Regioselective Synthesis of Imidazolo[1,2-a]pyrimidines

Abstract

The present disclosure provides a method for regioselectively synthesizing an imidazo[1,2-a]pyrimidine compound of formula (XXa) or (XXb), #imgabs0# the method comprising the step of coupling a first compound of formula XX-P1a or XX-P1b with a second compound of formula XX-P2. #imgabs1# The cyclization reaction between β-ethoxyacrylamide and phosphorylated aminoimidazole to generate imidazo[1,2-a]pyrimidine-amine relies on the directing effect from the intra- and extra-cyclic phosphorylated aminoimidazole. The reaction generates 2-amino or 4-amino structural isomers of imidazo[1,2-a]pyrimidine with good yields and a regioselectivity range of 90:10-99:1. The reaction can be used to synthesize a variety of tracer molecules used in neurological disease research, such as those in which R 3 and R 4 Together with the imidazole ring atom to which they are bonded, a benzene ring is formed, and the product is a substituted benzimidazolopyrimidine. The reaction can be summarized as forming an imidazo[1,2-a]pyrimidine substituted at its 2- and 4-positions by an alkoxy or thioalkyl group.

Description

[0001] Priority Claim

[0002] This application claims the benefit of priority under 35 U.S.C. §119(E) to U.S. Provisional Application Serial No. 62 / 845,840, filed on May 9, 2019, and U.S. Provisional Application Serial No. 62 / 937,069, filed on November 18, 2019, both of which are incorporated herein by reference in their entirety. Technical Field

[0003] The techniques described herein relate generally to organic synthesis, and more particularly to regioselective synthetic routes to molecules containing substituted imidazo-pyrimidine groups. Background Art

[0004] The imidazo-pyrimidine moiety is a frequently encountered fused-ring heterocyclic functional group in organic chemistry. It itself serves as a core member or part of the scaffold of so-called "small organic molecules" that are important in drug discovery and therapeutic and diagnostic applications. In particular, the benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine scaffold (3-fused ring system) has recently been found to be useful in a number of positron emission tomography (PET) imaging agents that have a strong binding affinity for tau protein plaques associated with neuropathologies such as Alzheimer's disease. (See, e.g., Zhang, W.; Arteaga, J.; Cashion, DK; Chen, G.; Gangadharmath, U.; Gomez, LF; Kasi, D.; Lam, C.; Liang, Q.; L iu, C.; Mocharla, VP; Mu, F.; Sinha, A.; Szardenings, AK; Wang, E.; Walsh, JC; Xia, C.; Yu, C.; Zhao, T.; Kolb, HC, "A "Highly selective and specific PET tracer for imaging of taupathologies", J. Alzheimer's Dis. 2012, 31, 601-612; Gobbi, LC; Knust, H.; M.;Honer,M.;Czech,C.;Belli,S.;Muri,D.;Edelmann,M.R.;Hartung,T.;Erbsmehl,I,;Grall-Ulsemer,S.;Koblet,A.;Rueher,M.;Steiner,S.;Ravert,H.T.;Mathews,W.B.;Holt,D.P.;Kuwabara,H.;Valentine,H.;Dannals,R.F.;Wong,D.F.;Borroni,E.,“Identification of three novel radiotracers for imaging aggregated tau inAlzheimer’s disease with positron emission tomography.”J.Med.Chem.,2017,60,7350-7370;Gao,M.;Wang,M.;Zheng,Q-.H.“Concise and high-yield synthesis of T-808and T808P for radiosynthesis of[ 18F]-T808, a PET tau tracer for Alzheimer's disease", Bioorg. Med. Chem. Lett., 2014, 24, 254-257.) This scaffold also exists in research tau degradation molecules (see, for example, Crew, AP; Berlin, M.; Flanagain, JJ; Dong, H.; Ishchenko, A., "Tau-protein targeting protacs and associated methods of use", US Patent App. Pub. 20180125821A1, May 10, 2018) and imaging agents for identifying other proteins associated with neurodegenerative diseases such as Huntington's disease (see, e.g., Dominguez, C.; Wityak, J.; Bard, J.; Kiselyov, A.; Brown, C.J.; Prime, M.E.; Johnson, P.D.; Clark-Frew, D.; Schaertl, S.; Herrmann, F.; Grimm, S.K.; Kahmann, J.D.; Scheich, C., "Probes for Imaging Huntington Protein", PCT Pub. 2016033440A1, March 3, 2016).More generally, benzo[4,5]imidazo[1,2-a]pyrimidine motifs have been incorporated into drugs that have demonstrated anti-neurodegenerative (see, e.g., Pavlov, P. Winblad, B. Pyrimidobenzimidazoles for use in the treatment and prevention of neurodegenerative disorders. PCTPub. 2017168137A1 October 5, 2017), anti-hypertensive (see, e.g., El-Shorbagi, A.-NA; Husein, MA An approach to hypertension crisis: Evaluation of new fused banzazoles; 2-ar-ylethenyl and 2,4-bis(arylethenyl) derivatives derived from 2,4-dimethylpyrimido[1,2-a]benzimidazole. Pharma Chemica 2015, 7, 319-328), anti-microbial (see, e.g., Algul, O.; Meric, A.; Polat, S.; Yuskek, ND; Serin, MS Comparative studies on conventional and microwave-assisted synthesis of a series of 2,4-di and 2,3,4-trisubstituted benzimidazo[1,2-a]pyrimidines and their antimicrobial ac-tivities. Cent. Eur. J. Chem. 2009, 7, 337-342) and antiviral activity (see, e.g., Farghaly, TA; Hafez, NAA; Ragab, EA; Awad, HM; Abdalla, MM Synthesis, anti-HCV, antioxidant, and per-oxynitrite inhibitory activity of fused benzosuberone derivatives. Eur. J. Med. Chem. 2010, 45, 492-500) molecules.

[0005] For clinical applications of biomarker molecules, a radioisotope such as 18F is introduced into the precursor molecule. Accordingly, efficient synthesis of the precursor is particularly desirable since the precursor must be available in large quantities for labeling.

[0006] Traditionally, benzo[4,5]imidazo[1,2-a]pyrimidine derivatives are synthesized via the condensation of aminoimidazoles with enones or enals bearing a leaving group at the -position. (See e.g. Bajwa, JS; Sykes, PJSynthesis and Structure of Some Azolo[a]pyrimidines,2,6,7,8-tetrahydro-1H-cyclopenta[e]azolo[a]pyrimidines,6,7-dihydro-5H-cyclopenta[f]-azolo[a]pyrim idines,7,8-dihydro-6H-cyclopenta[f]-s-triazolo[4,3-b]pyridazine,5,6,7,8-tetrahydro-azolo[blquinazolines,6,7,8,9-Tetra hydroazolo[a]quinazolines,and 7,8,9,10-Tetrahydro-s-triazolo[3,4-a]phthalazine.J.Chem.Soc.Perkin Trans. 11979, 12, 3085-3094; and Tseng, S-.S.; Epstein, JW; Brabander, HJ; Francisco, G., "A simple regioselective synthesis of pyrimido[1,2-a]benzimidazoles", J. Heterocycl. Chem., 1987, 24, 837-843. ) This method generally provides imidazopyrimidine products in high yields and good isoselectivity. However, the scope of this method is limited to α, β-unsaturated aldehydes and ketones, which means that the products are limited to unsubstituted or alkylated imidazopyrimidines. Therefore, there is a need for a scheme that provides direct access to other functionalized imidazo[1,2-a]pyrimidine-amines from aminoimidazoles.

[0007] The background discussion herein is included to explain the context of the technology. This should not be taken as an admission that any of the material referred to was published, known or part of the common general knowledge as at the priority date of any appended claim.

[0008] Throughout the description and claims of the present application, the word "comprise" and variations thereof (such as "includes" and "comprising") are not intended to exclude other additives, components, integers or steps. Summary of the invention

[0009] The present disclosure relates to the regioselective synthesis of heterocyclic organic molecules, particularly those containing imidazo-pyrimidine moieties. In particular, the present disclosure includes coupling steps that enable the preparation of substituted imidazo-pyrimidines in high yields.

[0010] In particular, the present disclosure includes methods for the synthesis of substituted imidazo-pyrimidines of formula (XXa) and (XXb).

[0011]

[0012] Coupling a first aminoimidazole compound of formula XX-P1a or XX-P1b with a second acrylamide compound of formula XX-P2

[0013]

[0014] It will be understood by those skilled in the art that the following structures are tautomers of each other:

[0015]

[0016] It has been observed that in the solid state a right-handed structure exists, whereas in solution the two structures are in tautomeric equilibrium. In the specification herein, the two tautomers are used interchangeably unless a specific tautomer is intended from the context.

[0017] In formula XX-P2, R 1 and R 2 are each independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, aryl or heteroaryl, wherein any such group may be optionally substituted at one or more of its available positions with a group independently selected from the group consisting of hydroxy, amino, alkoxy, aminoalkyl, carboxyl, cyano, thio, halo, aryl and heteroaryl, or R 1 and R 2 Together they form a cycloalkyl ring having 3-12 atoms, and wherein the cycloalkyl ring is optionally and independently substituted at any one or more of its available positions with a group selected from hydroxy, amino, alkoxy, aminoalkyl, carboxyl, cyano, thio, halo, aryl and heteroaryl.

[0018] In formula XX-P1a and XX-P1b, R 3 and R 4 Each is independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, aryl or heteroaryl, wherein any such group may be optionally substituted at one or more of its available positions with a group independently selected from the following: hydroxy, amino, alkoxy, aminoalkyl, thio, cyano, halo, aryl and heteroaryl.

[0019] In other embodiments, R 3 and R 4 Together they form a benzene ring, wherein the benzene ring is optionally and independently substituted at any one or more of its 4 available positions with a group selected from hydroxy, amino, alkoxy, aminoalkyl, thio, nitro, sulfonyl, carboxyl, cyano, halo, aryl and heteroaryl, wherein any such group may be optionally substituted at one or more of its available positions independently with a group selected from hydroxy, amino, alkoxy, aminoalkyl, thio, cyano, halo, aryl or heteroaryl.

[0020] In a preferred embodiment, the coupling between XX-P1a or XX-P1b and XX-P2 is carried out in POCl 3 , E.T. 3 N and a non-aqueous solvent. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 A method for the synthesis of a benzo[4,5]imidazo[1,2-a]pyrimidine scaffold from a benzimidazole precursor is shown, as further described herein.

[0022] Figure 2 : Selectively obtain aminophosphoric acid esters.

[0023] Figure 3 .Example of β-ethoxyacrylamide used to generate benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine.

[0024] Figure 4 Provide examples of amino (benz)imidazoles of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine.

[0025] Figure 5 Example of the reaction of β-ethoxyacrylamide with phosphoramidate 3 to prepare benzo[4,5]imidazo[1,2,a]pyrimidin-4-amine.

[0026] Figure 6 : Calculation of partial charges on nitrogen atoms in amino-benzimidazole coupling partners.

[0027] Figure 7 : X-ray crystallographic structures of various compounds as described herein. DETAILED DESCRIPTION

[0028] Reference will now be made in detail to certain embodiments of the synthesis method, examples of which are shown in the attached structures and formulas. Although the method will be described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit the invention to those embodiments. On the contrary, the description is intended to cover all substitutions, modifications and equivalent forms that may be included within the scope of the method as defined by the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to the methods and materials described herein can be used in the practice of the present method, so the present method is not limited to the described methods and materials. If one or more of the cited documents, patents and similar materials are different or contradictory from the description herein, including but not limited to defined terms, term usage, described technology or the like, this description shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the method belongs. Although in the practice or testing of the method, methods and materials similar or equivalent to those described herein can be used, suitable methods and materials are described below. Unless otherwise indicated, the nomenclature used in this application is based on the ACS Style Guide and the listing of "Standard Abbreviations and Acronyms" from The Journal of Organic Chemistry (both published by the American Chemical Society, Washington, DC), and the IUPAC systematic nomenclature.

[0029] definition

[0030] Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th edition).

[0031] The term "heteroatom" refers to any atom independently selected from atoms other than carbon or hydrogen, such as one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon, and any quaternized form of nitrogen).

[0032] The term "saturated" refers to functional groups in which all bonds between non-hydrogen atoms are single covalent bonds.

[0033] As used herein, the term "unsaturated" refers to a functional group having one or more pairs of non-hydrogen atoms connected by double or triple bonds. A pair of non-hydrogen atoms bonded to each other by a double or triple bond may be referred to as an unsaturated unit. A functional group comprising two or more unsaturated units separated from each other by a single bond is generally referred to as a conjugate.

[0034] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but the ring moiety is not aromatic.

[0035] Aromatic rings or ring systems (comprising one or more rings that share a pair of atoms as edges) are fully conjugated rings. Typically, aromatic rings are characterized by the so-called Huckel rule, where the number of conjugated π electrons follows the formula 4n+2, where n is an integer.

[0036] As used herein, the term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon group. In one embodiment, the alkyl group is one to eighteen carbon atoms (C 1 -C 18 In other embodiments, the alkyl group is C 1 -C 16 , C 1 -C 15 , C 1 -C 13 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 or C 1 -C 3 . C 0 Alkyl refers to a bond. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, isopropyl, -CH (CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl,

[0037] -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, sec-butyl, -CH (CH 3 )CH2 CH 3 ), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))、2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH2 CH 3 ), 4-methyl-2-pentyl (CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

[0038] As used herein, the term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon double bond. Alkenyl groups include groups having "cis" and "trans" orientations or "E" and "Z" orientations. In one example, an alkenyl group contains two to eighteen carbon atoms (C 2 -C 18 In other examples, alkenyl is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 Examples include, but are not limited to, ethenyl or vinyl (-CH=CH 2 ), prop-1-enyl (-CH=CHCH 3 ), prop-2-enyl (-CH 2 CH=CH 2 ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

[0039] As used herein, the term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, an alkynyl radical is two to eighteen carbon atoms (C 2 -C 18 In other examples, the alkynyl group is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 Other examples include, but are not limited to, ethynyl (—C≡CH), prop-1-ynyl (—C≡CCH 3 ), prop-2-ynyl (propargyl, -CH 2 C≡CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.

[0040] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, substituted with one or more (eg, 1, 2, 3 or 4) halo groups.

[0041] The term "carbocyclyl" used alone or as part of a larger moiety refers to a saturated, partially unsaturated or aromatic ring system having 3 to 20 carbon atoms. In one embodiment, carbocyclyl includes 3 to 12 carbon atoms (C 3 -C 12 In another embodiment, the carbocyclic group includes a C 3 -C 8 , C 3 -C 10 or C 5 -C 10 In other embodiments, the carbocyclic group includes C 3 -C 8 , C 3 -C 6 or C 5 -C 6 In another embodiment, the carbocyclyl as a bicyclic ring system includes C 7 -C 12 In another embodiment, the carbocyclic group as a spirocyclic ring system includes C 5 -C 12Examples of monocyclic carbocyclic radicals include, but are not limited to, cycloalkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl. Examples of bicyclic carbocyclic radicals having 7 to 12 ring atoms include [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems, such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, naphthyl, and bicyclo[3.2.2]nonyl. Examples of spiro-carbocyclyl include spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl and spiro[4.5]decyl. The term carbocyclyl includes aryl (but not heteroaryl) ring systems as defined elsewhere herein.

[0042] Alicyclic rings are carbon rings that are not aromatic or aromatic.

[0043] The term "alkoxy" refers to a straight or branched monovalent group represented by the formula -OR, where R is an alkyl group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and isopropoxy.

[0044] The term "aryl", used alone or as part of a larger moiety such as "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system, including fused rings, wherein at least one ring in the system is aromatic. The term "aryl" can be used interchangeably with the term "aromatic ring". In one embodiment, aryl includes groups having 6-18 carbon atoms. In another embodiment, aryl includes groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, phenanthrenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like, which may be substituted or independently substituted with one or more substituents described herein. A specific aryl is phenyl. In another embodiment, aryl includes an aromatic ring fused to one or more carbocyclic rings, such as indanyl, phthalimidyl, naphthyridinyl, phenanthridinyl, or tetrahydronaphthyl, and the like, wherein the radical or point of attachment is on the aromatic ring.

[0045] The term "heteroaryl", used alone or as part of a larger moiety such as "heteroarylalkyl" or "heteroarylalkoxy", refers to a monocyclic, bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein at least one ring is aromatic and contains at least one heteroatom. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups, wherein one or more ring atoms are independently optionally substituted nitrogen, sulfur or oxygen. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups, wherein one or more ring atoms are independently optionally substituted nitrogen, sulfur or oxygen. In another embodiment, heteroaryl includes bicyclic or tricyclic aromatic groups, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) ring atoms are independently optionally substituted nitrogen, sulfur or oxygen. Exemplary heteroaryl groups include thienyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, purinyl, benzoxazolyl, benzofuranyl, benzophenone ... The term "heteroaryl" also includes groups in which the heteroaryl is fused to one or more aryl, carbocyclyl or heterocyclyl rings, wherein the radical or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-onyl. The heteroaryl group can be monocyclic, bicyclic or tricyclic.

[0046] As used herein, the term "heterocyclyl" refers to a "carbocyclyl" as defined herein, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N or S). In some embodiments, heterocyclyl refers to a saturated ring system, such as a 3-12-membered saturated heterocyclyl ring system. In some embodiments, heterocyclyl refers to a heteroaromatic ring system, such as a 5-14-membered heteroaromatic ring system. The heterocyclyl may be optionally substituted by one or more substituents independently selected from those defined herein. In one embodiment, the heterocyclyl includes a 5-6-membered monocyclic cyclic group, wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are independently optionally substituted nitrogen, sulfur or oxygen. In another embodiment, the heterocyclyl includes a bicyclic or tricyclic group, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) ring atoms are independently optionally substituted nitrogen, sulfur or oxygen.

[0047] In one example, heterocyclic radical includes 3-12 ring atoms and includes monocycle, bicyclic, tricyclic and spirocyclic system, wherein ring atom is carbon, and one to five ring atoms are heteroatoms selected from nitrogen, sulfur or oxygen, which are independently optionally substituted by one or more groups. In one example, heterocyclic radical includes 1 to 4 heteroatoms. In another example, heterocyclic radical includes 3 yuan to 7 yuan monocycle, which has one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclic radical includes 4 yuan to 6 yuan monocycle, which has one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclic radical includes 3 yuan monocycle. In another example, heterocyclic radical includes 4 yuan monocycle. In another example, heterocyclic radical includes 5 yuan to 6 yuan monocycle. In one example, the heterocyclic radical includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom can be optionally oxidized (for example, NO, SO, SO2), and any nitrogen heteroatom can be optionally quaternized (for example, [NR 4 ]+Cl-, [NR 4] + OH-). Exemplary heterocyclic groups include oxirane, aziridinyl, thiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thiazinyl, homopiperazinyl, homopiperidinyl 1,1-dioxoisothiazolidinyl, oxazolidinyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzimidazolyl , 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidonyl, pyrimidinedione, pyrimidine-2,4-dione, piperazinonyl, piperazindione, pyrazolidinyl imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo-[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo-[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo-[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]-octanyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-yl, azaspiro[5.5] undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl and 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclic groups containing sulfur or oxygen atoms and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide; thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl; oxazolyl, for example oxazol-2-yl; and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Exemplary 5-membered ring heterocyclic groups containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl; and tetrazolyl, such as 1H-tetrazolyl. Exemplary benzo-fused 5-membered heterocyclic groups are benzooxazol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl. Exemplary 6-membered heterocyclic groups contain one to three nitrogen atoms and optional sulfur or oxygen atoms, such as pyridyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; pyrimidinyl, such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, especially pyridazin-3-yl and pyrazinyl. Pyridine N-oxides and pyridazine N-oxides as well as pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl and 1,3,4-triazin-2-yl groups are other exemplary heterocyclyl groups.

[0048] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0049] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms other than any isotopically enriched atom specifically indicated. For example, structures wherein one or more hydrogens are independently replaced or enriched with deuterium or tritium, carbon is independently replaced or enriched with 13 C- or 14 C carbon is replaced or enriched independently, nitrogen is 15 N nitrogen is replaced or enriched independently, sulfur is 33 S. 34 S or 36 S sulfur is replaced or enriched independently or oxygen is 17 O or 18 Compounds that independently replace or enrich for oxygen in O. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents.

[0050] The term "deuterated" refers to the replacement of hydrogen atoms by deuterium atoms at a level higher than their natural abundance at one or more positions of a molecule. When a particular position is deuterated, it is understood that the deuterium abundance at that position is significantly greater than the natural abundance of deuterium, i.e., 0.015%. Deuterated positions typically have a minimum isotopic enrichment factor of at least 3,000 (45% deuterium incorporation). As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and the natural abundance.

[0051] If there is any discrepancy between the chemical name and the structure shown, the structure shall prevail.

[0052] As used herein, "a" or "an" refers to one or more, unless expressly stated otherwise.

[0053] Overview of synthetic methods

[0054] In general, the disclosed methods provide efficient synthetic routes to compounds of formula Xa and Xb, wherein X is -OR 1 、-SR 1 or -NR 1 R 2 , where R 1 and R 2 Defined elsewhere herein.

[0055]

[0056] The present invention further includes methods for synthesizing compounds of formula (XXa) and (XXb), as described by specific synthetic schemes in the following examples:

[0057]

[0058] In preferred embodiments, selective N-phosphorylation of amino-imidazoles produces a key directing element that controls the isoselectivity in the condensation of β-ethoxyacrylamide and aminoimidazole to provide imidazo[1,2-a]pyrimidines, and in preferred embodiments, benzimidazolo[1,2-a]pyrimidines are prepared from benzimidazoles. Conditions that provide highly selective (such as 99:1) phosphorylation on either the endocyclic or exocyclic nitrogen of imidazole derivatives are also described.

[0059] For example, different N-phosphorylation coupling partners 2a and 2b provide highly selective access to the isomers of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (3a) or benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine (3b), respectively. Figure 1). The 2-amino or 4-amino isomers of the imidazo[1,2-a]pyrimidine products can be isolated in 64%-95% yields. Mass spectrometry and computational analysis provide insight into the mechanism of this selective transformation.

[0060] Synthesis of Amino-Imidazolo-Pyrimidine

[0061] One aspect of the methods described herein is to provide a method for synthesizing amino-imidazo-pyrimidines of formula (XXa) and (XXb).

[0062]

[0063] The method for synthesizing an imidazo-pyrimidine compound of formula (XXa) or (XXb) comprises coupling a first compound of formula XX-P1a or XX-P1b with a second compound of formula XX-P2

[0064]

[0065] in:

[0066] In Formula XX-P2 (and XXa, XXb, Xa and Xb herein), R 1 and R 2 Each is independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, aryl or heteroaryl, wherein any such group may be optionally substituted at one or more of its available positions with a group independently selected from the following: hydroxy, amino, alkoxy, aminoalkyl, thio, carboxyl, cyano, halo, alkyl, cycloalkyl, aryl and heteroaryl. In another embodiment, R 1 and R 2 Together with the nitrogen to which they are bound, they form a ring having 3-12 atoms, wherein the ring is optionally and independently substituted at any one or more of its available positions with a group selected from hydroxy, amino, alkoxy, aminoalkyl, carboxyl, cyano, thio, halo, alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl. 1 and R 2 If the ring is substituted with a group that allows further substitution, such as an alkyl, cycloalkyl, aryl or heteroaryl group, the group may also be substituted with another one or more groups selected from the following: amino, alkoxy, aminoalkyl, carboxyl, cyano, thio, halo, alkyl, haloalkyl, cycloalkyl, nitro or sulfonyl.

[0067] In formula XX-P1a and XX-P1b, R 3 and R 4Each is independently selected from alkyl, alkenyl, alkynyl, haloalkyl, carboxylate, carbocyclyl, aryl or heteroaryl, wherein any such group may be optionally substituted at one or more of its available positions with a group independently selected from the following: hydroxy, amino, alkoxy, aminoalkyl, thio, cyano, halo, aryl and heteroaryl. In other embodiments, R 3 and R 4 Together with the two carbon atoms of the imidazole ring to which they are respectively bonded, they form a benzene ring, wherein the benzene ring is optionally and independently substituted at any one or more of its 4 available positions by a group selected from hydroxy, amino, alkoxy, aminoalkyl, thio, nitro, sulfonyl, carboxyl, cyano, halo, alkyl, cycloalkyl, aryl and heteroaryl, wherein any such group may be optionally further substituted at one or more of its available positions by a group independently selected from hydroxy, amino, alkoxy, aminoalkyl, thio, nitro, haloalkyl, sulfonyl, cyano, halo, alkyl, cycloalkyl, aryl or heteroaryl.

[0068] In one embodiment, the compound of formula XX-P1a can be prepared by reacting 2-amino-imidazole with a phosphorylating agent such as (EtO) 2 P(=O)Cl is formed by reaction. Usually, a suitable phosphorylating agent is (RO) 2 P(=O)Cl, wherein R is alkyl, cycloalkyl, aryl or a halogenated version thereof. For example, R can be methyl, trifluoromethyl, phenyl, propyl or butyl.

[0069] In some embodiments, the phosphorylating agent is such as PCl(O)(OEt) 2 It is formed in situ by reacting an alkyl hydrogen phosphate, such as diethyl hydrogen phosphate, with a chlorinating agent, such as 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione.

[0070] In one embodiment, the compound of formula XX-P2 can be formed in two steps: first, (E)-3-ethoxy-acrylic acid is reacted with a chlorinating agent such as sulfonyl chloride (SOCl 2 ) reaction; secondly, then in an aprotic solvent (E)-3-ethoxyacryloyl chloride and amine R 1 R 2 NH (where R 1 and R 2 In such embodiments, other suitable chlorinating agents include oxalyl chloride (COCl) 2and alkyl chloroformate such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate. In other embodiments, the method of forming the amide bond in XX-P2 is by using an amide coupling reagent such as CDI (carbonyl diimidazole), EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) and HATU (tetramethyluronium hexafluorophosphate azabenzotriazole).

[0071] In a preferred embodiment, the coupling between XX-P1a or XX-P1b and XX-P2 is carried out in POCl 3 or PCl 5 , Et 3 N and a non-aqueous solvent such as MeTHF, MeCN or a mixture thereof. 3 (or PCl 5 ) can achieve the activation of acrylamide compounds (by converting C(=O)N into C(Cl)=N + ). Other reagents such as SOCl 2 This may also be achieved. It may be necessary to heat the reaction mixture, such as to 60°C to 100°C, for example 80°C. 3 N acts as a base, eliminating the acid produced as a byproduct during the reaction. Its role can be replaced by other bases such as n Bu 3 N、iPr 2 NEt and N-methylmorpholine play.

[0072] Examples

[0073] General information

[0074] All new compounds were 1 H NMR, 13 The products were characterized by C NMR, IR, melting point and HRMS.

[0075] 1 H. 13 C. 19 F and 31 P NMR spectra were recorded at room temperature on a Bruker 400 MHz instrument.

[0076] Unless otherwise stated, all 1 H NMR spectra were all measured in parts per million (ppm) relative to the residual chloroform signal in deuterated solvents (δ 7.26), methanol (δ 3.31), DMSO (δ 2.50), or acetic acid (δ 2.04). 1HNMR data are reported as follows: chemical shift, multiplicity (br = broad signal, s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m = multiplet), coupling constant and integration in Hertz.

[0077] Unless otherwise stated, all 13 C NMR spectra were expressed relative to deuterated chloroform (δ77.06), methanol-d 4 (δ49.00), DMSO-d 6 (δ39.53) or acetic acid-d 4 The units are reported in ppm (δ20.0) and are fully 1 Obtained with H decoupling.

[0078] all 19 F NMR spectra were completely 1 Obtained with H decoupling.

[0079] all 31 P NMR spectra were completely 1 Obtained with H decoupling.

[0080] HPLC analysis was performed using an Ace Super C18 column on an Agilent 1260 Infinity HPLC system with UV detector at 254 nm.

[0081] Melting points were obtained using a Buchi B-540 melting point apparatus and are uncorrected.

[0082] IR spectra were recorded on a Bruker Alpha Platinum-neat spectrometer and expressed as absorption frequency (cm -1 ) as unit report.

[0083] High-resolution mass spectrometry (HRMS) data were acquired on a Thermo Scientific Orbitrap Fusion mass spectrometer.

[0084] All reagents and solvents were purchased from commercial suppliers and used without additional purification. Anhydrous solvents (acetonitrile and 2-methyltetrahydrofuran) were used, but the purity of other commercially available solvents was not further improved. All reactions were carried out in screw-capped vials equipped with Teflon septa under a nitrogen atmosphere. The yields reported are the yields of the isolated materials.

[0085] Flash column chromatography used a Teledyne Isco with pre-packed RediSepRf Gold silica gel columns. Rf instrument.

[0086] Example 1: Synthesis of 2-(1-(benzo[4,5]imidazo[1,2-a]pyridin-3-yl)piperidin-4-yl)ethyl-1,1,2,2-d44-methylbenzenesulfonate

[0087] Example 1 describes a representative synthesis of a molecule using a procedure for conjugating acrylamide to phosphorylated imidazole.

[0088] Step 1 - Formation of diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate

[0089]

[0090] The reactor was charged with 1H-benzo[d]imidazol-2-amine (0.7882 kg, 6.002 mol, 1.00 equiv) and then MeCN (5.333 L) under nitrogen. N-methylimidazole (0.6693 kg, 8.103 mol, 1.35 equiv) was then added to the mixture, followed by MeCN (0.460 L) to rinse the reaction vessel. The slurry was then stirred at 20 °C for a minimum of 15 minutes. Next, PCl(O)(OEt) was added dropwise over 1 hour. 2 (1.4070 kg, 8.154 mol, 1.35 equiv), keeping the internal temperature below 30°C. PCl(O)(OEt) 2 After adding to complete, add MeCN (0.455L) to rinse the reaction vessel.Then the slurries were stirred at 20 ℃ for minimum 12 hours.After the reaction was completed, the container was cooled to 0 ℃ in minimum 30 minutes, and then stirred at this temperature for minimum 2 hours.Then filter the mixture, and wash the wet cake with two portions of MeCN (3.2L).Solid was dried in vacuo at 40 ℃ for minimum 12 hours, obtain (1H-benzo [d] imidazoles-2-yl) diethyl phosphoramidate, for off-white solid (1.2144kg, correction yield: 73%, 99.5%HPLC purity): 229 ℃ of fusing points.

[0091] 1 H NMR (400 MHz, methanol-d 4 )δ7.20(dt,J=7.6,3.8Hz,2H),7.11(dd,J=5.9,3.2Hz,2H),4.07(p,J=7.2Hz,4H),1.32(t,J=7.1Hz,6H); 13 C NMR (101 MHz, methanol-d 4 )δ123.4,111.2,63.4,63.4,16.6,16.6; 31 P NMR (162 MHz, methanol-d4) δ 7.31.

[0092] Step 2 – 2-(1-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperidin-4-yl)ethyl-1,1-d 2 Parabens

[0093]

[0094] The reactor was charged with MeCN (5.00 L) under nitrogen, followed by (E)-2-(1-(3-ethoxyacryloyl)piperidin-4-yl)ethyl-1,1-d 2 Benzoate (1.00 kg, 3.00 mol, 1.0 equiv) and diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate (888.5 g, 3.30 mol, 1.1 equiv). (The benzoate compound can be synthesized by methods known in the art, or as described in Example 2, or in the application to which this application claims priority.) MeTHF (5.00 L) was charged, followed by Et 3 Next, the reactor was cooled to between -10°C and 10°C and POCl was added over a minimum of 30 minutes. 3 (1.01 kg, 6.60 mol, 2.2 eq.) while maintaining the internal temperature between -10°C and 10°C. After the addition is complete, the contents are then heated to 65°C-95°C over a minimum of 2 hours, and the reaction is maintained at an internal temperature of 80°C for at least 1.5 hours. After confirming that the reaction is complete, the reactor is cooled to 15°C-25°C, and then 25 w / w% K 2 CO 3 Solution (by mixing water (5.0 L) with K 2 CO 3 (1.67 kg) was mixed and stirred at 20° C. for a minimum of 15 minutes to prepare the mixture. The internal temperature was kept below 30° C. It was then stirred for a minimum of 15 minutes before the layers were separated and the aqueous solution was drained to waste.

[0095] Example 2: Synthesis of 2-(1-(benzo[4,5]imidazo[1,2-a]pyridin-3-yl)piperidin-4-yl)ethyl-1,1,2,2-d44-methylbenzenesulfonate

[0096] Step 1 - Preparation of diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate

[0097]

[0098] A flask was charged with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (5.55 g, 23.8 mmol, 0.31 eq) and MeCN (35.0 mL) at 15°C-25°C under nitrogen. The mixture was stirred until homogeneous. Diethyl hydrogen phosphate (10.3 g, 75.1 mmol, 9.69 mL, 1.00 eq) and Et 3 N (15.2g, 150.2mmol, 20.9mL, 2.00eq), the flask was heated to 85°C and stirred for 30 minutes, at which time precipitation occurred. The jacket was then cooled to 0°C, and 1H-benzo[d]imidazole-2-amine (10.0g, 75.1mmol, 1.00 equivalent) dissolved in THF (35.0mL) was charged into the flask. The reaction mixture was then warmed to 15°C-25°C and stirred for 1 hour. After confirming that the reaction was complete, the reaction was quenched with water (100.0mL) and then extracted with two portions of ethyl acetate (200.0mL). The combined organic layer was washed with Na 2 SO 4 Drying, filtration, and concentration under reduced pressure afforded the compound (1H-benzo[d]imidazol-2-yl)phosphoramidate diethyl as a brown solid (13.0 g, 48.2 mmol, 64% yield).

[0099] 1 H NMR (400 MHz, CDCl 3 )δppm 7.34(dd,J=18.03,7.89Hz,2H),7.19(td,J=7.67,1.04Hz,1H),7.05(td,J=7.70,0.98Hz,1 H), 6.13-6.74 (m, 2H), 4.20-4.34 (m, 2H), 4.00-4.19 (m, 3H), 1.33 (td, J = 7.09, 0.86Hz, 6H).

[0100] Step 2 – Preparation of (E)-3-ethoxyacryloyl chloride

[0101]

[0102] To a solution of (E)-3-ethoxyacrylic acid (4.40 g, 37.8 mmol, 1.00 equiv) in DCM (20.0 mL) was added SOCl at 25 °C. 2 (4.51 g, 37.8 mmol, 2.75 mL, 1.00 equiv.). The mixture was stirred at 40 °C for 1 hour. After confirming the completion of the reaction, the mixture was evaporated to dryness to give (E)-3-ethoxyacryloyl chloride as a yellow oil (5.10 g, 37.9 mmol, 100% yield). The product was used directly in the next step without purification.

[0103] Step 3 – (E)-2-(1-(3-ethoxyacryloyl)piperidin-4-yl)ethyl-1,1,2,2-d 4 Parabens

[0104]

[0105] At 0°C-10°C, 2-(piperidin-4-yl)ethyl-1,1,2,2-d 4 Benzoate hydrochloride (8.52 g, 31.1 mmol, 1.00 equiv) and Et 3 To a solution of N (3.15 g, 31.1 mmol, 4.33 mL, 1.00 equiv) in THF (15.0 mL) was added crude (E)-3-ethoxyacryloyl chloride (5.02 g, 37.3 mmol, 1.2 equiv). The reaction was stirred at 0°C-10°C for 1 hour. After confirming the completion of the reaction, H 2 O (50.0 mL) and the resulting aqueous solution was extracted with three portions of EtOAc (50.0 mL). The organic phases were then combined and washed with Na 2 SO 4 The residue was then slurried in MTBE (10.0 mL) and filtered to give (E)-2-(1-(3-ethoxyacryloyl)piperidin-4-yl)ethyl-1,1,2,2-d 4 Benzoate (3.20 g, 9.54 mmol, 31% yield) as a yellow solid.

[0106] 1 H NMR(400MHz,DMSO-d6)δppm 8.03(br d,J=7.34Hz,2H),7.67-7.78(m,1H),7.51-7.65(m,2H),7.44(d,J=11.86Hz,1H),5.91(d,J=11.86Hz,1H),4.09- 4.60(m,2H),3.93-4.03(m,2H),2.66-3.12(m,2H),1.61-1.89(m,3H),1.29(t,J=7.03Hz,3H),1.00-1.18(m,2H).

[0107] Step 4 – 2-(1-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperidin-4-yl)ethyl-1,1,2,2-d 4 Parabens

[0108]

[0109] At 25 °C, diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate (2.30 g, 8.53 mmol, 1.10 equiv) and (E)-2-(1-(3-ethoxyacryloyl)piperidin-4-yl)ethyl-1,1,2,2-d 4 To a solution of the benzoate (2.60 g, 7.75 mmol, 1.00 equiv) in 2-MeTHF (13.0 mL) and MeCN (13.0 mL) was added Et 3 N (392 mg, 3.88 mmol, 539 μL, 0.50 equiv) and then POCl 3 (2.61 g, 17.0 mmol, 1.58 mL, 2.20 equiv.) The reaction was then heated to 80 °C and stirred for 4 h. After confirming the reaction was complete, saturated NaHCO 3 The aqueous solution (100.0 mL) was added and the aqueous layer was extracted with three portions of DCM (100.0 mL). The organic phases were then combined and washed with Na 2 SO 4 The crude product was then slurried in EtOAc (30.0 mL) and filtered. The slurrying process was repeated two more times. The resulting solid was then purified by preparative HPLC to give 2-(1-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)piperidin-4-yl)ethyl-1,1,2,2-d 4 Benzoate (0.900 g, 2.22 mmol, 29% yield) as a yellow solid.

[0110] 1 H NMR (400MHz, DMSO-d6): δppm 8.94(d,J=7.82Hz,1H),7.89-8.03(m,3H),7.61-7.72(m,1H),7.45-7.58(m,3H),7.2 4-7.34(m,1H),7.07-7.19(m,1H),6.89(d,J=7.82Hz,1H),4.39-4.82(m,2H),3.03(br t,J=11.55Hz,2H),1.74-1.96(m,3H),1.05-1.34(m,2H).

[0111] 13 C NMR (400MHz, DMSO-d6): δppm 166.2,158.3,152.5,144.6,134.8,133.7,130.3,129.5,129.2,128.2,124.5,119.4,117.5,110.6,96.3,44.9,32.9,32.0.

[0112] Examples 3.0-3.5 demonstrate representative syntheses of molecules using the basic steps of conjugating acrylamide to phosphorylated imidazole.

[0113] Example 3.0: 2-amino-imidazo[1,2-a]pyrimidine (R 1 =R 2 =R 3 =R 4 =H)

[0114]

[0115] Acrylamide (0.500 mmol, 1.0 eq), phosphorylated imidazole (0.550 mmol, 1.1 eq), 2-MeTHF (0.5 mL), and MeCN (0.5 mL) were combined in a vial. 3 (1.1 mmol, 2.2 equiv) was added to the resulting mixture and the reaction was heated to 80°C and stirred overnight. The crude reaction mixture was then cooled to 23°C and washed with 1 mL of Et 3 The mixture was quenched with N, dry loaded onto silica gel, and flash evaporated with a 0%-10% DCM:MeOH gradient mobile phase.

[0116] Example 3.1: Synthesis of 2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine

[0117]

[0118] The reaction mixture was prepared by using diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate (0.296 g, 1.10 mmol, 1.1 eq), (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.0 eq) and POCl 3 The general procedure was carried out using a solution of 2-Me (0.204 mL, 2.20 mmol, 2.2 equiv) in THF (1.0 mL) and MeCN (1.0 mL). After purification by flash chromatography, 2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine was isolated as an off-white solid (0.312 mg, 95% yield, 98:2 regioisomer ratio).

[0119] 1H NMR (400MHz, chloroform-d): δ8.23(d,J=7.7Hz,1H),7.73(d,J=8.1Hz,1H),7.55(d,J=8.0Hz,1H),7.37(t,J=7.7Hz,1H),7.31(t,J=7.5Hz,2H),7.26–7.14(m ,4H),6.44(d,J=7.8Hz,1H),4.77(s,2H),3.09(t,J=13.0Hz,2H),2.85(tt ,J=12.2,3.8Hz,1H),2.00(q,J=12.3Hz,2H),1.75(qd,J=12.8,4.2Hz,2H).

[0120] 13 C NMR (101 MHz, chloroform-d): δ 157.9, 152.9, 145.2, 144.9, 132.7, 128.7, 127.9, 126.9, 126.6, 124.8, 119.8, 118.7, 108.8, 95.5, 45.8, 43.0, 33.3.

[0121] Example 3.2: Synthesis of 7-(4-phenylpiperidin-1-yl)imidazo[1,2-a]pyrimidine

[0122]

[0123] The reaction mixture was prepared by using diethyl (1H-imidazol-2-yl)phosphoramidate (0.241 g, 1.10 mmol, 1.1 eq.), (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.0 eq.) and POCl 3 The general procedure was carried out using a solution of 2-Me (0.186 mL, 2.00 mmol, 2.0 equiv) in THF (1.0 mL) and MeCN (1.0 mL). After purification by flash chromatography, 7-(4-phenylpiperidin-1-yl)imidazo[1,2-a]pyrimidine was isolated as an off-white solid (0.215 g, 77% yield, 15:1 regioisomer ratio).

[0124] 1H NMR (400MHz, chloroform-d): δ8.02(d,J=7.7Hz,1H),7.37(d,J=1.6Hz,1H),7.34–7.24(m,2H),7.20(ddd,J=7.8,5.9,1.7Hz,3H),7.13(d,J=1.6Hz,1 H), 4.64 (d, J = 13.4Hz, 1H), 3.03 (td, J = 13.3, 2.6Hz, 2H), 2.80 (tt, J = 12.2, 3.7Hz, 1H), 1.95 (d, J = 12.8Hz, 2H), 1.72 (qd, J = 12.7, 4.1Hz, 2H).

[0125] 13 C NMR (101 MHz, chloroform-d): δ 156.2, 149.9, 145.5, 133.7, 132.5, 128.6, 126.8, 126.5, 108.8, 97.5, 45.8, 43.0, 33.1.

[0126] Example 3.3: Synthesis of ethyl 2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine-8-carboxylate

[0127]

[0128] The reaction mixture was prepared by using ethyl 2-((diethoxyphosphoryl)amino)-1H-imidazole-4-carboxylate (0.160 g, 0.550 mmol, 1.1 equiv), (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.130 g, 0.500 mmol, 1.0 equiv) and POCl 3 The general procedure was carried out with a solution of 2-Me (0.102 mL, 1.10 mmol, 2.2 equiv) in THF (0.5 mL) and MeCN (0.5 mL). After purification by flash chromatography, 7-(4-phenylpiperidin-1-yl)imidazo[1,2-a]pyrimidine was isolated as an off-white solid (0.152 g, 87% yield, 19:1 regioisomer ratio).

[0129] 1H NMR (400 MHz, CHLOROFORM-d): δ8.02 (d, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.35–7.25 (m, 3H), 7.25–7.15 (m, 3H), 6.55 (d, J=7.8 Hz, 1H), 4.66 (d, J=13.1 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.07 (td, J=13.2, 2.5 Hz, 2H), 2.83 (tt, J=12.2, 3.7 Hz, 1H), 2.02–1.90 (m, 2H), 1.73 (dtd, J=13.4, 12.4, 4.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H).

[0130] 13 C NMR (101 MHz, chloroform-d): δ 163.8, 156.6, 149.5, 145.3, 135.9, 133.8, 128.7, 126.9, 126.7, 114.0, 99.4, 60.9, 45.9, 43.0, 33.1, 14.5.

[0131] Example 3.4: Synthesis of N-benzylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine

[0132]

[0133] The mixture was prepared by using diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate (0.296 g, 1.10 mmol, 1.1 eq), (E)-N-benzyl-3-ethoxyacrylamide (0.205 g, 1.00 mmol, 1.0 eq), POCl 3 The general procedure was carried out using a solution of 2-Me (0.204 mL, 1.10 mmol, 2.1 equiv) in THF (0.5 mL) and MeCN (0.5 mL). After purification by flash chromatography, N-benzylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was isolated as an off-white solid (0.175 g, 64% yield, 98:2 regioisomer ratio).

[0134] 1H NMR (400MHz, DMSO-d6): δ8.82(d,J=7.4Hz,1H),8.39(t,J=5.8Hz,1H),7.88(d,J=7.9Hz,1H),7.50(d,J=8.0Hz, 1H),7.44–7.31(m,4H),7.31–7.23(m,2H),7.15(t,J=7.6Hz,1H),6.43(d,J=7.3Hz,1H),4.65(d,J=5.6Hz,2H).

[0135] 13 C NMR (101MHz, DMSO-d6): δ158.8,152.4,143.8,138.9,133.3,128.4,128.0,127.57,127.0,123.9,119.2,117.2,109.9,99.2,43.6.

[0136] Example 3.5: Synthesis of N,N-dibenzylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine

[0137]

[0138] The mixture was prepared by using diethyl (1H-benzo[d]imidazol-2-yl)phosphoramidate (0.148 g, 0.550 mmol, 1.1 eq.), (E)-N,N-dibenzyl-3-ethoxyacrylamide (0.148 g, 0.500 mmol, 1.0 eq.), POCl 3 (0.102 mL, 1.10 mmol, 2.1 equiv) in 2-Me THF (0.5 mL) and MeCN (0.5 mL) for the general procedure. After purification by flash chromatography, N,N-dibenzylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was isolated as an off-white solid (163 mg, 89% yield, 96:4 regioisomer ratio).

[0139] 1H NMR (400MHz, chloroform-d): δ8.21(d,J=7.6Hz,1H),7.76(d,J=8.1Hz,1H),7.54(d,J=8.0Hz,1H ),7.42–7.23(m,11H),7.19(t,J=7.6Hz,1H),6.29(d,J=7.7Hz,1H),5.09–4.69(bs,4H).

[0140] 13C NMR (101 MHz, chloroform-d): δ 159.1, 144.9, 133.0, 129.0, 127.8, 127.8, 125.0, 120.0, 118.9, 110.1, 108.9, 96.0, 51.1.

[0141] Example 4: Optimization of cyclization reaction

[0142]

[0143] We started by exploring the cyclization of 2-aminobenzimidazole and acrylamide (5) under thermal conditions (70 °C), where low conversion and no desired product were observed (Table 1, entry 1). Activation of the amide to the corresponding imidoyl chloride provided the necessary increase in reactivity. 5 (Table 1, entry 2) and POCl 3 (Table 1, entry 3) are all effective activation reagents, POCl 3 The product was provided in 71% yield, but the ratio of isomers 6a:6b was excellent at 75:25. We then found that by POCl 3 By activating the two reaction partners independently and then combining the reaction streams, the isomer selectivity increased significantly to 90:10 (Table 1, entry 4). However, this protocol proved difficult to replicate and cumbersome to operate. 3 The reaction mixture showed the formation of various N-phosphorylated products.

[0144] We hypothesized that phosphoramidates could serve as isolable analogs of transiently generated N-phosphorylated species and ultimately synthesize substrates 2a and 2b ( Figure 1) (see, e.g., Bandyopadhyay, P.; Sathe, M.; Tikar, SN; Yadav, R.; Sharma, P.; Kumar, A.; Kaushik, MP Synthesis of some novel phosphorylated and thiophosphorylated benzimidazoles and benzothiazoles and their evaluation for larvicidal potential to Aedes albopictus and Culex quinquefasciatus, Bioorg. Med. Chem. Lett., 2014, 24, 2934-2939). In particular, diethylphosphoramidate 2a provided a clean reaction curve and a selectivity of 98:2 to isomer 6a (Table 1, entry 5). Isomerized phosphoramidate 2b converted product selectivity to favor 6b, although yield and selectivity were slightly reduced (Table 1, entry 7), both of which were improved after further optimization (Table 1, entry 8; see also Example 7).

[0145] Table 1. Optimization of cyclization reaction

[0146]

[0147] a The reaction was performed on a 0.25 mmol scale, acrylamide (1.0 eq), aminobenzimidazole (1.1 eq), activator (2.2 eq), 0.5M.

[0148] b A% = HPLC area percentage at 254 nm.

[0149] c The ratio of 6a:6b was determined by HPLC analysis of the crude reaction mixture at 254 nm.

[0150] d Before combining, both 1 and 2b were treated with POCl at 0 °C. 3 The reaction was allowed to proceed for 30 minutes and then heated to 70°C.

[0151] e 5. Use POCl 3 Pre-treatment, heating to 70 °C for 20 min, then cooling to room temperature, then adding to 3.0 eq. of 2b. The reaction mixture was then heated to 50 °C.

[0152] We note that both isomeric phosphoramidates can be obtained from 2-aminobenzimidazole (1) with high selectivity and that the choice of base in the phosphorylation reaction determines the product selectivity. We found that the use of N-methylimidazole (NMI) provided the exocyclic phosphorylation product 2a with a ratio of >99:1 relative to 2b. In contrast, the use of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base provided the complementary intracyclic phosphorylation product 2b with an isomeric selectivity of 99:1. This differential phosphorylation in turn provided the basis for access to 2- and 4-aminobenzo[4,5]imidazo[1,2-a]pyrimidines. The structures of phosphoramidates 2a and 2b were confirmed by X-ray crystallographic analysis ( Figure 2 ).

[0153] Example 5: Variants of β-ethoxyacrylamide

[0154] After finding suitable conditions for the selective preparation of 2- or 4-aminobenzimidazolo[1,2-a]pyrimidines, we explored the scope of this reaction. Various β-ethoxyacrylamides (e.g., Figure 3 ). These pairings indeed produced benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine as the major product, as determined by X-ray crystallographic analysis of 6a (see Example 46).

[0155] We noted that a variety of secondary acrylamides reacted smoothly, affording the cyclized products in good yields and excellent selectivity. Both aromatic and aliphatic N-substituted acrylamides were well tolerated, and there were no significant electronic effects on the results. When primary acrylamides ( Figure 3 When the compound 13a) is used, the reaction produces several undesirable by-products, so the isolated yield is reduced.

[0156] exist Figure 3 The reaction was carried out on a 0.5 or 1.0 mmol scale with acrylamide (1.0 equivalent), 2 (1.1 equivalent), POCl 3 (2.2 equiv.), 0.5 M. The yields quoted are isolated yields after silica gel chromatography. The reported a:b isomer ratios were determined by HPLC analysis of the uncorrected A% crude reaction mixture at 254 nm.

[0157] Example 6: Variants of amino(benzi)imidazole

[0158] A variety of other N2-phosphorylated amino-imidazoles ( Figure 4). Under similar reaction conditions, both electron-rich and electron-deficient aminobenzimidazole derivatives reacted in 77-95% yields, with selectivity for 2-amino-imidazo[1,2-a]pyrimidine isomeric products ≥94:6.

[0159] exist Figure 4 The reaction was carried out on a 0.5 mmol scale with acrylamide (1.0 equiv), 2a (1.1 equiv), POCl 3 (2.2 equiv.), 0.5 M. The indicated yields are isolated yields after silica gel chromatography. The a:a':b:b' ratios were determined by HPLC analysis of the uncorrected A% crude reaction mixture at 254 nm. 3 N (1.5 equiv.) was added to the reaction to form 16a (and its isomers).

[0160] It can be seen that the use of asymmetrically substituted aminoimidazoles in the reaction can give another group of structural isomers, based on which the nitrogen of the imidazole ring participates in the formation of the CN bond, such as Figure 4 When the sterically required substituent is located at the 4-position of the phosphoramidate ( Figure 4 , 16a:16a'), yielding a 90:10 isomeric product ratio. Under these conditions, the selectivity of the substrate generated by 2-amino-6-methoxybenzimidazole was poor ( Figure 4 , 14a:14a'=55:45).

[0161] The reaction conditions can be 1.5 equivalents of Et 3 N buffer to allow coupling of substrates with acid-sensitive functional groups such as product 16a.

[0162] Example 7: Formation of 4-aminoimidazo[1,2-a]pyrimidine

[0163] This example addresses the formation of 4-aminoimidazo[1,2-a]pyrimidine products by condensation of acrylamide with N1 phosphoramidate 2b.

[0164] Mix all reagents together and add POCl last. 3 Initial experiments with , yielded a 6b:6a ratio of 80:20 (Table 1, entry 7). LCMS of the crude reaction mixture showed a large amount of 2-aminobenzimidazole 1, suggesting that 2b decomposed under the reaction conditions.

[0165] By using POCl 3 Pretreatment of 5 followed by addition of 3, preformation of the possible imidoyl chloride intermediate A may outweigh the decomposition pathway ( Figure 5). Such a protocol proved beneficial and the product was isolated in 89% yield and a 6b:6a ratio of 96:4 (Table 1, entry 8).

[0166] We then explored the cyclization of various acrylamides with phosphoramidate 3 using the protocol in Table 1, entry 8, to afford various 4-amino isomers ( Figure 5 ).exist Figure 5 The reaction was carried out on a 0.5 mmol scale with acrylamide (1.0 equivalent), 3 (3.0 equivalent), POCl 3 (1.2 equiv.), 0.5 M. Isolated yields are reported after silica gel chromatography. Reported a:b isomer ratios were determined by HPLC analysis of the uncorrected A% crude reaction mixture at 254 nm.

[0167] Good yields were observed using aliphatic secondary β-ethoxyacrylamide and electron-rich aromatic acrylamide. However, the use of electron-deficient acrylamide resulted in significantly lower yields of product 10b than other starting materials. The isoselectivity of b:a was ≥90:10 for all substrates.

[0168] Examples 8-13 demonstrate the synthesis of various phosphoramidates. Not all depicted structures correspond to actual X-ray structures, but are based on the X-ray confirmed structure of 2a, as shown in Example 44.

[0169] Example 8: Diethyl (2-amino-1H-benzo[d]imidazol-1-yl)phosphonate (2b)

[0170]

[0171] 1H-benzimidazole-2-amine (2.00 g, 15.0 mmol, 1.00 equivalent) was added to a 40 mL scintillation vial containing a stirring bar, and the reaction was covered with a septum cap. Acetonitrile (16 mL) was added, followed by 1,8-diazabicyclo [5.4.0] undec-7-ene (3.40 mL, 22.5 mmol, 1.50 equivalent). A portion of diethyl chlorophosphate (2.70 mL, 18.8 mmol, 1.25 equivalent) was added at room temperature. The reaction was then stirred at room temperature for 1 hour. The reaction mixture was concentrated onto silica gel (10.0 g) by rotary evaporation, and then filtered through silica gel (20.0 g) using dichloromethane (100 mL) as eluent. The resulting colorless solution was concentrated to dryness under vacuum. Diethyl (2-amino-1H-benzo[d]imidazol-1-yl)phosphonate (3) was isolated as a white solid in 96% yield (3.90 g, 14.3 mmol): melting point 74°C-79°C; FTIR (pure cm -1 )1680,1477,1192,1027,931,789,738;1 H NMR (400 MHz, CHLOROFORM-d) δ 7.32 (dd, J = 13.3, 7.9 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 6.61 (s, 2H), 4.33–4.17 (m, 2H), 4.17–3.96 (m, 2H), 1.31 (t, J = 7.1 Hz, 6H). 13 C NMR (101 MHz, chloroform-d) δ 155.7 (d, J = 5.8 Hz), 143.9 (d, J = 13.1 Hz), 132.3 (d, J = 5.0 Hz), 123.9, 120.5, 116.2, 111.5, 64.6 (d, J = 4.6 Hz), 16.0 (d, J = 7.2 Hz). 31 P NMR (162MHz, chloroform-d) δ-4.72. HRMS: C 11 H 17 N 3 O 3 P[M+H] + Calculated value = 270.1002, measured value = 270.0998.

[0172] Example 9: (Z)-(5-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate diethyl ester (19):

[0173]

[0174] In the 20mL scintillation bottle with stirring bar, add 5-methoxy-1H-benzimidazole-2-ylamine (1.00g, 5.80mmol, 1.00 equivalent) and acetonitrile (1.0M, 5.8mL), then add N-methylimidazole (0.693mL, 8.70mmol, 1.50 equivalent). The bottle is covered with a septum cap, and at room temperature, diethyl chlorophosphate (1.25mL, 8.70mmol, 1.50 equivalent) is slowly added over 30 minutes (by syringe pump). The reaction is stirred at room temperature for 18 hours. After stirring at room temperature overnight, MTBE (3.0mL) is added and the reaction mixture is filtered. The filter cake is then dried in a nitrogen stream vacuum for 4 hours at room temperature, and then dried in a vacuum oven at 40°C for 24 hours. The desired product, diethyl (Z)-(5-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate (19), was isolated as a yellow solid (0.75 g, 43%): mp 205°C-208°C; FTIR (neat cm -1 )1664,1611,1206,1056,952,801,700; 1H NMR (400 MHz, DMSO-d 6 )δ11.09(bs,2H),7.06(d,J=8.6Hz,1H),6.78(d,J=2.4Hz,1H),6.62(dd,J=8 .6, 2.4Hz, 1H), 3.98–3.84 (m, 4H), 3.71 (s, 3H), 1.21 (td, J = 7.1, 0.7Hz, 6H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 155.0, 152.3 (d, J = 7.1Hz), 130.8, 124.0, 110.3, 107.9, 96.0, 60.9 (d, J = 5.9Hz), 55.5, 16.2 (d, J = 6.6Hz). 31 PNMR (162MHz, DMSO-d 6 )δ7.35. HRMS: C 12 H 19 N 3 O 4 P[M+H] + Calculated value: 300.1108; Measured value: 300.1105.

[0175] Example 10: (Z)-(4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate diethyl ester (20):

[0176]

[0177] 4-bromo-1H-benzo[d]imidazole-2-amine (1.97 g, 9.40 mmol, 1.00 equivalent) and acetonitrile (1.0 M, 9.4 mL) were added to a 20 mL scintillation vial with a stirring bar, followed by N-methylimidazole (1.00 mL, 12.7 mmol, 1.35 equivalent). The vial was covered with a septum cap, and diethyl chlorophosphate (1.83 mL, 12.7 mmol, 1.35 equivalent) was added via a syringe pump over 30 minutes at room temperature. The reaction was stirred at room temperature for 18 hours. After stirring overnight at room temperature, the mixture was dry loaded onto silica gel and purified by automatic silica gel chromatography using 0%-10% CH 3 OH CH 2 Cl 2 The desired product, (Z)-(4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate (20), was isolated as a white solid (1.50 g, 46%): melting point 154°C-156°C; FTIR (pure cm -1)1648,1535,1431,1253,1009,741,665,571,526; 1 H NMR (400 MHz, DMSO-d 6 )δ7.30(dd,J=8.0,0.9Hz,1H),7.27–7.18(m,3H),6.91(t,J=8.0Hz,1H),4.21(ddq,J= 10.3, 9.2, 7.1Hz, 2H), 4.09 (ddq, J=10.3, 8.9, 7.0Hz, 2H), 1.22 (td, J=7.1, 0.8Hz, 6H). 13 C NMR (101 MHz, DMSO-d 6 ) δ155.7 (d, J = 5.1Hz), 142.8 (d, J = 13.1Hz), 132.6 (d, J = 5.1Hz), 126.0, 120.9, 110.6, 107.8, 64.7 (d, J = 5.0Hz), 15.7 (d, J = 6.5Hz). 31 P NMR (162 MHz, DMSO-d 6 )δ-5.22. HRMS: C 11 H 16 Bn 3 O 3 P[M+H] + Calculated value: 348.0107; Measured value: 348.0089.

[0178] Example 11: (Z)-tert-butyl 2-((diethoxyphosphoryl)imino)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (21)

[0179]

[0180] In a 20mL scintillation vial with a stirring bar, tert-butyl 2-amino-1H-benzo[d]imidazole-4-carboxylate (0.700g, 5.15mmol, 1.00 equivalent) and acetonitrile (1.0M, 5.2mL) were added, followed by N-methylimidazole (0.550mL, 7.00mmol, 1.35 equivalents). The vial was covered with a septum cap, and diethyl chlorophosphate (1.00mL, 5.15mmol, 1.35 equivalents) was added via a syringe pump over 30 minutes at room temperature. The reaction was stirred at room temperature for 18 hours. After stirring overnight at room temperature, the mixture was dry loaded onto silica gel and purified by automatic silica gel chromatography using 0%-10% CH 3 OH CH 2 Cl 2The desired product, (Z)-(5-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate (21), was isolated as a white solid (0.70 g, 37%): melting point 192°C-199°C; FTIR (pure cm -1 )1690,1644,1458,1366,1289,1145,1049,923,747; 1 H NMR (400 MHz, DMSO-d 6 )δ11.16(s,1H),10.83(s,1H),7.53(dd,J=8.0,1.1Hz,1H),7.35(dd,J=7.8,1.1Hz,1H ),7.15(t,J=7.9Hz,1H),4.07–3.83(m,4H),1.60(s,9H),1.22(td,J=7.0,0.7Hz,6H). 13 C NMR (101 MHz, DMSO-d 6 ) δ164.2, 150.0, 129.9, 122.2, 121.5, 82.0, 61.3 (d, J = 5.6Hz), 27.9, 16.1 (d, J = 6.7Hz). 31 PNMR (162MHz, DMSO-d 6 )δ9.20. HRMS: C 16 H 25 N 3 O 5 P[M+H] + Calculated value: 370.1526; Measured value: 370.1513.

[0181] Example 12: (1,3-Dihydro-2H-imidazole-2-ylidene)phosphoramidate diethyl ester (22)

[0182]

[0183] 1H-imidazole-2-amine (0.662 g, 8.00 mmol, 1.00 equivalent) and acetonitrile (8 mL, 1.0 M) were added to a 20 mL scintillation vial with a stirring bar, followed by N-methylimidazole (0.860 mL, 10.8 mmol, 1.35 equivalent). The vial was covered with a septum cap and diethyl chlorophosphate (1.56 mL, 10.8 mmol, 1.35 equivalent) was slowly added at room temperature over 30 minutes (via a syringe pump). The reaction was stirred at room temperature for 18 hours. After stirring at room temperature for 18 hours, the reactant was dry loaded onto silica gel and purified by automatic silica gel chromatography using 0%-10% CH 3 OH CH 2Cl 2 Solution gradient. Isolation of (1,3-dihydro-2H-imidazole-2-ylidene)phosphoramidate diethyl ester (22) as a white solid (0.41 g, 24%): melting point 155°C-166°C; FTIR (pure cm -1 )1638,1572,1182,1023,906,960; 1 H NMR (400 MHz, CHLOROFORM-d) δ 11.10 (bs, 2H), 6.44 (s, 2H), 4.03 (pd, J = 7.1, 1.6 Hz, 4H), 1.29 (t, J = 7.1 Hz, 6H). 13 C NMR (101 MHz, chloroform-d) δ 150.7 (d, J = 6.7 Hz), 111.5, 61.9 (d, J = 5.6 Hz), 16.5 (d, J = 7.7 Hz). 31 P NMR (162MHz, chloroform-d) δ10.06. HRMS: C 7 H 15 N 3 O 3 P[M+H] + Calculated value: 220.0846; Measured value: 220.0844.

[0184] Example 13: (Z)-2-((diethoxyphosphoryl)imino)-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (23)

[0185]

[0186] To a 20 mL scintillation vial with a stirring bar, ethyl 2-amino-1H-imidazole-4-carboxylate (0.759 g, 4.90 mmol, 1.00 equiv) and acetonitrile (4.9 mL, 1.0 M) were added, followed by N-methylimidazole (0.600 mL, 7.30 mmol, 1.35 equiv). The vial was covered with a septum cap, and diethyl chlorophosphate (1.10 mL, 7.30 mmol, 1.35 equiv) was slowly added at room temperature over 30 minutes (via a syringe pump). The reaction was stirred at room temperature for 18 hours. After stirring at room temperature for 18 hours, the reactant was dry loaded onto silica gel and purified by automatic silica gel chromatography using 0%-10% CH 3 OH CH 2 Cl 2 Solution gradient. Isolation of (Z)-2-((diethoxyphosphoryl)imino)-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (S5) as a white solid (0.44 g, 31%): melting point 114°C-118°C; FTIR (pure cm -1)1701,1642,1591,1441,1326,1179,1154,1028,955; 1 H NMR (400 MHz, CHLOROFORM-d) δ 10.72 (bs, 2H), 7.33 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.13 (pd, J = 7.3, 5.0 Hz, 4H), 1.33 (m, 9H). 13 C NMR (101 MHz, chloroform-d) δ 160.6, 147.8, 124.5, 121.3, 63.3 (d, J = 5.3 Hz), 60.8, 16.3 (d, J = 6.9 Hz), 14.5. 31 P NMR (162MHz, chloroform-d) δ4.43. HRMS: C 10 H 19 N 3 O 5 P[M+H] + Calculated value: 292.1057; Measured value: 292.1046.

[0187] Examples 14-21 demonstrate the synthesis of various acrylamides.

[0188] Example 14: (E)-3-Ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (24)

[0189]

[0190] At room temperature, in an active nitrogen line, (E)-3-ethoxyprop-2-enoic acid (9.42 g, 80.6 mmol, 1.30 equiv), 4-phenylpiperidine (10.0 g, 62.0 mmol, 1.00 equiv), 2-PrOH (50 mL, 5.0 mL / g), Et 3 N (34.6 mL, 248 mmol, 4.00 equiv), and then mixed with 50 wt% The reaction mixture was stirred for 1 h at 40 °C for 1 h and then quenched with distilled water (150 mL, 15.0 mL / g). The layers were separated and the aqueous layer was extracted twice with DCM (100 mL, 10 mL / g) and the organic layers were combined. The combined organic layers were then dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel, eluted with a 25%-50% IPAc: heptane gradient mobile phase, and then concentrated to give the product as a light yellow oil (84%), which was concentrated under high vacuum to form a white solid:

[0191] Melting point: 112℃-114℃. 1 H NMR (400 MHz, DMSO-d 6 )δ7.43(d,J=11.9Hz,1H),7.33–7.25(m,2H),7.25–7.14(m,3H),5.90(d,J=11.9Hz,1H),3.94(q,J=7.0Hz, 2H), 2.75(tt,J=12.1,3.6Hz,1H),1.83–1.73(m,3H),1.47(dd,J=12.7,4.0Hz,2H),1.24(t,J=7.0Hz,3H). 13 CNMR (101MHz, DMSO-d 6 )δ164.9,160.6,145.7,128.7,126.7,126.1,95.9,66.7,42.0,33.2,14.5. LRMS:C 16 H 22 NO 2 [M+H] + Calculated value: 260.2; Measured value: 260.2.

[0192] Example 15: (E)-3-Ethoxy-N-methyl-N-phenylacrylamide (25)

[0193]

[0194] To a solution of 1-methylpiperazine (2.81 g, 28.0 mmol, 1.00 equiv) in THF (30 mL, 10.0 mL / g) were added (E)-3-ethoxyprop-2-enoic acid (2.92 g, 25.1 mmol, 0.90 equiv), Et 3 N (11.7 mL, 84.1 mmol, 3.00 equiv) and 50 w% ethyl acetate (27.0 g, 42.4 mmol, 1.50 equiv) solution. After 22 hours at room temperature, H 2 O (300mL, 100.0mL / g) and ethyl acetate (300mL, 100.0V) are added to the mixture. The organic layer is separated and then concentrated. The residue is purified by silica gel flash chromatography and eluted with a mixture of petroleum ether / EtOAc (3 / 1) to obtain the product as a light yellow oil (3.85g, 67%): 1H NMR (400 MHz, CHLOROFORM-d) δ 7.44 (d, J = 12.0 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.6 Hz, 2H), 5.06 (d, J = 12.0 Hz, 1H), 3.66 (q, J = 7.1 Hz, 2H), 3.23 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, chloroform-d): 167.1, 160.4, 144.0, 129.4, 127.4, 127.2, 97.5, 67.1, 36.9, 14.5. HRMS C 12 H 16 O 2 N[M+H] + Calculated value: 206.1181; Measured value: 206.1181.

[0195] Example 16: (E)-3-Ethoxy-N-(4-methoxyphenyl)-N-methylacrylamide (26)

[0196]

[0197] To a solution of 4-methoxy-N-methyl-aniline (4.50 g, 32.8 mmol, 1.00 equiv) in THF (45 mL, 10.0 mL / g) were added (E)-3-ethoxyprop-2-enoic acid (4.20 g, 36.1 mmol, 1.10 equiv), Et 3 N (13.7 mL, 98.4 mmol, 3.0 equiv) and 50% ethyl acetate (31.3 g, 49.2 mmol, 1.50 equiv) solution. After 2 hours at room temperature, saturated Na 2 CO 3 Aqueous solution (400mL, 88.9mL / g) and ethyl acetate (400mL, 88.9mL / g) were added to the mixture. The organic layer was separated and then concentrated. The residue was purified by flash chromatography on silica gel and eluted with a mixture of petroleum ether / EtOAc (3 / 1) to give the product as a light yellow oil (3.10g, 40%): 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.42 (d, J = 12.0 Hz, 1H), 7.12-6.97 (m, 2H), 6.93-6.76 (m, 2H), 5.04 (br d, J = 12.2 Hz, 1H), 3.74 (s, 3H), 3.71-3.61 (m, 2H), 3.19 (s, 3H), 1.24-1.07 (m, 3H).13 C NMR (100 MHz, chloroform-d) 167.4, 160.3, 158.6, 136.9, 128.6, 114.6, 97.5, 67.1, 55.5, 37.2, 14.6. HRMS C 13 H 18 O 3 N[M+H] + Calculated value: 236.1287; Measured value: 236.1288.

[0198] Example 17: (E)-3-Ethoxy-N-methyl-N-(4-(trifluoromethyl)phenyl)acrylamide (27)

[0199]

[0200] To a solution of (E)-3-ethoxyprop-2-enoic acid (2.33 g, 20.1 mmol, 1.00 equiv) in DCM (35 mL, 15.2 mL / g) was added DMF (1.50 mL, 19.5 mmol, 1.00 equiv) at room temperature. Oxalyl chloride (2.57 mL, 29.9 mmol, 1.50 equiv) was then added dropwise over a period of 0.5 hours. The resulting solution was aged at room temperature for 3 hours and then concentrated to dryness under reduced pressure. The crude residue was then dissolved in anhydrous DCM (21 mL, 9.0 mL / g). The crude solution was then added dropwise to N-methyl-4-(trifluoromethyl)aniline (3.5 g, 20.0 mmol, 1.0 equiv), Et 3 N (7.0 mL, 50.3 mmol, 2.5 equiv) and DCM (21 mL, 9.0 mL / g). After 2 hours at room temperature, H 2 O (200mL, 87.0mL / g) and DCM (200mL, 87.0mL / g) were added to the mixture. The organic layer was separated and then concentrated. The residue was purified by flash chromatography on silica gel, eluted with a mixture of petroleum ether / EtOAc (6 / 1), and then further purified by preparative TLC to obtain the product as a light yellow oil (1.50g, 27%): 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.58 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 12.0 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 5.06 (d, J = 12.0 Hz, 1H), 3.72 (q, J = 7.1 Hz, 2H), 3.26 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, chloroform-d) 161.4, 147.3, 147.3, 129.3, 129.0, 126.6 (q, J = 3.9 Hz), 127.6, 122.5, 97.2, 67.5, 53.4, 36.9, 14.6. HRMS C 13 H 15 O 2 NF 3 [M+H] + Calculated value: 274.1055; Measured value: 274.1055.

[0201] Example 18: (E)-N-(4-Chlorophenyl)-3-ethoxy-N-methylacrylamide (28)

[0202]

[0203] To a solution of 4-chloro-N-methyl-aniline (4.50 g, 31.8 mmol, 1.00 equiv) in THF (45 mL, 10.0 mL / g) were added 3-ethoxyprop-2-enoic acid (3.69 g, 31.8 mmol, 1.00 equiv), Et 3 N (9.65 g, 95.4 mmol, 3.00 equiv.) and 50 w% The reaction was stirred at 15°C-25°C for 18 hours. The mixture was diluted with ethyl acetate (450 mL, 10.0 mL / g) and then with saturated Na 2 CO 3 (450 mL, 10.0 mL / g). The organic layer was concentrated. The residue was purified by flash chromatography on silica gel and eluted with a mixture of PE / EA (5 / 1) to give the product as a light yellow oil (2.64 g, 34.7%): 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.45 (d, J = 12.0 Hz, 1H), 7.33-7.24 (m, 2H), 7.10-7.01 (m, 2H), 5.04 (d, J = 12.0 Hz, 1H), 3.69 (q, J = 7.1 Hz, 2H), 3.28-3.16 (m, 3H), 1.17 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, chloroform-d): 161.2, 142.9, 133.3, 129.9, 129.0, 97.4, 67.6, 37.3, 14.8. HRMS C 12 H 15 ClNO 2 [M+H] +Calculated value: 240.0791; Measured value: 240.0794.

[0204] Example 19: (E)-3-Ethoxy-N-methyl-N-(o-tolyl)acrylamide (29)

[0205]

[0206] To a mixture of 3-ethoxyprop-2-enoic acid (4.79 g, 41.2 mmol, 1.00 equiv) and DMF (3.02 g, 41.3 mmol, 1.00 equiv) in DCM (50 mL, 10.4 mL / g) was added oxalyl chloride (7.86 g, 61.9 mmol, 1.50 equiv) at room temperature over 0.5 h. The mixture was aged at 15°C-25°C for 3 h. The mixture was concentrated to dryness, dissolved in DCM (30 mL, 6.3 mL / g), and then added dropwise to N-methyl-o-toluidine (5.00 g, 41.3 mmol, 1.0 equiv), Et 3 N (10.44 g, 103.2 mmol, 2.5 equiv) and DCM (30 mL, 6.3 mL / g). The reaction was stirred at 15°C-25°C for 1 hour. 2 The reaction was quenched with 10% CO (50 mL, 10.4 mL / g), extracted with three portions of DCM (50 mL, 10.4 mL / g), and washed with three portions of HCl. 2 The product was washed with 4% paraformaldehyde (100 mL, 20.8 mL / g) and then washed with brine (100 mL, 10.4 mL / g). The organic layer was concentrated. The residue was purified by flash chromatography on silica gel and then eluted with a mixture of petroleum ether / EtOAc (6 / 1) to give the product as a light yellow oil (5.79 g, 64%): 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.45 (d, J = 12.0 Hz, 1H), 7.23-7.11 (m, 3H), 7.08-7.00 (m, 1H), 4.87 (d, J = 12.2 Hz, 1H), 3.65 (q, J = 7.1 Hz, 2H), 3.14 (s, 3H), 2.13 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, chloroform-d): 167.3, 160.7, 142.5, 136.0, 131.3, 128.4, 128.2, 127.3, 97.0, 67.3, 35.7, 17.5, 14.6. HRMS C 13 H 18 O 2 N[M+H] +Calculated value: 220.1338; Measured value: 220.1337.

[0207] Example 20: (E)-N,N-dibenzyl-3-ethoxyacrylamide (30)

[0208]

[0209] To a solution of N-benzyl-1-phenyl-methylamine (4.99 g, 25.3 mmol, 1.00 equiv) in DMF (50 mL, 10.0 mL / g) were added (E)-3-ethoxyprop-2-enoic acid (3.24 g, 27.9 mmol, 1.10 equiv), Et 3 N (3.9 mL, 28.0 mmol, 1.10 equiv) and TBTU (9.0 g, 27.9 mmol, 1.10 equiv). After 2 h at room temperature, H 2 O (400 mL, 80.0 mL / g) and MTBE (400 mL, 80.0 mL / g) were added to the mixture. The organic layer was then separated and concentrated. The residue was purified by flash chromatography on silica gel and then eluted with DCM to give the product as a light yellow oil (1.58 g, 21%): 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.65 (d, J = 11.7 Hz, 1H), 7.36-6.98 (m, 10H), 5.59 (d, J = 11.7 Hz, 1H), 4.73-4.27 (m, 4H), 3.82 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, chloroform-d): 167.8, 162.1, 128.5, 128.3, 128.2, 127.9, 127.1, 126.9, 126.2, 119.6, 95.4, 67.2, 49.7, 48.1, 14.3. HRMS C 19 H 22 O 2 N[M+H] + Calculated value: 296.1651; Measured value: 296.1652.

[0210] Example 21: (E)-N-Benzyl-3-ethoxyacrylamide (31)

[0211]

[0212] In a 400 mL reactor equipped with an overhead stirrer at room temperature and under an active nitrogen line, (E)-3-ethoxyprop-2-enoic acid (3.48 g, 30.0 mmol, 1.30 equiv), benzylamine (2.47 g, 23.0 mmol, 1.00 equiv), 2-PrOH (12.5 mL, 5.0 mL / g), Et 3 N (13.0 mL, 93.0 mmol, 4.00 equiv), and then mixed with 50 w% The reaction was heated to 40 °C for 1 hour and then quenched with distilled water (37.5 mL, 15.0 mL / g). The layers were separated and the aqueous layer was extracted twice with DCM (25.0 mL, 10 mL / g) and the organic layers were combined. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel, eluting with a 25%-50% IPAc: heptane gradient mobile phase, and then concentrated to give the product as a white solid (61%): melting point: 67 °C-68 °C. FTIR (pure cm -1 )3284,2984,1655,1599,1584,1204,1185,849,811,602,521. 1 H NMR (400 MHz, DMSO-d 6 )δ8.12(t,J=6.0Hz,1H),7.37(d,J=12.4Hz,1H),7.34–7.28(m,2H),7.27–7.22(m,3H),5. 40(d,J=12.4Hz,1H), 4.31(d,J=6.0Hz,2H), 3.87(q,J=7.0Hz,2H), 1.24(t,J=7.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.8,158.1,139.8,128.2,127.3,126.7,99.4,66.1,41.9,14.5. LRMS:C 12 H 16 NO 2 [M+H] + Calculated value: 206.1; Measured value: 206.1.

[0213] Examples 22–36 demonstrate the synthesis of various benzo[4,5]imidazo[1,2-a]pyrimidin-2-amines.

[0214] Example 22: General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine

[0215] To a dram vial containing a stir bar was added: acrylamide (1.00 mmol, 1.00 equiv), N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.296 g, 1.10 mmol, 1.10 equiv) followed by 2-methyltetrahydrofuran (1.0 mL, 1.0 mL / mmol) and acetonitrile (1.0 mL, 1.0 mL / mmol). The reaction was then cooled to 0 °C and phosphoryl chloride (0.204 mL, 2.20 mmol, 2.2 equiv) was added in one portion and the reaction was then placed in a 70 °C heating block. The reaction was stirred at this temperature for 3 hours. After 3 hours at 70 °C, the reaction was cooled to room temperature and heated with Et 3 N (1.0 mL). The mixture was then dry loaded onto silica gel and purified by automated silica gel column chromatography.

[0216] Example 23: 2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (6a)

[0217]

[0218] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.296 g, 1.10 mmol, 1.10 equiv) to afford compound 6a (0.312 g, 95%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 241℃-243℃; FTIR (pure cm -1 )1646,1606,1473,1449,1195,738,662; 1 H NMR (400MHz, chloroform-d) δ8.23(d,J=7.7Hz,1H),7.73(d,J=8.1Hz,1H),7.55(d,J=8.0Hz,1H),7.37(t,J=7.7Hz,1H),7.31(t,J=7.5Hz,2H),7.26–7.14(m, 4H),6.44(d,J=7.8Hz,1H),4.77(s,2H),3.09(t,J=13.0Hz,2H),2.85(tt, J=12.2, 3.8Hz, 1H), 2.00 (q, J=12.3Hz, 2H), 1.75 (qd, J=12.8, 4.2Hz, 2H).13 C NMR (101 MHz, chloroform-d) δ 157.9, 152.9, 145.2, 144.9, 132.7, 128.7, 127.9, 126.9, 126.9, 124.8, 119.8, 118.7, 108.8, 95.5, 45.8, 43.0, 33.3. HRMS: C 21 H 21 N 4 [M+H] + Calculated value: 329.1761; Measured value: 329.1759.

[0219] Example 24: N-methyl-N-phenylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (7a)

[0220]

[0221] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-N-methyl-N-phenylacrylamide (0.103 g, 0.500 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.148 g, 0.550 mmol, 1.10 equiv) to afford compound 7a (0.137 g, 87%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 270℃-271℃; FTIR (pure cm -1 )1640,1588,1504,1449,1366,1247,1366,1247,1222,1121,762,702; 1 H NMR (400MHz, chloroform-d) δ8.08(d,J=7.6Hz,1H),7.76(d,J=8.1Hz,1H),7.54(d,J=8.0Hz,1H),7.49(t ,J=7.6Hz,2H),7.38(t,J=7.5Hz,2H),7.29(d,J=7.5Hz,2H),7.19(t,J=7.6Hz,1H),3.63(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 158.8, 144.8, 144.5, 131.7, 130.3, 127.9, 127.8, 127.3, 124.9, 120.1, 119.0, 108.9, 97.9, 39.1. HRMS: C 17 H 15 N 4[M+H] + Calculated value: 275.1291; Measured value: 275.1292.

[0222] Example 25: N-(4-methoxyphenyl)-N-methylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (8a)

[0223]

[0224] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-N-(4-methoxyphenyl)-N-methylacrylamide (0.118 g, 0.500 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.148 g, 0.550 mmol, 1.10 equiv) to afford compound 8a (0.152 g, 92%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 287℃-289℃; FTIR (pure cm -1 )1644,1609,1507,1438,1369,1264,1023,789,736; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.05 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.37 (s, 1H), 7.19 (dt, J = 8.7, 1.7 Hz, 5H), 6.99 (d, J = 7.3 Hz, 3H), 6.03 (dd, J = 7.7, 1.3 Hz, 2H), 3.86 (s, 3H), 3.58 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 159.2, 159.0, 152.8, 144.8, 137.2, 131.6, 128.6, 127.9, 124.8, 120.0, 118.9, 115.5, 108.8, 97.8, 55.7, 39.2. HRMS: C 18 H 17 N 4 O[M+H] + Calculated value: 305.1397; Measured value: 305.1398.

[0225] Example 26: N-methyl-N-(4-(trifluoromethyl)phenyl)benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (9a)

[0226]

[0227] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-N-methyl-N-(4-(trifluoromethyl)phenyl)acrylamide (0.137 g, 0.500 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.148 g, 0.550 mmol, 1.10 equiv) to afford compound 9a (0.142 g, 83%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 271℃-273℃; FTIR (pure cm -1 )1654,1608,1458,1319,1122,1103,1059,765,737; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (d, J = 7.7 Hz, 1H), 7.77 (dd, J = 14.6, 8.1 Hz, 3H), 7.59 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 17.4, 8.3 Hz, 3H), 7.32–7.18 (m, 1H), 6.16 (d, J = 7.6 Hz, 1H), 3.66 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 158.2, 144.6, 132.1, 127.7, 127.3, 127.3, 127.2, 125.0, 120.3, 119.1, 109.0, 97.5, 38.9. 19 F NMR (376MHz, chloroform-d) δ-62.50. HRMS: C 18 H 14 F 3 N 4 [M+H] + Calculated value: 343.1165; Measured value: 343.1166.

[0228] Example 27: N-(4-chlorophenyl)-N-methylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (10a)

[0229]

[0230] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-N-(4-chlorophenyl)-3-ethoxy-N-methylacrylamide (0.120 g, 0.500 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.148 g, 0.550 mmol, 1.10 equiv) to afford compound 10a (0.139 g, 90%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 248℃-250℃; FTIR (pure cm -1 )1640,1450,1361,810,762,733,554,430; 1 H NMR (400MHz, chloroform-d) δ8.12(d,J=7.6Hz,1H),7.77(d,J=8.1Hz,1H),7.56(d,J=8.0Hz,1H),7.46( d,J=8.3Hz,2H),7.40(t,J=7.7Hz,1H),7.34–7.17(m,2H),6.08(d,J=7.6Hz,1H),3.61(s,1H). 13 C NMR (101 MHz, chloroform-d) δ 158.6, 144.8, 143.1, 133.4, 132.0, 130.5, 128.7, 127.9, 125.0, 120.3, 119.1, 109.0, 97.6, 39.1. HRMS: C 17 H 14 C1N 4 [M+H] + Calculated value: 309.0902; Measured value: 309.0905.

[0231] Example 28: N-methyl-N-(o-tolyl)benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (11a)

[0232]

[0233] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-N-methyl-N-(o-tolyl)acrylamide (0.110 g, 0.500 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.148 g, 0.550 mmol, 1.10 equiv) to afford compound 11a (0.112 g, 78%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH2 Cl 2 Solution. Melting point 218℃-220℃; FTIR (pure cm -1 )1640,1449,1367,1250,1110,776,707; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.06 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.41–7.27 (m, 4H), 7.24–7.14 (m, 2H), 5.77 (d, J = 7.6 Hz, 1H), 3.55 (s, 3H), 2.19 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 158.8, 144.8, 142.7, 136.4, 132.0, 131.9, 128.7, 128.5, 128.1, 127.9, 124.8, 120.0, 118.9, 108.8, 97.3, 37.8, 17.6. HRMS: C 18 H 17 N 4 [M+H] + Calculated value: 289.1448; Measured value: 289.1443.

[0234] Example 29: N,N-dibenzylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (12a)

[0235]

[0236] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-N,N-dibenzyl-3-ethoxyacrylamide (0.148 g, 0.500 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.148 g, 0.550 mmol, 1.10 equiv) to afford compound 12a (0.163 g, 89%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 189℃-191℃; FTIR (pure cm -1 )1640,1583,1478,1443,1218,927,734,720,691; 1H NMR (400MHz, chloroform-d) δ8.21(d,J=7.6Hz,1H),7.76(d,J=8.1Hz,1H),7.54(d,J=8.0Hz,1H) ,7.42–7.23(m,11H),7.19(t,J=7.6Hz,1H),6.29(d,J=7.7Hz,1H),5.09–4.69(bs,4H). 13 C NMR (101 MHz, chloroform-d) δ 159.1, 144.9, 133.0, 129.0, 127.8, 127.8, 125.0, 120.0, 118.9, 110.1, 108.9, 96.0, 51.1. HRMS: C 24 H 21 N 4 [M+H] + Calculated value: 365.1761; Measured value: 365.1766.

[0237] Example 30: N-Benzylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-amine (13a)

[0238]

[0239] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-N-benzyl-3-ethoxyacrylamide (0.205 g, 1.00 mmol, 1.00 equiv) and N-diethoxyphosphoryl-1H-benzimidazol-2-amine (0.296 g, 1.10 mmol, 1.10 equiv) to afford compound 13a (0.175 g, 64%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 270℃-272℃; FTIR (pure cm -1 )1644,1585,1493,1444,1340,1320,1039,794,729; 1 H NMR (400 MHz, DMSO-d 6 )δ8.82(d,J=7.4Hz,1H),8.39(t,J=5.8Hz,1H),7.88(d,J=7.9Hz,1H),7.50(d,J=8.0Hz,1H),7.44– 7.31(m,4H),7.31–7.23(m,2H),7.15(t,J=7.6Hz,1H),6.43(d,J=7.3Hz,1H),4.65(d,J=5.6Hz,2H). 13C NMR (101 MHz, DMSO-d 6 )δ158.8,152.4,143.8,139.0,133.3,128.4,128.0,127.6,127.0,123.9,119.2,117.2,109.9,99.2,43.6. HRMS:C 17 H 15 N 4 [M+H] + Calculated value: 275.1291; Measured value: 275.1277.

[0240] Example 31: 8-Methoxy-2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (14a)

[0241] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.00 equiv) and (Z)-diethyl(5-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate (0.329 g, 1.10 mmol, 1.1 equiv) to afford a mixture of 14a and 14a' as a yellow solid (0.342 g, 95%, 55:45 14a:14a'). Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 The isomeric mixture was then purified by SFC (cellulose 3 column, eluent: 25% MeOH-isocratic) to obtain an analytically pure sample of 14a. Melting point 248℃-250℃; FTIR (pure, cm -1 )1666,1503,1477,1281,1210,1172,775,753,699; 1 H NMR (400 MHz, acetic acid-d 4)δ8.79(d,J=7.6Hz,1H),7.84(d,J=8.9Hz,1H),7.36–7.15(m,6H),7.12(d, J=7.7Hz,1H),7.00(dd,J=9.0,2.3Hz,1H),5.22(d,J=13.1Hz,1H),4.66–4. 28(m,1H),3.88(s,3H),3.46(t,J=13.2Hz,1H),3.15(t,J=12.8Hz,1H),2.9 9(tt,J=12.1,3.6Hz,1H),2.08(q,J=11.6,10.2Hz,2H),1.93–1.65(m,2H). 13 C NMR (101 MHz, acetic acid-d 4 )δ160.6,159.7,148.6,145.8,135.6,132.3,129.6,127.6,127.5,120.4,113.4,112.8,100.7,97.8,56.5,48.2,46.1,43.0,34.2,33.6. HRMS:C 22 H 23 N 4 O + [M+H] + Calculated value: 359.1866; Measured value: 359.1867.

[0242] Example 32: 7-methoxy-2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (14a')

[0243]

[0244] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.00 equiv) and (Z)-diethyl(5-methoxy-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate (0.329 g, 1.10 mmol, 1.10 equiv) to afford a mixture of 14a and 14a' as a yellow solid (0.342 g, 95%, 55:45 14a:14a'). Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 The isomeric mixture was then purified by SFC (cellulose 3 column, eluent: 25% MeOH-isocratic) to give an analytically pure sample of 14a'. Melting point 202℃-205℃; FTIR (pure, cm-1 )1638,1477,1443,1281,1210,1172,775,753,699; 1 H NMR (400 MHz, DMSO-d 6 )δ8.92(d,J=7.8Hz,1H),7.65(d,J=2.5Hz,1H),7.42(d,J=8.7Hz,1H),7.36–7.12(m,5H),6.98–6.64(m,2H),4.72(s,2 H), 3.82 (s, 3H), 3.08 (t, J = 12.7Hz, 2H), 2.89 (tt, J = 12.2, 3.6Hz, 1H), 2.03–1.80 (m, 2H), 1.63 (qd, J = 12.6, 4.0Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6 )δ157.4,153.7,151.5,145.6,138.2,134.1,128.4,128.0,126.7,126.2,117.7,112.9,109.5,95.8,94.9,55.7,44.9,41.9,32.8. HRMS:C 22 H 23 N 4 O + [M+H] + Calculated value: 359.1866; Measured value: 359.1867.

[0245] Example 33: 9-Bromo-2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (15a)

[0246]

[0247] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.00 equiv) and (Z)-diethyl(4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-ylidene)phosphoramidate (0.383 g, 1.10 mmol, 1.10 equiv) to afford compound 15a (0.407 g, 77%) as a yellow solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 196℃-198℃; FTIR (pure cm -1)1638,1476,1423,1221,765,735,684; 1 H NMR (400MHz, chloroform-d) δ8.16(d,J=7.7Hz,1H),7.52(d,J=7.8Hz,1H),7.43(d,J=7.9Hz,1H),7.34–7.25(m,2H),7.24–7.15(m,3H),7.00(t,J=7.9 Hz,1H),6.44(d,J=7.8Hz,1H),4.74(s,2H),3.18–2.96(m,2H),2.84(tt,J=12.1,3.7Hz,1H),2.04–1.92(m,2H),1.72(qd,J=12.7,4.2Hz,2H). 13 C NMR (101 MHz, chloroform-d) δ 157.9, 152.8, 145.0, 143.4, 132.8, 128.7, 128.1, 127.6, 126.8, 126.6, 120.4, 111.6, 108.0, 96.2, 45.8, 42.8, 33.2. HRMS: C 21 H 20 Bn 4 [M+H] + Calculated value: 407.0866; Measured value: 407.0845.

[0248] Example 34: tert-Butyl 2-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine-9-carboxylate (16a)

[0249]

[0250] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.065 g, 0.250 mmol, 1.00 equiv) and (Z)-tert-butyl 2-((diethoxyphosphoryl)imino)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.102 g, 0.275 mmol, 1.10 equiv) to afford compound 16a (0.089 g, 83%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 197℃-199℃; FTIR (pure cm -1 )1683,1633,1459,1222,1132,1006,702; 1H NMR (400MHz, chloroform-d) δ8.37(d,J=7.7Hz,1H),7.95(dd,J=7.8,1.1Hz,1H),7.73(dd,J=7.9,1.1Hz,1H),7.31(ddt,J=7.2,6.5,0.9Hz,2H),7.25–7.14( m,4H),6.52(d,J=7.8Hz,1H),4.78(s,2H),3.10(t,J=13.3Hz,2H),2.85(t t,J=12.2,3.7Hz,1H),2.08–1.93(m,2H),1.81–1.71(m,2H),1.67(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 165.0, 158.2, 153.8, 145.1, 144.1, 132.9, 129.1, 128.7, 127.1, 126.9, 126.7, 121.4, 118.7, 112.5, 96.3, 80.9, 42.9, 33.3, 28.5. HRMS: C 26 H 29 N 4 O 2 [M+H] + Calculated value: 429.2285; Measured value: 429.2286.

[0251] Example 35: 7-(4-phenylpiperidin-1-yl)imidazo[1,2-a]pyrimidine (17a)

[0252]

[0253] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.259 g, 1.00 mmol, 1.00 equiv) and diethyl (1,3-dihydro-2H-imidazol-2-ylidene)phosphoramidate (0.241 g, 1.10 mmol, 1.10 equiv) to afford compound 17a (0.215 g, 77%) as an off-white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 190℃-193℃; FTIR (pure cm -1 )1643,1542,1515,1477,1219,1008; 1H NMR (400MHz, chloroform-d) δ8.02(d,J=7.7Hz,1H),7.37(d,J=1.6Hz,1H),7.34–7.24(m,2H),7.20(ddd,J=7.8,5.9,1.7Hz,3H),7.13(d,J=1.6Hz,1H ), 4.64 (d, J = 13.4Hz, 1H), 3.03 (td, J = 13.3, 2.6Hz, 2H), 2.80 (tt, J = 12.2, 3.7Hz, 1H), 1.95 (d, J = 12.8Hz, 2H), 1.72 (qd, J = 12.7, 4.1Hz, 2H). 13 C NMR (101 MHz, chloroform-d) δ 156.2, 149.9, 145.4, 133.7, 132.5, 128.6, 126.8, 126.5, 108.8, 97.5, 45.8, 43.0, 33.1. HRMS: C 17 H 19 N 4 [M+H] + Calculated value: 279.1604; Measured value: 279.1599.

[0254] Example 36: Ethyl 7-(4-phenylpiperidin-1-yl)imidazo[1,2-a]pyrimidine-2-carboxylate (18a)

[0255]

[0256] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-2-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.130 g, 0.500 mmol, 1.00 equiv) and (Z)-ethyl 2-((diethoxyphosphoryl)imino)-2,3-dihydro-1H-imidazole-4-carboxylate (0.160 g, 0.550 mmol, 1.10 equiv) to afford compound 18a (0.152 g, 87%) as a white solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 205℃-207℃; FTIR (pure cm -1 )1715,1650,1519,1492,1208,1183,1120,752; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.02 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.35–7.25 (m, 3H), 7.25–7.15 (m, 3H), 6.55 (d, J = 7.8 Hz, 1H), 4.66 (d, J = 13.1 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.07 (td, J = 13.2, 2.5 Hz, 2H), 2.83 (tt, J = 12.2, 3.7 Hz, 1H), 2.02–1.90 (m, 2H), 1.73 (dtd, J = 13.4, 12.4, 4.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, chloroform-d) δ 163.8, 156.6, 149.5, 145.3, 135.9, 133.8, 128.7, 126.9, 126.7, 114.0, 99.4, 60.9, 45.9, 43.0, 33.1, 14.5. HRMS: C 20 H 23 N 4 O 2 [M+H] + Calculated value: 351.1816; Measured value: 351.1815.

[0257] Examples 37–42 demonstrate the synthesis of various benzo[4,5]imidazo[1,2-a]pyrimidin-4-amines.

[0258] Example 37: General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine

[0259] To a dram vial containing a stir bar was added acrylamide (0.50 mmol, 1.0 equiv) followed by 2-methyltetrahydrofuran (1.0 mL, 1.0 mL / mmol) and acetonitrile (1.0 mL, 1.0 mL / mmol). The reaction was then cooled to 0 °C and a portion of phosphoryl chloride (56 μL, 0.60 mmol, 1.2 equiv) was added. The reaction mixture was then heated to 80 °C for 15 minutes and then cooled to room temperature. At this point, the lid was removed from the dram vial and 1-diethoxyphosphorylbenzimidazol-2-amine (0.404 g, 1.5 mmol, 3.0 equiv) was added to the reaction mixture. The lid was then placed and the reaction was then placed in a 50 °C heating block and allowed to react for 3 hours. After 3 hours, the reaction mixture was allowed to cool to room temperature and then treated with Et 3 N (1.0 mL). The mixture was then dry loaded onto silica gel and purified by automated silica gel column chromatography.

[0260] Example 38: 4-(4-phenylpiperidin-1-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (6b)

[0261]

[0262] The general procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine was carried out with (E)-3-ethoxy-1-(4-phenylpiperidin-1-yl)prop-2-en-1-one (0.130 g, 0.500 mmol, 1.00 equiv) to afford compound 6b (0.146 g, 89%) as a light yellow solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 203℃-204℃; FTIR (pure cm -1 )1584,1505,1429,1177,761,740,703; 1 H NMR (400MHz, chloroform-d) δ8.64(d,J=4.8Hz,1H),8.16(d,J=8.3Hz,1H),8.00(d,J=8.2Hz,1H),7.56(t,J=7.7Hz,1H),7.45–7.24(m,6 H), 6.42 (d, J = 4.8Hz, 1H), 3.76 (d, J = 11.8Hz, 2H), 2.88 (dtd, J = 28.1, 11.0, 10.6, 5.0Hz, 3H), 2.18 (td, J = 10.3, 9.5, 3.6Hz, 4H). 13 C NMR (101 MHz, chloroform-d) δ 157.3, 155.9, 144.7, 144.6, 128.9, 127.1, 127.0, 126.8, 126.0, 121.2, 120.1, 115.2, 110.1, 95.0, 50.9, 42.0, 32.6. HRMS: C 21 H 21 N 4 [M+H] + Calculated value: 329.1761; Measured value: 329.1762.

[0263] Example 39: N-Methyl-N-phenylbenzo[4,5]imidazo[1,2-a]pyrimidin-4-amine (7b)

[0264]

[0265] General procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine was carried out with (E)-3-ethoxy-N-methyl-N-phenylacrylamide (0.103 g, 0.500 mmol, 1.00 equiv) to afford compound 7b (0.122 g, 89%) as a yellow solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point: 165℃-175℃; FTIR (pure cm -1 )1589,1470,1443,1368,755,723,690; 1 H NMR (400MHz, chloroform-d) δ8.70(d,J=4.7Hz,1H),7.96(d,J=8.7Hz,1H),7.69(d,J=8.5Hz,1H),7.47(t,J=7.7Hz,1H),7.28(t,J= 7.3Hz, 2H), 7.16 (t, J = 7.8Hz, 1H), 7.06 (t, J = 7.4Hz, 1H), 6.92 (d, J = 8.9Hz, 2H), 6.60 (dd, J = 4.7, 1.1Hz, 1H), 3.50 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 155.7, 153.3, 145.3, 144.6, 129.9, 127.3, 126.4, 126.2, 123.8, 121.5, 119.9, 118.7, 115.7, 100.7, 40.0. HRMS: C 17 H 15 N 4 [M+H] + Calculated value: 275.1291; Measured value: 275.1288.

[0266] Example 40: N-(4-methoxyphenyl)-N-methylbenzo[4,5]imidazo[1,2-a]pyrimidin-4-amine (8b)

[0267]

[0268] The general procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine was carried out with (E)-3-ethoxy-N-(4-methoxyphenyl)-N-methylacrylamide (0.118 g, 0.500 mmol, 1.00 equiv) to afford compound 8b (0.128 g, 84%) as a yellow-green solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2Solution. Melting point 176℃-177℃; FTIR (pure cm -1 )1593,1494,1445,1371,1238,1030,827,726,533; 1 H NMR (400MHz, chloroform-d) δ8.65(d,J=4.9Hz,1H),7.94(d,J=8.2Hz,1H),7.74(d,J=8.4Hz,1H),7.51–7.42(m,1H),7. 20–7.11(m,1H),6.90(d,J=8.7Hz,1H),6.81(d,J=8.9Hz,2H),6.50(d,J=4.8Hz,1H),3.74(s,2H),3.47(s,2H). 13 C NMR (101 MHz, chloroform-d) δ 156.7, 155.5, 154.0, 153.2, 144.6, 138.7, 126.5, 126.0, 121.5, 121.2, 119.8, 115.9, 115.2, 99.3, 55.6, 40.9. HRMS: C 18 H 17 N 4 O[M+H] + Calculated value: 305.1397; Measured value: 305.1395.

[0269] Example 41: N-(4-chlorophenyl)-N-methylbenzo[4,5]imidazo[1,2-a]pyrimidin-4-amine (10b)

[0270]

[0271] The general procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine was carried out with (E)-N-(4-chlorophenyl)-3-ethoxy-N-methylacrylamide (0.120 g, 0.500 mmol, 1.00 equiv) to afford compound 10b (0.101 g, 65%) as a yellow-green solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 199℃-202℃; FTIR (pure cm -1 )1594,1487,1444,1372,1117,813,738; 1H NMR (400MHz, chloroform-d) δ8.70(d,J=4.7Hz,1H),7.97(d,J=8.3Hz,1H),7.67(d,J=8.4Hz,1H),7.50( t,J=7.7Hz,1H),7.27–7.15(m,3H),6.84(d,J=8.6Hz,2H),6.60(d,J=4.6Hz,1H),3.48(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 155.7, 152.9, 152.8, 144.7, 144.0, 129.9, 129.0, 126.3, 126.2, 121.8, 120.2, 119.6, 115.5, 101.0, 39.9. HRMS: C 17 H 14 C1N 4 [M+H] + Calculated value: 309.0902; Measured value: 309.0888.

[0272] Example 42: N,N-dibenzylbenzo[4,5]imidazo[1,2-a]pyrimidin-4-amine (12b)

[0273]

[0274] The general procedure for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4-amine was carried out with (E)-N,N-dibenzyl-3-ethoxyacrylamide (0.148 g, 0.500 mmol, 1.00 equiv) to afford compound 12b (0.146 g, 80%) as a yellow solid. Elution gradient: 0%-10% CH 3 OH CH 2 Cl 2 Solution. Melting point 240℃-244℃; FTIR (pure cm -1 )1645,1610,1477,1192,1023,947,749; 1 H NMR (400MHz, chloroform-d) δ8.54(d,J=4.8Hz,1H),8.25(d,J=8.3Hz,1H),8.06(d,J=8.2Hz,1H),7.61(t,J=7.7Hz,1H),7.4 5(t,J=7.8Hz,1H),7.40–7.30(m,6H),7.09(dd,J=6.5,2.8Hz,4H),6.11(d,J=4.8Hz,1H),4.45(s,2H),4.31(s,2H). 13C NMR (101 MHz, chloroform-d) δ 155.2, 154.5, 153.5, 144.9, 134.5, 129.2, 128.9, 128.5, 127.2, 126.2, 121.6, 120.3, 115.6, 98.8, 53.9. HRMS: C 24 H 21 N 4 [M+H] + Calculated value: 365.1761; Measured value: 365.1761.

[0275] Example 43: Calculation

[0276] All calculations were performed using Gaussian 09 (Rev. E. 01; available from Gaussian, Inc., Wallingford, CT). The terminology used in this example may be further understood by reference to the documentation and user manual distributed with Gaussian 09.

[0277] Density functional theory (DFT) calculations of the charge density of nitrogen atoms in phosphoramidates 2a and 2b and 2-aminobenzimidazole 1 (theoretical level: M062X / Def2TZVP, SMD (acetonitrile)) showed that the charge density and charge amount on the relevant nitrogen atoms are similar ( Figure 6 ), indicating that the selectivity in the reaction described here is not solely controlled by electronic factors. This suggests that the reaction proceeds via a 1,4-addition mechanism, as this would allow for a less sterically hindered transition state during the initial CN bond formation event between 2a and 19.

[0278] To ensure the determination of the lowest energy structure, conformers and tautomers were exhaustively investigated. All geometry optimizations were performed using the B3LYP functional and the Grimme dispersion correction D3BJ of 6-311G(d,p). Frequency calculations were performed at the same level of theory to obtain thermal correction at 298K. All minima were confirmed by having zero negative frequencies. Single point energy calculations were performed with Def2-TZVP at the M062X level of theory. Implicit solvation was performed using SMD=acetonitrile. Partial charges were calculated using the keyword pop=nbo. All final Gibbs free energies correspond to the standard state at 1 atm.

[0279] exist Figure 6 In Figure 1, only the lowest energy structures of 1, 2a, and 2b are shown. They are calculated to be much lower in energy (>2.0 kcal / mol) than their tautomers and have almost identical partial charges.

[0280] Examples 44-47 provide crystallographic data for a variety of molecules described elsewhere herein.

[0281] Example 44: X-ray analysis of 2a

[0282] The X-ray quality crystal was used as received. The resulting crystal parameters are listed in Table 2. A colorless block of dimensions 0.260 x 0.190 x 0.120 mm was mounted on a Cryoloop with Paratone oil. Data were collected using φ and ω scans at 90(2)K in a nitrogen flow. The crystal to detector distance was 40 mm and a scan width of 0.5° was used with an exposure time of 0.05 seconds per frame. The data collection was 100.0% complete from 67.000° to 100.0%. A total of 28,327 reflections were collected covering the indices, -12 <= h <= 12, -17 <= k <= 17, -11 <= l <= 11. 2,654 reflections were found to be symmetry independent, R int is 0.0402. Index and unit cell refinement indicate a primitive monoclinic lattice. The space group was found to be P21 / c (number 14). The data were integrated and scaled using CrysAlisPro 1.171.40.14e. A complete heavy atom phased model was generated by solution using an iterative method (SHELXT-2014). Anisotropic refinements were performed on all non-hydrogen atoms using full-matrix least squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions were constrained relative to their parent atoms using the appropriate HFIX commands in SHELXL-2018.

[0283] Table 2

[0284] Crystallographic data and structure refinement of 2a

[0285]

[0286]

[0287] Example 45: X-ray analysis of 2b

[0288] The X-ray quality crystal was used as received. The resulting crystal parameters are listed in Table 3. A colorless prism of size 0.120x0.100x0.060 mm was mounted on a Cryoloop with Paratone oil. Data were collected using φ and ω scans at 90(2)K in a nitrogen flow. The crystal to detector distance was 40 mm and a scan width of 0.5° was used with an exposure time of 0.05 seconds per frame. The data collection was 100.0% complete from 67.000° to 100.0%. A total of 26838 reflections were collected covering the indices, -11<=h<=11, -13<=k<=12, -16<=l<=15. 2482 reflections were found to be independent of symmetry, R intis 0.0309. Index and unit cell refinement indicate the original monoclinic lattice. The space group was found to be P 21 / n (number 14). The data were integrated and scaled using CrysAlisPro 1.171.40.42a. A complete heavy atom phased model was generated by solution using an iterative method (SHELXT-2014). Anisotropic refinement was performed on all non-hydrogen atoms by full matrix least squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions were constrained relative to their parent atoms using the appropriate HFIX command in SHELXL-2018.

[0289] Table 3

[0290] Crystallographic data and structure refinement of 2b

[0291]

[0292]

[0293] Example 46: X-ray analysis of 6a

[0294] X-ray quality crystals were used as received. The crystal parameters obtained are listed in Table 4. A colorless blade with dimensions of 0.060 x 0.040 x 0.020 mm was mounted on a Cryoloop with Paratone oil. The crystals were used at 90(2) K in a nitrogen stream. Data were collected from θ and ω scans. The crystal to detector distance was 40 mm and a scan width of 0.5° was used with an exposure time of 0.05 seconds per frame. Theta was 67.000° and data collection was 100.0% complete. A total of 3584 reflections were collected covering the indices, -7 <= h <= 7, -9 <= k <= 9, and -20 <= l <= 20. 3584 reflections were found to be independent of symmetry, R int is 0.0398. Index and unit cell refinement indicate a primitive triclinic lattice. The space group was found to be P-1 (number 2). The data were integrated and scaled using CrysAlisPro 1.171.40.57a. A complete heavy atom phased model was generated by solution using an iterative method (SHELXT-2014). Anisotropic refinements were performed on all non-hydrogen atoms using full-matrix least squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions were constrained relative to their parent atoms using the appropriate HFIX commands in SHELXL-2018.

[0295] Table 4

[0296] Crystallographic data and structure refinement of 6a

[0297]

[0298]

[0299] Example 47: X-ray analysis of 6b

[0300] The X-ray quality crystal was used as received. The resulting crystal parameters are listed in Table 5. A yellow prism of size 0.120 x 0.100 x 0.100 mm was mounted on a Cryoloop with Paratone oil. Data were collected at 90(2)K in a nitrogen flow using φ and ω scans. The crystal to detector distance was 40 mm and a scan width of 0.5° was used with an exposure time of 0.05 seconds per frame. Data collection was 100.0% complete from θ. to 67.000°. A total of 17501 reflections were collected covering the indices, -9<=h<=9, -12<=k<=12, -14<=l<=14. 3203 reflections were found to be symmetry independent, R int is 0.0239. Index and unit cell refinement indicate a primitive triclinic lattice. The space group was found to be P-1 (number 2). The data were integrated and scaled using CrysAlisPro 1.171.40.57a. A complete heavy atom phased model was generated by solution using an iterative method (SHELXT-2014). Anisotropic refinements were performed on all non-hydrogen atoms using full-matrix least squares (SHELXL-2018). All hydrogen atoms were placed using the riding model. Their positions were constrained relative to their parent atoms using the appropriate HFIX commands in SHELXL-2018.

[0301] Table 5

[0302] Crystallographic data and structure refinement of 6b

[0303]

[0304]

[0305] All references cited herein are incorporated by reference in their entirety.

[0306] The foregoing description is intended to illustrate various aspects of the present technology. The examples provided herein are not intended to limit the scope of the appended claims. The present invention is now fully described, and it will be apparent to those of ordinary skill in the art that many changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A method for synthesizing an amino-imidazo-pyrimidine compound of formula (XXa), the method comprising: Coupling a first compound of formula XX-P1a with a second compound of formula XX-P2 in: R1 and R2 are each independently selected from alkyl, alkenyl, alkynyl, aryl or heteroaryl, wherein the above groups are optionally substituted at one or more of their available positions independently with a group selected from the following: hydroxy, amino, alkoxy, aminoalkyl, thio, halo, aryl and heteroaryl, or R1 and R2 together form a cycloalkyl ring having 3-12 atoms, wherein the cycloalkyl ring is optionally and independently substituted at any one or more of its available positions with a group selected from hydroxy, amino, alkoxy, aminoalkyl, thio, halo, aryl and heteroaryl; R3 and R4 are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, aryl and heteroaryl, wherein the above groups may be optionally substituted at one or more of their available positions independently with a group selected from the following: hydroxy, amino, alkoxy, aminoalkyl, thio, halo, aryl and heteroaryl; or R3 and R4 together form a benzene ring; and The coupling was performed in the presence of POCl3, Et3N and a non-aqueous solvent.

2. The method according to claim 1, wherein the compound of formula (XX-P1a) is synthesized by a method comprising the following steps: make Reacts with PCl(O)(OEt)2, N-methylimidazole and MeCN.

3. The method of claim 2, wherein the PCl(O)(OEt)2 is formed by reacting diethyl hydrogen phosphate with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione.

4. The method according to claim 1, wherein the non-aqueous solvent is a mixture of MeCN and MeTHF in a volume ratio of 1:1.

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