NZ624552B2 - Improved modulators of hec1 activity and methods therefor - Google Patents

Improved modulators of hec1 activity and methods therefor Download PDF

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NZ624552B2
NZ624552B2 NZ624552A NZ62455212A NZ624552B2 NZ 624552 B2 NZ624552 B2 NZ 624552B2 NZ 624552 A NZ624552 A NZ 624552A NZ 62455212 A NZ62455212 A NZ 62455212A NZ 624552 B2 NZ624552 B2 NZ 624552B2
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mmol
dimethylphenyl
ethanone
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NZ624552A
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Shih Hsien Chuang
Jiann Jyh Huang
Yu Ling Huang
Johnson Lau
Ying Shuan Eda Lee
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Taivex Therapeutics Corporation
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Priority claimed from PCT/US2012/067132 external-priority patent/WO2013082324A1/en
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Disclosed are thiozole compounds of formula (I), wherein the substituents are as defined in the specification. The compounds Hec1/Nek2 modulators useful as chemotherapeutic agents for neoplastic diseases. Examples of a compound of formula (I) are: (N-(4-(4-(5-(2-methoxyethoxy)pyrazin-2-ylthio)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide N-(4-(2,6-Dimethyl-4-(methylthio)phenyl)thiazol-2-yl)isonicotinamide N-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl)-2-nitroisonicotinamide -2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide N-(4-(2,6-Dimethyl-4-(methylthio)phenyl)thiazol-2-yl)isonicotinamide N-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl)-2-nitroisonicotinamide

Description

IMPROVED MODULATORS OF HECl ACTIVITY AND S THEREFOR This application claims priority to US. Provisional Application with serial number 61/564773, which was filed on 29 er 2011, and is further related to International application WO 15998, both of which are incorporated by reference herein.
Field of the Invention The field of the invention is various compounds, compositions, and s related to modulation of activity of Hecl, ularly as it related to inhibition of tumor cell propagation and growth.
Background
[003] While mechanisms associated with mitotic regulation are conceptually an attractive target in attempts to reduce tumor cell , compounds with high specific activity and selectivity and desirable pharmacological profile have been elusive. For e, the e apparatus can be targeted with spindle toxins (e,g., taxanes, vinca alkaloids, etc.) with relatively high activity, but many spindle toxins are unacceptable for pharmaceutical intervention as such poisons are often non-specific.
To improve city of treatment, components for spindle and kinetochore regulation or mitotic checkpoint control may be selected that have been shown to be functionally associated with cancer. For example, Hecl is a critical component in spindle checkpoint signaling that is highly expressed in cancer and helps assure correct segregation of chromosomes during cell division. Hecl interacts with various other kinetochore components including Nuf2, Spc 24, Spc25, and Zwint-l , as well as with mitotic kinases Nek2 and Aurora B. Overexpression of Hecl is a common feature of a large variety of s and cancer cell lines, and can often serve as a prognostic marker in primary breast cancer and other cancers. Based on the apparent importance of Hecl in tumor cell growth, inhibitory MA (siMA) has been used to reduce Hecl expression and has shown considerable promise, at least in an animal model. However, in vivo delivery of effective amounts of siMA with high specificity to the tumor is often problematic.
More recently, various small molecule inhibitors have been developed that interfere with the Nek2/Hecl interaction. Since Nek2ris a regulatory component of Hecl in mitosis, tion of the Hecl/Nek2 function was ed to result in chromosome this-segregation and cell death. l promising compounds have been reported (see Qiu et al, J. Med. Chem, 2009, 52 (6), pp 1757—1767; Wu et a], Cancer Res. 2008 Oct 15;68(20)28393-9) that had significant cell killing activity and directly targeted the Hecl/Nek2 pathway. These and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is istent or contrary to the ion of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. However, while the observed activity was in at least some cases ing, problems associated with solubility, toxicity, and the need to use vely high concentrations in order to be effective nevertheless remained.
Thus, there remains a pressing need for improved compounds, compositions, and s for Hecl inhibition, particularly as it relates to use of such compounds in the treatment of cancer and other erative diseases.
Summary of The Invention The inventors have discovered certain compounds that are capable of selectively disrupting a Hecl/Nek2 complex and/or to selectively preventing Heel from binding to Nek2.
Consequently, the compounds and compositions presented herein are capable of inducing abnormal mitosis and sis in cancer cells, and of accumulating sub G1 apoptotic cells.
Treatment of cells with plated compounds may also alter expression of a number of cell cycle and apoptotic tors. For example, especially contemplated compounds can induce caspase 3 and PARP cleavage, down- regulation of anti-apoptotic tors (including Mcl-l and XLAP), and induction of cyclin B1 and cyclin D1 degradation. All the above—mentioned cell- cycle and apoptotic regulators are key players in normal cell growth. ore, contemplated compounds can be used to te Hecl/NekZ function and may be used for anticancer therapy, to inhibit cancer cell proliferation, and/or induce cell death.
In one embodiment of the inventive concept, the inventive subject matter is drawn to - various compounds, compositions, and methods for Hecl inhibition. More particularly, contemplated compounds may include those according to Formula I RWRZ1 I 0 R3 I \>——NH R4 S Formula I . PCT/U82012/067132 where R1, R2, R3, R4, and R5 are described as further below. In some embodiments of the ive concept compounds can have a structure according to Formulae II and/or 111 (with respective radicals described in more detail below).
Formula II Formula III In still other embodiments of the inventive t, contemplated compounds can have a structure according to ae IV, V, and/or VI.
N S MeOwOIN/I Q/i“ OWI \>.,— Formula IV S FormulaV N\ S i I O ,— N \ /N M60 N \ \ NH Formula VI In some embodiments of the inventive concept, R1, R2, and R3 may be, independently, en, alkyl, alkenyl, alkynyl, alkoxy, aryl, halogen, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, 0R3, SR3, NRaRb, Ra, —S(O)2NRaRb, — , —C(O)NRaRb, —NRaC(O)Rb, —NRaS(O)2Rb, —N=CRaRb, and/0r —NRaC(O)NHRb; where RE, and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aryloxy, alkoxy, hydroxy, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, or R3 and Rb, together with a nitrogen atom to which they are bonded, are heteroaryl, cycloalkyl, or heterocycloalkenyl. In other embodiments of the inventive subject matter, R2, R3, and R4 may independently be hydrogen C1—C6 alkyl, halogen, or ORa. In still other embodiments of the inventive concept, R5 may be alkyl, phenylalkyl, arylalkyl, phenyalkenyl, arylalkenyl, phenyl, heteroaryl, cycloalkyl, or heterocycloalkenyl. Such aryl, heteroaryl, and/or pyridinyl groups may be substituted aryl, heteroaryl, and nyl groups, respectively. Each of R1, R2, R3, R4, R5, Ra, and Rb may be independently optionally substituted; in addition, n may be 0 or 1.
‘ In other embodiments of the inventive concept, X1 and X2 may be, independently, H, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, cycloalkyl, heterocycloalkyl, lkenyl, heterocycloalkenyl, ORa, NRaRb, —S(O)2Ra, —S(O)2NRaRb, —C(O)Ra, —C(O)NRaRb, O)Rb, —NRaS(O)2Rb, ~N=CRaRb,—NR3C(O)NHRb, or —A1(CH2)mA2(CH2)pA3(CH2)qA4Rc where n, m, p, and or q are, independently, 4 or less. In such embodiments A1, A2, A3, and A4 may be independently selected from null, CH2, CHRa, CRaRb, O, NH, NRa, S, SO, and 802. Similarly, RC may be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, n, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, 0R3, SRa, NRaRb, —S(O)2Ra, —S(O)2NRaRb, — C(O)Ra, —C(O)NRaRb, ~NRaC(O)Rb, —NRaS(O)2Rb, —N=CRaRb, or —NRaC(O)NHRb. In still other aspects of the inventive subject matter, Y may be CH2, CHRg, VCRaRb, O, NH, S, SO, or 802. Each of X1 and X2 may be independently optionally tuted.
[0012] In some ments of the inventive subject matter, where R1 and R2 are methyl and where R3 is en, R5 may not be thiazolyl, N—methylimidazolyl, pyrazinyl, pyridinyl, morpholinyl, phenyl, or dimethoxyphenyl. In other embodiments of the inventive subject , where R1, R2, and R3 are methyl, R5 may not be thiazolyl, N-methylimidazolyl, pyrazinyl, pyridinyl, morpholinyl, phenyl, methoxyphenyl, dihydroxyphenyl, hydroxymethoxyphenyl, trifluoromethylphenyl, or dimethoxyphenyl. In still other embodiments of the inventive concept, where R1 and R2 are methyl and where R3 is hydroxyl or methoxy, R5 may not be phenyl.
In other embodiments of the inventive concept, a thiazole ring may be substituted by a compound from the group 3“: ,N Er: ,N ,N "I? f N \ M—s 1H W: *Hfm,N “m £02, EVE/TE it? We fled5U“ In still other embodiments of the inventive concept, may be one or more of: H H N H N\ /> /©/\/N g[IN 2/ / 1&2, 7771 N NA N \ E\> It A, S where Rc and/or Rd may be Ra.
Compounds of the inventive concept may be in combination with an ion to form a salt, or as a free base. rly, compounds of the inventive concept may include metabolites of the nds described above, for example, where R1 is SRa and wherein the S is the form of a sulfone or sulphoxide.
[0016] In some aspects of the inventive subject matter, contemplated compounds are inhibitors of Hecl , and/0r may be characterized as ting Hecl/Nek2 interaction.
Consequently, the compounds presented herein may be particularly suitable for use as therapeutic agents that disrupt the mitotic y. Another embodiment of the inventive concept is a pharmaceutical composition that includes a compound of the inventive t and a pharmaceutically acceptable carrier. Such a compound may be formulated for oral administration, injection, and/or topical application. Such a pharmaceutical composition may n a compound of the inventive concept in a tration effective at modifying and/or disrupting ekl interactions in a patient when the pharmaceutical composition is administered to the patient, Such a pharmaceutical composition may, optionally, include a drug that interferes with microtubule formation and/or degradation.
Thus, in r aspect of the inventive t matter, a method of disrupting ec1 interaction is Contemplated that may include a step of contacting a Nek2/Hecl complex with one or more compounds presented herein in an amount that is effective to disrupt Nek2/Hec1 binding. While all manners of ting are lly contemplated, in such an embodiment the Hecl/Nek2 complex may be formed in vivo in a mammal, and a nd of the inventive concept may be administered orally, topically, or parenterally. Optionally, a method of the inventive concept may e co-administration of a drug that interferes with microtubule formation and/or degradation.
Another embodiment of the inventive concept is a method for treating neoplastic disease in a mammal, including the step of administering a compound of the ive COncept in an amount effective to disrupt Hecl/Nec2 binding and/or disrupt a Hecl/Nek2 complex. In such an embodiment a compound of the inventive concept may be administered orally, topically, or parenterally. Optionally, a method of the inventive concept may include co-administration of an antineoplastic drug.
Yet another embodiment of the inventive subject matter is a method for altering and/or improving a pharmacokinetic parameter of a compound of the inventive concept that includes the step of forming a tosylate salt of the compound. Such compounds may be selected from: ff 0 “’“N MeO / N W M O iNTO/ “>4?“\ / S ,and i IN\ o ,, N wk] MeO N \ \>”NH Similarly, another embodiment of the ive subject matter is a ceutical composition that es a earlier and a tosylate salt of a compound of the inventive concept.‘ Various objects, features, aspects and ages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawings and figures in which like numerals represent like components.
Brief Description of the Figures Figure 1 shows results of precipitation studies demonstrating disruption of Hecl -Nek2 interaction using an exemplary compound according to the inventive subject matter.
Figure 2 shows results of immunoblot analyses demonstrating reduction of Nek2 protein in cancer cells treated with exemplary compounds according to the inventive subject mater.
Figure 3 shows results of fluorescent microscopy studies demonstrating somal misalignment in cancer cells treated with exemplary compounds according to the inventive subject matter for various time s.
Figure 4 shows results of fluorescence activated cell g (FACS) studies trating the induction of apoptosis in cancer cells by cell cycle analysis after treatment with exemplary compounds according to the inventive subject matter.
[0025] Figure 5 shows induction of apoptosis in cancer cells by immunoblotting of apoptotic pathway proteins after treatment with exemplary compounds according to the inventive subject matter.
Figure 6 shows results of immunblotting studies demonstrating cyclin B1 and cyclin D1 ation in cancer cells after treatment with an exemplary compound according to the inventive subject matter.
Figure 7 shows results of tumor outgrowth studies. Figure 7A and Figure 7B show the effects of select compounds on MDA-MB-23l breast cancer xenografts. Figure 7C shows the effects of select compound on BT474 breast cancer xenografts. Figure 7D shows the effects of select compound on Huh7 liver cancer xenografts. Figure 7E shows the effects of re— treatment of usly treated, late stage MDA—MB-231 xenografts with select compound. In all instances tumor growth is inhibited.
[0028] Figure 8 shows results of permeability s of cells d with exemplary compounds according to the inventive t matter, demonstrating moderate Caco-2 permeability in both directions with no indication of icant active efflux.
Figure 9 shows results of binding studies, demonstrating hERG binding of exemplary compounds with IC50 of > 10—100 HM.
Detailed Description Contemplated nds The inventors have discovered that certain compounds according to Formula I can be prepared and have advantageous properties as moieties that interfere with Hecl. Particularly preferred compounds will include those according to Formula] R3 | >—NH R4 Formula I In some embodiments of the inventive concept, R1 may be hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, halogen, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, ORa, SRa, NRaRb, —S(O)2Ra, —S(O)2NRaRb, —C(O)Ra, —C(O)NRaRb, — )Rb, —NRaS(O)2Rb, —N=CRaRb, or —NRaC(O)NHRb; Ra1 and Rb are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, y, , hydroxy, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl, or Ra and Rb, together with a nitrogen atom to which they are bonded, are heteroaryl, heterocycloalkyl, or heterocycloalkenyl; R2, R3, and R4 are ndently hydrogen, C1—C6 alkyl, halogen, or ORa; and R5 is alkyl, phenylalkyl, heteroarylalkyl, phenyalkenyl, heteroarylalkenyl, phenyl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl; wherein each of R1, R2, R3, R4, R5, Ra, and Rb are independently optionally substituted. In other embodiments of the inventive concept compounds include those where (I) R1 and R2 are methyl and where R3 is hydrogen, R5 is not thiazolyl, N-methylimidazolyl, nyl, pyridinyl, morpholinyl, phenyl, or dimethoxyphenyl, (11) where R], R2, and R3 are methyl, R5 is not thiazoly], ylimidazolyl, pyrazinyl, pyridinyl, morpholinyl, phenyl, methoxyphenyl, dihydroxyphenyl, ymethoxyphenyl, tlifluoromethylphenyl, or dimethoxyphenyl, and/or (111) where R1 and R2 are methyl and where R3 is hydroxyl or y, R5 is not phenyl.
In some embodiments of the ive concept R1 may be alkoxy, SR3, ORa, or, — S(O)2Ra, such that R3 is alkyl or optionally substituted aryl, that R2, R3, and R4 are independently hydrogen or C1—C5 alkyl, and that R5 is optionally substituted heteroaryl. Other compounds of the inventive concept are among those where R1 is alkoxy, SRa, ORa, or, —S(O)2Ra, where R21 is alkyl or an ally substituted aryl, where R2 and R3 are C1—C6 alkyl, and where R5 is optionally substituted (e. g., halogenated) pyridinlen some embodiments of the inventive t matter, R1 can be ORa, wherein Ra is optionally substituted aryl, R2 and R? are C1—C6 alkyl, and R5 is an optionally substituted pyridinyl,
[0033] Consequently, and viewed from a ent perspective, compounds of the inventive concept may have a structure according to Formula 11 \ Y R1 9/ 0 x2 N )n R2 | \>—NH R3 S FormulaII in which wherein X1 and X2 can be independently H, alkyl, alkenyl, l, halogen, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkenyl, ORa, NRaRb, —S(O)2Ra, — S(O)2NRaRb, —C(O)Ra, —C(O)NRaR or — , —NRaC(O)Rb, —NRaS(O)2Rb, —N=CRaRb, NRaC(O)NHRb; alternatively, X1 and X2 may be independently — A1(CH2)mA2(CH2)pA3(CH2)qA4Rc; where A1, A2, A3, and A4 are independently selected from null, CH2, CHRa, CRaRb, O, NH, NR3, S, SO, and 802; where Rc is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, halogen, nitro, cyano, cycloalkyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, ORa, SRa, NRaRb, —S(O)2Ra, —S(O)2NRaRb, —C(O)Ra, —C(O)NRaRb, — NRaC(O)Rb, —NRaS(O)2Rb, —N=CRaRb, or O)NHRb; and where m, p and q are independently 0, 1, 2, 3, or 4-, Y is CH2, CHRa, CRaRb, 0, NH, NR,, 3, so, or 502; 111,112, and R3 are independently H, alkyl, alkoxy, or halogen; n is 0, l, or 2; and in which A is an optionally substituted aryl or an optionally substituted heteroaryl. Embodiments of the inventive concept may include a compound as shown below Ra Rb G: weQ RC N P“ P "1\ / / / 1% 11:, /Rb 71:, Ii 1% L/N / / 7??“ 772. 191 / N ,, “‘2 ’ a, ’2 N NA N wherein each of X1 and X2 is independently optionally substituted, and wherein RC and Rd are independently Ra. Among such compounds, it is further contemplated that Y may be 0, S, or 802, and/or that A may be an optionally substituted pyridinyl. Most typically, X1 and X2 in such compounds will be ndently H, alkyl, and , and n is 0 or 1. With respect to remaining radicals, the same considerations as provided for Formula I apply.
Still r compound of the inventive subject matter may have a ure according to Formula 111 X' Y R1 A x2 N )n R2 | >—NH R3 8 Formula III in which wherein X1 and X2 may be independently H, alkyl, alkenyl, alkynyl, n, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkenyl, cycloalkenyl, ORa, NRaRb, —S(O)2Ra, — S(O)2NRaRb, —C(O)Ra, RaRb, —NRaC(O)Rb, —NRaS(O)2Rb, —N=CRaRb, or — NRaC(O)NHRb. Alternatively, X1 and X2 may be independently — A1(CH2)mA2(CH2)pA3(CH2)qA4RC; where A‘, A2, A3, and A4 are independently selected from null, CH2, CHRa, CRaRb, O, NH, NR3, S, SO, and 802; where Rc is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, halogen, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, 0R3, SRa, NRaRb, —S(O)2Ra, —S(O)2NRaRb, —C(O)Ra, —C(O)NRaRb, -— NRaC(O)Rb, —NRaS(O)2Rb, —N=CRaRb, or —NRaC(O)NHRb; and where m, p and q are 0, , l, 2, 3, or 4;Y is CH2, CHRa, CRaRb, 0, NH, NR3, s, so, or 302; R1, R2, and R3 are independently H, alkyl, alkoxy, or n; n is O, 1, or 2; wherein each of X1 and X2 is independently optionally substituted; wherein Rc and Rd is independently Ra, and in which A and Het are independently an aromatic and optionally substituted aryl or heteroaryl. Among other suitable s, a compound of the inventive subject matter have a structure as described above, wherein REARb G): |\\/“—R° RC N J 1‘“ i‘ “D 771‘ \’// / / 7111 Rb ‘ZLL' 31/ , A) N / l i ’1 )0/” / a / a ‘a N H H ’3 / a a N N4\ N and wherein a/V' With respect to remaining radicals, the same considerations as noted for Formula I apply. Suitable compounds of the inventive concept according to Formula II may include those in which A is an optionally substituted pyridinyl, and/or n Y is O, S, or 802.
[0036] In view of the above and r experimental data (see below), compounds of the inventive concept may have a structure as shown below 3 CI o 0 _, N\ o ., N U N N \ / / N \ / M60 N \ \>’-—NH l \>-’NH s S , , N o 0 O __,- \ O ——’ | Y N N] N /N N \ I / N \ / \ \>’-’NH MeO \>’NH s S , , N s 0 \ o «— o , x N \ /N M oe N \ /N l \ NH \/\0 \>/NH s S , , N\\/O O \ o \ O I I r5\N I F;\N / / N\ \ / MeO / \ / MeO N \ NH \/\0 N \ N\>,NH S ' S , , s s Meowoi:IKit:0M3” WWI“; figng/QN\ s , x8 ,and Mao/[:j/3%Nyalil/QN\ o e“ In yet another apect of the inventive subject matter includes compounds as shown immediately below, their metabolites, prodrugs, and/or salts thereof.
N\ O O "’ N iNj/S O I MeO\/\ /[ I N \ / I MeO\/\ / N \ IN In still r s of the inventive concept, it should be appreciated that the central thiazole ring of the compounds having Formula I—III may be replaced with a number of cyclic and/or aromatic ring systems as is shown for Formula I*—D1* below Formula 1* Formula II* Forimtla 111* in which B is defined as shown below (with respect to remaining radicals, the same considerations as noted for Formula I-III above apply) :1 ,N :1 ,N \ f f \M ,N = g 3:; g 5M; W; 19%; Mfg fUNIN/f‘“UWTUtU‘r‘U‘i i:r‘ iU“ *‘U‘t tU‘ iUt The term "alkyl" as used herein refers to a arbon radical, which may be straight, cyclic, or branched. The term "alkeny ", refers to an alkyl having at least one double bond. Where more than one double bond is present, it is contemplated that the double bonds may be conjugated or un-conjugated. The term "alkynyl", as used herein refers to an alkyl having at least one triple bond. plated alkynyls may further include another triple bond or double bond, which may or may not be conjugated with the first triple bond. The term "alkoxy", as used herein, refers to an l group, n the "alkyl" is d as provided above.
A "cycloalkyl" as used herein refers to a non-aromatic monovalent monocyclic or polycyclic radical having from 3 to 14 carbon atoms, each of which may be saturated or unsaturated, and may be un-substituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more aryl groups, heteroaryl groups, cycloalkyl groups, or heterocycloalkyl groups which themselves may be un—substituted or substituted by one or more tuents. Examples of cycloalkyl groups include cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, yl, cyclohexyl, and cyclopentyl.
A "heterocycloalkyl" as used herein refers to a non-aromatic monovalent monocyclic or polycyclic radical having 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and may be unsubstituted or substituted by one or more suitable substituents as defined herein, and to which may be fused one or more aryl groups, heteroaryl groups, cycloalkyl groups, or heterocycloalkyl groups which themselves may be un-substituted or substituted by one or more substituents. Examples of heterocycloalkyl groups include oxiranyl, pyrrolidinyl, piperidyl, ydropyran, and morpholinyl.
An "aryl" (Ar) as used herein refers to an ic monocyclic or polycyclic radical comprising generally between 5 and 18 carbon ring members, which may be un-substituted or substituted by one or more suitable tuents as defined herein, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl , which themselves may be stituted or substituted by one or more suitable substituents. Thus, the term "aryl group" includes a benzyl group (le). Examples include phenyl, biphenyl, l,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, and phenanthryl.
A "heteroaryl" as used herein refers to an aromatic monocyclic or polycyclic radical comprising generally between 4 and 18 ring members, including 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be un-substituted or substituted by one or more suitable tuents as defined below, and to which may be fused one or more lkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Examples include thienyl, l, thiazolyl, lyl, imidazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrrolyl, thiadiazolyl, oxadiazolyl, oxathiadiazolyl, thiatriazolyl, pyrimidiny], isoquinolinyl, quinolinyl, napthyridinyl, phthalimidyl, benzimidazolyl, and benzoxazolyl.
The term "heterocycle" or ocyclic" as used herein refers to aromatic and non- aromatic heterocyclic groups, typically with 4 to 10 atoms forming a ring, and containing one or more heteroatoms (typically 0, S, or N). Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups typically have at least atoms in their ring system. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, ydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,23,6- tetrahydropyridinyl, 2—pyrrolinyl, 3—pyrrolinyl, indolinyl, ZH-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyrany], dihydrothienyl, dihydrofuranyl, pyrazolidinyl, zolinyl, imidazolidinyl, 3-azabicyclo(3.i.0)hexanyl, 3H-indolyl, and quinolizinyl.
Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl,'pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, yl, inyl, isoquinolinyl, indolyl, idazolyl, is benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, zinyl, triaziny1,isoindolyl, pteridinyl, puriny], zolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, quinazolinyl, hiazolyl, benzoxazolyl, quinoxalinyl, naphthyridinyl, and ridinyl. Contemplated 4- membered heterocycles may be ched or N-attached (where appropriate). For instance, a group derived from pyrrole may be pyrrol -i-y1 (N-attached) or pyrrolyl (C—attached).
As still further used herein, the term "substituted" as used herein refers to a replacement or modification of an atom (radical) or chemical group (e. g., NHz, or OH) in a molecule with a onal group to produce a substituted molecule, and particularly contemplated functional groups include philic groups (e. g., -NH2, -OH, —SH, -NC, etc), electrophilic groups (e.g., C(O)OR, C(O)OH, etc.), polar groups (e. g., —OH), lar groups (e. g., aryl, alkyl, alkenyl, alkynyl, etc), ionic groups (e.g., -NH3+), and halogens (e. g., —F, -Cl), and all chemically reasonable ations thereof. For example, where the molecule is an alkyl, the replaced radical is a hydrogen radical, and the functional group is a hydroxyl group, the H-atom is substituted by an OH group to form a substituted alkyl. In another example, where the molecule is an amino acid, the modified group is the amino group, and the functional group is an alkyl group, the amino group is alkylated to form an N-substituted amino acid.
[0047] For e, suitable substituents e halogen (chloro, iodo, bromo, or fluoro); C1_6—al_kyl; C1_5-alkenyl; lkynyl, hydroxyl, C145 alkoxyl; amino; nitro; thiol; thioether; imine', cyano; amido; phosphonato; phosphine; carboxyl; carbonyl; aminocarbonyl; thiocarbonyl; sulfonyl; sulfonamine; sulfonamide; ketone; aldehyde; ester; oxygen (:0); haloalkyl (e. g., trifluoromethyl); carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., ropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused clic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non- fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzirnidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether, r alkyl; 0— aryl, aryl; aryl-lower alkyl; COZCH3; CONHZ; OCHZCONHQ; NHZ; SOZNHz; OCHFZ; CF3; OCF3; etc. It should be appreciated that all substituents contemplated herein may be further optionally substituted by one or more substituents noted above. Suitable substituents include, but are not limited to, hydroxyl groups, halogens, oxo groups, alkyl groups (and especially lower alkyl), acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxyl groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, yl groups, amino groups, alkylamino groups, lamino groups, carbamoyl , aryloxyl groups, aryloxyl groups, io , heteroarylthio groups. er, it should also be appreciated that compounds according to the inventive subject matter may se one or more asymmetric centers, and may therefore exist in different enantiomeric forms, and that all enantiomeric forms of contemplated compounds are specifically contemplated herein. Accordingly, where contemplated compounds exhibit optical ty and/or have stereoisomers, all optical activities and/or isomeric forms are contemplated herein. Similarly, where double bonds distinguish a Z—form from an E-form (or cis- from trans-), both isomers are contemplated. Moreover, it is noted that the compounds according to the inventive subject matter may also be isotopically-labeled. Examples of suitable isotopes include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O 17O, 18F, or 36C1. Certain isotopically—labeled compounds of the inventive subject matter, for example those into which 14C and/or 3H is/are incorporated, may be useful in drug and/or substrate tissue distribution assays. Alternatively, substitution with non-radioactive isotopes (e.g., 2H or 13C) can afford certain therapeutic ages resulting from greater metabolic stability, for example increased in viva ife or reduced dosage requirements and, hence, may be able in some circumstances.
[0049] Contemplated nds may be ed as pharmaceutically acceptable salt(s), which especially include salts of acidic or basic groups that may be present in the plated compounds. For example, where contemplated compounds are basic in nature it should be noted that such compounds can form a wide variety of salts with various inorganic and organic acids.
Suitable acids will provide cologically able anions, including chloride, bromide, '20 iodide, nitrate, sulfate, bisulfate, phosphate, acid ate, isonicotinate, e, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p—toluenesulfonate, and pamoate (l,l’- methylene-bis-(Z—hydroxy-3~naphthoate)) anions. Similarly, where contemplated compounds are acidic in nature it should be noted that such compounds may form base salts with various pharmacologically acceptable cations, and especially suitable cations include alkali metal or ne earth metal ions (e.g., sodium and potassium cations).
In still further contemplated aspects, the compounds presented herein may be prepared as prodrugs, and all known manners and types of prodrugs are considered suitable for use herein, so long as such prodnig will increase the concentration of the drug (or lite of the prodrug) at a target organ, target cell, and/or Hecl. For example, where contemplated compounds have a free amino, amido, hydroxy, thio, or carboxylic group, it is contemplated that such groups can be ed to covalently and releasably bind and/or couple to a moiety that converts the drug into a prodrug. ore, prodrugs particularly include those in which 2012/067132 contemplated compounds form an ester, amide, ide bond, or any cleavable bond with a suitable moiety. Such moieties may assist in organ or cell-specific delivery of the drug, and therefore particularly include receptor ligands and their analogs, antibody or antibody fragments, single chain antibodies, peptides, aptamers, or other high—affinity ligands (Kd < 106M).
For example, a carboxyl group can be derived to form an amide or alkyl ester, which may include an ether, amine-, and/or carboxylic acid group. Free hydroxyl groups may be derived using hemisuccinates, ate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined by D. Fleisher et a] (Advanced Drug Delivery 40 Reviews (1996) 19, p.115). Carbamate prodrugs of hydroxyl and amino groups are also contemplated, as are carbonate prodrugs and sulfate esters of hydroxyl groups. Deriving hydroxyl groups as (acyloxy)methyl and (acyloxy)ethylethers, n the acyl group may be an alkyl ester (optionally substituted), or where the acyl group is an amino acid ester are also contemplated (prodrugs of this type are described in R. P. on et al., J. Medicinal Chemistry (1996) 39:p.10).
[0052] In still further contemplated s, it should be appreciated that the compounds according to the inventive subject matter may also be active as a metabolite (of a prodrug or non- prodrug form) and that all of such metabolites are contemplated herein. For example, suitable metabolites include hydroxylated forms, oxidized forms, glucuronidated forms, sulfated forms, etc. Moreover, it is also noted that the metabolites may be more active than the originally administered form.
Contemplated Compositions and Formulations Based on the activity of the compounds as Heel modulators, the inventors contemplate that the compounds and compositions according to the inventive subject matter may be ed for prophylaxis and/or treatment of various diseases associated with Hecl dysfunction and/or overexpression in a mammal, and in fact for all diseases that positively d to administration of plated compounds. The term "dysfunction of Hecl" as used herein refers to any abnormality in Hecl as it s to its association with Nek2 , especially function and spindle checkpoint signaling. Such abnormalities may be due to one or more of a mutation (e.g., increasing or reducing affinity to a binding partner), temporary or permanent overexpression (e.g., activated by inappropriate or mutated promoter), irreversible or tighter binding of an activator, inappropriate tion by non-physiological molecule, etc. uently, particularly plated diseases include neoplastic es, and especially cancerous neoplastic diseases (e. g., breast cancer, squamous cell cancer, r cancer, gastric cancer, pancreatic cancer, head cancer, neck cancer, oesophageal cancer, te cancer, colorectal cancer, lung cancer, renal , gynecological cancer, or thyroid cancer). Non cancerous neoplastic diseases include benign hyperplasia of the skin (e.g., psoriasis) or te (e.g., benign prostatic hypertrophy (BPH).
Therefore, the inventor also contemplates numerous pharmaceutical compositions that include the compounds presented herein and it is generally contemplated that nds according to the inventive subject matter may be formulated into pharmaceutical compositions that have a therapeutically effective amount of contemplated compounds (or pharmaceutically acceptable salt, hydrate, and/0r prodrug thereof), and a pharmaceutically acceptable carrier.
[0055] Activity, toxicity, and other pharmacological and pharmacodynamic parameters can be ished for the nds presented herein using numerous known protocols. Similarly, cytotoxicity can be established via MTS assay in various cell lines, while disruption of Hecl- Nek2 interaction can be monitored via co—immunoprecipitation or a yeast two-hybrid .
Cell cycle analysis can be performed by monitoring various stage populations (e.g., sub-G1, GO/Gl, S, etc), and metaphase chromosomal misalignment quantitation can be performed using immunofluorescence methods well known in the art. In vivo activity can be established using various animal models, and especially aft models. ary results are provided in the attached tables and data. uently, the inventors contemplate a pharmaceutical ition that es a pharmaceutically acceptable carrier and contemplated compounds herein wherein the compounds are present in a concentration effective to disrupt Hecl/Nek2 binding in a patient when the composition is administered to the patient. The inventors havealso discovered that numerous compounds according to the inventive t matter were ilable upon oral administration and could be detected in serum over prolonged s after oral administration or intravenous (i.v.), administration (see below).
[0056] Contemplated compounds may be formulated with one or more non—toxic pharmaceutically able carriers, preferably formulated for oral administration in solid or liquid form, or for parenteral injection. Thus, it should be appreciated that pharmaceutical compositions according to the inventive subject matter may be administered to humans and other animals using various routes, including orally, optically, rectally, parenterally, eritoneally, vaginally, or topiCally.
For example, suitable pharmaceutical compositions for injection preferably comprise pharmaceutically able sterile aqueous or nonaqueous solutions, dispersions, emulsions, or sions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Examples of suitable s and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, oils, and injectable organic esters (e.g., ethyl oleate). Contemplated compositions may also contain various inactive ingredients, including preservatives, g agents, emulsifying agents, and/or sing agents. Sterility may be ensured by inclusion of antibacterial and/or antifungal agents (e.g., n, phenol sorbic acid, chlorobutanol, etc.). Where appropriate, osmotically active agents may be included (e.g., sugars, sodium de, etc.).
Alternatively, contemplated compositions may be formulated into solid dosage forms for oral stration, and may therefore be capsules, tablets, pills, powders, and granules. In preferred solid dosage forms, contemplated nd are mixed with at least one of a pharmaceutically acceptable ent or r (e.g., sodium citrate or ium phosphate), a filler or extender (e.g., starch, lactose, sucrose, glucose, mannitol, or silicic acid), a binder (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, etc.), a humectant (e.g., glycerol), a disintegrating agent (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, or sodium ate), a solution retarding agent (e.g., paraffin), an absorption accelerator (e. g., quaternary ammonium compound), a wetting agents (e. g., cetyl alcohol and glycerol monostearate), and absorbents (e.g., kaolin, or bentonite clay), and a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate).
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene s and the like. The solid dosage forms of tablets, dragees, capsules, pills, and es can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Contemplated itions may further be formulated to release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Contemplated compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above—mentioned excipients.
[0060] Liquid dosage forms for oral stration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art (e. g., water, or other solvent, lizing ), emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, ene glycol, 1,3-butylene glycol, dimethyl formamide), oils (and in ular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl l, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions may also include nts such as wetting agents, fying and suspending agents, sweetening, flavoring, and perfuming agents.
Compounds according to the inventive subject matter can also be administered in form of mes, which may be ellar, oligolamellar, or polylamellar. Contemplated itions in liposome form may further contain stabilizers, preservatives, excipients, etc.
Preferred lipids for liposome formation include phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art (see, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY. (1976)., p. 33 et seq.).
Actual dosage levels of plated compounds in pharmaceutical compositions according to the inventive subject matter may be varied so as to obtain an amount of contemplated compound(s) that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of stration. Thus, the ed dosage level will depend upon various factors, including the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the d therapeutic effect and. to gradually increase the dosage until the desired effect is achieved. It is contemplated that specific concentration ranges within a patient may have desirable effects not found at concentrations below and above such specific ranges. In some embodiments of the inventive concept, therefore, trations of one or more nds of the inventive concept in a patient-derived sample ' may be monitored in order to maintain the concentration of such a compound or compounds within the desired range. Similarly, it is contemplated that genetic terization of a patient may be utilized to provide guidance as to effectiveness and suitable dosages for nds of the inventive concept. Generally, dosage levels of about 0.01 mg to about 500 mg, more preferably of about 0.5 mg to about 50 mg of contemplated compound per kilogram of body weight per day may be administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e. g., two to four separate doses per day. Therefore, contemplated formulations especially e those suitable for oral administration, parenteral administration, for administration as cream, or as eye-drops or other liquid l formulation.
Surprisingly, Hecl inhibitors were found to exhibit synergistic effect with selected chemotherapeutic inhibitors. Among other chemotherapeutic inhibitors, compounds including Taxol, vincristine, and stine showed synergistic effect. Hecl inhibitors may also be expected to have istic effect with respect to tubulin formation or polymerization inhibitors, as well as pretubulin inhibitors. Thus, suitable chemotherapeutic inhibitors may include one or more drugs that interfere with microtubule formation or degradation. Therefore, any drug that affects cell division and/or any anti—metabolite are deemed useful in ation with the Hecl inhibitors plated .
It should still further be appreciated that contemplated pharmaceutical compositions may also include additional pharmaceutically active compounds, and ally contemplated additional pharmaceutically active nds include antineoplastic agents, which may act on DNA ation, cell cycle, cell metabolism, angiogenesis, or induce apoptosis. Further suitable active agents include immunologically active agents (e. g., anti-inflammatory agents, suppressants, steroids, interferons (alpha, beta, or gamma) and fragments thereof, and those molecules that selectively increase or suppress Th1 and/or Th2 cytokine expression). Still other suitable active agents include antibacten'al and antiviral agents, drugs that stimulate or modify metabolism, neurologically active drugs, and/0r analgesic drugs. Of course, it should be recognized that additional pharmaceutically active compounds may be included in the same ceutical composition, or may be administered separately, and a person of ordinary skill in the art will readily determine schedule and route of suitable co-administration of the additional pharmaceutically active compounds.
Examples
[0065] Exemplary Synthesis of Hecl Inhibitors: plated compounds can be prepared by numerous synthetic routes, and the ing is provided to give exemplary guidance only. While the below scheme can be used to prepare most of the compounds presented herein, other compounds may require minor modifications to the general scheme that will be readily apparent to the skilled n.
Exemplary Route I Ar/Y R1 /U\Cl v Ar/Y R1 R1 CuBrz Ar/Y AICI3 EtOAc Br R2 R2 0 R2 O A B Ar/Y R1 Ar/Y R1 thiourea RCOOH N N >4; EtOH \ R2 S\>,NH2 CD|,Et3N \ R2 S\>’NH 3. 1 ‘2 we . :t The above scheme rates a method for the synthesis of 4—arylaminothiazoles E.
Aromatic compounds of ure A, including substituted benzene, pyridine, or other heterocyclic compound (5 -, 6-, or 7-membered) are reacted with acetyl chloride in the presence of A1C13 to afford acetylated arenes B. Bromination of the acetylated arenes give a-Br-acetylated arenes C, which are allowed to reacted thiourea to generate aminothiazoles D with a aryl substituent at the C—4 position. The aminothiazoles react with different acids give the final 4— -amidothiazoles E. sis of A.
R1 ligand Ar/Y R1 base A? heat Y= OH NH2, Z= FR,CI.Br,I NHR SH Compound A can be prepared by the above two reactants with or without catalyst and/or ligand and/0r base. The catalysts include Pd(PPh3)4, Pd(OAc)2, PdClg, CuI, Cu, CuBr, CuBrg, Cu20, and other transitional metal. Ligands include PPh3, X-Phos, and other phosphine ligands. Bases include Eth, Me3N, DIPEA, K2CO3, Na2C03, DMAP, K3PO4, etc. nd A can also be prepared by reversal of the substitution Y and Z in the substrates as shown in the scheme below. catalyst Y R1 ligand /Y R1 r; .. I; ArZ + —* heat Z = F, Cl, Br, I Y = 0H1NH2, NHR, SH Acetylation of A.
Ar/Y R1 0 Ar/Y R1 \Q )L R2 Lewis acid R2 O A B X = OH, Cl, Br, OAIkyi, OAryi Lewis acid = AICI3, ZnCI3, BiCI3, conc. acid The acetylation of A can be ed by use of different reagents as shown in the above Scheme.
Bromination of B.
Y R1 Y R1 Ar/ bromination agent Ar/ —-———’ R2 0 R2 O B C The bromination agents include Brz, HBr, NBS, TBABI'3, CuBrg, etc. in s solvents, including ether, THF, halogenated hydrocarbons, ester, etc.
Arnidation of Aminothiazoles AKY R'1 Y R1 Ar/ 0 RCOOH N __——» N YR \ NH2 coupling agent \ NH R2 R2 S S D E The coupling agents include CD1, EDC, CDC, etc. 1 Y 1 Ar/Y R R Ar/ o RCOOX . N yR \ \>"NH2 base \ \>”NH ' R2 R2 S S D E X = C1 or Br; base = Et3N, Me3N, DIPEA, K2C03, Na2C03, DMAP, etc Exemplary Route [1 catalyst 1 Y R1 ligand Ar/Y R base R yR l 93 z = F, Cl, Br,| Y = OH, NH2, NHR, SH 1 catalyst Y R1 Y R ligand Ar/ base N .
ArZ + N —--—> \ \>«-NH2 heat \ ‘>"NH2 Z=F,Cl,Br,l R S Y = OH, NHZ, NHR, SH Ar/Y R1 RCOOH or N >4; RCOOX \ \)’NH catalyst R1 O ligand Ar/Y 0 ‘ R ArY + N\ yR se \ NVE heat R2 \rSfNH R2 3 Y ‘ fiflkN'gfi_ z = F, Cl, Br, I catalyst 1 Z R1 ligand Ar/Y R base _ N ArY + N —-‘> \ NH Fl<2 \ S\>—’NH2 heat l 3% 2 Y = OH, NH2, NHR. SH Z = F, CI,’ Br, I Ar/Y R1 RCOOH or R RCOOX l V’NH R2 S Exemplary Route III ACI 0 CuBr2 0 ea A1 —-——————> ——-————> r ——H AICI3 Arl EtOAc AHJK/Br EtOH A B C Ar1 0 N\ RCOOH Ar1 N R I S>—NH2 _ _ CDI, Et3N \[ >—NH 4-Arylamidothiazoles D - E The above scheme illustrates a method for the sis of 4-aryl—2—aminothiazoles E. Aromatic nds of structure A, including substituted benzene, pyridine, or other heterocyclic compound (5-, 6—, or ered) are reacted with acetyl chloride in the presence of AlC13 to afford acetylated arenes B. Bromination of B give a-Br—acetylated arenes C, which are allowed to react with thiourea to generate aminothiazoles D with an aryl substituent at the C-4 position.
The so prepared aminothiazoles then react with different acids give the final -2— amidothiazoles E.
Acetylation of Ari: AX o Ar1—H ———~——> Lewis acid Aflk X = OH, Cl, Br, OAIkyI, OAryI Lewis acid = AICI3, ZnC|3, BiCls, conc. acid The acetylation of Ar1 can be achieved by use of different reagents as shown in the above Scheme.
Bromination of Acetyl Arlz O bromination agent 0 Ar1)J\ Arl/U\/Br Suitable bromination agents include Brz, HBr, NBS, TBABr3, CuBrg, etc. in various solvents, including ether, THF, halogenated hydrocarbons, ester, etc.
Amidation of Aminothiazoles: Ar1 0 \[SN RCOOH Arl N R \>-NH2 coupling agent \[S\>—NH Suitable coupling agents include CD1, EDC, CDC, etc.
Ar1 0 \[N RCOOX Ar1 \>_ N R base S \[ \>-—NH X is typically C1 or Br; base is typically Et3N, Me3N, DlPEA, K2CO3, N32CO3, DMAP, etc. atively, amidothiazoles can be ed as follows: X Br \\ N Pd catalyst, phosphine I + I >_NH2 / base R S x, ArCOOH x l 0 \ coupling N agent N >—Ar | >—NH2 | \>—NH S S Alternatively, coupling may also be performed as follows: \[S>—NH2N o Et3N or DMAP Ar1 N Ar2 \ + CIJ‘kAr2 \ CHzclz 13>—NH To a solution of 4-arylthiazolamine (1.0 equiv) in CH2C12 was added triethylarnine (3.0 equiv) or DMAP (3.0 equiv) followed by aryloxy chloride (1.5 equiv) or aryloxychloride hydrochloride (1.5 equiv). The reaction e was stirred at room temperature ovemight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give the ponding 4—arylamidothiazoles.
In an alternative procedure for the synthesis of 4-Aryl—2-amidothiazoles, to a suspension of arylcarboxylic acid (1.5 equiv) in dichloromethane was added 1,l'— carbonyldiimidazole (CDI, 3.0 equiv). After being stirred at room temperature for 2.0 h, the solution was added with 4-arylthiazolan1ine (q.O . The reaction mixture was stirred at room temperature overnight. The solution was trated and the residue was re-dissolved in dichloromethane. The solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give the corresponding 4—ary1amidothiazoles. For specific examples of synthesis, see below.
Synthesis ofExemplary nds and Related Intermediates N—{4-(4-(Dimethylamino)—2,6-dimethylpheny1)thiazolyl } isonicotinamide (l) Br IL HN / WI. Br ——-> ——> —> 1-1 1-2 1-3 | | ———-> \ l >—NH2 — ‘ l >——NH s s 1—4 1 1-(4-Amino-2,6-dimethylphenyl)br0moethanone (1-2). A solution of N—(4-(2- bromoacetyl)-3,5-dimethylphenyl)acetamide (1-1, 6.92 g, 24.4 mmol) in 20.0 mL of l and .2 mL of concentrated hydrochloric acid was heated at reflux for 1.5 h. The on was concentrated and added with ethyl acetate (100 mL) and ted aqueous Na2C03 (100 mL).
The organic layer was collected, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give l—(4-amino-2,6-dimethylphenyl)bromoethanone (1-2, 5.04 g) as yellow solids, which was used directly for the next step without further purification. 2-Bromo(4-(dimethylamino)-2,6-dimethylphenyl)ethanone (1-3). A mixture of 1-(4—amin0—2,6-dimethylphenyl)—2-bromoethanone (1-2, 2.80 g, 11.6 mmol), methyl iodide (8.21 g, 57.8 mmol), and potassium carbonate (4.80 g, 34.7 mmol) in 11.6 mL of acetone was stirred at 40 °C for 2.0 h. The reaction e was cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (20% EtOAc in hexanes) to give o—1-(4—(dimethy1amino)—2,6-dimethylphenyl)ethanone (1-3, 0.60 g) as brown oil: 1H NMR (500 MHZ, CDC13) 5 6.35 (s, 2 H), 4.23 (s, 2 H), 2.96 (s, 6 H), 2.29 (s, 6 H). 4-(4-(Dimethylamin0)-2,6-dimethylphenyl)thiazolamine (1-4). A mixture of 2-' bromo—l-(4-(dimethylamino)—2,6-dirnethylphenyl)ethanone (1-3, 0.900 g, 3.33 mmol) and thiourea (0.250 g,»3.33 mmol) in 95% EtOH (4.8 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (30 mL) and saturated aqueous Na2C03 (1.0 mL). The ant precipitate was filtered and purified by flash column chromatography on silica gel to give 4—(4-(dimethylamino)—2,6—dimethylphenyl)thiazol-2—amine (1-4, 0.50 g) as brown solids in 61% yield: 1H NMR (500 MHz, CDC13) 6 6.45 (s, 2 H), 6.25 (s, 1 H), 4.90 (bs, 2 H), 2.93 (s, 6 H), 2.15 (s, 6 H).
N-{4-(4-(Dimethylamino)-2,6-dimethylphenyl)thiazolyl}isonicotinamide (1).
To a solution of 4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazolamine (1-4, 0.50 g, 2.0 WO 82324 mmol) in CH2C12 (5.1 mL) was added ylamine (0.61 g, 6.1 mmol) followed by isonicotinoyl chloride hydrochloride (0.54 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-{4-(4-(dimethylamino)-2,6- dimethylphenyl)thiazoly1 }isonicotinamide (l, 0.55 g) as yellow solids in 77% yield: 1H NMR (500 MHz, CDC13) 5 8.64 (d, J = 5.5 Hz, 2 H), 7.55 (d, J: 5.5 Hz, 2 H), 6.74 (s, 1 H), 6.12 (s, 2 H), 2.89 (s, 6 H), 1.91 (s, 6 H). ESI-MS: m/z 352.6 (M + H)+.
N—{5-Bromo(4-(4-methoxyphenoxy)-2,6-dimethylpheny])thiazol y] }isonicotinamide (2) \0/0 \[Ffifly'wz—>0 ' \O0°@ENVNH _—> 2-1 s 2'2 77’ \O0°\(P/ENVNH _> \O 00 8 or \%N\>INH28 Br Br 2-3 2-4 \ G(EN l V’NH / \N s Org 2 N-{4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazol¥2-yl}acetamide (2-2).
To a solution of 4-(4-(4-methoxyphenoxy)-2,6-dimethylpheny1)thiazol—2—amine (2-1, 500 mg, 1.5 mmol) in acetic anhydride (2.0 mL) was added sodium acetate (125.7 mg, 1.5 mmol). The reaction was d at room temperature for 1.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous s), and concentrated under reduced pressure to give N—{4-(4-(4-methoxyphenoxy)—2,6- dimethylphenyl)thiazolyl}acetamide (2-2, 465 mg) as yellow oil in 82% yield: 1H NMR (500 MHz, fi) 5 12.09 (s, 1 H), 6.96—7.03 (m, 5 H), 6.64 (s, 2 H), 3.75 (s, 3 H), 2.15 (s, 3 H), 2.01 (s, 6 H). ESI—MS: m/z 368.9 (M + H)+.
[0083] N-{5-Bromo(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2— y1}acetamide (2-3). To a solution of N-{4-(4-(4-methoxyphenoxy)-2,6—dimethylpheny1)thiazol- 2-yl}acetamide (2—2, 465 mg, 1.3 mmol) in acetic acid (10.2 mL) was added bromine (0.060 mL, WO 82324 2012/067132 1.3 mmol) dropwisely. The reaction was stirred at room temperature for 4.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer‘was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N—{ 5—bromo—4- (4-(4—methoxyphenoxy)-2,6-dimethylphenyl)thiazol—2-yl}acetamide (2-3, 547 mg) as white . solids, which was used directly for the next step without further purification. o(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazolamine (2-4). A methanol solution (10.0 mL) containing N-{5-bromo(4-(4—methoxyphenoxy)-2,6- dimethylphenyl)thiazol—2-yl}acetamide (2-3, 465 mg, 1.3 mmol) and 6 N hydrochloric acid (6.0 mL) was heated at reflux for 4.0 h. The on was added with 10% aqueous NaOH and the resultant solids were collected to give 5-bromo(4—(4-methoxyphenoxy)-2,6— dimethylphenyl)thiazolamine (2-4, 325 mg) as white solids in 55% yield: 1H NMR (500 MHz, DMSO-d6) 6 6.97—7.04 (m, 4 H), 6.65 (s, 2 H), 3.76 (s, 3 H), 2.03 (s, 6 H). ESI—MS: m/z 405.3, 407.2 (M + H)+.
N—{5-Bromo(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (2). To a solution of 5-bromo—4-(4—(4-methoxyphenoxy)-2,6- ylphenyl)thiazol—2—amine (2-4, 325 mg, 0.70 mmol) in CH2C12 (10 ml) was added triethylamine (0.50 mL, 1.7 mmol) followed by isonicotinoyl chloride hydrochloride (302.5 mg, 3.4 mmol). The reaction mixture was stirred at room temperature ght. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give N—{5-bromo-4—(4-(4-methoxyphenoxy)-2,6- dimethylphenyl)thiazol-2—yl}isonicotinamide (2, 345 mg) as white solids in 99% yield: 1H NMR (500 MHz, DMSO—d6) 5 13.3 (s, 1 H), 8.82 (m, 2 H), 7.98 (m, 2 H), 7.05 (d, J = 9.0 Hz, 2 H), 6.99 (d, J = 9.0 Hz, 2 H), 6.70 (s, 2 H), 3.76 (s, 3 H), 1.99 (s, 6 H); ESI-MS: m/z 509.6, 511.1 (M + H)+.
[0086] N-{4-(2-Ch1oro—4-(4-methoxyphenylsulfanyl)-6—methylphenyl)thiazol-2— yl}isonicotinamide (3) CI 0 CI 0 0 BF \O/Q/ N 3'3 Cl 0 3.4 \\>”NH2 CIOC \ /N CI —-—————> MeOgs N \ /N I \>—NH 1-(2-Chlor0(4-methoxyphenylsulfanyl)methylphenyl)ethanone (3-2). A mixture of 1-(2-ch1oroiodomethylphenyl)ethanone (3-1, 0.720 g, 2.44 mmol), 4- methoxybenzenethiol (0.45 mL, 3.7 mmol), copper(I) oxide (17.0 mg, 0.12 mmol), and potassium ide (0.34 g, 6.1 mmol) in DMF (2.2 mL) and H20 (0.5 mL) was heated at reflux for 20 h. The mixture was quenched with H20 and ted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 1—(2—chloro(4- methoxypheny]sulfanyl)-6—methylphenyl)ethanone (3-2, 0.10 g. 0.33 mmol) as yellow oil in 13% yield: 1H NMR (500 MHz, CDCl3) 6 7.44 (d, J = 8.7 Hz, 2 H), 6.94 (d, J = 8.7 Hz, 2 H), 6.86 (d, J: 8.2 Hz, 2 H), 3.85 (s, 3 H), 2.50 (s, 3 H), 2.17 (s, 3 H). 2-Bromo(2-chloro-4—(4-methoxyphenylsulfanyl)methylphenyl)ethanone (3- 3). To a solution of l-(2—chloro(4-methoxyphenylsulfanyl)methylphenyl)ethanone (3-2, 0.10 g, 0.33 mmol) in acetonitrile (6.0 mL) was added TBABr3 (0.16 g, 0.33 mmol). The on mixture was d at room temperature for 30 min. The on was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over ous MgSO4(s), and concentrated under reduced pressure to give 2—bromo-1 -(2-ch1oro(4—methoxyphenylsulfanyl)-6—methy1pheny1)ethanone (3- 3, 0.127 g), which was used directly for the next step without further purification.
[0089] 4-(2-Chloro(4-methoxyphenylsulfanyl)methylphenyl)thiazolylamine (3- 4). A mixture of 2—bromo(2-chloro(4-methoxyphenylsulfanyl)—6-methy1phenyl)ethanone (3-3, 0.127 g) and thiourea (30 mg, 0.33 mmol) in 95% EtOH (3.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated s NaHCO3, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro—4-(4-methoxyphenylsulfanyl) phenyl)thiazol—2—ylamine (3-4, 70 mg, 0.19 mmol) as yellow solids in 58% yield: 1H NMR (500 MHz, CDC13) 5 7.44 (m, 2 H), 6.97 (d,_J = 1.45 Hz,1 H), 6.93 (m, 3 H), 6.34 (s, 1 H), 3.84 (s, 3 H), 2.13 (s, 3 H); ESI—MS m/z 363.1 (M + HT”.
N-{4-(2-Chloro(4-methoxyphenylsulfanyl)methylphenyl)-thiazol-2— nicotinamide (3). Compound 3 was synthesized from the reaction of 3-4 (70 mg, 0.19 mmol) with DMAP (46 mg, 0.38 mmol) and isonicotinoyl chloride hydrochloride (44 mg, 0.25 mmol). The reaction provided compound 3 (42 mg, 89.9 mmol) in 47% yield: 1H NMR (500 MHz, CDC13) 5 8.82 (d, J = 6.0 Hz, 2 H), 7.70 (d, J = 6.0 Hz, 2 H),7.46 (d, J = 8.8 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.92 (s, 1 H), 6.86 (s, 1 H), 6.82 (s, 1 H), 3.86 (s, 3 H), 2.01 (s, 3 H); ESI— MS: m/z 466.1 (M — H)‘. 4-(Cyclopropylmethoxy)-2,6—dimethylphenyl)thiazol-2—yl}isonicotinamide (4) HO k0 k0 4 er,» cc. k0 A\/O ———> _> N H N \ \ \ stHz\ \ S)! W/C/NN 4-5 4 o 1-(4-(Cyclopropylmethoxy)-2,6-dimethylphenyl)ethanone (4-3). A vigorously stirred mixture of 1—(4—hydroxy-2,6—dimethylphenyl)ethanone (4-2, 1.00 g, 10.9 mmol), chloromethylcyclopropane (4-1, 1.22 g, 7.4 mmol), and powdered potassium carbonate (1.54 g, 11.1 mmol) in DMF (10.0 mL) was heated at 80 °C for 16 h under N2. The mixture was allowed to cool and was filtered through Diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was ted with EtOAc. The organic layer was washed with saturated aqueous sodium carbonate and dried over NaZSO4. The solution was concentrated under reduced re to provide 1—(4-(cyclopropylmethoxy)-2,6-dimet hylphenyl)ethanone (4-3, 1.61 g) as off-white solids in 99% yield: 1H NMR (500 MHz, CDC13) 8 6.55 (s, 2 H), 3.77 (d, J = 6.9 Hz, 2 H), 2.45 (s, 3 H), 2.27 (s, 6 H), 1.19 (s, 1 H), 0.64 (m, 2 H), 0.33 (m, 2 H). o(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)ethanonve (4-4). To a solution of l-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)ethanone (4-3, 1.60 g, 7.3 mmol) in acetonitrile (20.0 mL) was added TBABr3 (3.66 g, 7.4 mmol). The reaction was stirred at room temperature for 80 min. The solution was concentrated under reduced pressure, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo(4— propylmethoxy)-2,6—dimethylphenyl)ethanone (4-4, 2.08 g), which was used directly for the next step t further purification: 1H NMR (500 MHz, CDC13) 5 6.57 (s, 2 H), 4.25 (s, 2 H), 3.78 (d, J = 6.9 Hz, 2 H), 2.22 (s, 6 H), 1.19 (s, 1 H), 0.64 (m, 2 H), 0.33 (m, 2 H).
[0094] 4-(4-(Cyclopropylmethoxy)-2,6-dimethylphenyl)thiazolamine (4-5). A mixture of 2-bromo-1—(4-(cyclopr0pylmethoxy)-2,6-dimethylphenyl)ethanone (4-4, 2.06 g, 7.0 mmol) and thiourea (0.61 g, 8.0 mmol) in 95% EtOH (30.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50.0 mL) and saturated aqueous NaZCO3 (1.0 mL). The resultant precipitate was d and washed with hot water. The solids were filtered and dried under vacuum to give 4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol—2-amine (4-5, 1.18 g) as yellow solids in 61% yield: 1H NMR (500 MHZ, DMSO-ds) 5 9.00 (s, 2 H), 6.73 (s, 2 H), 3.81 (d, J: 7.0 Hz, 1 H), 2.10 (s, 6 H), 1.19 (s, 1 H), 0.55 (m, 2 H), 0.30 (m, 2 H).
N-{4-(4-(Cyclopropylmethoxy)-2,6-dimethylphenyl)thiazolyl}isonicotinamide (4). To a solution of 4-(4-(Cyclopropy1methoxy)-2,6-dimethylphenyl)thiazol—2-amine (4-5, 0.410 g, 1.51 mmol) in CHZCIZ (10 mL) was added triethylarnine (1.0 mL, 7.2 mmol) followed by isonicotinoyl chloride hydrochloride (0.470 g, 2.62 mmol). The reaction mixture was stirred at room temperature ovemight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was d, and recrystallized in toluene to give N—{4-(4- (cyclopropylmethoxy)—2,6-dimethylphenyl)thiazol-2—y1}isonicotinamide (4, 0.41 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, DMSO—dé) 8 13.0 (s, 1 H), 8.80 (d, J: 4.9 Hz, 2 H), 7.99 (d, J: 6.0 Hz, 2 H), 7.10 (s, 1 H), 6.68 (s, 2 H), 3.81 (d, J = 7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J = 6.5 Hz, 2 H), 0.32 (d, J = 5.7 Hz, 2 H). ESI—MS: m/z 380.3 (M + H)+.
N-{4-(4—(6-Hydroxypyridinyloxy)-2,6-dimethylphenyl)thiazol-Z- yl}isonicotinamide (5) HO HO _> ——>- N l >—NH2 o o s 4'20 52'- HO \ I HO I /N o _ ___. N H3. ___,\ l >—NH / N, \ o _ HO \ 1 >—NH ’ 2-Bromo(4-hydroxy-2,6-dimethylphenyl)ethanone (5-1). To a solution of 1-(4- hydroxy-2,6-dimethylphenyl)ethanone (4-2, 1.60 g, 10.0 mmol) in acetonitrile (30.0 mL) was added TBABr3 (4.82 g, 10.0 mmol). The reaction was d at room temperature for 90 min.
The solution was trated under reduced pressure, added with water, and extracted with ethyl acetate. The c layer was washed with brine, dried over anhydrous MgSO4(s), and trated under reduced pressure to give 2-bromo(4-methoxy-2,6- dimethylphenyl)ethanone (5-1, 2.34 g), which was used directly for the next step without further purification.
[0098] 4-(2—Aminothiazolyl)-3,S-dimethylphenol (5-2). A mixture of 2-br0mo-1—(4- hydroxy-2,6-dimethylphenyl)ethanone (5-1, 2.43 g, 10.0 mmol) and thiourea (1.37 g, 18.0 mmol) in 95% EtOH (30 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous NazCO3 (5.0 mL). The resultant precipitate was filtered and washed with a solution of 50% EtOAc in hexanes. The solids were dried under vacuum to give 4-(2-amin0thiazolyl)-3,5-dimethylphenol (5-2, 1.74 g) as pale yellow solids in 79% yield: 1H NMR (500 MHz, CDC13) 5 8.7 (s, 2 H), 6.17(s, 2 H), 5.97 (s, 1 H), 1.71 (s, 6 H).
N-(4-(4-Hydr0xy-2,6-dimethylphenyi)thiazolyl)isonicotinamide (5-3). To a suspension of isonicotinic acid hydrochloride (1.48 g, 10.0 mmol, 1.2 equiv) in DMF was added EDC (3.90 g, 2.0 , HOBt (2.7 g, 2.0 equiv) and N33 (303 g, 3.0 equiv). After being stirred at room temperature for 1.0 h, the solution was added with 4-(2-amin0thiazol—4—yl)-3,5- ylphenol (5-2, 2.2 g, 1.0 equiv). The reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was re-dissolved in EtOAc. The WO 82324 solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure to brown solid. The brown solid was washed with 50% EtOAc in hexanes to give 5-3 (2.08 g) _ give as white solids in 64% yield: 1H NMR (500 MHz, CDC13)'5 9.29 (s, 1 H), 8.80 (d, 2 H), 7.98 (d, 2 H), 7.06 (s, 1 H), 6.51 (s, 2 H), 2.01 (s, 6 H).
N-{4-(4-(6-Hydroxy-pyridinyloxy)—2,6-dimethyl-phenyl)-thiazol yl}isonicotinamide (5). To a solution of N—(4-(4-hydroxy—2,6—dimethylphenyl)-thiazol—2— yl)isonicotina1nide (5-3, 325 mg, 1.0 mmol) in DMF (15 mL) were added cesium carbonate (650 mg, 2.0 mmol, 2.0 equiv) and Cu (19.5 mg, 0.30 mmol, 0.30 equiv). The mixture was stirred at 80—90 °C for 60 min. 5—Bromo-2—hydroxypyridine (261 mg, 1.5 mmol) was added to the solution and the reaction e was stirred at 100 °C for additional 24 hr. The solution was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with ted brine, and dried over anhydrous ium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on (NH silica gel, hexane/ethyl acetate = 3/1—1/3) to give 5 (0.75 g) in 18% yield: 1H NMR (500 MHZ, CDC13) 5 8.31 (d, J = 5.0 Hz, 2 H), 8.29 (d, J: 5.0 Hz, 2 H), 7.23 (d, J = 9.5 Hz, 1 H), 6.81 (s, 1 H), 6.60 (d, J: 4.76 Hz, 1 H), 6.49 (s, 2 H), 5.42 (s, 1 H), 2.04 (s, 6 H), ESI-MS = m/z 417.2 (M — H)’. [00101H] N—{4-(2,6-Dimethyl(pyrimidin-Z-yloxy)phenyl)thiazolyl}isonicotinamide (6) g. @322. Q.6-2 //N o —> CYol N —> K/TNK N OWN l >—NH2 I >—NH — s s 6-3 6 1-(2,6-Dimethyl(pyrimidinyloxy)phenyl)ethanone (6-1). A mixture of l-(4- 2O hydroxy-2,6-dimethylphenyl)ethanone (4-2, 2.15 g, 13.1 mmol), ropyrimidine (1.00 g, 8.73 mmol), copper (55.0 mg, 0.87 mmol), and potassium carbonate (3.62 g, 26.2 mmol) in 17.5 mL of DMF was stirred at 100 °C for 3.0 h. The reaction mixture was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1- (2,6—dimethy1—4-(py1imidinyloxy)phenyl)ethanone (6-1, 1.16 g) as white solids in 55% yield: 1H N1V.[R (500 MHZ, CDCl3) 5 8.58 (d, J = 4.5 Hz, 2 H), 7.05 (t, 1 H), 6.87 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H). 2-Bromo(2,6-dimethyl(pyrimidinyloxy)phenyl)ethan0ne (6-2). To a solution of 1-(2,6-dimethyl(pyrimidinyloxy)phenyl)ethanone (6-1, 1.16 g, 4.79 mmol) in acetonitrile (9.6 mL) was added TBABr3 (2.31 g, 4.79 mmol). The reaction was stirred at room' temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced re to give 2-bromo(2,6—dimethyl (pyrimidin-Z—yloxy)pheny1)ethanone(6-2, 1.8 g), which was used directly for the next step without further purification. 4-(2,6-Dimethyl(pyrimidinyloxy)phenyl)thiazol-2—amine (6-3). A mixture of 2—bromo(2,6-dimethyl-4—(pyrimidinyloxy)phenyl)ethanone (6-2, 1.54 g, 4.79 mmol) and thiourea (0.370 g, 4.86 mmol) in 95% EtOH (6.9 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2C03 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-=4=(pyrimidinyloxy)phenyl)thiazol-2—amine (6-3, 0.23 g) as brown solids in 91% yield: 1H NMR (500 MHz, DMSO-ds) 5 8.64 (d, J = 4.5 Hz, 2 H), 7.25 (m, 1 H), 6.99 (bs, 2 H), 6.89 (s, 2 H), 6.41 (s, 1 H), 2.11 (s, 6 H).
N-{4-(2,6-Dimethyl(pyrimidin-Z-yloxy)phenyl)thiazol-Z-yl}isonic0tinamide (6). To a solution of -dimethyl—4-(pyrimidinyloxy)phenyl)thiazol-2—amine (6-3, 0.23 g, 0.77 mmol) in THF (3.9 mL) was added ylamine (0.23 g, 2.30 mmol) followed by otinoyl chloride hydrochloride (0.27 g, 1.52 mmol). The reaction e was heated at 60 °C overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over ous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in MeOH to give 2,6-dimethyl(pyrimidin-2—yloxy)phenyl)thiazol-2—yl}isonicotinamide (6, 0.12 g) as yellow solids in 38% yield: 1H NMR (500 MHZ, CDC13) 5 8.75 (d, J = 6.0 Hz, 2 H), 8.589 (d, J = 4.5 Hz, 2 H), 7.65 (d, J = 6.0 Hz, 2 H), 7.04 (t, J = 4.8 Hz, 1 H), 6.83 (s, 1 H), 6.70 (s, 2 H), 3.47 (s, 3 H), 1.97 (s, 6 H). ESI-MS: m/z 403.8 (M + H)+.
[00106] N-{4-(2,6-Dimethyl(pyrazinyloxy)phenyl)thiazolyl}isonicotinamide (7) “0 19? [IrIWZ rIrIW 1-(2,6-Dimethy1-4—(pyrazin-Z-yloxy)phenyl)ethanone (7-1). A e of 1-(4- hydroxy-2,6-dimethy1phenyl)ethanone (4-2, 4.66 g, 28.4 mmol), 2-chloropyrazine (2.50 g, 21.8 mmol), copper (277 mg, 4.36 mmol), and potassium carbonate (9.05 g, 65.5 mmol) in 43.7 mL of DMF was stirred at 100 °C overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced re, and purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1-(2,6-dimethyl(pyrazin—2-yloxy)phenyl)ethanone (7-1, 4.65 g) as brown oils: 1H NMR (500 MHz, CDC13) 6 8.43 (bs, 1 H), 8.29 (bs, 1 H), 8.14 (bs, 1 H), 6.83 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H). 2-Bromo(2,6-dimethyl(pyrazin-Z-yloxy)phenyl)ethanone (7-2). To a solution of 1-(2,6-dimethyl—4-(pyrazinyloxy)phenyl)ethanone (7-1, 4.65 g, 19.2 mmol) in acetonitrile (38.4 mL) was added TBABr3 (9.26 g, 19.2 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced re, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous s), and concentrated under reduced pressure to give o(2,6-dimethy1—4—(pyrazin— 2-yloxy)phenyl)ethanone (7-2, 7.6 g), which was used directly for the next step without further purification. 4-(2,6-Dimethyl(pyrazinyloxy)phenyl)thiazol—2—amine (7-3). A mixture of 2- 2O bromo-l-(2,6-dimethy1(pyrazin—2—yloXy)phenyl)ethanone (7-2, 6.16 g, 19.2 mmol) and thiourea (1.46 g, 19.2 mmol) in 95% EtOH (27.4 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The ant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6—dimethyl(pyrazin-2—yloxy)phenyl)thiazol—2-amine (7-3, 3.07 g) as brown solids in 54% yield: 1H NMR (500 MHZ, CDCl3) 8 8.40 (s, 1 H), 8.25 (d, 1 H), 8.14 (s, 1 H), 6.86 (s, 2 H), 6.31 (s, 1 H), 5.09 (s, 2 H), 2.18 (s, 6 H).
N-{4-(2,6-Dimethyl(pyrazinyloxy)phenyl)thiazolyl}isonicotinamide (7).
To a solution of 4-(2,6-dimethyl(pyrazinyloxy)phenyl)thiazolamine (7-3, 0.500 g, 1.68 mmol) in THF (8.4 mL) was added triethylamine (0.510 g, 5.03 mmol) followed by isonicotinoyl chloride hydrochloride (0.750 g, 4.21 mmol). The reaction mixture was stirred at 60 OC overnight. The solution was concentrated under reduced pressure and added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was recrystallized in toluene to give N-{4-(2,6—dimethyl-4—(pyraziny10xy)phenyl)thiazolyl}isonicotinamide (0.17 g) as yellow solids in 25% yield: 1H NMR (500 MHz, CDC13) 5 8.76 (d, J = 6.0 Hz, 2 H), 8.42 (d, J = 1.0 Hz, 1 H), 8.28 (d, J = 1.0 Hz, 1 H), 8.13 (m, 1 H), 7.67 (d, J: 6.0 Hz, 2 H), 6.84 (s, 1 H), 6.68 (s, 2 H), 1.98 (s, 6 H). ESI—MS: m/z 403.8 (M + H)+. 4—(5-Methoxypyrimidin-2—yloxy)-2,6-dimethylphenyl)thiazol-2— yl}isonicotinamide (8) N Cl /NY0 I ‘Y + _. \ 'N _.
/ N MeO ' 4-2 N o N o Lt\ —> [J N MeO Br MeO l \>/NH2 8-3 o 8-4 N ' . — N —-—> N >—<\:N | \)—NH / 8 S
[00112] 1-{4-((5-Methoxypyrimidin-2—yl)oxy)-2,6-dimethylphenyl}ethanone (8-2). 2- Chloro—S—methoxypyrimidine (8-1, 5.13 g, 35.6 mmol) and 1-(4-hydroxy—2,6- dimethylpheny1)ethanone (4-2, 6.10 g, 37.2mmol) were suspended in DMF (80.0 ml) and added with copper powder (0.78 g, 7.8 mmol) and potassium ate (15.31 g, 0.11 mol). The reaction was heated at 120 °C for 16 h. The reaction was cooled to room ature and diluted with EtOAc (90 mL). The organic phase was washed with 15% NaOH and water, dried over sodium e, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40% EtOAc in hexanes as eluant) to give 1-{4-((5- _ methoxypyrimidinyl)oxy)-2,6-dimethylpheny1}ethanone (8-2, 2.33 g) as light yellow solids in 24% yield: 1H NMR (500 MHZ, DMSO-d6) 8 8.41 (s, 2 H), 6.86 (s, 2 H), 3.86 (s, 3 H), 2.47 (s, 3 H), 2.18 (s, 6 H). 2-Bromo{4-((5-methoxypyrimidinyl)oxy)-2,6-dimethylphenyl}ethan0ne (8- 3). To a solution of l—{4-((5—methoxypyrimidinyl)oxy)-2,6-dimethylpheny1}ethan0ne(8-2, 0.34 g, 1.2 mmol) in acetonitrile (4.0 mL) was added TBABr3 (0.65 g, 1.3 mmol). The reaction was stirred at room temperature for 80 min. The solution was concentrated under reduced with brine, pressure, added with water, and ted with EtOAc. The organic layer was washed dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-l -{4— ((5—methoxypyrimidinyl)oxy)-2,6—dimethylphenyl}ethan0ne (8-3, 0.51 g), which was used directly for the next step without further purification. 4-{4-((5-Methoxypyrimidinyl)oxy)-2,6-dimethylphenyl}thiazol-Z-amine (8—4).
A mixture of 2-brorno{4-((5-methoxypyrimidinyl)oxy)-2,6—dimethylphenyl }ethan0ne (8-3, 0.51 g, 1.5 mmol) and thiourea (0.13 g, 1.6 mmol) in 95% EtOH (10.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2C03 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-((5—methoxypyrimidinyl)oxy)—2,6- dimethylphenyl}thiazol-Z-amine (8-4, 0.41 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-dg) 5 9.00 (s, 2 H), 8.41 (s, 2 H), 6.99 (s, 2 H), 6.88 (s, 1 H), 3.87 (s, 3 H), 2.17 (s, 6 H).
N-(4-{4-((5-Methoxypyrimidinyl)oxy)-2,6-dimethylphenyl}thiazol-Z- yl)isonic0tinamide (8). To a solution of 4-{4-((5-methoxypyrirnidin—2—y1)oxy)—2,6- dimethylphenyl}thiazol-Z-amine (8-4, 0.41 g, 1.23 mmol) in CH2C12 (6.0 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by otinoyl de hydrochloride (0.35 g, 1.94 mmol). The on e was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The ant precipitate was filtered, and recrystallized in toluene to give N—(4-{4-((5—methoxypyrimidiny1)oxy)-2,6- dimethylphenyl}thiazoly1)isonicotinamide (8, 0.37 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, 6) 5 13.0 (s, 1H), 8.80 (d, J = 4.9 Hz, 2 H), 8.42 (s, 2 H), 7.99 (d, J = 6.0 Hz, 2 H), 7.10 (s, l H), 6.68 (s, 2 H), 3.81 (d, J: 7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J = 6.5 Hz, 2 H), 0.32 (d, J = 5.7 Hz, 2 H). ESI—MS: m/z 433.8 (M + H)+.
N-{4-(4—(6-Methoxypyridinyloxy)-2,6-dimethylphenyl)thiazol-2— yl}isonicotinamide (9) H300 N o _ \ / \ HCO3 N Br iS>—NH \ i \>_NH / 5-3 9 WO 82324 N-{4-(4-(6-Methoxy-pyridin-S-yloxy)-2,6-dimethyl-phenyl)thiazol-2— yl}isonicotinamide (9). To a solution of N-(4-(4—hydroxy-2,6-dimethylphenyl)thiazol yl)isonicotinamide (5-3, 1.92 g, 5.91 mmol) in DMF (15 mL) were added cesium carbonate (2.41 g, 7.39 mmol) and Cu (116 mg, 1.78 mmol, 0.30 equiv). The mixture was d at 80—90 °C for 60 min. 5—Br0momethoxy-pyridine (9-1, 1.67 g, 8.87 mmol) was added to the solution and the on mixture was stirred at 100 °C for additional 24 hr. The solution was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over ous ium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, hexane/ethyl e = 3/1—1/3) to give 5 (0.97 g) in 38% yield: 1H NMR (CDCl3, 500 MHz) 6 8.89 (d, J = 5.0 Hz, 2H), 8.23 (d, J = 5.0 Hz, 2 H), 8.02 (s, 1 H), 7.37 (d, J = 3.0 Hz, 1 H), 6.89 (s, 1 H), 6.80 (d, J: 9.0 Hz, 1 H), 6.69 (s, 2 H), 3.94 (s, 3H), 2.17 (s, 6 H), ESI—MS = m/z 433.2 (M + H)“.
N-(4-(2,6-Dichloromethoxyphenyl)thiazolyl)isonicotinamide (10) /O C! /0 CI /0 CI ———> —> —-> CI Cl 0 ‘ CI 0 -1 10-2 10-3 /0 Cl /0 CI N\ —> \ sfNH N 2 \ / Cl CI l 9"“O>—CN -4 10
[00119] 1-(2,6-Dichloromethoxyphenyi)ethanone (10-2). A mixture of aluminum chloride (4.50 g, 33.9 mmol) and acetyl chloride (2.40 mL, 33.9 mmol) in CH2C12 (20.0 mL) was stirred at 0 °C for 30 min. The reaction mixture was slowly added with 1,3-dichloro—5— methoxybenzene (10-1, 2.00 g, 11.3 mmol) in CH2C12 (10.0 mL), and the resultant solution was stirred at room temperature for additional 2.0 h. The solution was basified with ted aqueous NaHC03. The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1-(2,6-dichloromethoxyphenyl)ethanone (10-2, 1.0 g, 4.6 mmol) as yellow oil in 40% yield: 1H NMR(CDC13, 500 MHZ) 6 7.01 (d, J = 1.6 Hz, 2 H), 6.82 (d, J: 1.6 Hz, 2 H), 3.83 (s, 3 H), 2.49 (s, 3 H).
[00120] 2-Br0m0(2,6-dichloromethoxyphenyl)ethanone (10-3). To a solution of 1- (2,6-dichlor0methoxyphenyl)ethanone (10-2, 1.0 g, 4.6 mmol) in acetonitrile (30.0 mL) was added TBABr3 (2.2 g, 4.6 mmol). The reaction was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl e. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2—br0mo-1—(2,6-dichloromethoxyphenyl)ethanone (10-3, 1.3 g), which was used directly for the next step without further purification. ] 4-(2,6-Dichloromethoxyphenyl)thiazol-Z-ylamine (10-4). To a solution of 2— bromo-l-(2,6-dichloromethoxyphenyl)ethanone (10-3, 1.3 g) and thiourea (0.42 g, 5.5 mmol) in 95% EtOH (15.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHC03, dried over MgSO4, and concentrated under reduced re. The e was purified by column chromatography on silica gel to give 4—(2,6-dichloro—4— yphenyl)thiazol-2\-ylamine (10-4, 0.60 g, 2.2 mmol) as yellow solids in 47% yield: 1H NMR (500 MHz, CDC13) 6 7.08 (d, J: 1.8 Hz, 1 H), 6.83 (d, J = 1.8 Hz, 1 H), 6.49 (s, 1 H), 4.88 ‘ (brs, 2 H), 3.77 (s, 3 H); ESI—MS m/z 275.1 (M + H)+.
[00122] N—(4-(2,6-Dichloromethoxyphenyl)thiazolyl)isonicotinamide (10). To a on of 4—(2,6—dichloromethoxyphenyl)thiazol—2-ylamine (10-5, 0.10 g, 0.36 mmol) in CH2C12 (10 mL) was added DMAP (88 mg, 0.72 mmol) followed by isonicotinoyl chloride hydrochloride (83 mg, 0.47 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced re and added with water. The resultant precipitate was collected and recrystallized in toluene to give N—(4-(2,6-dichloro methoxyphenyl)thiazolyl)isonic0tinamide (50 mg, 0.13 mmol) as white solids in 37% yield: 1H NMR (500 MHz, 6) 5 8.80 (d, J: 5.8 Hz, 2 H), 7.99 (d, J: 6.0 Hz, 2 H), 7.31 (d, J = 1.7 Hz, 1 H), 7.26 (s, 1 H), 7.22 (d, J: 1.7 Hz, 1 H), 3.75 (s, 3 H). ESI—MS: m/z 381.4 (M + H)+.
N—{4-(2,6-Dimethyl(pyrazinylthio)phenyl)thiazolyl}isonicotinamide (11) N s N s N\ N / / U» 114:1\ ——» U / N N Br N CI N SH ' 0 11-4 0 11-1 11-2 1 13- N S ——> [\Nj/ N\ NH——> *2“ [ill/Sm“:‘SWC\ 11-5 0 11 Pyrazine-Z-thiol (ll-2). A mixture of 2-chloropyrazine (11-1, 2.00 g, 17.5 mmol) and thiourea (1.30 g, 17.5 mmol) in 95% EtOH (20 mL) was heated at reflux for 16 h. The solution was concentrated, added with 10% aqueous NaOH (20 mL), and extracted with ethyl acetate. The c layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced re to give pyrazine—2—thiol (ll-2, 1.96 g) as yellow solids in 100% yield: 1H NMR (500 MHz, DMSO-ds) 6 8.06 (s, 1 H), 7.70 (d, J = 2.6 Hz, 2 H), 7.44 (d, J = 2.6 Hz, 1 H); ESI-MS: m/z 113.2 (M + H)+. 1-(2,6-Dimethyl(pyrazinylthio)phenyl)ethanone (ll-3). A mixture of 1-(4- iodo-2,6-dimethylphenyl)ethanone (4-2, 3.20 g, 11.7 mmol), pyrazine-Z—thiol (ll-1, 1.96 g, 17.5 mmol), copper(I) oxide (83.5 mg, 0.6 mmol), and potassium hydroxide (1.64 g, 29.2 mmol) in DMF (9.6 mL) and H20 (2.4 mL) was heated at reflux for 24 h. The mixture was quenched with H20 (10 mL) and extracted with ether (2 X 50 mL). The organic layer was collected, dried over ), and concentrated under reduced pressure. The residue was purified by column tography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl—4- (pyrazin-2—ylthio)phenyl)ethanone (ll-3, 755.2 mg) as yellow oil in 25% yield: 1H NMR (500 MHz, CDC13) 8 8,47 (s, 1 H), 8.27 (s, 1 H), 8.22 (s, 1 H), 7.28 (s, 2 H), 2.51 (s, 3 H), 2.28 (s, 6 H); ESI-MS: m/z 259.3 (M + H)+. {00126} o(2,6—dimethyl=4=(pyrazins2=ylthie)phenyl)ethanone (1L4). To a solution of 1-(2,6-dimethy1—4-(pyrazin—2-ylthio)phenyl)ethanone (11-3, 4.50 g, 17.4 mmol) in acetonitrile (100 mL) was added TBABr3 (8.3 g, 17.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give o-l—(2,6-dimethyl-4—(pyrazin- 2-ylthio)phenyl)ethanone (ll-4, 4.0 g), which was used ly for the next step without further purification. 4-(2,6-Dimethyl(pyrazinylthio)phenyl)thiazol-2—amine (ll-5). A mixture of 2-br0mo—1—(2,6-dimethyl-4—(pyrazin-2—y1thio)phenyl)ethanone (ll-4, 4.00 g, 11.9 mmol) and thiourea (902.9 mg, 11.9 mmol) in 95% EtOH (15 mL) was heated at reflux for 16 hr. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (10.0 mL). The resultant precipitate was d and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl(pyraziny1thio)phenyl)thiazol- 2-amine(11-5, 1.56 g) as yellow solids in 42% yield: 1H NMR (500 MHz, CDC13) 5 8.43 (s, l H), 8.36 (s, 1 H), 8.31 (s,'1 H), 7.47 (s, 2 H), 6.34 (s, 1 H), 2.24 (s, 6 H). ESI-MS: m/z 315.2 (M + H)+. 2012/067132 N-{4-(2,6-Dimethyl(pyrazinylthio)phenyl)thiazolyl}isonicotinamide (11).
To a solution of 4-(2,6—dimethyl-4—(pyraziny1thio)phenyl)thiazolamine (11-5, 500 mg, 1.6 mmol) in CH2C12 (10.0 ml) was added triethylamine (0.7 ml, 4.0 mmol) followed by isonicotinoyl chloride hydrochloride (707.7 mg, 4.8 mmol). The reaction mixture was d at room temperature overnight. The solution was trated under d pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N—{4-(2,6- dimethyl-4—(pyrazin—2—ylthio)phenyl)thiazol-2—y1}isonicotinamide (11, 392.5 mg) as white solids in 59% yield: 1H NMR (500 MHz, DMSO—d6) 5 13.1 (s, 1 H), 8.81 (d, J = 5.7 Hz, 2 H), 8.50 (s, l H), 8.41 (s, 1 H), 8.36 (s, 1 H), 8.00 (d, J = 5.7 Hz, 2 H), 7.41 (s, 2 H), 7.30 (s, 1 H), 2.13 (s, 6 H). ESI—MS: m/z 420.2 (M + H)+.
N-(4-{4-(4-(2-Methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (12) Ho/\/O""e —> Tso/\/OMe ——> ”01203 —> 12-1 12—2 2-Methoxyethyl 4-methylbenzenesulfonate (12-2). To a solution of 2— methoxyethanol (12-1, 5.00 g, 65.7 mmol) in CHzClz (50.0 mL) was added tn'ethylamine (18.3 mL,,131.4 mmol) followed by 4—methylbenzene—1-sulfonyl chloride (16.3 mg, 85.4 mmol). The reaction mixture was stirred at room temperature ovemight. The solution was added with saturated aqueous Na2C03 (50.0 mL) and extracted with CH2C12. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and trated under reduced re to give 2- methoxyethyl 4-methylbenzenesulfonate (12-2, 10.46 g) as yellow solids in 69% yield: 1H NMR (500 MHz, CDC13) 5 7.80 (d, J = 8.3 Hz, 2 H), 7.34 (d, J = 8.3 Hz, 2 H), 4.15—4.16(m, 2 H), 3.57—3.59 (m, 2 H), 3.31 (s, 3 H), 2.44 (s, 3 H). ESI-MS: m/z 230.8 (M + H)+. 4-(2—Methoxyethoxy)phenol (12-3). To a solution of 60% sodium e (436 mg, 18.2 mmol) in DMF (2.0 mL) was added hydroquinone (1.0 g, 18.2 mmol) in DMF (10.0 mL) sely. The solution was added with 2-methoxyethyl 4—methylbenzenesulfonate (12-2, 2.10 solution was cooled g, 21.8 mmol) dropwisely. The reaction was stirred at 65 °C for 16 h. The to room temperature, poured into icy H20, and extracted with ethyl acetate. The organic layer was washed with brine, dried over ous s), and concentrated under reduced for the next pressure to give 4—(2-methoxyethoxy)phenol (12-3, 1.0 g), which was used directly step without further purification. 1-{4-(4—(2—Met-h0xyeth0xy)phenoxy)-2,6-dimethylphenyl}ethanone (12-4). To a solution of l-(4-chloro-2,6-dimethylphenyl)ethanone (12-3, 914 mg, 5.00 mmol), K3P04 (2.10 g, .0 mmol), and 4-(2—methoxyethoxy)phenol (12-3, 1.0 g, 6.0 mmol) in toluene (2.0 mL) was added 2-di-tert—butylphosphino‘-2',4',6'-triisopropy1biphenyl (63.8 mg, 0.15 mmol), Pd(OAc)2 (47.3 mg, 0.10 mmol). The reaction was heated at 100 0C for 16 h under N2. The solution was cooled to room temperature and filtered through a small pad of aceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was d by flash column chromatography on silica gel to give 4- (2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}ethanone (12-4, 797.5 mg) as yellow oil in 51% yield: 1H NMR (500 MHZ, DMSO—dé) 8 6.96—6.97 (m, 4 H), 6.57 (s, 2 H), 4.11—4.13 (m, 2 H), 3.75—3.77 (m, 2 H), 3.46 (s, 3 H), 2.46 (s, 3 H), 2.20 (s, 6 H). ESI—MS: m/z 315.2 (M + H)+. 2-Bromo{4-(4-(2-meth0xyethoxy)phenoxy)-2,6-dimethylphenyl}ethanone (12- ). To a solution of 1—{4-(4—(2-methoxyethoxy)phenoxy)-2,6—dimethylphenyl}ethanone (12-4, 797.5 mg, 2.5 mmol) in acetonitrile (15 mL) was added TBABr3 (1.22 g, 2.5 mmol). The reaction was stirred at room temperature overnight. The on was concentrated under reduced washed with re, added with water, and extracted with ethyl acetate. The organic layer was brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2- bromo-l-{4—(4—(2-methoxyethoxy)phenoxy)-2,6—dimethylphenyl}ethanone (12-5, 835.6 mg), which was used directly for the next step without further purification. 4-{4-(4-(2-Methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazolamine .
A mixture of 2-bromo-l-{4-(4—(2—methoxyethoxy)phenoxy)-2,6—dimethylphenyl}ethanone (12-5, 835.6 mg, 2.1 mmol) and thiourea (161.7 mg, 2.1 mmol) in 95% EtOH (5.0 mL) was heated at reflux for 2.0 h. The on was concentrated and added with water (10 mL) and saturated in toluene aqueous Na2C03 (10.0 mL). The resultant precipitate was filtered and recrystallized (30 mL). The solids were collected and dried under vacuum to give 4-{4—(4-(2- methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazolamine (12-6, 322.2 mg), which was used directly for the next step without further purification. 2012/067132 N-(4-{4-(4-(2-Methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (12). To a solution of 4—{4-(4-(2-methoxyethoxy)phenoxy)-2,6- dimethylphenyl}thiazolamine (12-6, 322.3 mg, 0.90 mmol) in CH2C12 (10.0 ml) was added ylamine (0.40 mL, 2.6 mmol) ed by isonicotinoyl chloride hydrochloride (387.2 mg, 2.1 mmol). The on mixture was stirred at room temperature overnight. The solution was concentrated under reduced re and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-(4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6- dimethylphenyl}thiazolyl)isonicotinamide (12, 230 mg) as white solids in 56% yield: 1H NMR (500 MHz, DMSO—dfi) 5 13.0 (brs, 1 H), 8.78 (d, J = 5.8 Hz, 2 H), 7.98 (d, J = 5.8 Hz, 2 H), 7.12 (s, 1 H), 6.96—7.00 (m, 4 H), 6.67 (s, 2 H), 4.01—4.07 (m, 2 H), 3.63—3.64 (m, 2 H), 3.26 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 476.4 (M + H)+.
N—(4-(2-Chlorofluoromethoxyphenyl)thiazol-Z-yl)isonic0tinamide (13) Cl CI 0 CI 0 \0D a UL“ UKF \o F F We 13-1 13-2 13-3 CI 0 CI 0 /0 Cl —> _> \ \>’-’NH \ \ o F o F F 3 13‘5 13-2 13-4 / CI 0 /—\_ F |\>-NH 1-(2-Chlor0fluor0methoxyphenyl)ethanone (13-2) and 1-(2-chlorofluoro- 6-methoxyphenyl)ethanone (13-3). A mixture of aluminum chloride (2.50 g, 18.7 mmol) and acetyl chloride (1.30 mL, 18.7 mmol) in CH2C12 (10.0 mL) was stirred at 0 CC for 30 min. The on mixture was slowly added with 1-chlorofluoro—5-methoxybenzene (13—1, 1.00 g, 6.23 mmol) in CHZCIZ (5.0 mL). The solution was stirred at room temperature for additional 2.0 h.
The solution was basified with saturated aqueous NaHCOg, and the organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give a mixture of 1-(2-chloro-6—fluoro 2012/067132 methoxyphenyl)ethanone (13-2) and 1-(2-chloroflu0ro—6-methoxypheny1)ethanone (13-3) as yellow oil in 1.2 g (5.9 mmol) total weight (95% yield). 2-Bromo(2-chloro-6—fluoromethoxyphenyl)ethanone (13-4). To a solution of l-(2-chlorofluoro-4—methoxyphenyl)ethanone (13-2, 0.60 g, 3.0 mmol) in acetonitrile (15.0 mL) was added TBABr3 (1.4 g, 3.0 mmol). The reaction was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure, added with water, and ted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under d pressure 2—bromo(2-chloro—6-fluoro—4— methoxyphenyl)ethanone (13-4, 0.80 g), which was used directly for the next step without further purification. 4-(2—Chlorofluoromethoxyphenyl)thiazolylamine (13-5). To a solution of 2-bromo(2-chlorofluoromethoxyphenyl)ethanone (13-4, 0.80 g) and thiourea (0.27 g, 3.6 mmol) in 95% EtOH (8.0 mL) was heated at reflux for 60 min. The solution was concentrated under reduced pressure, and the residue was solved in ethyl acetate. The solution was washed with saturated aqueous NaHCOg, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column tography 0-. silica gel to give 4-(2-chloro- 6—fluoro—4-methoxyphenyl)thiazol—2—y1amine (13-5, 0.30 g, 1.2 mmol) as yellow solids in 39% yield: 1H NMR (500 MHz, CDCl3) 6 6.84 (s, 1 H), 6.65 (m, 1 H), 6.57 (s, 1 H), 3.83 (s, 3 H).
N-(4-(2-Chloroflu0romethoxyphenyl)thiazol-Z-yl)isonicotinamide (13). To a solution of 4-(2—chlorofluoro—4—methoxyphenyl)thiazolylamine (0.10 g, 0.39 mmol) in CH2C12 (10 mL) was added DMAP (95 mg, 0.78 mmol) followed by isonicotinoyl chloride hydrochloride (90 mg, 0.51 mmol). The reaction mixture was stirred at room temperature ht. The solution was concentrated under reduced re and added with water. The resultant precipitate was collected and recrystallized in toluene to give N—(4-(2-chloro—6-fluoro methoxyphenyl)thiazol-2—yl)isonicotinamide (13, 60 mg, 0.17 mmol) as white solids in 42% yield: 1H NMR (500 MHz, CDC13)5 8.76 (s, 2 H), 7.85 (d, J = 4.5 Hz, 2 H), 7.12 (s, 1 H), 6.67 (s, 1 H), 6.45 (m, 1 H), 3.79 (s, 3 H). ESI-MS: m/z 364.2(M + H)+.
N-(4-(2-Chloroflu0romethoxyphenyl)thiazolyl)isonicotinamide (14) CI 0 on o F Cl d @Br——> —> E%HH, N F o F o /0 s 13-3 14_-1 14-2 N \ I \ H3 /o >‘NH 0(2-chloroflunro-6—methoxyphenyl)ethanone (14-1). To a solution of 1-(2—chlor0fluoro—6—methoxyphenyl)ethanone (13-3, 0.60 g, 3.0 mmol) in acetonitrile (15.0 mL) was added TBABr3 (1.4 g, 3.0 mmol). The reaction was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure 2-bromo(2-chloro-4—fluoro-6— methoxyphenyl)ethanone (14-1, 0.84 g), which was used directly for the next step without further ation.
[00143] 4-(2-Chloro—4—fluoromethoxyphenyl)thiazolylamine (14-2). A solution of 2- bromo-l-(2-chloro-4Ffluoroe6smeth0xypheny1)ethanone (14-1, 0.84 g) and thiourea (0.27 g, 3.6 mmol) in 95% EtOH (8.0 mL) was heated at reflux for 60 min. The solution was trated under reduced re, and the e was re-dissolved in ethyl acetate. The solution was washed with saturated aqueous NaHC03, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4-(2-chloro- 4-fluoromethoxyphenyl)thiazol-2—ylamine (14-2, 0.22 g, 0.85 mmol) as yellow solids in 28% yield: 1H NMR (500 MHz, CDC13) 6 6.81 (m, 1 H), 6.60 (m, 1 H), 6.49 (s, 1 H), 3.79 (s, 3 H). 2-Chloroflu0romethoxy-phenyl)thiazolyl)isonicotinamide (14). To a solution of 4-(2—ch10rofluoro-6~meth0xyphenyl)thiazol-2—ylamine (14-2, 0.10 g, 0.39 mmol) in CH2C12 (10 mL) was added DMAP (95 mg, 0.78 mmol) followed by isonicotinoyl chloride hydrochloride (90 mg, 0.51 mmol). The on mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added withvwater. The resultant precipitate was collected and recrystallized in toluene to give N—(4-(2-chlorofluoro—6- methoxyphenyl)-thiazolyl)isonicotinamide (14, 55 mg, 0.15 mmol) as white solids in 39% yield: 1H NMR (500 MHZ, CDC13) 5 8.81 (s, 2 H), 7.91 (d, J: 4.7 Hz, 2 H), 7.12 (s, 1 H), 6.72 (m, 1 H), 6.50 (m, 1 H), 3.75 (s, 3 H); ESI-MS: m/z 364.2(M + H)+.
N-{4-(4-(5-Methoxypyrazinyloxy)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (15) $3.. INI©3 a IIZI°13:3; IZIOQ/T:HH_.Z IIIIEHH -3 1-{4-((5-Methoxypyrazin-2—yl)oxy)-2,6—dimethylphenyl}ethanone (15-1). A mixture of ydroxy—2,6-dimethylphenyl)ethanone (4-2, 3.50 g, 21.3 mmol), 2-bromo—5- methoxypyrazine (6.04 g, 32.0 mmol), copper (271 mg, 4.26 mmol), and potassium carbonate (8.84 g, 64.0 mmol) in 35.5 mL of DMF was stirred at 100 °C overnight. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), concentrated under reduced pressure, and purified by column chromatography on silica gel (20% EtOAc in s as eluant) to give 1-{4-((5— methoxypyrazin—2-yl)oxy)-2,6=dirnethylphenyl}ethanene {15—1, 2.90 g) as yellow oils: 1H NMR (500 MHz, CDC13) 5 7.92 (s, 1 H), 7.87 (s, 1 H), 6.72 (s, 2 H), 3.96 (s, 3 H), 2.47 (s, 3 H), 2.24 (s, 6 H). 2-Brorno{4-((5-methoxypyrazin-Z-yl)oxy)-2,6-dimethylphenyl}ethanone (15- 2). To a solution of l-{4-((5~methoxypyrazin-2—yl)oxy)-2,6-dimethylphenyl}ethanone (15-1, 2.10 g, 7.71 mmol) in acetonitrile (15.4 mL) was added TBABr3 (3.72 g, 7.71 mmol). The reaction was stirred at 50 OC overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl e. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under d re to give 2-bromo{4- ((5—methoxypyrazinyl)oxy)-2,6-dimethylphenyl}ethanone (15-2, 3.1 g), which was used directly for the next step t further purification. ] 4-{4—((5-Methoxypyrazin-2—yl)0xy)-2,6-dimethylphenyl}thiazol-Z-amine (15-3).
A mixture of 2-bromo—l-{4-((5 -methoxypyrazin-2—yl)oxy)-2,6-dimethylphenyl }ethanone (15-2, 2.70 g, 7.69 mmol) and thiourea (0.59 g, 7.69 mmol) in 95% EtOH (11.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2C03 (1.0 mL). The resultant itate was purified by column chromatography on silica gel (EtOAc : hexanes = 2 : 1 as eluant) to give 4-{4-((5-meth0xypyrazinyl)oxy)—2,6- dimethylphenyl}thiazol—2—amine (15-3, 0.40 g) as yellow oils in 16% yield: 1H NMR (500 MHz, CDC13) 5 7.91 (s 1 H), 7.87 (s, l H), 6.77 (s, 2 H), 6.28 (s, 1 H), 5.19 (bs, 2 H), 3.96 (s, 3 H), 2.15 (s, 6 H).
] N-{4-(4-(5-Methoxypyrazinyloxy)-2,6-dimethylphenyl)thiazol-Z- yl}isonic0tinamide (15). To a solution of 4-{4-((5-methoxypyrazinyl)oxy)—2,6- dimethylphenyl}thiazolamine (15-3, 0.40 g, 1.22 mmol) in THF (6.1 mL) was added triethylamine (0.370 g, 3.65 mmol) followed by isonicotinoyl chloride hydrochloride (0.430 g, 2.42 mmol). The reaction mixture was stirred at 60 °C ovemight. The solution was concentrated under d pressure, added with water, and extracted with ethyl e. The organic layer was washed with brine, dried over anhydrous s), and concentrated under reduced pressure. The resultant precipitate was purified by column chromatography on silica gel (EtOAc : hexanes = 5 : l as eluant) to give N-{4-(4—(5-methoxypyrazin-2—yloxy)-2,6- dimethylphenyl)thiazol—2-yl}isonicotinamide (15, 0.12 g) as yellow solids in 23% yield: 1H NMR (500 MHz, CDCl3) 5 8.87 (d, J = 5.0 Hz, 2 H), 8.03 (cl, J = 6.5 Hz, 2 H), 7.96 (s, 1 H), 7.91 (s, 1 H), 6.81 (s, 3 H), 3.97 (s, 3 H), 2.08 (s, 6 H). ESI—MS: m/z 433.4 (M + H)+. ’15 [00150] N-{4-(4-(4-Isopropoxyphenoxy)-2,6-dimethylphenyl)thiazolyl}isonic0tinamide (16) 16-1 16-2 16—3 16-4 0 o _, xO I} .0 _. iOO 0 -NH2 16-5 16-6 Br 3 .
—» AO N H \ V'N / \N S ,- 16 0 1-Bromoisopr0p0xybenzene (16-3). A mixture of 4—bromophenol (16-2, 7.02 g, 39.4 mmol) and potassium carbonate (12.6 g, 90.9 mmol) in DMSO (20.0 mL) was added with 2— iodopropane (16-1, 5.2 mL, 49.0 mmol). The mixture was heated at 60 °C overnight. The solution was cooled to room temperature and added with water (200 mL). The reaction was extracted with EtOAc, dried over MgSO4, and concentrated under reduced re. The residue was purified by flash column chromatography on silica gel (EtOAc : hexanes = l : 100 as eluant) to give 1-bromo-4—isopropoxybenzene (6.66 g) as colorless oil in 79% yield: 1H NMR (CDC13) 5 7.34 (m, 2 H), 6.77 (dd, J: 8.9, 3.1 Hz, 2 H), 4.49 (m, 1 H), 1.33 (s, 3 H), 1.31 (m, 3 H). 1-(4-(4-Isopropoxyphenoxy)-2,6-dimethylphenyl)ethanone (16-4). A mixture of 1-bromo-4—isopropoxybenzene (16-3, 3.02 g, 14.0 mmol), l-(4-hydroxy-2,6— dimethylphenyl)ethanone (4-2, 3.54 g, 21.6 mmol), N,N—dimethylglycine HCl salt (0.50 g, 3.5 mmol), copper iodide (0.34 g, 1.8 mmol), and cesium carbonate (9.08 g, 27.9 mmol) in dioxane (30 mL) was heated at 90 °C for 48 h. The on mixture was cooled to room temperature, added with water, and ted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by colurrm chromatography on silica gel (EtOAc : hexanes = 1 2 20 as eluant) to give 1-(4-(4— isopropoxyphenoxy)-2,6-dimethylpheny1)ethanone (16-4, 2.07 g) as white solids in 79% yield: 1H NMR (500 MHz, CDC13) 5 6.94 (m, 2 H), 6.87 (m, 2 H), 6.58 (s, 2 H), 4.50 (t, J = 6.1 Hz, 1 H), 2.46 (s, 3 H), 2.21 (s, 6 H), 1.34 (s, 6 H), 1.26 (m, 3 H), 0.87 (In, 3 H). 2-Bromo(4-(4-isopropoxyphenoxy)—2,6-dimethylphenyl)ethanone (16-5). To a solution of l—(4—(4—isopropoxyphenoxy)—2,6—dimethylphenyl)ethanone (16-4, 2.00 g, 6.7 mmol) in acetonitrile (20.0 mL) was added TBABr3 (3. 0 g, 6.9 mmol). The reaction was stirred at room temperature for 16 h. The on was concentrated under reduced re, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under d re to give 2-bromo—1-(4-(4— isopropoxyphenoxy)-2,6—dimethylphenyl)ethanone (16-5, 2.57 g), which was used directly for the next step without further purification. 4-(4-(4-Isopropoxyphenoxy)-2,6-dimethylphenyl)thiazolamine (16-6). A e of 2-bromo—l-(4—(4-isopropoxyphenoxy)-2,6-dimethylphenyl)ethanone (16-5, 2.57 g, 6.8 mmol) and thiourea (0.60 g, 7.8 mmol) in 95% EtOH (30.0 mL) was heated at reflux for 4.0 h.
The solution was trated and added with water (10 mL) and saturated aqueous Na2C03 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(4-(4—isopropoxyphenoxy)-2,6-dimethy1pheny1)thiazol—2- amine (16-6, 1.48 g) as yellow solids in 61% yield: 1H NMR (500 MHZ, DMSO-dfi) 6 6.94 (m, 6 H), 6.62 (s, 2 H), 6.33 (s, 1 H), 4.54 (t, J: 6.0 Hz, 1 H), 2.05 (s, 6 H), 1.26 (s, 3 H), 1.25 (s, 3 H).
[00155] N-{4-(4-(4-Isopropoxyphenoxy)-2,6-dimethylphenyl)thiazolyl}isonicotinamide (16). To a solution of 4-(4—(4-isopropoxyphenoxy)-2,6-dimethylphenyl)thiazol—2-amine (16-6, 0.25 g, 0.72 mmol) in CH2C12 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) followed by isonicotinoyl chloride hydrochloride (0.35 g, 1.94 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced re and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-{4-(4—(4- isopropoxyphenoxy)-2,6-dimethy1phenyl)thiazol¥2-y1}isonicotinamide (16, 0.26 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, DMSO‘dé) 5 8.80 (d, J = 5.1 Hz, 2 H), 7.98 (d, J = 5.7 Hz, 1 H), 7.16 (s, 1 H), 6.95 (m, 4 H), 6.69 (s, 2 H), 4.55 (t, J = 6.0 Hz, 2H), 2.05 (s, 6 H), 1.27 (s, 3 H), 1.26 (s, 3 H). ESI-MS: m/z 460.1 (M + H)+.
N-(4-{4-(6-(2-Methoxyethoxy)pyridinyloxy)-2,6-dimethylphenyl}thiazol-2— yl)isonicotinamide (17) Br /0\/\OH \ 'Br I \ o.N N/ ——* | o , Na / ll O N 0 17-1 0 ~— 0 l/ 5-Bromo(2-methoxyethoxy)pyfidine . To a stirred solution of sodium (591 mg, 24.6 mmol) in oxyethanol (20 mL) was added a solution of 5-bromo—2-nitropyridine (17-1, 5.00 g, 24.6 mmol) in 2—methoxyethanol (10 mL) at room temperature. The reaction mixture was stirred at reflux for 2.5 h. The solution was concentrated and the residue was diluted with CHZCIZ and H20. The organic layer was dried and evaporated under reduced pressure to give 0—2—(2-methoxyethoxy)pyridine (17-2, 4.9 g) in 86% yield: 1H NMR (500 MHz, CDCl3) 5 8.16 (d, J: 2. 6 Hz, 1 H), 7.64 (dd, J: 8.7, 2.6 Hz, 1 H), 6.72 (d, J: 8.7 Hz, 1 H), 4.43 (t, J = 6.6 Hz, 2 H), 3.73 (t, 2 H), 3.41 (s, 3 H). ESI—MS: m/z 232.0 (M + H)+.
N—(4—{4—(6-(2—Methoxyethoxy)-pyridinyloxy)-2,6-dimethylphenyl}thiazol nicotinamide (17). To a solution of N—(4-(4—Hydroxy-2,6-dimethy1phenyl)-thiaz01-2— yl)isonicotinamide (5-3, 0.98 g, 3.0 mmol) in DMF (10 mL) were added cesium carbonate (1.95 stirred at g, 6.0 mmol, 2.0 equiv) and Cu (58.5 mg, 0.90 mmol, 0.3 equiv). The e was 100—1 10 °C for 1.0 h and added with 5-bromo(2-methoxyethoxy)pyridine (17-2, 1.04 g, 4.5 mmol). The solution heated at 130 °C for 24 h. The reaction mixture was added with water (40 mL) and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous ium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate = 3/1—1/3) to give 17 (0.94 g) in 66% yield: 1H NMR (500 MHz, CDC13) 5 8.81 (d, 2 H), 7.93 (d, 1 H), 7.88 (d, 2 H), 7.32 (m, 1 H), 6.82 (d, 2 H), 6.57 (s, 2 H), 4.45 (t, 2 H), 3.75 (t, 2 H), 3.44 (s, 3 H), 1.99 (s, 6 H), ESI-MS = m/z 477.2 (M + H)+.
N-(4-{4—((5-Methoxypyridinyl)oxy)-2,6-dimethylphenyl}thiazol yl)isonic0tinamide (18) HO 0 / N o / N MeO . 0 18-1 4-2 / N o ‘—’ \ MeO MeO N\ \ >77NH2 18' 184' Br S N o —* U <11 \ N H MeO \>”N\ / \ S —/ 18 0 ] 1-{4-((5-Methoxypyridinyl)oxy)-2,6-dimethylphenyl}ethan0ne (18-2). A mixture of 2-brorno—5—methoxypyridine (18-1, 1.03 g, 5.46 mmol), 1-(4-hydroxy-2,6— dimethylphenyl)ethanone (4-2, 0.80 g, 4.89 mmol), ethylglycine HCl salt (0.28 g, 1.95 mmol), copper iodide (0.24 g, 1.24 mmol), and cesium carbonate (3.57 g, 10.96 mmol) in dioxane (10 mL) was heated at 120 °C for 4.0 h. The reaction mixture was cooled to room temperature, added with water, and ted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated to give 1-{4-((5-methoxypyridin yl)oxy)—2,6—dimethylpheny1}ethanone (18-2, 1.42 g) as a yellow oil in 96% yield, which was used directly for the next step without r purification.
[00161] 2-Bromo{4-((S-methoxypyridin-Z-yl)oxy)-2,6-dimethylphenyl}ethanone (18-3).
To a solution of 1-{4—((5-methoxypyridin-2—yl)oxy)-2,6-dimethylphenyl}ethanone (18-2, 1.42 g, . 5.23 rnmol) in acetonitrile (20.0 mL) was added TBABr3 (2.70 g, 5.49 mmol). The reaction was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give 2-bromo{4—((5— methoxypyridin-Z-yl)oxy)-2,6—dimethylpheny1}ethanone (18-3, 1.89 g), which was used ly for the next step without further purification. 4-{4-((S-Methoxypyridinyl)oxy)-2,6-dimethylphenyl}thiazolamine (18-4). A mixture of 2-bromo-1—{4-((5-methoxypyridin—2-yl)oxy)-2,6-dimethy1phenyl}ethanone (18-3, 1.89 g, 5.40 mmol) and thiourea (0.47 g, 6.18 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated hot water. aqueous Na2C03 (1.0 mL). The resultant itate was d and washed with The solids were filtered and dried under vacuum to give 4—{4-((5—methoxypyridinyl)oxy)-2,6- dimethylphenyl}thiazol—2-amine (18-4, 0.10 g) as yellow solids in 5.7% yield: 1H NMR (500 MHz, CDC13) 6 7.60 (m, 1 H), 7.30 (in, 1 H), 6.89 (m, 1 H), 6.77 (s, 2 H), 6.25 (s, 1 H), 3.83 (s, 3 H), 2.17 (s, 6 H).
] N-(4-{4-((5-Methoxypyridinyl)oxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (18). To a solution of 4-{4-((5-methoxypyridin-2—y1)oxy)-2,6— dimethylphenyl}thiazolamine (18-4, 0.10 g, 0.31 mmol) in CH2C12 (5.0 mL) was added triethylamine (0.50 mL, 3.6 mmol) followed by isonicotinoyl de hloride (0.15 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N—(4-{4-((5—methoxypyridinyl)oxy)-2,6- dimethylphenyl}thiazolyl)isonicotinamide (18, 0.070 g) as light yellow solids in 52% yield: 1H NMR (500 MHZ, DMSO-dg) 5 8.81 (d, J = 5.5 Hz, 2 H), 7.99 (dt, J: 3.1, 1.5 Hz, 2 H), 7.92 (d, J: 3.1 Hz, 1 H), 7.52 (dt, J = 5.7, 3.2 Hz, 1 H), 7.20 (s, 1 H), 7.00 (d, J: 8.8 Hz, 1 H), 6.81 (s, 2 H), 3.81 (s, 3 H), 2.08 (s, 6 H). ESI—MS: m/z 433.0 (M + H)+.
N-{4-(2,6-Dimethyl(pyrazinylthio)phenyl)thiazolyl}-2— fluoroisonicotinamide (19) S x ’ MHz N I />~ LCNNH / E l/ N ———» N / N \N s \ l N S 19 11-5 N-{4-(2,6-Dimethyl(pyrazinylthio)phenyl)thiazolyl} fluoroisonicotinamide (19). To a solution of 4-(2,6-dimethyl—4-(pyrazin )phenyl)thiazolamine (ll-5, 200 mg, 0.60 mmol) in CHZClz (2.0 mL) was added triethylamine (0.20 mL, 1.9 mmol) followed by 2-fluoroisonicotinic acid (107.7 mg, 1.0 mmol), - l-ethyl(3-dimethylamin0propyl)carbodiimide hydrochloride (243.9 mg, 1.27 mmol) and hydroxybenzotriazole (172.0 mg, 1.27 mmol). The reaction mixture was stirred at room ature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was d, and dried under vacuum to give N—{4-(2,6-dimethyl- 4—(pyrazin-2—y1thio)phenyl)thiazoly1}—2-fluoroisonicotinamide (19, 68.4 mg) as yellow solids in 25% yield: 1H NMR (500 MHz, fi) 5 13.10 (s, 1 H), .50 (m, 2 H), 8.36—8.41 (m, 2 H), 7.96 (s, 1 H), 7.80 (s, 1 H), 7.41 (s, 2 H), 7.33 (s, 1 H), 2.13 (s, 6 H); ESI—MS: m/z 438.1 (M + H)+. 2-Fluoro-N-(4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (20) o O MeO\/\ O N —> MeO\/\O/©/ N 0 i ’1] >—NH2 \ ‘>’NH / \N ] -N—(4-{4-(4-(2-meth0xyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (20). To a solution of 4-{4-(4—(2—methoxyethoxy)phenoxy)—2,6- dimethylphenyl}thiazol-2—amine (12-6, 180 mg, 0.5 mmol) in CH2C12 (2.0 mL) was added triethylamine (0.20 mL, 1.5 mmoL) followed by 2-fluoroisonicotinic acid (82.3 mg, 0.70 mmol), 1-ethyl(3-dimethy1aminopropy1)carbodiimide hydrochloride (186.3 mg, 1.0 mmol), and L1ydto)(ybeniotriazole (131.4 mg, 1.0 mmol). The re°etion mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered, and dried under vacuum to give fluoro—N—(4-{4-(4- (2—methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2—yl)isonicotinamide (20, 186.3 mg) as yellow solids in 35% yield: 1H NMR (500 MHz, DMSO'd6) 8 13.10 (s, 1 H), 8.47 (s, 1 H), 7.94— 7.95 (m, 1 H), 7.80 (s, 1 H), 7.19 (s, 1 H), 6.97—7.02 (m, 4 H), 6.69 (s, 2 H), 4.02—4.09 (m, 2 H), 3.65—3.67 (m, 2 H), 3.29 (s, 3 H), 2.05 (m, 6 H). ESI—MS: m/z 494.1 (M + H)+.
N-(4-{4-(4-(3-meth0xypropoxy)phenoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (21) 162 21-1 212 l />~NH . 0° WM. 1?? . “WW/T1155“ 21“ Br 0 21-5 o(3-methoxypropoxy)benzene . A mixture of 4-bromophenol (16- 2, 1.01 g, 5.72 mmol), sodium iodide (1.02 g, 6.83 mmol), and potassium carbonate (1.88 g, 13.6 mmol) in acetonitrile (10.0 mL) was added with 1-chloromethoxyethane (21-1, 0.89 g, 8.0 mmol). The mixture was heated to 60 °C for 48 h. The on mixture was cooled to room ature and added with water (200 mL). The solution was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc : hexanes = 1 : 20 as eluant) to give o—4-isopropoxybenzene (21-2, 0.95 g) as a colorless oil in 68% yield: 1H NMR (CDC13) 6 7.36 (dt, J i 5 .0, 2.0 Hz, 2 H), 6.78 (m, 2 H), 4.02 (t, J: 6.3 Hz, 2 H), 3.54 (t, J = 6.1 Hz, 2 H), 3.35 (s, 3 H), 2.03 (t, J: 6.2 Hz, 2 H). 1-{4-(4-(3-Methoxypr0poxy)phenoxy)-2,6-dimethylphenyl}ethanone (21-3). A mixture of 1-bromo-4—isopropoxybenzene (21-2, 0.85 g, 3.9 mmol), l-(4—hydroxy-2,6- dimethylphenyl)ethanone (4-2, 1.10 g, 6.71 mmol), N,N—dimethylglycine HCl salt (0.21 g, 1.5 mmol), copper iodide (0.12 g, 0.60 mmol), and cesium carbonate (2.90 g, 8.91 mmol) in dioxane (15.0 mL) was stirred at 120 °C for 48 h. The reaction mixture was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated, and purified by flash column chromatography on silica gel ...........(EtOAc :hexanes .=.1 .: 5aseluant) to give. l-{.4-(4-(3:methoxypro.p.oxy.)phenoxy)—2,6—. . - . - - . . - - - - i -. . . . . . -. dimethylphenyl}ethanone (21-3, 0.27 g) as yellow oil in 21% yield: 1H NMR (CDC13) 5 6.96 (dd, J = 4.5, 2.2 Hz, 2 H), 6.89 (dd, J = 4.3, 2.4 Hz, 2 H), 6.57 (s, 2 H), 4.05 (m, 2 H), 3.57 (t, J = 6.2 Hz, 2 H), 3.36 (s, 3 H), 2.66 (s, 3 H), 2.20 (s, 6 H), 2.05 (t, J = 6.2 Hz, 2H). 2=Bromo=l={4=(4—(3-meth0xypropoxy)phenoxy)-2,6-dimethylphenyl}ethanone (21-4). To a solution of 1-{4-(4—(3-methoxypr0poxy)phenoxy)-2,6-dimethylphenyl}ethanone (21-3, 0.27 g, 0.82 mmol) in acetonitrile (5.0 mL) was added TBABr3 (0.46 g, 0.93 mmol). The reaction was stirred at room ature for 16 h. The solution was concentrated under reduced pressure, added with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give 2-bromo—l-{4-(4- (3—methoxypr0poxy)phenoxy)-2,6—dimethylphenyl}ethanone (21-4, 0.34 g), which was used directly for the next step without further cation.
[00172] 4-{4-(4-(3-Methoxypropoxy)phenoxy)—2,6-dimethylphenyl}thiazolamine (21- ). A mixture of 2—bromo{4-(4-(3-methoxypropoxy)phenoxy)-2,6—dimethylphenyl}ethanone (21-4, 0.34 g, 0.82 mmol) and thiourea (0.07 g, 0.96 mmol) in 95% EtOH (5 .0 mL) was heated at reflux for 2.0 h. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water.
The solids were filtered and dried under vacuum to give 4-{4—(4-(3-methoxypropoxy)phenoxy)- 2,6-dimethy1phenyl}thiazol-2—amine (21—5, 0.28 g) as yellow solids in 90% yield, which was used directly for the next step without further purification.
N-(4-{4-(4-(3-Methoxypropoxy)phen0xy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (21). To a solution of 4-{4—(4-(3-methoxypropoxy)phenoxy)-2,6- dimethylphenyl}thiazol—2-amine (21-5, 0.28 g, 0.74 mmol) in CH2C12 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) ed by isonicotinoyl chloride hydrochloride (0.22 g, 1.22 mmol). The reaction mixture was stirred at room temperature overnight. The solution was trated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-(4-{4-(4—(3-methoxypropoxy)phenoxy)-2,6— dimethylphenyl }thiazolyl)isonicotinamide (21, 0.99 mg) as light yellow solids in 27% yield: 1H NMR (500 MHz, DMSO-dé) 5 13.00 (s, 1 H), 8.81 (s, 2 H), 7.99 (d, J = 5.7 Hz, 2 H), 7.15 (s, 1 H), 6.98 (m, 4 H), 6.68 (s, 2 H), 4.00 (t, J = 6.3 Hz, 2 H), 3.47 (t, J = 6.3 Hz, 1 H), 2.05 (s, 6 H), 1.94 (t, J = 6.3 Hz, 2 H). ESI-MS: m/z 489.7 (M + H)+.
] N-(4—{4-(5-(Z-Methoxyethoxy)pyrazinyloxy)-2,6-dim"thylphenyi}thiazol yl)isonicotinamide (22) fl 3‘ ——'> 0 INF” —) / \/\0 Br \N \N 22-1 22-2 2-Bromo(2-methoxyethoxy)pyrazine . A mixture of 2,5-dibromopyrazine (22-1, 20.0 g, 84.1 mmol), 2-methoxyethanol (6.40 g, 84.1 mmol), and sodium tert—butoxide (11.3 g, 118 mmol) in 168 mL of THF was stirred at room temperature ovemight. The solution was concentrated under d pressure and added with ethyl acetate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The e was purified by column chromatography on silica gel (EtOAc : hexanes = 1 : 5 as eluant) to give 2-bromo(2- methoxyethoxy)pyrazine (22-2, 17.2 g) as yellow oil in 88% yield: 1H NMR (500 MHZ, CDC13) 6 8.16 (d, J: 1.0 Hz, 1H), 8.07 (d, J: 1.0 Hz, 1 H), 4.46 (t, J = 5.0 Hz, 2 H), 3.74 (m, 2 H), 3.43 (s, 3 H).
N-(4-(4-{(5-(2-Meth0xyethoxy)pyrazinyl)oxy}-2,6-dimethylphenyl)thiazol yl)isonicotinamide (22). A mixture of 5—3 (0.50 g, 1.54 mmol), 2-bromo(2- yethoxy)pyrazine (22-2, 0.540 g, 2.32 mmol), copper iodide (15.0 mg, 0.080 mmol), and potassium carbonate (0.64 g, 4.63 mmol) in 3.1 mL of DMF was heated at 100 °C for 6.0 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc : hexanes = 5 : 1 as eluant) to give N—(4-(4-{(5-(2— methoxyethoxy)pyrazin-2—y1)oxy}-2,6-dimethylphenyl)thiazolyl)isonicotinamide (22, 0.19 g) as brown solids: 1H NMR (500 MHz, CDC13) 8 8.77 (d, J =. 4.5 Hz, 2H), 7.91 (d, J = 1.0 Hz, 1 H), 7.88 (d, J: 1.0 Hz, 1 H), 7.73 (d, J = 5.5 Hz, 2 H), 6.79 (s, 1 H), 6.63 (s, 2 H), 4.46 (t, J = 4.5 Hz, 2 H), 3.75 (t, J = 4.5 Hz, 2 H), 3.43 (s, 3 H), 1.98 (s, 6 H). ESI-MS: m/z 478.2 (M + H)+.
N-(4-{4-(2-(Dimethylamino)ethoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (23)
[00178] N-(4-{4-(2-(Dimethylamino)ethoxy)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (23). From the reaction of 5-3 with equal molar of 2-chloro-N,N— dimethylethanamine and NaH in DMF: 1H NMR (500 MHz, DMSO-d6) 8 8.72 (s, 2 H), 8.19 (d, J = 5.9 Hz, 2 H), 6.91 (s, 1 H), 6.70 (s, 2 H), 4.63 (s, 1 H), 4.31 (t, J: 6.8 HZ, 2 H), 2.92 (s, 2 H), 2.50 (s, 6 H), 2.11 (s, 6 H). ESI-MS: m/z 397.2 (M + H)“.
[00179] N-{4-(2,6-Dimethyl(6-nitr0pyridinyloxy)phenyl)thiazol yl}isonicotinamide (24) 00. OZN o U‘BrN\ _ o __ . + N s0 4\ / N >5. 1 S\>—NH / OZN N \ I >—NH ’ 24-1 5-3 24 N-{4-(2,6-Dimethyl(6-nitropyridinyloxy)phenyl)thiazol-2— nicotinamide (24). A solution of 5-3 (1.92 g, 5.91 mmol) in DMF (15 mL) was added with cesium carbonate (2.41 g, 7.39 mmol). The reaction mixture was heated at 50 °C for 60 min and added with 5-bromonitropyridine (24-1, 1.80 g). The on e was heated at 50 °C for 4.0 h. The solution was quenched with water (40 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium e. The solvent was evaporated under reduced pressure and the residue was purified by column tography (NH silica gel, hexane/ethyl acetate 2 3/1—1/3) to give 24 (1.76 g) in 67% yield: 1H NMR (500 MHz, DMSO-ds) 5 8.78 (d, 2 H), 8.42 (d, 1 H), 8.33 (d, 1 H), 7.96 (d, 2 H), , l H), 7.21 (s, 1 H), 7.01 (s, 2 H), 2.08 (s, 6 H), ESI—MS =’m/z 447.5 (M + H)+.
N—{4-(4-(5-Methoxypyrazin-Z-ylthio)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (25) N\ \O/ENj/zlO/C:lj/8%“: \ S)” //N—>NH \ NH 0 fg/TCN -1 N-{4-(4-(5-Meth0xypyrazinylthio)-2,6-dimethylphenyl)thiazol-2— yl}isonicotinamide (25). A mixture of N-(4-(4—iodo-2,6-dimethylphenyl)thiazol—2- yl)isonicotinamide (25-1, 173.5 mg, 0.40 mmol), oxypyrazinethiol (25-2, 170 mg, 17.5 mmol), copper iodide (3.8 mg, 0.02 mmol), and potassium carbonate (165.3 mg, 1.2 mmol) in DMF (2 mL) was heated at 80 °C for 16 h. The solution was added with water and extracted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced re. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexanes as ) to provide N—{4—(4=(5amethoxypyrazinEZ-ylthio)-2,6- dimethylphenyl)thiazolyl}isonicotinamide (25, 135 mg) as yellow solids in 24% yield: 1H NMR (500 MHz, DMSO'dé) 5 8.77 (s, 2 H), 8.28 (s, 1 H), 8.18 (s, 1 H), 7.94—7.95 (m, 2 H), 7.14—7.21 (m, 3 H), 3.88 (s, 3 H), 2.03 (s, 6 H). ESI—MS: m/z 450.3 (M + H)+.
N—{4-(2,6-Dimethy1(4-phenoxyphenoxy)phenyl)thiazelyl}isonieotinamide “tsp 000%» 000% 26—1 26-2 26-3 —’ (>00 (2%,“HT; (100 1 ’1:Skit—C“ 26-4 26 To a solution of , 1-(2,6-Dimethyl(4-phenoxyphenoxy)phenyl)ethanone (26-2). 1-(4-chloro-2,6-dimethylphenyl)ethanone (26-1, 5.00 g, 27.4 mmol), K3PO4 (11.6 g, 54.6 mmol), and 4—phenoxyphenol (6.12 g, 32.9 mmol) in toluene (39.1 mL) was added 2—di-tert— WO 82324 butylphosphino—2',4',6'-triisopr0pylbiphenyl (349 mg, 0.82 mmol) and Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100 °C for 4.0 h under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc : hexanes = 1 : 10 as eluant) to give 1—(2,6-dimethyl(4-phenoxyphenoxy)phenyl)ethanone (26-2, 7.70 g) as white solids in 85% yield: 1H NMR (500 MHz, CDC13) 5 7.34—7.37 (m, 2 H), .13 (m, 1 H), .04 (m, 6 H), 6.65 (s, 2 H), 2.49 (s, 3 H), 2.24 (s, 6 H). 2-Bromo(2,6—dimethyl(4-phenoxyphenoxy)phenyl)ethanone . To a solution of 1-(2,6-dimethy1—4-(4—phenoxyphenoxy)pheny1)ethanone (26-2, 7.70 g, 23.2 mmol) in acetonitrile (46.3 mL) was added TBABr3 (11.2 g, 23.2 mmol). The reaction mixture was stirred at room temperature overnight. The solution was trated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo(2,6-dimethy1— 4—(4—phenoxyphenoxy)phenyl)ethanone (26-3, 11.2 g), which was used directly for the next step without further purification. 4-(2,6-Dimethyl(4-phenoxyphenoxy)phenyl)thiazolamine (26-4). A mixture of o-l-(2,6-dimethyl—4-(4—phenoxyphenoxy)phenyl)ethanone (26-3, 9.53 g, 23.2 mmol) and thiourea (1.76 g, 23.1 mmol) in 95% EtOH (33.1 mL) was heated at reflux for 60 min. The solution was trated and added with water (100 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and washed with ethyl acetate. The solids were dried under vacuum to give 4-(2,6-dimethyl—4-(4-phenoxyphenoxy)phenyl)thiazol-2—amine (26-4, 9.00 g) as brown solids in 100% yield, Which was used directly for the next step without r purification.
[00187] N—{4-(2,6-Dimethyl(4-phenoxyphenoxy)phenyl)thiazol-Z-yl}isonicotinamide (26). To a solution of 4-(2,6—dimethyl—4-(4-phenoxyphenoxy)phenyl)thiazolamine (26-4, 0.500 g, 1.29 mmol) in THF (6.4 mL) was added triethylamine (0.39 g, 3.86 mmol) followed by . isonicotinoyl chloride hydrochloride (0.46 g, 2.58 mmol). The reaction mixture was stirred at 60 oC overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was d and dried to give N—{4-(2,6—dimethyl(4- phenoxyphenoxy)pheny1)thiazolyl}isonicotinamide (26, 0.51 g) as light yellow solids in 80% yield: 1H NMR (500 MHz, CDC13) 8 8.72 (m, 2 H), 7.61 (m, 2 H), 7.31—7.34 (m, 2 H), 7.08—7.10 (m, 1 H), 6.94—7.02 (m, 6 H), 6.80 (s, 1 H), 6.49 (s, 2 H), 1.94 (s, 6 H). ESI-MS: m/z 494.2 (M + H)+.
N-(4—{4—(5-(2-methoxyethoxy)pyrazin-2—ylthio)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (27) \E I -—-> \ \ N SH N Br 27-1 27-2 N S I I 0 ’ l >—NH — ] 5-(2—Methoxyethoxy)pyrazinethiol (27-2). A mixture of o-5 —(2— methoxyethoxy)pyrazine (27-1, 5.00 g, 21.5 mmol) and NaSH-xHZO (4.81 g, 85.8 mmol) in 35.5 mL of DMF was d at 80 °C for 3.0 h. The reaction e was concentrated under reduced concentrated re and added with methanol. The mixture was filtered and the filtrate was ,.._. CD under reduced pressure and washed with ethyl acetate. The resultant precipitate was dried under reduced pressure to give 5—(2—methoxyeth0xy)pyrazinethiol (27-2, 3.90 g) as yellow solids.
N-(4-{4-(5-(2-Meth0xyethoxy)pyrazinylthio)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (27). A mixture of 25-1 (3.00 g, 6.89 mmol), 5-(2-meth0xyethoxy)pyrazine- 2—thiol (27-2, 2.57 g, 13.8 mmol), copper iodide (66.0 mg, 0.35 mmol), and potassium carbonate (2.86 g, 20.7 mmol) in 13.8 mL ofDMF was stirred at 100 °C for 7.0 h. The reaction mixture was trated under reduced pressure and purified by column chromatography on silica gel (EtOAc : hexnaes = 2 : l as eluant) to give N—(4—{4-(5—(2—methoxyethoxy)pyrazinylthio)—2,6- dimethylphenyl}th'iazol—2-yl)isonicotinamide (27, 2.00 g) as light yellow solids in 59% yield: 1H NMRtseoMH 9136326835, rd, 1? 4-0HH 2H1a§~l9(5171?,1-0112; 1H» 809,6 J,=,,,1:9, .
Hz, 1 H), 7.63 (d, J: 5.0 Hz, 2 H), 6.96 (s, l H), 6.79 (s, 2 H), 4.44 (t, J i 4.5 Hz, 2 H), 3.72 (t, J = 4.5 Hz, 2 H), 3.41 (s, 3 H), 1.95 (s, 6 H). ESI—MS: m/z 494.2 (M + H)+.
N-(4-(4-{5-(2-(Dimethylamino)ethoxy)pyrazinylthio}-2,6- dimethylphenyl)thiazolyl)isonicotinamide (28) WO 82324 N Br N Br Aw + —+ 0“ i \ / l. I I a\ Br N / \/\o N 28-1 23-2 28-3 /N s /N SH [L I \ j/ l N —> / \/\o N \ MLx. 23 er:«— 2-((5-Bromopyrazin-2—yl)0xy)-N,N-dimethylethanamine (28-3). To a solution of 2—(dimethylamino)ethanol (28-1, 8.00 g, 78.9 mmol) in THF (100 mL) was added sodium tert- butoxide (10.0 g, 102.0 mmol) at room temperature. The on was stirred for 15 min. The reaction mixture was cooled to 0 °C and added with a solution of 2,5—dibromopyrazine (28-2, .0 g, 82.4 mmol) in THF (100 ml) slowly in a period of 5.0 min. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with ethyl acetate and washed with saturated NH4C1. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give 2—((5 —bromopyrazinyl)oxy)-N,N— dimethylethanamine (28-3, 17.0 g) as yellow oils in 88% yield: 1H NMR (500 MHz, CDC13) 6 8.46 (s, 1H), 8.16 (d, J: 1.1Hz, 1 H), 8.06 (d, J: 1.1 Hz, 1 H), 4.68 (t, J: 4.8 Hz, 2 H), 3.20 (s, 2 H), 2.70 (s, 6 H). 5-(2-(Dimethylamino)ethoxy)pyrazinethiol (28-4). A mixture of 2-((5- bromopyrazin-2—y1)oxy)-N,N—dimethylethanamine (28-3, 3.10 g, 12.6 mmol) and NaSH-xHZO (5.20 g, 92.8 mmol) in DMF (30 mL) was heated at 80 0C for 3.0 h. The reaction mixture was concentrated under reduced pressure and added with methanol. The mixture was filtered and the e was concentrated under reduced pressure and washed with ethyl acetate. The resultant precipitate was dried to give 5—(2—(dimethylamino)ethoxy)pyrazinethiol (28-4, 1.87 g) as yellow solids, which was used directly for the next step without further purification. 2O [00194] N-(4-(4-{5-(2-(Dimethylamino)ethoxy)pyrazinylthi0}-2,6- ylphenyl)thiazolyl)isonicotinamide (28). A mixture of N—(4-(4-iodo-2,6- dimethylphenyl)thiazolyl)isonicotinamide (0.51 g, 1.2 mmol), 5-(2— (dimethylamino)ethoxy)pyrazine—2-thiol (28-4, 0.96 g, 4.8 mmol), copper iodide (73.0 mg, 0.38 mmol), and potassium ate (0.64 g, 4.6 mmol) in 5.0 mL of DMF was heated at 100 °C for 16 h. The reaction mixture was concentrated under reduced re and purified by column chromatography on silica gel (MeOH : CHzClz = 1 : 10 as eluant) to give 4-{5—(2- (dimethylamino)ethoxy)pyrazinylthio}-2,6—dimethylphenyl)thiazolyl)isonicotinamide (28, 0.28 g) as light yellow solids in 47% yield: 1H NMR (500 MHz, CD3OD) 5 8,75 (s, 2 H), 8.14 (d, 2012/067132 J: 1.1 Hz, 1 H), 8.04 (s, 1 H), 7.97 (d, J = 5.9 Hz, 2 H), 7.18 (s, 2 H), 7.00 (s, 1 H), 4.58 (s, 3 H), 4.46 (t, J: 5.5 Hz, 2 H), 2.81 (t, J: 5.4 Hz, 2 H), 2.37 (s, 6 H), 2.10 (s, 6 H). ESI-MS: m/z 507.1 (M + H)+.
N-(4-{4-(6-(2-Methoxyethylamino)pyridinyloxy)-2,6-dimethylphenyl}thiazol- 2-yl)isonicotinamide (29) /O\/\C| H sfl: N N / NaH/DMF \ 29-2 .
. N\>—NH\ S-Bromo-N-(2-methoxyethyl)pyridin-Z-amine (29-2). 5-Bromo-py1idinylamine (29-1, 1.43 g, 8.27 mmol) was dissolved in anhydrous DMF (20 mL) under N2. The solution was cooled to 0—5 °C and added with NaH (>1.0 equiv) until no hydrogen was formed. The solution j—A <3 was added with 1—chloromethoxy—ethane (2.5 ml, 14 mmol) dropwisely at 0—5 °C. The reaction mixture was stirred at 0 °C for 50 min. The solution was quenched with methanol and saturated aqueousiNIV—I47Cl. [Theisolution was concentrated under reduced pressure and distributed between water, brine, and dichloromethane. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column tography on silica gel to give 5- bromo-N—(2-methoxyethyl)pyridinarnine (29-2, 1.01 g) as brown solids in 53% yield: 1H NMR (500 MHz, CDCl3) 8 8.01 (d, 1 H), 7.57 (d, 1 H), 6.57 (d, 1 H), 3.97 (t, 2 H), 3.49 (t, 2 H), 3.35 (s, 3 H). ESI-MS; m/z 231.0 (M + H)+.
N—(4-{4—(6-(2—Methoxy-ethylamino)-pyridinyloxy)-2,6-dimethyl-phenyl}- lyl)-isonicotinamide (29). To a solution of 5-3 (325 mg, 1.0 rnmol) in DMF (15 mL) were added cesium carbonate (650 mg, 2.0 mmol, 2.0 equiv) and Cu (19.5 mg, 0.30 mmol, 0.3 equiv). The solution was stirred at 100—1 10 °C for 60 min and added with 5-bromo—N—(2- xyethyl)pyridinamine (29-2, 347 mg). The reaction mixture was d at 140 0C for 48 h. The reaction was quenched with water (40 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and trated under reduced pressure. The residue was purified by column chromatography (NH silica gel, /ethyl acetate = 3/1—1/3) to give 29 (96 mg) in 16% yield: 1H NIVIR (500 MHZ, CDC13) 8 8.81 (d, 1 H), 7.72 (d, 1 H), 7.71 (d, 1 H), 7.24 (In, 1 H), 6.81 (s, 1 H), 6.72 (d, 1 H), 6.49 (s, 1 H), 3.59 (t, l H), 3.51 (t, 1 H), 3.35 (s, 3 H), 2.01 (s, 6 H), ESI-MS = m/z 447.5 (M + H)+.
N-{4-(2-Fluoro-4—(4—methoxyphenoxy)methylphenyl)thiazol yl}isonicotinamide (30) M7969999% -1 F F -2 30-3F a £1fly Um_. -5 306 N >—(: >—NH2 l >‘NH N-(4-Acetylfluoromethylphenyl)acetamide (30-2). A dry CS; solution (42 mL) containing N-(3 —fluorornethylpheny1)acetamide (30-1, 5.00 g, 29.9 mmol) and acetyl chloride (3.2 mL, 45 mmol) was slowly added with aluminum chloride (10 g, 74.8 mmol). The reaction mixture was heated at reflux for 2.0 h. The solution was cooled to room temperature and CS2 was decanted. The remaining syrup was poured into icy HCl, and the resultant solids were collected, re-dissolved in EtOH, and decolorized by charcoal. The solution was filtered and the filtrate was trated under vacuum to give N—(4-acetylfluoro-5 -methy1—phenyl)acetamide (30-2, 6.10 g, 29.2 mmol) as light yellow solids in 97% yield: 1H NMR (500 MHZ, CDCI3) 8 7.46 (d, J: 12.4 Hz, 1H), 6.93 (s, l H), 2.53 (d, J: 3.8 Hz, 3 H), 2.31 (s, 3 H), 2.18 (s, 3 H).
[00200] 1-(4-Aminofluoromethylphenyl)ethanone (30-3). An ethanol solution (51 mL) containing N—(4—acetyl-3—fluoro-5—methy1pheny1)acetamide (30-2, 5.80 g, 27.7 mmol) and concentrated hydrochloric acid (20.0 mL) was heated at reflux for 15 h. The solution was added with 10% aqueous NaOH and the resultant solids were ted to give 1-(4—aminochloro methylphenyl)ethanone (30-3, 4.00 g, 23.9 mmol) as light yellow solids in 86% yield: 1H NMR (500 MHz, g) 5 6.22 (m, 2 H), 2.37 (m, 3 H), 2.22 (s, 3 H). ESI-MS: m/z 167.8 (M + H)+. luoroiodomethylphenyl)ethanone (30-4). A CH3CN solution (48 mL) containing KI (4.80 g, 28.8 mmol) and tert—butyl nitrite (3.90 mL, 32.4 mmol) was added with 1— (4-aminofluoro—6-methy1pheny1)ethanone (30-3, 4.0 g, 24.0 mmol) in CH3CN (32 mL) at —10 °C. The reaction mixture was warmed to room temperature and poured into aqueous HCl. The on was extracted with EtOAc, and the organic layer was separated, washed with H20, dried over MgSO4(s), and concentrated under d pressure. The e was purified by flash column chromatographyon silica gel to give 1-(2-f1uoro-4—iodo-6—methylphenyl)ethanone (30-4, 1.4 g, 5.0 mmol) as brown oil in 21% yield: 1H NMR (500 MHZ, CDC13) 5 7.36 (s, 1 H), 7.29 (d, J: 9.2 Hz, 1 H), 2.49 (d, J = 3.2 Hz, 3 H), 2.26 (s, 3 H). 1-(2-Fluoro(4-methoxyphen0xy)methylphenyl)ethanone (30-5). To a solution of 1—(2-fluoro—4-iOdo—6-methy1phenyl)ethanone (30-4, 1.1 g, 4.0 mmol), K3PO4 (1.7 g, 8.0 mmol), 4—methoxy-phenol (0.60 g, 4.8 mmol) in toluene (20 mL) was added ert— butylphosphino-Z'A',6'-triisopropylbiphenyl (51 mg, 0.12 mmol), Pd(OAc)2 (38 mg, 0.08 mmol).
The on was heated at 100 °C overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced re. The residue was purified by flash column chromatography on silica gel to give 1-(2-fluoro(4— methoxyphenoxy)methy1pheny1)ethanone (0.47 g, 1.7 mmol) as yellow oil in 43% yield: 1H NMR (500 MHz, CDC13)'6 6.97 (In, 2 H), 6.90 (m, 2 H), 6.54 (s, 1 H), 6.42 (m, 1 H), 3.80 (s, 3 H), 2.50 (d, J = 4.1 Hz, 3 H), 2.30 (s, 3 H). ESI—MS: m/z 275.0 (M + H)+. ] 2-Bromo(2-fluoro(4-methoxyphenoxy)methylphenyl)ethanone . To a solution of 1—(2-fluoro(4-methoxyphenoxy)methylphenyl)ethanone (0.470 g, 1.71 mmol) in acetonitrile (23.0 mL) was added TBABr3 (0.830 g, 1.71 mmol). The reaction was stirred at room temperature for 30 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo(2—fluoro(4- methoxyphenoxy)—6-methylphenyl)ethan0ne (30-6, 0.60 g), which was used directly for the next step without further purification. 4-(2-Fluor0(4-methoxyphenoxy)methylphenyl)thiazolylamine (30-7). A mixture of 2-bromo(2-fluor0—4-(4-methoxyphenoxy)methylphenyl)ethan0ne (30-6, 0.60 g) and thiourea (0.160 mg, 2.05 mmol) in 95% EtOH (12.0 mL) was heated at reflux for 60 min.
The solution was concentrated under reduced pressure, and the residue was re—dissolved in ethyl acetate. The on was washed with saturated aqueous , dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 4~(2—fluoro(4-methoxyphenoxy)—6-methylphenyl)thiazol—2-ylamine (30-7, 0.450 g, 1.36 mmol) as yellow solids in 80% yield: 1H NMR (500 MHz, CDClg) 5 6.98 (d, J = 9.0 Hz, 2 H), 6.89 (d, J: 9.0 Hz, 2 H), 6.60 (s, 1 H), 6.49 (d, J: 10.9 Hz, 1 H), 6.41 (s, 1 H), 3.80 (d, J: 3.4 Hz, 3 H), 2.26 (s, 3 H). ESI-MS: m/z 331.0 (M + H)+.
N-{4-(2-Fluoro(4-methoxyphenoxy)methylphenyl)thiazol nicotinamide (30). To a solution of 4-(2-fluoro(4-methoxyphen0Xy) methylpheny1)thiazolylamine (30-7, 0.10 g, 0.30 mmol) in CH2C12 (10 mL) was added DMAP (73 mg, 0.60 mmol) followed by isonicotinoyl chloride hydrochloride (69 mg, 0.39 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced re and added with water. The resultant precipitate was collected and recrystallized in toluene to give N—{4-(2-dluoro-4—(4-methoxyphenoxy)-6— phenyl)thiazol yl}isonicotinamide (30, 42 mg, 0.10 mmol) as white solids in 32% yield: 1H NMR (500 MHZ, CDC13) 5 8.86 (d, J = 5.8 Hz, 2 H), 8.04 (d, J = 5.6 Hz, 2 H), 6.99 (d, J: 7.2 Hz, 3 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.61 (s, 1 H), 6.50 (m, 1 H), 3.82 (s, 3 H), 2.26 (s, 3 H). ESI—MS: m/z 436.1 (M + H)+.
[00206] N-(4-{4-(5-(2-Methoxyethoxy)pyrazin-Z-ylsulfonyl)-2,6-dimethylphenyl}thiazol- 2-yl)isonicotinamide (31) m-CPBA N\ o 27 —————> MeO\/\ /[ j/ / N \ / 0 N CHZCIZ \ \ NH N-(4-{4—(5-(2-Methoxyethoxy)pyrazinylsulfonyl)-2,6-dimethylphenyl}thiazol- 2-yl)isonicotinamide (31). A mixture of 27 and m-chloroperoxybenzoic acid (249.7 mg, 1.01 2O mmol, 2.5 equiv) in dichloromethane (2.0 mL) was stirred at room ature for 16 h. The solution was concentrated under reduced re, and the residue was solved in EtOAc (30 mL). The solution was washed with saturated aqueous NaHCO3 (20 mL), dried over MgSO4, and concentrated under reduced pressure to give 31 (88.8 mg, 0.17 mmol) as 1ight-yellow solids in 42% yield: 1H NMR (DMSO—dé, 500 MHz) 5 13.09 (s, 1 H), 8.98 (d, J = 0.95 Hz, 1 H), 8.81 (d, J = 5.7 Hz, 2 H), 8.46 (d, J: 0.95 Hz, 1 H), 7.98 (d, J = 5.7 Hz, 2 H), 7.75 (s, 2 H), 7.31 (s, 1 H), 4.52—4.53 (m, 2 H), 3.69—3.70 (m, 2 H), 3.29 (s, 3 H), 2.17 (s, 6 H). ESI—MS: m/z 526.1 (M + H)+.
N-(4-{4-(5-(2—Methoxyethoxy)pyrazin-Z-ylsulfinyl)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (32) 2012/067132 AC20,H202 MeO\/\O/[N/]/N\ O ,,_ N \ /N silica gel CH2CI 1 2 \ ‘f’NH ] N-(4-{4-(5-(2-Methoxyethoxy)pyrazin-Z-ylsulfinyl)-2,6-dimethylphenyl}thiazol yl)isonicotinamide (32). A mixture of 27 (200.0 mg, 0.41 mmol, 1.0 equiv), acetic anhydride (0.040 mL, 0.45 mmol, 1.1 , 30% hydrogen peroxide (201.1 mg, 5.94 mmol, 4.4 equiv), and silica gel (81.1 mg, 230—400 mesh) in dichloromethane (5.0 mL) was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re—dissolved in EtOAc (30 mL). The on was washed with ted aqueous NaHCO3 (20 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (90% EtOAc in hexanes as eluant) to provide to provide N- (4—{4-(5-(2—methoxyethoxy)pyrazin-2—ylsulfinyl)-2,6-dimethylphenyl }thiazol-2— yl)isonicotinamide (32, 100.3 mg, 0.2 mmol) as yellow solids in 49% yield: 1H NMR (DMSO—d6, 500 MHz) 5 13.05 (s, 1H), 8.81 (d, J: 5.5 Hz, 2 H), 8.68 (s, l H), 8.40 (s, 1 H), 7.98 (d, J: 5.5 Hz, 2 H), 7.50 (s, 2 H), 7.26 (s, 1 H), 4.47—4.48 (m, 2 H), 3.67—3.69 (m, 2 H), 3.29 (s, 3 H), 2.14 (s, 6 H); ESI-MS: m/z 510.1 (M + H)+. ,, , ' 7N—{4:(4¥(3,4-Difneth03iyphénylsulfanyl)'42,6idiniéthylphenylfihiamI-ZL ' ' " ' ' ' ' ' ' "7175' [07072710] yl}isonicotinamide (33) / \ N N N-{4-(4-(3,4-Dimethoxyphenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}is0nicotinamide (33). 1H NMR (500 MHz, CDCl3) 5 8.69 (t, J = 4.5 Hz, 2 H), 7.53 (d, J = 6.0 Hz, 2 H), 7.08 (m, 1 H), 6.99 (d, J: 2.0 Hz, 1 H), 6.87 (d, J: 8.0 Hz, 1 H), 6.74 (s, 1 H), 6.54 (s, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 1.81 (s, 6 H). ESI—MS: m/z 478.3 (M + H)+.
N-{4-(4-(4-Hydroxyphenylsulfanyl)-2,6-dimethylphenyl)thiazol-Z- yl}isonicotinamide (34) l >—NH0%— S N-{4-(4-(4-Hydroxyphenylsulfanyl)-2,6-dimethylphenyl)thiazol-2— yl}isonicotinamide (34). 1H NMR (500 MHz, CDC13) 5 8.77 (d, J = 6.0 Hz, 2 H), 7.70 (d, J = 6.0 Hz, 2 H), 7.37 (d, J = 8.5 Hz, 2 H), 6.80 (m, 3 H), 6.70 (s, 1 H), 1.91 (s, 6 H). ESI—MS: m/z 434.1 (M + H)+.
[00214] N—{4-(4-(4-Aminophenylsulfanyl)-2,6-dimethylphenyl)th1azol yl}isonicotinamide (35) O >-|—<—:-:O / \ N N HZN l N-{4-(4-(4-Aminophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (35). 1H NMR (500 MHz, CDC13) 5 8.69 (m, 2 H), 7.52 (m, 2 H), 7.30 (In, 2 H), 6.74 (s, 1 H), 6.70 (m, 2 H), 6.53 (s, 2 H), 1.81 (s, 6 H). ESI-MS: m/z 433.2 (M + H)+. (g. gogaagm 26-1 26-3 1Qg0% OOfifidwj l >_NH2 l >—NH/ 26-4 AMOS0 INVZE—CN
[00216] N-{4-(4-(4-Acetylaminophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (36). 1H NMR (500 MHZ, CDC13) 5 10.11 (s, 1 H), 8.70 (bs, 2 H), 8.00 (s, 2 H), 7.64 (d, J: 8.5 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.16 (s, 1H), 6.95 (s, 2 H), 2.05 (s, 6 H). : m/z 475.2 (M + H)+.
N-{4-(4-(4-Bromophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (37) O \ / I N\>_N2|—<_:_/\No 4-(4-Br0m0phenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (37). 1H NMR (500 MHz, CDC13) 6 8,76 (d, J = 5.8 Hz, 2 H), 7.60 (d, J = .8 Hz, 2 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.20 (d, J = 8.4 Hz, 2 H), 6.83 (m, 3 H), 1.93 (s, 6 H).
ESI-MS: m/z 496.3 (M + H)+.
N-{4-(4-(3-IChlorophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (38) C!US (FE: / \N , ”\Hfi—Q 4-(3-Chlorophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (38). 1H NMR (500 MHz, CDC13) 5 8,78 (d, J = 4.7 Hz, 2 H), 7.62 (d, J = 4.3 Hz, 2 H), 7.22 (m, 4 H), 6.93 (d, J = 2.3 Hz, 2 H), 6.83 (s, 1 H), 1.96 (s, 6 H). ESI—MS: m/z 452.1 (M + H)+.
N {4-(4-(2-Chlorophenylsulfanyl)-2,6-dimethylphenyl)thiazol-2— CrS 0 / \ N N . WEE—Q S N-{4-(4-(2-Chlorophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (39). 1H NMR (500 MHz, CDC13) 5 8,75 (d, J = 5.9 Hz, 2 H), 7.60 (d, J = 6.0 Hz, 2 H), 7.22 (m, 4 H), 6.91 (s, 2 H), 6.85 (s, 1 H), 1.95 (s, 6 H). ESI-MS: m/z 452.3 (M + H)+.
N-{4-(4-(4-Chlorophenylsulfanyl)-2,6-dimethylphenyl)thiazol-Z- yl}isonicotinamide (40) WSW A A) I/ U N \N
[00224] N-{4-(4-(4-Chlorophenylsulfanyl)-2,6-dimethylphenyl)thiazol yl}isonicotinamide (40). 1H NMR (500 MHz, CDC13) 5 8.68 (m, 2 H), 7.53 (d, J = 5.7 Hz, 13.5 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 4.3 Hz, 4 H), 6.78 (d, J = 11.9 HZ, 1 H), 6.66 (s, 2 H), 1.83 (S, 6 H).
ESI-MS: m/z 452.3 (M + H)+.
N-(4-(2,6-Dimethyl((l-methyl-1H-imidazolyl)thi0)phenyl)thiazol-2— yl)isonicotinamide (41) 6:qu\ O I N\>—N\Zi—<:/N/ s _ N-(4-(2,6-Dimethyl((l-methyl-lH-imidazolyl)thio)phenyl)thiazol yl)isonic0tinamide (41). 1H NMR (500 MHZ, CDC13) 5 8.78 (m, 2 H), 7.85 (m, 2 H), 7.19 (d, J = 1.0 Hz, 1 H), 7.08 (d, J: 1.0 Hz, 1 H), 6.75 (m, 3 H), 3.66 (s, 3 H), 1.95 (s, 6 H). ESI-MS: m/z 422.4 (M + H)+. 2,6-Dimethyl((4-(N- (methylsulfonyl)methylsu]f0namido)phenyl)thio)phenyl)thiazolyl)isonicotinamide (42) / \ 82 l 1 O / \ \ / /"“N' ' N N ' I >—NH \=/ 023\ s
[00228] N-(4-(2,6-Dimethyl((4-(N- (methylsulfonyl)methylsulfonamido)phenyl)thio)phenyl)thiazolyl)isonicotinamide (42). 1H NMR (500 MHz, CDC13) 8 8.86 (d, J = 5.5 Hz, 2 H), 7.99 (d, -J = 5.5 Hz, 2 H), 7.25 (m, 6 H), 6.85 (s, 1 H), 3.39 (s, 6 H), 2.10 (s, 6 H). ESI—MS: m/z 589.0 (M + H)+.
] N-(4-(2,6-Dimethyl((4-(methylsulfonamido)phenyl)thio)phenyl)thiazol yl)isonic0tinamide (43) H \/)—NH __ s020 W N-(4-(2,6-Dimethyl((4-(methylsulfonamido)phenyl)thi0)phenyl)thiazol yl)isonicotinamide (43). 1H NMR (500 MHZ, CDC13) 5 8.90 (d, J = 6.0 HZ, 2 H), 8.37 (d, J.= 6.5 Hz, 2 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.25 (d, J: 8.5 Hz, 2 H), 6.99 (m, 3 H), 3.05 (s, 3 H), 2.08 (s, 6 H). ESI—MS: m/z 511.1 (M + 10*.
N-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (44) O __ ~ 80 N-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (44). 1H NMR (500 MHz, CDC13) 6 8.67 (d, J = 5.5 Hz, 2 H), 7.55 (d, J = 6.0 Hz, 2 H), 6.77 (s, 1 H), 6.32 (s, 2 H), 3.73 (s, 3 H), 1.91 (s, 6 H); ESI—MS: m/z 340.0 (M + H)+. 1-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)—3-(pyridinyl)urea (45)) MeO <// \> O _ N )—NH | \)—NH ‘ S 45 1-(4-(4-Methoxy-2,6-dimethylphenyl)thiazol-Z-yD(Pyridin-4—yl)urea (45). 1H NMR (500 MHz, DMSO—d6) 5 10.49 (bs, 1 H), 8.54 (d, J = 6.5 Hz, 2 H), 7.94 (s, 2 H), 6.88 (s, 1 H), 6.74 (S, 2 H), 3.76 (S, 3 H), 2.10 (S, 6 H); ESI-MS: m/z 354.8 (M + H)+.
N-(4-(4-Isopropoxy-2,6-dimethylphenyl)thiazolyl)isonic0tinamide (46) HgI:\>—N>H—<\://N0 ..
N-(4-(4-Isoprop0xy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (46). 1H NMR (500 MHz, CDC13)6 8.67 (d, J = 6.0 Hz, 2 H), 7.55 (d, J = 6.0 Hz, 2 H), 6.77 (s, 1 H), 6.30 (s, 2 H), 4.43 (m, 1 H), 1.89 (s, 6 H), , J = 6.0 Hz, 6 H); : m/z 368.1 (M + H)+.
[00237] N—(4-Mesitylthiazolyl)(pyridinyl)acetamide (47) IN)—NH WO 82324 N-(4-Mesitylthiazolyl)—2-(pyridinyl)acetamide (47). 1H NMR (500 MHz, DMSO-d6) 5 8.52—8.53 (m, 2 H), 7.35—7.36 (m, 2 H), 6.99 (s, 1 H), 6.91 (s, 1 H), 3.84 (s, 1 H), 2.25 (s, 3 H), 2.02 (s, 6 H); ESI-MS: m/z 338.1 (M + H)+.
N-(4-(4—(4-Meth0xyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (43) 0 — M CGe :1 | :N\>—NZ—<\://\N 4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (48). 1H NMR (500 MHz, CDC13) 8 8.73 (m, 2 H), 7.62 (m, 2 H), 6.90—6.96 (111, 4 H), 6.80 (s, 1 H), 6.45 (s, 2 H), 3.83 (s, 3 H), 1.92 (s, 6 H); ESI-MS: m/z 431.7 (M + H)+. 2-Fluoro-N—(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (49) (Egg o .. o / J__ Me 'N\>_N%'—§\_//N 49 2-Flu0ro-N-(4-(4-(4-methoxyphen0xy)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (49). 1H—NMR (500 MHz, CDC13) 8 .40 (m, 1 H), 7.66—7.67 (m, 2 H), 7.43 (s, 1 H),6.98—7.00 (m, 2 H), 6.91—6.93 (m, 2 H), 6.84 (s, 1 H), 6.54 (s, 1 H), 3.83 (s, 3 H), 2.0 (s, 6 H); ESI-MS: m/z 450.0 (M + H)+.
] (E)-N-(4—Mesitylthiazolyl)(pyridinyl)acrylamide (50) N OW I S)—\ NH (E)-N-(4-Mesitylthiazol-2—yl)(pyridin-S-yl)acrylamide (50). 1H NMR (DMSO— d5, 500 MHz) 5 12.48 (s, 1 H), 8.82—8.83 (m, 1 H), 8.60—8.61 (m, 1 H), 8.04—8.05 (m, 1 H), 7.76—7.79 (m, 1 H), 7.49—7.51 (m, 1 H), 7.00—7.03 (m, 2 H), 6.92 (s, 2 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI—MS: m/z 350.7 (M + H)+.
N—(4—(4-(4—Meth0xybenz’yl)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (51) O MeO©/\anBr / ‘N—~ _ O O:SOVCN \ \>—NH 3)4 THF MeO N\ NH 4-(4-Methoxybenzyl)-2,6-dimethylphenyl)thiazolyl)isonic0tinamide (51).
A THF solution of 4—methoxylbenzylzinc(11) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of 4-iodo-2,6-dimethylphenyl)thiazol—2—yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl e, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-(4-methoxybenzyl)-2,6-dimethylphenyl)thiazol yl)isonicotinamide: 1H NMR (500 MHz, CDC13) 6 8.69 (d, J = 5.2 Hz, 2 H), 7.66 (d, J = 4.9 Hz, 2 H), 7.11 (d, J = 8.4 Hz, 2 H), 6.86 (d, 2 H), 6.80 (s, 1 H), 6.75 (s, 2 H), 3.80 (s, 2 H), 3.78 (s, 2 H), 1.98(s, 6 H); ESI-MS: m/z 399.9 (M + H)+.
N-(4-(4-(4-Bromophenylamino)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (52) 0” “ Br \h£>——§%r_<<::;>q° N-(4-(4-(4-Bromophenylamino)-2,6-dimethylphenyl)thiazolyl)isonic0tinamide (52). 1H NMR (500 MHz, CDC13) 5 8.79 (d, J = 4.5 Hz, 2 H), 7.85 (d, J = 4.5 Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.83 (s, 1 H), 2.05 (s, 6 H); ESI—MS: m/z 479.2 (M + H)+.
N-(4-(4—(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamideI (53) cc 0' 0 _ 4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide (53). Yield: 24%; 1H NIVIR (500 MHz, CDC13) 8 8.80 (s, 2H), 7.70 (d, J = 5.1 Hz, 2 H), 6.97 (m, 2 H), 6.92 (m, 3 H), 6.70 (d, J = 2.4 Hz, 1 H), 6.61 (d, J: 2.3, 1 H), 3.83 (s, 3 H), 2.02 (s, 3 H); ESI-MS: m/z 452.4 (M + H)+. esitylthiazolyl)morpholinoisonicotinamide (II-83) C. [:1 » I Q’N /©:EN/>\NHOLC<N O \ ‘ NMP. reflux fii‘hfi‘g 11-83 N-(4-Mesitylthiazol-2—yl)—2-morpholinoisonicotinamide ). A mixture of 2- chloro-N—(4-mesitylthiazol-2—yl)isonicotinamide (500.0 mg, 1.4 mmol, 1.0 equiv) and morpholine (1.5 mL, 16.8 mmol, 12 equiv) in methylpyrrolidone (15.0 mL) was stirred at 150 °C for 16 h. The mixture was poured into icy H20 (20.0 mL), and the resultant solids were filtered to provide N—(4—mesitylthiazolyl)—2-morpholinoisonicotinamide (358.6 mg, 0.90 mmol) as yellow solids in 63% yield: 1H NMR (DMSO-d6, 500 MHz) 6 8.30 (d, J = 5.1 Hz, 2 H), 7.50 (s, 1 H), 7.22 (d, J: 5.1 Hz, 2 H), 7.10 (s, 1H), 6.92 (s, 2 H), 3.70-3.73 (m, 4 H), 3.53—3.55 (m, 4 is H), 2.26 (s, 3 H), 2.05 (s, 6 H);ESI-MS: m/z 409.3 (M +H)+.
N-(4-Mesitylthiazolyl)-2°(4-methylpiperazin-l=yl)isonicotinamide (II-84) I N/ CI N 0 f S NJ />—‘NH \N E j 0 l \ ~ / u 8 ——> I />\NH \ /N NMP, reflux N 11-84 N-(4-Mesitylthiazolyl)(4-methylpiperazin-l-yl)isonicotinamide (II-84).
A mixture of 2-chloro—N—(4-mesitylthiazol—2-yl)isonicotinamide (300.0 mg, 0.8 mmol, 1.0 equiv) and 1-methylpiperazine (1.12 mL, 10.1 mmol, 12 equiv) in methylpyrrolidone (9.0 mL) was stirred at 150 °C for 16 h. The mixture was poured into icy H20 (15.0 mL) and the resultant solids were ed to provide N—(4—mesitylthiazolyl)-2—(4-methylpiperazin yl)isonicotinamide (95.6 mg, 0.20 mmol) as yellow solids in 27% yield: 1H NMR (CDClg, 500 MHz) 5 8.27 (d, J = 5.1 Hz, 1 H), 7.12 (s, 1 H), 6.83-6.86 (m, 3 H), 6.78 (s, 1 H), 3.63- 3.65 (m, 4 H), 2.35 (s, 3 H), 2.27 (s, 3 H), , 6 H); ESI-MS: m/z 422.1 (M +H)+.
N-(4-Mesitylthiazol-Z-yl)(piperidin-l-yl)isonicotinamide (II-91) 0' 0 1%NW.s " O N S N ' ————> I N/>\N \ NMP, reflux OLCNNH / 11-91 N-(4-Mesitylthiazol-Z-yl)(piperidinyl)isonicotinamide (II-91). A mixture of 2—chlor0-N—(4-mesitylthiazol-2—yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv) and piperidine (0.70 mL, 6.7 mmol, 12 equiv) in methylpyrrolidone (6.0 mL) was d at 150 °C for 16 h. The mixture was poured into icy H20 (10.0 mL) and the resultant solids were filtered. The solids were purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to e N—(4-mesitylthiazol—2-yl)—2-(piperidin—1-yl)isonicotinamide (87.2 mg, 0.20 mmol) as yellow solids in 38% yield: 1H NMR (CDC13, 500 MHZ) 6 8.29 (d, J = 5.1 Hz, 1 H), 7.15 (s, 1 H), 6.83—6.90 (m, 3 H), 6.79 (s, 1 H), 3.61-3.63 (m, 4 H), 2.31 (s, 3'H),’2.08'(s, 6 H),'1’.57—1.67 (m, 6 H); ESI—MS: m/z 407.2 (M *+*H')+'. ] 2-(Dimethylamino)-N-(4-mesitylthiazol-Z-yl)isonicotinamide (II-92) CI \ O N‘ s ‘ 0 s ‘ 1 N>‘ 2M(CH3)2NH/THF , NH \ /N 1 />~NH \ /N NMP, reflux N - II-92 2-(Dimethylamino)-N-(4-mesitylthiazolyl)isonicotinamide (II-92). A mixture of 2-chloro—N—(4—mesitylthiazolyl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv), cesium carbonate (2.73 g, 0.6 mmol, 15 equiv) and 2.0 M dimethylamine in THF (3.4 mL, 6.7 mmol, 12 equiv) in DMF (6.0 mL) was heated at reflux for 16 h. The mixture was poured into icy H20 (10.0 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced silica gel (15% re. The residue was purified by column chromatography on EtOAC in hexanes as eluant) to provide 2—(dimethylamino)—N—(4—mesity1-thiazol—2— yl)isonicotinamide (5.5 mg, 0.10 mmol) as yellow solids in 3.0% yield: 1HNMR (CDC13, 500 MHZ) 6 8.32 (d, J = 5.1 Hz, 1 H), 7.02 (s, 1 H), 6.92 (s, 2 H), 6.85 (d, J =5.1 Hz, 1H), 6.80 (s,1 H), 3.16 (s, 6 H), 2.31 (s, 3 H), 2.09 (s, 6 H); ESI—MS: m/z 367.1 (M+H)+.
N-(4-(4-Benzyl-2,6-dimethylphenyl)thiazolyl)isonicotinamide 8) / 0 ©/\ZnBr | /_\ _______> \ N \ \>—NH 3)4, THF 8 \N;NH/ 11-118 N—(4—(4-Benzyl-Z,6-dimethylphenyl)thiazolyl)isonic0tinamide (II-118). A THF solution of benzylzinc(11) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N—(4- (4—iodo-2,6-dimethylpheny1)thiazolyl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 and then poured into saturated aqueous .
The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated .15, under reduced pressure. The residUe was pUrified by flash column Chromatography on silica gel ' ' ’ ' ' to give N-(4-(4—benzyl-2,6—dimethy1phenyl)thiazolyl)isonicotinamide: 1H NMR (500 MHz, CDC13 6 8.70 (d, J = 4.9 Hz, 2 H), 7.67 (d, J: 4.9 Hz, 2 H), 7.33 (d, J = 8.6 Hz, 2 H), 7.10—7.26 (m, 3 H), 6.80 (s, 1 H), 6.24 (s, 1 H), 3.86 (s, 2 H), 2.04 (s, 6 H); ESI—MS: m/z 399.9 (M + H)+.
N-(4-(4-(4-Methoxybenzyl)-2,6-dimethylphenyi)thiazolyl)isonicotinamide (II- 1 19) ° / ‘N ———> N O 0 _\~ — \ \)—NH Pd(PPh3)4.THF MeO 8 \N\7_NH 11-119 N-(4-(4-(4-Methoxybenzyl)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 119). A THF solution of 4—methoxylbenzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N—(4-(4-iodo—2,6-dimethylphenyl)thiazol-2—y1)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine ium (57.8 mg, 0.10 mmol) in THF (50 mL). The reaction mixture was heated at reflux for 16 h under N2 then poured into saturated dried s NaHC03. The mixture was extracted with ethyl acetate, washed with brine, MgSO4, and concentrated under d pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-(4-methoxybenzyl)—2,6-dimethylphenyl)thiazol yl)isonicotinamide: 1H NMR (500 MHz, CDC13) 5 8.69 (d, J = 5.2 Hz, 2 H), 7.66 (d, J = 4.9 Hz, 2 H), 7.11 (d, J: 8.4 Hz, 2 H), 6.86 (d, 2 H), 6.80 (s, 1 H), 6.75 (s, 2 H), 3.80 (s, 2 H), 3.78 (s, 2 H), 1.98 (s, 6 H); ESI—MS: m/z 399.9 (M + H)+. 2—Bromomesity1ethanone. To a solution of 1-mesitylethanone (1.02 g, 6.27 mmol) in EtOAc (50 mL) was added copper(II) bromide (CuBrz, 2.85 g, 12.8 mmol). The reaction mixture was heated at reflux for 90 min. The solution was allowed to cool down, and the resultant solids were filtered off and washed with EtOAc. The filtrate was concentrated under d pressure to give crude 2-bromomesitylethanone (1.67 g) as yellow oil: 1H NMR (500 MHz, CDC13) 6 6.87 (s, 2 H), 4.27 (s, 2 H), 2.31 (s, 3 H), 2.22 (s, 6 H). 4-Mesitylthiazolamine. o-1—mesitylethanone (2.43 g, 10.1 mmol) and thiourea (0.810 g, 10.6 mmol) were dissolved in 95% ethanol (20 mL). The reaction e was heated at reflux for 2.0 h. The solution was concentrated under reduced re, and the residue was -ecrystallized from 2-propanol to give the desired tylthiazolamine (2.36 g) as white solids: 1H NMR (500 MHz, CD3OD) 5 7.00 (s, 2 H), 6.67 (s, 1 H), 2.31(s, 3 H), 2.19 (s, 6 H). 4-(p-Tolyl)thiazol-2—amine. A mixture of 2-bromo—1-(p-toly1)ethanone. (5.00 g, 23.5 mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 60 min. The on was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.05 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(p-tolyl)thiazol-2—amine (4.40 g) as white solids in 99% yield: 1H NMR (500 MHZ, CDC13) 8 7.66 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 7.5 Hz, 2 H), 6.66 (s, 1 H), 5.25 (s, 2 H), 2.36 (s, 6 H).
[00266] 5-Methyl(p-tolyl)thiazol-Z-amine. A mixture of 2—bromo-l-(p—toly1)propan—1- one (6.88 g, 30.3 mmol) and thiourea (2.54 g, 33.4 mmol) in 95% EtOH (43 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated in toluene. aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized The solidwere filtered and dried under vacuum to give 5-methyl-4—(p-toly1)thiazol—2-amine (6.10 g) as white solids in 99% yield: 1HNMR (500 MHz, CDC13) 5 7.40 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 3.18 (s, 2 H), 2.37 (s, 3 H), 2.35 (s, 3 H). 2-Bromo(4-methoxy-2,6-dimethylphenyl)ethanone. To a on of 1-(4- y-2,6-dimethylphenyl)ethanone (5.7 g, 32 mmol) in acetonitrile (64 mL) was added tetrabutylammoniumtribromide (TBABI'g, 15.4 g, 32.0 mmol). The reaction was stirred at room temperature for 80 min. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under d pressure to give 2-bromo—1-(4—methoxy— methylphenyl)ethanone (9.14 g), which was used directly for the next step without further purification. 4-(4—Methoxy-2,6-dimethylphenyi)thiazoi-Z-amine. A mixture of 2—bromo-l —(4- y-2,6-dimethylphenyl)ethanone (8.65 g, 33.6 mmol) and thiourea (2.56 g, 33.6 mmol) in 95% EtOH (48 mL) was heated at reflux for 60 min. The solution was trated and added with water (50 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was d and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give 4-(4-methoxy—2,6—dimethylphenyl)thiazol-2 amine (5.9 g) as white solids in 66% yield: 1H NMR (500 MHz, CDC13) 5 6.61 (s, 2 H), 6.27 (s, 1 H), 4.91 (s, 2 H), 3.79 (s, 3 H), 2.15 (s, 6 H). 2-Bromo(2,4,6-trimethylpyridinyl)ethanone hydrobromide. To a solution of 1-(2,4,6-trimethylpyridin-3—yl)ethanone (5 .0 g, 30.6 mmol) in 33% HBr in acetic acid solution (10.2 mL) was added bromine (1.57 m], 30.6 mmol) in acetic acid (10.2 mL) dropwi'sely. The reaction was stirred at 70 °C for 2.0 h. The Solution was cooled to room temperature and washed 2O with ether. The residue was dried under reduced pressure to give 2-bromo(2,4,6- trimethylpyridinyl)ethanone hydrobromide, which was used directly for the next step without further purification. 4-(2,4,6-Trimethylpyridinyl)thiazol-2—amine. A mixture of 2-bromo—l—(2,4,6- trimethylpyridinyl)ethanone hydrobromide (9.00 g, 27.9 mmol) and thiourea (2.12 g, 27.9 ' mmol) in 95% EtOH (39.8 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (50 mL) and saturated aqueous NazCO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4—(2,4,6-trimethy1pyridinyl)thiazol—2-amine (3.80 g) as yellow solids in 62% yield: 1H NMR (500 MHz, CDC13)8 6.87 (s, 1 H), 6.31 (s, 1 H), 5.07 (s, 2 H), 2.49 (s, 3 H), 2.38 (s, 3 H), 2.14 (s, 3 H). 2-Bromo(4-ethoxy-2,6-dimethy1pheny1)ethanone. To a solution of 1-(4- ethoxy-2,6—dimethylphenyl)ethanone (4.00 g, 20.8 mmol) in acetonitrile (41.6 mL) was added utylammoniumtribromide '3, 10.0 g, 20.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under d re to give 2-bromo(4-ethoxy-2,6— dimethylphenyl)ethanone (6.40 g), which was used directly for the next step without r purification. 4-(4-Ethoxy-2,6-dimethylpheny1)thiazolamine. A mixture of 2-bromo(4— ethoxy-2,6-dimethy1phenyl)ethanone (6.35 g, 23.4 mmol) and thiourea (1.78 g, 23.4 mmol) in 95% EtOH L) washeatedat reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-ethoxy-2,6-dimethylphenyl)thiazol-2—amine (4.18 g) as white solids in 72% yield: 1H NMR (500 MHz, DMSO-ds) 6 6.84 (s, 2 H), 6.60 (s, 2 H), , 1 H), 3.99 (q, J = 6.5 Hz, 2 H), 2.06 (s, 6 H), 1.31 (t, J = 6.95 Hz, 3 H). 4-Acety1-3,5-dimethylphenyl trifluoromethanesulfonate. A solution of 1-(4- hydroxy-2,6-dimethylphenyl)ethanone (3.30 g, 20.1 mmol), triethylamine (4.07 g, 40.2 mmol) in anhydrous CHZCIZ (20.1 mL) was cooled to 0 °C, and then added with romethanesulfonic anhydride (4.0 mL, 24 mmol) dropwise. After the addition was completed, the reaction mixture was warmed to room temperature and stirred for 1.0 h. The solution was added with water and extracted with ethyl acetate (60 mL). The organic layer was separated, dried over MgSO4(s), trated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 4—acetyl—3,5-dimethylphenyl trifluoromethanesulfonate (5 .0 g) as yellow oil in 85% yield. 1-(3,5-Dimethyl-(1,l '-biphenyl)yl)ethan0ne. To a solution of 4-acetyl-3,5- dimethylphenyl trifluoromethanesulfonate (1.00 g, 3.38 mmol), KF (0.65 g, 11 mmol), and boronic acid (0.49 g, 4.0 mmol) in» THF (4.0 mL) was added tlicyclohexylphosphine (11.4 mg, 0.04 mmol) and Pd(OAc)2 (7.6 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 5.0 h under N2. The reaction mixture was filtered h a small pad of diatomaceous earth, and the cake was washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give 1—(3,5—dimethyl-(1,1'-biphenyl)yl)ethanone (0.68 g) in 90% yield: 1H NMR (500 MHz, CDC13) 8 7.56 (d, J = 8.0 Hz, 2 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.35 (m, 1H), 7.25 (s, 2 H), 2.52 (s, 3 H), 2.33 (s, 6 H). 2-Brom0(3,5-dimethyl-(1,1'-biphenyl)yl)ethanone. To asolution of 1-(3,5— dimethyl-(1,1'-biphenyl)yl)ethanone (1.89 g, 8.43 mmol) in acetonitrile (16.9 mL) was added tetrabutylammoniumtribromide (TBABrg, 4.07 g, 8.43 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl e. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give o(3,5—dimethyl—(1,1'- biphenyl)yl)ethanone (3.2 g), which was used directly for the next step without r purification. 4-(3,5-Dimethyl-(1,1':biphenyl)yl)thiazolamine. A mixture of 2-bromo—1— (3,5-dimethyl-(l,1'-biphenyl)yl)ethanone (2.56 g, 8.44 mmol) and thiourea (0.64 g, 8.44 mrnol) in 95% EtOH (12.1 mL) was heated at reflux for 60 min. The on was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene (10 mL). The solids were filtered and dried under vacuum to give 4-(3,5—dimethy1-(1,1 '-biphenyl)y1)thiazolarnine (0.66 g) as yellow solids in 28% yield: 1H NMR (500 MHz, CDC13) 5 7.60 (d, J =1Hz, 2 H), 7.43 (t, J: 7.5 Hz, 1 H), 7.32 (m, 1 H), 7.25 (s, 2 H), 6.34 (s, 1 H), 5.03 (s, 2 H), 2.24 (s, 6 H). 1-(4-Chlore-2,6dimethylphenyl)ethanone. Anhydrous copper(fl) chloride (98.9 g, 0.74 mol) was mixed with tert—butyi nitrite (94.8 g, 0.83 mol) in abetdnitrile (1.02 L). The solution was cooled to 0 °C and slowly added with l-(4-amino-2,6 dimethylphenyl)ethanone (100 g, 0.61 mol) in a period of 5.0 min. After the addition was completed, the on mixture was warmed to room temperature, and was poured into an aqueous hydrochloric acid solution (20%, 1.0 L). The on was extracted with EtOAc (800 mL), and the organic layer was ted, washed with H2O (1.0 L), dried over MgSO4 (s), and concentrated under reduced pressure. The liquid was distilled to give 1—(4-chloro—2,6-dimethylphenyl)ethanone (85.0 g) as yellow oil in 76% yield: 1H NMR (500 MHz, CDC13) 5 7.02 (s, 2 H), 2.45 (s, 3 H), 2.22 (s, 6 H). 2-brom0( ro-2,6-dimethylphenyl)ethanone . To a solution of 1-(4-chloro— 2,6-dirnethylphenyl)ethanone (5.0 g, 27 mrnol) in itrile (54.8 mL) was added tetrabutylammoniumtribrornide (TBABr3, 13.2 g, 27.4 mrnol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and ted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give o—l-(4-chloro-2,6- dimethylphenyl)ethanone (7.2 g), which was used directly for the next step without further purification. 4-(4-Chloro-2,6-dimethylphenyl)thiazol-Z-amine. A mixture of 2-bromo(4— chloro—2,6-dimethylphenyl)ethanone (6.54 g, 25.0 mmol) and thiourea (1.90 g, 25.0 mmol) in 95% EtOH (35.7 mL) was heated at reflux for 60 min. The on was concentrated and added with water (50 mL) followed by ted aqueous Na2C03 (4.0 mL). The ant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-chloro-2,6—dimethylpheny1)thiazol-2—amine (4.30 g) as white solids in 72% yield: 1H NMR (500 MHZ, DMSO—d6) 8 7.16 (s, 2 H), 6.43 (s, I H), 2.10 (s, 6 H).
N-(4-(2—Bromoacetyl)-3,5-dimethylphenyl)acetamide. To a solution of N-(4- acety1-3,5-dimethylphenyl)acetamide (5.00 g, 24.4 mmol) in acetonitrile (48.7 mL) was added tetrabutylammoniumtribromide (TBABrg, 11.7 g, 24.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under d pressure, added with water, and extracted with ethyl acetate. The c layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromoacetyl)-3,5- ylphenyl)acetamide (7.00 g), which was used directly for the next step without further purification.
N-(4-(2-aminotl1jazoly!)-3,5-dimethylphenyl)acetamide. A mixture of N—(4-(2- bromoacetyl)-3,5-dimethylphenyl)acetamide (7.34 g, 25.9g mmol) and ea (1.97 g, 25.9 mmol) in 95% EtOH (36.9 mL) was heated at reflux for 120 min. The solution was concentrated and added with water (100 mL) and saturated aqueous NazCO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (50 mL). The solids were filtered and dried under vacuum to give N—(4-(2-aminothiazol-4—y1)-3,5-dimethy1phenyl)acetamide (5.83 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO'dfi) 5 9.80 (s, 1 H), 7.26 (s, 2 H), 6.90 (s,2 H), 6.30 (s, 1 H), 2.06 (s, 6 H), 2.02 (s, 3 H). 2-Bromo(2,4,6-triisopropylphenyl)ethanone. To a solution of 1 (2,4,6- triisopropylphenyl)ethanone (10.0 g, 65.3 mmol) in itrile (81 mL) was added tetrabutylammoniumtribromide (TBABfg, 19.6 g, 40.6 mmol). The reaction was stirred at room - temperature for 3.0 h. The solution was concentrated under reduced pressure, added with water, and ted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2—bromo(2,4,6- triisopropylphenyl)ethanone (13.2 g), which was used directly for the next step without further purification. 4-(2,4,6-Triisopropylphenyl)thiazol-Z-amine. A mixture of 2-bromo—1—(2,4,6- triisopropylphenyl)ethanone (13.9 g, 42.7 nunol) and thiourea (3.24 g, 42.6 mmol) in 95% EtOH (60.9 mL) was heated at reflux overnight. The solution was concentrated and added with water (100 mL), saturated aqueous Na2C03 (10 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced in hexanes as pressure, which was purified by column chromatography on silica gel (33% EtOAc eluant) to give ,6-triisopropylphenyl)thiazolamine (3.28 g) as white solids in 25% yield: 1H NMR (500 MHz, CDC13) 6 7.03 (s, 2 H), 6.22 (s, 1 H), 4.75 (s, 2 H), 2.89 (m, 1 H), 2.68 (m, 2 H), 1.27—1.14 (m, 18 H). ] 1-(2,6-Dimethylphenoxyphenyl)ethanone. To a solution of l-(4-chloro-2,6- dimethylphenyl)ethanone (4.50 g, 24.6 mmol), K3PO4 (10.5 g, 49.3 mmol), and phenol (2.78 g, 29.5 mmol) in toluene (49.3 mL) was added 2-(di-tert-butylphosphino)biphenyl (221 mg, 0.74 mmol) and )2 (233 mg, 1.04 mmol). The reaction was heated at 100° C for 2.0 h under N2. The solution was cooled to room temperature and filtered through a small pad of aceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl—4phenoxyphenyl)ethanone as a yellow oil in 68% yield: 1H NMR (500 MHz, CDC13) 5 7.35 (t, J: 8.0 Hz, 2 H), 7.12 (t, J: 7.5 Hz ,1 H), 7.00 (d, J = 7.5 Hz, 2 H), 6.65 (s, 2 H), 2.48 (s, 3 H), 2.22 (s, 6 H). 2-Bromo(2,6-dimethylphenoxyphenyl)ethanone. To a solution of 1-(2,6- yl-4—phenoxyphenyl)ethanone (3.60 g, 15.0 mmol) in acetonitrile (30 mL) was added utylammoniumtribromide (TBABr3, 7.95 g, 15.0 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over ous s), and concentrated under reduced pressure to give 2-bromo(2,6-dimethyl—4- phenoxyphenyl)ethanone (4.8 g), which was used directly for the next step without further purification.
-Dimethylphenoxyphenyl)thiazol-2—amine. A mixture of 2-bromo(2,6- dimethylphenoxyphenyl)ethanone (5.18 g, 16.2 mmol) and thiourea (1.24 g. 16.3 mmol) in 95% EtOH (23.2 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6—dirnethylphenoxyphenyl)thiazol-2—arnine (2.84 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDCng 5 7.33 (t, J =7.5 Hz, 2 H), 7.26 (t, J: 7.5 Hz ,1 H), 7.10 (d, J = 7.3, 2 H), 6.72 (s, 2 H), 6.30 (s, l H), 5.18 (s, 2 H), 2.14 (s, 6 H). o(4-isoprop0xy-2,6-dimethylphenyl)ethanone. To a solution of 1-(4- isopropoxy-2,6-dimethylphenyl)ethanone (4.3 g, 20.9 mmol) in acetonitrile (41.7 mL) was added tetrabutylamrnoniumtribromide (TBABI‘3, 11. l g, 22.9 mmol). The on was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and ted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-br0mo(4—isoprop0xy-2,6- dimethylphenyl)ethanone (5.9 g), which was used directly for the next step without further purification. 4-(4-Isopropoxy-2,6-dimethylphenyl)thiazolamine. A mixture of 2-br0mo(4- poxy-2,6-dimethylphenyl)ethanone (5.18 g, 18.2 mmol) and thiourea (1.38 g, 18.2 mmol) in 95% EtOH (26 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and ted aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isopropoxy-2,6 dimethylphenyl)thiazolamine (3.44 g) as yellow solids in 72.2% yield: 1H NMR (500 MHz, CDC13) 5 6.60 (s, 2 H), 6.26 (s, 1 H), 4.97 (s, 2 H), 4.54 (m, 1 H), 2.13 (s, 6 H), 1.32 (d, J: 6.1 Hz, 6 H). 2-Bromo(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethan0ne. To a solution of 1- (4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (4.60 g, 19.8 mmol) in acetonitrile (39.6 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.5 g, 21.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1—(4— (cyclopentyloxy)-2,6—d!methylphenyl)ethanone (6.2 g), which was used directly for the next step without further purification.
[00290] 4-(4—(Cyclopentyloxy)-2,6-dimethylphenyl)thiazol-Z-amine. A mixture of 2- l-(4—(cyclopentyloxy)—2,6—dimethylphenyl)ethanone (6.16 g, 19.8 mmol) and thiourea (1.51 g, 19.8 mmol) in 95% EtOH (28.3 mL) was heated at reflux for 90 min. The on was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-(cyclopentyloxy)-2,6—dimethylphenyl)thiazol—2-amine (4.2 g) as white solids in 73.7% yield: 1H NMR (500 MHz, CDC13) 5 6.58 (s, 2 H), , 1 H), 4.75 (m, 1H), 2.13 (s, 6 H), 1.88-1.78 (m, 6 H), 1.62-1.59 (m, 2 H). 1-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)ethan0ne. To a solution of l-(4- chloro-2,6—dimethylphenyl)ethanone (10.0 g, 54.8 mmol), K3PO4 (23.2 g, 110 mol) 4- methoxyphenol (8.16 g, 65.7 mmol) in toluene (78.2 mL), was added 2—di—tert-Butylphosphino- 2',4',6'-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100°C for 5.0 h under N2. The solution was cooled to room temperature and filtered h a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was recrystallized in MeOH to give 1-(4—(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (11.1 g) as white solids in 75.0%: 1H NMR (500 MHz, CDC13) 6 6.96 (m, 2 H), 6.88 (m, 2 H), 6.57 (s, 2 H), 3.81 (s, 3 H), 2.46 (s, 3 H), 2.20 (s, 6 H). 2-Bromo(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4—(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (3.80 g, 14.1 mmol) in acetonitrile (28.1 mL) was added tetrabutylammoniumtribromide (TBABI'3, 7.46 g, 15.5 mmol). The reaction was stirred at room temperature overnight. The solution was trated under reduced with pressure, added with water, and extracted with ethyl acetate. The organic layer was washed brine, dried over anhydrous s), and concentrated under reduced pressure to give 2— bromo-l-(4—(4-methoxyphenoxy)—2,6—dimethylphenyl)ethanone (5.25 g), which was used directly for the next step without further purification. 4-(4-(4-Methoxyphenoxy)-2,6-dimethy1phenyl)thiazolamine. A mixture of 2— bromo—l—(4-(4—methoxyphenoxy)—2,6-dimethylphenyl)ethanone (4.90 g, 14.0 mmol) and ea (1.07 g, 14.1 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 100 min. The on was concentrated and added with water (100 mL) and saturated aqueous NagCO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4—(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazolamine (3.10g) as yellow solids in 68% yield: 1H NMR (500 MHz, CDC13) 5 6.98 (m, 2 H), 6.88 (m, 2 H), 6.64 (s, 2 H), 6.27 (s, 1 H), 5.40 (s, 2 H), 3.81 (s, 3 H), 2.13 (s, 6 H). 1-(4-(4-Fluorophenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4— chloro-2,6-dimethylpheny1)ethanone (4.50 g, 24.6 mmol), K3PO4 (10.5 g, 49.3 mmol), 4— fluorophenol (3.31 g, 29.5 mmol) in toluene (49.3 mL), was added 2—di-tert-butylphosphino- 6'-triisopropylbiphenyl (314 mg, 0.74 mmol), Pd(OAc)2 (233 mg, 1.04 mmol). The reaction was heated at 100 °C overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (100 mL), and ed filtrate was trated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(4—(4-Fluorophenoxy)-2,6— dimethylphenyl)ethanone (4.40 g) as yellow oil in 68% yield: 1H NMR (500 MHz, CDClg) 5 7.03 (m, 2 H), 6.98 (m, 2 H), 6.60 (s, 2 H), 2.47 (s, 3 H), 2.22 (s, 6 H). 2-Brom0(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1—(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone (4.40 g, 17.0 mmol) in acetonitrile (34.1 mL) was added tetrabutylammoniumtribromide (TBABT3, 9.04 g, 18.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The c layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-brorno(4- rophenoxy)—2,6-dimethylphenyl)ethanone (5.8 g), which was used directly for the next step without further purification. 4-(4-(4—Fluorophenoxy)-2,6-dimethylphenyl)thiazolamine. A mixture of 2- bromo—l-(4-(4-fluorophenoxy)-2,6-dimethylphenyl)ethanone (5.74 g, 17.0 mmol) and ea (1.30 g, 17.1 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2C03 (5.0 mL). The .esrltant itate was filteed and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4—(4-fluorophenoxy)-2,6-dimetbylphenyl)thiazol-2—amine (4.50 g) as yellow solids in 84% yield: 1H NMR (500 MHz, CDC13) 5 6.97 (m, 4 H), 6.66 (s, 2 H), 6.28 (s, 1H), 5.95 (s, 2 H), 2.14 (s, 6 H).
[00297] 2-Bromo(4-isobutoxy-2,6—dimethylphenyl)ethanone. To a solution of 1-(4- isobutoxy—2,6-dimethylpheny1)ethanone (4.3 g, 19.5 mmol) in acetonitrile (39 mL) was added tetrabutylammoniumtribromide (TBABI'3, 9.41 g, 19.5 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give l-(4-isobut0xy-2,6— dimethylphenyl)ethanone (6.1 g), which was used directly for the next step t r purification. 4-(4-Isobutoxy-2,6-dimethylphenyl)thiazolamine. A e of 2-bromo(4— isobutoxy-2,6-dimethylphenyl)ethanone (5.84 g, 19.5 mmol) and thiourea (1.49 g, 19.6 mmol) in 95% EtOH (28 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-isobutoxy-2,6-dimethylphenyl)thiazol-2—arnine (4.4 g) as white solids in 82% yield: 1H NMR (500 MHz, CDC13) 5 6.61 (s, 2 H), 6.24 (s, 1H), 3.70 (d, J = 6.5 Hz, 2 H), 2.15 (s, 6 H), 2.07 (m, 1H), 1.01 (d, J = 6.7 Hz, 6 H).
Benzo(d)(l,3)dioxolyloxy)-2,6-dimethylphenyl)ethanone. To a solution of hloro-2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), sesamol (4.54 g, 32.9 mmol) in toluene (54.8 mL), was added 2-di—tert-butylphosphino-2',4',6'- triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100° C ovemight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was tallized in MeOH to give 1-(4-(benzo(d)(1,3)dioxol—5-yloxy)-2,6-dimethylpheny1)ethanone (4.80 g) as white solids in 62% yield: 1H NMR (500 MHz, CDClg) 5 6.77 (d, J = 8.5 Hz, 1H), 6.59 (s, 2 H), 6.56 (s, 1 H), 6.48 (m, 1 H), 5.98 (s, 2 H), 2.46 (s, 3 H), 2.21 (s, 6 H). 1-(4-(Benzo(d)(1,3)dioxolyloxy)-2,6-dimethylphenyl)bromoethanone. To a solution of 1-(4-(benzo(d)(1,3)dioxol—S—y1oxy)-2,6-dimethylphenyl)ethanone (4.80 g, 16.9 mmol) in acetonitrile (33.8 mL) was added tetrabutylammoniumtribrornide (TBABr3, 8.14 g, 16.9 mmol). The reaction was d at room. temperature overnight. The solution was concentrated under reduced re, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under ' reduced pressure to give 1—(4-(benzo(d)(1,3)dioxol—5—yloxy)-2,6-dimethylpheny1)—2- bromoethanone (6.70 g), which was used directly for the next step without further ation. 4-(4-(Benzo(d)(1,3)dioxolyloxy)-2,6-dimethylphenyl)thiazol—2-amine. A mixture of 1-(4-(benzo(d)(1,3)dioxolyloxy)-2,6-dimethylpheny1)brom0ethanone (6.13 g, 16.9 mmol) and thiourea (1.29 g, 16.9 mmol) in 95% EtOH (24.1 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (100 mL) and ted aqueous Na2C03 (5.0 mL). The resultant precipitate was ed and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4—(benzo(d)(1,3)dioxolyloxy)-2,6- dimethylphenyl)thiazol-2—amine (5.50 g) as yellow solids 20 in 96% yield: 1H MVIR (500 MHZ, CDC13) 6 6.75 (d, J = 8.5 Hz, 1H), 6.66 (s, 2 H), 6.58 (In, 1 H), 6.49 (m, 1 H), 6.28 (s, 1 H), 5.98 (s, 2 H), 5.05 (s, 2 H), 2.13 (s, 6 H).
[00302] 1-(4-(3,S-Dimethylphenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4— chloro—2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 3,5— dimethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL), was added 2—di-tert-butylphosphino- 2',4',6'-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100 °C overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 3,5-dimethy1phenoxy)—2,6- dimethylphenyl)ethanone (6.3 g) as yellow solids in 86% yield: 1H NMR (500 MHz, CDC13) 8 6.76 (s, 1 H), 6.63 (s, 2 H), 6.62 (s, 2 H), 2.48 (s, 3 H), 2.29 (s, 6 H), 2.22 (s, 6 H). o-l-(4-(3,5-dimethylphenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4-(3,5-dimethy1phenoxy)-2,6-dimethylphenyl)ethanone (6.30 g, 23.5 mmol) in acetonitrile (47.0 mL) was added tetrabutylammoniumtribromide (TBABI'3, 11.9 g, 24.7 mmol).
The reaction was stirred at room temperature overnight. The solution was concentrated under reduced re, added with water, and ted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo(4-(3,5-dimethylphenoxy)-2,6-dimethylpheny])ethanone (8.3 g), which was used ly for the next step without further purification.
[00304] 3,5-Dimethylphenoxy)-2,6-dimethylphenyl)thiazolamine. A mixture of 2- bremo=1=(4—(3,5-dimethylphenoxy)—2,6—dime.hylphenyl)ethanone (8.15 g, 23.5 mmol) and thiourea (1.79 g, 23.5 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 120 min, The solution was trated and added with water (100 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(3,5 dimethylphenoxy)—2,6-dimethylphenyl)thiazol—2-amine (4.50 g) as yellow solids in 59% yield: 1H NMR (500 MHz, CDC13) 5 6.76 (s, 1H), 6.68 (s, 2 H), 6.64 (s, 2 H), 6.26 (s, 1 H), 2.29 (s, 6 H), 2.16 (s, 6 H). ] 1-(4-(3-Methoxyphenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4— chloro-2,6-dimethylphenyl)ethanone (5.00 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mol), 3- methoxyphenol (4.08 g, 32.9 mmol) in toluene (54.8 mL) was added 2-di-tert-butylphosphino- 2',4',6'-triisopropylbiphenyl (349 mg, 0.82 mmol), Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100 °C ovemight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced re. The residue was purified by flash column chromatography on silica gel to give 1—(4—(3-methoxyphenoxy)-2,6— dimethylphenyl)ethanone (5.4 g) as yellow oil in 73% yield: 1H NMR (500 MHZ, CDC13) 5 7.24 (m, 1H), 6.68—6.66 (m, 3 H), 6.57—6.56 (m, 2 H), 3.79 (s, 3 H), 2.48 (s, 3 H), 2.22 (s, 6 H). 2-Bromo(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4-(3-methoxyphenoxy)-2,6—dimethylpheny1)ethanone (5.40 g, 20.0 mmol) in acetonitrile (40.0 mL) was added tetrabutylammoniumtribrornide (TBABI3, 10.1 g, 21.0 mmol). The reaction was stirred at room temperature ht. The solution was concentrated under reduced washed with pressure, added with water, and extracted with ethyl acetate. The organic layer was brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2- bromo—l—(4—(3-methoxyphenoxy)-2,6—dimethy1phenyl)ethanone (7.00 g), which was used ly for the next step without further ation. 3-Methoxyphen0xy)—2,6-dimethylphenyl)thiazolamine. A mixture of 2- bromo-l-(4-(3-methoxyphenoxy)-2,6—dimethylphenyl)ethanone (6.98 g, 20.0 mmol) and thiourea (1.52 g, 20.0 mmol) in 95% EtOH (28.5 mL) was heated at reflux for 5.0 h. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (1.0 mL), and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over anhydrous MgSO4(S), and concentrated under reduced pressure to give 4-(4-(3— methoxyphenoxy)—2,6-dimethylphenyl)thiazolamine (4.30 g) as deep-brown oil, which was used directly for the next step without further ation. 1-(2,6-Dimethyl(4-(trifluoromethyl)phenoxy)pheny1)ethanone. To a solution of 1-chloro—4-(trifluoromethyl)benzene (6.60 g, 36.6 mmol), K3PO4 (12.9 g, 60.9 mmol),.l-(4- hydroxy-2,6—dimethylphenyl)ethanone (5.00 g, 30.5 mmol) in toluene (60.9 mL) was added 2-di- tert-butylphosphino-2',4',6'-triisopropylbipheny1 (388 mg, 0.91 mmol) and Pd(OAc)2 (288 mg, 1.28 mmol). The reaction was heated at 100 0C for 120 min under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and ed filtrate was concentrated under reduced silica gel to give 1-(2,6- pressure. The residue was purified by flash column chromatography on dimethyl-4—(4-(trifluoromethyl)phenoxy)phenyl)ethanone (1.8 g) as yellow oil in 19% yield: 1H NMR (500 MHz, CDCI3) 5 7.58 (d, J = 8.5 Hz, 2 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.70 (s, 2 H), 2.50 (s, 3 H), 2.25 (s, 6 H). 2-Bromo(2,6-dimethyl(4-(trifluoromethyl)phenoxy)phenyl)ethanone. To a solution of 1-(2,6-dimethyl—4-(4-(trifluoromethy1)phenoxy)pheny1)ethanone (1.80 g, 5.84 mmol) in acetonitrile (11.7 mL) was added utylammoniumtribromide (TBABr3, 2.82 g, 5.84 mmol). The on was stirred at room temperature ght. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous s), and concentrated under reduced re to give 2—bromo(2,6-dimethyl(4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.16 g), which was used directly for the next step without further ation. 4-(2,6-Dimethyl(4-(tritluoromethyl)phenoxy)phenyl)thiazol-2—amine. A mixture of 2—bronio(2,6-dimethyl( 4-(trifluoromethyl)phenoxy)phenyl)ethanone (2.20 g, .68 mmol) and ea (0.43 g, 5.68 mmol) in 95% EtOH (8.1 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (1.0 mL). The ant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4—(4- (trifluoromethyl)phenoxy)phenyl)thiazolarnine (1.30 g) as yellow solids in 63% yield: 1H NMR (500 MHz, CDCl3) 6 7.56 (d,J = 8.5 Hz, 2 H), 7.05 (d, J = 8.5 Hz, 2 H), 6.76 {s, 2 H), 6.32 (s, 1 H), 5.03 (s, 2 H), 2.17 (s, 6 H). 1-(4-(4-Ethy1phenoxy)-2,6-dimethylphenyl)ethanone. To a solution of 1-(4- chloro—2,6-dimethylphenyl)ethanone (5.0 g, 27.4 mmol), K3PO4 (11.6 g, 54.7 mmol), 4- ethylphenol (4.01 g, 32.8 mmol) in toluene (54.8 mL) was added 2-di-tert-buty1phosphino- 6‘-triisopropylbiphenyl (349 mg, 0.82 mmol) and Pd(OAc)2 (259 mg, 1.15 mmol). The reaction was heated at 100 °C ht under N2. The solution was cooled to room tempera.ur.. and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1—(4-(4-ethylphenoxy)-2,6— dimethylphenyl)ethanone (6.0 g) as yellow oil in 82% yield: 1H NMR (500 MHZ, CDC13) 8 7.17 {d, J: 8.5 Hz, 2 H), 6.93 (d, J: 8.5 Hz, 2 H), 6.63 (s, 2 H), 2.64 (q, J = 7.5 Hz, 2 H), 2.47 {s, 3 H), 2.21 {s, 6 H), 1.25 {t, J: 7.5 Hz, 3 H). 2-Br0mo(4-(4-ethylphen0xy)-2,6-dimethylphenyl)ethanone. To a solution of 1- (4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (6.00 g, 22.4 mmol) in acetonitrile (44.7 mL) was added tetrabutylammoniumtribromide (TBABT3, 10.8 g, 22.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2—bromo(4- (4—ethylphenoxy)—2,6¥dimethylphenyl)ethanone (8.2 g), which was used ly for the next step without further purification. ] 4-(4-(4-Ethylphenoxy)-2,6-dimethylphenyl)thiazol-Z-amine. A mixture of 2- bromo—l-(4—(4—ethylphenoxy)-2,6-dimethylphenyl)ethanone (7.70 g, 22.2 mmol) and thiourea (1.69 g, 22.2 mmol) in 95% EtOH (31.7 mL) was heated at reflux for 180 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and tallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)thiazolamine (6.30 g) as yellow solids in 88% yield: 1H NMR (500 MHz, CD_C13) 5 7.18 (d, J = 7.5 Hz, 2 H), 6.95 (d, J = 8.5, 2 H), 6.71 (s, 2 H), 6.29 (s, 1 H), 5.45 (bs, 2 H), 2.64 (q, J: 7.5 Hz, 2 H), 2.14 (s, 6 H), 1.25 (t, J: 8.0 Hz, 3 H). 2-Bromo(3,5-diflnoromethoxyphenyl)ethanone. To a CH3CN solution (56 mL) ning 1-(3,5-difluoro-4—methoxyphenyl)ethanone (5.0 g, 26.9 mmol, 1.0 equiv) was added TBABr3 (12.95 g, 26.9 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the e was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and concentrated under reduced re. The residue was purified by column chromatography on silica gel (2.0% EtOAc in hexanes as eluant) to provide 2—bromo-1— (3,5-difluoro-4—methoxyphenyl)ethanone (5.05 g, 19.0 mmol) as white solids in 71% yield: 1H NMR (DMSO-dG, 500 MHz) 8 7.76-7.81 (m, 2 H), 4.91 (s, 2 H), 4.07 (s, 3 H).
-Difluoro-4—methoxyphenyl)thiazol-_-amine. A on mixture containing 2-br0mo(3,5-difluoromethoxypheny1)ethanone (2.0 g, 7.5 mmol, 1.0 equiv) and thiourea (0.57 g, 7.5 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 3.0 h. The residue was basified with saturated aqueous NaHC03 (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was separated, dried over MgSO4(s), and trated under reduced pressure. The resultant solids were washed with hexanes to give 4-(3,5-difluoromethoxyphenyl)thiazol amine (1.54 g, 6.4 mmol) as white solids in 84% yield: 1H NMR (DMSO'dfi, 500 MHz) 8 7.49—7.54 (m, 2 H), 7.12—7.14 (m, 3 H), 3.92 (s, 3 H); ESI-MS: m/z 243.0 (M +H)+. ] l-(2,6-Difluoromethoxyphenyl)ethanone. A mixture of aluminium chloride (10.0- 15 g, 69.4 mmol, 5.0 equiv) and acetyl chloride (2.0 mL, 28 mmol, 2.0 equiv) in CHZCIQ (50.0 mL) was stirred at 0 0C for 30 min. The reaction mixture was slowly added with 1,3- difluoro-5—methoxy-benzene (2.0 g, 13.9 mmol, 1.0 equiv) in CH2C12 (10.0 mL), and the resultant solution was stirred at room temperature for additional 2.0 h. The solution was basified with saturated aqueous NaHC03 (20 mL) to pH 8-9. The c layer was separated, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to give 1—(2,6-difluoro-4— methoxyphenyl)ethanone (1.5 g, 8.1 mmol) as yellow oil in 58% yield: 1H NMR (CDC13, 500 MHz) 6 6.46-6.48 (m, 2 H), 3.83 (s, 3 H), 2.56 (s, 3 H); ESI-MS: m/z 187.0 (M +H)+. 2-Bromo(2,5-difluoro—4-methoxyphenyl)ethanone. A CH3CN solution (20 mL) containing 1-(2,6-difluoromethoxyphenyl)ethanone (1.5 g, 8.1 mmol, 1.0 equiv) was added with TBABr3 (3.88 g, 8.1 mmol, 1.0 equiv). The reaction mixture was d at room temperature for 16h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The on was washed with saturated aqueous NaHC03 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The e was purified by column chromatography on silica gel (2.0% EtOAc in hexanes as eluant) to e 2-bromo (2,5-difluoromethoxyphenyl)ethanone (5.05 g, 19.1 mmol) as yellow oil in 84% yield: 1H NMR (CDC13, 500 MHz) 6 6.50-6.52 (m, 2 H), 4.34 (s, 2 H), 3.85 (s, 3 H).
[00318] 4-(2,6-Difluoromethoxyphenyl)thiazol-Z-amine. A reaction mixture containing 2-bromo(2,5-difluoromethoxyphenyl)ethanone (1.5 g, 5.7 mmol, 1.0 equiv) and thiourea (430.8 mg, 5 .7 mmol, 1.0 equiv) in EtOH (15.0 mL) was heated at reflux for 6.0 h. The residue was basified with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3 x 30 mL).
The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure.
The residue was d by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to e 4-(2,6-difluoro—4-methoxy—phenyl)—thiazolamine (928.6 mg, 3.8 mmol) as white solids in 68% yield: 1H NMR(CDC13, 500 MHz) 5 6.68 (s, 1H), 6.50-6.52 (m, 2 H), 5.07 (s, 2 H), 3.81 (s, 3 H); ESI—MS: m/z 243.7 (M + H)+. 2-Hydroxypropoxy)-2,6-dimethylphenyl)ethanone. A re glass vessel charged with 1-(4—hydroxy-2,6—dimethy1phenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 2- methyloxirane (0.22 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was stirred at 140 °C for 4.0 h. The mixture was diluted with H20 (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The e was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2-hydroxypropoxy)—2,6-dimethylphenyl)ethanone (445.9 mg. 2.1 mmol) as yellow oil in 66% yield: 1H NMR (CDC13, 500 MHz) 5 6.57 (s, 2 H), 4.10-4.20 (s, 1 H), 3.90-3.93 (m, 2 H), 3.75-3.79 (m, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 1.25—1.28 (m, 3 H); ESI—MS: m/z 223.4 (M + H)+. 2-Bromo(4-(2-hydroxypropoxy)-2,6-dimethylphenyl)ethanone. To a CH3CN solution (6.0 mL) containing 2—hydroxypropoxy)-2,6-dimethylphenyl)ethanone (445.9 mg, 2.0 mmol, 1.0 equiv) was added TBABr3 (967.3 mg, 2.0 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. The solvent was trated under reduced pressure, and the residue was re-dissolved in EtOAc (SOmL). The solution was washed with saturated WO 82324 reduced pressure. 2- aqueous NaHCO3 (30mL), dried over MgSO4, and concentrated under Bromo-l-(4—(2-hydroxypropoxy)-2,6—dimethylphenyl)ethanone (547.8 mg, 1.8 mmol) was ed as brown oil in 91% yield: 1H NMR (CDC13, 500 MHz) 6 6.60 (s, 2 H), 4.25 (s, 2 H), 4.10—4.20 (s, 1 H), 3.91-3.94 (m, 2 H), 3.79—3.80 (s, 1 H), 2.24 (s, 6 H), 1.27-1.29 (m, 3 H). 2-Aminothiazolyl)-3,5-dimethylphenoxy)propanol. A on mixture containing o-1—(2,5-difluoro-4—methoxyphenyl)ethanone (547.8 mg, 1.8 mmol, 1.0 equiv) and thiourea (138.5 mg, 1.8 mmol, 1.0 equiv) in EtOH (3.0 mL) was heated at reflux for 16 h.
The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (30 mL). The solution was washed with saturated s NaHC03 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2-aminothiazol- 4—yl)—3,5-dimethylphenoxy)propanol (332.5 mg, 1.2 mmol) as yellow oil in 66% yield: 1H NMR , 500 MHZ) 5 6.62 (s, 2 H), 6.26 (s, 1H), 4.95 (s, 2 H), 4.10-4.20 (s, 1H), 3.91- 3.94(m, 2 H), 3.75-3.79 (m, 1 H), 2.15 (s, 6 H), 1.26-1.28 (m, 3 H); ESI-MS: m/z 279.7 (M + H)+.
[00322] 1-(4-(2,3-Dihydroxyprop0xy)-2,6-dimethylphenyl)ethanone. Apressure glass vessel charged with 1-(4—hydroxy—2,6-dimethylphenyl)ethanone (2.00 g, 12.2 mmol, 1.0 equiv) and 3-chloropropane-1,2-diol (1.02 mL, 122 mmol, 1.0 equiv) in 50% aqueous NaOH solution (200 mL) was heated at 140 °C for 16 h. The mixture was diluted with H20 (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1—(4-(2,3-dihydroxyprop0xy)-2,6— dimethylphenyl)ethanone (1.66 g, 7.0 mmol) as yellow oil in 57% yield: IH N1V1R , 500 MHz) 5 o 6.57 (s, 2 H), 4.10-4.11 (m, 1 H), 4.08-4.09 (m, 2 H), 4.01—4.02 (m, 1 H), 3.74-3.75 (m, 1 H), 2.58—2.59 (s, 1 H), 2.45 (s, 3 H), 2.23(s, 6 H), 2.05—2.10(s, 1 H); ESI—MS: m/z 239.9 (M + H)+. 2-Bromo(4-(2,3-dihydr0xypropoxy)-2,6-dimethylphenyl)ethanone. To a CH3CN solution (10.0 mL) containing 1-(4—(2,3-dihydroxypropoxy)—2,6 dimethylphenyl)ethanone (1.0 g, 4.2 mmol, 1.0 equiv) was added TBABr3 (2.04 g, 4.2 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4, and trated under reduced pressure. 2-Bromo-1—(4-(2,3-dihydroxypropoxy)-2,6- dimethylphenyl)ethanone (741.9 mg, 2.3 mmol) was obtained as yellow solids in 56% yield: 1H NMR (CDC13, 500 MHZ) 5 6.60 (s, 2 H), 4.25 (s, 2 H), 4.10-4.11 (m, 1 H), 4.03-4.04 (m, 2 H), 3.82—3.85 (m, 1 H), .76 (m, 1 H), 2.24 (s, 6 H). 3-(4-(2-Amin0thiazol-4—yl)-3,5-dimethylphenoxy)propane-1,2-diol. A reaction e containing 2—bromo(4—(2,3-dihydroxypropoxy)-2,6—dimethylphenyl)ethanone (741.9 mg, 2.3 mmol, 1.0 equiv) and thiourea (178.1 mg, 2.3 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under d pressure, and the residue was solved in EtOAc (30 mL). The solution was washed with saturated aqueous NaHC03 . (30 mL), dried over MgSO4, and concentrated under reduced re. The residue was purified by column chromatography on silica gel (30.0% EtOAc in hexanes as eluant) to provide 3-(4-(2- arninothiazol-4—yl)—3,5-dimethylphenoxy)propane-1,2-diol (694.1 mg, 2.4 mmol) as yellow solids in >99% yield: 1H NMR (CDC13, 500 MHz) 5 6.76 (s, 2 H), 5.31—5.32 (m, 1 H), 3.99-4.00 (m, 1 H), 3.79-3.87 (m, 1H), 3.78-3.79 (m, 1 H), 3.43—3.44 (m, 2 H), 3.37 (s, 2 H),2.15 (s, 6 H); ESI—MS: m/z 295.6 (M + H)+. ] 1-(4-(2-Methoxyethoxy)-2,6-dimethylphenyl)ethanone. A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethy1phenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 1- chloro—2-methoxyethane (0.28 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was heated at 140 0C for 16 h. The residue was diluted with H20 (20 mL) and extracted with EtOAc (3 X 30 mL). The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to give 1—(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (430.9 mg, 1.9 mmol) as yellow oil in 64% yield: 1H NMR (CDC13, 500 MHz) 5 6.58 (s, 2 H), 4.09—4.10 (m, 2 H), 3.72—3.74 (m, 2 H), 3.44 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H); ESI-MS: m/z 223.6 (M + H)+. ] 2-Bromo(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone. To aCHgCN solution (6.0 mL) containing 1-(4-(2-methoxyethoxy)—2,6-dimethylphenyl)ethanone (400 mg, 1.8 , ‘ mmol, 1.0 equiv) was added TBABr3 (867.7 mg, 1.8 mmol, 1.0 . The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. o (4-(2-methoxyethoxy)—2,6-dimethylpheny1)ethanone (322.9 mg, 1.1 mmol) was obtained as yellow solids in 60% yield: 1H C13, 500 MHz) 8 6.61 (s, 2 H), 4.25 (s, 2 H), 4.09-4.11 (m, 2 H), 3.73—3.75 (m, 2 H), 3.45 (s, 3 H), 2.24 (s, 6H). 4-(4-(2-Methoxyethoxy)—2,6-dimethylphenyl)thiazol-Z-amine. A reaction mixture containing 2-bromo—1—(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (322.9 mg, 1.1 mmol,1.0 equiv) and thiourea (81.61 mg, 1.1 mmol, 1.0 equiv) in EtOH (3.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re— dissolved in EtOAc (20 mL). The solution was washed with saturated s NaHC03 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4-(4—(2- methoxyethoxy)—2,6-dimethylphenyl)thiazol-2—arnine (281.0 mg, 1.0 mmol) as yellow solids in 94% yield: 1H NMR (DMSO'dfi, 500 MHz) 8 6.76 (s, 2 H), 5.31—5.33 (m, 1 H), 4.09-4.11(m, 2 H), 3.64-3.65 (m, 2 H), 3.30 (s, 3 H), 2.12 (s, 6 H); ESI-MS: m/z 279.7 (M + H)+. 1-(4-(3-Methoxypropoxy)-2,6-dimethylpheny1)ethanone. A pressure glass vessel charged with ydroxy-2,6-dimethy1phenyl)ethanone (800 mg, 4.9 mmol, 1.0 equiv) and 1- chloro-3—methoxypropane (528.97 mg, 4.9 mmol, 1.0 equiv) in 50% aqueous NaOH solution (10.0 mL) was stirred at 140 °C for 16 h. The residue was d with H20 (20 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure to give 1-(4-(3-methoxypropoxy)—2,6- dimethylphenyl)ethanone (987.8 mg, 4.2 mmol) as yellow oil in 86% yield: 1H NMR (DMSO—dé, 500 MHZ) 5 6.56 (s, 2 H), 4.02-4.04 (m, 2 H), .55 (m, 2 H),—3.36 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.02-2.04 (m, 3H); ESI—MS: m/z 237.7 (M + H)+. 2-Bromo(4-(3-methoxypropoxy)-2,6-dimethy1phenyl)ethanone. To aCHgCN solution (15.0 mL) containing 3-rnethoxypropoxy)-2,6-dimethylphenyl)ethanone (987.8 mg, 4.2 mmol, 1.0 equiv) was added TBABr3 (2.02 g, 4.2 mmol, 1.0 equiv). The reaction mixture was stirred at room ature for 16 h. The solution was concentrated under reduced with pressure, and the residue was re—dissolved in EtOAc (50 mL). The solution was washed saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. o-l-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (1.23 g, 3.9 mmol) was obtained as yellow oil in 93% yield: 1H NMR(CDC13, 500 MHZ) 5 6.58 (s, 2 H), 4.24-4.35 (m, 2 H), 4.03-4.05 (rn, 2 H), 3.53-3.55 (m, 2 H), 3.35 (s, 3 H), 2.24 (s, 6H), 2.01-2.06 (m, 2 H). ] 3-Methoxypropoxy)-2,6-dimethylphenyl)thiazol-Z-amine. A reaction mixture containing 2-bromo—1-(4—(3—methoxypropoxy)-2,6-dimethylphenyl)ethanone (500.0 mg, 1.6 mmol, 1.0 equiv) and thiourea (126.8 mg, 1.6 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under d pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was d by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 4- (4-(3-methoxypropoxy)-2,6-dimethylphenyl)thiazolamine (328.9 mg, 1.1 mmol) as yellow 10 solids in 71% yield: 1H NMR (CDCI3, 500 MHz) 5 9.35 (s, 1H), 9.00 (s, 1 H), 6.64 (s, 2 H), 6.22 (s, 1 H), 4.04-4.05 (m, 2 H), 3.54—3.56 (m, 2 H), 3.37 (s, 3 H), 2.19 (s, 6 H), 2.03—2.06 (m, 2 H); ESI-MS m/z 293.8 (M + H)+. l-(2,6-Dimethyl(phenylthio)phenyl)ethan0ne. A mixture of 1-(4-iodo—2,6— dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), benzenethiol (0.60 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, DMF (4.4 mL) and H20 (1.1 mL) was heated at reflux for 20 h. The . 11.0 mmol, 2.0 equiv) in mixture was quenched with H20 (10 mL) and extracted with ether (2 x 20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6—dimethyl(phenylthio)phenyl)ethanone (931 mg, 3.6 mmol) as yellow oil in 66% yield: 1H NMR (CDgOD, 500 MHz) 5 7.34-7.35 (m, 5 H); 6.97 (s, 2 H), 2.46 (s, 3 H), 2.17 (s, 6 H); ESI—MS: m/z 257.0 (M + H)+. 2-Bromo(2,6-dimethyl(phenylthio)phenyl)ethanone. To a CH3CN solution (15.0 mL) containing 1-(2,6—dimethyl(phenylthio)phenyl)ethan0ne (816.3 mg, 3.2 mmol, 1.0 equiv) was added TBABr3 (1.54 g, 3.2 mmol, 1.0 equiv). The reaction mixture was sti-.ed at room ature for 16 h. The solution was concentrated under reduced re, and the residue was re—dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous, NaHCO3 (30 mL), dried over s), and concentrated under reduced pressure. The residue 2O was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as the ) to provide 2-brom0(2,6-dimethyl(phenylthio)phenyl)ethanone (591.7 mg, 1.6 mmol) as yellow oil in 55% yield: 1H NMR (DMSO-dé, 500 MHz) 5 7.36-7.42 (m, 5 H), 7.01 (s, 2 H), 4.75 (s, 2 H), 2.13 (s, 6 H). 4-(2,6-Dimethy1(pheny1thio)pheny1)thiazolamine. ion mixture containing 2-bromo-1—(2,6-dimethyl—4-(phenylthio)phenyl)ethanone (591.7 mg, 1.8 mmol, 1.0 equiv) and thiourea (134.3 mg, 1.8 mmol, 1.0 equiv) in EtOH (15.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the e was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHC03 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The e was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl—4- lthio)phenyl)thiazolamine (483.7 mg, 1.6 mmol) as yellow Solids in 88% yield: 1H NMR (DMSO‘dé, 500 MHz) 5 7.33—7.38 (m, 2 H), 7.29—7.33 (m, 3 H), 7.06 (s, 2 H), 6.89 (s, 2 H), 6.38 (s, 1 H), 2.07 (s, 6 H); ESI-MS: m/z 313.8 (M + H)+.
WO 82324 -Dimethy1(p-tolylthio)phenyl)ethanone. A mixture of 1-(4-iod0-2,6- ylpheny1)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4-methylbenzenethiol (1.02 g, 8.2 mmol, equiy), copper(I) oxide (392 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H20 (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H20 (10 mL) and extracted with ether (2 x 20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1—(2,6-dimethy1(p-tolylthio)phenyl)ethanone (1.16 g, 4.3 mmol) as yellow oil in 79% yield: 1H NMR (CD301), 500 MHz) 6 7.29 (d, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 6.88 (s, 2 H), 2.45 (s, 3 H), 2.35 (s, 3 H), 2.15 (s, 6 H); ESI—MS: m/z 271.8 (M + H)+. 2-Bromo(2,6-dimethy!(p-tolylthio)phenyl)ethanone. To a CH3CN solution (20.0 mL) containing 1-(2,6-dimethyl(p-toly1thio)phenyl)ethanone (1.0 g, 3.7 mmol, 1.0 equiv) was added TBABr3 (1.79 g, 3.7 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. The on was trated under reduced re, and the residue was re—dissolved in EtOAc (50 mL). The solution was washed with saturated s NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as the eluant) to provide 2-bromo—1—(2,6—dimethy1(p—tolylthio)phenyl)ethanone (394.8 mg, 1.1 mmol) as yellow oil in 31% yield: 1H NMR (DMSO—d6, 500 MHz) 8 7.33 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.92 (s, 2 H), 4.76 (s, 2 H), 2.32 (s, 3 H), 2.11 (s, 6 H). 4-(2,6-Dimethyl(p-tolylthio)phenyl)thiazolamine. ion e containing 2-bromo-1—(2,6—dimethy1(p-tolylthio)phenyl)ethanone (394.8 mg, 1.1 mmol, 1.0 equiv) and ea (86.04 mg, 1.1 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl—4-(p- tolylthio)phenyl)thiazol—2-amine (371.9 mg, 1.1 mmol) as yellow solids in >99% yield: 1H NMR (DMSO-d6, 500 MHz) 5 7.27 (d, J: 8.0 Hz, 2 H), 7.21 (d, J: 8,0 Hz, 2 H), 6.97 (s, 2 H), 6.87 (s, 2 H), 6.36 (s, 1 H), 2.30 (s, 3 H), 2.05 (s, 6 H); ESI—MS: m/z 327.0 (M + H)+. 1-(4-(4-Methoxyphenylthio)-2,,6-dimethylphenyl)ethanone. A mixture of 1-(4— iodo—2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), 4—methoxybenzenethiol (1.01 mL, 8.2 mmol, 1.5 equiv), copper(1) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H20 (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H20 (10 mL) and extracted with ether (2 x 20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced silica gel (3.0% EtOAc in pressure. The residue was purified by column chromatography on hexanes as eluant) to provide 1—(4—(4-methoxyphenylthio )-2,6-dimethylpheny1)ethanone (1.41 g, 4.9 mmol) as yellow oil in 90% yield: 1H NMR (DMSO-dé, 500 MHz) 8 7.39 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2 H), 6.79 (s, 2 H), 3.82 {s, 3 H), 2.43 (s, 3 H), 2.13 (s, 6 H); ESI—MS: m/z 287.6 (M + H)+. 2-Bromo(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone. To a CH3CN solution (20.0 mL) containing 1-(4-(4-methoxyphenylthio )-2,6 dimethylphenyl)ethanone (1.0 g, 3.5 mmol, 1.0 equiv) was added TBABr3 (1.684 g, 3.5 mmol, 1.0 . The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated s NaHC03 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to e o—1-(4-(4-methoxyphenylthi0)- 2,6-dimethy1phenyl)ethanone (1.06 g, 2.9 mmol) as yellow oil in 83% yield: 1H NMR (DMSO- d6, 500 MHz) 8 7.44 (d, J = 8.7 Hz, 2H), 7.03 {d, 1:8.7 Hz, 2 H), 76.83 (s, 2 H), 4.71 (s, 2 H), 3.80 (s, 3 H), 2.10 (s, 6 H). 2O [00339] 4-(4-(4-Methoxyphenylthio)-2,6-dimethylphenyl)thiazolamine. A reaction mixture containing 2-bromo( 4-(4—methoxyphenylthio )-2,6-dimethylphenyl)ethan0ne (1.06 in EtOH (20.0 mL) was g, 2.9 mmol, 1.0 equiv) and thiourea (221.5 mg, 2.9 mmol, 1.0 equiv) heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under d pressure. The residue was . ed by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4—(4-(4—methoxyphenylthio)-2,6-dimethy1phenyl)thiazol—2-amine (890.9 mg, 2.6 mmol) as yellow solids in 90% yield: 1H NMR(DMSO—d6, ) 6 7.40 (d, J = 8.7Hz, 2 H), 7.00 (d, J = 8.7 Hz, 2 H), .87 (m, 4 H), 6.33 (s, 1 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS m/z 343.9 (M + H)+. ] 2—Bromo(4-(4-methoxyphenylsulfony1)-2,6-dimethy1pheny1)ethan0ne. A mixture of 2-bromo(4-(4-methoxyphenylthio )-2,6-dimethylphenyl)ethanone (1.0 g, 2.7 mmol, 1.0 equiv) and m-chloroperoxybenzoic acid (1.69 g, 6.8 mmol, 2.5 equiv) in dichloromethane (10.0 mL) was d at room temperature for 16 h. The on was concentrated under reduced pressure, and the residue was solved in EtOAc (50 mL). The solution was washed with saturated s NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure to give 2-bromo(4-(4 methoxyphenylsulfonyl)-2,6—dimethylphenyl)ethanone (1.09 g, 2.7 mmol) as white solids in >99% yield: 1H NMR (CDC13, 500 MHz) 8 .90 (m, 2 H), 7.57-7.60 (m, 2 H), 6.97-6.90 (m, 2 H), 4.21 (s, 2 H), 3.85 (s, 3 H), 2.30 (s, 6 H). 4-(4-(4-Methoxyphenylsulfonyl)-2,6-dimethylphenyl)thiazolamine. A reaction mixture containing 2—bromo(4-(4-methoxyphenylsulfonyl)-2,6 dimethylphenyl)ethanone (1.33 g, 3.4 mmol, 1.0 equiv) and thiourea (254.8 mg, 3.4 mmol, 1.0 equiv) in EtOH (5.0 mL) was heated at reflux for 1.0 h. The solution was trated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with ted aqueous NaHCO 3 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The resultant solids were washed with hexanes to give 4—(4-(4-methoxyphenylsulfonyl)—2,6- dimethylphenyl)thiazol—2—amine (839.2 mg, 2.2 mmol) as yellow solids in 65% yield: 1H NMR (DMSO-dé, 500 MHz) 8 7.89 (d, J: 8.9 Hz, 2 H), 7.61 (s, 2 H), 7.13 (d, J: 8.9 Hz, 2 H), 6.95 (brs, 2 H), 6.43 (s, 1 H), 3.83 (s, 3 H), 2.16 (s, 6 H); ESI-MS: m/z 375.6 (M + H)+. 2-Bromo(4-(4-methoxyphenylsulfinyl)-2,6—dimethylphenyl)ethanone. A e of 2-bromo(4-(4—methoxyphenylthio )-2,6-dimethylphenyl)ethanone (500.0 mg, 1.3 mmol, 1.0 equiv), acetic anhydride (0.14 mL, 1.5 mmol, 1.1equiv), 30% hydrogen peroxide (55.86 mg, 1.6 nmlOl, 1.2 equiv) and silica gel (273.75 mg, 230--400 mesh) in dichloromethane (10.0 mL) was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the e was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHC03 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure to give 2—bromo—1-(4-(4 methoxyphenylsulfinyl)—2,6-dimethylphenyl)ethanone (235.4 500 MHz) 6765 (d, J = mg, 0.6 mmol) as pale- yellow oil in 48% yield: 1H NMR (DMSO-d6, 8.8 Hz, 2 H), 7.41 (s, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 4.78 (s, 2 H), 3.79 (s, 3 H), 2.21 (s, 6 H).
N-(4-(4-(4-Meth0xyphenylsulfinyl)-2,6-dimethylphenyl)thiazol-2— yl)isonicotinamide. A reaction mixture containing 2-bromo(4-(4-methoxyphenylsulfiny1)— 2,6-dimethylphenyl)ethanone (235.4 mg, 0.6 mmol, 1.0 equiv) and thiourea (47.0 mg, 0.60 mmol, 1.0 equiv) in EtOH (5.0 mL) was heated at reflux for 1.0 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHC03 (30 mL), dried over MgSO4, and concentrated under reduced pressure. The resultant solids were washed with hexanes to give N-(4-(4-(4- methoxyphenylsulfinyl)—2,6-dimethylphenyl)thiazol- 2 yl)isonicotinamide (236.7 mg, 0.70 mmol) as yellow solids in >99% yield: 1H NIVIR (DMSO'dfi, 500 MHz) 8 7.64 (d, J = 8.9 Hz, 2 H), 7.34 (s, 2 H), 7.09 (d, J = 8.9 Hz, 2 H), 6.90 (s, 2 H), 6.39 (s, 1 H), 3.79 (s, 3 H), 2.13 (s, 6 H); ESI-MS m/z 359.0 (M + H)+. 5-Methylphenylthiazolamine. A mixture of 2-bromo-l-phenylpropan-l-one (3.00 g, 19.5 mmol) and thiourea (1.56 g, 20.5 mmol) in 95% EtOH (30 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was d and recrystallized in toluene.
The solids were filtered and dried under vacuum to give ylphenylthiazol-2—amine (4.07 g) as yellow solids in 77% yield: 1H NMR (500 MHz, DMSO—d6) 5 8.85 (s, 2 H), 7.54-7.49 (m, 5 H), 2.28 (s, 3 H). 2-Bromo(4-methoxypheny1)propan-l-one. To a solution of 1-(4- methoxyphenyl)propan-1—one (5.01 g, 30.2 mol) in EtOAc (120 mL) was added copper(H) bromide , 13.6 g, 6.8 mmol). The reaction mixture was heated at reflux for 90 min. The solution was allowed to cool down, and the resultant solids were d off and washed with EtOAc. The filtrnte was concentrated under reduced pressure to give crude 2-br0m0—1—(4~ methoxyphenyl)propan-l—one (10.4 g) as yellow oil: 1H NMR (500 MHz, CDC13) 6 8.02 (m, 2 H), 6.96 (m, 2 H), 5.28-5.25 (m, 1 H), 3.89 (s, 3 H), 1.89 (d, 3 H). 4-(4-Methoxypheny1)methylthiazol-2—amine. A mixture of 2-bromo(4— methoxyphenyl)propan—l—one (10.4 g, 36.1 mmol) and thiourea (2.76 g, 36.2 minol) in 95% EtOH (70 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with. water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4- methoxyphenyl)-_5-methylthiazolamine (6.16 g) as yellow solids in 78% yield: 1H NMR (500 MHz, DMSO—ds) 5 8.90 (s, 2 H), 7.46—7.44 (m, 2 H), 7.09—7.07 (m, 2 H), 3.81 ($.73 H), 2.47 (s, 3 2-Brom0(2,4,6-trimethoxyphenyl)ethanone. To a on of l-(2,4,6- trimethoxyphenyl)ethanone (5.0 g, 23.3 mmol) in EtOAc (100 mL) was added copper(II) bromide (CuBrg, 10.4 g, 46.7 mmol). The reaction e was heated at reflux for 90 min. The . solution was allowed to cool down, and the ant solids were filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure to give crude 2-br0mo(2,4,6- trimethoxyphenyl)ethanone (2.70 g) 2-bromo(2,4,6—trimethoxyphenyl)ethanone as yellow oil: 1H NMR (500 MHz, CDC13) 5 6.11 5 (m, 2 H), 4.36 (m, 2 H), 3.86 (s, 3 H), 3.82 (s, 6 H). 4-(2,4,6-Trimethoxyphenyl)thiazol-Z-amine. A mixture of 2-bromo(2,4,6- trimethoxyphenyl)ethanone (2.49 g, 8.6 mmol) and thiourea (0.67 g, 8.7 mmol) in 95% EtOH (16 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated s Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4,6- trimethoxyphenyl)thiazolamine (1.75 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO—d6) 5 9.00 (s, 2 H), 6.78 (s, 1 H), 6.36 (s, 2 H), 3.84 (s, 3 H), 3.79 (s, 6 H). ] 2-Br0mo(4-methoxyphenyl)ethanone. To a solution of 1-(4- methoxyphenyl)ethanone (15.2 g, 0.10 mol) in EtOAc (250 mL) was added copper(II) e (CuBr2, 45.1 g, 0.20 mol). The reaction mixture was heated at reflux for 90 min. The solution was allowed to cool down, and the resultant solids were d off and washed with EtOAc. The filtrate was concentrated under reduced pressure to give crude 2-bromo(4- methoxyphenyl)ethanone (15.8 g) as yellow oil: 1H NMR (500 MHz, CDC13) 5 7.98 (m, 2 H), 6.97 (m, 2 H), 4.41 (s, 3 H), 3.89 (s, 6 H).
[00350] 4-(4-Methoxyphenyl)thiazolamine. A mixture of o(4- yphenyl)ethanone (5.00 g, 21. mmol) and thiourea (1.72 g, 22.6 mmol) in 95% BO“ (40 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2C03 (5.0 mL). The resultant precipitate was filtered and recrystallized in e. The solids were filtered and dried under vacuum to give 4—(4- methoxyphenyl)thiazol—2-amine (5.24 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO-d6) 5 7.72 (d, 2 H), 6.99 (s, 2 H), 6.92-6.91 (m, 2 H), 6.82 (s, 1 H), 3.76 (s, 3 H). 2-Br0m0(2,4-dimethoxyphenyl)ethanone. To a solution of 1—(2,4- dimethoxyphenyl)ethanone (10.0 g, 54.4 mmol) in EtOAc (220 mL) was added copper(II) bromide (CuBrz, 24.3 g, 0.11 mol). The reaction mixture was heated at reflux for 90 min. The solution was allowed to cool down, and the resultant solids were filtered off and washed with EtOAc. The filtrate was concentrated under reduced pressure to give crude 2-bromo(2,4— dimethoxyphenyl)ethanone (14.5 g) as yellow oil: 1H NMR (500 MHz, CDC13) 6 7.91 (m, 2 H), 6.52 (m, 2 H), 4.57 (s, 3 H), 3.98 (s, 3 H), 3.85 (s, 3 H). 4-(2,4-Dimethoxyphenyl)thiazolamine. A mixture of 2-bromo(2,4— dimethoxyphenyl)ethanone (14.5 g, 55.8 mmol) and thiourea (4.32 g, 56.7 mmol) in 95% EtOH (110 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated s NazCO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4- WO 82324 dimethoxyphenyl)thiazol—2-amine (10.9 g) as yellow solids in 62% yield: 1H NMR (500 MHz, DMSO—dg) 5 8.60 (s, 2 H), 7.53 (s, 1 H), 6.97 (s, 1 H), 6.69 (s, 1H), .63 (m,1 H), 3.86 (s, 3 H), 3.80 (s, 3 H). 2-Chlor0(2,4,6-trifluorophenyl)ethanone. To a mechanically stirred solution of trifluorobenzene (6.0 mL, 58 mmol) in dichloroethane (14.0 mL) was added gradually AlCl3 (15.5 g, 116 mmol) in a period of 15 min with caution. Violent bumping and HCl gas evolution was observed. The mixture was carefully heated to reflux, and chloroacetyl chloride (5.5 mL, 69 mmol) was added drop wisely in a period of 45 min. The reaction e was heated at reflux for an additional 6.0 h. The solution was cooled, carefully poured onto an ice/water slush (200 mL) and the aqueous solution was extracted with ether (3 x 50 mL). The combined ethereal layers were washed with 10% aqueous HCl (2 X 30 mL), 1.0 N aqueous NaOH (3 x 30 mL), and brine (25 mL). The solution was dried over MgSO4(s) and concentrated under reduced pressure to give 2-chloro—l-(2,4,6-trifluorophenyl)ethanone (5.28 g) as yellow solids in 51% yield: 1H NMR (500 MHz, CDC13) 5 6.79—6.76 (m, 2 H), 4.50 (s, 2 H).
[00354] 4-(2,4,6-Triflu0rophenyl)thiazol-Z'amine. A mixture of 2-chlor0—1-(2,4,6- trifluorophenyl)ethanone (9.04 g, 43.5 mmol, and thivurea (3.51 g, 46.1 mmol) in 95% EtOH (50 mL) was heated at reflux overnight. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The solids were filtered and dried under vacuum to give ,6-trifluorophenyl)thiazolamine (9.71 g) as pink-white solids in 97% yield: 1H NMR (500 MHZ, DMSO-dfi) 5 .22 (m, 2 H), 7.09 (s, 2 H), 6.77 (s, 1 H). 1-(2,6-Dimethyl(phenylamino)phenyl)ethanone. To a solution of 1-(4-amino— 2,6-dimethylphenyl)ethanone (3.26 g, 20.0 mmol), K3PO4 (9.2 g, 40 mmol), and l-iodobenzene (4.08 g, 20.0 mmol) in DMF (35.0 mL) was added CuI (761.8 mg, 40 mmol). The reaction was heated at 110 °C overnight under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash . column chromatography on silica gel to give 1—(2,6-dimethyl—4-(phenylamino )pheny])ethanone as red-brown syrup: 1H NMR (500 MHz, CDCl3) 6 7.30 (d, J = 8.2 Hz, 2 H), 7.10 (d, J = 7.7 Hz, 2 H), 6.99 (d, J = 4.2 Hz, 1 H), 6.71 (s, 1 H), 2.47 (s, 3 H), 2.18 (s, 6 H); ESI—MS: m/z 239.5 (M +H)+. 1-(4-(4-Bromophenylamino)-2,6—dimethylphenyl)bromoethanone. To a solution of 1-(2,6-dimethyl(phenylamino)pheny1)ethanone (2.10 g, 8.78 mmol) in acetonitrile (50 mL) was added utylammoniumtribrornide (TBABr3, 4.24 g, 8.78 mmol). The reaction was stirred at room temperature for 60 min. The solution was concentrated under reduced washed with pressure, added with water, and ted with ethyl acetate. The organic layer was brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 1—(4-(4— bromophenylamino )—2,6-dimethylpheny1)bromoethanone (2.01 g), which was used directly for the next step without further purification. 4-(4-(4-Bromophenylamin0)-2,6-dimethylphenyl)thiazolamine. A on of l-(4—(4—bromophenylamino)-2,6—dimethylphenyl)-2—bromoethanone (1.6 g, 4.0 mmol) and thiourea (0.79 g, 7.2 mmol) in acetonitrile (30 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2C03 (1.0 mL), and extracted with ethyl acetate. The c layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give product (1.1g), which was used directly for the next step without further purification. 3-Chloromethyl-phenylamine. An ethanol on (75 mL) ning l-chloro- 3-methylnitro-benzene (5.0 g, 29 mmol) were mixed with SHC12'2H20 (32.8 g, 146 mmol).
The reaction mixture was refluxed for 3.0 h. The solution was concentrated under , and the residue was re—disselved in aqueous NaOI-I, filtered, and ted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4(s), and concentrated under reduced 3—chloro-5— pressure. The residue was purified by column chromatography on silica gel to give methyl-phenylamine (4.0 g) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDC13) 5 2O 6.56 (s, 1 H), 6.48 (s, 1 H), 6.36 (s, 1 ), 3.66 (s, 2 H), 2.23 (s, 3 H); ESI-MS: m/z 141.7 (M + H)+. ] hloromethyl-phenyl)-acetamide. Acetic anhydride (6.7 mL) and 3- chloromethy1-phenylamine (5.0 g, 35 mmol) was mixed and stand for 2.0 h. The reaction mixture was cooled to room temperature to give N—(3-chloromethyl-phenyl)acetamide (5.1 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, CDC13) 6 7.38 (s, I H), 7.19 (s, 1 H), 7.12 (s, l H), 6.91 (s, 1 H), 2.31 (s, 3 H), 2.16 (s, 3 H).
N-(4—Acetylchlor0methyl-phenyl)-acetamide. A dry CS2 solution (30 mL) containing N-(3—chloro—5 -methyl—phenyl)acetamide (5 .0 g, 27 mmol) and acetyl chloride (2.9 ml, 40.8 mmol) was slowly mixed with aluminum chloride (9.1 g, 68 mmol). The reaction mixture was heated at reflux for 30 min, cooled to room temperature, and d to stand for 4.0 h. The C82 was decanted and the remaining syrup was poured into icy HCl. The resultant solids were collected, re-dissolved in EtOH, and decolorized with charcoal. The solution was filtered and the filtrate was trated under vacuum to give N—(4—acetyl-3—chlor0methylphenyl)acetamide I (5.2 g) as light yellow solids in 85% yield: 1H NMR (500 MHZ, CDC13) 5 s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 2.52 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H). 1-(4-Amin0chloromethylphenyl)ethanone. An l solution (4.0 mL) containing N-(4-acetylchloro—5—methylphenyl)acetamjde (0.53 g, 2.3 mmol) and concentrated hydrochloric acid (1.6 mL) was heated at reflux for 15 h. The solution was added with 10% aqueous NaOH and the resultant solids were collected to give 1-(4-amin0—2-chloro methylphenyl)ethanone (0.37 g) as light yellow solids in 88% yield: 1H NMR (500 MHz, CDC13) 6.46 (d, J: 1.77 Hz, 1H), 6.34 (s, 1 H), 3.85 (bs, 2 H), 2.49 (s, 3 H), 2.14 (s, 3 H): EST-MS: m/z 183.4 (M + H)+.
[00362] 1-(2-Chloro-4—i0d0methyl-phenyl)-ethanone. A CH3CN solution (20 mL) containing KI (2.5 g, 15 mmol) and tert—butyl nitrite (2.00 mL, 16.9 mmol) was added with 1-(4- amino—2-chloro—6-methyl—phenyl)ethanone (2.3 g, 12.5 mmol) in CH3CN (13 mL) at -10 °C. The reaction e was warmed to room temperature and poured into aqueous HCl (20%, 23 mL).
The solution was extracted with EtOAc (20 mL), and the organic layer was separated, washed with H20 (23 mL), dried over MgSO4(s), and trated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1—(_-chlor0—4-iodo—6- methylphenyl)ethanone (1.28 g) as yellow oil in 35% yield: 1H NMR (500 MHZ, CDC13) 5 7.58 (s, 1 H), 7.49 (s, 1 H), 2.51 (s, 3 H), 2.21 (s, 3 H). 1-(2-Chloro(4—methoxy-phenoxy)methyl-phenyl)-ethanone. To a solution of 2O 1-(2-chloro—4-iodomethylphenyl)ethanone (1.1 g, 3.7 mmol), K3PO4 (1.6 g, 7.4 mmol), and 4- methoxyphenol (0.55 g, 4.44 mmol) in DMF (55 mL) was added tetrabutylammomium bromide (0.12 g, 0.37 mmol) and copper(I) iodide (70 mg, 0.37 mmol). The reaction was heated at reflux for 22 h. The solution was extracted with EtOAc (10 mL), and the organic layer was separated, washed with H20 (11 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was ed by flash column chromatography on silica gel to give hloro—4-(4- methoxyphenoxy)-6—methylphenyl)ethanone as yellow oilin 19% yield: 1H NMR (500 MHz, CDC13) 6 6.97 (m, 2 H), 6.90 (m ,2 H), 6.73 (d, J = 2.19 Hz, 1 H), 6.67 (d, J = 1.99 Hz, 1 H), 3.81 (s, 3 H), 2.52 (s, 3 H), 2.20 (s, 3 H). 2-Bromo(2-chloro(4-methoxyphen0xy)—6-methylphenyl)ethanone. To a solution of 1-(2-chloro(4-methoxyphenoxy)—6-methylphenyl)ethanone (0.20 g, 0.69 mmol) in acetonitrile (6.0 mL) was added TBABr3 (0.33 g, 0.69 mmol). The reaction was stirred at room temperature for 30 min. The solution was trated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous s), and Concentrated under reduced re to give o(2,6-dimethyl- 4-phenoxyphenyl)ethanone, which was used directly for the next step without further ation. 4-(2-Chloro(4-meth0xy-phenoxy)methy1-pheny1)-thiazolylamine. A mixture of 2-bromo-1—(2,6—dimethy1—4-phenoxyphenyl)ethanone and thiourea (63 mg, 0.83 mmol) in 95% EtOH (3.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous NaHC03 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(2-chloro(4—methoxyphenoxy)methylphenyl)thiazolylamine (0.10 g) as yellow solids in 42% yield: 1H NMR (500 MHZ, CDClg) 5 6.98 (m, 2 H), 6.90 (in, 2 H), 6.83 (d, J: 2.4 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1 H), 6.41 (s, 1H), 4.97 (s, 2 H), 3.81 (s, 3 H), 2.16 (s, 3 H). 2-Bromo(2,6-dimethyl(methylthio)pheny1)ethanone. To a solution of 1—(4— (cyclopentyloxy)-2,6-dimethylphenyl)ethanone (3.30 g, 17.0 mmol) in acetonitrile (34.0 mL) was added tetrabutylammoniumtribromide (TBABrg, 8.19 g, 17.0 mmol). The reaction was stirred at room temperature overnight. The solution was concent-..ted under reduced pressure, mixed with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced re to give 2-bromo(2,6-dimethyl- hylthio)phenyl)ethanone (5.2 g), which was used directly for the next step without further purification. 4-(2,6-Dimethyl(methylthio)phenyl)thiazol-Z-amine. A mixture of 2—bromo-l- (2,6—dimethyl-4—(methylthio )phenyl)ethanone (4.64 g, 17.0 mmol) and thiourea (1.29 g, 17.0 mmol) in 95% EtOH (24.3 mL) was heated at reflux for 120 min. The solution was concentrated and mixed with water (50 mL) and saturated aqueous Na2C03 (4.0 mL). The resultant precipitate was filtered and recrystallized in e (30 mL). The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4 (methylthio)phenyl)thiaz01amine (1.9 g) as light yellow solids in 45% yield: 1H NMR (500 MHz, CDC13) 6 6.97 (s, 2 H), 6.26 (s, 1H), 2.47 (s, 3 H), 2.15 (s, 6 H). (2-Br0mo(2,6-dimethyl(methylsnlfonyl)phenyl)ethanone. To a solution of 2-bromo—1-(2,6-dimethyl(methylthio)phenyl)ethanone (4.92 g, 0.653 mol) in CH2C12, (36 mL) at 0 °C was added mCPBA (70%, 11.1 g, 1.63 mol). The e was stirred at room temperature for 7.0 h. The solution was filtered, and the filtrate was added with saturated aqueous NaHCO3 (50 mL). The organic layer was dried over anhydrous MgSO4(s) and concentrated under d pressure to give 2-bromo(2,6-dimethyl (methylsulfonyl)phenyl)ethanone (7.6 g), which was used directly for the next step without further purification. ] 4-(2,6-Dimethyl(methylsulfonyl)phenyl)thiazolamine. A mixture of 2- bromo-l-(2,6-dimethyl-4—(methylsulfonyl)pheny1)ethanone (7.60 g, 24.9 mmol) and thiourea (1.90 g, 25.0 mmol) in 95% EtOH (35.6 mL) was heated at reflux for 90 min. The solution was concentrated and mixed with water (100 mL) and ted aqueous Na2C03 (5.0 mL). The. resultant precipitate was filtered and recrystallized in toluene (20 mL). The solids were filtered and dried under vacuum to give -diniethy1-4—(methylsulfonyl)phenyl)thiazol—2—amine (3.28 g) as yellow solids in 47% yield: 1H NMR (500 MHz, CDClg) 6 7.64 (s, 2 H), 6.34 (s, 1 H), 5.19 (m, 1 H), 3.04 (s, 3 H), 2.26 (s, 6 H). 2-Amino-N-(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotin amide. A mixture of N-(4-(4-(4-methoxyphenoxy)-2,6-dimethy1phenyl)thiazol-2— y1)-2— nitroisonicotinamide (0.20 g, 0.40 mmol) and Pd/C (0.15 g, 10% w/w) in ethanol (10 mL) was stirred under H2 overnight. The reaction was filtered through diatomaceous earth and concentrated under reduced pressure to provide 2-amin0-N—(4-(4-(4—methoxyphenoxy)-2,6— dimethylphenyl)thiazolyl)is0nicotinamide (0.11 g) as yellow solids in 59% yield: 1H NMR (500 MHz, DMSO—d6) 6 7.88-7.89 (m, 1 H), 7.10—7.11 (m, 2 H), 6.95—6.97 (m, 2 H), 6.62 (s, 1 H), 5.76 (s, 1 H), 3.29 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 446.6 (M + H)". 2O [00371] N-(4—Mesitylthiazolyl)—2-morpholinoisonicotinamide. A mixture of 2-chloro-N- ity1thiazolyl)isonicotinamide (500.0 mg, 1.4 mmol, 1.0 equiv) and morpholine (1.5 mL, 16.8 mmol, 12 equiv) in methylpyrrolidone (15.0 mL) was stirred at 150 °C for 16 h. The mixture was poured into icy H20 (20.0 mL), and the resultant solids were d to provide N- (4-mesitylthiazol—2—yl)-2—morpholinoisonicotinamide (358.6 mg, 0.90 mmol) as yellow solids in 63% yield: 1H NMR (DMSO—d6, 500 MHz) 6 8.30 (d, J = 5.1 Hz, 2 H), 7.50 (s, 1H), 7.22 (d, J = .1 Hz, 2 H), 7.10 (s, 1 H), 6.92 (s, 2 H), 3.70-3.73 (m, 4 H), 3.53—3.55 (m, 4 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI—MS: m/z 409.3 (M +H)+.
Exemplary Corhpounds and Physicochemical Data N-(4-Mesitylthiazolyl)isonicotinamide (II-1) O _ N N I 3H3 N-(4-Mesitylthiazolyl)isonicotinamide compound II-l N-(4-Mesitylthiazolyl)isonicotinamide (II-1) Yield: 77%; 1H NMR (500 MHz, CD30D) 5 8.75-8.76 (m, 2 H), 7.96—7.99 (m, 2 H), 6.90-6.92 (m, 3 H), 2.29 (s, 3 H), 2.08 (s, 6 H); ESI-MS: m/z 324.0 (M + H)“.
N-(5-Methylphenylthiazol-Z-yl)isonicotinamide (H-2) |\>—N?-|—<\:/’\0 _ N N N-(S-Methylphenylthiazolyl)isonic0tinamide compound II-2 N-(5-Methylphenylthiazol-Z-yl)isonicotinamide (II-2) Yield: 77%; 1H NMR (500 MHZ, CDC13) 5 11.7 (s, 1 H), .62 (m, 2 H), 7.51—7.53 (m, 2 H), 7.41—7.43 (m, 2 H), 7.26-7.30 (m, 2 H), .22 (m, 1 H), 2.54 (s, 3 H); ESI—MS: m/z 295.3 (M + H)+.
N-(S-Methylphenylthiazolyl)nicotinamide (II-3) O —N N W\ I \>—NH -/ . S N-(5-Methylphenylthiazolyl)nicotinamide compound II-3 N-(S-Methylphenylthiazolyl)nicotinamide (II-3) Yield: 15%; 1H NMR (500 MHz, CDC13) 6 11.7 (s, 1 H), 9.03 (s, 1 H), .69 (m, 1 H), 8.06-8.08 (m, 1 H), 7.45—7.47 (m, 2 H), 7.22-7.31 (m, 4 H), 2.54 (s, 3 H); ESI—MS: m/z 2959 (M + H)+. 4-Cyano-N-(4-mesitylthiazolyl)benzamide (II-4) >rCN l N>_NHH 4- Cyano-N-(4-mesitylthiazolyl)benzamide compound II-4 4-Cyano-N-(4-mesitylthiazol-Z-yl)benzamide (II-4) Yield: 67%; 1HNMR(500MHz, DMSO—d6) 5 8.23 (d, 2 H), 8.02(d, 2 H), 7.09 (s, 1 H), 6.92 (s, 2 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI—MS: m/z 348.0 (M + H)+.
N-(4-mesitylthiazol-Z-yl)pyrimidinecarboxamide (II-5) N 0m\ N I >-NH N—// N-(4-mesitylthiazol-2—yl)pyrimidine-4—carboxamide compound II-S esitylthiazolyl)pyrimidinecarboxamide (II-5) Yield: 62%; 1H NMR (500 MHz, DMSO—dé) o 9.41 (s, 1H), 9.15 (d, 1 H), 8.14 (d, 1 H), 7.17 (s, 1 H), 6.89 (s, 2 H), 2.25 (s, 3 H), 2.03 (s, 6 H); ESI—MS: m/z 325.1 (M + H)+.
N-(4-p-Tolylthiazolyl)isonicotinamide (II-6) UEg—NE—QNO _ N-(4-p-Tolylthiazol—Z-yl)isonicotinamide compound II-6
[00383] Yield: 8.6%; 1H NMR (500 MHz, _ N-(4-p-Tolylthiazolyl)isonic0tinamide (II-6) CDC13) 5 8.70 (d, J: 5.5 Hz, 2 H), 7.65—7.63 (m, 2 H), 7.60 (d, J: 8.0 Hz, 2 H), 7.17 (s, 1 H), 7.14 (d, J = 7.5 Hz, 2 H), 2.34 (s, 6 H); ESI-MS: m/z 295.9 (M + H)+. 4-Cyano-N-(4-p-tolylthiazolyl)benzamide (II-7) | \>—NH 4-Cyano-N—(4-p-tolylthiazol-Z-yl)benzamide compound II-7 o-N-(4-p-tolylthiazolyl)benzamide (II-7) Yield: 63%; 1H NMR (500MHz, CDC13) 5 7.89 (d, J =8.5 Hz, 2H), 7.62(d,J :85 Hz, 2 H), 7.55 (d, J = 8.5 Hz, 2 H), 7.17 (s, l H), 7.12 (d, J: 8.0 Hz, 2 H), 2.34 (s, 6 H); ESI-MS: m/z 317.9(M --H)‘.
] N-(4-Mesitylthiazolyl)pyridazinecarboxamide (II-8) WE \)-NI>-I—<‘:—’/o _N N N N-(4-Mesitylthiazol-Z-yl)pyridazine-4—carboxamide nd II—8 N-(4-Mesitylthiazolyl)py1fidazinecarb0xamide (II-8) Yield: 62%; 1H NMR (500 MHz, DMSO-d6) 5 9.72 (s, 1 H), 9.50 (d, 1 H), 8.21 (m, 1 H), 7.13 (s, 1 H), 6.94 (s, 2 H), 2.27 (s, 3 H), 2.06 (s, 6 H); ESI—MS: m/z 324.5 (M + H”.
N-(4-mesitylthiazolyl)thiazole-S-carboxamide (II-9) O S I SHIN esitylthiazolyl)thiazolecarboxamide ' nd II—9 N-(4-mesitylthiazolyl)thiazolecarb0xamide (H-9) Yield: 40%; 1H NMR (500 MHz, DMSO—dé) 5 9.36 (s, I H), 8.82 (s, I H), 7.06 (s, 1 H), 6.93 (s, 2 H), 2.26 (s, 3 H), 2.05 (s, 6 H); ESI—MS: m/z 329.3 (M +H)+.
N-(4-(4-Methoxyphenyl)methylthiazol-2—yl)isonic0tinamide (II-10) 0 __ ~ >—<:~ S N—(4-(4-Methoxypheny1)methy1thiazol—2—yl)i sonicotinamide compound 11-10 N-(4—(4-Methoxyphenyl)methylthiazolyl)isonicotinamide (II-10) Yield: 12%; 1H NMR (500 MHz, DMSO—dé) 5 12.9 (s, 1 H), 8.80-8.81 (m, 2 H), 7.99-8.00 (m, 2 H), 7.61—7.63 (m, 2 H), 7.02-7.04 (m, 2 H), 3.80 (s, 3 H), 2.49 (s, 3 H); ESI—MS: m/z 326.0 (M + H)+.
N-(4-(2,4,6-Trimethoxyphenyl)thiazolyl)isonicotinamide (II-11) o _ ~ >0\ MeO I >_NH N-(4-(2,4,6-Trimethoxyphenyl)thiazolyl)isonicotinamide compound 11-11 N-(4-(2,4,6-Trimethoxyphenyl)thiazolyl)isonic0tinamide (II-1 1) Yield: 12%; 1H NMR (500 MHZ, DMSO—dfi) 6 13.0 (s, 1 H), 8.78 (s, 2 H), 7.98-8.00 (m, 3 H), 6.98 (s, 1 H), 6.29 (s, 2 H), 3.82 (s, 3 H), 3.68 (s, 3 H); ESI—MS: m/z 369.9 (M - H)’.
N-(4-(4-Methoxyphenyl)thiazol-2—yl)isonicotinamide (II-12) 0 __ ~ >90\ | \)—NH ’ N-(4-(4-Meth0xyphenyl)thiazolyl)isonicotinamide compound II-12 N—(4-(4-Methoxyphenyl)thiazolyl)is0nicotinamide (II-12) Yield: 50%; 1H NMR (500 MHz, CDC13) 5 11.7 (s, 1 H), .62 (m, 2 H), 7.51-7.53 (m, 2 H), 7.41-7.43 (m, 2 H), 7.26-7.30 (m, 2 H), 7.20-7.22 (m, 1 H), 2.54 (s, 3 H); ESI-MS: m/z 310.1 (M - H)‘. 2,4-Dimethoxyphenyl)thiazolyl)isonicotinamide (II-13) O _ ~ >90\/ MeO |\>—NH N-(4-(2,4-Dimethoxyphenyl)thiazolyl)isonicotinamide compound II—13 7 '
[00397] N-(4-(2,4-Dimethoxyphenyl)thiazolyl)is0nicotinainide ) Yield: 10%; 1H NMR (500 MHz, DMSO-d6) 6 12.97 (s, 1 H), 8.81-8.82 (m, 2 H), 8.00—8.07 (m, 3 H), 7.59 (s, 1 H), 6.64-6.68 (111,2 H), 3.92 (s, 3 H), 3.81 (s, 3 H); ESI—MS: m/z 340.3 (M — H)‘.
N-(4-(4-Methoxyphenyl)methylthiazol—2—yl)nic0tinamide (II- 14) N \ / | H N N-(4-(4-Methoxyphenyl)methylthiazoly])nic0tinamide compound II-14 N-(4-(4-Methoxyphenyl)methylthiazolyl)nicotinamide (II- 14) Yield: 74%; 1H NMR (500 MHZ, CDC13) 5 9.09 (d, 1 H), 8.73-8.72 (m, l H), 8.15—8.14(m, 1 H), 7.42-7.41 (m, 2 H), 7.35 (m, 1 H), 6.87-6.85 (m, 2 H), 3.82 (s, 3 H), 2.51 (s, 6 H); ESI—MS: m/z 325.3 (M + H)+.
N-(4-(2,4-Dimethoxyphenyl)thiazolyl)nic0tinamide (II-15) N OH?)\ / MeO I S\>_NH N N-(4-(2,4-Dimeth0xyphenyl)thiazolyl)nic0tinamide compound II-15 2,4-Dimeth0xyphenyl)thiazolyl)nicotinamide (II-15) Yield: 87%; 1H NMR (500 MHz, CDC13) 6 9.30 (s, 1H), 8.82-8.81 (m, 1 H), 8.39—8.36 (m, 1 H), 7.80—7.79 (m, 1 H), 7.48—7.46 (m, 1 H),7.43—7.39 (m, 1 H), .55 (m, 2 H), 3.92 (s, 3 H), 3.86 (s, 3 H); ESI- MS: m/z 341.4 (M + H)+.
N—(4-(4-Methoxyphenyl)methylthiazolyl)picolinamide (II-16) O _ I\>—NH N/ s N-(4-(4-Meth0xyphenyl)methylthiazolyl)picolinamide compound II-16 N-(4-(4-Methoxyphenyl)methylthiazolyl)picolinamide (II-16) Yield: >99%; 1H NMR (500 MHZ, CDC13) 6 10.55 (s, 1 H), 8.65-8.64 (m, 1 H), 8.30-8.29 (m, 1 H), 7.93 (m, 1 H), 7.60-7.58 (m, 2 H), 7.54--7.53 (m, 1 H), 6.99—6.98 (m, 2 H), 3.86 (s, 3 H), 2.54 {5, 3 H); ESI- MS: m/z 325.6 (M + H)+.
N-(4-(4—Methoxypheny1)thiazolyl)picolinamide(II-17) N “H?\ / | >—NH N N-(4-(4-Methoxyphenyl)thiazol-2—yl)picolinamide , compound 11-17 N-(4-(4-Methoxyphenyl)thiazolyl)picolinamide (II-17) Yield: >99%; 1H NMR (500 MHz, DMSO—ds) 6 11.98 (s, 1 H), 8.78-8.77 {m, 1 H), 8.19—8.17 (m, 1 H), 8.11-8.09 (m, 1H), 7.89-7.87 {m, 2 H), 7.74--7.71 (m, 1 H), 7.58 (m, 1 H), 7.00-6.99 (m, 2 H), 3.79 (s, 3 H), 2.54 {s, 3 H); ESI—MS: m/z 310.0 (M — H)‘.
[00406] 2,4-Dimethyoxyphenyl)thiazolyl)picolinamide (II-18) 2012/067132 N W?\ / me if»! N N-(4-(2,4-Dimeth0xyphenyl)thiazolyl)picolinamide compound II-18 N—(4-(2,4-Dimethyoxyphenyl)thiazolyl)picolinamide ) Yield: 89%; 1H NMR (500 MHz, DMSO-d6) 5 11.9 (s, 1 H), 8.79-8.78 (m, 1 H), 8.20—8.19(m, 1H), 8.12-8.07 (m, H), 7.75-7.74 (m, 2 H), 7.61 (s, 1H), 6.68-—6.63 (m, 2 H), 3.92 (s, 3 H), 3.82 (s, 3 H);- ESI MS: m/z 340.3 (M - H)‘.
N-(5-Methylphenylthiazolyl)picolinamide (II-19) O __ I 1W N—(5-Methylphenylthiazol-Z-yl)picolinamide nd II-19 N-(S-Methylphenylthiazol-Z-yl)picolinamide (II-19) Yield 90%: 1H NMR (500 MHz, DMSO—dé) 5 11.9 (s, 1 H), 8.76—8.77 {m, 1 H), 8.18—8.19 (m, 1 H), 8.10 (m, 1 H),7.69-7.73 (m, 3 H), 7.45-7.48 (m, 1 H), 7.36-7.38 {m, 1 H), 2.50 (s, 3 H); ESI-MS: m/z 295.4 (M + H)+.
N-(4-(3,4,5-Trimethoxyphenyl)thiazolyl)nic0tinamide (II-20) O _ MeO N >—<:>\ |\>—NH N N-(4-(3,4,5-Trimethoxyphenyl)thiazol-Z-yl)nic0tinamide compound II-20
[00411] N-(4-(3,4,5-Trimethoxyphenyl)thiazol-Z-yl)nicotinamide (II-20) Yield 78%: 1H NMR (500 MHz, DMSO-dé) 5 9.24 (d, 1 H), 8.79 (t, 1 H), 8.44 (d, 1 H), 7.75 (s, 1 H), 7.58-7.60 (m, 1 H), 7.26 (s, 2 H), 3.85 (s, 6 H), 3.69 (s, 3 H); : m/z 372.5 (M + H)+.
N-(4-(2—Fluoromethoxyphenyl)thiazolyl)nicotinamide (II-21) o __ F |\)—NH \N N-(4-(2-Fluor0methoxyphenyl)thiazolyl)nicotinamide compound II-21 2-Fluor0methoxyphenyl)thiazol-Z-yl)nicotinamide (II-21) Yield 81%: 1H NMR (500 MHz, 6) 6 9.23 (d, 1 H), 8.80 (t, 1 H), 8.44 (d, l H), 8.00—8.03 (m, 1 H), 7.58-7.60 (m, l H), 7.46 (d, 1 H), 6.90——6.98 (In, 2 H), 3.82 (s, 3 H); ESI-MS: m/z 330.0 (M + H)+.
N-(4-(2-Fluorometh0xyphenyl)thiazolyl)(4-methoxyphenyl)propanamide (II-22) F | \>—NH N-(4-(2-Fluoromethoxyphenyl)thiazol-Z-yl)(4-methoxyphenyl)propanamide compound 11-22 ] N-(4-(2-Fluoromethoxyphenyl)thiazolyl)(4-methoxyphenyl)propanamide (II-22) Yield 53%: 1H NMR (500MHz, CDC13) 5 1 1.01 (s, l H), 7.82—7.86 (m, 1 H), 7.27 (d, 1 H), 6.63—6.84 (m, 6 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 2.77 (t, 2 H), 2.29 (t, 3 H); ESI—MS: m/z 387.0 (M + H)+.
N-(4-(2-Fluor0methoxyphenyl)thiazol-Z-yl)—3-phenylpropanamide (II-23) F I ’ S\>—NH N-(4-(2-Fluoromethoxyphenyl)thiazol-Z-yl)phenylpropanamide compound 11-23 N=(4=(2=Fluo‘ro=4-methoxyphenyl)thiazol-Z-yl)phenylpropanamide (II-23) Yield 45%: 1H NMR (500 MHz, CDC13) 5 10.87 (s, 1 H), 7.83—7.87 (m, 1 H), .27 (m, 5 H), 7.95 (d, 2 H), 6.62-6.73 (m, 2 H), 3.80 (s, 3 H), 2.86 (t, 2 H), 2.36 (t, 2 H); ESI-MS: m/z 356.0 (M + H)+.
N-(4-(2-Fluoromethoxyphenyl)thiazol-Z-yl)picolinamide (II-24) 0 _ F |\>—NH N/ N-(4-(2-Fluoromethoxyphenyl)thiazo]yl)picolinamide compound 11-24 N-(4-(2-Fluoromethoxyphenyl)thiazolyl)picolinamide (II-24) Yield 77%: 1H NMR (500 MHz, DMSO-dfi) 6 12.04 (s, 1 H), 8.79 (d, 2 H), 8.02-8.21 (m, 3 H), 7.74 (t, 1 H), 7.49 (d, 2 H), 6.90-6.97 (m, 2 H), 3.82 (s, 3 H); ESI—MS: m/z 330.0 (M + H)+. 2012/067132 N—(4-(3,4,5-Trimethoxyphenyl)thiazolyl)picolinamide (II-25) 0 _ MeO N m/ I \)—NH N N-(4-(3,4,5-Trimethoxyphenyl)thiazol-Z-yl)picolinamide compound II-25
[00421] N-(4-(3,4,5-Trimethoxyphenyl)thiazolyl)picolinamide (II-25) Yield 75%: 1H NMR (500 MHz, DMSO-ds) 5 12.04 (s, 1 H), 8.78 (s, 1 H), 8.18 (d, 1 H), 8.11 (t, 1 H), 7.78-7.82 (m, 2 H), 7.28 (s, 2 H), 3.86 (s, 6 H), 3.69 (s, 3 H);ESI-MS: m/z 372.0 (M + H)+. 2-Fluoromethoxyphenyl)thiazolyl)isonicotinamide II-26 O _ F I S\>—NH N-(4-(2-Fluoremethoxyphenyl)thiazol-Z—yl)isonic0tinamide compound II-26 N-(4-(2-Flu0romethoxyphenyl)thiazoly1)isonic0tinamide II-26 Yield 84%: 1H NMR (500 MHZ, DMSG-d6) 5 8.82 (d, 2 H), 39—803 (m, 3 H), 7.48 (d, 1 H), 6.91—6.98 (n‘, 2 H), 3.83 (s, 3 H); ESI-MS: m/z 330.0 (M + H)+.
[00424] N-(4-(3,4,5-Trimethoxyphenyl)thiazolyl)isonicotinamide (II-27) 0 _ MeO N | \>—<::N\ >—NH / N-(4-(3,4,5-Trimethoxyphenyl)thiazolyl)isonicotinamide compound II-27 N-(4-(3,4,5-Trimeth0xyphenyl)thiazolyl)isonic0tinamide (II-27) Yield 82%: 1H NMR (500 MHz, e) 5 8.79 (d, 2 H),- 8.00—8.01 (m, 2 H), 7.71 (s, 1 H), 7.26 (s, 2 H), 3.85 (s, 6 H), 3.70 (s, 3 H); ESI-MS: m/z 72.0 (M + H)+.
N-(4-p-Tolylthiazolyl)picolinamide (II-28) O ._ N-(4-p-Tolylthiazolyl)picolinamide ' compound II-28 N-(4-p-T0lylthiazolyl)picolinamide (II-28) Yield: 6.7%; 1H NMR (500 MHz, CDC13) 6 10.96 (s, 1 H), 9.11 (s, 1 H), 8.75 (s, 1 H), 8.14(d, J = 8.0Hz, 1 H), 7.60 (d, J = 7.5Hz, 2 H), 7.34 (s, 1 H), 7.15 (s, 1 H), 7.12 (d, J = 7.5 Hz, 2 H), 2.33 (s, 6 H); : m/z 293.7 (M — H): N-(4-p-T01ylthiazolyl)nicotinzimide (II-29) .meo _ N N—(4—p-Tolyithiazol-Z-yl)nicotinamide compound 11-29 N-(4—p-Tolylthiazol—2-yl)nicotinamide (II-29) Yield: 83%; 1H NMR (500 MHz, CDC13) 6 11.24 (s, 1H), 8.68 (d, J: 4.5 Hz, 1H), 8.31 (d, J: 8.0 Hz, 1 H), 7.95 (m, 1 H), 7.78 (d, J = 8.0 Hz, 2 H), 7.54 (m, 1 H), 7.24 (m, 2 H), 7.17 (s, 1 H), 2.39 (s, 6 H); ESI-MS: m/z 295.6 (M + H)“. ] 4-Cyano-N-(5-methylp-tolylthiazolyl)benzamide (11-30) I NyNWCN 4- Cyano-N-(S-methylp-tolylthiazol—Z—yl)benzamide compound 11-30 4-Cyano-N-(5-methylp-tolylthiazolyl)benzamide (II-30) Yield: 36%; 1H NMR (500 MHz, CDC13) 6 7.72 (d, J = 8.5 Hz, 2 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 6.99 (d, J: 8.0 Hz, 2 H), 2.51 (s, 3 H), 2.27 (s, 3 H); ESI-MS: m/z 332.0 (M - H)‘. 2O [00432] N-(5-Methylp-tolylthiazolyl)nic0tinamide (II-31) EIEENHWO —N ' S N-(5-Methylp-tolylthiazol-Z—yl)nicotinamide compound 11-31 N-(5-Methylp-tolylthiazolyl)nicotinamide (II-31) Yield: 56%; 1H NMR (500 MHZ, CDC13) 5 8.99 (s, 1 H), 8.63 (d, J = 5.0 Hz, 1 H), 8.01 (d, J = 7.9 Hz, 1-H), 7.29-7.21 (m, 3 H), 7.03 (d, J = 7.8 Hz, 2 H), 2.49 (s, 3 H), 2.29 (s, 3 H); ESI-MS: m/z 310.3 (M + H)“.
] N-(5-Methylp-tolylthiazolyl)picolinamide (11-32) 2012/067132 O _ | \)—NH N N-(5-Methylp-tolylthiaz0lyl)picolinamide compound II-32 ] N-(5-Methylp-t0lylthiazolyl)picolinamide (II-32) Yield: 79%; 1H NMR (500 MHz, CDC13)6 11.11 (s, l H), 8.64 (d, J = 4.5 Hz, 1 H), 8.29 (d, J: 7.5 HZ, 1 H), 7.93 (t, J = 8.0 Hz, 1 H), 7.55-7.51 (m, 3 H), 7.25 (d, J = 7.5 Hz,l H), 2.54 (s, 3 H), 2.40 (s, 3 H); ESI-MS: m/z 309.0 (M - H)‘.
N-(4-Mesitylthiazolyl)thiophenecarboxamide (II-33) m>—N?-I—<\:lsO \ N-(4-Mesitylthiazolyl)thi0phenecarboxamide compound II-33 ] N-(4—Mesitylthiazol-Z-yl)thiophenecarboxamide (II-33) Yield: 37%; 1H NMR (500 MHz, DMSO-dé) 6 12.59 (s, 1 H), 8.60 (s, 1 H), 7.69—7.76 (m, 2 H), 7.04 (s, 1 H), 6.93 (s, 2 H), 2.27 (s, 3 H), 2.06 (s, 6 H); ESI—MS: m/z 327.1 (M - H)‘.
[00438] N-(4-(4-Hydroxymethoxyphenyl)thiazolyl)isonic0tinamide (II-34) O>—<::N_ MeO N N-(4-(4-Hydroxymethoxyphenyl)thiazol-2—yl)isonicotinamide compound II-34 N-(4'(4-Hydroxymethoxyphenyl)thiazolyl)isonicotinamide (II-34) Yield: 54%; 1H NMR (500 MHz, DMSO'dé) 5 8.89 (d, 2 H), 8.00 (d, 2 H), 7.57 (d, 1 H), 7.44—7.46 (m, 1 H), 7.26 (d, 1 H), 7.11 (s, 3 H), 3.81 (s, 3 H); ESI-MS: m/z 327.9 (M + H)+.
N-(4-(4-Hydroxymethoxyphenyl)thiazol-Z-yl)nicotinamide (II-35) 'l—_<\:‘/)O —N M Oe N N-(4-(4-Hydroxymeth0xyphenyl)thiazol-Z-yl)nicotinamide compound II-35 N-(4-(4-Hydroxymeth0xyphenyl)thiazolyl)nicotinamide ) Yield: 44%; 1H NMR (500 MHz, 6) 6 9.25 (s, 1 H), 8.91 (s, 1 H), 8.45—8.48 (m, l H), 7.65-7.67 (m, 1 H), 7.57 (d, 1 H), 7.44-7.46 (m, 1 H), 7.26 (d, 1 H), 7.10 (s, 2 H), 3.81 (s, 3 H); ESI—MS: m/z 328.0 (M + H)+.
N-(4-(4-Hydroxymethoxypbenyl)thiazolyl)picolinamide (II-36) O __ Mao N H} |\>—NH N/ N=(4=(4=Hydroxy=3-methoxyphenyl)thiazol-Z-yl)picolinamide compound II-36 N-(4-(4-HydroxymethOxypbenyl)thiazolyl)picolinamide (II-36) Yield: 37%; 1H NMR (500 MHz, DMSO-d6) 6 8.82 (d, 1 H), 8.23 (d, l H), 8.08 (d, 1 H), 7.74-7.75 (m, 1 H), 7.57 (d, 1 H), 7.44-7.46 (m, 1 H), 7.23 (d, 1 H), 7.10 (s, 2 H), 3.81 (s, 3 H); ESI—MS: m/z 328.1 (M + H)+.
N-(4-(4-Methoxyphenyl)thiazol-Z-yl)nic0tinamide (II-37) O _N I N\>—N%_<\:/) S N—(4-(4-Methoxyphenyl)thiazol-Z-yl)nicotinamide compound II-37 4-Meth0xyphenyl)thiazolyl)nicotinamide (II-37) Yield: 94%; 1H NMR (500 MHz, DMSO'dfi) 6 12.98 (s, 1 H), 9.23 (m, 1 H), 8.80 (m, 1 H), 8.46—8.43 (m, 1 H), 7.90- 7.88 (m, 2 H), 7.61—7.56 (m, 1 H), 7.02-7.00 (m, 2 H), 3.80 (s, 3 H); ESl-MS: m/z 310.0 (M — H)‘. 4-Cyano-N-(5-methylphenylthiazolyl)benzamide (II-38) N @CN I \>—NH 4—Cyano-N—(5-methy1—4—phenylthiazol-2—yl)benzamide compound II-38 ] 4-Cyano-N-(5-methylphenylthiazolyl)benzamide (II-38) Yield: 99%; 1H NMR(500 MHz, DMSO—dé) 5 .80 (m, 2 H), 7.60-7.58 (m, 2 H), 741-7.40 (m, 2 H), 7.30- 7.29 (m, 2 H), 7.22—7.19 (m, 1 H), 2.54 (s, 3 H); ESI-MS: m/z 320.0 (M + H)+. 4-Cyano-N-(4-(4-methoxyphenyl)-5—methylthiazolyl)benzamide (II-39) I N\>—NHH >—CN’ 4-Cyano—N-(4—(4—methoxyphenyl)methylthiazolyl)benzamide compound 11-39 4-Cyan0-N-(4-(4-methoxyphenyl)methylthiazolyl)benzamide (II-39) Yield: 66%; 1H NMR (500 MHz, CD3OD) 5 .17 (m, 2 H), .90 (m, 2 H), 7.60—7.58 (m, 2 H), 7.01-7.00 (m, 2 H), 3.84 (s, 3 H), 2.50 (s, 2 H); ESI-MS m/z 349.5 (M + H)+.
N-(4-(2,4—Dimethoxyphenyl)thiazolyl)—2-(2-methoxyphenyl)acetamide ) N OMe MeO l S\>—NH N-(4-(2,4-Dimethoxyphenyl)thiazolyl)—2—(2-meth0xyphenyl)acetamide compound 11-40 2,4-Dimethoxyphenyl)thiazolyl)(2-methoxyphenyl)acetamide (II-40) Yield: 85%; 1H NMR (500 MHz, DMSO—ds) 6 12.3 (s, I H), 7.99—7.97 (m, 1 H), 7.64 (s, I H), 7.24 (m, 1 H), 6.91 (m, 2 H), 6.90 (m, 1H), 6.66—6.61 (m, 2H), 3.89 (s, 3 H), 3.80 (s, 3 H), 3.75- 3.74 (m, 5 H); ESI—MS: m/z 385.1 (M + H)+.
[00452] 2-(2-Methoxyphenyl)-N—(5-methylphenylthiazol42'-yl)aceta’mide (II441) N .-OMe I \)—NH 2—(2-Methoxyphenyl)—N—(5—methyl—4—phenylthiazoly1)acetamide compound II-41 2-(2-Methoxyphenyl)-N—(5-methylphenylthiazolyl)acetamide (II-41) Yield: 76%; 1H NMR (500 MHz, CDC13) 6 8.90 (s, 1 H), 7.56-7.55 (m, 2 H), 7.43-7.40 (m, 2 H), 7.34— 7.33 (m, 1 H), 7.26-7.22 (m, 1 H), 3.77 (s, 3 H), 3.47 (s, 2 H), 2.49 (s, 3 H); ESI—MS: m/z 339.2 (M + H)+.
N-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)is0nicotinamide (II-42) O __ N H} N-(4-(4-Meth0xy-2,6-dimethylphenyl)thiaz0]yl)isonic0tinamide compound 11-42 116.
N-(4-(4-Meth0xy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-42) Yield: 69%; 1H NMR (500MHz, CDC13) 5 8.67 (d, J :55 Hz, 2 H), 7.55 (d, J =6.0Hz, 2 H), 6.77 (s, 1 H), 6.32 (s, 2 H), 3.73 (s, 3 H), 1.91 (s, 6 H); ESI—MS: m/z 340.0 (M + H)+.
N-(5-Methylp-tolylthiazolyl)isonicotinamide (II-43) O _ N N | yNE—Q N-(5-Methylp-tolylthiazol-Z-yl)isonicotinamide compound II-43 N-(5-Methylp-tolylthiazolyl)isonicotinamide (II-43) Yield: 54%; 1H NMR (500 MHZ, CDC13) 5 8.57 (d, J = 5.0 Hz, 2 H), 7.46 (d, J = 5.5 Hz, 2 H), 7.25 (d, J = 4.5 Hz, 2 H), 7.02 (d, J: 7.5 Hz, 2 H), 2.51 (s, 3 H), 2.28 (s, 3 H); ESI-MS: m/z 309.9 (M + H)+.
N-(4-(2,4,6-Trimethylpyridinyl)thiazol-Z-yl)isonic0tinamide (II-44) /I O _ ~x HEN I l\)—NH " N-(4-(2,4,6-Trimethylpyridinyl)thiazolyl)isonicotinan1ide compound II-44
[00459] N—(4—(2,4,6-Trimethylpyridinyl)thiazolyl)isonic0tinamide (II-44) Yield: 51%; 1H NMR (500 MHZ, CDC13) 5 8.79 (d, J 25.5 Hz, 2 H), 7.70 (d, J =5.5 Hz, 2 H), 6.86 (s, 1 H), 6.77 (s, 1 H), 2.45 (s, 3 H), 2.23 (s, 3 H), 2.03 (s, 3 H); ESI-MS: m/z 324.5 (M + H)+.
N-(4-(2,4,6-Trimethylpyridinyl)thiazolyl)picolinamide II-45 KIE \>—N?-I—<N:/>I 0 — N-(4-(2,4,6-Trimethylpyridinyl)thiazol-Z-yl)picolinamide > compound II-45 N-(4-(2,4,6-Trimethylpyridinyl)thiazolyl)picolinamide ) Yield: 18%; 1H NMR (500 MHz, CDC13) 6 11.22 {5, 1 H), 8.65 (d, J = 4.5 Hz, 1 H), 8.31 (d, J = 7.5 Hz, 1 H), 7.96 (t, J = 7.5 Hz, 1H), 7.54 (m, 1 H), 6.92 (s, 1 H), 6.85 {5, 1 H), 2.52 (s, 3 H), 2.37 (s, 3 H), 2.133 (s, 3 H); : m/z 325.0 (M + H)+.
N-(4-(2,4,6-Trimethylpyridinyl)thiazol-2—yl)nicotinamide (II-46) I O _ N-(4-(2,4,6-Trimethylpyridinyl)thiazol-Z-yl)nicotinamide compound II-46 2,4,6-Trimethylpyridinyl)thiazolyl)nicotinamide (II-46) Yield: 18%; 1H NMR (500 MHz, CDCl3) 6 9.11 {s, 1 H), 8.77 (s, 1 H), 8.17 (d, J = 7.5 Hz, 1 H), 7.42 (m, 1 H), 6.85 {s, 1 H), 6.78 (s, 1 H), 2.45 (s, 3 H), 2.27 (s, 3 H), 2.02 (s, 3 H); ESI-MS: m/z 325.1 (M + H)+.
N-(4-(4-Hydroxymethoxyphenyl)thiazolyl)pyridazinecarboxamide (II- O __ MeO N WN l \>—NH N S N-(4-(4-Hydroxymethoxyphenyl)thiazol—2-yl)pyridazinecarboxamide compound II-47 N—(4—(4—Hydrexymethoxypheny!)thlazolyl)py-idazme-A-carboxamide (II- 47) Yield: 54%; 1H NMR (500 MHz, DMSO—d6) 5 9.75 (s, 1 H), 9.61 (s, 1 H), 8.28-8.30 (m, 1 H), 7.58 (d, 1 H), 7.46-7.48 (m, 1 H), 7.29 (d, l H), 7.12 (s, 3 H), 3.82 (s, 3 H); ESI—MS: m/Z 329.4 (M + H)+. 4-Hydr0xymethoxyphenyl)thiazolyl)pyrimidinecarb0xamide (II- O __ MeO N WM | \)—NH N—/ 2O N-(4-(4-Hydroxymeth0xyphenyl)thiazol-Z-yl)pyrimidine-4—carboxamide compound II-48 N-(4-(4-Hydr0xymeth0xyphenyl)thiazolyl)pyrimidine—4-carboxamide (II- 48) Yield: 44%; 1H NMR (500 MHz, DMSO-d6) 6 9.49 (d, 1 H), 9.19 (d, 1 H), .23 (m, 1 H), 7.58 (d, 1 H), 7.45-7.47 (m, 1 H), 7.27 (d, 1 H), 7.12 (s, 3 H), 3.82 (s, 3 H); ESI-MS: m/z 328.9 (M + H)+.
N-(4-(4-Hydroxymeth0xyphenyl)thiazolyl)thi0phenecarb0xamide (II-49) M oe N OW\ | \>—NH S N—(4-(4-Hydroxymethoxyphenyl)thiazolyl)thiophene-S-carboxamide compound II-49 N-(4-(4-Hydroxymethoxyphenyl)thiazolyl)thiophenecarboxamide (II-49) Yield: 37%; 1H NMR (500 MHz, DMSO—dé) 5 8.58 (d, 1 H), .75 (m, 1 H), 7.60 (d, 1 H), 7.55 (d, 1 H), 7.42-7.44 (m, 1 H), 7.18 (d, 1 H), 7.09 (m, 3 H); : m/z 333.0 (M + H)+.
N—(4-(4-Hydroxymethoxyphenyl)thiazolyl)thiazolecarhoxanfide (II-50) O S | NyNW N-(4-(4-Hydroxymethoxyphenyl)tiiazol—Z—yl)thiazole-S-carboxamide compound II-50 N-(4-(4-Hydroxymethoxyphenyl)thiazolyl)thiazole-S-carhoxamide (II-50) Yield: 37%; 1H NMR (500 MHz, DMSO—d6) 6 9.49 (s, 1 H), 8.75 (s, 1 H), 7.56 (s, 1 H), 7.43- 7.45 (m-- 1 1 H), 7.11 (m, 3 H), 3.81 --/), 7.2401, __ \- (s, 3 H); ESI—MS: m/z 333.9 (M + H)+. 4-Hydroxymethoxyphenyl)thiazol-Z-‘nyurancarboxamide (II-51) MOe N OW\O |\)—NH s N-(4-(4-Hydroxymethoxyphenyl)thiazolyl)furan—3—carboxamide compound II-51 N-(4-(4-Hydroxymethoxyphenyl)thiazolyl)furancarboxamide (II-51) Yield: 32%; 1H NMR (500 MHz, DMSO—ds) 6 8.63 (s, 1 H), 7.91 (s, 1 H), 7.54 (s, 1 H), 7.41- 7.43 (m, 1 H), 7.08—7.18 (m, 4 H), 6.93 (s, 1 H), 3.80 (s, 3 H); ESI—MS: m/z 316.9 (M + H)+.
N-(4-(4-Eth0xy-2,6-dimethylphenyl)thiazolyl)isonicotinamide ) N OH?\ N | \)—NH / N-(4-(4-Ethoxy-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide compound II-52
[00475] N-(4-(4-Ethoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-52) Yield: 88%; 1H NMR (500 MHz, CDC13) 6 8.70 (d, J = 6.0 Hz, 2 H), 7.58 (d, J: 6.0 Hz, 2 H), 6.78 (s, l H), 6.37 (s, 2 H), 3.95 (q, J = 7.0 Hz, 2 H), 1.94 (s, 6 H), l.4l(t, J: 7.0 Hz, 3 H); ESI—MS: m/z 353.6 (M + H)+.
N-(4-(3,5-Dimethylbiphenylyl)thiazolyl)isonicotinamide (II-53) .‘ggfiflflO N-(4-(3,5-Dimethylbiphenylyl)thiazol-Z-yl)isonicotinamide compound 11-53 N-(4-(3,5-Dimethylbiphenylyl)thiazolyl)isonicotinamide (II-53) Yield: 78%; 1H NMR (500 MHZ, CDCl3) 6 8.58 (In, 2 H), 7.53—7.44 (m, 5 H), 7.37 (m, 1 H), 7.03 (s, 2 H), 6.86 (s, 1 H), 2.02 (s, 6 H); ESI—MS: m/z 385.7 (M + H)+.
[00478] ro—N-(4-(4-methoxyphenyl)thiazolyl)isonicotinamide (II-54) M60 CI |N\)—NHMi\ ’N 2- Chloro-N-(4-(4-methoxyphenyl)thiazol-Z-yl)isonicetinamide compound 11-54 2-Chloro-N-(4-(4-methoxyphenyl)thiazolyl)isonicotinamide (II-54) Yield: 95%; 1H NMR (500 MHz, CDC13) 6 8.33-8.34 (m, 1 H), 7.47-7.54 (m, 4 H), 7.11 (s, 1H), 6.79- 6.80 (m, 2 H), 3.81 (s, 3 H); ESI-MS: m/z 345.7 (M + H)+.
] N-(4-(4-Chloro-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-55) 0 _ N H)\ | \)—NH / N-(4-(4-Chloro-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide compound 11-55 N-(4-(4-Chloro-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-55) Yield: 89%; 1H NMR (500 MHz, CDC13) 5 8.76 (d, J = 6.0 Hz, 2 H), 7.57 (m, 2 H), 6.81 (m, 3 H), 1.92 (s, 6 H); ESI-MS: m/z 343.8 (M + H)+. ] 4-Cyano-N—(4-(4-11ydroxyphenyl)thiazolyl)benzamide(II-56) I >—©*CN \)—NH 3 4-Cyano-N-(4-(4-hydr0xyphenyl)thiazol-Z-yl)benzamide compound 11-56 ] 4-Cyano-N-(4-(4-hydroxyphenyl)thiazolyl)benzamide (II-56) Yield: 38%; 1H NMR (500 MHz, 6) 6 8.28 (d, 2 H), 8.09 (d, 2 H), 7.88 (d, 2 H), 7.31 (d, 2 H), .08 (m, 3 H); ESI—MS: m/z 322.0 (M + H)+.
N-(4-(4-Hydroxyphenyl)thiazolyl)isonicotinamide (II-57) N 0H?\ N I \>—NH ’ N-(4-(4-Hydroxyphenyl)thiazol-Z-yl)isonicotinamide compound 11-57
[00485] N-(4-(4-Hydr0xyphenyl)thiazolyl)isonicotinamide (II-57) Yield: 75%; NMR (500 MHz, DMSO—d6) 5 8.89 (d, 2 H), 8.01—8.06 (m, 2 H), 7,89 (d, 2 H), 7.32 (d, 2 H), 7.05-7.09 (m, 3 H); ESI—MS: m/z 297.6 (M + H)+. 4-Hydr0xyphenyl)thiazolyl)pyrimidinecarb0xamide (II-58) 9%gm N-(4-(4-Hydroxyphenyl)thiazols-yl)pyrimidinecarboxamide compound 11-58 N-(4-(4-Hydroxyphenyl)thiazol-Z-yl)pyrimidine—4-carboxamide (II-58) Yield: 48%; 1H NMR (500 MHz, DMSO-d6) 5 9.49 (s, 1 H), 9.18 (d, 1 H), 8.23 (d, 1 H), 7.86—7.91 (m, 2 H), 7.33 (d, 2 H), 7.06—7.09 (m, 3 H); ESI-MS: m/z 192.5 ( i- 106, aminothiazole).
[00488] 4-Hydroxypbenyl)thiazolyl)picolinamide (II-59) N M?\ / >—NH N N-(4-(4-Hydroxyphenyl)thiazolyl)picolinamide compound 11-59 N-(4-(4-Hydroxypbenyl)thiazolyl)picolinamide (II-59) Yield: 49%; 1H NMR (500 MHz, DMSO'dfi) 5 8.82 (d, 1 H), 8.24 (d, l H), 807-81 (m, 1 H), 7.88 (d, 2 H), 7.73-7.75 (m, 1 H), 7.30 ('d, 2 H), 7.05-7.08 (m, 3 H); ESI—MS: m/z 297.7 (M + H)+.
N-(4-(4-Hydroxyphenyl)thiazol-2—yl)nicotinamide (II-60) 0 __N | N\>—N?-l—<\:/) N—(4-(4-Hydroxyphenyl)thiazol-Z—yl)nic0tinamide compound II-60 N-(4-(4-Hydroxyphenyl)thiazol-Z-yl)nicotinamide ) Yield: 49%; 1H NMR (500 MHz, DMSO'd6) 6 9.26 (d, 1 H), 8.91 (d, 1H), 8.47 (d, 1 H), 7.89 (d, 2 H), 7.65—7.67 (m, 1H), 7.32 (d, 2 H), 7.05—7.08 (m, 3 H); ESI—MS: m/z 297.6 (M + H)+. 4-Cyano-N—(4-(4-hydroxymetbylphenyl)thiazolyl)benzamide (II-61) N @CN | \>—NH o-N-(4-(4-hydroxymethylphenyl)thiazol-Z-yl)benzamide ' compound II-61 4-Cyano-N-(4-(4-hydroxymetbylphenyl)thiazol-Z-yl)benzamide (II-61) Yield: 48%; 1H NMR (500 MHz, é) 6 8.24-8.30 (m, 2 H), 8.04—8.11 (m, 2 H), 7.63 (d, 1 H), 7.00—7.20 (m, 4 H), 6.67 (s, 1 H); ESI-MS: m/z 335.7 (M + H)+.
N-(4-(3,S-Difluoromethoxyphenyl)thiazolyl)isonicotinamide (11-62) O _ |\)—NH\’ s N-(4—(3,5-Difluoromethoxyphenyl)thiazolyl)isonicotinamide compound 11-62 N-(4-(3,5-Difluoro—4-methoxyphenyl)thiazolyl)isonicotinamide (II-62) Yield: 67%; 1H NMR (DMSO—d6, 500 MHz) 5 13.10 (s, 1 H), 8.82 (d, J = 5.6 Hz, 2 H), 8.00 (d, J = 5.6 Hz, 2 H), 7.88 (s, 1 H), 7.70-7.72 (m, 2 H), 3.96 (s, 3 H); ESI-MS m/z 348.0 (M + H)+. 2-Chloro-N-(4-(3-fluoromethoxyphenyl)thiazolyl)isonicotinamide (II-63) M90 CI NHMi\ /N 2-Chloro-N-(4-(3-fluoromethoxyphenyl)thiazolyl)isonicotinamide compound 11-63 2-Chloro-N—(4-(3-fluoromethoxyphenyl)thiazol-Z-yl)isonicotinamide (II-63) Yield: 83%; 1H NMR (500 MHz, CDC13) 6 8.52-8.53 (m, 1 H), .70 (m, 1 H), 7.59—7.60 (m, 1 H), 7.28-7.47 (m, 2 H), 7.16 (s, 1 H), 6.93-6.97 (m, 1 H), 3.93 (s, 3 H); ESI-MS: m/z 363.7 (M + H)+.
[00498] 2-Chloro-N-(4-mesitylfhiazolyl)isonicotinamide (II-64) N \ /N I S)—\ 0%NH ro-N-(4-mesitylthiazolyl)isonicotinamide compound 11-64 2-Chloro-N-(4-mesitylthiazolyl)isonicotinamide ) Yield: 87%; 1H NMR (500 MHz, CDC13) 6 8.49-8.50 (m, l H), 7.74 (m, 1 H), 7.62 (m, 1 H), 6.83 (s, 1 H), 6.72 (m, 2 H), 2.26 (s, 3 H), 1.97(s, 6 H); ESI—MS: m/z 357.7 (M + H)“. 2-Chloro-N-(4-(4-methoxy-2,6-dimethylphenyl)thiazolyl)is0nicotinamide (II- 2-Chloro-N—(4-(4-methoxy-2,6-dimethylphenyl)thiazol-Z-yl)isonic0tinamide compound II-65 2-Chloro-N-(4-(4-methoxy-2,6-dimethylphenyl)thiazol-2—yl)isonicotinamide (II- 65) Yield: 63%; 1H NMR (500 MHz, CDC13) 5 8.60—8.61 (m, 1 H), 7.91—7.96 (m, 2 H), 6.87 (s, 1 H), 6.58 (m, 2 H), 3.81 (s, 3 H), 2.11(s, 6 H); ESI—MS: m/z 373.9 (M + H)+. ] 2-Chloro-N-(4-(4-ethoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-66) EtO CI |N\)—NH(’wa\ ’N 2-Chloro-N—(4-(4-eth0xy-2,6-dimethylphenyl)thiazol-2—yl)isonicotinamide compound II-66 ' [00503] 2-Chloro-N-(4-(4-ethoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-66) Yield: 95%; 1H NMR (500 MHz, CDCl3) 5 8.53-8.54 (m, 1 H), 7.74-7.84 (m, 2 H), 6.83 (s, 1 H), 6.48 (m, 2 H), 3.98-4.02 (m, 2 H), 2.01(s, 6 H), 1.41-1.44 (m, 3 H); ESI—MS: m/z 387.9 (M + H)+. 1-(4-(4-Methoxy-2,6-dimetbylphenyl)thiazolyl)(pyridinyl)urea (11-67) MeO / \ O _ | \)—NH 1-(4—(4—Methoxy-2,6-dimethylphenyl)thiazol-Z-yl)(pyridin-4—yl)urea compound 11-67
[00505] 1-(4-(4-Methoxy-2,6-dimetbylphenyl)thiazolyl)(pyridinyl)urea (II-67) Yield: 40%; 1H NMR (500 MHz, DMSO—dfi) 5 10.49 (s, 1 H), 8.54 (d, J = 6.5 Hz, 2 H),7.94 (s, 2 H), 6.88 (s, 1 H), 6.74 (s, 2 H), 3.76 (s, 3 H), 2.10 (s, 6 H); ESI-MS: m/z 354.8 (M + H)+.
N-(3,5-Dimethyl(2-(3-pyridinylureido)thiazolyl)phenyl)acetamide (II-68) H N YN / \ 0 _ N NH | \)—NH -Dimethyl(2-(3-pyridinylureido)thiazolyl)phenyl)acetamide compound 11-68 N-(3,5¥Dimethyl(2-(3-pyridinylureido)thiazolyl)phenyl)acetamide ) Yield: 73%; 1H NMR (500 MHz, DMSO-dé) 6 9.87 (s, 1 H), 9.40 (s, 1 H), 8.39 (d, J = 6.0 Hz, 2 H), 7.49 (d, J = 6.5 Hz, 2 H), 7.32 (s, 2 H), 6.92 (s, 1 H), 2.06 (s, 6 H), 2.04 (s, 3 H); ESI-MS: m/z 381.8 (M + H)+. 2-Flu0ro-N—(4-(4-meth0xy-2,6-dimethylphenyl)thiazolyl)iSonicotinamide (II- M60 F N N | Mi \)—NH / . 2-Fluoro-N—(4-(4-methoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound 11-69 ] 2-Flu0ro-N-(4-(4-methoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 69) Yield: 68%; 1H NMR (500 MHz, CDC13) 5 8.36-8.38 (m, 1 H), 7.72 (s, 1 H), 7.42 (s, 1 H), 6.84 (s, 1 H), 6.48 (s, 2 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS: m/z 357.5 (M + H)+.
N-(4-(4-Ethoxy-2,6-dimethylphenyl)thiazolyl)flu0roisonicotinamide (11-70) E10 F N Mi\ /N |\S>—NH- 2012/067132 N-(4-(4-Ethoxy-2,6-dimethylphenyl)thiazol-2—yl)-2—fluor0isonicotinamide cempound [1-70 N—(4—(4-Ethoxy-2,6-djmethylphenyl)thiazol-Z-yl)fluor0isonic0tinamide (II-70) Yield: 94%; 1H NMR (500 MHz, CDC13) 5 8.39-8.40 (m, 1 H), 7.78 (s, 1 H), 7.48 (s, 1 H), 6.85 (s, 1 H), 6.50 (s, 2 H), 3.98—4.01 (q, 2 H), 2.05(s, 6 H), 1.42-1.44 (t, 3 H); ESI—MS: m/z 371.8 (M + H)+. 4-(4-Mesitylthiazolylcarbamoyl)pyridine l-oxide (11-71) 0 _ N N+-0‘ | >—N/H U 4-(4-Mesitylthiazolylcarbamoyl)pyridine l-oxide compound 11—71 ] 4-(4-Mesitylthiazolylcarbamoyl)pyridine 1-oxide (II-71) Yield: 75%; 1H NMR (500 MHz, CDC13) 6 8.15—8.16 (d, 2 H), 7.78—7.79 (d, 2 H), 6.83 (s, l H), 6.80 (s, 2 H), 2.23 (s, 3 H), 2.01 (s, 6 H); ESI-MS: m/z 340.1 (M + H)+. 4-Methoxy-2,6-dimethylphenyl)thiazolylcarbamoyl)pyridine l-oxide (II- 72) %.H3o _ N N‘O‘ 4-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolylcarbamoyl)pyridine 1-oxide compound 11-72 4-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolylcarbamoyl)pyridine l-oxide (II- 72) Yield: 43%; 1H NMR (500 MHz, CDC13) 6 8.23 (s, 2 H), 8.04 (s, 2 H), 6.85 (s, 1 H), 6.60 (s, 2 H), 3.80 (s, 3 H), 2.12 (s, 6 H); : m/z 355.8 (M + H)+.
N-( 4-(2,4,6-Triisopropylphenyl)thiazolyl)isonicolinamide (11-73) myNZ—QN0 _ N-(4-(2,4,6-Triisopropylphenyl)thiazol-Z-yl)isonicotinamide compound 11-73 N-( 4-(2,4,6-Triisopropylphenyl)thiazol-Z-yl)isonicolinamide (II-73) Yield: 62%; 1H NMR (500 MHz, CDC13) 5 8.83 (d, J :55 Hz, 2 H), 7.83 (d, J = 6.0 Hz, 2 H), 7.06 (s, 2 H), 6.82 (s, 1 H), 2.94 (In, 1 H), 2.64 (m, 2 H), 1.29 (d, J 27.0 HZ, 6 H), 1.13 (d, J: 7.0 Hz, 12 H); ESI—MS: m/z 407.9 (M + H)+.
N-(4-(4-Acetamido-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-74) N 0H?\ N | \>—NH / N-(4-(4—Acetamid0-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound 11-74 N-(4-(4-Acetamido-2,6-dimethylphenyi)thiazoiy1)isonicotinamide(II-74) Yield: 39%; 1H NMR (500 MHz, 6) 6 13.03 (s, 1 H), 9.86 (s, 1 H), 8.80 (d, J = 5.5 Hz, 2 H), 7.99 (d, J = 5.5 Hz, 2 H), 7.34 (s, 2 H), 7.13 (S, 1 H), 2.06 (s, 6H); ESI—MS: m/z 385.7 (M + H)+.
N-( 4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)thiaz01ecarboxamide (II- N-(4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)thiazolecarboxamide compound 11-75 N-( 4-(4-Methoxy-2,6-dimethylphenyl)thiazolyl)thiazolecarboxamide (II- 75) Yield: 18%; 1H NMR (500 MHz, CDC13) 5 9.01 (s, 1 H), 8.66 (s, 1 H), 6.82 (s, 1 H), 6.59 (s, 2 H), 3.81 (s, 3 H), 2.13 (s, 6 H); ESI-MS: m/z 345.6 (M + H)+.
N-(4-(2,4,6-Trifluorophenyl)thiazol-Z-yl)isonicotinamide (II-76) N \ N F I SVNH°>LC/ N-(4-(2,4,6-Trifluorophenyl)thiazol—Z—yl)isonic0tinamide compound H-76 N-(4-(2,4,6-Trifluorophenyl)thiazolyl)isonicotinamide ) Yield: 46%; 1H NMR (500 MHZ, CDC13) 6 8.78-8.79 (m, 2 H), .74 (m, 2 H), 7.26—7.28 (m, 1H), 6.76-6.79 (m, 1 H), 6.67—6.70 (m, 2 H); ESI—MS: m/z 335.5 (M + H)+. 3-Fluoro-N-(4-mesitylthiazol-Z-yl)isonic0tinamide (II-77) WO 82324 o _ N N I MW 8 F 3-Fluor0-N-(4-mesitylthiazolyl)isonicotinamide compound II-77 3-Fluoro-N-(4-mesitylthiazolyl)isonicotinamide (II-77) Yield: 23%; 1H NMR (500 MHz, CDC13) 6 11.32 (s, 1 H), 8.57 (m, 2 H), 7.80 (t, J = 5.5 Hz, 1H), 6.80 (s, 1H), 6.71 (s, 2 H), 2.23 (s, 3 H), 1.96 (s, ‘6 H); ESI-MS: m/z 341.9 (M + H)+.
N—(4-(2,6-Diflu0remethoxyphenyl)thiazolyl)isonicotinamide (1148) ly‘NH\/N M?N F N-(4-(2,6-Difluoro-4—methoxyphenyl)thiazolyl)isonicotinamide compound II-78 N-(4-(2,6-Diflu0romethoxyphenyl)thiazolyl)isonicotinamide (II-78) Yield: 49%; 1H NMR (500 MHz, DMSO-ds) 5 13.13 (s, 1 H), 8.81 (d, J = 5.9 Hz, 2 H), 8.00 (d, J: 5.9 Hz, 2 H), 7.46 (s, 1 H),6.86—6.88 (m, 2 H), 3.83 (s, 3 H); ESI—MS: m/z 348.7 (M + H)+.
N-(4-(2,6-Dimethylphen0xyphenyl)thiazolyl)isonicotinamide (II-79) cgo I>-I—QN. _ N-(4-(2,6-Dimethylphenoxyphenyl)thiazol-Z-yl)isonicotinamide nd 11-79 N-(4-(2,6-Dimethylphenoxyphenyl)thiazolyl)isonicotinamide (II-79) Yield: %; 1H NMR (500 MHz, CDC13) 5 8.81 (d, J = 5.5 Hz, 2H), 7.99 (d, J = 5.5 Hz, 2 H), 7.41 (t, J = 8.0 Hz, 2 H), 7.19 (s, 1 H), 7.15 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.2 Hz, 2 H), 6.78 (s, 2 H), 2.07 (s, 6 H); ESl-MS: m/z 401.8 (M + H)+. 3-Chlor0-N-(4-mesitylthiazol-2.-yl)isonicotinamide (II-80) O _ I NHEQN S CI 3-Chlor0-N-(4-mesitylthiazolyl)isonicotinamide compound 11-80 3-Chloro-N-(4-mesitylthiazol-2—yl)isonicotinamide (II-80) Yield: 21%; 1H NMR (500 MHz, CDC13) 6 8.68 (s, 1 H), 8.59—8.60 (m, 1 H), 7.54-7.55 (m, 1 H), 6.81-6.83 (m, 2 H), 2.30 (s, 3 H), 2.01 (s, 6 H); ESI-MS: m/z 357.8 (M + H)+. 2-Chloro-N-(4-mesitylthiazolyl)isonicotinamide (II-81) ]N\)—NHMi\ ’N 2-Chloro—N—(4-mesitylthiazol-Z-yl)isonicotinamide compound 11-81 ro-N-(4-mesitylthiazolyl)isonicotinamide (H-Sl) Yield: 42%; 1H NMR (500 MHz, DMSO-dfi) 6 8.63-8.64 (m, 1H), 8.11 (s, 1 H), 7.98-7.99 (m, 1H), 7.12 (s, 1 H), 6.93 (m, 2 H), 2.50 (s, 3 H), 2.05 (s, 6 H); : m/z 357.9 (M + H)+.
N—(4-(4-Isopropoxy-2,6-dimethy1pheny1)thiazol—2-y1)isonicotinamide (II—82) YE;l:\>—N>I\-I—<\:/:No _ N-(4-(4-Isoprepoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide nd II-82
[00535] N-(4-(4-Isopropoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-82) Yield: 80%; 1H NMR (500 MHz, CDC13) 6 8.67 (d, J = 6.0 Hz, 2 H), 7.55 (d, J = 6.0 Hz, 2 H), 6.77 (s, 1 H), 6.30 (s, 2 H), 4.43 (m, 1 H), 1.89 (s, 6 H), 1.31 (d, J = 6.0 Hz, 6 H); : m/z 368.1 (M + H)+.
N-(4-(4-(Cyclopentyloxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide (II- 85) G0 o _ | :yNz—QN N-(4-(4-(Cyclopentyloxy)-2,6-dimethylphenyl)thiazol—2—yl)isonicotinamide compound 11-85 N-(4-(4-(Cyclopentyloxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide (II- 85) Yield: 62%; 1H NMR (500 Hz, CDC13) 6 8.71 (d, J = 6.0 Hz, 2 H), 7.60 (d, J = 6.0Hz, 2 H), 6.78 (s, 1 H), 6.37 (s, 2 H), 4.68 (m, 1 H), 1.95 (s, 6 H), 1.80-1.92 (m, 6 H), 0.85 (m, 2 H); ESI- MS: m/z 394.1 (M + H)+.
N—(4-Mesitylthiazol-2—yl)methoxyisonicotinamide (II-86) 2012/067132 N “Hi\ N \>-—NH ’ N-(4-Mesitylthiazolyl)-2—methoxyisonicotinamide compound 11-86 N—(4—Mesitylthiazolyl)—2-methoxyisonicotinamide (II-86) Yield: 40%; 1H NMR (500 MHz, CDC13) 3 .39 (m, 1 H), 7.55-7.56 (m, 1 H), 7.41 (s, 1H), 6.91—6.93 (m, 2 H), 6.86 (s, 1 H), 5.30 (s, 1H),.4.00 (s, 3 H), 2.32 (s, 3 H), 2.12 (s, 6 H); ESI-MS: m/z 355.0 (M + H)+. 2-Chloro-N—(4-mesitylthiazolyl)meth0xyisonic0tinamide (II-87) O _ \ /N l N\>_NH 3 CI 2—Chloro-N-(4-mesitylthiazol-Z-yl)methoxyisonicotinamide compound 11-87 2-Chloro-N-(4-mesitylthiazolyl)methoxyisonicotinamide (II-87) Yield: 63%; 1HVNMR (500 MHz, CDC13) 5 7.31 (s, 1 H), 7.06 (s, 1 H), 6.81 (s, 1 H), 6.76 (s, 2 H), 4.00 (s, 3 H), 2.32 (s, 3 H), 1.98 (s, 6 H); : m/z 387.9 (M + H)“.
[00542] 2,6-Dichloro—N-(4-mesitylthiazoly1)isonicotinamide (II-88) 6% M?N CI \\ /N l 8)—\ NH 2,6-Dichloro-N-(4-mesitylthiazolyl)isonic0tinamide compound 11-88 2,6-Dichloro-_N—(4-inesitylthiazolyl)isonicotinamide (II-88) Yield: 70%; 1H NMR (500 MHz, CDC13) 5 7.61 (s, 2 H), 6.80 (s, 1H), 6.73 (s, 2 H), 2.29 (s, 3 H), 1.94 (s, 6 H); ESI—MS: m/z 392.0 (M + H)+. 2-Acetamido-N—(4-mesitylthiazol-2—yl)isonicotinamide (II-89) |S>—\ NH 2-Acetamido-N-(4-mesitylthiazolyl)isonic0tinamide compound 11-89 ] 2-Acetamido-ZX-(4-mesity1thiazolyl)isonicotinamide (II-89) Yield: 61%; 1H NMR (500 MHz, CDC13) 6 8.81 (s, 1 H), 8.37 (s, 1H), 7.80-7.77 (m, 1 H), 6.91 (s, 2 H), 6.80 (s, 1H), 2.30 (s, 3 H), 2.26 (s, 3 H), 2.11 (s, 6 H); ESI—MS: m/z 381.2 (M + H)+. 2,6-Difluoro-N-(4-mrsitylthiazolyl)isonicotinamide (11-90) O _ N N S F 2,6-Difluoro-N-(4-mesitylthiazolyl)isonic0tinamide compound II-90 2,6-Difluoro-N-(4-mrsitylthiazolyl)isonic_otinamide (II-90) Yield: 67%; 1H NMR (500 MHz, CDC13) 6 7.11 (s, 2 H), 6.81 (s, 1H), 6.68 (s, 1 H), 2.30 (s, 3 H), 1.91 (s, 6 H); ESI-MS: m/z 360.0 (M + H)+.
N-(4-Mesitylthiazolyl)(pyridinyl)acetamide (II-93) O _ l I N\>._NH N-(4-Mesitylthiazoly1)(pyridinyl)acetamide nd 11-93
[00549] N-(4-Mesitylthiazolyl)(pyridinyl)acetamide (II-93) Yield: 65%; 1H NMR (500 MHz, DMSO-ds) 6 8.52—8.53 (m, 2 H), 7.35-7.36 (m, 2 H), 6.99 (s, 1 H), 6.91 (s, 1 H), 3.84 (s, 1 H), 2.25 (s, 3 H), 2.02 (s, 6 H); ESI-MS: m/z 338.1 (M + H)+.
N-(4-(4-(2-Hydroxypropoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-94) O _ I H—<\3N s N-(4-(4-(Z-Hydroxypropoxy)-2,6-dimethylphenyl)thiazol-2—yl)isonicotinamide compound 11-94 N-(4-(4-(2-Hydr0xypropoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-94) Yield: 4.0%; 1H NMR (500 MHz, CDC13) 5 8.80 (d, J = 5.9 Hz, 2 H), 7.69 (d, J = 5.9 Hz, 2 H), 6.81 (s, 1 H), 6.55 (s, 2 H), 4.19-4.25 (s, 1 H),4.10-4.15 (m, 1 H), 3.91—3.98 (m, 1 H), 3.78- 3.82 (m, 1 H), 2.05 (s, 6 H), 1.28 (s, 3 H); ESI—MS: m/z 384.7 (M + H)+.
N-(4-(4-(4-Meth0xyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-95) o _ M oI:W ' NyNZ—QN N-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound II-95 N-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-95) Yield: 95%; 1H NMR (500 MHz, CDC13) 5 8.73 (m, 2 H), 7.62 (m, 2 H), 6.90-6.96 (m, 4 H), 6.80 (s, 1 H), 6.45 (s, 2 H), 3.83 (s, 3 H), 1.92 (s, 6 H); ESI-MS: m/z 431.7 (M + H)+.
N-(4-(4-(4-Fluorophenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 96) U0: 1% O _ I N\>—N>H—<\://N N-(4-(4-(4-Fluorophenoxy)—2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide compound 11-96 N-(4-(4-(4-Fluorophenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 96) Yield: 17%; 1H NMR(500 MHZ, CDC13) 5 8.72 (d, J' = 5.5Hz, 2 H), 7.60 (d, J: 5.5 Hz, 2 H), 7.04 (m, 2 H), 6.94 (m, 2 H), 6.81 (s, 1 H), 6.43 (s, 2 H), 1.92 (s, 6 H); ESI-MS: m/z 420.2 (M + H)+.
N-(4-(4-(2,3-Dihydr0xypropoxy)-2,6-dimethylphenyl)thiazol-2— yl)isonicotinamide (II-97) H0\/K/O O .— S 4-(2,3-Dihydroxypropoxy)-2,6-dimethylphenyl)thiazolyl)isonic0tinamide compound 11-97 N-(4-(4-(2,3-Dihydroxypr0poxy)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (II-97) Yield: 12%; 1H NMR (500 MHz 5 8.78 (d, J = 4.5 Hz, 2 , DMSO—da) H), 7.98 (d, J = 4.5 Hz, 2 H), 7.15 (s, 1 H), 6.69 (s, 2 H), 4.95—4.96 (m, 1 H), 4.68—4.69 (m, 1 H), 3.97—3.98 (m, 1 H), 3.84-3.85 (m, 1 H), .79 (m, l H), 2.06 (s, 6 H); ESI—MS: m/z 400.7 (M + H)+. 2-Fluor0-N-(4-(4-(4-methoxyphen0xy)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (11-98) (>0 .
N OPCN | \)—NH ’ 2-Fluoro-N-(4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide compound 11-98 2-Flu0ro-N-(4-(4-(4-meth0xyphenoxy)-2,6-dimethylphenyl)thiazOI yl)isonicotinamide ) Yield: 70%; 1H NMR (500 MHz, CDC13) 5 8.38-8.40 (m, 1 H), 7.66- 7.67 (m, 2 H), 7.43 (s, 1 H), 6.98-7.00 (m, 2 H), 6.91—6.93 (m, 2 H), 6.84 (s, 1 H), 6.54 (s, 1 H), 3.83 (s, 3 H), 2.0 (s, 6 H); ESI-MS: m/z 450.0 (M + H)+. 2-Fluoro-N-(4-(4-isopropoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-99) To 9% F I N\>—NH“HiN\ / S 2-Flu0ro-N-(4—(4—isopropoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide nd H-99 2-Fluor0-N-(4-(4-isopropoxy-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-99) Yield: 83%; 1H NMR (500 MHZ, CDC13) 5 8.40 (m, 1 H), 7.78 (s, 1 H), 7.50 (s, 1 H), 6.84 (s, 1H), 6.53 (s, 2 H), 4.52-4.56 (m, 1 H), 2.06 (s, 6 H), 1.33 (s, 6 H); : m/z 385.8 (M, + H)+.
N-(4-(4-Isobutoxy-2,6-dimethylphenyl)thiazolyl)isonic0tinamide (II- 100) 1 ly—NwO __.
N N N—(4-(4—Isobutoxy-2,6-dimethylphenyl)thiazol-.2-yl)isonic0tinamide compound 11-100 N-(4-(4-Isobutoxy-2,6-dimethylphenyl)thiazolyl)i'sonicotinamide (II- 100) Yield: 99%; 1H N1V[R (500 MHz, CDCI3) 6 8.68 (d, J = 6.0 Hz, 2 H), 7.56 (d, J = 6.0 Hz, 2 H), 6.77 (s, 1 H), 6.33 (s, 2 H), 3.62 (d, J: 6.5 Hz, 2 H), 2.08 (m, 1 H), 1.91 (s, 6 H), 1.05 (d, J = 6.7 Hz, 6 H); ESI—MS: m/z 381.1 (M + H)+.
[00564] N-(4-(4-(Benzo(d)(1,3)dioxol-S-yloxy)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (II-101) <°I )0O _ i [l ”wk—Q” N-(4-(4-(Benzo[d] [1,3]dioxolyloxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide II-101 , compound N-(4-(4-(Benz0(d)(1,3)dioxolyloxy)-2,6-dimethylphenyl)thiazol-Z- yl)isonicotinamide (II-101) Yield: 92%; 1H NMR (500 MHz, CDC13) 6 8.73 (m, 2 H), 7.62 (m, 2 H), 6.81 (s, 1 H), 6.78 (d, J = 8.5 Hz, 1 H), 6.43—6.52 (m, 4 H), 6.00 (s, 2 H), 1.93 (s, 6 H); ESI— MS: m/z 445.9 (M + H)+.
N-(4-(4-(3,5-_Dimetbylphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (11-102) I N\>-N%|—<\:\//N0 N-(4—(4-(3,5-Dimethylphenoxy)-2,6-dimethylphenyl)thiazol-2—yl)isonic0tinamide compound II-102 ] N—(4—(4-(3,5-Dimetbylphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-102) Yield: 94%; 1H NMR (500 MHz, CDC13) 6 8.81 (d, J = 5.1 Hz, 2 H), 7.78 (d, J: .6Hz, 2 H), 6.84 (s, 1 H), 6.78 (s, 1 H), 6.64 (s, 2 H), 6.61 (s, 2 H), 2.31 (s, 6 H), 2.02 (s, 6 H); ESI—MS: m/z 429.8 (M + H)+.
(E)-N—(4—Mesitylthiazol—2-yl)(pyridinyl)acrylamide (II-103) | \>—NH (E)-N-(4-Mesitylthiazol-2—yl)(pyridinyl)acrylamide compound 11-103
[00569] (E)-N—(4-Mesitylthiazol-2—yl)(pyridinyl)acrylamide (II-103) Yield: 34% yield; 1H NMR (500 MHz 5 12.48 (s, 1 H), .83 (m, l H), 8.60—8.61 (m, 1 H), , DMSO'dfi) 8.04—8.05 (m, 1 H), 7.76-7.79 (m, 1H), 7.49-7.51 (m, 1H), 7.00-7.03 (m, 2 H), 6.92 (s, 2 H), 2.26 (s, 3 H), 2.05 (s, 6 H); : m/z 350.7 (M + H)+.
N-( 4-Mesitylthiazol-2—yl)- 1H-indazolecarboxamide (II-104) 0‘3 C u | \)—NH 3 N-(4-Mesitylthiazolyl)-1H-indazolecarboxamide compound 11-104 N-( tylthiazolyl)— lH-indazolecarboxamide (II-104) Yield: 25%; 1H NMR (500 MHz 5 13.20 (s, 1 H), 8.36 (s, 1 H), 8.19 (s, 1 H), 7.87-7.88 (m, 1 H), , DMSO—dé) 7.72—7.83 (m, 1 H), 7.00 (s, 1 H), 6.93 (s, 2 H), 2.27 (s, 3 H), 2.07 (s, 6 H); ESI-MS: m/z 363.9 (M + H)+.
N—(4-Mesitylthiazolyl)—1H-indazole-S-carboxamide (11-105) 0 \E“ | \>—NH N-(4-Mesitylthiazolyl)-1H-indazolecarb0xamide compound 11-105 ' N—(4-Mesitylthiazol-Z-yl)—1H-indazolecarboxamide (II-105) Yield: 38%, 1H NMR (500 MHz 6 13.20 (s, 1 H), 8.66 (s, 1 H), 8.26 (s, 1 H), 8.08 (d, J = 8.4 Hz, 1 , DMSO'dfi) H), 7.65 (d, J = 8.4 Hz, 1 H), 7.02 (s, l H), 6.93 (s, 2 H), 2.36 (s, 3 H), 2.07 (s, 6 H); ESI—MS: m/z 363.9 (M + H)+.
N-(4-Mesitylthiazolyl)—1H-benzo(d)(1,2,3)triazolecarboxamide (II-106) o 'x" | \>—NH m«vnmmI—z—vn-LEI-benzqd][1,2,31triazo1e-s-carboxa__id-Ava-NJ nun-unv- J A, nd 11-106
[00575] N-(4-Mesitylthiazol-2—yl)—lH-benzo(d)(1,2,3)triazolecarboxamide (II-106) Yield: 41%; 1H NMR (500 MHz, DMSO—d6) 6 8.78 (s, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.07 (s, 1 H), 6.93 (s, 2 H), 2.27 (s, 3 H), 2.07 (s, 6 H); ESI-MS: m/z 364.9 (M + H)+.
N-(4-(4-(3-Methoxyphenoxy)—2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-107) l i 1 o _ | N\>—N>H_<\3N N-(4-(4-(3-Methoxyphen0xy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound II-107 4-(3-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-107) Yield: 51%; 1H NMR (500 MHz, CDC13) 6 8.75 (m, 2 H), 7.62 (m, 2 H), 7.25 (m, 1 H), 6.82 (s, 1 H), 6.69 (m, 1 H), 6.56 (d, 1 H), 6.51 (m, 2 H), 6.47 (s, 2 H), 3.81 (s, 3 H), 1.94 (s, 6 H); ESI—MS: m/z 431.6 (M + H)“.
N-(4-(2,6-Dimethyl(4-(trifluoromethyl)phenoxy)phenyl)thiazol yl)isonic0tinamide 8) |\>—N>H—<\:\// 2,6-Dimethyl—4-(4-(trifluoromethyl)phenoxy)phenyl)flfiazol-Z—yl)isonic0tinamide compound 11-108 N-(4-(2,6-Dimethyl(4-(trifluoromethyl)phenoxy)phenyl)thiazol yl)isonic0tinamide (II-108) Yield: 87%; 1H NMR (500 MHz, CDC13) 6 8.76 (m, 2 H), 7.64 (m, 2 H), 7.58 (d, J: 8.5 Hz, 2 H), 7.01 (d, J = 8.5 Hz, 2 H), 6.86 (s, 1 H), 6.57 (s, 2 H), 1.98 (s, 6 H); ESI—MS: m/z 469.7 (M + H)+.
[00580] N-(4-(4-(2-Meth0xyethoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 109) ] [l -1—<\://\NO _ N-(4-(4-(2-Methoxyethoxy)-2,6-dimethylphenyl)thiazolyl)isonic0tinamide compound 11-109
[00581] N-(4-(4-(2—Methoxyethoxy)—2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 109) Yield: 19%; 1H NMR (500 MHz, DMSO-ds) 5 8.79-8.80 (m, 12 H), 7.98—7.99 (m, 2 H), 7.08 (s, 1 H), 6.70 (s, 2 H), 4.08-4.10 (m, 2 H), 3.65-3.66 (m, 2 H), 3.31 (s, 3 H), 2.06 (s, 6 H); ESI—MS: m/z 384.6 (M + H)+.
N-(4-(4-(3-Methoxypropoxy)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide (II=110) 1 _ | N\>—NI>-1—<\:\’/No N-(4-(4-(3-Meth0xypropoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound II-110 N-(4-(4-(3-Methoxypropoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-110) Yield: 58%; 1H NMR (500 MHz, DMSO-dé) 5 8.78-8.79 (m, 2 H), 7.98—7.99 (m, 2 H), 7.05 (s, 1 H), 6.69 (s, 2 H), 4.00-4.02 (m, 2 H), 3.46—3.48 (m, 2 H), 3.25 (s, 3 H), 2.06 (s, 6 H), 1.93-1.95 (m, 2 H); ESI—MS: m/z 398.8 (M + H)+.
N-{4-(4-(2-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonic0tinamide (II-111) Gog|N\>—N>H—<\:\JNO _ N—(4-(4-(2—Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound 11-] 11 N-{4-(4-(2-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide 1) Yield: 85%; 1H NMR (500 MHz, DMSO-d5) 6 8.80—8.81 (m, 2 H), 7.98—7.99 (m, 2 H), 7.16-7.21 (m, 3 H), 6.99—7.06 (m, 2 H), 6.59 (s, 2 H), 3.76 (s, 3 H), 2.03' (s, 6 H); ESI—MS: m/z 431.5 (M + H)+.
N-(4-(2,6-Dimethyl(p-tolyloxy)phenyl)thiazolyl)isonicotinamide 2) fig0 ?-l—<\:/>N0 _ N-(4-(2,6-Dimethyl(p-tolyloxy)phenyl)thiazol-Z-yl)isonicotinamide compound 11-1 12 N-(4-(2,6-Dimethyl(p-tolyloxy)phenyl)thiazolyl)isonicotinamide (II-112) Yield: 89%; 1H NMR (500 MHz, DMSO—ds) 5 8.80—8.81 (m, 2 H), 7.98-7.99 (m, 2 H), 7.18—7.22 (m, 3 H), 6.94—6.95 (m, 2 H), 6.73 (s, 2 H), 2.30 (s, 3 H), 2.06 (s, 6 H); ESI—MS: m/z 414.9 (M - H): N-(4-(4-(4-Ethylphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 113) 593o l °~>—<:\ \>—NH ’ N-(4-(4-(4-Ethylphenoxy)-2,6-dimethylphenyl)thiazol—2—yl)isonicotinamidé compound II-113 N-(4—(4-(4-Ethylphen0xy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II- 113) Yield: 91%; 1H N1V[R (500 MHz, CDCl3) 5 8.78 (d, J = 6.0 Hz, 2 H), 8.67 (m, 2 H), 7.18 (d, J: 8.0 Hz, 2 H), 6.93 (d, J: 8.5 Hz, 2 H), 6.83 (s, l H), 6.56 (s, 2 H), 2.65 (m, 2 H), 1.98 (s, 6 H), 1.26 (t, J = 7.5 Hz, 3 H); : m/z 429.6 (M + H)“.
[00590] N-(4-(4—Iodo-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-114) N M?N N-(4-(4-Iodo-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound 11-114 N-(4-(4-Iodo-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-114) Yield: 61%; 1H NMR (500 MHZ, CDC13) 5 8.76 (m, 2 H), 7.52 (m, 2 H), 7.11 (s, 2 H), 6.80 (s, 1 H), 1.84 (s, 6 H); ESI—MS: m/z 435.6 (M + H)+.
N-(4-(2,6-Dimethyl(phenylthio)phenyl)thiazolyl)isonicotinamide (II-115) G Kgs IZVNEQN0 — N-(4-(2,6-Dimethyl-4—(phenylthio)phenyl)thiazol-2—yl)isonicotinamide compound II-115 2,6-Dimethyl(phenylthio)phenyl)thiazol-Z-yl)isonicotinamide (II-115) Yield: 63%; 1H NMR(500 MHZ, DMSO-dé) 5 8.77 (d, J = 5.4Hz, 2 H), 7.98 (d, J: 5.4 HZ, 2 H), 7.38—7.40 (m, 2 H), 7.31—7.35 (m, 3 H), 7.11 (s, 3 H), 2.07 (s, 6 H); ESI—MS: m/z 418.8 (M + H)+.
] N—(4-(2,6-Dimethyl(p-tolylthio)phenyl)thiazolyl)isonic0tinamide (II-116) /©/8 l 0 '— 1 3%an N-(4-(2,6—Dimethyl(p-tolylthio)phenyl)thiazol=2=yl)isonicotinamide nd II-116 N-(4-(2,6-Dimethyl(p-tolylthio)phenyl)thiazol-Z-yl)isonicotinamide (II-116) Yield: 84%; 1H NMR(500 MHz, DMSO-d6) 6 8.78 (d, J = 5.2 HZ, 2 H), 7.98 (d, J :52 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 HZ, 2 H), 7.10 (s, 1H), 7.02 (s, 2 H), 2.36 (s, 3 H), 2.04 (s, 6 H); ESI—MS: m/z 432.5 (M + H)+.
] N-(4-(4-(4-Methoxyphenylthio)-2,6-dimethylphenyl)thiazolyl)isonicotinamide (II-117) Mao/gS 9%.88—00 - N-(4-(4—(4—Methoxyphenylthio)-2,6-dimethylphenyl)thiazolyl)isonic0tinamide compound II-117
[00597] N-(4-(4-(4-Methoxyphenylthio)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide (II-117) Yield: 64%; 1H NMR (500 MHZ, DMSO-dg) 5 8.79 (d, J = 5.0 HZ, 2 H), 7.98 (d, J = .0 HZ, 2 H), 7.43 (d, J: 8.4 HZ, 2 H), 7.12 (S, l H), 7.02 (d, J: 8.4 HZ, 2 H), 6.92 (s, 2 H), 3.79 (s, 3 H), 2.02 (s, 6 H); ESI—MS: m/z 448.1 (M + 10*. 4-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolylcarbam0yl)pyridine l-oxide (II-120) o _ M O(:r QQHXQW'O‘ 4-(4-(4-(4-Meth0xyphen0xy)-2,6-dimethylphenyl)thiazolylcarbamoyl)pyrlidine l-oxide compound 11—120 4-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazol-Z—ylcarbamoyl)pyridine l-oxide (II-120) Yield: 69%; 1H NMR (500 MHz, CDC13) 6 8.46-8.48 (m, 1 H), 8.39-8.43 (m, 2 H), 8.32—8.33 (m, I H), 7.02—7.05 (m, 2 H), 6.93-6.95 (m, 3 H), 6.70 (s, 2 H), 3.84 (s, 3 H), 2.19 (s, 3 H), 2.16 (s, 3 H); ESI—MS: m/z 447.8 (M + H)+.
] N-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazolyl) methylisonicotinamide (II-121) . /©/o N \—N I \>—NH / N-(4-(4-(4-Methoxyphenoxy)-2,6-dimethylphenyl)thiazol-Z-yl)methylisonicofinamide compound 11-121
[00601] 4-(4-Meth0xyphenoxy)-2,6-dimethylphenyl)thiazol-Z-yl) isonicotinamide (II-121) Yield: 62%; 1H NMR (500 MHz, DMSO—dfi) 5 12.8 (s, 1 H), 8.54--8.58 (m, 2 H), .56 (m, 1 H), 7.14 (s, 1H), 6.96--7.03 (n1, 4 H), 6.67 (s, 2 H), 3.76 (s, 3 H), 2.40 (s, 3 H), 2.05 (s, 6 H); ESI—MS: m/z 445.7 (M + H)+.
N-(4-(4-(4-Br0m0phenylamino)-2,6-dimethylpbenyl)thiazol-2—yl)isonicotinamide (II-122) U” 0 — \ NYNa—Q N-(4-(4-(4-Br0mophenylamino)-2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide compound 11-122 N-(4-(4-(4-Bromophenylamino)-2,6-dimethylpbenyl)thiazolyl)isonicotinamide (II-122) Yield: 60%; 1H NMR (500 MHz, CDC13) 5 8.79 (d, J = 4.5 Hz, 2 H), 7.85 (d, J = 4.5 Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.83 (s, 1 H), 2.05 (s, 6 H); ESI— MS: m/z 479.2 (M + H)+.
N-(4-(3-Brom0-2,6-dimetbyl-4—(pbenylamino)pbenyl)tbiazol yl)isonicotinamide (II-123) GN O ‘ , \ N\>_N%l—<\:\// N—(4—(3-Bromo—2,6-dimethyl(phenylamino)phenyl)thiazolyl)isonicotinamide compound 11-123 N-(4-(3-Bi‘omo-2,6-dimetbyl(pbenylamino)pbenyl)tbiazol-2— yl)isonicotinamide (II-123) Yield: 58%; 1H NMR (500 MHz, CDC13) 6 8,87 (d, J = 4.5 Hz, 2 H), 8.02 (d, J: 4.5 Hz, 2 H), 7.47 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H), 6.89 (s, l H), 6.85 (s, 1 H), 6.24 (s, I H), 2.04 (s, 6 H); : ri1/z 479.3 (M + H)+.
[00606] N-(4-(4-(4-Metboxypbenoxy)-2,6-dimetbylpbenyl)tbiazolyl) sonicotinamide (II-124) Dr" O _ I \>—NH 4-(4-Meth0xyphen0xy)-2,6-dimethylphenyl)thiazolyl)nitroisonic0tinamide compound 11-124
[00607] N-(4-(4-(4—Metboxypbenoxy)-2,6-dimetbylpbenyl)tbiazolyl)—2— nitroisonicotinamide (II-124) Yield: 94%; 1H NMR (500 MHz, DMSO-d6) 6 8.82 (s, 1 H), 8.71-8.72 (m, l H), 8.39-8.40 (m, 1H), 7.01—7.03 (m, 2 H), 6.96—6.99 (m, 2 H), 6.64—6.67 (m, 3 H), 3.75 (s, 3 H), 2.03 (s, 6 H); : m/z 476.8 (M + H)+.
N-(4-(2,6—Dimethyl(methylthi0)phenyl)thiazolyl)isonicotinamide (II- 125) O _ | NyNE—QN s N-(4-(2,6-Dimethyl(methylthi0)phenyl)thiaz01yl)isonicotinamide compound 11-125 N-(4-(2,6-Dimethyl(methylthio)phenyl)thiazolyl)isonicotinamide (II-125) Yield: 94%; 1H NMR (500 MHz, CDC13) 6 8.66—8.68 (m, 2 H), 7.49-7.50 (m, 2 H), 6.77 (s, l H), 6.57 (s, 2 H), 2.42 (s, 3 H), 1.87 (s, 6 H); ESI—MS: m/z 355.6 (M + H)+. ] 2-Fluoro-N-(4-(4-(4-meth0xyphenylthio)-2,6-dimethylphenyl)thiazol yl)isonic0tinamide 6) MeO(Esq | N\>—N?-l—<\::NO . 2-Fluor0-N-(4-(4-(4-methoxyphenylthio)—2,6—dimethylphenyl)thiazol-Z-yl)isonicotinamide compound II- 126 2-Flu0ro-N-(4-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)thiazol yl)isonic0tinamide (II-126) Yield: 65%; 1H NMR (500 MHz, fi) 5 13.1 (s, l H), 8.46— 8.47 (m, 1H), 7.93—7.94 (m, 1 H), 7.78 (s, 1H), 7.42-7.44 (m, 2 H), 7.19 (s, 1 H), 7.Dl-7.Q3 (m, 2 H), 6.91 (s, 2 H), 3.79 (s, 3 H), 2.02 (s, 6 H); ESI—MS: m/z 465.4 (M + H)+.
[00612] N-(4-(2,6-Dimethyl(methylsulfonyl)phenyl)thiazolyl)isonicotinamide (II- 127) o _ I N\>—Nz—‘QN N—(4-(2,6-Dimethyl(methylsulfonyl)phenyl)thiazolyl)isonic0tinamide compound II-127 ] N-(4-(2,6-Dimethyl(methylsulfonyl)phenyl)thiazolyl)isonicofinamide (II- 127) Yield: 39%; 1H NMR (500 MHz, CDC13) 5 8.80-8.81~(m, 2 H), 7.98—8.00 (m, 2 H), 7.70 (s, 2 H), 7.30 (s, l H), 3.30 (s, 1 H), 2.20 (s, 6 H); ESI—MS: m/z 387.6 (M + H)+.
N—(4—(4-(4-Methoxyphenylsulfonyl)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (11-129) N N l >—N>l:—_<\://\o s N-(4-(4-(4-Meth0xyphenylsulfonyl)-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound 11-129 N-(4-(4-(4-Methoxyphenylsulfonyl)-2,6-dimethylphenyl)thiazol yl)isonic0tinamide (II-129) Yield: 61%; 1H NMR (500 MHz, DMSO—dé) 6 8.79 (s, 2 H), 7.97 (d, J = 6.0 Hz, 2 H), 7.91 (d, J = 8.9 Hz, 2 H), 7.69 (s, 2 H), 7.27 (s, 1 H), 7.15 (d, J = 8.9 Hz, 2 H), 3.84 (s, 3 H), 2.16 (s, 6 H); ESI-MS: m/z 480.6 (M + H)+.
N-(4-(4-(4-Methoxyphenylsulfinyl)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (11-130) o _ N>—N>:_<\://\ N N-(4-(4-(4-Methoxyphenylsulfinyl)-2,6—dimethylphenyl)thiazolyl)isonicotinamide compound 11-130 N-(4-(4-(4-Methoxyphenylsnlfinyl)-2,6-dimethylphenyl)thiazol yl)isonicotinamide (II-130) Yield: 43%; 1H NMR (500 MHz 6 13.1(s, 1 H), 8.80 , DMSO'dfi) (d, J = 6.0 Hz, 2 H), 7.97 (d, J = 6.0 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 2 H), 7.42 (s, 2 H), 7.23 (s, 1H), 7.10 (d, J = 8.8 Hz, 2 H), 3.80 (s, 3 H), 2.13 (s, 6 H); ESI—MS: m/z 464.7 (M + H)+.
[00618] N-(4-(4-(4-methoxyphenoxy)—2,6-dimethylphenyl)thiazolyl)isonicotinamide QC CI I \>—NH N-(4-(4-(4-meth0xyphenoxy)-2,6-dimethylphenyl)thiazolyl)isonicotinamide compound 11-131
[00619] N-(4-(4—(4-methoxyphenoxy)—2,6-dimethylphenyl)thiazol-Z-yl)isonicotinamide (II-131) Yield: 24%; 1H NMR (500 MHz, CDC13) 6 8.80 (s, 2 H), 7.70 (d, J = 5.1 Hz, 2 H), 6.97 (m, 2 H), 6.92 (m, 3 H), 6.70 (d, J = 2.4 Hz, 1 H), 6.61 (d, J: 2.3, 1H), 3.83 (s, 3 H), 2.02 (s, 3 H); : m/z 452.4 (M + H)+.
. Exemplary Compounds and Inhibitory Activity
[00620] The following Table 1 lists exemplary results for selected compounds rating the antiproliferative activity on selected canCer cells using exposure of the cells in growth medium with the compounds as indicated. Antiproliferative effect is expressed as IC50 values in nanomolar final concentration. (nM)Anti- roliferative ICSO ure MDA-MB- MDA-MB- WO 82324 33.4 374 9 246.6 1024.0 386 3 2986 8 3686.0 9431.0 6352.0 WO 82324 (110 091) 59.2 74.5 8.3 1.7 >”(j/I08.2 106.6 57.4 634.8 WO 82324 Table 1 The following Table 2 lists exemplary results for r selected compounds illustrating the antiproliferative activity on selected cancer cells using exposure of the cells in growth medium with the compounds as indicated. Antiproliferative effect is expressed as IC50 values in olar final concentration.
Anti roliferative IC50 ( M) Compound Structure MDA-MB- MDA-MBK562 468 231 WO 82324 WO 82324 11—12 >10 3.91 2.88 1.41 11-13 >10 >10 >10 >10 II-14 >10 >10 >10 >10 II-15 >10 >10 >10 >10 II-16 >10 >10 >10 >10 II-17 >10 >10 11-18 >10 >10 >10 >10 II-19 >10 >10 6.85 6.75 >10 >10 >10 >10 11-21 >10 >10 >10 >10 11-22 >10 >10 4.19 >10 11-23 N >10 >10 7.12 >10 F | s\>—NH WO 82324 WO 82324 0 _N 11-35 Meo >10 >10 >10 >10 N \ / | \>—NH 11.36 >10 >10 >10 >10 11.37 >10 >10 >10 >10 II-38 >10 >10 3.40 5.68 11-39 >10 >10 >10 >10 11-40 >10 >10 >10 >10 O ' 1141' >10 >10 >10 >10 N OMe N 0.10 0117 0.15 0.16 11.43 >10 >10 >10 >10 11-44 >10 1.96 1.01 1.24 11-45 >10 >10 7.68 . >10 y o _ [1-46 \ N >10 >10 7.19 7.41 \ , l _\>—NH N O _ 11-47 MeO N ,\N >10 >10 .>10 >10 I \>—NH N >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 >10 11-51 MeO N m >10 >10 >10 >10 0>_<\::N_ 11-52 N 0.04 0.21 0.17 0.17 | \>—NH 11-53 0 O — 0.48 0.62 0.48 0.43 .92 6.65 6.95 4.56 11-55 0.73 0.76 0.89 0.59 11-56 >10 >10 >10 >10 WO 82324 WO 82324 WO 82324 1.72 >10 8.30 15.47 7.98 1.22 0.80 4.66 6.06 3.29 2.21 0.30 0.31 039 030 11-95 (Hec1001, 0.04 0.03 0.25 0.24 3.11 8.30 (He01015, 0.04 0.02 0.04 0.02 101015) 0.17 0.04 0-1 1 n 0.28 0.11 0.39 0.28 WO 82324 11-101 0.11 0.05 0.13 0.07 N \ [N 11-102 1.62 0.73 1.48 0.93 [1.103 >10 2.48 2.17 1.11 I ’ 11-104 \ >10 2.44 7.64 1.10 | \>—NH o ‘9‘ 11.105 NH >10 >10 8.02 >10 II-106 >10 >10 4.95 11-107 0.10 0.20 0.20 011 0.11 11-109 0.31 0.24 0.28 0.26 11-110 0.11 0.10 0.13 II-111 0.33 0.18 0.33 0.25 11-112 0.24 0.13 0.22 0.14 11.113 0.17 0.17 0.17 WO 82324 Table 2 ] Metabolism Studies: Compound 27 0f the above Table 1 was treated with human microsomes in the presence of NADPH for metabolite identification. After the sample was analyzed by LC/MS, molecular ion peaks with m/z values of 510.1, 480.2, 495.1, 383.5, and other peaks were observed (positive mode). The peaks may correspond to the ion, demethylation, oxidation, demethylation, etc. of compound 27. Possible metabolic sites of compound 27 are represented in the following structure: so] 302 CHZOH, COOH OH l \ *0 l S / O , MeO N \ / T \so.302 COOH Reactions of the metabolite formation from compound 27 may occur at a single site or at a combination of sites. ary Biological Activities ofSelected Compounds The ing data provide exemplary guidance with respect to the biological activity of certain compounds in vitro and in vivo. Where compounds are referenced by number, the number is with regard to the compounds listed in the tables above.
The following data provide exemplary ce with respect to the biological ty of n compounds (and especially compound 11-95 of Table 2 and compounds 22, 25, and 27 of Table 1) in vitro and in viva. Selected compounds of the invention, ed as described in the es, were subject to the following series of biological and immunochemical assays.
Descriptions of different assays are as follows:
[00625] Cell Culture: MDA—MB—231, MDA-MB ~468, HeLa, and K562 cell lines were ed in 10% FBS (Hyclone, Logan UT 84321 USA) in DMEM medium (P/N D5523, Sigma Aldrich, St. Louis MO USA). Cells were grown at 37 °C in a humidified atmosphere consisting of 5% C02 and 95% air.
Antiproliferation Assays: Cells were plated in a 96—well culture plate with 2000-8000 cells per well. The compounds were prepared in DMSO and used to rea cells in a in 1 concentration of less than 1% DMSO. nd ent started after overnight incubation of cells (TO). Compound was prepared in an eight point 3x dilution from 10 M to 4.6 nM.
Compound was added to the plate in triplicate wells, and the plates were then incubated for 96 hours. DMSO (compound t) was also included and added to the plate in control wells.
Cell Viability was then determined by MTS assay using the CellTiter 96® aqueous non- radioactive cell proliferation assay system (Promega, Madison, WI 53711 USA). A plate reader (Vmax, Molecular Devices, Sunnyvale CA 94089 USA) was used to determine the l densities, and the results were used to deduce concentration-response curves. All data were determined in triplicate, with the mean of three separate determinations having variations of less than :20%. The results were analyzed using linear regression software (GraphPad Prism 5; GraphPad Software Inc. La Jolla CA 92037 USA). The IC50 value refers to a concentration that results in 50% growth inhibition. The % inhibition of test drugs were calculated using the formula: (1- (T — TO)/(C - T0)) x 100 (T is treatment; C is control); these value were used to plot the concentration-response curves and analyzed with linear regression software (GraphPad Prism 5; GraphPad Software Inc. La Jolla CA 92037 USA).
] Co-Immunoprecipitation Analysis: Co-immunoprecipitation (Co-IP)/Westem blotting assays were performed to assess the effects of Hecl inhibitory compounds on Hecl- Nek2 interaction. K562 cells were treated with Hecl inhibitory compounds as ted. After harvesting and washing once with cold PBS, cells were lysed on ice in lysis buffer (50 rnM Tris (pH 7.5), 250 rnM NaCl, 5 mM EDTA (pH 8.0), 0.1% NP—40, 1 HM PMSF, 50 mM NaF, and protease inhibitor cocktail (P/N P8340 Sigma Aldrich, St. Louis MO USA) for 30 min. Lysates were then centrifuged at 12,000 rpm at 4 °C for 20 minutes. Input supernatant was incubated in the presence of anti Nek2 dy (rabbit anti—Nek2, Rockland Immunochemicals, Gilbertsville, PA 19525 USA) or IgG control antibody for 2 h at 4 °C, followed by the addition protein G coupled to agarose beads (GE care, Anaheim CA 92805 USA). After mixing for 1 h at 4 °C, the e beads were centrifuged at 12,000 rpm at 4 °C for 20 seconds. The beads were then washed 5 times with cold Co—IP buffer, boiled in GE sample buffer followed by SDS-PAGE. The presence of Heel and Nek2 was detected by Western blotting with mouse monoclonal antibodies directed to Hecl (GeneTex, Inc., Irvine CA 92606 USA) and Nek2 (BD Biosciences, San Jose CA 95131 USA).
Figure 1 depicts an exemplary result of such an ment where it is readily apparent that the Hecl inhibitory compound 110095 (compound 27 of Table 1) icantly disrupted Heel/Nek2 interaction. K562 cells were d with 110095 or control (DMSO) for 8 or 16 hours, lysed, and lysates immunoprecipitated by Nek2 antibody to see co- immunoprecipitated Hecl. Control IgG was used as control dy for immunoprecipitation.
Results show decreased Hecl level in the Nek2 immunoprecipitates of 110095-treated cells, indicating that 110095 exposure leads to a decreased interaction between Hecl and Nek2.
Immunoblot Analysis: For immunoblotting ments, cells were plated in a 6—well culture plate and cultured overnight. Cells were ted with the test compounds for the indicated time and whole cell lysate was ted by adding 1X SDS-PAGE Sample Buffer (62.5 rnM Tris—HCl (pH 6.8 at 25°C), 2% w/v SDS, 10% glycerol, 50 mM DTT, and 0.01% W/V bromophenol blue or phenol red). Proteins were ted by SDS-PAGE electrophoresis and transferred to PVDF membrane. Protein expression was immunoblotted using various primary antibodies and detected using Immobilon Westem Chemiluminescent HRP Substrate (Millipore, Billerica MA 01821 USA). Antibodies used include anti-Cleaved Caspase3, (Rabbit, Cell Signaling Technology, Danvers MA 01923 USA); anti-PARP (Rabbit, Cell Signaling Technology, Danvers MA 01923 USA); anti-MCL—l (mouse, BD Biosciences, San Jose CA 95131 USA); IAP (rabbit, Cell Signaling Technology, Danvers MA 01923 USA); anti-BC]- 2 (mouse, Santa Cruz hnology, Santa Cruz CA. 95060); anti-Cyclin B1 (mouse, BD Biosciences, San Jose CA 95131 USA); anti-Cyclin D1 (mouse, Santa Cruz Biotechnology, Santa Cruz CA. 95060); Anti—Nek2 (mouse, BD Biosciences, San Jose CA 95131 USA); Anti-HECI, (rabbit, GeneTex, Inc, Irvine CA 92606 USA); and anti—actin (mouse, Millipore, Billerica MA 01821 USA).
] Figure 2 shows reduction of Nek2 protein in 110095 (compound 27 of Table 1)- treated cancer cells. Control (DMSO) and 110095-treated cells were immunoblotted for their levels of Nek2 protein expression level. K562 cells were incubated for various time points up to 24 hrs with 1 M of tested compounds. Results show that Nek2 content of K562 cells is le over time after ent with Hecl inhibitor. 110095 induced a reduction of Nek2 protein levels in Table 2) was used as a control.
. Compound 101015 (compound II—98 staining and copy: Cells were grown on polylysine-coated lips.
Cells were gently washed with BRB 80 buffer (80 mM piperazine-N,N’-bis(2-ethanesulfonic acid) (PIPES) pH 6.8, 5 mM EGTA, 1 mM MgC12) before fixation with cold 100% methanol or 4% paraformaldehyde in BRB80 or ate-buffered saline (PBS). Following permeabilization with 0.4% Triton X—100, cells were d with 2% bovine serum albumin (BSA) in PBS and then incubated with anti-oc-Tubulin antibodies (mouse, FITC Conjugate; Sigma Aldrich, St.
Louis MO USA) diluted in 2% BSA in PBS. DAPI (4’,6'—diamidinophenylindole) staining was d after secondary antibody incubation, and cells were mounted on cover slides with Prolong gold antifade reagent (Life Technologies, Carlsbad CA USA 92008). Images were captured with a Zeiss Axioplan 2 cope equipped with a deconvolution module or with a Zeiss LSM-510 META laser scanning confocal cope (Carl Zeiss Microscopy, Thomwood NY 10594 USA).
Figure 3 shows images of chromosomal misalignment in 110095-treated cancer cells and the effect of select Hec1 inhibitors on cell populations. In order to image chromosome misalignment HeLa cell were grown on polylysine—coated lips and treated with 110095 (compound 27 of Table 1) or control (DMSO). After fixation, cells are stained with anti-tubulin antibody and DAPI to stain for microtubules and DNA, respectively, and imaged. Similar studies were performed with select Hec1 inhibitory comounds in order to determine the phenotypic arrangements of the cellular DNA in cell cycle phases. Fluorescent images were taken of the cells and the tage of cells with metaphase misalignment were counted and recorded.
Results show that the Hec1 inhibitory compounds 110091 (compound 22 of Table 1), 110093 (compound 25 of Table 1), and 110095 caused a time-dependent increase in the number of cells with metaphase misalignment compared to control cells. This suggests that these compounds target the Hec1 pathway and lead to chromosomal aberrations.
WO 82324 DNA content analysis: Cells were plated in a 10-cm culture plate and cultured overnight. Cells were incubated with the nd for the indicated time and collected at the indicated time points. Cells were fixed with 70% ethanol overnight, stained with propidium iodide solution (1.25 mg/ml propidium iodide (Sigma) and 20 til/ml Mase A in PBS) and subjected to fluorescence activated cell sorting (FACS). The results were analyzed by Cell Quest software (BD Biosciences, San Jose CA 95131 USA).
] Figure 4 shows induction of sis by Hecl inhibitory compounds in cancer cells by cell cycle analysis. Cells treated with compounds 101015 (compound II-98 of Table 2) and 110095 (compound 27 of Table l) or control (DMSO) were analyzed for their DNA content by staining with propidium iodide followed by analysis of the cellular population with FACS. The table shows the percentage of cells in G1 (M1: non cycling cells), S (M2: DNA ation) and sub-G1 stages (M4: apoptotic cells). Results show an increase in the sub—G1 population. This is tive of DNA fragmentation during apoptosis, suggesting the induction of apoptosis by 101015 and , which leads to drug-induced cell death.
[00635] Figure 5 shows induction of apoptosis by 110095 (compound 27 of Table 1) in cancer cells by immunoblotting of apoptotic pathway ns. s from cancer cells treated with Control (DMSO) or 1 |JM of seelct Hecl tory compounds, including 110091 (compound 22 of Table 1), 110093 (compound 25 of Table 1), 110078 (compound 19 of Table 1), 110079 (compound 20 of Table 1), and 110095 (compound 27 of Table 1), were immunoblotted to characterize levels of apoptotic proteins (caspase-3 and PARP) and anti- apoptotic proteins (Mel—1 and XIAP) at time points 24 or 48 hours. 100 nM Taxol was used as a positive control drug for apoptosis. Results show cleavage of the apoptotic proteins accompanied by down—regulation of the anti-apoptotic proteins, indicative of the activation of apoptotic pathway, suggesting that these Hecl compounds causes cell death through apoptosis.
[00636] Figure 6 shows cyclin B1 and cyclin D1 degradation in 110095-treated cancer cells.
Control (DMSO) or 1 HM 110095 (95, nd 27 of Table 1) treated cells were immunoblotted for their cyclin B1 (protein levels peak in G2/M phase) and cyclin D1 (protein levels peak in G1 phase) to see their relative change during the cell cycle. Results show that control cells progress through G2/M to G1 phase during the experimental time period while the —treated cells shows cyclin levels that are unexpected and difficult to interpret. Hecl inhibitors such as 110095 may induce cell cycle arrest in the S phase, which will induce an increase in cyclin A levels, however this remains to be elucidated.
Mouse Xenograft Studies: Xenograft s d from a previous published protocol (Wu et al, Cancer Res. 2008 Oct 15;68(20):8393-9). Female BALB/c nude (nu/nu) mice (5—8 weeks) were obtained from Lasco (Industrial Park,Tai-Ping Area,Taichung City,Taiwan). The animals were maintained under specific pathogen-free conditions, and food and water were supplied ad libitum. Housing and all procedures involving animals were performed ing to protocols approved by the IACUC in DCB. Nude mice were inoculated with stradiol pellets 72 to 96 h before implantation of BT-474 cells. For subcutaneous implantation of BT-474 cells, cells (1 x 107 in matrix imal) were injected subcutaneously into the right subaxillary . Treatment started when average tumor volume reached about 200 mm3; mice were treated (p.0., QD/28 cycles in total) with vehicle A (0.5% methylcellulose), or candidate compounds formulated in vehicle A (10-50 mg/kg body weight). Perpendicular diameter measurement of each tumor were made with digital calipers and the volume of the tumor calculated using formula (L X W x W)/2, in which L and W ent the length and the width, respectively. Body weights were measured three times weekly. Mean tumor growth inhibition of each treated group was compared with vehicle control and a Tumor growth inhibition value calculated using the a: (l-(T/C) x100%) .
Figure 7A to Figure 71) show inhibition of xenograft tumor outgrowth by compound 27 (110095, of Table 1) and compound II-95 Ol; , of Table 2) in MDA—MB-231 (Figure 7A and Figure 7B) and BT474 (Figure 7C) on xenografted breast cancer models and a Huh-7 liver cancer (Figure 7D) model in nude mice. The in vivo effectiveness of contemplated compounds in the reduction of tumor volume in nude mice is readily apparent. Surprisingly despite the tumor ion body weight remained constant in all cases, suggesting that overall toxicity of Heel inhibitory compounds is low.
Development of resistance to treatment in advanced stage tumors is a well known phenomenen. Activity of select Hecl inhibitor in such late stage tumors was determined by re— dosing of BT474 xenografted animals that had previously ted to 35 days of treatment with 110095 (compound 27 of Table 1). Re-treatment with 110095 was starting on day 42 and continued for 21 days. Results are shown in Figure 7E, which demonstrates that the Hecl inhibitor remained effective with late stage . This suggests that such compounds may have a reduced tendency to induce ance in tumors and other proliferative diseases. Similar to early stage treatment studies described above, body weight remained constant.
Cell Permeability: Figure 8 shows moderate Caco-2 permeability of compound 110095 (compound 27 of Table 1) and 110091 (compound 22 of Table 1) in both directions, with no indication of significant active efflux. Here, Caco-2 cell line (cat. HTB—37TM) was purchased from the ATCC. Cells were cultivated in T-75 flasks in a cell culture incubator set at 37 °C, 5% C02, 95% relative ty. Cells were allowed to grow to reach 80-90% confluence before seeding. Caco-2 cells were seeded onto filter membranes at a density of 1.25x104 cells/mL for 12 well Caco-2 cell plates. The cells were grown in e medium consisting of Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin and 100 ug/mL streptomycin. The culture medium was replaced every 2 days and the cells were ined at 37 °C, 95% relative humidity and 5% C02. Permeability studies were conducted with the monolayers cultured for approximately 21 days with the cell passage numbers between 58 and 78. ine 123 was used as a model substrate for in vitro Caco—2 assay.
For a y integrity control of the monolayers of seeded cells, the r yellow (LY) ort experiment was performed to evaluate monolayer integrity. As for a quality control of each filter, the transepithelial electrical resistance (TEER) was ed before the start of and at the end of transport experiments. Physiologically and morphologically well developed Caco-2 cell monolayers with TEER values greater than 400 9 cm2 were used for the studies.
Test and reference control compounds (Rhodamine 123) were added to either the apical or basolateral chambers of the transwell plate assembly at a concentration of 10 M. The solution volumes in apical and teral chambers were set to 0.4 and 0.6 ml respectively.
Samples were taken from both the apical and basolateral compartment at the end of the 2 hour incubation at 37 °C. Lucifer Yellow and Rhodamine 123 were ed by FusionTM (Packard BioSceince Company). The excitation and emission wavelengths were 490nm and 530nm, respectively. Concentrations of TAI-l in the samples were measured byLC-MS/MS.
Hecl Inhibitory Compound binding to hERG: Figure 9 shows hERG binding of compounds 110095 und 27 of Table 1), 110093 (compound 25 of Table 1), and 110091 (compound 22 of Table 1) with IC50 of > 10~100 uM. Here, [3H]Astemizole competitive binding assays were performed to determine the ability of compounds to displace the known igand [3H]—astemizole from the hERG potassium channels, ing standard protocol with minor modifications. In brief, assays were performed in 200ul of binding buffer (50 mM HEPES, pH 7.4, 60 mM KCl, and 0.1% BSA) containing 1.5 nM of [3H]astemizole, 3ug/well of hERG membrane protein (PerkinElmer), and TAI-l (in 1% DMSO final concentration) at 27°C for 60 min. Nonspecific binding (NSB) was determined in the presence of 10 M astemizole.
IC50 assay for TAI-l contained 8 concentration points with lO-fold serial dilution in triplicate.
Binding was terminated by rapid filtration onto polyethyleneimine—presoaked, buffer-washed UniFilter—96, GF/C (Perkin Elmer) using a vacuum manifold (Porvair Sciences). Captured radiolabel signal was detected using TopCount NXT (Perkin . The data were analyzed with nonlinear curve fitting software (PRISM, ad) and IC50 value (defined as the concentration at which 50% of [3H]-astemizole binding is inhibited) was ated. All results are derived from two independent experiments.
Pharmacokinetics of Heel Inhibitor Salts: .Pharmacokinetic comparison of different salt forms (HCl, tosylate, mesylate salt) was studied for the compounds as shown in Table 3 below: 110095-HCl-1007 1 10095-03 —03 110095-0202 M30VAOI:jKEISN|:\>/NH Table 3 ations for both PO (oral) and IV (intravenous) doses were prepared in saline with 2% Tween 80 and 10% DMSO. Concentrations were adjusted based on the molecular weights of the freebase and salts.
PO studies: A single dose of 10 mg/kg of each of the three test compounds was orally administered to 21 healthy male CD-1 mice (weight ranged from 18-27 g). The dosing volume was 10 mL/kg. Animals were fasted approximately 16 hours prior to dosing until 4 hours post dosing; Water was available to all animals during the experiment .
IV studies: A single dose of 1 mg/kg of each of the three test articles was IV administered to 21 y male CD-1 mice t ranged from 18-27 g). The dosing volume was 5 mL/kg. Food and water were available to all animals during the experiment period.
Three mice were bled(ca. 1 mL) at each timepoint (0.5, 1, 1.5, 2, 4, 6, and 24 hours ose for P0 study and 0.083, 0.5, 1, 2, 4, 6, and 24 hours post-dose for IV study) by cardiac puncture and blood was collected into K3EDTA blood collection tubes. Blood samples were centrifuged immediately at 4 °C at 3000 rpm for 10 min. Plasma samples were erred and stored at -20 °C prior to analysis.
No adverse events were observed for all CD-1 mice after a single oral dose of 10 mg/kg or a single IV dose of 1 mg/kg of each of the test articles. The plasma concentrations of 110095 (compound 27 of Table 1, the free base of all three test articles) were ined by LC MS/MS in the positive MRM mode; all doses were normalized to the freebase (110095) concentration. Results are presented in Table 4 and Table 5. The mean plasma concentration from each time point (n=3) were used to calculate the PK parameters using a non—compartmental model. cokinetic parameters (Cmax, Tmax, tl/z, AUC, etc.) were calculated using WinNonlin Software (version 5.3, Pharsight, Sunnyvale CA 94086 USA), the results and te bioavailability results are presented in Table 6. Table 4 lists mean concentrations (ng/mL) of 110095 in mouse plasma following a single oral dose of 10 mg/kg of -HG]- 1007, 11009503 or 11009502 to CD—1 mice, and Table 5 lists mean concentrations (ng/mL) of 110095 in mouse plasma following a single IV dose of l rug/kg of 110095—HC1—1007, 11009503 or 110095-02—02 to CD-1 mice. Table 6 lists PK parameters and absolute bioavailability result of 110095-HC1-1007, 11009503 or 110095—02-02 in CD—1 mice.
[00650] Surprisingly, the toyslate salt unexpectedly provided the best AUC with a desirable absorption fraction (F%) as ed to the other two compounds.
Time (h) Compound 0.5 1 1.5 2 4 6 24 110095-HCl-1007 1801 4063 3660 3563 2173 1137 14.8 110095—03—03 3117 4013 3797 3887 2210 1590 16.9 02 2870 3740 4167 3833 1074 1080 21.2 Table 4 Time (h) Compound 0.083 0.5 1 2 4 6 24 1 10095-HCl-1007 870 684 549 422 202 93.2 3.68 110095—03-03 1100 624 643 568 307 139 2.87 110095-02—02 1348 772 659 365 182 175 8.65 Table 5 Compound Route PK ters 1 10095—HCl—1007 1 10095 —03 -03 I 02402 dose (mg/kg) 1.00 1.00 1.00 rm (h) 3.61 2.96 4.38 IV MRT(h) 3.30 3.46 3.92 AUC 0., (ng-h/mL) 2983 3976 3987 AUC 0..., (ng-h/mL) 3002 3988 4043 dose (mg/kg) 10.0 10.0 10.0 Tm.cm 1.00 - 1.00 1.50 Cmax 4063 4013 4167 p0 rm (h) 2.81 2.81 3.38 MRT(h) 4.11 4.29 4.00 AUC 0., (ng-h/mL) 25065 30794 23319 AUC 25125 30863 23424 0.0., (ng-h/mL) F%fl 84.0 77.4 58.5 % F =Wx100 AUCIV x DosePO Table 6 It should be apparent to those skilled in the art that many more cations besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other ts, components, or steps that are not expressly referenced. Where the specification claims refers to at least one of something selected from the group consisting of A, B, C and N, the text should be reted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims (22)

CLAIMS What is d is:
1. A compound having a structure according to Formula I Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 is ORa, SRa, –S(O)2Ra, or –S(O)Ra; Ra is pyrazine, optionally substituted with alkoxy or methoxyalkoxy; R2 and R3 are independently hydrogen, C1–C6 alkyl, halogen, and R4 is en or halogen R5 is wherein Ra, Rb, Rc, and Rd in R5 are independently hydrogen, halogen, C1–C6 alkyl, or amino.
2. The compound of claim 1 wherein R1 is SRa,–S(O)Ra, or –S(O)2Ra.
3. The nd of claim 2 wherein Ra is substituted with alkoxy or methoxyalkoxy.
4. The compound of claim 3 wherein Ra, Rb, Rc, and Rd in R5 are independently hydrogen or halogen.
5. The compound of claim 1 wherein R5 is optionally substituted pyridinyl.
6. The nd of claim 1 having a structure according to Formula II Formula II wherein X1 is alkoxy or methoxyalkoxy and X2 is hydrogen; Y is O, S, SO, or SO2; R1, R2 are independently H, alkyl, alkoxy, or halogen; R3 is en; n is 0; ; and wherein Ra, Rb, Rc, and Rd in are independently hydrogen, halogen, C1–C6 alkyl, or amino.
7. The compound of claim 6 wherein Y is O, S, or SO2.
8. The compound of claim 6 wherein is .
9. The compound of claim 6 n Y is O, S, or SO2, wherein is
10. The compound of claim 1 having a structure selected from the group consisting of , , , , , , , and .
11. The compound of claim 1 having a structure selected from the group consisting of , and
12. The compound of any one of claim 1, claim 10, or claim 11, in combination with an ion to thereby form a pharmaceutically acceptable salt.
13. The compound of any one of claim 1, claim 10, or claim 11, wherein R1 is SRa, and wherein the S in SRa is a sulfone or a sulphoxide.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, optionally present as a ceutically acceptable salt, according to claim 1 in a concentration effective to disrupt Hec1/Nek2 binding in a mammal when the composition is administered to the .
15. The pharmaceutical composition of claim 14, further comprising a drug that interferes with ubule formation or degradation.
16. The pharmaceutical composition of claim 14 wherein the compound is a compound according to claim 11.
17. The pharmaceutical composition of claim 14 formulated as an orally administerable drug or an injectable drug.
18. Use of a compound according to claim 1 for the cture of a medicament to treat a neoplastic disease, wherein the compound according to claim 1 is present in the medicament in an amount ive to disrupt Nek2/Hec1 binding upon administration of the medicament.
19. The use of claim 18 wherein the medicament is formulated for stration , topically, or parenterally.
20. The use of claim 18 n the medicament is formulated for co-administration with an agent that interferes with microtubule formation or degradation.
21. A method of improving a pharmacokinetic parameter for a compound having a structure selected from the group consisting of , and comprising a step of g a tosylate salt of the compound.
22. A pharmaceutical composition comprising a carrier and a tosylate salt of a compound having a structure selected from the group consisting of , and
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