown solid. ESI-MS m / z 253.8, [M+H]+; LC / MS method 11. 7-bromo-6-methoxy-2-methylisoquinolin-1(2H)-one (Intermediate 4) To a mixture of 7-bromo-6-methoxyisoquinolin-1(2H)-one (2.0 g, 1.0 equiv, 7.9 mmol) in DMF (10 mL) at 25 °C were added Cs2CO3(6.42 g, 2.5 equiv, 19.7 mmol) and MeI (0.98 mL, 2.0 equiv, 15.7 mmol). After stirring for 5 min, the reaction mixture was heated to 50 °C for 1 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was diluted with ice cooled water and EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to obtain a crude residue, which was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100:0 to 80:20; a 12 g Redisep Silver column using a 5 g solid cartridge) to give the product, 7-bromo-6-methoxy-2- methylisoquinolin-1(2H)-one (1.1 g, 3.5 mmol, 44% yield, 86% purity) as a white solid. ESI-MS m / z 267.90, [M+H]+; LC / MS method 8. 7 ate 5) A mixture of 7-bromo-6-methoxy-2-methylisoquinolin-1(2H)-one (1.1 g, 1.0 equiv, 4.1 mmol), and tributyl(1-ethoxyvinyl) stannane (3.7 g, 2.5 equiv, 10.3 mmol) in DMF (10 mL) at 25 °C was degassed with argon. Bis(triphenylphosphine)palladium(II) dichloride (317 mg, 0.11 equiv, 451 μmol). After stirring for 10 min, the reaction mixture was heated to 110 °C for 16 h. The reaction mixture was then cooled to 0 °C and 1M HCl (0.6 mL) was added. After stirring for 10 min, the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water and EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to obtain a crude residue which was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 80:20 to 0:100; a 12 g Redisep Silver column using a 5 g solid cartridge) to give the product 7-acetyl-6-methoxy-2-methylisoquinolin-1(2H)-one (600 mg, 2.5 mmol, 62% yield, 98% purity) as a white solid. ESI-MS m / z 232.00, [M+H]+; LC / MS method 9. 7-(2-bromoacetyl)-6-methoxy-2-methylisoquinolin-1(2H)-one (Intermediate 6) To a mixture of 7-acetyl-6-methoxy-2-methylisoquinolin-1(2H)-one (300 mg, 1.0 equiv, 1.29 mmol), in THF (6.0 mL) at 0 °C was added dropwise phenyltrimethylammonium tribromide (487 mg, 1.0 equiv, 1.29 mmol) in THF (5.0 mL). After stirring for 15 min, the reaction mixture was stirred at RT for 3 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, the reaction was quenched with water and EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic extracts were washedwith brine, dried over Na2SO4, filtered and concentrated to give a crude residue which was purified by flash column chromatography on silica gel (eluent: heptane / EtOAc = 100:0 to 60:40; a 12 g Redisep Silver column using a 5 g solid cartridge) to give 7-(2-bromoacetyl)-6-methoxy-2- methylisoquinolin-1(2H)-one (220 mg, 0.57 mmol, 44% yield, 81% purity) as an off-white solid. ESI-MS m / z 312.00, [M+H]+; LC / MS method 8. 6-methoxy-2-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)isoquinolin-1(2H)-one (Intermediate 7) 7-(2-bromoacetyl)-6-methoxy-2-methylisoquinolin-1(2H)-one (200 mg, 1.0 equiv) and 4-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (104 mg, 0.70 equiv, 451 μmol) were combined in isopropanol (2.0 mL) at 25 °C. After stirring for 5 min, the reaction mixture was heated to 80 °C for 32 h. The progress of the reaction was monitored by TLC. Upon completion of the reaction, Ether (10 mL) was added to the reaction mixture, and it was stirred for 10 min. The solid that separated was filtered through a Buchner funnel and washed with ether (5 mL) and dried to obtain the crude product, which was purified by flash column chromatography on silica gel (eluent: DCM / MeOH = 100:0 to 80:20; a 12 g Redisep Silver column using a 5 g solid cartridge) to give 6-methoxy-2-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)isoquinolin-1(2H)-one (100 mg, 166 μmol, 25% yield, 74% purity) as a light brown solid. ESI-MS m / z 444.5, [M+H]+; LC / MS method 10 6-hydroxy-2-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- To a mixture of 6-methoxy-2-methyl-7-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin- 4-yl)imidazo[1,2-a]pyrimidin-2-yl)isoquinolin-1(2H)-one (100 mg, 1.0 equiv, 225 μmol) in DCM (3.0 mL) at -78 °C were added BBr3in DCM (4.0 mL, 1.0 molar, 0.01774 equiv, 4.000 μmol). Upon complete addition, the reaction mixture was left to warm up to RT over the course of 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-cold water. The aqueous layer was extracted once with EtOAc. Then, the pH of the aqueous layer was adjusted to 7 by adding saturated aqueous NaHCO3solution at 0 °C and extracted twice with MeOH:DCM [10:90], and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give a crude residue, which was suspended in acetonitrile (10 mL) and sonicated for 5 min. After letting the solid settle, the solvent was decanted and the solid was dried under vacuum to give the product, 6-hydroxy-2-methyl-7-(7-(2,2,6,6-tetramethyl- 1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)isoquinolin-1(2H)-one (compound 117, 38 mg, 37% yield, 95% purity) as a yellow solid. ESI-MS m / z 430.15, [M+H]+; LC / MS method 10 HPLC: Rt 5.17 mins; 95.02% 1H NMR (400 MHz, methanol-d4) δ = 8.85 (s, 1H), 8.79 (d, J = 7.2 Hz, 1H), 8.37 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.06 (s, 1H), 6.88 – 6.84 (m, 1H), 6.57 (d, J = 7.2 Hz, 1H), 3.60 (s, 3H), 2.62 (bs, 2H), 1.41 (s, 6H), 1.31 (s, 6H). 3,4-difluoro-5-(1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 465.25 [M+H]+, compound 118, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.87 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.24 (d, J = 4.0 Hz, 1H), 8.12 – 8.08 (m, 1H), 7.92 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.03 (dd, J = 6.0, 2.1 Hz, 1H), 6.90 – 6.88 (m, 1H), 3.96 (s, 3H), 2.84 (bs, 2H), 1.59 (s, 6H), 1.48 (s, 6H).19F NMR (376 MHz, methanol-d4) δ -139.14, -155.25. 2-(7-(((1S,2R)-2-aminocyclopentyl)oxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 378.05 [M+H]+, compound 119, formate salt;1H NMR (400 MHz, DMSO-d6) δ = 11.80 (s, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 8.15 - 8.11 (m, 3H), 7.63 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.5, 2.1 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 5.38 – 5.31 (m, 1H), 3.56 – 3.50 (m, 1H), 2.16 – 2.08 (m, 1H), 2.00 – 1.93 (m, 1H), 1.88 – 1.77 (m, 2H), 1.66 – 1.58 (m, 2H). 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H- 1,2,3-triazol-1-yl)pyridin-3-ol ESI-MS m / z 417.1 [M+H]+, compound 120;1H NMR (600 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.87 (d, J = 7.2 Hz, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.33 (d, J = 7.1 Hz, 1H), 6.96 (s, 1H), 6.81 (s, 1H), 2.44 – 2.38 (m, 2H), 1.24 (s, 6H), 1.14 (s, 6H). 2-(7-(((1S,2S)-2-aminocyclopentyl)oxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 378.15 [M+H]+, compound 121, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.68 (d, J = 7.2 Hz, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.92 (s, 2H), 7.69 – 7.62 (m, 2H), 6.62 (d, J = 7.2 Hz, 1H), 5.35 – 5.24 (m, 1H), 3.71 – 3.63 (m, 1H), 2.39 – 2.23 (m, 2H), 2.07 – 1.87 (m, 3H), 1.76 – 1.66 (m, 1H). 1-methyl-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-1H-indol-5-ol Tert-butyl 6-bromo-5-methoxy-1H-indole-1-carboxylate (Intermediate 2) To a mixture of 6-bromo-5-methoxy-1H-indole (3.0 g, 1 equiv., 13.27 mmol) in DCM (30 mL) at 0 °C were added DMAP (324 mg, 0.2 equiv., 2.65 mmol) followed by (Boc)2O (4.34 g, 4.57 mL, 1.5 equiv., 19.9 mmol). Then reaction mixture was stirred at 27 °C for 2 h. The progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude product, which was purified by flash column chromatography on silica gel (eluent: hexane / EtOAc 90 : 10 to 80 : 20; 40 g Redisep Silver column via liquid injection) to give tert-butyl 6-bromo-5-methoxy- 1H-indole-1-carboxylate as a white solid (3.7 g, 11 mmol, 84% yield, 98% purity). ESI-MS m / z 327, [M+2H]+; LC / MS method 8. Tert-butyl 6-acetyl-5-methoxy-1H-indole-1-carboxylate (Intermediate 3) A mixture of tert-butyl 6-bromo-5-methoxy-1H-indole-1-carboxylate (3.4 g, 1 equiv., 10.4 mmol) and (1-ethoxyvinyl)tributylstannane (7.52 g, 7.050 mL, 2 equiv., 20.9 mmol) in toluene (60 mL) was purged with argon for 5 min at rt. Then, Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 0.2 equiv., 2.08 mmol) was added under argon purging. After 5 mins, the reaction mixture was heated to 100 °C for 16 h. The progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and the combined filtrate was concentrated to get the crude product, which was purified by flash column chromatography on silica gel (eluent: hexane / EtOAc 80 : 20 to 70 : 30; 40 g Redisep Silver column via liquid injection) to give tert-butyl 6-acetyl-5-methoxy-1H-indole-1-carboxylate as a brown solid (2.6 g, 8.8 mmol, 84% yield, 98% purity). ESI-MS m / z 290, [M+H]+; LC / MS method 8. Tert-butyl 6-(2-bromoacetyl)-5-methoxy-1H-indole-1-carboxylate (Intermediate 4) To a mixture of tert-butyl 6-acetyl-5-methoxy-1H-indole-1-carboxylate (1.2 g, 1 equiv., 4.14 mmol) in THF (24 mL) at 0 °C was added dropwise phenyltrimethylammoniumtribromide (1.24 g, 0.8 equiv., 3.31 mmol) in THF (3.0 mL). After addition the reaction mixture was stirred at 27 °C for 2 h. The progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was passed through celite, the celite was washed with EtOAc. The combined filtrate was concentrated under reduced pressure to get the crude product which was purified by flash column chromatography on silica gel (eluent: DCM / Hexane 70 : 30 to 50 : 50; 24 g Redisep Silver column via liquid injection) to give tert-butyl 6-(2-bromoacetyl)-5-methoxy- 1H-indole-1-carboxylate as a white solid (0.6 g, 1.6 mmol, 38% yield, 96% purity). ESI-MS m / z 369.85, [M+2H]+; LC / MS method 8. tert-butyl 5-methoxy-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)-1H-indole-1-carboxylate (Intermediate 5) To a mixture of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (300 mg, 1 equiv., 1.29 mmol) in IPA (5.0 mL) at RT was added tert-butyl 6-(2-bromoacetyl)-5- methoxy-1H-indole-1-carboxylate (570 mg, 1.2 equiv., 1.50 mmol) and reaction mixture stirred at 80 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion of the reaction the reaction mixture was concentrated under reduced pressure to get the crude product which was purified by flash column chromatography on silica gel (eluent: MeOH / DCM 2 to 4%; 12 g Redisep Silver column using a 25 g solid cartridge) to give tert-butyl 5-methoxy-6-(7-(2,2,6,6- tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)-1H-indole-1-carboxylate as a yellow solid (0.5 g, 0.89 mmol, 69% yield, 89% purity). ESI-MS m / z 502.15, [M+H]+; LC / MS method 8. 2-(5-methoxy-1H-indol-6-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidine (Intermediate 6)

[0008] Tert-butyl 5-methoxy-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)-1H-indole-1-carboxylate (0.38 g, 1.0 equiv., 758 μmol) was dissolved in 2,2,2-trifluoroethanol (10 mL). The reaction mixture was stirred at 135 °C for 20 min under microwave irradiation. The progress of the reaction was monitored by TLC & LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the crude product 2-(5-methoxy-1H-indol-6-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidine (0.31 g, 0.67 mmol, 89% yield, 87% purity) which was used in next step without further purification. ESI-MS m / z 402.10, [M+H]+; LC / MS method 8. 2-(5-methoxy-1-methyl-1H-indol-6-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (Intermediate 7) To a mixture of 2-(5-methoxy-1H-indol-6- yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (100 mg, 1 equiv., 249 μmol) in DMF (4.0 mL) were added Cs2CO3(243 mg, 3 equiv., 747 μmol) and methyl iodide (70 mg, 31.2 μL, 2 equiv., 498 μmol) . The reaction was stirred at 27 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude product 2- (5-methoxy-1-methyl-1H-indol-6-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidine (90 mg, 0.17 mmol, 69% yield, 80% purity) which was used in next step without further purification. ESI-MS m / z 416.10, [M+H]+; LC / MS method 8 1-methyl-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)-1H-indol-5-ol To a mixture of 2-(5-methoxy-1-methyl-1H-indol-6-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (60 mg, 1 equiv., 144 μmol) in DCE (3.0 mL) at 0 °C was added boron trichloride (1.4 mL, 1.0 molar, 10 equiv., 1.44 mmol). The reaction mixture was stirred at 27 °C for 16 h. The progress of the reaction was monitored by LCMS. After completion of the reaction, it was quenched with ice water and extracted with EtOAc. Then, the aqueous layer was basified with NaHCO3and the products were extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by RP-HPLC (mobile Phase: A = 0.1% HCOOH in water, B = acetonitrile, column: X SELECT (250 mm × 20.0 mm), 5.0 μm, flow: 15mL / min, gradient: time-%B: 0-5.2-10, 8-40). The pure fractions containing the desired product were lyophilized to give 1-methyl-6-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-1H-indol-5-ol (21 mg) as a brown-yellow solid. The above purified compound was purified additionally by SFC: CHIRAL PAK IG, 250 mm × 30 mm, 5 μm, mobile phase : CO2(A) and 10 mM ammonia in IPA / MeOH (B), flow :80 mL / min Isocratic: 50 (A) : 50 (B) to give 1-methyl-6-(7- (2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-1H-indol-5-ol as a yellow solid (compound 122, 6.5 mg, 16.0 μmol, 11% yield, 98.6% purity). ESI-MS m / z 402.10, [M+H]+; LC / MS method 8. HPLC: 98.6%, Rt: 5.34 min. 1H NMR (400 MHz, methanol-d4) δ 8.72 (d, J = 7.1 Hz, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.39 (d, = 7.1 Hz, 1H), 7.15 (d, 3.0 Hz, 1H), 7.03 (s, 1H), 6.88 – 6.78 (m, 1H), 6.32 – 6.24 (m, 1H), 3.83 (s, 3H), 2.62 (br s, 2H), 1.39 (s, 6H), 1.30 (s, 6H). 1-phenethyl-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- a]pyrimidin-2-yl)-1H-indol-5-ol ESI-MS m / z 492.20 [M+H]+, compound 123, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 7.1 Hz, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 7.99 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.27 – 7.21 (m, 2H), 7.18 – 7.14 (m, 3H), 7.04 – 6.99 (m, 2H), 6.84 (d, J = 1.6 Hz, 1H), 6.22 (d, J = 3.1 Hz, 1H), 4.42 (t, J = 7.2 Hz, 2H), 3.19 – 3.11 (m, 2H), 2.87 (s, 2H), 1.58 (s, 6H), 1.49 (s, 6H). 6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-1H- indol-5-ol ESI-MS m / z 388.05 [M+H]+, compound 124, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.80 (d, J = 7.1 Hz, 1H), 8.53 (s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.25 (d, J = 3.1 Hz, 1H), 7.05 (s, 1H), 6.94 – 6.79 (m, 1H), 6.31 (d, J = 3.0 Hz, 1H), 2.92 (s, 2H), 1.62 (s, 6H), 1.53 (s, 6H). (E)-2-(7-(3-amino-3-methylbut-1-en-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 362.05 [M+H]+, compound 125, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.85 (d, J = 7.0 Hz, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 8.07 (dd, J = 8.2, 0.7 Hz, 1H), 7.93 (s, 2H), 7.70 – 7.63 (m, 2H), 7.27 (d, J = 7.0 Hz, 1H), 7.10 (d, J = 16.1 Hz, 1H), 6.79 (d, J = 16.1 Hz, 1H), 1.58 (s, 6H). (E)-2-(7-(3-aminoprop-1-en-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 334.00 [M+H]+, compound 126;1H NMR (400 MHz, methanol-d4) δ 8.92 (d, J = 7.0 Hz, 1H), 8.44 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.94 (s, 2H), 7.74 – 7.65 (m, 2H), 7.34 (d, J = 6.9 Hz, 1H), 7.11 – 7.02 (m, 1H), 6.93 (d, J = 15.9 Hz, 1H), 3.88 (d, J = 6.2 Hz, 2H). 2-(7-(3-aminopropyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 336.00 [M+H]+, compound 127, formate salt;1H NMR (400 MHz, dimethylsulfoxide- d6) δ = 8.95 (d, J = 6.8 Hz, 1H), 8.40 (m, 2H), 8.19 (m, 1H), 8.13 (s, 2H), 7.62 (m, 2H), 7.04 (d, J = 6.8 Hz, 1H), 2.92 (t, J = 7.4 Hz, 2H), 2.85 - 2.82 (m, 2H), 2.01 (m, 2H). 2-(7-(azetidin-3-ylidenemethyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 345.95 [M+H]+, compound 128, formate salt;1H NMR (400 MHz, dimethylsufoxide- d6) δ = 8.42 (s, 2H), 8.21 - 8.16 (m, 2H), 8.10 (m, 2H), 7.87 - 7.84 (m, 2H), 7.70 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.57 (s, 1H), 3.90 (s, 2H).2 proton resonances missing due to being eclipsed by solvent peak. (E)-2-(7-(2-(pyrrolidin-2-yl)vinyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol Racemic mixture. ESI-MS m / z 374.05 [M+H]+, compound 129;1H NMR (400 MHz, dimethylsulfoxide-d6) δ = 11.97 - 11.68 (m, 1H), 8.97 - 8.91 (m, 1H), 8.45 - 8.39 (m, 1H), 8.21 - 8.18 (m, 1H), 8.14 - 8.12 (m, 3H), 7.66 - 7.58 (m, 3H), 7.34 - 7.31 (m, 1H), 6.99 - 6.91 (m, 1H), 6.68 - 6.60 (m, 1H), 3.79 - 3.72 (m, 1H), 2.97 - 2.83 (m, 2H), 1.78 - 1.68 (m, 2H), 1.52 - 1.46 (m, 2H). ]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 364.00 [M+H]+, compound 130, formate salt;1H NMR (400 MHz, dimethylsufoxide- d6) δ = 8.94 (d, J = 6.8 Hz, 1H), 8.41 (m, 3H), 8.20 (d, J = 8.4 Hz, 1H), 8.12 (s, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.60 (dd, J = 8.5, 2.0 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 2.94 - 2.89 (m, 2H), 2.02 - 1.98 (m, 2H), 1.27 (s, 6H). 2-(7-(2-(pyrrolidin-2-yl)ethyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol . ESI-MS m / z 376.05 [M+H]+, compound 131, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.78-8.77 (m, 1H), 8.56 - 8.54 (m, 0.3 H), 8.29 (m, 1H), 8.06 - 8.01 (m, 1H), 7.94 - 7.91 (m, 2H), 7.67 - 7.65 (m, 1H), 7.69 - 7.62 (m, 1H), 7.05 - 7.02 (m, 1H), 3.39 - 3.33 (m, 1H), 3.20 - 3.13 (m, 1H), 3.11 - 3.00 (m, 3H), 2.22 - 2.09 (m, 3H), 2.00 - 1.86 (m, 2H), 1.62 - 1.54 (m, 1H). 2-(7-((2-amino-2-methylpropyl)(methyl)amino)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol ESI-MS m / z 379.10 [M+H]+, compound 132,1H NMR (400 MHz, methanol-d4) δ = 8.70 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 7.98 - 7.95 (m, 2H), 7.89 (m, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.6, 2.0 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 4.06 (s, 2H), 3.42 (s, 3H), 1.53 (s, 6H). 2-(7-(1-ethyl-2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-(2H-1,2,3-triazol-2-yl)phenol ESI-MS m / z 444.25 [M+H]+, compound 133,1H NMR (400 MHz, dimethylsulfoxide-d6) δ = 11.89 (s, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.41 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.13 (s, 2H), 7.64 - 7.60 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 6.75-6.77 (m, 1H), 2.72 (m 2H), 2.46 (bs, 2H), 1.25 (s, 6H), 1.15 (s, 6H), 1.05 (t, J = 6.9 Hz, 3H). 3-fluoro-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2- yl)-5-(1H-1,2,4-triazol-1-yl)phenol ESI-MS m / z: 434.20 [M+H]+, compound 134, hydrobromide salt;1H NMR (400 MHz, dimethylsulfoxide-d6) δ = 13.79 (s, 1H), 9.41 (s, 1H), 9.11 (d, J = 7.2 Hz, 1H), 8.75 (s, 2H), 8.40 (d, J = 4.4 Hz, 1H), 8.29 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.48 (dd, J = 12.2, 2.0 Hz, 1H), 7.42 (m, 1H), 7.04-7.06 (m, 1H), 2.85 (s, 2H), 1.60 (s, 6H), 1.47 (s, 6H). 3-fluoro-5-(3-methyl-1H-1,2,4-triazol-1-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 450.15 [M+H]+, compound 135, formate salt; 1H NMR (400 MHz, methanol-d4) δ = 9.04 (s, 1H), 8.90 (d, J = 6.8 Hz, 1H), 8.55 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.20 (d, J = 6.8 Hz, 1H), 3.61 - 3.53 (m, 1H), 2.46 (s, 3H), 2.14 - 2.11 (m, 2H), 1.92 - 1.85 (m, 2H), 1.57 (s, 6H), 1.46 (s, 6H).19F NMR (376 MHz, methanol-d4) δ -110.33. 3-fluoro-5-(5-methyl-1H-1,2,4-triazol-1-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4- nol ESI-MS m / z 450.15 [M+H]+, compound 136, formate salt;1H NMR (400 MHz, methanol-d4) δ = 8.92 (d, J = 7.2 Hz, 1H), 8.55 (s, 0.4 H), 8.29 (d, J = 4.4 Hz, 1H), 8.03 (s, 1H), 7.22 (d, J = 6.8 Hz, 1H), 7.05 - 7.02 (m, 2H), 3.59 (m, 1H), 2.62 (s, 3H), 2.14 (m, 2H), 1.94 - 1.87 (m, 2H), 1.59 (s, 6H), 1.49 (s, 6H).19F NMR (376 MHz, methanol-d4) δ -110.58. 5-(3-fluoro-1H-pyrazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)pyridin-3-ol ESI-MS m / z 415.05 [M+H]+, compound 138, enantiomer 1, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.89 (m, 1H), 8.84 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.01 (s, 2H), 7.98 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.05 (m, 1H), 2.82 (m, 2H), 2.20 (m, 1H), 1.91 (m, 3H), 1.54 (s, 6H). Second-eluting peak using the following column and conditions for enantiomer separation by chiral HPLC: Column: Chiralpak-IG (250 x 20 mm x 5 μM) Flow rate: 20 mL per minute Mobile phase: 90% of 10 mM NH3 in MeCN (A) and 10% of 10 mM NH3 in EtOH / iPrOH (1:1) (B) 2-(7-(1,5-dimethyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H- 1,2,3-triazol-2-yl)pyridin-3-ol ESI-MS m / z 415.05 [M+H]+, compound 138, enantiomer 2, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.89 - 8.85 (m, 2H), 8.54 (s, 1H), 8.39 (s, 1H), 8.00 (m, 3H), 7.49 (d, J = 7.2 Hz, 1H), 7.05 (m, 1H), 2.87 (m, 2H), 2.23 (m, 1H), 1.95 - 1.91 (m, 3H), 1.57 (s, 6H). First-eluting peak using the following column and conditions for enantiomer separation by chiral HPLC: Column: Chiralpak-IG (250 x 20 mm x 5 μM) Flow rate: 20 mL per minute Mobile phase: 90% of 10 mM NH3 in MeCN (A) and 10% of 10 mM NH3 in EtOH / iPrOH (1:1) (B) 3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 447.15 [M+H]+, compound 139;1H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 7.2 Hz, 1H), 8.17 (d, J = 4.4 Hz, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.49 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.94 (m, 1H), 6.87 (m, 1H), 3.96 (s, 3H), 2.71 (m, 2H), 1.49 (s, 6H), 1.37 (s, 6H).19F NMR (377 MHz, methanol-d4) δ -113.4. 1-cyclopropyl-4-(3-fluoro-5-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenyl)pyridin-2(1H)-one ESI-MS m / z 500.20 [M+H]+, compound 140, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.84 (d, J = 7.2 Hz, 1H), 8.54 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.12 (m, 1H), 7.08 (s, 1H), 6.89 (m, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.71 (dd, J = 7.2, 2.0 Hz, 1H), 3.41 - 3.37 (m, 1H), 2.71 (m, 2H), 1.48 (s, 6H), 1.38 (s, 6H), 1.17 - 1.14 (m, 2H), 0.98 - 0.96 (m, 2H).19F NMR (377 MHz, methanol-d4) δ -112.1. 1-ethyl-4-(3-fluoro-5-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo[1,2-a]pyrimidin-2-yl)phenyl)pyridin-2(1H)-one ESI-MS m / z 488.20 [M+H]+, compound 141, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 8.28 (d, J = 4.0 Hz, 1H), 7.75 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.13 (s, 1H), 7.10 (m, 1H), 6.90 (m, 1H), 6.82 (d, J = 1.6 Hz, 1H), 6.75 (dd, J = 7.1, 2.0 Hz, 1H), 4.10 (q, J = 7.2 Hz, 2H), 2.84 (m, 2H), 1.57 (s, 6H), 1.46 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H).19F NMR (377 MHz, methanol-d4) δ -112.1. (S)-2-(7-(3-aminopyrrolidin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- yl)phenol ESI-MS m / z 363.05 [M+H]+, compound 142, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.52 (d, J = 7.6 Hz, 1H), 8.41 (m, 2H), 7.94-7.87 (m, 3H), 7.86 (d, J = 8.4 Hz, 1H), 7.63 - 7.60 (m, 2H), 6.59 (d, J = 7.6 Hz, 1H), 4.07 (m, 1H), 3.97 (m, 1H), 3.80 (m, 3H), 2.53 (m, 1H), 2.22 (m, 1H). 2-(7-(2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol Single diastereomer (two methyl substituents on piperidine are syn), racemic mixture. ESI-MS m / z 388.05 [M+H]+, compound 143, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.82 (d, J = 6.8 Hz, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.94 (s, 2H), 7.68 - 7.65 (m, 2H), 7.44 (d, J = 6.8 Hz, 1H), 6.90 (m, 1H), 4.21 (m, 1H), 3.68 (m, 1H), 3.20 - 3.14 (m, 1H), 2.61 (dd, J = 17.8, 8.3 Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H). 2-(7-(1,5-dimethyl-8-azabicyclo[3.2.1]oct-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H- Racemic mixture. ESI-MS m / z 414.05 [M+H]+, compound 144, formate salt;1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.43 (s, 1H), 8.22 - 8.19 (m, 2H), 8.13 (s, 2H), 7.65-7.60 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.09 (m, 1H), 2.62 (m, 2H), 2.01 (m, 1H), 1.75 (m, 3H), 1.43 (s, 6H). 2-(7-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol ESI-MS m / z 402.10 [M+H]+, compound 145, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.85 (d, J = 6.8 Hz, 1 H), 8.54 (br s, 1 H), 8.35 (s, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.93 (s, 2 H) 7.71 - 7.65 (m, 2 H) 7.10 (d, J = 6.90 Hz, 1 H) 3.94 - 3.85 (m, 2 H) 3.24 - 3.19 (m, 1 H) 2.56 - 2.46 (m, 2 H) 2.24 – 1.89 (m, 6 H) 1.82 - 1.79 (m, 2 H). HPLC method and conditions used for separation of the diastereomers (compounds 145 and 146): Rt = 5.49 min (Second-eluting peak) Column: LUNA C-18 (150 x 4.6mm x 5μM) Gradient: 0min / 5% B, 1min / 5% B 6min / 100%B, 8min / 100%B, 10min / 5%B, 12 min / 5%B Mobile phase: A = 0.1% HCOOH in water, B = MeCN, 1 mL / min flow 2-(7-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3- triazol-2-yl)phenol ESI-MS m / z 402.10 [M+H]+, compound 146;1H NMR (400 MHz, methanol-d4) δ 8.86 (d, J = 6.8 Hz, 1H), 8.39 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.94 (s, 2H), 7.69 - 7.66 (m, 2H), 7.19 (d, J = 6.8 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.80 (m, 2H), 3.13 (m, 1H), 2.49 (m, 2H), 2.37 - 2.33 (m, 2H), 2.23 - 2.10 (m, 4H), 1.85 - 1.78 (m, 2H). HPLC method and conditions used for separation of the diastereomers (compounds 145 and 146): Rt = 5.42 min (First-eluting peak) Column: LUNA C-18 (150 x 4.6mm x 5μM) Gradient: 0min / 5% B, 1min / 5% B 6min / 100%B, 8min / 100%B, 10min / 5%B, 12 min / 5%B Mobile phase: A = 0.1% HCOOH in water, B = MeCN, 1 mL / min flow 2-(7-(9-azabicyclo[3.3.1]non-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- ESI-MS m / z 400.15 [M+H]+, compound 147, enantiomer 1;1H NMR (400 MHz, methanol-d4) δ 8.75 (d, J = 7.2 Hz, 1H), 8.32 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.92 (s, 2H), 7.67 – 7.64 (m, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.05 (m, 1H), 3.83 (m, 1H), 3.59 (m, 1H), 3.07 - 3.01 (m, 1H), 2.69 (d, J = 18.8 Hz, 1H), 1.94 - 1.89 (m, 2H), 1.74 (m, 3H), 1.57 (m, 1H). Second-eluting peak using the following column and conditions for enantiomer separation by chiral HPLC: Column: Chiralpak-IG (250 x 21 mm x 5 μM) Flow rate: 20 mL per minute Mobile Phase: 40% Acetonitrile (A) and 60% of 10 mM ammonia in EtOH: MeOH (1:1) (B) 2-(7-(9-azabicyclo[3.3.1]non-2-en-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2- ESI-MS m / z 400.15 [M+H]+, compound 147, enantiomer 2;1H NMR (400 MHz, methanol-d4) δ 8.81 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.91 (s, 2H), 7.69-7.65 (m, 2H), 7.45 (d, J = 7.2 Hz, 1H), 7.00 (m, 1H), 4.11 (m, 1H), 3.84 (m, 1H), 2.89 (m, 1H), 2.03 - 1.97 (m, 3H), 1.90 - 1.81 (m, 3H), 1.63 (m, 1H). First-eluting peak using the following column and conditions for enantiomer separation by chiral HPLC: Column: Chiralpak-IG (250 x 21 mm x 5 μM) Flow rate: 20 mL per minute Mobile Phase: 40% Acetonitrile (A) and 60% of 10 mM ammonia in EtOH: MeOH (1:1) (B) 3-fluoro-5-(5-methyl-1H-1,2,4-triazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 448.15 [M+H]+, compound 148, formate salt;1H NMR (400 MHz, methanol-d4) δ 8.92 (m, 1 H) 8.46 (bs, 1 H) 8.32 (d, J = 4.1 Hz, 1 H) 8.02 (s, 1 H) 7.59 (d, J = 7.2 Hz, 1 H) 7.04 (m, 2 H) 6.92 (m, 1 H) 2.97 (m, 2 H) 2.62 (s, 3 H) 1.66 (s, 6 H) 1.56 (s, 6 H).19F NMR (377 MHz, methanol-d4) δ -110.39. 3-fluoro-5-(3-methyl-1H-1,2,4-triazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6- tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 448.15 [M+H]+, compound 149, formate salt;1H NMR (400 MHz, methanol-d4) δ 9.04 (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J = 4.4 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.29 (m, 1H), 7.26 (m, 1H), 6.91 (m, 1H), 2.95 (m, 2H), 2.46 (s, 3H), 1.66 (s, 6H), 1.56 (s, 6H).19F NMR (377 MHz, methanol-d4) δ -110.3. 5-(3-methyl-1H-1,2,4-triazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4- yl)imidazo [1,2-a]pyrimidin-2-yl)phenol ESI-MS m / z 430.50 [M+H]+, compound 150;1H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.72 (d, J = 6.7 Hz, 1H), 8.44 (br s, 1H), 8.26 (br s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 6.7 Hz, 1H), 7.30 – 7.22 (m, 2H), 6.80 – 6.72 (m, 1H), 2.78 (br s, 2H), 2.35 (s, 3H), 1.50 (s, 6H), 1.40 (s, 6H). 5-(1H-imidazol-1-yl)-2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2- ESI-MS m / z 416.20 [M+H]+, compound 151;1H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 7.3 Hz, 1H), 8.47 (s, 1H), 8.41 – 8.35 (m, 2H), 7.71 (s, 1H), 7.68 – 7.50 (m, 3H), 7.25 (s, 1H), 6.88 – 6.82 (m, 1H), 2.89 (br s, 2H), 1.59 (s, 6H), 1.49 (s, 6H). Biological Activity of Exemplary Compounds Disclosed Herein To determine the effects of low molecular weight compounds on HTT protein, the ELISA- based Meso Scale Discovery (MSD) electrochemiluminescence assay platform was used. MSD 384-well plates (L21XA-4) were coated overnight at 4 °C with 2B7 antibody (prepared in house, otherwise available from CHDI Foundation, New York, NY) at concentration of 2 μg / mL in PBS. The plates were then washed three times with 40 μl / well PBS and blocked (5% BSA in PBS, 40 μl / well) for 4-5 hours at room temperature with rotational shaking. After washing the plates three times with PBS, Cell lysates (72 hours of compound treated SH-SY5Y cells (ATCC, CRL-2266)) were transferred to the antibody-coated MSD plate and incubated overnight at 4 °C. The plates were washed three times with wash buffer (0.05% Tween-20 in PBS) to remove the lysates. The secondary antibody, D7F7 (Cell Signaling, 5656S) at concentration of 0.1 μg / mL in blocking buffer (0.5% BSA in PBS) was added into the plate and incubated for 1.5 hours at room temperature. The plates were wash three times with wash buffer and incubated with 1:1000 dilution of anti-rabbit SULFO-TAG antibody (Mesoscale, R32AB-1) for 1 hour at room temperature. After rinsing three time with wash buffer, 1x MSD reading buffer (Mesoscale, R92TC-1) was added into each well, and the plates were read by SI 6000 imager (MSD) according to manufacturer’s instructions. The AC50 (μM) value from the HTT MSD assay for compounds tested are shown below.

[0009] * compound 85-1 is compound 85, enantiomer 1; compound 85-2 is compound 85, enantiomer 2; compound 89-1 is compound 89, enantiomer 1; compound 89-2 is compound 89, enantiomer 2; compound 138-1 is compound 138, enantiomer 1; compound 138-2 is compound 138, enantiomer 2; compound 147-1 is compound 147, enantiomer 1; and compound 147-2 is compound 147, enantiomer 2. Pharmacokinetics and Pharmacodynamics The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the compounds in mice can be assessed by the following in vivo studies as described below. Brain protein and plasma protein binding can be assessed in vitro as described further below and used to calculate unbound expsoures. Animals Species, Strain, Gender Mouse, BacHD, male and female Age / Body weight 14-16 weeks / 30-45 grams Animal model Huntington’s disease No of animals 30-50 mice / study Housing Animals were housed three – five per cage, in polypropylene cages (11.75"L x 7.25"W x 5"H) containing autoclaved 1 / 8 pelleted cellulose . Over the duration of the study, the temperature was maintained between 73 ± 3°F and the relative humidity between 30% and 70%.12 hour light and 12 hour dark photocycle was maintained in all rooms using automated timers. Feeding / Water The animals had free access to food and water throughout the entire experiment. Animal model This mouse model of Huntington's disease expresses full-length human mutant huntingtin gene (htt) and was utilized for assessing changes in mutant HTT protein levels after treatment with oral novel molecules. Experimental conditions Body weight Body weights were measured weekly before the study, then, animals were weighed daily prior to dose administration and the weight was recorded in raw data file during the course of the study. Dosing regimen Oral administration The test article was administered as a solution or suspension into the esophagus via a gavage tube to conscious BacHD mice. The dose volume was 10 mL / kg body weight. The exact start time of dosing and exact dose volume were noted. No. of Route of Study design Group Dose (mg / kg) animals administration I 5-7 Oral 3 Discrete (non- II 5-7 Oral 10 crossover) Oral 30 The compound or vehicle (0.5% Methylcellulose, 0.1% Tween 80 in water) was administered to BacHD mice once daily for 21 or 28 consecutive days by oral gavage. The dose volume was 10mL / kg body weight. The exact start time of dosing and exact dose volume were recorded. Clinical signs Animal was monitored daily before and following dosing, and any clinical signs observed was recorded. No adverse events were observed, and no mice were removed from the study. Sample collection At different timepoints after the first and last treatment, blood and tissue samples were obtained for PK / PD analyses. Whole blood was collected by tail vein or cardiac puncture (terminal) into EDTA-coated tubes. Whole blood for PK analysis was immediately snap frozen in liquid nitrogen. For PD analysis, plasma was isolated through centrifugation at 14.000 rpm for 10 minutes at 4°C. The supernatants to be used were transferred into 1.5mL microcentrifuge tubes and stored in -80°C until analysis. Brain and liver tissues were carefully dissected out, weighed and snap frozen, and stored in -80°C until analysis. Pharmacokinetic analysis For PK analysis, samples were analyzed on a LC-MS system consisting of a Sciex Exion AD LC-system and a Sciex QTrap 6500 MS controlled by Analyst 1.7 from AB Sciex (Darmstadt, Germany). Compound specific parameters (parent ion, fragment, and collision energy) were obtained by automatic tuning using DiscoveryQuant 3.0.7. These parameters were stored in a database to be used for selective quantitation of each test article. Samples (2 μl) were injected onto a Waters Acquity BEH Polar C18, 2.1 × 50 mm, 1.7 μm column (Milford, Massachusetts, USA) and were eluted with a gradient of 0.1% formic acid in water (mobile phase A) versus 0.1% formic acid in acetonitrile (mobile phase B) at a flow of 0.8 ml / min at 50°C using the following gradient: 0 minutes, 20% B; 0.2 minutes, 20% B; 1.2 minute, 60% B; 1.3 minutes, 95% B; 1.7 minutes, 95% B; 1.8 minutes, 20% B; and 2.0 minutes, 20% B. The entire column effluent was diverted from the Turbo Ionspray source (550°C, 9 l / min of nitrogen) of a PE-Sciex Qtrap API-6500+ single quadrupole mass spectrometer. Compounds and internal standard were measured using multiple reaction monitoring or single ion monitoring with positive ionization and retention times between 0.89 and 0.95 min for the test article and internal standard, respectively. Pharmacodynamic analysis To detect mutant HTT protein levels, the ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence assay platform was used.96-well multi array MSD assay Plate (L15XA-3) were coated overnight at 4 °C with 2B7 antibody at concentration of 2 μg / mL in PBS. The plates were then washed three times with 40 μl / well PBS and blocked (5% BSA in PBS, 40 μl / well) for 4-5 hours at room temperature with rotational shaking. After washing the plates tissue lysates or plasma diluted in artificial cerebrospinal fluid (aCSF) solution (aCSF, 10% Tween20, Thermo Halt Protease Cocktail (ThermoFisher 79444)) were transferred to the antibody-coated MSD plate and incubated overnight at 4 °C. The plates were washed with wash buffer (0.05% Tween-s20 in PBS) to remove the lysates. The secondary antibody, SULFO- TAGGED MW1 antibody (EMD MIllipore, MABN2427) at concentration of 0.1 μg / mL in blocking buffer (0.5% BSA in PBS) was added into the plate and incubated for 1.5 hours at room temperature. The plates were wash with wash, 1x MSD reading buffer (Mesoscale, R92TC-1) was added into each well, and the plates were read by SI 6000 imager (MSD) according to manufacturer’s instructions. From the assay, the values for the experiment group were normalized to the vehicle group. Statistical comparisons were performed using one-way ANOVA followed by Dunnett’s post hoc test. All data represented as mean ± SEM. Data were analyzed using Prism GraphPad 10. Rat brain homogenate protein binding assay Binding to proteins was measured using Rapid equilibrium dialysis (RED device form ThermoFisher). Test articles were dissolved at a concentration of 5 μM in matrix (rat brain homogenate diluted at 25% in 100 mM phosphate buffer pH 7.4).300 μL of the matrix solutions were dispensed to the RED chamber of a RED device and 500 μL 100 mM phosphate buffer to the white chamber. The RED device was sealed with a gas permeable membrane and incubated for 4 hours on an orbital shaker (750 rpm) at 37ºC under 5% CO2.50 μL aliquots from both compartments were transferred to 600 μL acetonitrile containing the analytical internal standard (0.2 μM glyburide) and 50 μL buffer or matrix for a matrix match. The samples were centrifuged at 5000g for 15 minutes at 4°C and the supernatant was analyzed by LC-MS analysis for measuring test article and internal standard. The free fraction (fu) was calculated by dividing the AREA-ratio of the receiver compartment to the AREA-ratio of the donor compartment and corrected for the dilution factor (d=4) with the Kalvass equation below (Kalvass and Maurer, 2002). Plasma protein binding assay Binding to plasma proteins was measured in triplicate by equilibrium dialysis using the rapid equilibrium dialysis (RED) device from ThermoFisher (Rockford, IL). Test articles (5 μM) were incubated with plasma (100%). Aliquots of 300 μl were dispensed in the red chamber of the RED device and 500 μl of 100 mM phosphate buffer (pH 7.4) in the white chamber. The RED device was sealed with a gas permeable membrane and was incubated for 4 hours on an orbital shaker at 750 rpm (Kisker model V 2000) in an incubator (HERA cell 150 from Thermo Scientific) at 37°C with 5% CO2. At the end of the incubation period, 50-μl aliquots from both compartments were transferred to a 96 deep-well-plate prefilled with 600 μl acetonitrile containing the analytical internal standards (0.2 μM glyburide) and 50 μl buffer or matrix for a matrix match. The samples were centrifuged at 5000 × g for 20 minutes at 4°C, and the supernatant was transferred to a new 384-well plate prefilled with 30 μl water. Test articles and internal standard were subsequently measured by LC-MS (methodology description below). The values for the fraction unbound in (100%) plasma (fup) based on the below equation: Mouse plasma protein binding was measured for compound 11 (75.3%), for compound 7 (95.4%) and for compound 10 (>99%). Human plasma protein binding was measured for compound 11 (88.2%), for compound 7 (not determined) and for compound 10 (>99%). Quantification of brain and plasma samples Analysis of samples was performed on a LC-MS system consisting of a Shimadzu Nexera LC-system and a Sciex QTrap 6500 MS controlled by Analyst 1.7 from AB Sciex (Darmstadt, Germany). Compound specific parameters (parent ion, fragment, and collision energy) were obtained by automatic tuning using DiscoveryQuant 3.0.7. These parameters were stored in a database to be used for selective quantitation of each test article. Samples (2 μl) were injected onto a Phenomenex Kinetex Polar C18, 2.1 × 30 mm, 2.6 μm column (Brechbühler, Schlieren, Switzerland) and were eluted with a gradient of 0.1% formic acid in water (mobile phase A) versus 0.1% formic acid in acetonitrile (mobile phase B) at a flow of 0.8 ml / min at 50°C using the following gradient: 0 minutes, 2% B; 0.2 minutes, 2% B; 1 minute, 60% B; 1.3 minutes, 100% B; 1.7 minutes, 100% B; 1.71 minutes, 2% B; and 1.95 minutes, 2% B. Rat brain protein binding was measured for compound 11 (98.2%), for compound 7 (>99%), and for compound 10 (>99%). Results: mHTT protein lowering and compound concentration (in nM) in selected tissues after 14 days of once-daily oral dosing (BacHD mouse model) mHTT protein levels and compound concentrations in tissue were measured 24 hours after the last dose. n.a. – not applicable. Accurate unbound concentrations cannot be calculated since brain protein binding is >99%. n.m. – not measured. Ctotal– total concentration of compound in respective tissue. Cunbound– unbound concentration of compound in respective tissue. OTHER EMBODIMENTS While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure that come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are in the claims.

Claims

CLAIMS What is claimed is 1. A compound of Formula (I): ,or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein X1is CR2or N; X2is CR6or N; each of X3and X4is independently CH, CR8, or N, wherein R8is halogen; W is O or NRN, wherein RNis hydrogen or C1-6alkyl; R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, halogen, and -N(RN1)2; C1-6alkyl substituted with -N(RN1)2or heterocyclyl; C2-6alkenyl substituted with -N(RN1)2or heterocyclyl; C3-8cycloalkyl substituted with -N(RN1)2; or -CH=C(RN2)2, wherein each RN1is independently H or C1-6alkyl, and both RN2, together with the atom to which they are attached, combine to form a heterocyclyl comprising at least one endocyclic nitrogen atom; R2is hydrogen, halogen, C1-6alkyl, or C1-6haloalkyl; each of R3and R6is independently hydrogen, hydroxyl, C1-6alkoxy, or halogen; R4is halogen, cyano, or heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, C3-8cycloalkyl, C1-6alkoxy, hydroxyl, oxo, and halogen, and each R5, when present, is independently halogen; or R4and one R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen; R7is hydrogen, C1-6alkyl, C1-6haloalkyl, or -OR9, wherein R9is C1-6alkyl or C1-6haloalkyl; n is 0 or 1; and m is 0, 1, or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is of Formula (I’): .

3. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is of Formula (I-A):. (I-A) 4. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is of Formula (I-B):. (I-B) 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R6is hydrogen.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R6is fluorine.

7. The compound of claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is of Formula (I-C):.(I-C) 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R3is hydroxyl.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R3is fluorine.

10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R3is C1-6alkoxy.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is a 5- membered monocyclic heteroaryl comprising 1, 2, 3, or 4 nitrogen atoms in the ring and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen.

12. The compound of claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, race4group cons ,, , , , , , , ,, , , , , , , , , and .

13. The compound of claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is selected from the group consisting of: ,and14. The compound of claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is selected from the group consisting of:,, , , and .

15. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is a 6- membered monocyclic heteroaryl comprising 1, 2, or 3 nitrogen atoms in the ring and optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen.

16. The compound of claim 15, or a pharmaceutically acceptable salt, hydrate, solvate, racemate enantiomer diastereomer or tautomer thereof wherein R4is selected from the group cons ,,, and .

17. The compound of claim 15 or a pharmaceutically acceptable salt, hydrate, solvate, race of, wherein R4is selected from the group cons,, , and .

18. The compound of claim 15, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is selected from the group consisting of:

29. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is cyano.

20. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is chloro.

21. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is an N- heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen.

22. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4is a bicyclic N-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, hydroxyl, oxo, and halogen.

23. Th m nd f l im 22, or a pharmaceutically acceptable salt, hydrate, solvate, race er, or tautomer thereof, wherein R4isor .

24. ound of claim 22, or a pharmaceutically acceptable salt, hydrate, solvate, race mer, diastereomer, or tautomer thereof, wherein R4is.

25. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4and R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl, and the remaining R5, when present, is halogen, wherein the bicyclic aryl or bicyclic heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C6-10aryl C1-6alkyl, hydroxyl, oxo, and halogen.

26. The compound of claim 25, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R4and R5, together with the atoms to which they are attached combine to form a bicyclic aryl or bicyclic heteroaryl selected from the group consisting of: ,and.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein m is 1.

28. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein m is 2.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, R5is fluorine.

30. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein m is 0.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein n is 1.

32. The compound of claim 31, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein W is O.

33. The compound of claim 31, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein W is NRN.

34. The compound of claim 33, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein RNis methyl.

35. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein n is 0.

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is a heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms and substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen.

37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is a 6- membered monocyclic heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen.

38. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is a bicyclic heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen.

39. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is a 7- membered monocyclic heterocyclyl comprising 1, 2, 3, or 4 nitrogen atoms and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen.

40. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R1is a spirocyclic heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl, C1-6haloalkyl, hydroxyl, and halogen.

41. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6alkyl substituted with -N(RN1)2or heterocyclyl.

42. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R1is C2-6alkenyl substituted with -N(RN1)2or heterocyclyl.

43. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R1is C3-8cycloalkyl substituted with -N(RN1)2.

44. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R1is -CH=C(RN2)2, wherein each RN1is independently H or C1-6alkyl, and both RN2, together with the atom to which they are attached, combine to form a heterocyclyl comprising at least one endocyclic nitrogen atom.

45. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is bonded to the core through the endocyclic carbon atom of R1.

46. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R1is a heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of C1-6alkyl and hydroxyl.

47. The compound of claim 37, or a pharmaceutically acceptable salt, hydrate, solvate, racemate enantiomer diastereomer or tautomer thereof wherein R1is selected from the group cons,, , , and .

48. The compound of claim 37, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is selected from the group consisting of:,49. The compound of claim 37, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is selected from the group consisting of:and .

50. The compound of claim 38, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is selected from the group cons ,and.

51. m 38, or a pharmaceutically acceptable salt, hydrate, solvate, race, , reomer, or tautomer thereof, wherein R1is or .

52. pound of claim 39, or a pharmaceutically acceptable salt, hydrate, solvate, race iomer, diastereomer, or tautomer thereof, wherein R1is.

53. The compound of claim 40, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is selected from the group consisting of: .

54. The compound of claim 41, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is selected from the group consisting of: ,and.

55. The compound of claim 42, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is selected from the group cons,, and .

56. The compound of claim 43, or a pharmaceutically acceptable salt, hydrate, solvate, racemate enantiomer diastereomer, or tautomer thereof, wherein R1is selected from the group consand .

57. ound of claim 44, or a pharmaceutically acceptable salt, hydrate, solvate,racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1is: .

58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R1-(W)n- comprises a nitrogen atom, and the shortest chain of atoms connecting this nitrogen atom to the core of the compound of formula (I) comprises a total of three atoms, wherein the core is:

59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein R7is hydrogen.

60. A compound selected from the group consisting of:71727364656657585951 1 1 11041 1 1 1 1 1 1 1 11141 1 1 1 1 1 1 1 11 1 1 1 1 1 1 1 1 11341 1 1 1 1 1 1 11431 1 1 1 1 11501 and p, , , acemates, enantiomers, diastereomers, and tautomers thereof.

61. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is selected from the group consisting of compounds 1-73, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof.

62. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is selected from the group consisting of compounds 1-33, 64, 65, 69, 73, 83, 86, 88, 89, 93-95, 99, 110- 113, 115, 117, 118, 134, 135, 139, 144-147, 149, 150, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof.

63. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is selected from the group consisting of compounds 1-33, 64, 65, 69, 73, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof.

64. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is selected from the group consisting of compounds 1-20, 64, 65, 69, 83, 86, 88, 89, 93-95, 99, 110-113, 115, 117, 118, 134, 135, 139, 144-147, 149, 150, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof.

65. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is selected from the group consisting of compounds 1-20, 64, 65, 69, and pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers thereof.

66. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is compound 1 or a pharmaceutically acceptable salt thereof.

67. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is compound 2 or a pharmaceutically acceptable salt thereof.

68. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is compound 7 or a pharmaceutically acceptable salt thereof.

69. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is compound 10 or a pharmaceutically acceptable salt thereof.

70. The compound of claim 60, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, wherein the compound is compound 11 or a pharmaceutically acceptable salt thereof.

71. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof and one or more pharmaceutically acceptable carriers.

72. A method of treating Huntington’s disease, spinal muscular atrophy, or familial dysautonomia, the method comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, or the pharmaceutical composition of claim 71.

73. The method of claim 72, wherein the method is of treating Huntington’s disease.

74. The method of claim 72, wherein the method is of treating spinal muscular atrophy.

75. The method of claim 72, wherein the method is of treating familial dysautonomia.

76. The method of any one of claims 72 to 75, wherein the method further comprises administering an effective amount of an MSH3 inhibitor.

77. The compound of any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof, or thepharmaceutical composition of claim 71, for use in the treatment of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia.

78. The compound or pharmaceutical composition for use of claim 77, wherein the use is in the treatment of Huntington’s disease.

79. The compound or pharmaceutical composition for use of claim 77, wherein the use is in the treatment of treating spinal muscular atrophy.

80. The compound or pharmaceutical composition for use of claim 77, wherein the use is in the treatment of treating familial dysautonomia.

81. The compound or pharmaceutical composition for use of any one of claims 77 to 80, wherein the use is in combination with an MSH3 inhibitor.

82. The compound of any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition of claim 71, for treating of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia.

83. The compound or pharmaceutical composition of claim 82, wherein the compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition, is for treating Huntington’s disease.

84. The compound or pharmaceutical composition of claim 82, wherein the compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition, is for treating spinal muscular atrophy.

85. The compound or pharmaceutical composition of claim 82, wherein the compound or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition, is for treating familial dysautonomia.

86. The compound or pharmaceutical composition for use of any one of claims 82 to 85, wherein the treating is in combination with an MSH3 inhibitor.

87. Use of a compound of any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof in the manufacture ofa medicament for the treatment of Huntington’s disease, spinal muscular atrophy, or familial dysautonomia.

88. The use of claim 87, wherein the medicament is for the treatment of Huntington’s disease.

89. The use of claim 87, wherein the medicament is for the treatment of treating spinal muscular atrophy.

90. The use of claim 87, wherein the medicament is for the treatment of treating familial dysautonomia.

91. The use of any one of claims 87 to 90, wherein the use is in combination with an MSH3 inhibitor.

92. A method of forming a complex comprising a component of a spliceosome, a nucleic acid, and the compound of any one of claims 1 to 70, the method comprising contacting the nucleic acid with the compound of any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof.

93. The method of claim 92, wherein the component of a spliceosome is a major spliceosome component or a minor spliceosome component.

94. The method of claim 92 or 93, wherein the nucleic acid is a DNA or RNA.

95. The method of claim 94, wherein the nucleic acid is a pre-mRNA transcript.

96. A method for modifying RNA splicing in order to produce a mature mRNA transcript having an intronic exon, the method comprising contacting the compound of any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer thereof with a cell comprising a pre-mRNA transcript comprising at least two exons and at least one intron, wherein at least one of the exons is upstream of the intron and at least one of the exons is downstream of the intron.

97. The method of claim 96, wherein the intron comprises in 5' to 3' order: a first 5' splice site, a first branch point, a first 3' splice site, an intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3' splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide.

98. The method of claim 97, wherein the intron further comprises in 5′ to 3′ order: a 5′ splice site, a branch point, and a 3′ splice site, wherein the 5′ splice site, the branch point, and the 3′ splice site are upstream of the iREMS.

99. The method of any one of claims 95 to 98, wherein the pre-mRNA transcript is a pre- mRNA transcript of a gene selected from the group consisting of: ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR- 0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3,TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25; and HTT, SMN2, ELP1, FOXM1, and MAPT.

100. The method of claim 99, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: C12orf4, CDH18, CHEK1, DHFR, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, POMT2, TAF2, TRIM65, and WDR27; ADAMTS19, BECN1, CACNB4, CADM2, CHEK1, CHRM2, CMAHP, DENND4A, DHFR, EVC, GXYLT1, MEMO1, MYCBP2, NUPL1, PDXDC1, SENP6, SPIDR, TNRC6A, TRIM65, URGCP-MRPS24, WDR90, ZFP82, ZNF618, and ZNF680; and AGPS, AKT1, ANXA11, ARHGAP5, ARL15, ATF6, BIN3, C11orf30, C11orf73, CDH18, CENPI, DCAF17, DENND4A, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777.

101. The method of claim 99, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: HTT;ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHRM2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AGPS, AKT1, ANXA11, ARHGAP5, ATF6, ASAP1, BHMT2, BIN3, C11orf30, C11orf73, C1orf27, CENP1, DCAF17, ENAH, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1524, KIAA1715, KIDINS220, LYRM1, MFN2, MORF4L1, NGF, RERE, SF3B3, SLC25A17, SNX24, SNX7, STRADB, STXBP6, TA5P1, TBCA, TCF4, TMEM214, UBE2D3, UBE2L3, VDAC2, WNK1, XRN2, ZNF138, ZNF350, and ZNF777; and DIAPH3, NIPA1, RAF1, DCAF172a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF176a, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H.

102. The method of claim 99, wherein the pre-mRNA transcript is a pre-mRNA transcript of the HTT, SMN2, ELP1, FOXM1, or MAPT gene.

103. The method of claim 99, wherein the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene.

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