Substituted imidazoarenes and methods of use thereof

Abstract

Disclosed are substituted imidazoaromatic hydrocarbons having formula (I) or pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, or tautomers thereof; methods for manufacturing the compounds disclosed herein; and their therapeutic uses. (I)

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 601,402, filed November 21, 2023, the contents of which are incorporated herein by reference in their entirety and for all purposes. Technical Field

[0003] This disclosure relates to the use of splice regulators in the treatment of slowing the progression of Huntington's disease. Background Technology

[0004] Huntington's disease (HD) is a genetic, neurodegenerative, and progressive disorder affecting approximately 5 out of every 100,000 people worldwide. It is caused by a CAG trinucleotide repeat amplification in the huntingtin protein gene (i.e., the gene encoding the protein huntingtin) and is characterized by a decline in motor, cognitive, mental, and functional abilities. CAG trinucleotide repeat amplification produces a mutant huntingtin protein (mHTT), which is associated with neurological dysfunction and eventual death.

[0005] In healthy individuals, the number of CAG repeats in the HTT gene ranges from 6 to 35. Individuals carrying 36 to 39 CAG repeats have reduced disease penetrance, but individuals with 40 or more CAG repeats are almost certain to develop the disease. European Journal of Neurology [ European Journal of Neurology ] , The clinical diagnosis of HD, as described in 2017, 24-34, is based on: - A confirmed family history or positive gene testing (i.e., confirmed CAG repeat amplification ≥ 36); and - Motor episodes diagnosed by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) with confidence score (DCS), ranging from 0 (no motor abnormalities suggestive of HD) to 4 (motor abnormalities ≥ 99% likely attributable to HD), where a score of 4 defines "motor episode" or "manifested" HD.

[0006] Typically, the age of onset (i.e., once DCS reaches 4) ranges from 30 to 50 years, and the average survival time after clinical diagnosis is 15 to 20 years. Currently, after onset, disease staging is determined by "function" (i.e., assessment of functional capacity) rather than motor signs (e.g., in...). Neurology Neurology , 1979, 29, 1-3 or in Neurology Neurology(See *Movement Disorders*, 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 the independence level for patients with HD ranges from 0 (completely dependent on all care) to 13 (completely independent). This scale assesses the functional status of patients with HD based on their ability to work, manage household finances, manage household chores, perform activities of daily living, and the level of care required. HD is classified into stages 1 through 5 of disease progression based on the UHDRS Total Functional Capacity (TFC). HD is also classified based on TFC scores (also known as Shoulson and Fahn stages) as early (corresponding to stage 1 or 2 based on TFC scores), moderate or intermediate HD (corresponding to stage 3 based on TFC scores), and late or advanced HD (corresponding to stage 4 or 5 based on TFC scores).

[0007] Currently, only symptomatic treatment is available. Therefore, to date, there are no therapies available to slow the progression of HD. Therefore, there is a need to find disease-modifying therapies for HD, such as treatment options that can slow disease progression. Summary of the Invention

[0008] In one aspect, a compound having formula (I) is disclosed: , Or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer. in X 1 It is CR 2 Or N; X 2 It is CR 6 Or N; X 3 and X 4 Each is independently CH and CR 8 , or N, where R 8 It is a halogen (e.g., fluorine); W is O or NR N , where R N Is it hydrogen or C? 1-6 alkyl; R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, halogens and -N(R) N1 )2; by -N(R N1C2 or heterocyclic substituted 1-6 Alkyl; with -N(R) N1 C2 or heterocyclic substituted 2-6 alkenyl; with -N(R) N1 )2 replaced by C 3-8 cycloalkyl; or -CH=C(R) N2 )2, where each R N1 Independently, it is H or C 1-6 Alkyl group, and two R groups N2 Together with the atoms to which they are attached, they form a heterocyclic group containing at least one nitrogen atom within the ring; R 2 It is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R 3 and R 6 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkoxy or halogen; R 4 It is a heteroaryl group consisting of a halogen, a cyano group, or optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl, oxo, and halogen, and each R 5 —When present—it is independently a halogen or C 1-6 alkoxy; or R 4 And an R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen; R 7 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or -OR 9 , where R 9 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0 or 1; and m can be 0, 1, or 2.

[0009] In some embodiments, the compound is a compound having formula (I): , Or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer. in X 1 It is CR 2 Or N; X 2 It is CR 6 Or N; X 3 and X 4 Each is independently CH and CR 8 , or N, where R 8 It is a halogen (e.g., fluorine); W is O or NR N , where R N Is it hydrogen or C? 1-6 alkyl; R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens; R 2 It is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R 3 and R 6 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkoxy or halogen; R 4 It is a heteroaryl group consisting of a halogen, a cyano group, or optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl, oxo, and halogen, and each R 5 —When present—it is independently a halogen or C 1-6 alkoxy; or R 4 And an R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen; R 7 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or -OR 9 , where R 9 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0 or 1; and m can be 0, 1, or 2.

[0010] In some embodiments, X 3 It is N. In some embodiments, X 3 It is CH. In some embodiments, X 3 It is CR 8 In some embodiments, R 8 It's fluorine.

[0011] In some embodiments, X 4 It is CH. In some embodiments, X 4 It is N.

[0012] In some embodiments, the compound has the formula (I'): .

[0013] In some embodiments, the compound has formula (IA): .

[0014] In some embodiments, X 1 It is N. In some embodiments, X 1 It is CR 2 .

[0015] In some embodiments, X 2 It is N. In some embodiments, X 2 It is CR 6 .

[0016] In some embodiments, the compound has the formula (IB): .

[0017] In some embodiments, R 6 It is hydrogen. In some embodiments, R 6 It's fluorine.

[0018] In some embodiments, the compound has the formula (IC): .

[0019] In some embodiments, R 3 It is a hydroxyl group. In some embodiments, R 3 It is fluorine. In some embodiments, R 3 It is C 1-6 Alkyl group.

[0020] In some embodiments, R 4 It is a 5-membered monocyclic heteroaryl group containing 1, 2, 3, or 4 nitrogen atoms in the ring, optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

[0021] In some embodiments, R 4 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0022] In some embodiments, R 4 Choose from the following groups: , , , , , , , and .

[0023] In some embodiments, R 4 Choose from the following groups: , , , , , , , , , , , , and .

[0024] In some embodiments, R 4 Choose from the following groups: , , , and .

[0025] In some embodiments, R 4 It is a 6-membered monocyclic heteroaryl group containing 1, 2, or 3 nitrogen atoms in the ring and optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

[0026] In some embodiments, R 4 Choose from the following groups: , , , , , , , , and .

[0027] In some embodiments, R 4 Choose from the following groups: , , and .

[0028] In some embodiments, R 4 Choose from the following groups: and .

[0029] In some embodiments, R 4 It is cyano. In some embodiments, R 4 It is chlorine.

[0030] In some embodiments, R 4 It is an N-heteroaryl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkyl groups, hydroxyl groups, oxo groups, and halogens. In some embodiments, R 4 It is a bicyclic N-heteroaryl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

[0031] In some embodiments, R 4 yes or .

[0032] In some embodiments, R 4 yes .

[0033] In some embodiments, R 4 and R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen or C 1-6 Alkyl group, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen.

[0034] In some embodiments, R 4 Choose from the following groups: , , , , , and .

[0035] 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.

[0036] In some embodiments, R 5 It's fluorine.

[0037] In some embodiments, W is 0. In some embodiments, W is NR. N In some embodiments, R N It is a methyl group.

[0038] In some embodiments, R 1 It is a heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

[0039] In some embodiments, R 1 It is a 6-membered monocyclic heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

[0040] In some embodiments, R 1 It is a 7-membered monocyclic heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

[0041] In some embodiments, R 1 It is a bicyclic heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms (e.g., 1 or 2 nitrogen atoms) and optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

[0042] In some embodiments, R 1 Through R 1 The carbon atoms in the ring are bonded to the nucleus.

[0043] In some embodiments, R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl and hydroxyl groups.

[0044] In some embodiments, R 1 It is a spirocyclic heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

[0045] In some embodiments, R 1 It is -N(R) N1 C2 or heterocyclic substituted 1-6 alkyl.

[0046] In some embodiments, R 1 It is -N(R) N1 C2 or heterocyclic substituted 2-6 Alkenyl group.

[0047] In some embodiments, R 1 It is -N(R) N1 )2 replaced by C 3-8 Cycloalkyl.

[0048] In some embodiments, R 1 It is -CH=C(R) N2 )2, where each R N1 Independently, it is H or C 1-6 Alkyl group, and two R groups N2 Together with the atoms to which they are attached, they form a heterocyclic group containing at least one nitrogen atom within the ring.

[0049] In some embodiments, R 1 Choose from the following groups: , , , , , , , , and .

[0050] In some embodiments, R 1 Choose from the following groups: , , , , , , , , , and .

[0051] In some embodiments, R 1 Choose from the following groups: , , , , , and .

[0052] In some embodiments, R 1 yes or .

[0053] In some embodiments, R 1 Choose from the following groups: , , , , , and .

[0054] In some embodiments, R 1 yes or .

[0055] In some embodiments, R 1 yes .

[0056] In some embodiments, R 1 Choose from the following groups: , , and .

[0057] In some embodiments, R 1 Choose from the following groups: , , , , and .

[0058] In some embodiments, R 1 Choose from the following groups: , and .

[0059] In some embodiments, R 1 Choose from the following groups: and .

[0060] In some embodiments, R 1 yes: .

[0061] In some embodiments, R 7 It is hydrogen.

[0062] On the other hand, a compound selected from the group consisting of:

[0063] And its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers and tautomers.

[0064] In some embodiments, the compounds are 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 compounds are 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 compounds are 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 compounds are selected from the group consisting of compounds 1-33, 64, 65, 69, 73, and their pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers. In some embodiments, the compounds are 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 their pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers. In some embodiments, the compound is selected from the group consisting of compounds 1-20, 64, 65, 69, and their pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, and tautomers. In some embodiments, the compound is compound 1 or its pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer. In some embodiments, the compound is compound 2 or its pharmaceutically acceptable salt. In some embodiments, the compound is compound 7 or its pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer. In some embodiments, the compound is compound 10 or its pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer. In some embodiments, the compound is compound 11 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0065] In another aspect, a pharmaceutical composition is disclosed comprising an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers.

[0066] In another aspect, a method for treating Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction is disclosed, comprising administering to a subject in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0067] In some embodiments, the method is used to treat Huntington's disease. In some embodiments, the method is used to treat spinal muscular atrophy. In some embodiments, the method is used to treat familial autonomic dysfunction.

[0068] In some embodiments, the method further includes administering an effective amount of an MSH3 inhibitor.

[0069] In another aspect, the use of the compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, or tautomers thereof, or pharmaceutical compositions disclosed herein, in the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction is disclosed.

[0070] In some embodiments, this use is in the treatment of Huntington's disease. In some embodiments, this use is in the treatment of spinal muscular atrophy. In some embodiments, this use is in the treatment of familial autonomic dysfunction.

[0071] In some embodiments, this use is in combination with an MSH3 inhibitor.

[0072] In other respects, the compounds disclosed herein or pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, or tautomers, or pharmaceutical compositions disclosed herein, are disclosed for the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction.

[0073] In some embodiments, the compound or pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or pharmaceutical composition is used to treat Huntington's disease. In some embodiments, the compound or pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or pharmaceutical composition is used to treat spinal muscular atrophy. In some embodiments, the compound or pharmaceutically acceptable salt, hydrate, solvate, racemate, enantiomer, diastereomer, or tautomer, or pharmaceutical composition is used to treat familial autonomic dysfunction.

[0074] In some embodiments, the treatment is performed in combination with an MSH3 inhibitor.

[0075] On the other hand, the use of the compounds disclosed herein, or pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, or tautomers thereof, in the manufacture of medicaments for the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction is disclosed.

[0076] In some embodiments, the agent is used for the treatment of Huntington's disease. In some embodiments, the agent is used for the treatment of spinal muscular atrophy. In some embodiments, the agent is used for the treatment of familial autonomic dysfunction.

[0077] In some embodiments, this use is in combination with an MSH3 inhibitor.

[0078] On another aspect, a method for forming a complex comprising a spliceosome component, a nucleic acid, and a compound disclosed herein is disclosed, comprising contacting the nucleic acid with the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof.

[0079] In some embodiments, the components of the spliceosome are major or minor spliceosome components. In some embodiments, the nucleic acid is DNA or RNA. In some embodiments, the nucleic acid is a precursor mRNA transcript.

[0080] In another aspect, a method for modifying RNA splicing to produce a mature mRNA transcript having an intronicexon is disclosed, the method comprising contacting a cell containing a precursor mRNA transcript comprising at least two exons and at least one intron, wherein at least one of the exons is upstream of an intron and at least one of the exons is downstream of an intron.

[0081] In some embodiments, the intron comprises, in order from 5' to 3': a first 5' splice site, a first branching point, a first 3' splice site, an intron recognition element (iREMS) for a splicing modifier, a second branching point, and a second 3' splice site, wherein the iREMS comprises the RNA sequence GAgurngn, where r is adenine or guanine, and n is any nucleotide.

[0082] In some embodiments, the intron further comprises, in order of 5' to 3', 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.

[0083] In some embodiments, the precursor mRNA transcript is a precursor mRNA transcript of a gene selected from the group consisting of: ADAL、ADAM23、ADAMTS19、AGPS、AKAP8L、ANKRD13C、ANXA11、ARL15、ARSJ、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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, AHRGAP1, AHRGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD 10、C10orf76、C11orf30、C11orf73、C12orf4、C1orf27、C1QTNF9B-AS1、CCN L2、CDH18、CENPI、CEP57、CMSS1、CNOT7、COPS7B、CRISPLD2、CUX1、DCAF17、D DX42、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、INPP 4B、ITCH、IVD、KDM6A、KDSR、KIAA1524、KIAA1715、KIDINS220、L3MBTL2、LGA LS3、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、R AF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA 2、SPIDR、SSBP1、STRADB、STXBP6、SUPT20H、TAF2、TASP1、TBCA、TBL1XR1、TC F4、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.

[0084] In some embodiments, the precursor mRNA transcript is a precursor 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, H OXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777.

[0085] In some embodiments, the precursor mRNA transcript is a precursor 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, CHR M2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AG PS, 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, DCAF17 2a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H.

[0086] In some embodiments, the precursor mRNA transcript is the precursor mRNA transcript of the HTT, SMN2, ELP1, FOXM1, or MAPT gene.

[0087] In some embodiments, the precursor mRNA transcript is the precursor mRNA transcript of the HTT gene. Detailed Implementation

[0088] This disclosure relates to compounds having formula (I) (including (I'), (IA), (IB), (IC)), exemplified compounds, their salts, particularly their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds), as well as intrinsically formed moieties.

[0089] For the purposes of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular form will also include the plural form, and vice versa.

[0090] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon substituent. C 1-10 Alkyl groups are alkyl groups having 1 to 10 carbon atoms. The term "C" is used in this context. 1-6 "alkyl" and "C" 1-4 The term "alkyl" should be interpreted accordingly. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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.

[0091] As used herein, the term "alkenyl" refers to a branched or unbranched hydrocarbon substituent having one or two carbon-carbon double bonds. 2-10 Alkenyl groups are alkenyl groups having 2 to 10 carbon atoms. The term "C" is used to describe this. 2-6 "alkyl" and "C" 2-4 The term "alkyl" should be interpreted accordingly. Representative examples of alkenyl groups include, but are not limited to, vinyl, propen-1-yl, propen-1-yl, isopropenyl, 2-methylpropen-1-yl, buten-1-yl, buten-2-yl, buten-1-yl, buten-3-yl, buten-2-yl, buten-2-yl, buten-2-yl, penten-1-yl, penten-2-yl, penten-3-yl, and penten-4-yl. -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 structural isomers.

[0092] As used herein, the term "alkoxy" refers to -O-alkyl, where alkyl is defined above. The term "C"...1-6 "Alkoxy" should be interpreted accordingly. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, octoxy-, and decoxy-.

[0093] The term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring moiety. Typically, an aryl group is a monocyclic, bicyclic, or tricyclic aryl group having 6-20 carbon atoms and includes one or more aromatic rings optionally fused to one or more non-aromatic hydrocarbon rings. The term "C"... 6-10 "Aryl" should be interpreted accordingly. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0094] The term "arylalkyl" refers to the group -LR, where L is an alkyl group substituted with R, which is an aryl group.

[0095] As used herein, the term "cycloalkyl" refers to a saturated or non-aromatic, unsaturated monocyclic, bicyclic, or tricyclic hydrocarbon group. 3-12 Cycloalkyl groups are cycloalkyl groups with 3-12 carbon atoms. The term "C" is used in this context. 3-8 "Cycloalkyl" refers to a fully saturated or non-aromatic, unsaturated monocyclic hydrocarbon group with 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 borneol, indolyl, hexahydroindolyl, 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, and bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include, for example, adamantyl.

[0096] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein at least one of the hydrogen atoms is replaced by a halogen atom. Haloalkyl groups can be monohaloalkyl, dihaloalkyl, or polyhaloalkyl, including perhaloalkyl. Monohaloalkyl groups have an iodine, bromine, chlorine, or fluorine atom on the alkyl group. Dihaloalkyl and polyhaloalkyl groups have two or more of the same halogen substituents or a combination of different halogen substituents on the alkyl group. The term "C"... 1-6 "Halogenated alkyl" should be interpreted accordingly. Non-limiting examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A fully halogenated alkyl group is an alkyl group in which all hydrogen atoms are replaced by halogen substituents.

[0097] As used in this article, the term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine.

[0098] As used herein, the term "heteroaryl" refers to a 5-membered, 6-membered, or 7-membered monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms selected from O, S, and N; an 8-membered, 9-membered, or 10-membered fused bicyclic system containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N; or an 11-membered, 12-membered, 13-membered, or 14-membered fused tricyclic system containing 1, 2, 3, 4, 5, or 6 heteroatoms selected from O, S, and N, wherein at least one of the rings in the bicyclic or tricyclic system is completely aromatic. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrroleyl, 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-isooxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,4-triazolyl, and 4- or 5-1,2,4-triazolyl.3-Triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indazinyl, 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-purineyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl; 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl; 2-, 3-, 4-, 5-, or 6-naphthidyl; 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl; 3-, 4-, 5-, 6-, 7-, or 8-pyrolinyl; 2-, 4-, 6-, or 7-pteridyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aHcarbazoyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbazoyl; 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbazoyl; 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridyl; 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl; 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-vinidinyl; 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenanthroline; 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl; 1-, 2-, 3-, 4-, 6- 7, 8, 9, or 10-phenthiazinyl, 1, 2, 3, 4, 6, 7, 8, 9, or 10-phenoxazinyl, 2, 3, 4, 5, 6, or 1, 3, 4, 5, 6, 7, 8, 9, or 10-benzisoquinolinyl, 2, 3, 4, or thieno[2,3-b] Furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazole, 2-, 3-, 5-, 6-, or 7-2H-furan[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazo[4,3-d]-oxazinyl, 2-, 4-, or 5-4H-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-furan[3,4-c] pyridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10-, or 11-4H-pyrido[2,3-c]carbazole, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiophene, 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-benzoxepinyl, 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]benzozaheptanyl, 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]thiopheneyl, 2-, 4-, 5-, 6-, or 7-benzooxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.

[0099] 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 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 system containing 1, 2, 3, 4, 5, 6, or 7 heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states. Heterocyclic groups can be attached via heteroatoms or carbon atoms. Heterocyclic groups can include fused or bridged rings and spirocyclic rings. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazoline, pyrrolidine, pyrrolidine, tetrahydropyran, dihydropyran, oxothionecyclopentane, dithionecyclopentane, 1,3-dioxane, 1,3-dithiane, oxothionecyclohexane, and thiomorpholine.

[0100] As used herein, the term "isomer" refers to different compounds having the same molecular formula but different arrangements and configurations of atoms. Also as used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that a given compound disclosed herein can exist in, and include geometric isomers. It should be understood that substituents may be attached at the chiral center of a carbon atom. Therefore, this disclosure includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of enantiomer pairs is a "racemic" mixture. This term is used to specify racemic mixtures where appropriate. A "diastereomer" is a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be determined by… R or S The designation is specified. Depending on the direction (right-handed or left-handed) of their rotation of the polarization plane at the wavelength of the sodium D line, a resolving compound with an unknown absolute configuration can be designated as (+) or (-). Some of the compounds described herein contain one or more asymmetric centers or axes, and therefore can produce enantiomers, diastereomers, and other stereoisomers (which, in terms of absolute stereochemistry, can be defined as (…). R )-or( S This disclosure is intended to include all of these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optical activity ( R )-and( S (-)Isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent can be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration. All tautomers are also intended to be included.

[0101] As used in this article, the term "oxo" refers to the =O group.

[0102] As used herein, the term "optionally substituted" refers to unsubstituted or substituted groups.

[0103] As used herein, the term "protecting group" refers to those groups designed to protect functional groups (e.g., -OH or -NH2) from unwanted reactions during the synthetic procedure. 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 (and the oxygen atom to which they are attached) include, for example, esters, carbonates, carbamates, sulfonates, and ethers.

[0104] As used herein, the term "salt" refers to the acid addition salt or base addition salt of the compounds disclosed herein. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means a salt that retains the biological efficacy and properties of the compounds disclosed herein, and that such salts are typically not biologically or otherwise undesirable. In many cases, the compounds disclosed herein are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0105] The term “therapeutic effective amount” or “effective amount” as used herein refers to the amount of the compound disclosed herein that will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of condition, slowing or delaying disease progression, or prevention of disease, etc.). In one embodiment, the term “therapeutic effective amount” refers to an amount of the compound disclosed herein that, when administered to a subject, effectively (1) at least partially relieves, prevents, and / or improves (i) a condition or disorder or disease mediated by HTT, SMN2, or ELP1, or (ii) related to [receptor] activity, or (iii) characterized by [receptor] activity (normal or abnormal); or (2) reduces or inhibits [receptor] activity; or (3) reduces or inhibits [receptor] expression. In another embodiment, the term "therapeuticly effective amount" refers to an amount of the compound disclosed herein that, when applied to cells, tissues, non-cellular biological materials, or media, effectively at least partially reduces or inhibits the activity of [receptor]; or at least partially reduces or inhibits the expression of [receptor]. The meaning of the term "therapeuticly effective amount" as illustrated in the above embodiments is also applicable in the same manner to any other related protein / peptide / enzyme, such as [receptor YZ] or other [receptor AB], etc.

[0106] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject can also refer to, for example, a primate (e.g., a human, male or female). In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0107] As used herein, the term “inhibit (inhibition or inhibiting)” means to reduce or suppress a given condition, symptom, disorder, or disease, or to significantly reduce the baseline activity of a biological activity or process.

[0108] 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 reduces or inhibits the activity of MSH3 in cells upon contact with MSH3, for example, by reducing or inhibiting the activity or production of the MSH3 protein. Non-limiting examples of MSH3 inhibitors are known in the art, such as those disclosed in US 20210355491, US 20220072028, US 20230313185, US20240263179, WO 2021247020, and WO 2023168304 (the disclosures of which are hereby incorporated by reference).

[0109] As used herein, the term “treatment” for any disease or condition means to reduce or improve the disease or condition (i.e., to slow or stop the development of the disease or at least one of its clinical symptoms); or to reduce or improve at least one physical parameter or biomarker associated with the disease or condition, including those physical parameters or biomarkers that the patient may not be able to identify.

[0110] As used in this article, subjects who will benefit from the treatment biologically, medically, or in terms of quality of life are considered “in need” of such treatment.

[0111] As used herein, the terms “a / an”, “the”, and similar terms used in the context of this disclosure (especially in the context of the claims) should be interpreted as covering both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context.

[0112] All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all instances or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate this disclosure and does not limit the scope of this disclosure as otherwise claimed.

[0113] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds disclosed herein may exist in racemic or enantiomer-enriched forms, for example ( R )-、( S )-or( R,S (R)- or (S)- configuration. In some embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess in the (R)- or (S)- configuration. If possible, substituents at atoms having unsaturated bonds may be in cis-(Z)- or trans-(E)- form.

[0114] Therefore, as used herein, the compounds disclosed herein may be in the form of one of the possible isomers, rotational isomers, transisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric ( cis or trans Isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0115] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or fractional crystallization, based on the physicochemical differences of the components.

[0116] The racemic derivatives of any resulting end product or intermediate can be resolved into optical enantiomers by known methods, for example, by separating their diastereomer salts obtained with optically active acids or bases, releasing the optically active acidic or basic compounds. In particular, the compounds disclosed herein can therefore be resolved into their optical enantiomers using a basic moiety, for example, by fractional crystallization with optically active acids, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di- O,O' - It can be resolved by salts formed from p-toluyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using chiral adsorbents).

[0117] The compounds disclosed in this article are obtained in free form, as their salts, or as their prodrug derivatives.

[0118] When both basic and acidic groups are present in the same molecule, the compounds disclosed herein can also form internal salts, such as zwitterionic molecules.

[0119] Furthermore, the compounds disclosed herein (including their salts) may also be obtained as their hydrates, or may 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, this disclosure is intended to include both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds disclosed herein (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical industry and are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0120] The compounds disclosed herein (including their salts, hydrates and solvates) can be polymorphically formed, either by their own design or by design.

[0121] This disclosure further includes any variations of the methods disclosed herein, wherein an intermediate product available at any stage is used as the starting material and the remaining steps are carried out, or wherein the starting material is under reaction conditions in situ Formation, or in which the reactive components are used in the form of their salts or optically pure materials.

[0122] The compounds and intermediates disclosed in this article can also be based on person skilled in the art Commonly known methods can be used to convert between each other.

[0123] Generally, this disclosure provides compounds that can be used in the treatment of Huntington's disease. Without being bound by theory, the compounds disclosed herein can promote the degradation of huntingtin mRNA by facilitating pseudoexon inclusion during the splicing of huntingtin precursor mRNA. The compounds disclosed herein are those having formula (I): , (I) Or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer. in X 1 It is CR 2 Or N; X 2 It is CR 6 Or N; X 3 and X 4 Each is independently CH and CR 8 , or N, where R 8 It is halogen; W is O or NR N , where R N Is it hydrogen or C? 1-6 alkyl; R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, halogens and -N(R) N1 )2; by -N(R N1 C2 or heterocyclic substituted 1-6 Alkyl; with -N(R) N1 C2 or heterocyclic substituted 2-6 alkenyl; with -N(R) N1 )2 replaced by C 3-8 cycloalkyl; or -CH=C(R) N2 )2, where each R N1 Independently, it is H or C 1-6 Alkyl group, and two R groups N2 Together with the atoms to which they are attached, they form a heterocyclic group containing at least one nitrogen atom within the ring; R 2 It is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R 3 and R 6 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkoxy or halogen; R 4 It is a heteroaryl group consisting of a halogen, a cyano group, or optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl, oxo, and halogen, and each R 5 —When present—it is independently a halogen or C 1-6 alkoxy; or R 4 And an R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen; R 7 It is hydrogen, C 1-6 Alkyl, C 1-6Halogenated alkyl, or -OR 9 , where R 9 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0 or 1; and m can be 0, 1, or 2.

[0124] In some embodiments, the compound is a compound having formula (I): , (I) Or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer. in X 1 It is CR 2 Or N; X 2 It is CR 6 Or N; X 3 and X 4 Each is independently CH and CR 8 , or N, where R 8 It is a halogen (e.g., fluorine); W is O or NR N , where R N Is it hydrogen or C? 1-6 alkyl; R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens; R 2 It is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R 3 and R 6 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkoxy or halogen; R 4 It is a heteroaryl group consisting of a halogen, a cyano group, or optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl, oxo, and halogen, and each R 5 —When present—it is independently a halogen or C 1-6alkoxy; or R 4 And an R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen; R 7 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or -OR 9 , where R 9 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0 or 1; and m can be 0, 1, or 2.

[0125] Non-limiting examples of compounds disclosed herein include the following:

[0126] And its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers and tautomers.

[0127] Pharmaceutically acceptable salts

[0128] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, gluconate, gluconate, glucuronates, hippurates, hydroiodates / iodides, hydroxyethyl sulfonates, lactobionates, lacturonates, lauryl sulfate, malates, maleates, malonates, mandelates, methanesulfonates, methyl sulfates, naphthates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propions, stearates, succinates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0129] Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0130] Organic acids that can be used to form salts 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, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[0131] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0132] Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins. Some organic amines include isopropylamine, benzylamine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0133] The pharmaceutically acceptable salts disclosed herein can be synthesized from the basic or acidic portions of parent compounds using conventional chemical methods. Typically, such salts are prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or organic solvents, or mixtures of both. Generally, where feasible, the use of non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable. Other suitable lists of salts can be found, for example, Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, Pa. (1985); and Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0134] Isotope-enriched compounds

[0135] Any formulas given herein are also intended to represent the unlabeled form of the compound as well as the isotopically labeled form. Isotopically labeled compounds have the structure represented by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl、 125 I. This disclosure includes compounds labeled with various isotopes as defined herein, such as those containing radioactive isotopes (e.g., 3 H, 13 C and 14 Those of type C). Compounds labeled with this type of isotope can be used for metabolic studies (using...). 14C) Reaction kinetic studies (e.g., using...) 2 H or 3 H) 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 for use in patient radiation therapy. Specifically, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds disclosed herein and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the procedures disclosed in the embodiments and preparations described below.

[0136] Furthermore, heavier isotopes, especially deuterium (i.e., 2 H or D substitution can provide certain therapeutic advantages arising from greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, or improved therapeutic index. It should be understood that, in this context, deuterium is considered a substituent in compounds having formula (I). The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a particular isotope. If the substituents in the compounds disclosed herein specify deuterium, then such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0137] Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0138] Pharmaceutically acceptable solvates according to this disclosure include those in which the crystallization solvent can be replaced by an isotope, such as D2O, d6-acetone, and d6-DMSO.

[0139] Eutectic

[0140] The compounds disclosed herein, i.e., compounds of formula (I) containing groups capable of acting as donors and / or acceptors of hydrogen bonds, are capable of forming cocrystals with suitable cocrystal forgings. These cocrystals can be prepared from compounds of formula (I) by known cocrystal formation methods. Such methods include grinding, heating, co-sublimation, co-melting, or contacting the compound of formula (I) with the cocrystal forging in solution under crystallization conditions and separating the resulting cocrystal. Suitable cocrystal forgings include those described in WO 2004 / 078163. Therefore, this disclosure further provides cocrystals comprising compounds of formula (I).

[0141] Tautomerism

[0142] The compounds disclosed herein may also exist in their tautomeric forms. Although not explicitly stated in this application, such forms are intended to be included within the scope of this disclosure.

[0143] Pharmaceutical Composition

[0144] This disclosure also provides a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions disclosed herein can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical processes, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0145] Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient along with the following: Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; Lubricants, such as silica, talc, stearic acid, their magnesium or calcium salts, and / or polyethylene glycol; also, in the case of tablets, include... Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, astragalus gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; if desired Disintegrants, such as starch, agar, alginate or its sodium salt or effervescent mixture; and / or Adsorbents, colorants, flavorings, and sweeteners.

[0146] Tablets can be film-coated or enteric-coated using methods known in the art.

[0147] Suitable compositions for oral administration include effective amounts of the compounds 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 manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable formulation. Tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period of time. For example, time-delayed materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0148] Some injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterile and / or contain excipients (e.g., preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure). Additionally, they may contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain about 0.1%–75%, or about 1%–50%, of the active ingredient.

[0149] Suitable compositions for transdermal applications include an effective amount of the compound disclosed herein with a suitable carrier. Carriers suitable for transdermal delivery include absorbable, pharmacologically acceptable solvents that facilitate passage through the host skin. For example, a transdermal device may be in the form of a bandage comprising a back member, a reservoir containing the compound optionally having a carrier, a rate control barrier optionally for delivering the compound to the host skin at a controlled and predetermined rate over an extended period of time, and a device for securing the device to the skin.

[0150] Compositions suitable for topical applications (e.g., application to skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, for example, for delivery via aerosols, etc. Such topical delivery systems are particularly suitable for dermal applications, such as for the treatment of skin cancer, and for preventative uses, such as in sunscreens, lotions, sprays, etc. Therefore, they are particularly suitable for topical applications, including cosmetics and formulations well known in the art. Such systems may contain solubilizers, stabilizers, tension enhancers, buffers, and preservatives.

[0151] As used herein, topical applications may also involve inhalation or intranasal application. They can be conveniently delivered, with or without a suitable propellant, from a dry powder inhaler in the form of dry powder (alone as a mixture, such as a dry blend with lactose, or mixed component particles, such as component particles mixed with phospholipids) or from a pressurized container, pump, spray, nebulizer, or nebulizer in the form of an aerosol spray.

[0152] This disclosure further provides anhydrous pharmaceutical compositions and dosage forms comprising one or more of the compounds disclosed herein as one or more active ingredients, since water can promote the degradation of certain compounds.

[0153] The anhydrous pharmaceutical compositions and dosage forms disclosed herein can be prepared using anhydrous or low-aqueous components and low-moisture or low-humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous properties. Therefore, anhydrous compositions are packaged using materials known to prevent exposure to water, so that they can be included in suitable pre-designated kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0154] This disclosure further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate of degradation of the compounds disclosed herein as active ingredients. Such agents (referred to herein as “stabilizers”) include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or saline buffers.

[0155] How to use

[0156] Compounds of Formula I, whether in free or salt form, exhibit valuable pharmacological properties, such as regulatory properties in full-length proteins (e.g., HTT).

[0157] Therefore, as an additional embodiment, this disclosure provides the use of compounds having formula (I) or pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, or tautomers thereof in a therapy. In another embodiment, the therapy is selected from diseases that can be treated by modulating the production of full-length proteins (e.g., HTT).

[0158] In another embodiment, this disclosure provides a method of treating a disease by regulating the production of a full-length protein (e.g., HTT), comprising administering to a patient in need of such therapy a therapeutically acceptable amount of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, racemic, enantiomer, diastereomer, or tautomer thereof.

[0159] Therefore, as an additional embodiment, this disclosure provides the use of a compound having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof for the manufacture of a pharmaceutical agent. In another embodiment, the pharmaceutical agent is used to treat a disease that can be treated by regulating the production of a protein (e.g., HTT).

[0160] In one embodiment, the methods and uses described above relate to the regulation of protein production, wherein the protein (e.g., a full-length protein) is selected from the group consisting of: ADAL、ADAM23、ADAMTS19、AGPS、AKAP8L、ANKRD13C、ANXA11、ARL15、ARSJ、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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, AHRGAP1, AHRGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD 10、C10orf76、C11orf30、C11orf73、C12orf4、C1orf27、C1QTNF9B-AS1、CCN L2、CDH18、CENPI、CEP57、CMSS1、CNOT7、COPS7B、CRISPLD2、CUX1、DCAF17、D DX42、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、INPP 4B、ITCH、IVD、KDM6A、KDSR、KIAA1524、KIAA1715、KIDINS220、L3MBTL2、LGA LS3、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、R AF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA 2、SPIDR、SSBP1、STRADB、STXBP6、SUPT20H、TAF2、TASP1、TBCA、TBL1XR1、TC F4、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.

[0161] 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 autonomic dysfunction.

[0162] Regulation of protein production can involve the regulation of gene transcript (e.g., precursor mRNA) splicing. Therefore, in one embodiment, this disclosure provides a method for modifying RNA splicing to produce a mature mRNA transcript containing exons, the method comprising contacting a compound described herein or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof with a cell containing a precursor 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 a 5' to 3' order: a first 5' splice site, a first branching point, a first 3' splice site, an intron recognition element (iREMS) for a splice modifier, a second branching point, and a second 3' splice site, wherein the iREMS comprises the RNA sequence GAgurngn, where r is adenine or guanine, and n is any nucleotide. The intron may further include, in order from 5' to 3', 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.

[0163] Not wanting to be bound by theory, it is assumed that RNA splicing regulation occurs through the formation of a complex comprising components of the spliceosome, nucleic acids, and the compounds disclosed herein. Therefore, this disclosure also provides a method for forming a complex comprising components of the spliceosome, nucleic acids, and the compounds disclosed herein. The nucleic acid can be RNA (e.g., in the context of RNA splicing regulation), such as precursor mRNA.

[0164] In one embodiment, the precursor mRNA is a precursor mRNA transcript of a gene selected from the group consisting of: ADAL、ADAM23、ADAMTS19、AGPS、AKAP8L、ANKRD13C、ANXA11、ARL15、ARSJ、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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, AHRGAP1, AHRGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD 10、C10orf76、C11orf30、C11orf73、C12orf4、C1orf27、C1QTNF9B-AS1、CCN L2、CDH18、CENPI、CEP57、CMSS1、CNOT7、COPS7B、CRISPLD2、CUX1、DCAF17、D DX42、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、INPP 4B、ITCH、IVD、KDM6A、KDSR、KIAA1524、KIAA1715、KIDINS220、L3MBTL2、LGA LS3、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、R AF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA 2、SPIDR、SSBP1、STRADB、STXBP6、SUPT20H、TAF2、TASP1、TBCA、TBL1XR1、TC F4、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 precursor mRNA transcript is the precursor mRNA transcript of the HTT gene, and the disease is Huntington's disease. In one embodiment, the precursor mRNA transcript is the precursor mRNA transcript of the SMN2 gene, and the disease is spinal muscular atrophy (SMA). In one embodiment, the precursor mRNA transcript is the precursor mRNA transcript of the ELP1 gene, and the disease is familial autonomic dysfunction.

[0165] In one embodiment, this disclosure provides a method for treating Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction, the method comprising administering to a subject in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or a pharmaceutical composition disclosed herein.

[0166] In one embodiment, this disclosure provides the use of the compounds disclosed herein or their pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers, or tautomers, or the pharmaceutical compositions disclosed herein, for the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction.

[0167] In one embodiment, this disclosure provides the use of the compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, racemic, enantiomer, diastereomer, or tautomer thereof, in the manufacture of a medicament for the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction.

[0168] For subjects weighing approximately 0.05–70 kg or 1–20 kg, the compounds, pharmaceutical compositions, or combinations disclosed herein may be administered in unit doses of approximately 0.01–1000 mg of one or more active ingredients, or approximately 1–500 mg, 1–250 mg, 1–150 mg, 0.5–100 mg, 0.01–1 mg, 0.01–0.1 mg, or 1–50 mg of active ingredients. The effective dose of the compound, pharmaceutical composition, or combination thereof depends on the subject's species, weight, age, and the individual condition, disorder, or disease being treated, or its severity. A physician, clinician, or veterinarian with general skills can readily determine the effective amount of each active ingredient necessary for the prevention, treatment, or inhibition of the progression of a disorder or disease.

[0169] Using beneficial mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and products in body in vitro and in vivo The above-mentioned dosage characteristics were demonstrated in testing. The compounds disclosed herein may be in solution form (e.g., aqueous solution). in vitro Administration, as well as intravenous, parenteral (advantageously, intravenous), for example as a suspension or in an aqueous solution. in vivo Apply. in vitro The dosage can be around 10 -3 molar concentration and 10 -9 The range of molar concentrations. Depends on the route of application. in vivo The effective dose can be between about 0.1-500 mg / kg, or in the range of about 1-100 mg / kg.

[0170] The compounds disclosed herein may be administered concurrently with one or more other therapeutic agents, or before or after one or more other therapeutic agents. The compounds disclosed herein may be administered alone via the same or different routes of administration, or together with other pharmaceutical agents in the same pharmaceutical composition.

[0171] In one embodiment, this disclosure provides a product comprising a compound having formula (I) and at least one other therapeutic agent, as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is treatment for Huntington's disease. The product provided as a combination formulation comprises a composition comprising a compound having formula (I) and one or more other therapeutic agents together in the same pharmaceutical composition, or comprises a compound having formula (I) and one or more other therapeutic agents in a separate form (e.g., in the form of a kit).

[0172] In one embodiment, this disclosure provides a pharmaceutical composition comprising a compound having formula (I) and one or more additional therapeutic agents. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0173] In one embodiment, this disclosure provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound having formula (I). In one embodiment, the kit includes means (such as containers, separate bottles, or separate foil packs) for separately retaining the compositions. An example of such a kit is blister packaging, as typically used for packaging tablets, capsules, etc.

[0174] The kits disclosed herein can be used to administer different dosage forms (e.g., oral and parenteral), to administer individual compositions at different dose intervals, or to titrate individual compositions against each other. To aid compliance, the kits disclosed herein typically include instructions for use.

[0175] In the combination therapies disclosed herein, the compounds and other therapeutic agents disclosed herein may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds and other therapeutic agents disclosed herein may be used together to form a combination therapy: (i) before the delivery of the combination product to a physician (e.g., in the case of a kit containing the compounds and other therapeutic agents disclosed herein); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); and (iii) in the patient himself, for example, during successive administration of the compounds and other therapeutic agents disclosed herein.

[0176] Preparation of compounds

[0177] It should be understood that, in the following description, the combination of substituents and / or variables depicted in the formulas is permitted only if such contributions produce stable compounds.

[0178] The compounds disclosed herein can be prepared in many ways well known to those skilled in the art of organic synthesis. For example, the compounds disclosed herein can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art.

[0179] Typically, compounds having formula (I) can be prepared according to the methods provided below.

[0180]

[0181] As shown above, compounds having formula (I) can be prepared from intermediates I4 or I5, for example, via R 3 Deprotection of the -O- (protecting group) in R to provide as R3 The -OH group can be removed using techniques and methods known in the art. In a non-limiting example, a hydroxyl group masked as a methoxy group can be demasked by reaction with a strong Lewis acid (e.g., BBr3). A hydroxyl group masked as a silyl ether can be demasked using a fluoride source (e.g., a fluoride salt such as KF or TBAF). Alternatively, a hydroxyl group protected as a TMS or TES ether can be demasked by reaction with a Brønsted acid (e.g., a carboxylic acid). In another non-limiting example, a hydroxyl group protected as an ester can be demasked by reaction with C... 1-6 Alkoxides (e.g., alkali metal C) 1-6 Alkoxides or alkaline earth metals C 1-6 Deprotection can be achieved through reactions involving alkoxides. In yet another non-limiting example, the hydroxyl group protected as an arylalkyl ether (e.g., 1-arylalkyl-1-yl ether) can be deprotected using a reduction reaction (e.g., with Pd / C and H2 or with Na / NH3). Alternatively, the hydroxyl group protected as an alkoxy-arylalkyl ether (e.g., MPM ether) can be deprotected by reacting with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In yet another non-limiting example, the hydroxyl group protected as an alkoxyalkyl ether (e.g., 1-alkoxyalkyl-1-yl) or THP ether can be deprotected by reacting with Brønsted acids. Cyclic protected diols, such as acetals or ketals (e.g., 2-alkyl-1,3-dioxolane, 2,2-dialkyl-1,3-dioxolane, 2-alkyl-1,3-dioxolane, or 2,2-dialkyl-1,3-dioxolane), can be deprotected by reaction with Brønsted acids (e.g., carboxylic acids).

[0182] Intermediate I4 or I5 can be prepared from intermediate I3, for example, via cross-coupling reactions (CN cross-coupling for I4 or CC cross-coupling for I5). CN cross-coupling reaction conditions are known in the art, for example, Pd-catalyzed variants such as Buchwald-Hartwig CN cross-coupling, and Cu-catalyzed variants such as Ullmann-type coupling. CC cross-coupling reaction conditions are known in the art, for example, Pd-catalyzed variants such as Suzuki-Miyaura coupling, Hiyama coupling, Stille coupling, Negishi coupling, and Kumada coupling.

[0183]

[0184] Intermediate I3 can be prepared from intermediates I1 and I2, for example, through a cyclization reaction between I1 and I2. Suitable reaction conditions for cyclization reactions are known in the art. Such reactions typically involve the use of polar solvents (e.g., alcohol solvents, such as 2-propanol) at high temperatures (e.g., under solvent reflux, such as at 80°C–100°C).

[0185] The following examples are intended to illustrate this disclosure and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporation is carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods. Unless otherwise stated, the abbreviations used are those conventional in the art.

[0186] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds disclosed herein are commercially available or can be produced by organic synthetic methods known to those skilled in the art (Houben-Weyl, 4th edition, 1952, Methods of Organic Synthesis, Thieme, Vol. 21). Furthermore, the compounds disclosed herein can be produced by organic synthetic methods known to those skilled in the art, as illustrated in the following examples.

[0187] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by suitable protecting groups. Such functional groups include hydroxyl, phenol, amino, and carboxylic acids. Protecting groups suitable for hydroxyl or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, etc. Protecting groups suitable for amino, amidine, and guanidine include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl esters, aryl esters, or arylalkyl esters.

[0188] Protecting groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TW, and PGM Wutz. Protective Groups in Organic Synthesis Groups in Organic Synthesis (1999), 3rd edition, Wiley. The protecting group can also be a polymer resin, such as Wang resin or 2-chlorotriphenylmethyl-chloro resin.

[0189] Those skilled in the art will also understand that although such protected derivatives of the compounds disclosed herein may not be pharmacologically active on their own, they may be administered to a subject and subsequently metabolized in vivo to form the pharmacologically active compounds disclosed herein. Therefore, such derivatives may be described as “prodrugs.” All prodrugs of the compounds disclosed herein are included within the scope of this disclosure.

[0190] The following examples are intended to illustrate this disclosure. They are not intended to limit this disclosure in any way.

[0191] Example

[0192] General methods

[0193] Unless otherwise specified, use reagents and solvents obtained from commercial suppliers. Unless otherwise specified, obtain proton nuclear magnetic resonance (NMR) spectra on a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer. NMR spectra are given in ppm (δ), and the coupling constant is reported in Hertz. J Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts were reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents shown in the NMR spectral data. Small amounts of dried sample (2 mg–5 mg) were dissolved in a suitable deuterated solvent (1 mL). Mass spectra (ESI-MS) were collected using a Waters system (Acquity UPLC and Micromass ZQ spectrometer) or an Agilent-1260 Infinity (6120 quadrupole); all reported masses are m / z of the protonated parent ion unless otherwise specified. Chemical names were generated using ChemDraw Professional v22 from Perkin Elmer Informatics.

[0194] Temperatures are given in degrees Celsius. As used herein, unless otherwise stated, the terms "room temperature" or "ambient temperature" refer to temperatures between 15 and 30 degrees Celsius, e.g., 20 to 30 degrees Celsius, e.g., 20 to 25 degrees Celsius. Unless otherwise mentioned, all evaporation is carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., trace analysis and spectroscopic properties (e.g., MS, IR, NMR). Abbreviations used are those commonly used in the art.

[0195] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used in the synthesis of the compounds disclosed herein are commercially available or can be prepared by organic synthesis methods known to those skilled in the art.

[0196] Abbreviations

[0197] The following LC-MS methods are used to characterize instances and intermediates: LC / MS Method 1 Pump: Waters AcQuity UPLC Column: AcQuity UPLC BEH C18 1.7 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 rate: 1.0 mL / min ELSD: SofTA 1100 ELSD Mass spectrometry: Waters QDa

[0198] LC / MS Method 2

[0199] Pump: Waters AcQuity UPLC

[0200] Column: AcQuity UPLC BEH C18 1.7 µM, 2.1x30 mm

[0201] Column temperature: 50°C

[0202] Gradient (time (min.) / %B): 0.0 / 2, 0.1 / 2, 1.5 / 98, 1.8 / 98, 1.9 / 2, 2.0 / 2

[0203] Eluent A: 5 mM ammonium hydroxide in water

[0204] Eluent B: 5 mM ammonium hydroxide in acetonitrile

[0205] Flow rate: 1.0 mL / min

[0206] ELSD: SofTA 1100 ELSD

[0207] Mass spectrometry: Waters QDa

[0208] LC / MS Method 3

[0209] Pump: Waters AcQuity UPLC

[0210] Column: AcQuity UPLC BEH C18 1.7 µM, 2.1x50 mm

[0211] Column temperature: 50°C

[0212] Gradient (time (min.) / %B): 0.0 / 2, 4.4 / 98, 5.15 / 98, 5.19 / 2

[0213] Eluent A: 0.1% formic acid in water

[0214] Eluent B: 0.1% formic acid in acetonitrile

[0215] Flow rate: 1.0 mL / min

[0216] ELSD: SofTA 1100 ELSD

[0217] Mass spectrometry: Waters QDa

[0218] LC / MS Method 4

[0219] Pump: Waters AcQuity UPLC

[0220] Column: AcQuity UPLC BEH C18 1.7 µM, 2.1x50 mm

[0221] Column temperature: 50°C

[0222] Gradient (time (min.) / %B): 0.0 / 2, 4.4 / 98, 5.15 / 98, 5.19 / 2

[0223] Eluent A: 5 mM ammonium hydroxide in water

[0224] Eluent B: 5 mM ammonium hydroxide in acetonitrile

[0225] Flow rate: 1.0 mL / min

[0226] ELSD: SofTA 1100 ELSD

[0227] Mass spectrometry: Waters QDa

[0228] LC / MS Method 5

[0229] System: Shimadzu -LCMS 2020 (single quadrupole)

[0230] Column: ACQUITY UPLC BEH C18 1.7 µm, 2.1 50 mm

[0231] Column temperature: 40°C

[0232] Gradient (time (min.) / %B): 0.01 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5

[0233] Eluent A: 0.1% HCOOH in water

[0234] Eluent B: 0.1% HCOOH in CH3CN

[0235] Flow rate: 0.8 mL / min

[0236] Ion source: DUIS-ESI & APCI

[0237] Atomizing airflow: 1.5 L / min; DL temperature: 250°C Hot block temperature: 300°C

[0238] LC / MS Method 6

[0239] System: Shimadzu -LCMS 2020 (single quadrupole)

[0240] Column: ACQUITY UPLC BEH C18 1.7 µm, 2.1 50 mm

[0241] Column temperature: 40°C

[0242] Gradient (time (min.) / %B): 0.01 / 5, 1.20 / 50, 2.10 / 75, 2.80 / 95, 3.20 / 5, 4.0 / 5

[0243] Eluent A: 0.1% HCOOH in water

[0244] Eluent B: 0.1% HCOOH in CH3CN

[0245] Flow rate: 0.8 mL / min

[0246] Ion source: DUIS-ESI & APCI

[0247] Atomizing gas flow rate: 1.5 L / min; DL temperature: 250°C Hot block temperature: 300°C

[0248] LC / MS Method 7

[0249] System: Shimadzu -LCMS 2020 (single quadrupole)

[0250] Column: Synergi 2.5 μ MAX-RP 100 A Mercury

[0251] Column temperature: 40°C

[0252] Gradient (time (min.) / %B): 0.01 / 5, 1.20 / 50, 2.10 / 75, 2.80 / 95, 3.20 / 5, 4.0 / 5

[0253] Eluent A: 0.1% HCOOH in water

[0254] Eluent B: 0.1% HCOOH in CH3CN

[0255] Flow rate: 0.8 mL / min

[0256] Ion source: DUIS-ESI & APCI

[0257] Atomizing gas flow rate: 1.5 L / min; DL temperature: 250°C Hot block temperature: 300°C

[0258] LC-MS Method 8

[0259] System: Shimadzu -LCMS 2020 (single quadrupole)

[0260] Column: ACQUITY UPLC BEH C18 1.7 µm, 2.1 50mm

[0261] Column temperature: 40°C

[0262] Gradient (time / %B): 0.01 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5

[0263] Eluent A: 0.1% HCOOH in water

[0264] Elution buffer B: 0.1% HCOOH CH3CN

[0265] Flow rate: 0.8 mL / min

[0266] Ion source: DUIS-ESI & APCI

[0267] Atomizing gas flow rate: 1.5 L / min

[0268] DL temperature: 250°C

[0269] Hot block temperature: 300°C

[0270] LC-MS Method 9

[0271] System: Shimadzu -LCMS 2020 (single quadrupole)

[0272] Column: ACQUITY UPLC BEH C18 1.7 µm, 2.1 50mm

[0273] Column temperature: 40°C

[0274] Gradient (time / %B): 0.01 / 5, 1.20 / 50, 2.10 / 75, 2.80 / 95, 3.20 / 5, 4.0 / 5

[0275] Eluent A: 0.1% HCOOH in water

[0276] Elution buffer B: 0.1% HCOOH CH3CN

[0277] Flow rate: 0.8 mL / min

[0278] Ion source: DUIS-ESI & APCI

[0279] Atomizing gas flow rate: 1.5 L / min

[0280] DL temperature: 250°C

[0281] Hot block temperature: 300°C

[0282] LC-MS Method 10

[0283] System: Shimadzu -LCMS 2020 (single quadrupole)

[0284] Column: ACQUITY UPLC BEH C18 1.7 µm, 2.1 50mm

[0285] Column temperature: 40°C

[0286] Gradient (time / %B): 0.01 / 5, 0.3 / 5, 0.5 / 100, 1.8 / 100, 2.0 / 5, 3.0 / 5

[0287] Eluent A: 0.1% HCOOH in water

[0288] Elution buffer B: 0.1% HCOOH CH3CN

[0289] Flow rate: 0.8 mL / min

[0290] Ion source: DUIS-ESI & APCI

[0291] Atomizing gas flow rate: 1.5 L / min; DL temperature: 250°C Hot block temperature: 300°C

[0292] LC-MS Method 11

[0293] System: Shimadzu Nexera LCMS-2020 with a single quadrupole.

[0294] Column: ACQUITY UPLC BEH C18 1.7 µm, 2.1 50mm.

[0295] Gradient: A - 0.1% formic acid in water, B - 0.1% formic acid in acetonitrile.

[0296] Time / %B: 0.01 / 5, 0.30 / 5, 0.50 / 100, 1.80 / 100, 2.0 / 5, 3.0 / 5; Flow rate: 0.8 mL / min.

[0297] UV detection array 200 - 400.

[0298] Quality testing 100-1000 (multi-mode - electrospray ionization / atmospheric pressure chemical ionization); Column temperature: 40°C Atomizing airflow: 1.5 L / min; DL temperature: 250°C Hot block temperature: 300°C

[0299] Synthesis of amino-pyrimidine intermediates

[0300] Key amino-pyrimidine intermediates

[0301] Synthesis of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-amine (intermediate A1)

[0302] 2,2,6,6-Tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (3.0 g, 1.3 equivalents, 9.9 mmol), 4-chloropyrimidin-2-amine (1.0 g, 1.0 equivalents, 7.7 mmol), THF (5.0 mL), 2 wt% TPGS-750-M surfactant aqueous solution (20.0 mL), and triethylamine (4.7 g, 6.5 mL, 6.0 equivalents, 46 mmol) were added to a 250 mL round-bottom flask. PdCl2(dppf)CH2Cl2 (315 mg, 0.050 equivalents, 386.0 μmol) was added, and the resulting mixture was degassed with nitrogen for 30 min. The resulting mixture was magnetically stirred at 50°C for 1 day, during which LCMS showed conversion to the target product. The reaction was allowed to cool to ambient temperature, diluted with EtOAc, and filtered through a diatomaceous earth pad, followed by washing with EtOAc. The solution was washed with brine. The brine layer was extracted with EtOAc. All organic compounds were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified by automated rapid chromatography (80 g Redesep Silver silica column, dry loading, 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).

[0303] ESI-MS m / z 233.3, [M+H] + Rt = 0.66 min., LC / MS method 2.

[0304] 1 H 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).

[0305] Synthesis of 4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2-amine (intermediate B1)

[0306] At room temperature and under an argon atmosphere, palladium hydroxide / carbon (302 mg, 1 equivalent, 2.2 mmol) was added 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 equivalent) in ethanol (5 mL). The reaction mixture was stirred at room temperature under H2 balloon pressure for 5 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was diluted with ethanol and filtered through a diatomaceous earth pad, and washed with ethanol. The combined filtrates were concentrated under reduced pressure. The residue was analyzed by rapid column chromatography at C1000 ppm. 18 On-column (elution buffer: water / CH3CN (using 0.1% formic acid) = 100:0 to 60:40; 13 g RediSep Rf reversed-phase C 18 The sample was purified using a 5 g solid column for dry loading to give 4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2-amine (0.5 g, 1.9 mmol, 90% yield) as a grayish-white solid.

[0307] ESI-MS m / z 235.25, [M+H] + .

[0308] 1 H 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).

[0309] Synthesis of 5-fluoro-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-amine (intermediate A2)

[0310] Add 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,2,3,6-tetrahydropyridine (2.07 g, 7.79 mmol, 1.15 equivalents), 4-chloro-5-fluoropyrimidin-2-amine (1.0 g, 6.8 mmol, 1.0 equivalents), THF (4.0 mL), 2 wt% TPGS-750-M surfactant aqueous solution (16.0 mL), and triethylamine (2.74 g, 3.78 mL, 27.1 mmol, 4.0 equivalents) to the mixture. Add PdCl2(dppf).CH2Cl2 (277 mg, 339 μmol, 0.05 equivalents) to the mixture, and degas the resulting mixture with nitrogen for 30 min. The magnetically stirred mixture was then heated at 50°C for 1 day. Heating was stopped and the mixture was allowed to return to room temperature. The mixture was diluted with EtOAc and filtered through a diatomaceous earth pad, then washed with EtOAc. The filtrate was washed with brine, and the brine layer was back-extracted twice with EtOAc. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by automated rapid chromatography (40 g Redisep Silver column, dry loading, 0–30% (10% 7N NH4OH in MeOH) / DCM). The fractions containing the product were combined, concentrated, and further dried under high vacuum to provide 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).

[0311] ESI-MS m / z 251.0, [M+H] + Rt = 0.76 min., LC / MS method 2.

[0312] 1 H 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).

[0313] Synthesis of 5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2-amine (intermediate B2)

[0314] Under nitrogen atmosphere, 5-fluoro-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-amine (A2) (1.22 g, 4.87 mmol, 1.0 equivalent) and 10% palladium hydroxide / carbon (684 mg, 0.10 equivalent, 487 μmol) were combined in methanol (42 mL). The reaction vessel was evacuated and the atmosphere was replaced with hydrogen from a balloon. This was repeated three times. The reaction mixture was then stirred for 7 hours under a hydrogen atmosphere from a balloon. The mixture was filtered through a diatomaceous earth pad using DCM and methanol, and the filtrate was concentrated under reduced pressure to provide 5-fluoro-4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2-amine (1.20 g, 4.76 mmol, 97% yield).

[0315] ESI-MS m / z 253.5, [M+H]+; Rt = 0.70 min, LC / MS method 2.

[0316] 1 H 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).

[0317] Synthesis scheme for intermediates A3 and B3

[0318] Synthesis of 5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-amine (intermediate A3)

[0319] 2,2,6,6-Tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,2,3,6-tetrahydropyridine (3.67 g, 13.9 mmol) and K₂CO₃ (5.67 g, 41.7 mmol) were added 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). The reaction mixture was purged with argon for 15 min. Then, Pd(dppf)Cl₂·DCM (1.14 g, 1.39 mmol) was added, and the reaction mixture was again purged with argon for 5 min. The reaction mixture was stirred at 90°C for 12 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, and washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue obtained was purified by reversed-phase rapid chromatography (CombiFlash, 24 g C18 column, gradient elution, 0-50% acetonitrile in water) to give 5-methyl-4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-amine (A3) as a pale yellow clump (0.6 g, 2.43 mmol, 17% yield).

[0320] ESI-MS m / z 247.15, [M+H] + .

[0321] Synthesis of 5-methyl-4-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-2-amine (B3)

[0322] Under argon atmosphere, 10% Pd(OH)₂ / carbon (500 mg) was added 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). The reaction mixture was stirred at room temperature under H₂ balloon pressure for 6 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad and washed twice with ethyl acetate. The combined organic layers were concentrated under reduced pressure. Purification by reversed-phase HPLC (CombiFlash, 12 g C18 column, gradient elution, 0-50% acetonitrile in water) gave 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 viscous oil.

[0323] ESI-MS m / z249.10, [M+H] + .

[0324] Synthesis scheme for intermediates A4 and B4

[0325] Synthesis of 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine (2a) and 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (2b)

[0326] At 0°C, 5.0 mL of 28% NH3 aqueous solution was added via syringe to a stirred solution of 6.0 g (27.65 mmol, 1 equivalent) of 2,4-dichloro-5-(trifluoromethyl)pyrimidine in 60 mL of THF. After the addition was complete, the reaction mixture was slowly heated to room temperature and stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was poured into ice water and extracted with EtOAc (150 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified three times by MPLC (CombiFlash, 12 g RediSep Silver column, gradient elution, 30%-40% EtOAc in hexane) to give 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) as a white solid (1.8 g, 33% yield, 9.11 mmol), ESI-MS m / z 199.8, [M+H+2] + .

[0327] Synthesis of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (intermediate A4)

[0328] 2,2,6,6-Tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1,2,3,6-tetrahydropyridine (1.34 g, 5.06 mmol) was added 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), followed by the addition of Na₂CO₃ (1.61 g, 15.186 mmol). The mixture was bubbled with argon for 5 min. Then, Pd(dppf)Cl₂·DCM (0.41 g, 0.51 mmol) was added, and the mixture was bubbled with argon again for 5 min, followed by heating to 80°C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad and washed with EtOAc (50 mL). The filtrate was evaporated under reduced pressure to obtain the residue, which was poured into water and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The solution was purified by MPLC (CombiFlash, C18, 40 g column, gradient elution, 20%–30% CH3CN in H2O) to give 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (A4) as a brown solid (0.65 g, 43%, 2.16 mmol).

[0329] ESI-MS m / z 301.1, [M+H] + .

[0330] Synthesis of 4-(2,2,6,6-tetramethylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (intermediate B4)

[0331] At room temperature, 10% Pd(OH)₂ / carbon (0.6 g) was added 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). The reaction mixture was stirred at room temperature under H₂ balloon pressure for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth pad and washed with EtOH (50 mL). The filtrate was concentrated under reduced pressure to give 4-(2,2,6,6-tetramethylpiperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (0.49 g, 1.62 mmol, 81% yield) as a light brown viscous oil.

[0332] ESI-MS m / z 303.05, [M+H] + .

[0333] Synthesis of α-bromo-one intermediates

[0334] 1-(2-(benzyloxy)-4-bromophenyl)-2-bromoethyl-1-one (Intermediate D)

[0335] At room temperature, bromine dissolved in 50 mL of 1,4-dioxane (0.76 mL, 14.7 mmol, 0.9 equivalent) was added dropwise over a 10-min time to a stirred solution of 1-(2-(benzyloxy)-4-bromophenyl)ethyl-1-one (5.0 g, 16.4 mmol, 1 equivalent) in 50 mL of 1,4-dioxane. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into ice water and extracted three times with DCM. The combined organic layers were washed with sodium thiosulfate solution (1×), water (1×), and brine (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(2-(benzyloxy)-4-bromophenyl)-2-bromoethyl-1-one (4.6 g, 11.97 mmol, 73% yield) as a pale yellow solid.

[0336] ESI-MS m / z 384.8, [M+H] + .

[0337] The synthesis of intermediate D is reported in WO 2007037187.

[0338] 2-Bromo-1-(5-Bromo-3-methoxypyridin-2-yl)ethyl-1-one (Intermediate E)

[0339] At room temperature and under nitrogen atmosphere, 1-(5-bromo-3-methoxypyridin-2-yl)ethyl-1-one (1.1 g, 1.0 equivalent, 4.9 mmol) was dissolved in 1,4-dioxane (44 mL) and diethyl ether (22 mL) in a 500 mL round-bottom flask. Bromine (2.4 g, 759 μL, 3.0 equivalent, 14.7 mmol) was slowly added to the solution. The reaction mixture was allowed to stir for 2 days, at which point LCMS showed a 75% conversion to the target product. A large amount of solid was formed after dilution with a small amount of EtOAc (10 mL). The solid was filtered off and dried under high vacuum. The thus separated solid (1.6 g) was dissolved in DCM (350 mL), and the solution was washed with water (3 × 30 mL) and brine (1 × 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)ethyl-1-one (1.06 g, 3.44 mmol, 70% yield), as a grayish-white solid.

[0340] ESI-MS m / z 307.9, [M+H] + Rt = 0.89 min., LC / MS method 2.

[0341] 1 H 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).

[0342] 1-(3-(benzyloxy)-5-bromopyridin-2-yl)-2-bromoethyl-1-one (intermediate F)

[0343] Synthesis of 3-(benzyloxy)-5-bromopyridinecarboxynitrile (2)

[0344] At 0°C, 5-bromo-3-nitropyridinecarboxylonitrile (10.0 g, 44.1 mmol, 1 equivalent) was added to a stirred solution of NaH (2.11 g, 87.9 mmol, 1.2 equivalent) in THF (20 mL) over a 10-min time interval using a syringe. After the addition was complete, the reaction was stirred for 10 min. Then, benzyl alcohol (4.72 g, 43.6 mmol, 1 equivalent) was added to THF (20 mL), and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction was quenched with ice water and extracted with EtOAc (2 × 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was then ground with n-pentane to give 3-(benzyloxy)-5-bromopyridinecarboxylonitrile (10.0 g, 31.1 mmol, 70% yield) as a brown solid.

[0345] ESI-MS m / z 289.9, [M+H] + .

[0346] Synthesis of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)ethyl-1-one (3)

[0347] At 0°C, 3.0 M methyl magnesium bromide in diethyl ether (16.5 mL) was added dropwise over a 10-min time to a stirred solution of 3-(benzyloxy)-5-bromopyridinecarboxynitrile (2) (5.0 g, 17.3 mmol, 1 equivalent) in THF (70 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with ice water, the pH was adjusted to acidic with 10% H2SO4 solution, and the mixture was stirred at room temperature for 30 min. The aqueous layer was poured into a saturated sodium bicarbonate solution (40 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC (CombiFlash, 24 g RediSep Silver column, gradient elution, 15% EtOAc in hexane) to give 3,1-(3-(benzyloxy)-5-bromopyridin-2-yl)ethyl-1-one (2.6 g, 8.5 mmol, 49% yield) as a pale yellow solid.

[0348] ESI-MS m / z 307.75, [M+H] + .

[0349] Synthesis of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)-2-bromoethyl-1-one (4) (intermediate F)

[0350] A solution of hydrogen bromide in acetic acid (8.0 mL) was added to a stirred solution of 1-(3-(benzyloxy)-5-bromopyridin-2-yl)ethyl-1-one (3) (1.0 g, 3.3 mmol, 1 equivalent) in acetic acid (230 mg, 164 μL, 0.5 equivalent, 1.63 mmol) and the mixture was cooled to 0°C. Bromine (365 mg, 118 μL, 0.7 equivalent, 2.29 mmol) was added and the mixture was stirred at 55°C for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture 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 a crude product, which was then purified by MPLC (CombiFlash, 24 g RediSep Silver column, gradient elution, 10% EtOAc in hexane) to give 1-(3-(benzyloxy)-5-bromopyridin-2-yl)-2-bromoethyl-1-one (550 mg, 1.32 mmol, 40% yield, 92% purity) as a grayish-white solid.

[0351] ESI-MS m / z 385.80, [M+H] + .

[0352] Synthesis of intermediate G

[0353] Synthesis of 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethyl-1-one (2)

[0354] Iodomethane (9.14 g, 64.4 mmol, 3.0 equivalent) was added to a mixture of 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethyl-1-one (5.0 g, 21.5 mmol, 1.0 equivalent) and K₂CO₃ (8.9 g, 64.4 mmol, 3.0 equivalent) in acetonitrile (50 mL). 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. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by rapid column chromatography on silica gel (elution: heptane / EtOAc = 100:0 to 80:20; 24 g RediSep Silver column, using 5 g solid column) to give 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethyl-1-one (4.0 g, 16.2 mmol, 75% yield) as a colorless liquid.

[0355] ESI-MS m / z 247.0, [M+H] + .

[0356] Synthesis of 2-bromo-1-(4-bromo-2-fluoro-6-methoxyphenyl) ethyl-1-one (3) (intermediate G)

[0357] At room temperature, a solution of bromine (2.85 g, 1.1 equivalent, 17.8 mmol) in dioxane (20 mL) was added dropwise to a stirred solution of 1-(4-bromo-2-fluoro-6-methoxyphenyl)ethyl-1-one (2) (4.0 g, 16.2 mmol, 1.0 equivalent) in 1,4-dioxane (30 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, 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 was performed by rapid column chromatography on silica gel (elution buffer: hexane / DCM = 95:5 to 90:10; 12 g RediSep Silver column, using 5 g solid column) to give 2-bromo-1-(4-bromo-2-fluoro-6-methoxyphenyl) ethyl-1-one (2.0 g, 6.1 mmol, 38% yield) as a colorless liquid.

[0358] 1 H NMR (400 MHz, CDCl3) δ 6.98 - 6.91 (m, 2H), 4.32 (s, 2H), 3.88 (s, 3H).

[0359] Synthesis scheme for intermediate H

[0360] Synthesis of 3-bromo-2-fluorophenylacetate (2)

[0361] Triethylamine (7.15 mL, 52.4 mmol) was added to a stirred solution of 3-bromo-2-fluorophenol (5.0 g, 26.2 mmol) in dichloromethane (50 mL). After 5 min, acetyl chloride (2.8 mL, 39.3 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, 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 rapid chromatography using a CombiFlash system, eluting with 0–10% ethyl acetate in hexane to give 3-bromo-2-fluorophenyl acetate (5.8 g, 24.9 mmol, 95% yield) as a pale yellow, viscous mass.

[0362] ESI-MS m / z Non-ionizing.

[0363] 1 H NMR (CDCl3) δ 7.44-7.40 (m, 1H), 7.09-7-02 (m, 2H), 2.34 (s, 3H).

[0364] Synthesis of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (3)

[0365] Aluminum trichloride (5.14 g, 38.6 mmol) was added fractionally to a round-bottom flask containing 3-bromo-2-fluorophenyl acetate (3.0 g, 12.9 mmol). After the addition of aluminum trichloride, the reaction mixture was stirred at 140°C for 3 h. The reaction mixture was then cooled to 80°C and ice was added, followed by the addition of 10% hydrochloric acid. After the reaction was determined to be complete by TLC, the reaction mixture was extracted with ethyl acetate (2×). The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was purified by automated rapid chromatography using a CombiFlash system, eluting with 0–10% ethyl acetate in hexane to give 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (2.8 g, 12 mmol, 93% yield) as a grayish-white solid.

[0366] ESI-MS m / z 234.80 [M+H] + .

[0367] Synthesis of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (4)

[0368] Potassium carbonate (8.30 g, 60.1 mmol) was added to a stirred solution of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (2.80 g, 12.0 mmol) in 30 mL of ACN at room temperature, followed by the addition of methyl iodide (3.74 mL, 60.1 mmol). The reaction mixture was then heated at 60°C for 4 h. The reaction progress was monitored by TLC. After the reaction was complete, it 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 give 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (2.6 g, 10.5 mmol, 87% yield) as a grayish-white solid.

[0369] ESI-MS m / z 248.80 [M+H] + .

[0370] Synthesis of 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (5) (intermediate H)

[0371] At 0°C, a solution of bromine (0.26 mL, 5.3 mmol) in 1,4-dioxane (5 mL) was added dropwise to a stirred solution of 1-(4-bromo-3-fluoro-2-methoxyphenyl)ethyl-1-one (1.0 g, 4.1 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction was quenched with ice water and partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by automated rapid chromatography using a CombiFlash system, eluting with 0-10% ethyl acetate in hexane to give 1-(4-bromo-3-fluoro-2-hydroxyphenyl)ethyl-1-one (0.8 g, 2.5 mmol, 60% yield) as a pale brown solid.

[0372] ESI-MS m / z 326.8 [M+H+2] + .

[0373] General Scheme for the Synthesis of Imidazolo-Pyrimidine Cores

[0374] The final compound was synthesized through the functionalization of the imidazo-pyrimidine core.

[0375] Compound 4: A 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

[0376] 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)

[0377] A mixture of 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one and 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-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 for 3 hours in a microwave reactor. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was diluted with 10% MeOH in DCM and concentrated under reduced pressure. The residue obtained was purified by automated reversed-phase rapid 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 brick-red solids (0.30 g, 0.57 mmol, 44% yield).

[0378] ESI-MS m / z 523.65, [M+H] + Rt = 1.49 min., LC / MS method 5.

[0379] 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)

[0380] Trifluoromethanesulfonic acid (0.5 mL) was added 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). The resulting mixture was stirred at 70°C for 1 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in 10% MeOH in DCM and alkalized 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 phase A = 0.1% HCOOH in water and B = acetonitrile, column: X SELECT (250 mm x 20.0 mm), 5.0 µ. The fractions containing the product 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 formate (formate salt of compound 4) as a grayish-white solid (0.10 g, 0.23 mmol, 24% yield).

[0381] ESI-MS m / z 433.15, [M+H] + Rt = 1.78 min., LC / MS method 7.

[0382] 1 H 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).

[0383] Compound 7: 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

[0384] Step 1: 4-(2,2,6,6-Tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (A1) (350 mg, 1.0 equivalent, 1.50 mmol) and 2-bromo-1-(4-chloro-2-methoxyphenyl)ethyl-1-one (C) (596 mg, 1.5 equivalent, 2.26 mmol) were combined in isopropanol (14.00 mL). The resulting mixture was heated at 85°C for 2 days, during which time LCMS showed conversion to the target product. Initially, a large amount of solids formed from the clear reaction mixture. A saturated aqueous solution of sodium bicarbonate, along with EtOAc and water, was added to the mixture. The phases were separated, and the aqueous phase was extracted with EtOAc (3×). All organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified by automated rapid chromatography (40 g Redesep Silver silica column, dry loading, 0–30% (10% 7N NH4OH in MeOH) / DCM). Fractions containing the product 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).

[0385] ESI-MS m / z 397.3, [M+H] + Rt = 1.17 min., LC / MS method 2.

[0386] Step 2: Under nitrogen atmosphere, Pd2(dba)3 (95 mg, 0.20 equivalent, 104 μmol) and 2-(di-tert-butylphosphino)-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (100 mg, 0.40 equivalent, 208 μmol) were combined in a screw-capped glass vial, followed by the addition of anhydrous toluene (4.0 mL) and 1,4-dioxane (1.0 mL). The mixture was degassed by bubbling with nitrogen for 5 minutes. The magnetically stirred mixture was then heated at 120°C for 5 minutes in a heating block. The vial was then allowed to cool to ambient temperature. Individually, 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 equivalent, 520 μmol), triazacyclopentadiene (54 mg, 45 μL, 1.5 equivalent, 780 μmol), and potassium phosphate (221 mg, 86 μL, 2 equivalent, 1.04 mmol) were combined in anhydrous toluene (4.0 mL) and 1,4-dioxane (1.0 mL) in a microwave-safe vial. The mixture was degassed by bubbling with nitrogen for 10 min. Then, the palladium complex solution was transferred from the screw-cap vial to the microwave-safe vial via syringe, and the combined mixture was degassed again with nitrogen for 5 min. The resulting mixture was irradiated in the microwave at 120°C for 4 h, during which LCMS showed the conversion to the target product.

[0387] The reaction mixture was cooled to ambient temperature, diluted with EtOAc, water, and brine, and filtered through a diatomaceous earth mat, then washed with EtOAc. The aqueous layer was extracted with EtOAc. All organic compounds were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified by rapid chromatography (24 g Redesep Silver silica gel column, dry loading, 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).

[0388] ESI-MS m / z 430.4, [M+H] + Rt = 1.06 min., LC / MS method 2.

[0389] Step 3: BBr3 (1M in DCM) (717 mg, 2.86 mL, 10 equivalents, 2.86 mmol) was added dropwise to 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 equivalents, 286 μmol) in a glass vial of DCM (4.0 mL) under cold (0°C) magnetic stirring. The ice bath was removed, and the resulting suspension was stirred at room temperature for 2 h, during which time LCMS showed conversion to the target product. The vial was then placed in an ice bath (0°C), and the reaction was slowly quenched with MeOH (2 mL), followed by the slow addition of ammonium hydroxide (30% solution) (5 mL); a large amount of gas was observed to escape. Allow the reaction mixture to return to ambient temperature, stir for 45 min, and then concentrate under reduced pressure.

[0390] The mixture was then purified directly via a C18 basic reversed-phase silica column (50 g column, 0.1% formic acid modifier, 0-100% ACN / H2O). The fraction containing the product was 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).

[0391] Calculate the HRMS of the desired product, C 23 H 26 N7O [M+H] + = 416.2199, measured value = 416.2182.

[0392] ESI-MS m / z 416.4, [M+H] + Rt = 0.67 min., LC / MS method 1.

[0393] 1 H 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 = 7.2Hz, 1H), 6.74 - 6.69 (m, 1H), 2.51 (s, 2H), 1.28 (s, 6H), 1.19 (s, 6H).

[0394] 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

[0395] 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)

[0396] A mixture of 2-bromo-1-(4-bromo-2-fluoro-6-methoxyphenyl)ethyl-1-one (intermediate G) (2.0 g, 2 equivalents, 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 equivalent, 3.07 mmol) in isopropanol (20 mL) was stirred at 90°C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC: column: Gemini NX (250 mm x 21.2 mm), 5.0 µ, flow rate: 18 mL / min, mobile phase: A = 0.1% HCOOH in water, B = acetonitrile. The fraction containing the product was concentrated under reduced pressure to give 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) as a white solid (0.80 g, 1.1 mmol, 37% yield, 65% purity).

[0397] ESI-MS m / z 460.95, [M+H] + .

[0398] 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)

[0399] Under a nitrogen atmosphere, Pd₂(dba)₃ (60 mg, 0.20 equivalent, 65 μmol) and 2-(di-tert-butylphosphino)-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (63 mg, 0.40 equivalent, 0.13 mmol) were combined in anhydrous toluene (3.0 mL) and anhydrous 1,4-dioxane (1.0 mL). The mixture was degassed by bubbling with nitrogen for 10 minutes. The magnetically stirred mixture was heated at 120°C for 10 minutes. The mixture was then allowed to cool to ambient temperature. Individually, 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 equivalent, 0.33 mmol), 1,2,3-triazole (68 mg, 3.0 equivalent, 0.98 mmol), and potassium phosphate (139 mg, 2.0 equivalent, 0.65 mmol) were combined in toluene (3.0 mL) and 1,4-dioxane (1.0 mL). The mixture was degassed by bubbling with nitrogen for 10 min. Then, the palladium complex solution was transferred to a container containing the reactants via a syringe. The resulting mixture was stirred at 120°C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was diluted with ethyl acetate and filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure, and the crude product was subjected to reversed-phase column chromatography, eluting with 50% acetonitrile in water using 23 g C. 18 The solution was purified by column chromatography to give 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) as a yellow solid (100 mg, 0.223 mmol, 68% yield).

[0400] ESI-MS m / z 448.10, [M+H] + .

[0401] 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 formate)

[0402] At 0°C, boron tribromide (280 mg, 10.0 equivalent, 1.11 mmol) was added 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 equivalent, 0.11 mmol) in 1,2-dichloroethane (2.0 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. Purification was performed by preparative HPLC: column: X-bridge (C18, 19 mm x 150 mm), flow rate: 18 mL / min, mobile phase: A = 0.1% HCOOH in water, B = acetonitrile. The fractions containing the product were combined and concentrated under reduced pressure to give 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 (3, formate of compound 10) as a yellow solid (40 mg, 0.082 mmol, 73% yield).

[0403] ESI-MS m / z 434.05, [M+H] + Rt = 2.14 min., LC / MS method 6.

[0404] 1 H 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).

[0405] 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

[0406] Step 1: 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (A1) (120 mg, 1 equivalent, 516 μmol) and 2-bromo-1-(5-bromo-3-methoxypyridin-2-yl)ethyl-1-one (E) (239 mg, 1.5 equivalent, 775 μmol) were combined in isopropanol (5.5 mL) in a microwave-safe vial. The resulting mixture was heated at 50°C for 2 days, during which time LCMS showed conversion to the target product. Initially, a large amount of solids formed from the clear reaction mixture. A saturated aqueous solution of sodium bicarbonate, along with ethyl acetate and water, was added to the mixture. The phases were separated, and the aqueous phase was extracted with EtOAc (3×). All organics were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then purified by automated rapid chromatography (24 g Redesep Silver silica column, dry loading, 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).

[0407] ESI-MS m / z 444.3, [M+H]; Rt = 0.85 min, LC / MS method 2.

[0408] Step 2: Under nitrogen atmosphere, Pd2(dba)3 (70.4 mg, 0.20 equivalent, 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 equivalent, 154 μmol) were combined in a screw-capped glass vial, followed by the addition of anhydrous toluene (3.0 mL) and anhydrous 1,4-dioxane (0.75 mL). The mixture was degassed by bubbling with nitrogen for 5 minutes. The magnetically stirred mixture was heated in a heating block at 120°C for 5 minutes. The vial was then allowed to cool to ambient temperature. Individually, 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 equivalent, 384 μmol), triazacyclopentadiene (39.8 mg, 33.4 μL, 1.5 equivalent, 577 μmol), and potassium phosphate (163 mg, 63.6 μL, 2 equivalent, 769 μmol) were combined in anhydrous toluene (3.0 mL) and anhydrous 1,4-dioxane (0.75 mL) in a microwave-safe vial. The mixture was degassed by bubbling with nitrogen for 10 min. Then, the palladium complex solution was transferred from the screw-cap glass vial to the microwave-safe vial via syringe, and the combined mixture was degassed again with nitrogen for 5 min. The resulting mixture was irradiated in a microwave at 120°C for 4 hours, during which time LCMS showed the conversion to the target product.

[0409] The reaction mixture was cooled to ambient temperature, diluted with EtOAc, water, and brine, and filtered through a diatomaceous earth mat, then washed with EtOAc. The aqueous layer was extracted with EtOAc. All organic compounds were combined, dried over Na2SO4, and concentrated under reduced pressure.

[0410] The residue was then purified by rapid chromatography (24 g Redisep Silver silica column, dry loading, 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).

[0411] ESI-MS m / z 431.4, [M+H] + Rt = 0.82 min., LC / MS method 2.

[0412] Step 3: BBr3 (1 M in DCM) (704 mg, 2.8 mL, 1.0 mol, 10 equivalents, 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 equivalent, 281 μmol) in a glass vial of DCM (4.0 mL). The ice bath was removed, and the resulting suspension was stirred at room temperature for 2 h, during which time LCMS showed conversion to the target product. The vial was then placed in an ice bath (0°C), and the reaction was slowly quenched with MeOH (1.5 mL), followed by the slow addition of ammonium hydroxide (30% solution) (3 mL). A large amount of gas was observed to escape. Allow the reaction mixture to slowly return to room temperature, then stir for 45 min, and then concentrate under reduced pressure.

[0413] Then pass it via C 18 Direct purification was performed by alkaline reversed-phase silica gel column chromatography (50 g reversed-phase column, 0.1% formic acid modifier, 0-100% ACN / H2O). The fraction containing the product was 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 formate (the formate of compound 11) (18.8 mg, 39 μmol, 14% yield).

[0414] Calculate the HRMS of the desired product, C 22 H 25 N8O [M+H] + = 417.2151, Measured value = 417.2142

[0415] ESI-MS m / z 417.3 [M+H]+; Rt = 0.64 min, LC / MS method 1.

[0416] 1 H 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 = 2.2Hz, 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).

[0417] 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

[0418] Synthesis of 4-acetyl-3-(benzyloxy)benzyl nitrile (2)

[0419] At room temperature, cuprous cyanide (8.8 g, 98.3 mmol, 6.0 equivalent) was added to a magnetically stirred solution of 1-(2-(benzyloxy)-4-bromophenyl)ethyl-1-one (5.0 g, 16.4 mmol, 1.0 equivalent) in DMF (50 mL). The reaction mixture was stirred at 150°C for 7 hours. After the reaction was complete, 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 rapid column chromatography on silica gel (elution: heptane / EtOAc = 0:100 to 20:80; 40 g Redisep Silver column, using a 25 g solid column) to give 4-acetyl-3-(benzyloxy)benzyl nitrile (1.1 g, 4.3 mmol, 26% yield) as a white solid.

[0420] ESI-MS m / z 250.10 [MH] - .

[0421] Synthesis of 1-(2-(benzyloxy)-4-(1H-tetrazol-5-yl)phenyl)ethyl-1-one (3)

[0422] At room temperature, triethylamine hydrochloride (1.81 g, 13.1 mmol, 3.0 equivalent) and sodium azide (854 mg, 13.1 mmol, 3.0 equivalent) were added to a stirred solution of 4-acetyl-3-(benzyloxy)benzylnitrile (1.1 g, 4.4 mmol, 1.0 equivalent) in DMF (20 mL). 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 resulting organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained therefrom was purified by rapid column chromatography on silica gel (elution buffer: DCM / MeOH = 0:100 to 10:90; 40 g Redisep Silver column, using 25 g solid column) to give 1-(2-(benzyloxy)-4-(1H-tetrazol-5-yl)phenyl)ethyl-1-one (1.1 g, 2.7 mmol, 62% yield) as a colorless liquid.

[0423] ESI-MS m / z 295.05, [M+H] + .

[0424] Synthesis of 1-(2-(benzyloxy)-4-(2-methyl-1H-tetrazol-5-yl)phenyl)ethyl-1-one and 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)ethyl-1-one (4a & 4b)

[0425] Potassium carbonate (1.55 g, 11.2 mmol, 3.0 equivalent) was added to a stirred solution of 1-(2-(benzyloxy)-4-(1H-tetrazol-5-yl)phenyl)ethyl-1-one (1.1 g, 3.74 mmol, 1.0 equivalent) in DMF (10 mL) at room temperature. The mixture was cooled to 0°C and methyl iodoform (1.6 g, 0.70 mL, 11.2 mmol, 3.0 equivalent) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding ice water and extracted once with EtOAc. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a mixture of two isomers: 1-(2-(benzyloxy)-4-(2-methyl-1H-tetrazol-5-yl)phenyl)ethyl-1-one and 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)ethyl-1-one (1.0 g, 2.6 mmol, 69% yield). This mixture was used directly in the next step.

[0426] ESI-MS m / z 309.05, [M+H] + .

[0427] Synthesis of 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one and 1-(2-(benzyloxy)-4-(1-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one (5a & 5b)

[0428] At 0°C, a solution of bromine in 1,4-dioxane (8.0 mL) (166 mg, 54.0 μL, 1.04 mmol, 0.8 equivalent) was added dropwise to a stirred solution of 1-(2-(benzyloxy)-4-(2-methyl-1H-tetrazol-5-yl)phenyl)ethyl-1-one and 1-(2-(benzyloxy)-4-(1-methyl-1H-tetrazol-5-yl)phenyl)ethyl-1-one (0.40 g, 1.3 mmol, 1.0 equivalent) in 1,4-dioxane (15 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction was then quenched by adding ice water. The mixture was extracted twice with EtOAc, and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a mixture of 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one and 1-(2-(benzyloxy)-4-(1-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one (0.50 g, 1.29 mmol). This mixture was used directly in the next step without further purification.

[0429] ESI-MS m / z 386.95, [M+H] + .

[0430] 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)

[0431] The mixture of 1-(2-(benzyloxy)-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one and 1-(2-(benzyloxy)-4-(1-methyl-2H-tetrazol-5-yl)phenyl)-2-bromoethyl-1-one (0.50 g, 1.29 mmol, 1.0 equivalent) and 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (240 mg, 1.03 mmol, 0.80 equivalent) from the previous step 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 rapid column chromatography on a C18 column (elution: water / CH3CN = 0:100 to 50:50; 13 g Redisep Rf, reversed-phase C18 column, using a 25 g solid column) 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).

[0432] ESI-MS m / z 521.25 [M+H] + .

[0433] 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)

[0434] At 0°C, trifluoromethanesulfonic acid (0.50 g, 0.30 mL, 1.78 mmol, 4.6 equivalents) was added 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 (200 mg, 384 μmol, 1.0 equivalent) in TFA (3 mL). The reaction mixture was stirred at 70°C for 40 min. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in 10% MeOH in DCM and alkalized to pH ~8-9 by treatment with Amberlyte-A21 resin. The mixture was filtered and the filtrate was concentrated under reduced pressure.

[0435] 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 μm, A = 1% formic acid in water, B = acetonitrile, flow rate 15 mL / min). The fractions containing the product 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 formate (8b, formate of compound 28) as a pale yellow solid (41 mg, 90 μmol, 23% yield).

[0436] ESI-MS m / z 431.10, [M+H] + Rt = 1.51 min., LC / MS method 5.

[0437] 1 H 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= 7.1Hz, 1H), 6.86 (s, 1H), 4.43 (s, 3H), 2.91 (s, 2H), 1.62 (s, 6H), 1.52 (s, 6H).

[0438] Compound 39: The N1-isomer, isolated during the preparation of compound 28, was further purified using reversed-phase HPLC (H2O / CH3CN (containing 0.1% formic acid)). The fractions containing the product 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 formate (8a, the formate of compound 39): ESI-MS m / z 431.05, [M+H] + Rt = 1.49 min., LC / MS method 5.

[0439] 1 H 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).

[0440] Compound 40: A 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

[0441] Step 1: 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-ol

[0442] A mixture of 1-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-2-bromoethyl-1-one (1.0 g, 2.7 mmol), 2-aminopyrimidine-4-ol (298 mg, 2.69 mmol), NaHCO3 (226 mg, 2.69 mmol), EtOH (12.0 mL), and water (4.0 mL) was heated in a microwave oven to 120°C for 30 minutes. The reaction mixture was then cooled to room temperature 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]pyrimidine-7-ol (673 mg, 33% yield, 50% purity) as a yellow solid.

[0443] ESI-MS m / z 385.1, [M+H] + .

[0444] Step 2: 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yltrifluoromethane sulfonate

[0445] DIPEA (146 mg, 1.13 mmol, 3.0 equivalents) was added to crude 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidine-7-ol (283 mg, 0.375 mmol, 50% purity) from the previous step in DCM (10.0 mL). The solution was cooled to 0°C and trifluoromethanesulfonic anhydride (1.0 M, 751 µL, 0.751 mmol, 2.0 equivalents in DCM) 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 sodium bicarbonate aqueous 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-yltrifluoromethanesulfonate (484 mg, ~60% purity as determined by UV DAD). The substance was ready for use in the next step without further purification.

[0446] ESI-MS m / z 517.0, [M+H] + .

[0447] 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

[0448] The crude 2-(2-(benzyloxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yltrifluoromethanesulfonate (484 mg, 0.590 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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) from the previous step were sequentially added to a vial equipped with a stir bar. The reaction mixture was degassed with nitrogen and then heated at 80°C for 3 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was purified directly by automated rapid chromatography using a silica gel column, first eluting with ethyl acetate / heptane and then with 10% MeOH in EA (containing 1 vol% 7N NH3 in MeOH) to give 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).

[0449] ESI-MS m / z 506.2, [M+H] + .

[0450] 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

[0451] 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 open to air at room temperature for 1 hour. The mixture was then concentrated under reduced pressure and the residue was dry-loaded onto a silica gel column. The impurities were first eluted with ethyl acetate by an automated rapid chromatography method, and then purified by elution with 10%–50% MeOH in ethyl acetate (containing 1% by volume of 7N NH3 in MeOH) to give 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).

[0452] ESI-MS m / z 524.3, [M+H] + .

[0453] 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

[0454] Under N2 gas, EtOH (10 mL) was added 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). The reaction mixture was stirred at room temperature under balloon pressure of H2 gas (1 atm) for 4 hours. The reaction mixture was then filtered through a diatomaceous earth mat. The filtrate was concentrated and purified by automated rapid chromatography using a silica gel column, eluting with 10%–30% MeOH in DCM (with 1% 7N NH3 in MeOH as a basic modifier) ​​to give 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).

[0455] ESI-MS m / z 434.3, [M+H] + Rt = 1.94 min., LC / MS method 4.

[0456] 1 H 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 = 6.9Hz, 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).

[0457] Other exemplary compounds

[0458] The following compounds were prepared according to a modified version of the procedure described above.

[0459] 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)-1-methylpyridin-2(1H)-one

[0460] ESI-MS m / z474.30, [M+H] + Compound 1; 1 H 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, 2.1Hz, 1H), 3.61 (s, 3H), 2.80 (s, 2H), 1.54 (s, 6H), 1.44 (s, 6H).

[0461] 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 carboxylate

[0462] ESI-MS m / z 433.2 [M+H] + Compound 2, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.86 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.20 (d, J = 4.2 Hz, 1H), 8.02 (s,2H), 7.52 (d, J = 7.3 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.99 (dd, J = 12.6, 1.7Hz, 1H), 6.90 - 6.83 (m, 1H), 2.93 - 2.89 (m, 2H), 1.63 (s, 6H), 1.53 (s, 6H).

[0463]

[0464] ESI-MS m / z 415.3 [M+H] + Compound 3: 1 H 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).

[0465] 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

[0466] ESI-MS m / z 433.15 [M+H] + Compound 4, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ11.84 (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 = 6.9Hz, 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).

[0467] 5-(1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol carboxylate

[0468] ESI-MS m / z 417.1 [M+H] + Compound 5, formate: 1 H NMR (400 MHz, DMSO- d6 ) δ11.39 (width 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).

[0469] 4-(3-fluoro-5-hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenyl)-1-methylpyridine-2(1H)-ketocarboxylate

[0470] ESI-MS m / z 476.25 [M+H] + Compound 6; 1 H 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).

[0471] 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

[0472] Calculate the HRMS of the desired product, C 23 H 26 N7O [M+H] + = 416.2199, Measured value = 416.2182

[0473] ESI-MS m / z: 416.4 [M+H] + Compound 7; 1 H 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).

[0474] 4-(3-hydroxy-4-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenyl)-1-methylpyridin-2(1H)-ketocarboxylate

[0475] ESI-MS m / z 456.15 [M+H] + Compound 8, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.83 (d, J = 7.2 Hz, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.1 Hz, 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, 2.1Hz, 1H), 3.62 (s, 3H), 2.92 (s, 2H), 1.62 (s, 6H), 1.53 (s, 6H).

[0476] 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

[0477] ESI-MS m / z: 460.2 [M+H] + Compound 9; 1 H 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 = 8.2Hz, 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).

[0478] 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 carboxylate

[0479] ESI-MS m / z 434.05, [M+H] + Compound 10, formate; 1 H NMR (400 MHz, methanol-) d4) δ8.90 - 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).

[0480] 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

[0481] Calculate the HRMS of the desired product, C 22 H 25 N8O [M+H] + = 417.2151, Measured value = 417.2142

[0482] ESI-MS m / z 417.3 [M+H] + Compound 11; 1 H 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).

[0483] 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H-1,2,3-triazol-1-yl)phenol formate

[0484] ESI-MS m / z 418.1 [M+H] + Compound 12, formate: 1 H NMR (400 MHz, methanol-) d4 ) δ8.72 (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 (t, J = 13.4 Hz, 2H), 1.51 (s, 6H), 1.42 (s, 6H).

[0485] 4-(3-hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenyl)-1-methylpyridine-2(1H)-ketocarboxylate

[0486] ESI-MS m / z: 458.25 [M+H] + Compound 13, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.84 (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).

[0487] 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 carboxylate

[0488] ESI-MS m / z 436.1 [M+H] + Compound 14, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.91 (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 = 6.9Hz, 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).

[0489] 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2 H -1,2,3-triazol-2-yl)phenol

[0490] ESI-MS m / z 418.4 [M+H] + Compound 15: 1 H 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).

[0491] 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

[0492] ESI-MS m / z 416.0 [M+H] + Compound 16: 1 H 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).

[0493] 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

[0494] Calculate the HRMS of the desired product, C 23 H 25 FN7O [M+H] + = 434.2105, Measured value = 434.2095

[0495] ESI-MS m / z 434.1 [M+H] + Compound 17; 1 H 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).

[0496] 5-(1H-pyrazol-1-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol carboxylate

[0497] ESI-MS m / z 417.20 [M+H] + Compound 18, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.82 (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).

[0498] 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

[0499] Calculate the HRMS of the desired product, C 21 H 20 N7O [M+H] += 386.1729, Measured value = 386.1722 ESI-MS m / z 386.4 [M+H] + Compound 19; 1 H NMR (400 MHz, methanol-) d4 ) δ 8.62 (d, J = 7.2 Hz,1H), 8.19 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.84 (s, 2H), 7.60 - 7.50 (m,2H), 7.24 (d, J = 7.2 Hz, 1H), 7.12 - 7.06 (m, 1H), 3.87 - 3.80 (m, 2H), 3.00- 2.90 (m, 1H), 2.53 (d, J = 17.7 Hz, 1H), 2.10 - 1.98 (m, 2H), 1.95 - 1.86 (m, 1H), 1.69 - 1.59 (m, 1H).

[0500] 2-(7-(8-azabicyclo[3.2.1]oct-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0501] ESI-MS m / z 388.15 [M+H] + Compound 20; 1 H NMR (400 MHz, methanol-) d4 ) δ 9.12(d, J = 7.0 Hz, 1H), 8.63 (s, 1H), 7.98 (s, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.7, 2.1 Hz, 1H), 7.65 (d, J = 7.0Hz, 1H), 4.24 (br s, 2H), 3.75 - 3.64 (m, 1H), 2.35 - 2.17 (m, 8H).

[0502] 6-(3-hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenyl)-3-methylpyrimidin-4(3H)-one

[0503] ESI-MS m / z: 459.2 [M+H] + Compound 21: 1 H 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).

[0504] 5-(pyridin-4-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol

[0505] ESI-MS m / z 428.5 [M+H] + Compound 22: 1 H NMR (400 MHz, DMSO- d6 ) δ 11.84 (width 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).

[0506] 5-Hydroxy-1'-methyl-6-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-[3,4'-bipyridine]-2'(1'H)-ketocarbamate

[0507] ESI-MS m / z 459.05 [M+H] + Compound 23, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ12.54 (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).

[0508] 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'-bipyridine]-2'(1'H)-one

[0509] 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). 19 F NMR (377 MHz, methanol-) d4 ) δ -151.85.

[0510] 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

[0511] Calculate the HRMS of the desired product, C 22 H 26 FN8O [M+H] + = 437.2214, Measured value = 437.2208

[0512] ESI-MS m / z 437.4 [M+H] + Compound 25; 1 H 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).

[0513] 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

[0514] Calculate the HRMS of the desired product, C 22 H 24 FN8O [M+H] + = 435.2057, Measured value = 435.2027

[0515] ESI-MS m / z 435.3 [M+H] + Compound 26; 1 H NMR (400 MHz, DMSO) δ 12.57 (s,1H), 9.23 (d, J = 6.9 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.39 (s, 1H), 8.18 -8.15 (m, 2H), 7.83 (d, J = 2.2 Hz, 1H), 6.73 - 6.67 (m, 1H), 2.35 (s, 2H), 1.20 (s, 6H), 1.11 (s, 6H).

[0516] 2-(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

[0517] Calculate the HRMS of the desired product, C 22 H 27 N8O [M+H] + = 419.2308, Measured value = 419.2296

[0518] ESI-MS m / z 419.3 [M+H] + Compound 27; 1 H 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).

[0519] 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 carboxylate

[0520] ESI-MS m / z 431.1 [M+H] + Compound 28, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.83 (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).

[0521] 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

[0522] Calculate the HRMS of the desired product, C 23 H 29 N8O [M+H] + = 433.2462, Measured value = 433.2509

[0523] ESI-MS m / z 433.2 [M+H] + Compound 29; 1 H 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).

[0524] 2-(2,5-Difluoro-4-(1H-pyrazol-4-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidinecarboxylate

[0525] ESI-MS m / z 437.15 [M+H] + Compound 30, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.83 (d, J = 6.9 Hz, 1H), 8.53 (s, 1H), 8.22 (d, J = 3.8 Hz, 1H), 8.10 (s,2H), 7.98 (dd, J = 11.8, 6.2 Hz, 1H), 7.63 (dd, J = 11.9, 6.2 Hz, 1H), 7.13(d, J = 7.0 Hz, 1H), 3.62 - 3.53 (m, 1H), 2.17 (dd, J = 14.5, 3.2 Hz, 2H), 1.96 (t, J = 13.4 Hz, 2H), 1.62 (s, 6H), 1.52 (s, 6H). 19 F NMR (282 MHz, methanol-) d4 ) δ -120.44, -121.74.

[0526] 3-Hydroxy-4-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)benzyl nitrile carbamate

[0527] ESI-MS m / z 376.10 [M+H] + Compound 31, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ8.97 (d, J = 7.0 Hz, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.21 (d, J = 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).

[0528] 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

[0529] ESI-MS m / z 421.3 [M+H] + Compound 32; 1 H 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).

[0530] 5-Chloro-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol carboxylate

[0531] ESI-MS m / z 385.5 [M+H]+ Compound 33, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.72 (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, 3.2Hz, 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).

[0532] 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)-ketocarboxylate

[0533] ESI-MS m / z 472.1 [M+H] + Compound 34, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.65 (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).

[0534] 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

[0535] ESI-MS m / z 476.2 [M+H] + Compound 35; 1 H 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).

[0536] 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]pyrimidinecarboxylate

[0537] ESI-MS m / z 435.15 [M+H] + Compound 36, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.83 (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). 19 F NMR (282 MHz, methanol-) d4 ) δ -120.45, -121.67.

[0538] 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 carboxylate

[0539] ESI-MS m / z 432.1 [M+H] + Compound 37, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ12.11 (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).

[0540] 5-(1-methyl-1H-pyrazol-4-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol

[0541] Calculate the HRMS of the desired product, C 24 H 31 N6O [M+H] + = 431.2559, Measured value = 431.2546

[0542] ESI-MS m / z 431.4 [M+H] + Compound 38; 1 H 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).

[0543] 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 carboxylate

[0544] ESI-MS m / z 431.0 [M+H] + Compound 39, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.75 (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).

[0545] 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

[0546] ESI-MS m / z 434.3, [M+H] + Compound 40; 1 H 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).

[0547] 2-(7-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol carboxylate

[0548] ESI-MS m / z 389.10 [M+H] + Compound 41, formate; 1 H NMR (400 MHz, DMSO) δ8.65 - 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).

[0549] 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

[0550] ESI-MS m / z 486.15 [M+H] + Compound 42; 1 H NMR (400 MHz, DMSO- d6) δ 11.52(br s, 1H), 9.60 (s, 1H), 8.55 (s, 1H), 8.34 - 8.28 (m, 2H), 8.14 (s, 2H),7.72 - 7.69 (m, 1H), 7.63 (dd, J = 8.5, 2.2 Hz, 1H), 3.49 - 3.41 (m, 1H), 1.84 - 1.70 (m, 4H), 1.32 (s, 6H), 1.25 (s, 6H).

[0551] 6-(6-fluoro-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-hydroxy-1'-methyl-[3,4'-bipyridine]-2'(1'H)-one

[0552] ESI-MS m / z: 477.3 [M+H] + Compound 43: 1 H 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). 19 F NMR (377 MHz, methanol-) d4 ) δ -155.57.

[0553] 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 carboxylate

[0554] ESI-MS m / z 436.1 [M+H] + Compound 44, formate; 1¹H 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).

[0555] 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)-ketocarboxylate

[0556] ESI-MS m / z 526.6 [M+H] + Compound 45, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ11.23 (br s, 1H), 9.61 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 8.22 (d, J = 8.1Hz, 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).

[0557] 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

[0558] Calculate the HRMS of the desired product, C 23 H 27 FN7O [M+H] + = 436.2261, Measured value = 436.2246

[0559] ESI-MS m / z 436.1 [M+H] + Compound 46; 1 H 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).

[0560] 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidinecarboxylate

[0561] ESI-MS m / z 402.15 [M+H] + Compound 47, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.82 (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).

[0562] 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

[0563] ESI-MS m / z 416.2 [M+H] + Compound 48; 1 H 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).

[0564] 5-(1-methyl-1H-tetrazol-5-yl)-2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol carboxylate

[0565] ESI-MS m / z 433.1 [M+H] + Compound 49, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ12.00 (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).

[0566] 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

[0567] ESI-MS m / z 439.3 [M+H] + Compound 50; 1 H 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 = 13.1Hz, 2H), 1.39 (s, 6H), 1.28 (s, 6H).

[0568] 2-(7-(2,2,6,6-tetramethylpiperidin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H-tetrazole-5-yl)phenol

[0569] ESI-MS m / z : 419.10 [M+H] + Compound 51; 1 H NMR (400 MHz, DMSO) δ 11.48 (brs, 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).

[0570] 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

[0571] ESI-MS m / z 437.3 [M+H] + Compound 52; 1 H NMR (400 MHz, DMSO- d6 ) δ 9.20 -9.10 (m, 2H), 8.38 - 8.33 (m, 2H), 8.22 (s, 2H), 6.65 (s, 1H), 2.34 (s, 2H), 1.18 (s, 6H), 1.10 (s, 6H).

[0572] 2-(6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidinecarboxylate

[0573] ESI-MS m / z 430.1 [M+H] + Compound 53, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.80 (d, J = 7.2 Hz, 1H), 8.54 (br s, 1H), 8.36 (s, 1H), 8.15 (br s, 2H), 8.08 (d, J = 7.7 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 6.86 (s, 1H), 4.17 (s, 3H), 2.92 - 2.80 (m, 2H), 1.59 (s, 6H), 1.49 (s, 6H).

[0574] 5-(7-fluoro-2-methyl-2H-indazol-5-yl)-2-(6-fluoro-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol

[0575] ESI-MS ​ 515.4 [M+H] + Compound 54; 1 H 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).

[0576] 2-(7-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol formate

[0577] ESI-MS ​ 376.85 [M+H] + Compound 55; 1 H 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).

[0578] 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

[0579] ESI-MS ​ 419.4 [M+H] + Compound 56; 1 H 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 = 7.7Hz, 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).

[0580] 2-(7-(3,3,5,5-tetramethyl-1,4-diazacycloheptane-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(1H-1,2,3-triazol-1-yl)phenol

[0581] ESI-MS ​ 433.4 [M+H] + Compound 57; 1 H 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).

[0582] 2-(7-(3,3,5,5-tetramethyl-1,4-diazacycloheptane-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0583] ESI-MS ​ 433.3 [M+H] + Compound 58; 1 H 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).

[0584] 2-(7-(3,5-dimethylpiperazin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0585] ESI-MS ​ 391.1 [M+H] + Compound 59; 1 H 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 = 8.3Hz, 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).

[0586] 5-(1H-pyrazol-4-yl)-2-(7-(1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol

[0587] ESI-MS ​ 359.3 [M+H] + Compound 60: 1 H NMR (400 MHz, DMSO- d6 ) δ 12.97(s, 1H), 11.92 (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.36 (s, 1H), 8.27 - 7.90(m, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.19 (m, 2H),7.01 (s, 1H), 3.49 (d, J = 3.1 Hz, 2H), 2.93 (t, J = 5.6 Hz, 2H).

[0588] 3-Fluoro-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

[0589] Calculate the HRMS of the desired product, C 23 H 24 F2N7O [M+H] + = 452.2010, Measured value = 452.2005

[0590] ESI-MS ​ 452.3 [M+H] + Compound 61; 1 H NMR (400 MHz, DMSO- d6 ) δ 13.68(s, 1H), 9.31 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 4.4 Hz, 1H), 8.22 (s, 2H), 7.52 (dd, J= 12.1, 2.2 Hz, 1H), 7.49 - 7.44 (m, 1H), 6.83 - 6.76 (m, 1H), 2.44 (s, 2H), 1.28 (s, 6H), 1.20 (s, 6H).

[0591] 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

[0592] ESI-MS ​ 447.3 [M+H] + Compound 62; 1 H NMR (400 MHz, methanol-) d4 ) δ 8.39 (d, J = 7.5 Hz, 1H), 7.93 - 7.84 (m, 4H), 7.62 - 7.54 (m, 2H), 6.64 (d, J = 7.3Hz, 1H), 5.31 - 4.99 (m, 1H), 3.03 (s, 3H), 1.68 (dd, J = 12.6, 3.6 Hz, 2H), 1.55 (t, J = 12.4 Hz, 2H), 1.41 (s, 6H), 1.23 (s, 6H).

[0593] 2-(7-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0594] ESI-MS ​ 432.1 [M+H] + Compound 63; 1 H NMR (400 MHz, methanol-) d4 ) δ 8.59 (d, J = 7.2 Hz, 1H), 8.17 - 8.12 (m, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.90 (s, 2H),7.65 - 7.61 (m, 1H), 7.59 (d,J = 8.7 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 5.79- 5.67 (m, 1H), 2.18 (dd, J = 12.5, 4.1 Hz, 2H), 1.42 - 1.38 (m, 2H), 1.37 (s, 6H), 1.23 (s, 6H).

[0595] 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

[0596] ESI-MS ​ 416.4 [M+H] + Compound 64; 1 H 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 = 8.4Hz, 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).

[0597] 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

[0598] ESI-MS ​ 416.2 [M+H] + Compound 65; 1 H 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).

[0599] 3-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)naphthalene-2-ol carboxylate

[0600] N,3-Dimethoxy-N-methyl-2-naphthylcarboxamide (Intermediate 2)

[0601] At 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (3.79 g, 2 equivalents, 19.8 mmol) and HOBt (1.81 g, 1.2 equivalents, 11.9 mmol) were added to a stirred solution of 3-methoxy-2-naphthoic acid (2 g, 1 equivalent, 9.89 mmol) in N,N-dimethylformamide (20 mL). After the addition, the reaction mixture was stirred at 0°C for 2 h. Then, N,O-dimethylhydroxylamine hydrochloride (1.43 g, 1.5 equivalents, 14.8 mmol) was added at 0°C, followed by DIPEA (10.3 mL, 6.0 equivalents, 59.3 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, 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 obtain a crude product, which was purified by rapid column chromatography on silica gel (elution buffer: heptane / EtOAc = 100:0 to 50:50; on a 24 g Redisep Silver column) to give N,3-dimethoxy-N-methyl-2-naphthylcarboxamide as a white solid (1.6 g, 6.13 mmol, 62% yield, 94% purity).

[0602] ESI-MS ​ [M+H] + ;246.1 LC / MS Method 8.

[0603] 1-(3-Methoxynaphth-2-yl)ethyl-1-one (Intermediate 3)

[0604] MeMgBr (2.18 g, 6.11 mL, 3.0 mol, 3 equivalents, 18.4 mmol in THF) was added to a stirred solution of N,3-dimethoxy-N-methyl-2-naphthylcarboxamide (1.5 g, 1 equivalent, 6.1 mmol) in tetrahydrofuran (30 mL) over a 5-minute period at 0°C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography on silica gel (elution buffer: hexane / EtOAc = 100:0 to 80:20; on a 24 g Redisep column, via liquid injection) to give 1-(3-methoxynaphth-2-yl)ethyl-1-one as a white solid (800 mg, 3.84 mmol, 62% yield, 96% purity).

[0605] ESI-MS ​ [M+H] + ;201 LC / MS Method 8.

[0606] 2-Bromo-1-(3-methoxynaphth-2-yl)ethyl-1-one (Intermediate 4)

[0607] At 0°C, over a 5-min time interval, phenyltrimethylammonium tribromide (1.41 g, 1.0 equivalent, 3.75 mmol) in tetrahydrofuran (10 mL) was added to a stirred solution of 1-(3-methoxynaphth-2-yl)ethyl-1-one (750 mg, 1 equivalent, 3.75 mmol) in tetrahydrofuran (10 mL). The resulting reaction mixture was then stirred at room temperature for 16 h. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth bed and the filtrate was concentrated under reduced pressure to obtain a crude compound, which was purified by rapid column chromatography on silica gel (eluent: hexane / EtOAc = 100:0 to 90:10; on a 24 g Redisep column, via liquid injection) to give 2-bromo-1-(3-methoxynaphth-2-yl)ethyl-1-one as a white solid (700 mg, 2.37 mmol, 63% yield, 94.4% purity).

[0608] ESI-MS ​ [M+H] + ;280.90 LC / MS Method 10.

[0609] 2-(3-methoxynaphth-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (intermediate 5)

[0610] 2-Bromo-1-(3-methoxynaphthyl-2-yl)ethyl-1-one (180 mg, 1.5 equivalent, 646 μmol) was added 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 equivalent, 430 μmol) in isopropanol (5 mL). The reaction mixture was gradually heated to 100°C for 16 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude compound, which was dissolved in DCM and loaded onto silica gel (~1 g). Silica gel was placed in a sample-loaded column and purified by column chromatography (12 g RediSep, CombiFlash, gradient elution 0-10% MeOH) to obtain the desired product 2-(3-methoxynaphthyl-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).

[0611] ESI-MS ​ [M+H] + ;413.05 LC / MS Method 9.

[0612] 3-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)naphth-2-ol

[0613] Boron tribromide (0.200 mL, 8.73 equivalents, 2.12 mmol) was added to a stirred solution of (3-methoxynaphthyl-2-yl)-7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidine (100 mg, 1.0 equivalent, 242 μmol) in 1,2-dichloroethane (2 mL). Following the addition, the reaction mixture was stirred at 25°C for 16 h. After 16 h, LCMS showed residual starting material, so the reaction mixture was heated to 60°C for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (mobile phase: A = 0.1% HCOOH in water, B = ACN, column: X SELECT C18 (250 mm × 19 mm) 5.0 µm, flow rate: 15 mL / min). The fraction containing the desired product was lyophilized to give 3-(7-(2,2,6,6-tetramethyl1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)naphth-2-ol (compound 66, formate, 40 mg, 86.4 μmol, 35% yield, 96% purity) as a pale yellow solid.

[0614] ESI-MS ​ 399.05 [M+H] + LC / MS method 8.

[0615] HPLC: Rt 6.80 min, 96%.

[0616] 1 H 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).

[0617] 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

[0618] ESI-MS ​ 441.2 [M+H] + Compound 67: 1 H 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). 19 F NMR (376 MHz, DMSO) δ -68.06 (t, J = 10.2 Hz).

[0619] 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

[0620] ESI-MS ​ 449.2, [M+H] + Compound 68; 1 H NMR (400 MHz, methanol-) d4 +CDCl3) δ8.82 (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).

[0621] 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)-ketocarbamate

[0622] Methyl 4-bromo-5-methoxy-2-nitrobenzene [Intermediate 2]

[0623] Potassium tert-butoxide (8.1 g, 2.0 equivalent, 72 mmol) was added to a stirred solution of methyl 4-bromo-5-fluoro-2-nitrobenzene (10 g, 1.0 equivalent, 36 mmol) in methanol (100 mL) at room temperature. The reaction mixture was stirred at 25°C for 1 h. The reaction was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to obtain a crude residue, which was then ground with n-pentane. The resulting solid was collected by filtration, washed with n-pentane, and dried under reduced pressure to give methyl 4-bromo-5-methoxy-2-nitrobenzene (7.5 g, 21 mmol, 58% yield, 81% purity) as a pale yellow solid.

[0624] ESI-MS ​ 291.85 [M+H] + ; LC / MS Method 10

[0625] 4-Bromo-5-methoxy-2-nitrobenzoic acid [Intermediate 3]

[0626] Lithium hydroxide monohydrate (5.4 g, 3.6 mL, 5.0 equivalent, 129 mmol) was added to a stirred solution of methyl 4-bromo-5-methoxy-2-nitrobenzene (7.5 g, 1.0 equivalent, 25.86 mmol) in THF (60 mL) and water (10 mL). The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with 1 M HCl to pH = 7. 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 the residue, which was then milled with Et2O. The resulting solid was collected by filtration, washed with Et2O, and dried under reduced pressure to give 4-bromo-5-methoxy-2-nitrobenzoic acid (7.0 g, 24.6 mmol, 95% yield, 97% purity) as a pale yellow solid.

[0627] ESI-MS ​ 275.9 [M+H] + ; LC / MS Method 8

[0628] 4-Bromo-5-methoxy-N-methyl-2-nitrobenzamide [Intermediate 4]

[0629] At 0°C, DIPEA (22.1 mL, 5.0 equivalence, 127 mmol) and HATU (11.6 g, 1.2 equivalence, 30.4 mmol) were added to a stirred solution of 4-bromo-5-methoxy-2-nitrobenzoic acid (7.0 g, 1.0 equivalence, 25.4 mmol) in N,N-dimethylformamide (70 mL). The reaction mixture was stirred at 0°C for 15 min. After 15 min, methylamine hydrochloride (3.4 g, 2.0 equivalence, 50.7 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to a crude residue, which was diluted with water. The separated solids were filtered through a Buchner funnel and washed with excess water, and dried under vacuum to obtain a crude residue. The crude residue was ground with Et2O and dried under reduced pressure to give 4-bromo-5-methoxy-N-methyl-2-nitrobenzamide (5.7 g, 19.05 mmol, 75% yield, 97% purity) as a pale yellow solid.

[0630] ESI-MS ​ 288.9 [M+H] + ; LC / MS Method 8

[0631] 2-Amino-4-bromo-5-methoxy-N-methylbenzamide [Intermediate 5]

[0632] At 0°C, ammonium chloride (10.55 g, 10 equivalents, 197.2 mmol) was added to a stirred solution of 4-bromo-5-methoxy-N-methyl-2-nitrobenzamide (5.7 g, 1.0 equivalent, 19.7 mmol) in tetrahydrofuran (60 mL) and water (15 mL). After stirring at 0°C for 15 min, zinc (12.89 g, 10 equivalents, 197.2 mmol) was added partically at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered through a diatomaceous earth bed and washed with excess ethyl acetate. The combined filtrates were dried over sodium sulfate and concentrated to obtain the crude product. Purification: The crude product was dissolved in DCM and loaded onto silica gel (~10 g). Silica gel was placed in a sample-loaded column for purification 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.

[0633] ESI-MS ​ 260.9 [M+H] + ; LC / MS Method 9

[0634] 7-Bromo-6-methoxy-3-methylquinazoline-4(3H)-one [Intermediate 6]

[0635] Triethyl orthoformate (6.2 g, 6.9 mL, 3.0 equivalent, 41.7 mmol) was added to a stirred solution of 2-amino-4-bromo-5-methoxy-N-methylbenzamide (3.6 g, 1.0 equivalent, 13.89 mmol) in ethanol (40 mL). 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 rapid column chromatography on silica gel (elution: hexane / EtOAc = 100:0 to 0:100; 24 g Redisep Silver column, using 5 g solid column) to give 7-bromo-6-methoxy-3-methylquinazoline-4(3H)-one (2.2 g, 7.9 mmol, 56% yield, 96% purity) as a white solid.

[0636] ESI-MS ​ 270.85 [M+H] +; LC / MS Method 9

[0637] 7-Acetyl-6-methoxy-3-methylquinazoline-4(3H)-one [Intermediate 8]

[0638] To a stirred solution of 7-bromo-6-methoxy-3-methylquinazoline-4(3H)-one (2.1 g, 1.0 equivalent, 7.8 mmol) in toluene (20 mL), add (1-ethoxyvinyl)tributyltinane (3.4 g, 3.2 mL, 1.2 equivalent, 9.36 mmol) and potassium carbonate (3.23 g, 3 equivalent, 23.41 mmol). The reaction mixture was purged with argon for 15 min. After 15 min, Pd(PPh3)4 (1.8 g, 0.2 equivalent, 1.56 mmol) was added, and the reaction mixture was purged with argon again for 10 min. The reaction mixture was heated to 90°C for 16 h. The reaction mixture was then filtered through a diatomaceous earth bed and washed with excess ethyl acetate. The combined filtrates were dried over sodium sulfate and concentrated under reduced pressure to obtain a residue (3 g), which was dissolved in tetrahydrofuran (30 mL). Hydrochloric acid (23 mL, 1 mol) 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% NaHCO3 and EtOAc. The layers were separated. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography on silica gel (eluent: hexane / EtOAc = 100:0 to 0:100; 40 g Redesep Silver column, using a 25 g solid column) to give 7-acetyl-6-methoxy-3-methylquinazoline-4(3H)-one (0.9 g, 3.15 mmol, 27% yield, 81% purity) as a pale yellow solid.

[0639] ESI-MS ​ 233.0 [M+H] + ; LC / MS Method 8

[0640] 7-(2-Bromoacetyl)-6-methoxy-3-methylquinazoline-4(3H)-one [Intermediate 10]

[0641] At 0°C, phenyltrimethylammonium tribromide (Jacques reagent) (809 mg, 1.0 equivalent, 2.15 mmol) in tetrahydrofuran (10 mL) was added to a stirred solution of 7-acetyl-6-methoxy-3-methylquinazoline-4(3H)-one (500 mg, 1.0 equivalent, 2.15 mmol) in tetrahydrofuran (10 mL). The resulting reaction mixture was heated to 60°C for 4 h. The reaction mixture was filtered through a diatomaceous earth bed and the filtrate was concentrated to give a crude product, which was purified by rapid column chromatography on silica gel (elution: hexane / EtOAc = 100:0 to 0:100; 12 g Redisep column, via injection of the compound solution) to give 7-(2-bromoacetyl)-6-methoxy-3-methylquinazoline-4(3H)-one (270 mg, 608 μmol, 28% yield, 70% purity) as a pale yellow solid.

[0642] ESI-MS ​ 312.9 [M+H] + ; LC / MS Method 10

[0643] 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 [Intermediate 11]

[0644] 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 equivalent, 646 μmol) in isopropanol (3 mL), 7-(2-bromoacetyl)-6-methoxy-3-methylquinazoline-4(3H)-one (241 mg, 1.2 equivalent, 775 μmol) was added, and the reaction mixture was heated to 80°C for 16 h. The reaction mixture was diluted with 10% NaHCO3 aqueous solution 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 rapid column chromatography on silica gel (elution buffer: DCM / [MeOH / (28% NH3 aqueous solution) (9:1)] = 100:0 to 90:10; 12 g Redisep Silver column, via injection of the compound solution) to give 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.

[0645] ESI-MS ​ 445.10 [M+H] + ; LC / MS Method 9

[0646] 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

[0647] Boron tribromide (1 mL, 29.4 equivalence, 10.6 mmol) was added 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 equivalent, 360 μmol) in 1,2-dichloroethane (2 mL). The reaction mixture was heated to 60°C for 3 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by reversed-phase HPLC (preparative conditions: mobile phase: A = 0.1% HCOOH in water, B = ACN, column: Gemini NX (250 mm x 21.2 mm), 5.0 µm, flow rate: 18 mL / min). The fractions containing the product were combined 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 (compound 69, formate; 30 mg, 61 μmol, 16% yield, 97% purity) as a pale yellow solid as a formate.

[0648] ESI-MS ​ [M+H] + ;431.05 LC / MS Method 8

[0649] HPLC: Rt 5.13 min, 97% pure.

[0650] 1 H 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).

[0651] 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

[0652] ESI-MS ​ 386.2 [M+H] + Compound 70; 1 H 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 - 7.56 (m, 2H), 7.40 (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).

[0653] The first elution peak was obtained using the following column and conditions for enantiomer separation: Column: Chiralcel OX-H 21x250mm 5um - (CPC117) Flow rate: 80 g / min Co-solvent: 50% 4:1 MeOH:ACN w / 10mM NH3 in CO2 Detection: 272nm BPR setting point: 125 bar Injection size: 3 mg (2.0 mg / mL in MeOH) System: Thar80 Acronyms: MeOH = methanol, ACN = acetonitrile, NH3 = ammonia

[0654] 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

[0655] ESI-MS ​ 386.2 [M+H]+ Compound 71; 1 H 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).

[0656] The second elution peak was achieved using the following column and conditions for enantiomer separation: Column: Chiralcel OX-H 21x250mm 5um - (CPC117) Flow rate: 80 g / min Co-solvent: 50% 4:1 MeOH:ACN w / 10mM NH3 in CO2 Detection: 272nm BPR setting point: 125 bar Injection size: 3 mg (2.0 mg / mL in MeOH) System: Thar80 Acronyms: MeOH = methanol, ACN = acetonitrile, NH3 = ammonia

[0657] 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 carboxylate

[0658] 1-(4-bromo-2-methoxyphenyl)ethyl-1-one

[0659] Iodomethane (5.81 mL, 2 equivalents, 93.0 mmol) was added to a mixture of 1-(4-bromo-2-hydroxyphenyl)ethyl-1-one (10 g, 1 equivalent, 46.501 mmol), potassium carbonate (19.27 g, 3 equivalents, 139.5 mmol), and acetonitrile (100 mL), and the reaction was stirred at 50°C for 16 h. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude residue was purified by rapid column chromatography on silica gel (elution: heptane / EtOAc = 100 / 0 to 80 / 20; 24 g Redisep Silver column, using a 25 g solid column) to give 1-(4-bromo-2-methoxyphenyl)ethyl-1-one (10 g, 43.65 mmol, 93.88%) as a white solid.

[0660] ESI-MS ​ [M+H] + ;229.0 LC / MS Method 10

[0661] 1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl-1-one

[0662] The mixture of Pd2(dba)3 (3.198 g, 0.2 equivalent, 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 equivalent, 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)ethyl-1-one (4 g, 1 equivalent, 17.46 mmol), 2H-1,2,3-triazole (6.03 g, 5 equivalent, 87.31 mmol), and potassium phosphate (11.12 g, 4.337 mL, 3 equivalent, 52.39 mmol) in toluene (15 mL) and 1,4-dioxane (7.5 mL) were purged with argon for 5 min. Preheated catalyst was added to the mixture, and the mixture was purged with argon for 5 min. The reaction mixture was heated to 120°C for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, 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 give the crude product. The crude residue was purified by rapid column chromatography on silica gel (elution buffer: hexane / EtOAc (10%–15%), 24 g Redisep Silver column, using a 25 g solid column) to give 1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl-1-one (2.8 g, 13 mmol, 72% yield, 98% purity) as a white solid.

[0663] ESI-MS ​ [M+H] + ;218.10 LC / MS Method 10

[0664] 2-Bromo-1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl-1-one

[0665] At room temperature, bromine (2.06 g, 664.0 μL, 1 equivalent, 12.89 mmol) in 1,4-dioxane (10 mL) was added dropwise to a mixture of 1-(2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl)ethyl-1-one (2.8 g, 1 equivalent, 12.89 mmol) in 1,4-dioxane (40 mL). After the addition, the reaction mixture was stirred at 27°C for 4 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, 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 give the crude product. The crude residue was purified by rapid 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)ethyl-1-one (2.3 g, 7.6 mmol, 59% yield, 98% purity) as a white solid.

[0666] ESI-MS ​ [M+H] + ; 297.85 LC / MS Method 8

[0667] 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

[0668] At room temperature, 2-bromo-1-(2-methoxy-4-(2H-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (300 mg, 1 equivalent, 1.291 mmol) was added to a stirred solution of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl-1-one (458.8 mg, 1.2 equivalent, 1.550 mmol) in isopropanol (5 mL). The reaction mixture was gradually heated to 80°C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with saturated NaHCO3 and extracted three times with chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was then ground with Et2O. The resulting solid was collected by filtration, washed with Et2O, and dried under reduced pressure to give 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.

[0669] ESI-MS ​ [M+H] + ; 430.25 LC / MS Method 8

[0670] 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

[0671] At 0°C, a selective fluorine reagent (329.9 mg, 1 equivalent, 931.3 μmol) was added 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 equivalent, 931.3 μmol) in acetonitrile (5 mL). The reaction mixture was then stirred at 25°C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product. The crude product was purified by column chromatography (12 g Redisep Silver column, solvent gradient of 0-10% MeOH in DCM) to obtain the final product. The product was further purified by preparative RP-HPLC. The pure fraction was 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 as a yellow solid (70 mg, 95 μmol, 10% yield, 61% purity).

[0672] ESI-MS ​ [M+H] + ;448.10 LC / MS Method 8

[0673] 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 [SO-EE-NBFI]

[0674] Boron tribromide (0.5 mL, 33.8 equivalents, 5.29 mmol) was added 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 equivalent, 156.4 μmol) in 2 mL of 1,2-dichloroethane. The reaction mixture was gradually heated to 60°C for 3 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product as a brown solid. The crude product was purified by RP-HPLC.

[0675] The pure fraction containing the product was lyophilized to give 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, as a yellow solid (compound 72, 16 mg, 35.53 μmol, 22% yield, 96.25% purity).

[0676] ESI-MS ​ [M+H] + ; 434.05 LC / MS Method 8

[0677] HPLC: Rt 5.67 min; 96% purity

[0678] 1 H 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 = 7.4Hz, 1H), 6.90 (s, 1H), 2.86 (s, 2H), 1.59 (s, 6H), 1.49 (s, 6H). 19 F NMR (282MHz, methanol-) d4 ) δ -136.93 (m).

[0679] ESI-MS ​ 434.1 [M+H] + Compound 72, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.68 (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). 19 F NMR (282 MHz, methanol-)d4 ) δ -136.93 (m).

[0680] 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

[0681] ESI-MS ​ 430.5 [M+H] + Compound 73; 1 H 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).

[0682] 2-(7-(2-amino-2-methylpropoxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0683] ESI-MS ​ 366.05 [M+H] + Compound 74, formate; 1 H 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).

[0684] 3-Chloro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinoline-7-ol (Compound 75)

[0685] (E)-3-((4-bromo-3-methoxyphenyl)imino)-2-chloropropanal [Intermediate 2]

[0686] 2-Chloropropanedialdehyde (3.16 g, 1.2 equivalent, 29.7 mmol) was added to a stirred mixture of 4-bromo-3-methoxyaniline (5.0 g, 1 equivalent, 24.75 mmol) in ethanol (50 mL) at 0°C. After the addition, the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure to give a crude product, which was then ground with diethyl ether to give (E)-3-((4-bromo-3-methoxyphenyl)imino)-2-chloropropane (6.0 g, 20.79 mmol, 84% yield) as a yellow solid.

[0687] ESI-MS ​ 291.10, [M+H] + ; LC / MS Method 8

[0688] 6-Bromo-3-chloro-7-methoxyquinoline [Intermediate 3]

[0689] A mixture of (E)-3-((4-bromo-3-methoxyphenyl)imino)-2-chloropropanal (6.0 g, 1 equivalent, 20.6 mmol) in PPA (50 g, 24.27 mL, 13.60 equivalent, 280.9 mmol) was stirred at 140°C for 4 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 solution 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 give the crude reaction product. The crude product was purified by rapid column chromatography on silica gel (elution: hexane / ethyl acetate = 0:100 to 80:20; 40 g Redisep Silver column, using 5 g solid column) to give 6-bromo-3-chloro-7-methoxyquinoline (1.2 g, 5.92 mmol, 21% yield, 97.2% purity) as a yellow solid.

[0690] ESI-MS​ 273.8, [M+H] + Rt = 1.82 min (LC / MS method 8)

[0691] 1-(3-Chloro-7-methoxyquinoline-6-yl)ethyl-1-one [Intermediate 4]

[0692] Tributyl(1-ethoxyvinyl)stanane (1.59 g, 1 equivalent, 4.4 mmol) was added to a mixture of 6-bromo-3-chloro-7-methoxyquinoline (1.2 g, 1 equivalent, 4.4 mmol) in toluene (3.0 mL). The reaction mixture was purged with argon for 10 min, then Pd(PPh3)4 (1.02 g, 0.2 equivalent, 880.6 μmol) was added, and the reaction mixture was stirred at 90°C for 16 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and filtered through a diatomaceous earth bed. The diatomaceous earth bed was washed twice with ethyl acetate. The combined filtrates were concentrated under reduced pressure to give crude 3-chloro-6-(1-ethoxyvinyl)-7-methoxyquinoline (1.7 g) as a brown solid, which was used directly in the next step.

[0693] At 0°C, 2M HCl (3.2 mL, 2 mol, 1 equivalent, 6.446 mmol) was added to a mixture of 3-chloro-6-(1-ethoxyvinyl)-7-methoxyquinoline (1.7 g, 1 equivalent, 6.446 mmol) in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 4 h. After the reaction was complete, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by rapid column chromatography on silica gel (elution: hexane / ethyl acetate = 100:0 to 90:10; 40 g Redisep Silver column, using 5 g solid column) to give 1-(3-chloro-7-methoxyquinoline-6-yl)ethyl-1-one (600 mg, 2.448 mmol, 37.98% yield, 96.16% purity) as a yellow solid.

[0694] ESI-MS ​ 235.9, [M+H] + ; LC / MS Method 8

[0695] 2-Bromo-1-(3-chloro-7-methoxyquinoline-6-yl)ethyl-1-one [Intermediate 5]

[0696] At 0°C, mono(N,N,N-trimethylaniline)tribromide, 98% (319 mg, 1 equivalent, 848.64 μmol), was added partically to a mixture of 1-(3-chloro-7-methoxyquinoline-6-yl)ethyl-1-one (200 mg, 1 equivalent, 848.64 μmol) in THF (5.0 mL) and stirred for 5 min. After 16 h at room temperature, the reaction mixture was heated at 80°C for 36 h. Subsequently, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by rapid chromatography using a 24 g Silicycle silica column, eluting with 30%–100% DCM in hexane. The pure fraction was collected and concentrated under reduced pressure to give the product 2-bromo-1-(3-chloro-7-methoxyquinoline-6-yl)ethyl-1-one (200.0 mg, 582 μmol, 68.6% yield, 91.5% purity) as a grayish-white solid.

[0697] ESI-MS ​ 315.8, [M+H] + ; LC / MS Method 8

[0698] 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]

[0699] At room temperature, 2-bromo-1-(3-chloro-7-methoxyquinoline-6-yl)ethyl-1-one (193.6 mg, 1.3 equivalent, 615.5 μmol) was added to a stirred mixture of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (110 mg, 1 equivalent, 473.5 μmol) in IPA (4.0 mL), and the reaction mixture was subsequently heated at 80°C for 48 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with ice followed by 2 mL of saturated aqueous NaHCO3 solution, and extracted twice with 10% methanol in DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was then ground with diethyl ether to give a light brown solid 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).

[0700] ESI-MS ​448.10, [M+H] + ; LC / MS Method 8

[0701] 3-Chloro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinoline-7-ol

[0702] At 0°C, boron trichloride (608 mg, 0.6 mL, 1.0 mol, 4.48 equivalence, 600 μmol) was added dropwise to a 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 equivalent, 133.9 μmol) in DCM (3 mL). After the addition, the temperature was gradually increased to room temperature and the reaction mixture was stirred for 16 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was quenched with ice, alkalized with saturated aqueous NaHCO3 solution (1-2 drops), and extracted twice with ethyl acetate, followed by extraction with 10% methanol in DCM. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product as a pale brown solid. The crude product was purified by preparative HPLC (mobile phase: A = 0.1% HCOOH in water, B = CAN; column: LUNA (C18, 20 mm x 250 mm); flow rate: 15 ml / min; gradient program (time / %B): 0 min / 40, 2 min / 50, 8 min / 65). The purified fractions were combined and lyophilized to give the product 3-chloro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)quinoline-7-ol formate as a yellow solid (compound 75, formate, 18.00 mg, 36.70 μmol, 27.40% yield, 97.87% purity).

[0703] ESI-MS ​ 434.04 [M+H] + ; LC / MS Method 8

[0704] HPLC: 97.87%, 4.885 min

[0705] 1 H 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).

[0706] 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

[0707] ESI-MS ​ 417.10 [M+H] + Compound 76; 1 H 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).

[0708] 2-(7-(1-ethyl-2,2-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0709] ESI-MS ​ 416.20 [M+H] + Compound 77; 1 H 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).

[0710] ( R )-2-(7-(3-aminopyrrolidone-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0711] ESI-MS ​ 363.02 [M+H] + Compound 78, formate; 1 H 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).

[0712] 2-(7-(3-(ethylamino)-3-methylbutyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0713] ESI-MS ​ 392.10 [M+H] + Compound 79, formate; 1 H 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).

[0714] 2-(7-(3-methyl-3-(methylamino)butyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0715] ESI-MS ​ 378.15 [M+H] + Compound 80, formate; 1 H 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).

[0716] 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

[0717] ESI-MS ​ 401.20 [M+H] + Compound 81, formate; 1 H 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 = 7.2Hz, 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).

[0718] 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

[0719] ESI-MS ​ 415.15 [M+H] + Compound 82, formate; 1 H 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).

[0720] 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

[0721] ESI-MS ​ 492.50 [M+H] + Compound 83, formate; 1 H 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). 19 F NMR (376 MHz, methanol-) d4 ) δ -112.24, -147.95.

[0722] 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

[0723] ESI-MS ​ 386.05 [M+H] + Compound 84; 1 H 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).

[0724] 2-(7-(4-azaspiro[2.5]oct-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0725] ESI-MS ​ 388.10 [M+H] + Compound 85, enantiomer 1; 1 H 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).

[0726] The following column and conditions were used for the second elution peak of the enantiomers separated by chiral SFCs: Rt = 11.09 min.

[0727] Column: LUX-AMYLOSE-2, 4.6 mm x 150 mm x 5 µM

[0728] Flow rate: 3 mL / min

[0729] Export pressure: 100 bar

[0730] Temperature: 40°C

[0731] Co-solvent: 40% 1:1:1 IPA:EtOH:MeOH with 10 mM ammonia in CO2

[0732] Acronyms: MeOH = methanol, IPA = isopropanol, EtOH = ethanol

[0733] 2-(7-(4-azaspiro[2.5]oct-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0734] ESI-MS ​ 388.10 [M+H] + Compound 85, enantiomer 2; 1 H 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).

[0735] The following column and conditions were used for the first elution peak of the enantiomers separated by chiral SFCs: Rt = 8.42 min.

[0736] Column: LUX-AMYLOSE-2, 4.6 mm x 150 mm x 5 µM

[0737] Flow rate: 3 mL / min

[0738] Export pressure: 100 bar

[0739] Temperature: 40°C

[0740] Co-solvent: 40% 1:1:1 IPA:EtOH:MeOH with 10 mM ammonia in CO2

[0741] Acronyms: MeOH = methanol, IPA = isopropanol, EtOH = ethanol

[0742] 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

[0743] ESI-MS ​429.20 [M+H] + Compound 86; 1 H 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).

[0744] 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)pyridin-3-ol

[0745] ESI-MS ​ 387.10 [M+H] + Compound 87, formate; 1 H 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).

[0746] 5-Hydroxy-1'-methyl-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-[3,4'-bipyridine]-2'(1'H)-one

[0747] ESI-MS ​457.20 [M+H] + Compound 88, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.90 (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).

[0748] 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

[0749] Single enantiomer.

[0750] ESI-MS ​ 401.05 [M+H] + Compound 89, enantiomer 1, formate; 1 H 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).

[0751] To obtain compound 89 as a single enantiomer, chiral separation of the intermediates as shown below was performed. The enantiomerically pure intermediate was then converted to compound 89, enantiomer 1, by demethylation followed by Boc-deprotection.

[0752]

[0753] Column name: REGIS(S,S) WHELK-01, 4.6 mm x 1 50 mm x 5 µm

[0754] Mobile phase: CO2 and co-solvent

[0755] Co-solvent: 50%

[0756] Cosolvent name: 10 mM ammonia in CAN:MeOH:isopropanol (2:1:1)

[0757] Flow rate: 3 mL / min.

[0758] Export pressure: 100 bar

[0759] Temperature: 40°C

[0760] Rt = 13.38 min. (Second eluted enantiomer)

[0761] 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

[0762] Single enantiomer.

[0763] ESI-MS ​ 401.05 [M+H] + Compound 89, enantiomer 2, formate; 1 H 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).

[0764] To obtain compound 89 as a single enantiomer, chiral separation of the intermediates as shown below was performed. The enantiomerically pure intermediate was then converted to compound 89, enantiomer 2, by demethylation followed by Boc-deprotection.

[0765]

[0766] Column name: REGIS(S,S) WHELK-01, 4.6 mm x 1 50 mm x 5 µm

[0767] Mobile phase: CO2 and co-solvent

[0768] Co-solvent: 50%

[0769] Cosolvent name: 10 mM ammonia in CAN:MeOH:isopropanol (2:1:1)

[0770] Flow rate: 3 mL / min.

[0771] Export pressure: 100 bar

[0772] Temperature: 40°C

[0773] Rt = 9.44 min. (First eluted enantiomer)

[0774] 2-(7-(4-azaspiro[2.5]oct-7-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)pyridin-3-ol

[0775] Racemic mixture.

[0776] ESI-MS ​ 389.05 [M+H] +Compound 90, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.92 (d, J = 7.2 Hz, 1H), 8.91 - 8.87 (m, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 8.01 (s, 2H), 8.00 - 7.97 (m, 1H), 7.16 (d, J = 7.0 Hz, 1H), 3.52 - 3.45 (m,1H), 3.40 - 3.35 (m, 1H), 3.25 - 3.16 (m, 1H), 2.48 (t, J = 12.9 Hz, 1H), 2.32 - 2.23 (m, 1H), 2.13 - 2.03 (m, 1H), 1.70 - 1.60 (m, 1H), 1.04 - 0.95 (m, 2H), 0.91 - 0.82 (m, 2H).

[0777] 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)pyridin-3-ol

[0778] ESI-MS ​ 432.05 [M+H] + Compound 91; 1 H 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).

[0779] 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

[0780] ESI-MSm / z 417.3 [M+H] + Compound 92, formate: 1 1H NMR (400 MHz, dimethyl sulfoxide-) d 6) δ 12.71 (s, 1H), 9.00 (d, J = 7.2 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.52(s, 1H), 8.32 (s, 1H), 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).

[0781] 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

[0782] ESI-MS m / z 448.3 [M+H] + Compound 93, formate: 1 1H NMR (400 MHz, dimethyl sulfoxide-) d 6) 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-) d 6) δ -134.66.

[0783] 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

[0784] ESI-MS m / z 448.2 [M+H] + Compound 94, formate: 1 1H NMR (400 MHz, dimethyl sulfoxide-) d 6) 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).

[0785] 6-(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)-3-methylpyrimidin-4(3H)-one

[0786] ESI-MS ​ 475.3, [M+H] + Compound 95; 1 H 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 = 4.5Hz, 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). 19 F NMR (377 MHz, DMSO- d6 ) δ -111.0.

[0787] 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

[0788] ESI-MS ​ 457.5, [M+H] + Compound 96; 1 H 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).

[0789] 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

[0790] ESI-MS ​ 458.4, [M+H] + Compound 97; 1 H NMR (400 MHz, dichloromethane- d2) δ12.49 (s, 1H), 8.92 (s, 1H), 8.42 (d, J = 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, J = 1.7 Hz, 1H), 4.14 (s, 3H), 2.52 (d, J = 1.6 Hz, 2H), 1.31 (s, 6H), 1.22 (s, 6H).

[0791] 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

[0792] ESI-MS ​ 489.3, [M+H] + Compound 98; 1 H NMR (400 MHz, dichloromethane- d2 ) δ13.31 (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). 19 F NMR (377 MHz, dichloromethane- d2 ) δ -111.4.

[0793] 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

[0794] ESI-MS ​ 444.3 [M+H] + Compound 99; 1 ¹H NMR (400 MHz, dichloromethane-d²) δ 12.20 (s, ¹H), 8.47 (d, ¹H) 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).

[0795] 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

[0796] ESI-MS ​ 431.4 [M+H] + Compound 100, formate; 1 H NMR (400 MHz, DMSO- d6) δ9.02 (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)

[0797] 3'-Fluoro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-[3,4'-bipyridine]-5-ol

[0798] ESI-MS ​ 445.5 [M+H] + Compound 101; 1 H 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).

[0799] 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

[0800] ESI-MS ​ 481.6 [M+H]+ Compound 102, 1 H 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).

[0801] 5-Fluoro-6'-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-[2,3'-bipyridine]-5'-ol

[0802] ESI-MS ​ 445.0 [M+H] + Compound 103; 1 H 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). The CH2 resonance is masked by the solvent peak.

[0803] 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

[0804] ESI-MS ​ 484.4 [M+H] + Compound 104, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ12.54 (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 = 7.3Hz, 1H), 6.99 - 6.95 (m, 1H), 2.45 (s, 2H), 1.28 (s, 6H), 1.17 (s, 6H).

[0805] 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

[0806] ESI-MS ​ 444.4 [M+H] + Compound 105; 1 H NMR (400 MHz, dichloromethane- d2 ) δ12.10 (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).

[0807] 5'-Fluoro-6-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-[3,3'-bipyridine]-5-ol

[0808] ESI-MS ​ 445.5 [M+H] + Compound 106; 1 H NMR (400 MHz, dichloromethane- d2 ) δ12.43 (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).

[0809] 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

[0810] ESI-MS ​ 417.5 [M+H] + Compound 107; 1 H 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).

[0811] 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

[0812] ESI-MS ​ 430.0 [M+H] + Compound 108; 1 H 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).

[0813] 5-(4-methyl-1H-1,2,3-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

[0814] ESI-MS ​ 431.5 [M+H] + Compound 109; 1 H NMR (400 MHz, dichloromethane- d2) δ12.41 (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).

[0815] 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

[0816] ESI-MS ​ 431.4 [M+H] + Compound 110; 1 H NMR (400 MHz, dichloromethane- d2 ) δ12.49 (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).

[0817] 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

[0818] ESI-MS ​ 431.5 [M+H] + , 1 H NMR (400 MHz, dichloromethane- 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).

[0819] 5-(2-methyl-2H-1,2,3-triazol-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

[0820] ESI-MS ​ 431.4 [M+H] + Compound 112; 1 H 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 = 1.9Hz, 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).

[0821] 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

[0822] ESI-MS ​ 431.3 [M+H] + Compound 113; 1 H 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).

[0823] 2-(7-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(thiazo-2-yl)pyridin-3-ol

[0824] ESI-MS ​ 433.3 [M+H] + Compound 114; 1 H NMR (400 MHz, dichloromethane- 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 = 3.2Hz, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 7.2Hz, 1H), 6.70 - 6.66 (m, 1H), 2.45 - 2.42 (m, 2H), 1.23 (s, 6H), 1.14 (s,6H).

[0825] 5-(2-methylthiazolyl-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

[0826] ESI-MS ​ 447.4 [M+H] + Compound 115, formate; 1 H NMR (400 MHz, methanol-) d4) δ8.95 (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).

[0827] 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

[0828] ESI-MS ​ 431.4 [M+H] + Compound 116; 1 H NMR (400 MHz, dichloromethane- 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 = 2.0Hz, 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).

[0829] 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)isoquinoline-1(2H)-one

[0830] 7-Bromo-6-methoxyisoquinoline 2-oxide 2-bromo-1-(5-bromo-3-methoxypyridin-2-yl)ethyl-1-one (Intermediate 2)

[0831] At 0°C, m-CPBA (5.8 g, 2.0 equivalent, 33.6 mmol) was added partically to a mixture of 7-bromo-6-methoxyisoquinoline (4.0 g, 1.0 equivalent, 16.8 mmol) in DCM (80 mL). After stirring for 15 min, the reaction mixture was stirred at 25°C for 16 h. The reaction mixture was then diluted with ice-cooled water and 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, 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.

[0832] ESI-MS ​ 255.85, [M+H] + ; LC / MS method 8.

[0833] 7-Bromo-6-methoxyisoquinoline-1(2H)-one (Intermediate 3)

[0834] Sodium acetate (3.1 g, 3.0 equivalent, 37.8 mmol) and bromo-tri-pyrrolidinyl-phosphonium hexafluorophosphate (11.74 g, 2.0 equivalent, 25.2 mmol) were added to a mixture of 7-bromo-6-methoxyisoquinoline 2-oxide (3.2 g, 1.0 equivalent, 12.6 mmol) in water (20 mL) and 1,2-dichloroethane (40 mL) at 25°C. After stirring for 10 min, the reaction mixture was heated to 85°C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, 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 rapid column chromatography on silica gel (elution buffer: heptane / EtOAc = 70:30 to 60:40; 12 g Redisep Silver column, using 5 g solid column) to give the product 7-bromo-6-methoxyisoquinoline-1(2H)-one (2 g, 7.73 mmol, 61% yield, 98.7% purity) as a brown solid.

[0835] ESI-MS ​253.8, [M+H] + ; LC / MS method 11.

[0836] 7-Bromo-6-methoxy-2-methylisoquinoline-1(2H)-one (Intermediate 4)

[0837] At 25°C, Cs₂CO₃ (6.42 g, 2.5 equivalents, 19.7 mmol) and MeI (0.98 mL, 2.0 equivalents, 15.7 mmol) were added to a mixture of 7-bromo-6-methoxyisoquinoline-1(2H)-one (2.0 g, 1.0 equivalent, 7.9 mmol) in DMF (10 mL). After stirring for 5 min, the reaction mixture was heated to 50°C for 1 h. The reaction progress was monitored by TLC. After the reaction was complete, 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 rapid column chromatography on silica gel (elution: heptane / EtOAc = 100:0 to 80:20; 12 g RedisepSilver column, using 5 g solid column) to give the product 7-bromo-6-methoxy-2-methylisoquinoline-1(2H)-one (1.1 g, 3.5 mmol, 44% yield, 86% purity) as a white solid.

[0838] ESI-MS ​ 267.90, [M+H] + ; LC / MS method 8.

[0839] 7-Acetyl-6-methoxy-2-methylisoquinoline-1(2H)-one (Intermediate 5)

[0840] A mixture of 7-bromo-6-methoxy-2-methylisoquinoline-1(2H)-one (1.1 g, 1.0 equivalent, 4.1 mmol) and tributyl(1-ethoxyvinyl)stanane (3.7 g, 2.5 equivalent, 10.3 mmol) in DMF (10 mL) was degassed with argon at 25°C. Bis(triphenylphosphine)palladium(II) dichloride (317 mg, 0.11 equivalent, 451 μmol) was also added. 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 1 M 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 rapid column chromatography on silica gel (elution: heptane / EtOAc = 80:20 to 0:100; 12 g Redisep Silver column, using 5 g solid column) to give the product 7-acetyl-6-methoxy-2-methylisoquinoline-1(2H)-one (600 mg, 2.5 mmol, 62% yield, 98% purity) as a white solid.

[0841] ESI-MS ​ 232.00, [M+H] + ; LC / MS method 9.

[0842] 7-(2-Bromoacetyl)-6-methoxy-2-methylisoquinoline-1(2H)-one (Intermediate 6)

[0843] At 0°C, phenyltrimethylammonium tribromide (487 mg, 1.0 equivalent, 1.29 mmol) was added dropwise to a mixture of 7-acetyl-6-methoxy-2-methylisoquinoline-1(2H)-one (300 mg, 1.0 equivalent, 1.29 mmol) in THF (6.0 mL). After stirring for 15 min, the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was quenched 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 rapid column chromatography on silica gel (elution: heptane / EtOAc = 100:0 to 60:40; 12 g Redisep Silver column, using 5 g solid column) to give 7-(2-bromoacetyl)-6-methoxy-2-methylisoquinoline-1(2H)-one (220 mg, 0.57 mmol, 44% yield, 81% purity) as a grayish-white solid.

[0844] ESI-MS ​ 312.00, [M+H] + ; LC / MS method 8.

[0845] 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)isoquinoline-1(2H)-one (intermediate 7)

[0846] At 25°C, 200 mg (1.0 equivalent) of 7-(2-bromoacetyl)-6-methoxy-2-methylisoquinoline-1(2H)-one and 104 mg (0.70 equivalent, 451 μmol) of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-amine (451 μmol) were combined in isopropanol (2.0 mL). After stirring for 5 min, the reaction mixture was heated to 80°C for 32 h. The reaction progress was monitored by TLC. After the reaction was complete, 10 mL of ether was added to the reaction mixture and it was stirred for 10 min. The separated solid was filtered through a Buchner funnel, washed with ether (5 mL), and dried to obtain a crude product, which was purified by rapid column chromatography on silica gel (elution buffer: DCM / MeOH = 100:0 to 80:20; 12 g Redisep Silver column, using 5 g solid column) 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)isoquinoline-1(2H)-one (100 mg, 166 μmol, 25% yield, 74% purity) as a light brown solid.

[0847] ESI-MS ​ 444.5, [M+H] + ; LC / MS Method 10

[0848] 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)isoquinoline-1(2H)-one

[0849] At -78°C, BBr3 (4.0 mL, 1.0 mol, 0.01774 equivalence, 4.000 μmol) in DCM was added 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)isoquinoline-1(2H)-one (100 mg, 1.0 equivalent, 225 μmol) in DCM (3.0 mL). After the addition was complete, the reaction mixture was allowed to warm to room temperature over a 16 h process. The reaction progress was monitored by TLC. The reaction mixture was diluted with ice-cold water. The aqueous layer was extracted once with EtOAc. Then, at 0°C, the pH of the aqueous layer was adjusted to 7 by adding a saturated aqueous solution of NaHCO3 and extracted twice with MeOH:DCM [10:90]. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a crude residue, which was then suspended in acetonitrile (10 mL) and sonicated for 5 min. After the solid was allowed to settle, the solvent was decanted and the solid was dried under vacuum to give a yellow solid 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)isoquinoline-1(2H)-one (compound 117, 38 mg, 37% yield, 95% purity).

[0850] ESI-MS ​ 430.15, [M+H] + ; LC / MS Method 10

[0851] HPLC: Rt 5.17 min; 95.02%

[0852] 1 H 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).

[0853] 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

[0854] ESI-MS ​ 465.25 [M+H] + Compound 118, formate; 1 H 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, 2.1Hz, 1H), 6.90 - 6.88 (m, 1H), 3.96 (s, 3H), 2.84 (bs, 2H), 1.59 (s, 6H), 1.48(s, 6H). 19 F NMR (376 MHz, methanol-) d4 ) δ -139.14, -155.25.

[0855] 2-(7-(((1S,2R)-2-aminocyclopentyl)oxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0856] ESI-MS ​ 378.05 [M+H] + Compound 119, formate; 1 H 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).

[0857] 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

[0858] ESI-MS ​ 417.1 [M+H] + Compound 120; 1 H 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).

[0859] 2-(7-(((1S,2S)-2-aminocyclopentyl)oxy)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0860] ESI-MS ​ 378.15 [M+H] + Compound 121, formate; 1 H NMR (400 MHz, methanol-) d4) δ8.68 (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).

[0861] 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

[0862] 6-Bromo-5-methoxy-1H-indole-1-carboxylic acid tert-butyl ester (intermediate 2)

[0863] At 0°C, DMAP (324 mg, 0.2 equivalents, 2.65 mmol) was added to a mixture of 6-bromo-5-methoxy-1H-indole (3.0 g, 1 equivalent, 13.27 mmol) in DCM (30 mL), followed by (Boc)₂O (4.34 g, 4.57 mL, 1.5 equivalents, 19.9 mmol). The reaction mixture was then stirred at 27°C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, 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 obtain a crude product, which was purified by rapid column chromatography on silica gel (elution: 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).

[0864] ESI-MS ​ 327, [M+2H] + ; LC / MS method 8.

[0865] 6-Acetyl-5-methoxy-1H-indole-1-carboxylic acid tert-butyl ester (intermediate 3)

[0866] A mixture of tert-butyl 6-bromo-5-methoxy-1H-indole-1-carboxylate (3.4 g, 1 equivalent, 10.4 mmol) and (1-ethoxyvinyl)tributyltinane (7.52 g, 7.050 mL, 2 equivalent, 20.9 mmol) in toluene (60 mL) was purged with argon at room temperature for 5 min. Then, tetrakis(triphenylphosphine)palladium(0) (2.4 g, 0.2 equivalent, 2.08 mmol) was added under argon purging. After 5 min, the reaction mixture was heated to 100°C for 16 h. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, 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 obtain a crude product, which was purified by rapid column chromatography on silica gel (elution: 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 (2.6 g, 8.8 mmol, 84% yield, 98% purity) as a brown solid.

[0867] ESI-MS ​ 290, [M+H] + ; LC / MS method 8.

[0868] 6-(2-bromoacetyl)-5-methoxy-1H-indole-1-carboxylic acid tert-butyl ester (intermediate 4)

[0869] At 0°C, 1.2 g (1 equivalent, 4.14 mmol) of tert-butyl 6-acetyl-5-methoxy-1H-indole-1-carboxylate (24 mL) was added dropwise to a mixture of phenyltrimethylammonium tribromide (3.0 mL) in THF (1.24 g, 0.8 equivalent, 3.31 mmol). After the addition, the reaction mixture was stirred at 27°C for 2 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was passed through diatomaceous earth, which was then washed with EtOAc. The combined filtrates were concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography on silica gel (elution: 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-carboxylic acid (0.6 g, 1.6 mmol, 38% yield, 96% purity) as a white solid.

[0870] ESI-MS ​ 369.85, [M+2H] + ; LC / MS method 8.

[0871] 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-carboxylic acid tert-butyl ester (intermediate 5)

[0872] At room temperature, tert-butyl 6-(2-bromoacetyl)-5-methoxy-1H-indole-1-carboxylic acid (570 mg, 1.2 equivalent, 1.50 mmol) was added to a mixture of 4-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-amine (300 mg, 1 equivalent, 1.29 mmol) in IPA (5.0 mL), and the reaction mixture was stirred at 80°C for 16 h. The progress of the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by rapid column chromatography on silica gel (elution: MeOH / DCM 2% to 4%; 12 g Redisep Silver column, using a 25 g solid column) 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-carboxylic acid (0.5 g, 0.89 mmol, 69% yield, 89% purity).

[0873] ESI-MS ​ 502.15, [M+H] + ; LC / MS method 8.

[0874] 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)

[0875] 0.38 g (1.0 equivalent, 758 μmol) of 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-carboxylic acid was dissolved in 10 mL of 2,2,2-trifluoroethanol. The reaction mixture was stirred at 135°C for 20 min under microwave irradiation. The reaction progress was monitored by TLC and LCMS. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give 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 the next step without further purification.

[0876] ESI-MS ​ 402.10, [M+H] + ; LC / MS method 8.

[0877] 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)

[0878] Cs₂CO₃ (243 mg, 3 equivalents, 747 μmol) and iodomethane (70 mg, 31.2 μL, 2 equivalents, 498 μmol) were added 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 equivalent, 249 μmol) in DMF (4.0 mL). The reaction mixture was stirred at 27°C for 2 h. After the reaction was complete, 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 give 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 the next step without further purification.

[0879] ESI-MS ​ 416.10, [M+H] + ; LC / MS Method 8

[0880] 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

[0881] At 0°C, boron trichloride (1.4 mL, 1.0 mol, 10 equivalence, 1.44 mmol) was added 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 equivalent, 144 μmol) in a DCE (3.0 mL). The reaction mixture was stirred at 27°C for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, it was quenched with ice water and extracted with EtOAc. The aqueous layer was then alkalized with NaHCO3, and the product was 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: XSELECT (250 mm × 20.0 mm), 5.0 μm, flow rate: 15 mL / min, gradient: time - %B: 0-5, 2-10, 8-40). The purified fraction containing the desired product was 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-indo-5-ol (21 mg) as a brownish-yellow solid. The above-purified compound was further purified by SFC: CHIRAL PAK IG, 250 mm × 30 mm, 5 µm, mobile phase: CO2 (A) and 10 mM ammonia in IPA / MeOH (B), flow rate: 80 mL / min, isocratic ratio: 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 (compound 122, 6.5 mg, 16.0 μmol, 11% yield, 98.6% purity) as a yellow solid.

[0882] ESI-MS ​ 402.10, [M+H] + ; LC / MS method 8.

[0883] HPLC: 98.6%, Rt: 5.34 min.

[0884] 1 H 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,J = 7.1 Hz, 1H), 7.15 (d, J = 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).

[0885] 1-Phenylacetyl-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

[0886] ESI-MS ​ 492.20 [M+H] + Compound 123, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.79 (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).

[0887] 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

[0888] ESI-MS ​ 388.05 [M+H] + Compound 124, formate; 1H NMR (400 MHz, methanol-) d4 ) δ8.80 (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).

[0889] (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

[0890] ESI-MS ​ 362.05 [M+H] + Compound 125, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.85 (d, J = 7.0 Hz, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 8.07 (dd, J = 8.2, 0.7Hz, 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).

[0891] (E)-2-(7-(3-aminopropyl-1-en-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0892] ESI-MS ​ 334.00 [M+H]+ Compound 126; 1 H 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).

[0893] 2-(7-(3-aminopropyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0894] ESI-MS ​ 336.00 [M+H] + Compound 127, formate; 1 1H NMR (400 MHz, dimethyl sulfoxide-) 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).

[0895] 2-(7-(azacyclobutane-3-methylenemethyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0896] ESI-MS ​ 345.95 [M+H] + Compound 128, formate; 1 1H NMR (400 MHz, dimethyl sulfoxide-) d6δ = 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 = 7.2Hz, 1H), 6.57 (s, 1H), 3.90 (s, 2H). Due to being masked by the solvent peak, the two proton resonances are missing.

[0897] (E)-2-(7-(2-(pyrrolidin-2-yl)vinyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0898] Racemic mixture.

[0899] ESI-MS ​ 374.05 [M+H] + Compound 129; 1 1H NMR (400 MHz, dimethyl sulfoxide-) 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).

[0900] 2-(7-(3-amino-3-methylbutyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0901] ESI-MS ​ 364.00 [M+H] + Compound 130, formate; 1 1H NMR (400 MHz, dimethyl sulfoxide-) 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).

[0902] 2-(7-(2-(pyrrolidone-2-yl)ethyl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0903] Racemic mixture.

[0904] ESI-MS ​ 376.05 [M+H] + Compound 131, formate; 1 H NMR (400 MHz, methanol-) d 4 ) 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).

[0905] 2-(7-((2-amino-2-methylpropyl)(methyl)amino)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0906] 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).

[0907] 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

[0908] ESI-MS ​ 444.25 [M+H] + Compound 133 1 1H NMR (400 MHz, dimethyl sulfoxide-) 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).

[0909] 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

[0910] ESI-MS ​ 434.20 [M+H] + Compound 134, hydrobromide; 1 1H NMR (400 MHz, dimethyl sulfoxide-) 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).

[0911] 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

[0912] ESI-MS ​ 450.15 [M+H] + Compound 135, formate; 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). 19 F NMR (376 MHz, methanol-) d4 ) δ -110.33.

[0913] 3-Fluoro-5-(5-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

[0914] ESI-MS ​ 450.15 [M+H] + Compound 136, formate; 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). 19 F NMR (376 MHz, methanol-) d4 ) δ -110.58.

[0915] 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

[0916] ESI-MS m / z 434.4 [M+H] + Compound 137, formate.

[0917] 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

[0918] ESI-MS ​ 415.05 [M+H] + Compound 138, enantiomer 1, formate; 1 H 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).

[0919] The following column and conditions were used for the second elution peak of enantiomers separated by chiral HPLC: Column: Chiralpak-IG (250 x 20 mm x 5 µM) Flow rate: 20 mL / min Mobile phase: 90% 10 mM NH3 in MeCN (A) and 10% 10 mM NH3 in EtOH / iPrOH (1:1) (B)

[0920] 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

[0921] ESI-MS ​ 415.05 [M+H] + Compound 138, enantiomer 2, formate; 1 H 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).

[0922] The first elution peak was obtained 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 / min Mobile phase: 90% 10 mM NH3 in MeCN (A) and 10% 10 mM NH3 in EtOH / iPrOH (1:1) (B)

[0923] 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

[0924] ESI-MS ​ 447.10 [M+H] + Compound 139, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.86 (d, J = 7.2 Hz, 1H), 8.54 (s, 1H), 8.19 (d, J = 4.4 Hz, 1H), 8.03 (s,1H), 7.86 (s, 1H), 7.52 (d, J = 7.2 Hz, 1H), 7.00 (m, 1H), 6.95 (m, 1H), 6.88(m, 1H), 3.94 (s, 3H), 2.84 (m, 2H), 1.57 (s, 6H), 1.45 (s, 6H). 19 F NMR (376MHz, methanol-) d4 ) δ -113.4.

[0925]

[0926] ESI-MS ​ 447.15 [M+H] + Compound 139; 1 H 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). 19 F NMR (377 MHz, methanol-) d4) δ -113.4.

[0927] 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

[0928] ESI-MS ​ 500.20 [M+H] + Compound 140, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.84 (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). 19 F NMR (377 MHz, methanol-) d4 ) δ -112.1.

[0929] 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

[0930] ESI-MS ​ 488.20 [M+H] + Compound 141, formate; 1 H NMR (400 MHz, methanol-) d4) δ8.87 (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). 19 F NMR (377 MHz, methanol-) d4 ) δ -112.1.

[0931] (S)-2-(7-(3-aminopyrrolidone-1-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0932] ESI-MS ​ 363.05 [M+H] + Compound 142, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.52 (d, J = 7.6 Hz, 1H), 8.41 (m, 2H), 7.94-7.87 (m, 3H), 7.86 (d, J = 8.4Hz, 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).

[0933] 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

[0934] A single diastereomer (the two methyl substituents on piperidine are) ​(cis)), racemic mixture.

[0935] ESI-MS ​ 388.05 [M+H] + Compound 143, formate; 1 H NMR (400 MHz, methanol-) d4 ) δ8.82 (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, 8.3Hz, 1H), 1.52 (d, J = 6.9 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H).

[0936] 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)phenol

[0937] Racemic mixture.

[0938] ESI-MS ​ 414.05 [M+H] + Compound 144, formate; 1 H NMR (400 MHz, DMSO- d6 ) δ11.85 (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).

[0939] 2-(7-((1R,3r,5S)-9-azabicyclo[3.3.1]non-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0940] ESI-MS ​ 402.10 [M+H] + Compound 145, formate; 1 H NMR (400 MHz, methanol-) d 4) δ8.85 (d, J = 6.8 Hz, 1 H), 8.54 (br s, 1 H), 8.35 (s, 1 H), 8.07 (d, J = 8.4Hz, 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, 6H) 1.82 - 1.79 (m, 2 H).

[0941] HPLC methods and conditions for separating diastereomers (compounds 145 and 146): Rt = 5.49 min (second elution peak) Column: LUNA C-18 (150 x 4.6mm x 5µM) Gradient: 0 min / 5% B, 1 min / 5% B, 6 min / 100% B, 8 min / 100% B, 10 min / 5% B, 12min / 5% B Mobile phase: A = 0.1% HCOOH in water, B = MeCN, flow rate 1 mL / min

[0942] 2-(7-((1R,3s,5S)-9-azabicyclo[3.3.1]non-3-yl)imidazo[1,2-a]pyrimidin-2-yl)-5-(2H-1,2,3-triazol-2-yl)phenol

[0943] ESI-MS ​ 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).

[0944] HPLC methods and conditions for separating diastereomers (compounds 145 and 146): Rt = 5.42 min (first elution peak) Column: LUNA C-18 (150 x 4.6 mm x 5 µM) Gradient: 0 min / 5% B, 1 min / 5% B, 6 min / 100% B, 8 min / 100% B, 10 min / 5% B, 12min / 5% B Mobile phase: A = 0.1% HCOOH in water, B = MeCN, flow rate 1 mL / min

[0945] 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)phenol

[0946] ESI-MS ​ 400.15 [M+H] + Compound 147, enantiomer 1; 1 H 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).

[0947] The following column and conditions were used for the second elution peak of enantiomers separated by chiral HPLC: Column: Chiralpak-IG (250 x 21 mm x 5 µM) Flow rate: 20 mL / min Mobile phase: 40% acetonitrile (A) and 60% 10 mM ammonia (B) in EtOH:MeOH (1:1).

[0948] 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)phenol

[0949] ESI-MS ​ 400.15 [M+H] + Compound 147, enantiomer 2; 1 H 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).

[0950] The first elution peak was obtained 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 / min Mobile phase: 40% acetonitrile (A) and 60% 10 mM ammonia (B) in EtOH:MeOH (1:1).

[0951] 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

[0952] ESI-MS ​ 448.15 [M+H] + Compound 148, formate; 1 H NMR (400 MHz, methanol-) d 4) δ8.92 (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). 19 F NMR (377 MHz, methanol-) d4 ) δ -110.39.

[0953] 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

[0954] ESI-MS ​ 448.15 [M+H] + Compound 149, formate; 1 H NMR (400 MHz, methanol-) d4) δ9.04 (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). 19 F NMR (377 MHz, methanol-) d4 ) δ-110.3.

[0955] 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

[0956] ESI-MS ​ 430.50 [M+H] + Compound 150; 1 H 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).

[0957] 5-(1H-imidazol-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

[0958] ESI-MS ​ 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).

[0959] Bioactivity of the exemplary compounds disclosed herein

[0960] To determine the effect of low molecular weight compounds on HTT proteins, an 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 (internally prepared, or otherwise available from the CHDI Foundation, New York, NY) in PBS at a concentration of 2 µg / mL. These plates were then washed three times with 40 µl / well of PBS and blocked at room temperature with rotational shaking (40 µl / well of 5% BSA in PBS) for 4–5 hours. After washing these plates three times with PBS, cell lysates (72-hour compound-treated SH-SY5Y cells (ATCC, CRL-2266)) were transferred to antibody-coated MSD plates and incubated overnight at 4°C. These plates were washed three times with washing buffer (0.05% Tween-20 in PBS) to remove the lysates. Secondary antibody D7F7 (Cell Signaling, 5656S) at a concentration of 0.1 µg / mL was added to the plates in blocking buffer (0.5% BSA in PBS) and incubated at room temperature for 1.5 h. These plates were washed three times with wash buffer and incubated at room temperature for 1 h with a 1:1000 dilution of anti-rabbit SULFO-TAG antibody (Mesoscale, R32AB-1). After washing three times with wash buffer, 1x MSD reading buffer (Mesoscale, R92TC-1) was added to each well, and the plates were read using an SI 6000 imager (MSD) according to the manufacturer's instructions. The AC50 (µM) values ​​from the HTT MSD assays of the test compounds are shown below.

[0961] 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.

[0962] Pharmacokinetics and Pharmacodynamics

[0963] The pharmacokinetic (PK) and pharmacodynamic (PD) properties of these compounds in mice can be assessed through the following in vivo studies as described below. Binding to brain and plasma proteins can be assessed in vitro as further described below and used to calculate unbound exposure.

[0964]

[0965] ​

[0966] This mouse model of Huntington's disease expresses the full-length human mutant huntingtin protein gene (htt) and was used to assess changes in mutant HTT protein levels after oral treatment with a novel molecule.

[0967] Experimental conditions

[0968] ​

[0969] Animals were weighed weekly before the study began, then daily before dose administration, and their weights were recorded in raw data files throughout the study.

[0970] ​

[0971] Oral administration

[0972] The test sample was administered as a solution or suspension via tube feeding into the esophagus of conscious BacHD mice.

[0973] The dosage volume is 10 mL / kg body weight.

[0974] Record the exact start time and exact dose volume of the drug.

[0975]

[0976] ​

[0977] The compound or mediator (0.5% methylcellulose, 0.1% Tween 80 in water) was administered orally to BacHD mice via tube feeding once daily for 21 or 28 consecutive days. The dose volume was 10 mL / kg body weight. The exact start time and exact dose volume of administration were recorded.

[0978] ​

[0979] Animals were monitored daily before and after administration, and any observed clinical signs were recorded. No adverse events were observed, and mice were not removed from the study.

[0980] Sample collection

[0981] Blood and tissue samples were obtained for PK / PD analysis at different time points following the first and last treatments. Whole blood was collected into EDTA-coated tubes via tail vein or distal cardiac puncture. Whole blood for PK analysis was immediately and rapidly frozen in liquid nitrogen. For PD analysis, plasma was separated by centrifugation at 14,000 rpm for 10 minutes at 4°C. The supernatant to be used was transferred to 1.5 mL microcentrifuge tubes and stored at -80°C until analysis. Brain and liver tissues were carefully dissected, weighed, and rapidly frozen, and stored at -80°C until analysis.

[0982] Pharmacokinetic analysis

[0983] For PK analysis, samples were analyzed on an LC-MS system consisting of a Sciex Exion AD LC-MS system and a Sciex QTrap 6500 MS controlled by an Analyst 1.7 from AB Sciex (Darmstadt, Germany). Compound-specific parameters (precursor ion, fragments, and collision energies) were obtained through automatic adjustment using DiscoveryQuant 3.0.7. These parameters were stored in a database for use in selective quantification of each sample. Samples (2... µ l) Inject the sample into a WatersAcquity BEH Polar C18, 2.1 × 50 mm, 1.7 µElution was performed on a m-column (Milford, Massachusetts, USA) at 50°C and at a flow rate of 0.8 ml / min using a gradient of 0.1% formic acid in water (mobile phase A) versus 0.1% formic acid in acetonitrile (mobile phase B), using the following gradients: 0 min, 20% B; 0.2 min, 20% B; 1.2 min, 60% B; 1.3 min, 95% B; 1.7 min, 95% B; 1.8 min, 20% B; and 2.0 min, 20% B. The entire column eluent was transferred from the Turbo Ionspray source (550°C, 9 l / min nitrogen) of a PE-Sciex Qtrap API-6500+ single quadrupole mass spectrometer. Compounds and internal standards were measured by positive ionization using multiple reaction monitoring or single ion monitoring, with retention times for the test sample and internal standard between 0.89 and 0.95 min, respectively.

[0984] Pharmacodynamic analysis

[0985] To detect mutant HTT protein levels, a Meso Scale Discovery (MSD) electrochemiluminescence assay platform based on ELISA was used. 96-well multiarray MSD assay plates (L15XA-3) were coated overnight at 4°C with 2 µg / mL 2B7 antibody in PBS. These plates were then washed three times with 40 µl / well PBS and blocked at room temperature with rotational shaking (40 µl / well of 5% BSA in PBS) for 4–5 hours. After washing these plates, tissue lysates or plasma diluted in artificial cerebrospinal fluid (aCSF) solution (aCSF, 10% Tween-20, Thermo Halt Protease Cocktail (ThermoFisher79444)) were transferred to the antibody-coated MSD plates and incubated overnight at 4°C. These plates were then washed with washing buffer (0.05% Tween-20 in PBS) to remove lysates. The secondary antibody SULFO-TAGGED MW1 antibody (EMDMIllipore, MABN2427) at a concentration of 0.1 µg / mL was added to the plates in blocking buffer (0.5% BSA in PBS) and incubated at room temperature for 1.5 hours. The plates were washed with washing buffer, and 1x MSD readout buffer (Mesoscale, R92TC-1) was added to each well. The plates were read using an SI 6000 imager (MSD) according to the manufacturer's instructions. From the assays, the values ​​of the experimental groups were normalized to the media group. One-way ANOVA was then performed, followed by Dunnett's... ​Statistical comparisons were performed. All data are presented as mean ± SEM. The data were analyzed using Prism GraphPad 10.

[0986] Rat brain homogenate protein binding assay

[0987] Binding to proteins was measured using rapid equilibration dialysis (RED device from Thermo Fisher Scientific). The test sample was dissolved at a concentration of 5 µM in a matrix (25% diluted rat brain homogenate in 100 mM phosphate buffer, pH 7.4). 300 µL of the matrix solution was aliquoted into the red chamber of the RED device, and 500 µL of 100 mM phosphate buffer into the white chamber. The RED device was sealed with a gas-permeable membrane and incubated at 37°C for 4 hours at 5% CO2 on an orbital oscillator (750 rpm). 50 µL aliquots from both chambers were transferred to 600 µL of acetonitrile containing an analytical internal standard (0.2 µM glibenclamide) and 50 µL of buffer or a matrix for matrix matching. These samples were incubated at 4°C with 5000... g Centrifuge for 15 minutes and analyze the supernatant by LC-MS to measure the test sample and internal standard. The free fraction (fu) was calculated by dividing the AREA ratio of the recipient compartment by the AREA ratio of the donor compartment, and the dilution factor (d = 4) was corrected using the following Kalvass equation (Kalvass and Maurer, 2002).

[0988]

[0989] Plasma protein binding assay

[0990] Binding to plasma proteins was measured in triplicate via equilibration dialysis using a Rapid Equilibration Dialysis (RED) device from Thermo Fisher Scientific (Rockford, Illinois). The test sample (5 µM) was incubated with plasma (100%). 300 µL aliquots of the sample were dispensed into the red chamber of the RED device, and 500 µL of 100 mM phosphate-buffered saline (pH 7.4) was dispensed into the white chamber. The RED device was sealed with a gas-permeable membrane and incubated for 4 hours at 37°C with 5% CO2 in an incubator (HERA Cell 150 from Thermo Scientific) on an orbital oscillator at 750 rpm (Kisker V 2000). At the end of the incubation period, 50 µl aliquots from both compartments were transferred to 96-well plates pre-filled with an analytical internal standard (0.2 µM glibenclamide) and 50 µl of buffer or a matrix for matrix matching, containing 600 µl of acetonitrile. These samples were centrifuged at 5000 × g for 20 min at 4°C, and the supernatant was transferred to a new 384-well plate pre-filled with 30 µl of water. The test samples and internal standard were then measured by LC-MS (methodology described below).

[0991] The value of the unbound fraction (fup) in 100% plasma is based on the following equation:

[0992] The binding of compounds 11 (75.3%), 7 (95.4%), and 10 (>99%) to mouse plasma proteins was measured. The binding of compounds 11 (88.2%), 7 (undetermined), and 10 (>99%) to human plasma proteins was measured.

[0993] Quantitative analysis of brain and plasma samples

[0994] Sample analysis was performed on an LC-MS system consisting of a Shimadzu Nexera LC-MS system and a Sciex QTrap 6500 MS controlled by an Analyst 1.7 from AB Sciex (Darmstadt, Germany). Compound-specific parameters (precursor ion, fragments, and collision energies) were obtained via automatic adjustment using DiscoveryQuant 3.0.7. These parameters were stored in a database for selective quantification of each sample. Samples (2...) were... µ l) Inject the sample into a Phenomenex Kinetex Polar C18, 2.1 × 30 mm, 2.6 µElution was performed on a Brechbühler column (Brechbühler, Schlielen, Switzerland) at 50°C using 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 rate of 0.8 ml / min. The gradients were as follows: 0 min, 2% B; 0.2 min, 2% B; 1 min, 60% B; 1.3 min, 100% B; 1.7 min, 100% B; 1.71 min, 2% B; and 1.95 min, 2% B.

[0995] The binding of compound 11 (98.2%), compound 7 (>99%) and compound 10 (>99%) to rat brain proteins was measured.

[0996] Results: After 14 days of once-daily oral administration, mHTT protein and compound concentration (in nM) decreased in the selected tissues (BacHD mouse model).

[0997] The mHTT protein level and compound concentration in the tissue were measured 24 hours after the last dose.

[0998] na - Not applicable. Because brain protein binding is >99%, it is impossible to calculate the accurate unbound concentration.

[0999] nm - Unmeasured.

[1000] C 总计 - The total concentration of compounds in the corresponding tissue.

[1001] C 未结合 - The unbound concentration of the compound in the corresponding tissue.

[1002] Other embodiments

[1003] While this disclosure has been described in conjunction with specific embodiments thereof, it should be understood that further modifications are possible and this application is intended to cover any changes, uses, or adaptations of this disclosure (which generally follow the principles of this disclosure and include such deviations from this disclosure that are known or customary in the field to which this disclosure pertains and may be applied to the essential features set forth above) and that comply with the scope of the claims.

[1004] Other embodiments are described in the claims.

Claims

1. A compound having formula (I): ， Or its pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer. in X 1 It is CR 2 Or N; X 2 It is CR 6 Or N; X 3 and X 4 Each is independently CH and CR 8 , or N, where R 8 It is halogen; W is O or NR N , where R N Is it hydrogen or C? 1-6 alkyl; R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, halogens and -N(R) N1 )2; by -N(R N1 C2 or heterocyclic substituted 1-6 Alkyl; with -N(R) N1 C2 or heterocyclic substituted 2-6 alkenyl; with -N(R) N1 )2 replaced by C 3-8 cycloalkyl; or -CH=C(R) N2 )2, where each R N1 Independently, it is H or C 1-6 Alkyl group, and two R groups N2 Together with the atoms to which they are attached, they form a heterocyclic group containing at least one nitrogen atom within the ring; R 2 It is hydrogen, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups; R 3 and R 6 Each is independently hydrogen, hydroxyl, and C. 1-6 Alkoxy or halogen; R 4 It is a heteroaryl group consisting of a halogen, a cyano group, or optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, C 1-6 Alkyl, hydroxyl, oxo, and halogen, and each R 5 —When present—it is independently a halogen; or R 4 And an R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen; R 7 It is hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or -OR 9 , where R 9 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0 or 1; and m can be 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the formula (I'): 。 3. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the formula (IA): 。 4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the formula (IB): 。 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 6 It is hydrogen.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 6 It's fluorine.

7. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compound has the formula (IC): 。 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 3 It is a hydroxyl group.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 3 It's fluorine.

10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 3 It is C 1-6 Alkyl group.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 It is a 5-membered monocyclic heteroaryl group containing 1, 2, 3, or 4 nitrogen atoms in the ring, optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

12. The compound of claim 11 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , and .

13. The compound of claim 11 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 Choose from the following groups: , , , , , , , and .

14. The compound of claim 11 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 Choose from the following groups: , , , and .

15. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 It is a 6-membered monocyclic heteroaryl group containing 1, 2, or 3 nitrogen atoms in the ring and optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

16. The compound of claim 15 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 Choose from the following groups: , , , , , , , , and .

17. The compound of claim 15 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 Choose from the following groups: , , and .

18. The compound of claim 15 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 Choose from the following groups: and .

19. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 It is a cyano group.

20. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 It is chlorine.

21. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 It is an N-heteroaryl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

22. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 It is a bicyclic N-heteroaryl group optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, and halogen.

23. The compound of claim 22 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 yes or .

24. The compound of claim 22 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 yes 。 25. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 and R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups, and the remaining R 5 —When present—is a halogen, wherein the bicyclic aryl or bicyclic heteroaryl group is optionally substituted by 1, 2, 3, or 4 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl C 1-6 Alkyl, hydroxyl, oxo, and halogen.

26. The compound of claim 25 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 4 and R 5 Together with the atoms to which they are attached, they combine to form bicyclic aryl or bicyclic heteroaryl groups selected from the following: , , , , , and .

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, 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, racemic mixture, 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, racemic mixture, enantiomer, diastereomer, or tautomer thereof, R 5 It's fluorine.

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

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

33. The compound of claim 31 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, W is NR N .

34. The compound of claim 33 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R N It is a methyl group.

35. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, 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, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 It is a heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms and substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

37. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 It is a 6-membered monocyclic heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms and optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

38. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 It is a bicyclic heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms and optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

39. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 It is a 7-membered monocyclic heterocyclic group containing 1, 2, 3, or 4 nitrogen atoms and optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

40. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is a spirocyclic heterocyclic group optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, hydroxyl groups, and halogens.

41. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is -N(R) N1 C2 or heterocyclic substituted 1-6 alkyl.

42. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is -N(R) N1 C2 or heterocyclic substituted 2-6 Alkenyl group.

43. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is -N(R) N1 )2 replaced by C 3-8 Cycloalkyl.

44. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is -CH=C(R) N2 )2, where each R N1 Independently, it is H or C 1-6 Alkyl group, and two R groups N2 Together with the atoms to which they are attached, they form a heterocyclic group containing at least one nitrogen atom within the ring.

45. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Through R 1 The carbon atoms in the ring are bonded to the nucleus.

46. ​​The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein, R 1 It is a heterocyclic group that is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: C 1-6 Alkyl and hydroxyl groups.

47. The compound of claim 37 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: , , , , , , , , , and .

48. The compound of claim 37 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: , , , , , , , and .

49. The compound of claim 37 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: and .

50. The compound of claim 38 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: , , , , , and .

51. The compound of claim 38 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 yes or .

52. The compound of claim 39 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 yes 。 53. The compound of claim 40 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: , , and .

54. The compound of claim 41 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: , , , , and .

55. The compound of claim 42 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: , and .

56. The compound of claim 43 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 Choose from the following groups: and .

57. The compound of claim 44 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 yes: 。 58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 1 -(W) n - The shortest atomic chain containing a nitrogen atom, and to which the nitrogen atom is attached, to the nucleus of the compound having formula (I) comprises a total of three atoms, wherein the nucleus is: 。 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, R 7 It is hydrogen.

60. A compound selected from the group consisting of: And its pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers and tautomers.

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

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

64. The compound of claim 60 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, wherein, The compounds are 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 their pharmaceutically acceptable salts, hydrates, solvates, racemates, enantiomers, diastereomers and tautomers.

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

66. The compound of claim 60 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, 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, racemic mixture, 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, racemic mixture, 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, racemic mixture, 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, racemic mixture, 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 the compound as described in any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers.

72. A method for treating Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction, the method comprising administering to a subject in need an effective amount of a compound as described in any one of claims 1 to 70 or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer, or a pharmaceutical composition as described in claim 71.

73. The method of claim 72, wherein, The method described is used to treat Huntington's disease.

74. The method of claim 72, wherein, The method is used to treat spinal muscular atrophy.

75. The method of claim 72, wherein, The method is used to treat familial autonomic dysfunction.

76. The method according to any one of claims 72 to 75, wherein, The method further includes 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, racemic mixture, enantiomer, diastereomer, or tautomer thereof, or the pharmaceutical composition of claim 71, for use in the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction.

78. A compound or pharmaceutical composition used as described in claim 77, wherein, The aforementioned use is in the treatment of Huntington's disease.

79. A compound or pharmaceutical composition used as described in claim 77, wherein, The application is in the treatment of spinal muscular atrophy.

80. A compound or pharmaceutical composition used as described in claim 77, wherein, The aforementioned use is in the treatment of familial autonomic dysfunction.

81. A compound or pharmaceutical composition used as described in 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, racemic mixture, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition of claim 71, for the treatment of Huntington's disease, spinal muscular atrophy, or familial autonomic dysfunction.

83. The compound or pharmaceutical composition of claim 82, wherein, The compound or pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition thereof, is used to treat Huntington's disease.

84. The compound or pharmaceutical composition of claim 82, wherein, The compound or pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition thereof, is used to treat spinal muscular atrophy.

85. The compound or pharmaceutical composition of claim 82, wherein, The compound or pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer, or the pharmaceutical composition thereof, is used to treat familial autonomic dysfunction.

86. A compound or pharmaceutical composition used as described in any one of claims 82 to 85, wherein, The treatment is in combination with an MSH3 inhibitor.

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

88. The use as described in claim 87, wherein, The medication is used to treat Huntington's disease.

89. The use as described in claim 87, wherein, The medication is used to treat spinal muscular atrophy.

90. The use as described in claim 87, wherein, The medication is used to treat familial autonomic dysfunction.

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

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

93. The method of claim 92, wherein, The components of the spliceosome are either primary spliceosome components or secondary spliceosome components.

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

95. The method of claim 94, wherein, The nucleic acid is a precursor mRNA transcript.

96. A method for modifying RNA splicing to produce a mature mRNA transcript containing exons, the method comprising contacting a compound as described in any one of claims 1 to 70, or a pharmaceutically acceptable salt, hydrate, solvate, racemic mixture, enantiomer, diastereomer, or tautomer thereof, with a cell containing a precursor mRNA transcript, said precursor mRNA transcript comprising at least two exons and at least one intron, wherein at least one of said exons is upstream of and downstream of said intron.

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

98. The method of claim 97, wherein, The intron further comprises, in order from 5′ to 3′, 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 according to any one of claims 95 to 98, wherein, The precursor mRNA transcript is a precursor mRNA transcript selected from the following groups: ADAL、ADAM23、ADAMTS19、AGPS、AKAP8L、ANKRD13C、ANXA11、ARL15、ARSJ、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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、BE CN1、BIN3、BTBD10、C11orf30、C12orf4、C1orf27、C2orf47、CACNB1、CACNB4、 CADM2、CDH18、CEP162、CEP170、CEP192、CHEK1、CHRM2、CMAHP、CNRIP1、CNTN 1、CUX1、DAAM1、DCAF17、DCUN1D4、DDX42、DET1、DENND1A、DENND4A、DENND5A、 DGKI、DHFR、DIAPH3、DLG5、DYRK1A、DZIP1L、ELMO2、ENAH、ENOX1、EVC、FAM16 2A、FAM174A、FAM208B、FAM69B、FBXL16、FGD4、FHOD3、GALC、GOLGB1、GTSF1、G XYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3 MBTL2、LINCR-0002、LINGO2、LOC400927、LPHN1、LRRC1、LRRC42、LYRM1、MACR OD2、MAPK10、MARCH8、MDN1、MEAF6、MEMO1、MFN2、MLLT10、MRPL39、MRPL45、M RPS28、MTMR3、MYB、MYCBP2、NSUN4、NUPL1、OSBPL3、PAPD4、PCDH10、PDE3A、PD E7A、PDXDC1、PDXDC2P、PELI1、PITPNB、PMS1、POMT2、PSMA4、RAB23、RAF1、RC OR3、RERE、RNF130、RNF144A、RNF213、RPF2、RPS10、SCO1、SENP6、SF3B3、SGMS 1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJ P2、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, AHRGAP1, AHRGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD 10、C10orf76、C11orf30、C11orf73、C12orf4、C1orf27、C1QTNF9B-AS1、CCN L2、CDH18、CENPI、CEP57、CMSS1、CNOT7、COPS7B、CRISPLD2、CUX1、DCAF17、D DX42、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、INPP 4B、ITCH、IVD、KDM6A、KDSR、KIAA1524、KIAA1715、KIDINS220、L3MBTL2、LGA LS3、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、R AF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA 2、SPIDR、SSBP1、STRADB、STXBP6、SUPT20H、TAF2、TASP1、TBCA、TBL1XR1、TC F4、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 precursor mRNA transcript is a precursor mRNA transcript selected from the following groups: 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, H OXB3, 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 precursor mRNA transcript is a precursor mRNA transcript selected from the following groups: HTT; ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHR M2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AG PS, 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, DCAF17 2a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17 6a, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1 and SUPT20H.

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

103. The method of claim 99, wherein, The precursor mRNA transcript is the precursor mRNA transcript of the HTT gene.

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