AU2015215863B2 - Inhibitors of jun n-terminal kinase - Google Patents

Abstract

The present disclosure provides inhibitors of oJn Nkeninakkirjases (JNK hasin a strsugure according to the 1ooigfoml r ato solvate thereof. wherein ring A, Ca. Gb, Z R> W and Cy are defined herein. The disclosure tudher provides phamrnaoeutcal compoositions includ ng the con c't fheyeetdsisr n menhodsl aan using the compounds and compositions of the present disclosure og in the treatment and prevent of various disorders such as, Ahh.e s disease,

Description

background of the disclosure [Ml] This application claims priority from U.S. IfrovMofral Patent

Application No, 61/207,126 filed on February 6,2009, and from U.S. Provisional Patent Application No. 61/2-14,390 filed on September 21,2009, the disclosures each of which are incorporated herein by reference in their entirety.

[002] The present disclosure relates to inhibitors ofc-Jun N-terminal kinases (JNKs). The disclosure also provides pharmaceutical compositions comprising the inhibitors of the present disclosure and methods of utilizing those compositions in the treatment of various disorders, such as Alzheimer’s disease.

[Ό03] Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which: include the extracellular signal kinases (ERKs), the p3| MAP kinases and the c-.hm N«temunal kinases (JNM&b MAP kinases (MAPKs) are serirse/thrednine kinases and are activated by a variety Of signals ifi|luding growth factors, cytokines, U? radiation, and stress-inducing agents. MAPKs phosphoryiate various substrates mciuding transcription factors. winch in turn regulate the expression of specific genes.

[M4] Members of the JNK. family are activated by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta), as well as by environmental stress, including UV irradiation, hypoxia, and osmotic shock (see, e.g., Minden etal., Biochemica el Biopkysica Acta 1997, 1333:F85-F1Q4). Three distinct JNK genes, jnkl,jnk2 and jnk3 were identified and at. least ten different splicing isofonns Mist in mammalian cells (see, e.g., Gupta et a!,, EMBOJ, 1996, 15:2760-2770).

[005] Down-stream substrates of JNKs include transcription factors c-Jun, ATF-2, Efkl, p53 and a cell death domain, protein (DENN) (see, e.g., Zhang et gL Proc. Natl Acad. Sci, USA 1998, 95:2586-2591). Each INK isoftum binds to these substrates with different affinities, suggesting a regulation of signaling pathways by substrate specificity in vivo (Gupta ei al,, supra).

[6ίδ] jNKs have been implicated in mediating a number of physiological responses and disorders including cellular-response to cancer, ihrombin-induced platelet aggregation, immunoddldeney disorders, autoimmune diseases, ceil death, allergies, osteoporesisiund heart disease. The therapeutic targets related to activation of : he J N K. pathway include chrome myelogenous letinmia (CML), Htnatoid arthritis, asthma, osteoarthritis, ischemia, various cancers and neurodegeneraUve diseases, [007] Several reports have detailed thesiniporfanee of JNK .activation associated with liver disease of e|iSbdbS ofhepatic ischemia (sei, e,g,:, Nat. &$net. 1999, 2i-V,6^29;F£nSUn. 1997,420:201-204;/ Gin. Invest 1998, 102:1942-1 fc; Hepatology: .1998,28:1022-1030); A role for JNK in cardiovascular disease such as myocardial infarction or congesti ve heart failure has also been reported (see, e.g., Cire, Res. 1998, 83:167-178; Circulation 1998, 97:1731-7). The JNK cascade also plays a role in T-cdl activation, including activation of the 11..-2 promoter (see, e.g ../. hnmunol. 1999, 162:3176-87; Bur. J. Immunol 1991 28:3867-77( 1 Exp. Med. 1997], A role for IN K activation in various forms of cancer has also been established. For example, eonstitutively activated JNK is associated with HTLV-1 mediated tuiitorigetiOids {Oncogene i 996, 13:135-42). INk may play a role in Kaposi's sareoma (KS) because it is thought that the proliferative effects of brGF and OSM on KS cells are mediated by their activation of the JNK signaling pathway (see e.g., J. Gin. invest. 1997, 99:1798-804). Offer prcli lento ve effects of certain cytokines impiicatei in K.S proliferation. such as vascular endothelial growth factor (VEGF). 1L-6 and TNF alpha, may also be mediated by JNK, In addition, regulation of the c-jun gene in p210 BCR-ABL transformed cells corresponds with activity of JNK, suggesting a role for JNK inhibitors in the treatment for chronic myelogenous leukemia (CML) (see, e.g,, Blood 1998, 92-2450-60).

[008] While JNK.1 and JNK2 arc widely expressed in a variety of tissues, jNKJsinsselectively expressed in the brain and, to a lesserexient, in the heart and testis (see, e.g.. Gupta et a!.. supra: Meliit et al, Neuron 1995( 14:67-78; Martin et a!,, Brain Res. Mol Brain. Res. 1996, 35:47-57). JNK3 has been baked to neuronal apoptosis induced by kainic add, indieating a role of JNK in the pathogenesis of glutamate neurotoxicity. In the adult human brain, JNK3 expression is Idealized to a subpopulation of ipam'dai neurons is the CA1, CA4 and sufcieulum regions of this: hippocampus and layers 3 and 5 of the neocortex (Mohit etal , supra). The CA1 neurons of patients wit! :; acute hypoxia showed strong nuclear .ΓΝΟ-immuuoreactmty compared ίο minimal, diffuse cytoplasmic staining of the hippocampal neurons from brain tissues of normal patients (Zhang et ah, supra). Thus, JNK3 appears to be involved in hypoxic and ischemic damage of CA1 neurons in the hippocampus.

[0®9] Disruption of the JNK3 gene caused resistance of mice to the excitotoxic glutamate receptor agonist kamie acid, including the effects on seizure activity» AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the JNK3 signaling pathway is a critical component in the pathogenesis of glutamate neurotoxicity'· (Yang etal, Nature 1997, 389:865-870).

[0010] In addition, JNK.3 ce-iocalizes immunoehemically with neurons vulnerable in Alzheimer's disease (Mohit etai., supra). Based on these findings, INK signalling, especially that of JNK3, has been implicated in the areas of apoptosis-driven neuro degenerative diseases such as Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke. poll] Drug molecules that Inhibit MAlMs, such as pM are known (sees e>g,, WO 98/27898 and WO 95/31451). However, inhibitors that are selective tor JNKs versus other members of the MAPK family are rare (see, e.g., U.S. Patent Application Publication 2(1080033022), There is an unmet medical need for the development of potent, JNK specific iidilbitors that are useful in treating the various conditions associated with JNK activation.

SUMMARY OF THE DISCLOSURE

[0012 j in various aspects, the present disclosure provides for a compound having a structure according to Formula (1):

Cy

W

OassV^ /1^

GX v* (1) m a salt mtsolvate thereof, wherein ring A is S^emhered heteroaTy! comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyi, heteroalkyi, CrCur cycloalkyl, 3- to 8-mcmbcred heteroeycloaikyl, aryl, 5~ or 6-mcmbercd hctcroaryl, CM, halogen, OR12, SR12, NRnRu, C(0)R14, C(0)NR12R,s, OC(Q)NR,2R'3, C(0)QRfl NRJ5C(0)R14, NRl'C(0)0RX2, NRi5C(0)NRI2R13, NRI5C(S)NR12R13, NRlsS(0}>Ri4, S(0)2NR52R33, S(Q)R14 and S(0)zRM, whereinft*2, Ri3 ant! R15 are iridefehdently chosen from H, acyl, CrQ-alkyl, 2- to 6-mcmbcred hotepplkybaryi, 5- or 6-mem|cred helerearyl., teh-C? cycloalkyl and 3- to 8-membered heteroeycloaikyl, or R!2 and R1?>; logeiher with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and Ri4 is chosen from acyl, Q-C<,-alkyl, 2- to b-membered heteroalkyi, aryl, 5- or ό-merobered heteroaryl, CrQ eye balky I and 3- to 8-membered heteroeycloaikyl. C1 and Cb ate carbon atoms, which ate adjacent to each Other and are pan of ring A; Z is; 5- or 6*membered heteroaryl., with the proviso that (i) when ring A is thiophene, then Z is not a heferaaryi chosen from benzoimid,azole. thiazole, and benz.otiuanole:; (il) when ring A is thiazole, then Z is not henzoimkhzoie.. (Hi) when ring A is thiophene, themZ is not substituted osudiazole; and (iy) when ring A is thiophene, then Z issnotpyrimidinone; R5 is chosen from H, acyl, Ci-Ce alkyl and Cs-Cg cycloalkyl; W is chdSCh from Ci-Ci alkyleme, whefbin the alkylene is optionally shhstittlpd with 1 -d substituents independently chosen from alkyl alkenyl alkynyl. haioalkyl, heteroalkyi, CV€,y cycles. 1 kyi, 3~ to 8-metitbered heterocyelo&amp;lkyl, aryl, 5s or 6-mernbered heteroaryi. Cm halogen, OR42, SR42, NR42R4\ QOR44, C(0)NR42RJ\ 0C(0)NR42R4?, C(O)OR42, MR':f'Ct0)R44, NR4SC|D)OR42, NR4iC(0)NR42RJ!3?NR45C(S)NR42Ri3, NR^QfcR44, S(0)2'NR4‘''R43, S(G)R44, and S(0)2R44, wherein R*4, R'3 and R4i are members independently chosen itom ϋ, acyl. th-Cg-alkyl, 2- to 6-roembered heteroalkyJ, aryl, 5~ or 6-membered hetcronry 1, Ci-C* eyclcaikyl and 3- to 8-membered heierocycloalkyl. wherein 11- and &amp;4'\ together with the nitrogen atom to which they are bound are optionally joined to form a 5~ to 7-mcmbcred heterocyclic ring: and K‘M is independently chosen rtont acyl, Γj-Ci-alkyl, 2- to 6-membered hctcroahcyJ. aryl, 5· or 6-membered heteroaryb Q-Ch cyeioalkyl and 3- to 8-mcmbered bctCTOcydoalkyl; Cy is chosen from cydoalkyh befcrocyefoalkyl; m$i and !;.cteroa;yL whereto the cydoaikyl, he! erne ydo alky;, aryl or hetcroary! is optionally substituted with 1 - 6 subsdtuc-ms independently chosen from substituted or unsubsinutod alkyl, substituted or nnsubsunted alkenyl, substituted or unsubstituted alkynyl, hafoalkyl, substituted or uUMbstituted hetero&amp;lkyl, Substimted or unsubstituted oyclbalkyh substituted or unsubstituted b.derocycloalkyl, substituted or unsubstituted aryl, substituted or «^substituted hetemaryl.CN, halogen. OR52. SR22, NRi2Rs% G(0)R54, CIWS^R3, 0C{0)NRwR5\ G(0}GRs% WR35C;(0)R: \ NR^CtO)OR52, NR5%(0)NR52RS5s NRi5C(S)NRS2R5\ NR'^StGhR3'1, S(0>;· b R'i2R:;::, SiO)R’4 and S{Q)2R5T wherein R52, R53 and RSi are independently chosen from H, acyl Ci-Ce-afl^l, 2- to tomcnihered hetomtohyl. aryl, 5* or 6-thern.bered hetemaiyl* CyC* cyctoaikyl an| 3- to hrmcminmd heterocycloalliyh wherein Rs* and R5 together with the sltrogerr atom to which they are bound are optionally joined to term a 5- to Tmlrinbcred hetemepsie ring; and R54 is independently chosen from aevL Ci-C^-alkyl, 2- to heteroalkyl, aryl, 5- or 6-membered heteroaryl, GjC1® sycloaikyi and 3- to 8«f®emhered beterocycloalkyi. The present disclosure forther provides for &amp; pharmaceutical composition comprising a compound according to Formula (Ϊ) and a pharmaceutically acceptable carrier.

[0013J The present disclosure also provides for compound having a structure according to Formula (VIII);

(VIII) or a tautomer, mixture oftautomcrs, salt or solvme thereof wherein ring A is 6- or 6~ membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-3 substituents independently chosen from alkyl, alkenyl, aikynyl, haloalkyl, heteroalkyl, C-j-Cio-cycloalkyl, 3- to 8-raerofeered hsterocycloalkyl, aryl, 5- or 6-membered MderoaryL CN, halogen, OR12, SR12, NRVl G(0)R54, CM))NR%i?, 0C(0)NRI?R13, C{0)0Rli, Nt3Sqp)Ri45 NR,5C(0)OR}2, NR”C<0)NR"R13, NRI5C(S)NR}2R13, NR:5S(OhR1S(0)a»^R335 S#)R14 and SfO):;R/\ wherein R12, R{3 and R15 are independently chosen fitith H, acyl, Ci-Cs-alky!, 2- tp b-memherod heteroalkyh aryl, 5-or 6-mcmbered heteroaryi, C?-Q cydoalkyi and 3- to 8-membered heteroeycloalkyf or RK< and R‘\ together with the nitrogen atom to which they are bound form a 5~ to 2-membered heterocyclic ring; an! R!4 is chosen Mttn apyi, Cj-Q-alfcyf, 2- to ό-membered heteroalkvl, aryl, 5- or 6-membered heteroaryl, Cj-C's oycloalkyl and 3» to S-membered heteroeydoaikyl; Ca and Cb are carbon atoms, which are adjacent to each other and, which are part of ring A; R4 is chosen from. H, independently chosen from H, CrCri alkyl, Ci-C4 alkenyl, Cs-C4 aikynyl, C1-C4 haloalkyl, CVO, cycloalkyl, 3- to 6-membered heteroeydoaikyl, aryl, and 5- or 6-membered heteroaiyl, CN, halogen, ORl7, SRl7 and NRi7R18, wherein R1' and R18 are independently chosen from H, acyl Q-Co-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaiyl, CrCg cycloalkyl and 3- to 8-menrbered heteroeydoaikyl, or Ri7 and Rin, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; R‘ is chosen, from H, acyl, CV Cft alkyl, and CVC* cycloalkyl; W is chosen from C1-C4 alkylene, wherein the alkyl ene is optionally substituted with from 1 to 4 substituents chosen from alkyl, alkenyl, aikynyl, haloalkyl, heteroalkyl, Cs-Cs-cycloalkyl, 3- to 8-mem.hered heteroeydoaikyl, aryl, 5- or 6-membered heteroaryi, CN, halogen, OR42, SR42, NR42R43, C(0)R4iS, C(0)NR42R43, OC(0)NR4V3, C(0)0R42, NR43C(0)R44, NR4SC(0)QR42, NR43C(0)NR42R43, NR45C(SJNR42R43, NR45S(G)2R44, S(0)2NR42R43, S(0)R44, and S(0)2R44, wherein R42, R42 and R45 are independently chosen from II, acyl, Cj-CValkyl, 2- to 6-membered heteroalkyl, aryl, 5-- or 6-membered heteroaryi, C3-C* cycloalkyl and 3- to 8-membered heteroeycloalkyi, wherein R4' and R43, together with the nitrogen, atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R44 is independently chosen from acyl, Ct-Q-alkyl, .2- to 6-membered heteroalky], aryl, 5- or 6-membered heteroaryi, Ga-Cg cycloalkyl and 3- to 8-membered heterocycioalkyl; Cy is chosen from cycloalkyl, heterocycioalkyl, and, and heteroaryi, wherein the cycloalkyl, heterocycioalkyl, aryl, or heteroaryi is optionally substituted with 1-6 substituents independently chosen from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloalkyi, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycioalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryi, CN, halogen, OR52, SR52, NR52R5\ C(0)R54, C(0)NR52R53, OC(OJNR52RS3, C(0)0R52, NR55C(0)R54, NRssC(0)0R52, NR33C(0)NRS2R53s NR55C(S)NR52R53, NR15S{0)2R54, S(0)2NR52R53, S(0)RS4 and 8(0)^34. wherein R52, R33 and R55 are independently chosen from H, acyl, CrQj-alkyl, 2- to 6-membered heteroalkyl, aryl, or 6-membered heteroaryi, Cj-Cg cycloalkyl and 3- to 8-membered heterocycioalkyl, wherein R52 and R'w, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R54 is independently chosen from acyl, Cj-Q-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryi, Q-C* cycloalkyl and 3- to 8-membered heterocycioalkyl. The present disclosure further provides for a pharmaceutical composition comprising a. compound according to Formula (¥10) and a pharmaceutically acceptable carrier, [0014| The present disclosure further provides for a compound having a structure according to Formula (X) or Formula (XI):

m or

(XI) or a salt or solvate thereof, wherein X* is chosen ίτοτη N and CR2*; R* and R2* are independently chosen from H, Ci-CValkyi, Cj-C^aikenyl, Cj-Ci-alkynyi, C1-C4- haloalkyl, 2- to 4-membered heteroaikyl, C.yCs-cycloalkyl, 3- to 6-membered heterocycloalkyl, CN, and halogen; Ri0 and R'!i are independently chosen from H, Ct-Gr alkyl, Ci-Ce-alkenyi, CvCs-alkynyl, Cj-Q-haloalkyl, 2- to 6-membered heteroaikyl, C3- i-Vcycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5- or 6~menibered heieroaryi, CN, halogen, OR42, SR42, NR42R4\ C(0)R44, C(0)NR42R43, 0C(0)NR42R43, C(0)0R4i, NR45C(0)R44, NR45C(())0R42, NR45C(0)NR42R43, NR45C(S)NR%4\ NR‘1iS(0'bR44, S(0)2NR42R'L\ S(0)R4·* and S{0)2R44, wherein R42, R4' and R4'1 are independently chosen from H, acyl, Ci-Q-alkyl, 2- to 6~membered heteroaikyl, aryl, 5- or 6-mernbered heieroaryi, Q?-Cs cyeloalkyl and 3~ to 8-membered heterocycloalkyl, or R42 and R43, together with the nitrogen atom to w'hich they are bound form a 5- to 7-membered heterocyclic ring; and R44 is chosen from acyl, CrQ-aikyl, 2- to 6-membered heteroaikyl, aryl, 5- or d-membered heteroaryl, Cj-Cb cyeloalkyl and 3- to 8-membered heterocycloalkyl; Rs is chosen from H and substituted or unsubstituted Ci-Ce alkyl; Cy is chosen from cyeloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cyeloalkyl, heteroeydoalkyi, and or heteroaryl is optionally substituted with from 1 to 6 substituents independently chosen from Ci-Ce-alkyl, Cj-Cs-alkenyl, Ci-Ce-alkynyl, Cj-Ce-haloalkyl, 2-- to d-roembcred heterealkyi, Ca-Ci rcycloalkyi, 3- to 8~niembered heterocyeloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen., OR52, SR52, NR^R33, C(0)R^, C(f))Ml52R5\ 0C(0)NRsRs-\ C(0)0Ri:\ NR55C(0)R54, NR55C(0)0R52, NR5SCp)NR%5\ *55C(S)NR%53, NR^Sp^R54, S(O^R53R53, SCOjR54 and 3(0);;.ΚΛ4, wherein R32, R" and R:'1' are independently chosen from Ej, acyl, Cj-CV.-alkyh 2- to 6~meinhered heieroaikyh aryl 5- or d-rnemhered heteroaryl CVC* eye balky! and 3- to 8--roerohered beterocyeloaikyl, wherein and R"'\ together with the mtroghii atom to which they are bound are optionally joined to form a 5- to 7-racmbcred heterocyclic ring; and RM is independently chosen from acyl, Cj-Ca-alkyf, 2- to 6-rac.mbored heieroaikyi, toyi, 5- or 6-membered heterdaryh €3-¾ cyeioaikyf and 3- to S-rne inhered heicroeycloaikyl; and Z is chosen from:

and

wherein Y' Is chosen from O, S and NR3, wherein R3 is chosen from H, alkyl, alkenyl, alkynyi, haioaikyl, cycioalkyl, 3~ to 8-membered heieroeycloalkyJ, aryl, and 5- or 6-membered heteroaryl; and R\ R4* and R16 are independently chosen from H, alkyl, alkenyl, alkynyi, haioaikyl, cycioalkyl, 3- to 8-menibered heterocycloalkyL. aryl, 5- or 6-membered hctcroaryl, CM, halogen, OR17, SR1, and NR.1'R18, wherein R.i? and R18 are independently chosen from H, acyl. CrQ-alkyl, 2- to 6-membered heteroalkyl, aryl, 5-or 6-membered heteroaryl, C3-Cs cycioalkyl a£id 3~ to 8~rn umbered heterocycloalkyl, or R17 and R18, together with the nitrogen atom to which they are bound form a 5* to ?-membered heterocyclic ring, or two of R4, R4* and R3, together with the atoms to which, they are attached, form a 5- to 7~membered ring, or adjacent R3* groups, together with the carbon atoms to which they arc attached, form a 5- to 7-membered ring; n is an integer chosen from 0 to 4; and m is an integer chosen from 0 to 3. The present disclosure further provides for a pharmaceutical composition comprising a compound according to Formula (X) or {XTjand a pharmaceutically acceptable carrier.

[ΘΦ15] The present disclosure also provides for a method of treating a neurDdegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound having a structure according to Formula (I):

m or a salt or solvate thereof, wherein ring Λ is 3~membered heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkvnyl, haloalkyl, hcteroaikyl, Cs-Cjo-cycloalkyl, 3- to 8-membered heteroeycloalkyl, aryl, 5- or 6-mcmbered heteroaryl, CN, halogen, OR12, SR12, NR12R13, C(G)R14, C(0)MR12R5% 0C(0)NRi2RB, C(0)GR!2, NRiSC(0)R34, NR33C(0)0R12, NRlsC(G)NR12Rf33 NRl5C(S}NRi2R3\ NR!5S(0)?Rw, S(0)2NRJ2Rl,j S(0)R14 and S(0)2RM, wherein R12, Ru and R1'’ are independently chosen from H, acyl, Ci-C-Valkyl, 2- to 6-mcmbcrcd hcteroaikyl, aryl, 5- or 6-mcmhered heteroaryl, Ca-Cs cycloalky! and 3- to 8-membered heteroeycloalkyl or R12 and RiJ, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and R14 is chosen from acyl, Ci-CValkyl, 2- to 6-membered hcteroaikyl, aryl, 5“ or 6-mem.bered heteroaryl, Ch-C* cycloaikyi and 3- to 8-membered heteroeycloalkyl; Ca and €b are carbon atoms, which are adjacent to each, other and are part of ring A; Z is 5- or 6-membered heteroaryl; R3 is chosen from H, acyl, C;-C$ alkyl, and C-3-Cg cycloaikyi; W is chosen from. C1-G4 alkyl cue, wherein the alkyiene is optionally substituted with I - 4 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, Cj-Gs-cycloalkyl, 3- to 8-membered heteroeycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR42, SR42, NR42R43, €{0)R44, C(0)NR42R4-\ 0C(0)NR42R43, C(0)0R42, NR4SC(0)R44, NR4SC(0)0R42, NR43C(0)Mt42R43, NR43C(S)NR42R4\ NR45S(0)7R44, S(Q)7NR42R433 S(0)R44, and S(0)iR44, wherein R*2, R4i and R45 are members independently chosen from H, acyl, Cr Cs-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cj-Cg cycloaikyi and 3- to 8-membered heteroeycloalkyl, wherein R42 and R43, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R44 is independently chosen, from aeyf Cj-Ce-alkyl, 2.- to 6- hetsrbalkyf aryl, 5- or 6-membercd h^ebbhryi, (¾¾ cycioalkyl and 3· to 8~ membered kueroeydoulkyi; Cy is chosen from cycioalkyl, heterocydoalkyl, aryl, and heieroatyl, wherein the cycioalkyl, heterocycloalkyi, aryl or heteroaryl is optionally substituted with 1 - 6 substituents independently chosen from substituted or urtsubsiituted alkyl, substituted or unsuhstituted alkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted or unsubstituied heteroalkyl, substituted or unsubstituted cycioalkyl, substituted or unsubstituied heterocycloalkyi, substituted or unsubstituted axyl, substituted or unsubstituted hetemaryl, CN, halogen, OR52, SR5'', NR52R5'\ CCOjR54, C(0)NR5V\ OC(Q)NRsR53, C(OpR52, NR55C(0)R54, NR5'C(0}0R52s NR55C(0)NR52RS3, NR55C(S)NR52R5\ NR^SCO’hR54, S(O>2NRS2R53, S(0)RS4 and S(0)2R-\wherein RS2, R53 and R55 are independently chosen from H, acyl, Ci-Cs-alkyl, 2- to 6-roembered heteroalkyl, aryl, 5- or 6-membernd heteroaryl, C.?-Cs cycioalkyl and 3- to 8-memfeered heterocycloalkyi, wherein Ri2 and R33, together with tire nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R54 is independently chosen from acyl, Ci-CValkyi, 2- to ό-mcmbered heteroalkyl, aryl, 5- or 6-membered heteroaryl, CVCg cycioalkyl and 3- to 8-membered heterocycloalkyi.

[0(116] The present disclosure also provides for a method of reducing p-ejun concentration in brain tissue of a subject in need thereof, the method comprising administering to the subject a compound having a structure according to Formula (I):

m or a sail or solvate thereof, wherein ring A is 3-membered heteroaryl comprising a sulfuf atom, wherein the heleroaryl. is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C;~C<o-cydoaH^l, 3- to Ssmemhered beteroeyetealkyl, aryl, 5-m (immeim&amp;d hetetoaryl, CM, halogen, OR*? SR52, NR32RU, CpfR14, C(0)NRt2R13, 0C(0)NRV, CdOR12, MR1SC(0)R14, NR:iS€(0)0Ri2, NR,sC(0)NRnRi3, NRiSC(S)NR,2Ru, NRjsS(0)2RP, S(0)2NR.i:?RB, S(0)R14 and 8{0)2&amp;14, wherein Ru, R° and R35 are independently chosen from H, acyl, Cj-Cs-alkyL, 2- to 6-membered beteroalkyl, aryl, 5- or 6-membcrcd heteroaryl, C3-C* cycloalkyi and 3- to S~rnembered heterocyeloalkyl, or R‘2 and R3^ together with the nitrogen atom to which they are bound form a 5- to 7-rnemfeered heterocyclic ring; and R14 is chosen from acyl. Ci-Ce-alkyl, 2- to 6~membered heteroalkyi, aryl, 5- or 6-membered heteroaryl, CrCs cycloalkyi. and 3- to 8-membered heterocycloalkyl; C® and Cb are carbon atoms, which are adjacent to each other and are part of ring A; Z is 5- or 6-mem.bered hetexoaryl; R5 is chosen from H, acyl, Cj-Ce alkyl, and C3-C6 cycloalkyi; W is chosen from C1-C4 alkylene, wherein the alkvlene is optionally substituted with 1 - 4 substituents independently chosen from alky!, alkenyl, alkynyi, haloalkyl, heteroalkyi, G^fe^gloalkyh 3- to 8toR®lered heterocycloalkyl, aryl; 5* or ό-membered heteroaryl, CM, halogen, CM42, SRP, i®l42R4·4, C(0)R44, C(0)NR4IR43, G€(0)NR%4i, CtO)OR42, MR4SGfCp44, MR45C(0)0R4i, NR4iC(0)NR42R:#! MR^G Sifg|%43, NR4SS{0)*R44, SCOj^V, S(0)R*\ and S(D):iR44, wherem R42, R43 and R45 are roc rubers independently chosen from =1, acyl, Cr Cs-alkyi, 2- to 6-membered heteroalkyi, aryl, 3- or 6-rnernbered heteroaryl, C:rC&amp; cycloalkyi and 3- to 8-membered heterocycloalkyl; wherein Ru and R''\ together with the nitrogen atom to which they arc bound are optionally joined to form a 5- to 7-membored heterocyclic ring; and R4* is independently chosen from acyl, Ci-CValkvl, 2- to 6-membered heteroalkyi, aryl, 5- or 6unemhered heteroaryl, Cj-C* cycloalkyi and 3- to 8-membered betcrocyctoaIkyI; Cy is chosen from cycloalkyi, hererocydoalkyi, aryl, and heterohip, wheriilfr #© cycloalkyi, heterocycloalkyl, aryl or hclftroaryl is optionally substituted with 1 - 6 sefestiteents independently chosen front substituted or unsubstituted alkyl, substituted or iffisuhsrituted alkenyl, substituted or unsubstiiuted alkynyi, Mloaikyl, substituted or unsubstituted heteroalkyi, substituted or unsubsituted cycloalkyi, substituted or unsubstiiuted heisroeycloalkyl:, subsritutedor unsubstiiuted aryl, substituted or ^substituted heteroaryl. CM. halogen, uR52, SR43, NR^R*3, C(0}R44.. C(0)NR52R” OC(0)NRS2R5'\ C(0)0R52, NR5SC(0)R34, NRssC(0)QR52, NR55C(Q)NR52RS', NR5SC{S)NR52R5% NRS5SCO)2R54, S{G)2MR52R5i, S(0)R54 and SCO^R54, "wherein R52, RS3 and RsS are independently chosen from H, acyl, Ci -Ce-eJkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cj-Gs eycloalkyl and 3- to 8-membered heterocydoalkyl, wherein R53 and R'"\ together with the nitrogen atom to which they are bound are optionally joined to form a 5~ to 7-membered heterocyclic ring; and R'4 is independently chosen from acyl, €rC-alkyl, 2~ to 6-membered heteroalkyL aryl, 5- or 6-membered heteroaryl, Ci-Ca cycloalkyl and 3- to 8-membered heterocyc loalkyl.

[0O17J in addition, the present disclosure provides for use of a compound in an in vitro assay measuring kinase activity, said compound having a structure according to Formula (I):

0) or a salt or solvaie thereof, wherein r ing A is 5-membered heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1. or 2 substituents independently chosen from alkyl, alkenyl, alkynyi. haloalkyl, heteroalkyl, CVCiq-cycloalkyl, 3- to 8-membered heterocyc loalkyl, aryl, 5- or 6-membered heteroaryl, CN. halogen, OR12, SR12, NRl2RL\ C(0)R14, C(0)NR52RB, 0C{0)NR12RB C(G)OR!\ NRlsC(0)Ri4, NRiSC(O)0R12, NR,sC(0)NR,2RB NRi5C(S)NRI2Rs3, NRlsS(0)2R:4, S(0)2NR12R13, S(0)R*4 and S(0)2RM, wherein Ri2, RB and R15 are independently chosen from H, acyl, Cj-Ce-alkyl, 2- to 6-membercd heteroalkyl, aryl, 5- or ό-menihered heteroaryl, Ch-Cs cycloalkyl and 3- to 8-membered beterocydoalkyl, or R12 and Ru, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and R1'4 is chosen from acyl, Cj-Cs-alkyl, 2- to 6-membercd heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-C« eycloalkyl and 3- to 8-membered heterocycloaikyk C* and Cb are carbon atoms, which are adjacent to each other and are part of ring A; Z is 5- or 6-membered hcteroafyl, Rs is chosen from FL acyl. Ci-Ce alkyl, and C.rCfi cycioalkyi; W is chosen from Ch-Cb alkylene, wherein the alkylene is optionally substituted with 1 - 4 substituents independently chosen from alkyl, alkenyl, aikynyl, haloalkyl, hsicroalkyl, Ci-C^-c/cloalkyl. 3- to 8-mernbereci hetcrocyehi.uksL aryl, 5- or 6~membcred heteroaryl, CM, halogen.. OR4', SR43, NR4;'R4·'. €(0}R4i, C(Q)NR'aR':\ QCYO)KR'!'R4J, C(0)0R4a, NR45C(0}ir4, NR45CCO>OR4l ΝΚ'!5·αθ)Ν1Γ3Η4’. NK^CiSlNR^R43, NR41S{C>).:;R'!4, SCOkNR^R4', S(0)R44« aid S(G}>R“\ wherein IV2,. R4i and R“? are members independently chosen from R, acyl, Ci-Cralkyl, 2- to 6-membered heteroalkyl, aryl, 5·· or 6-mem.hsred heieroatyl, €?-€« cycloalkyl aid: 3* to 8-membered heiet^dycloalkyi, wherein R42 and R44, together with the nitrogen atpp to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ting; and R+i is independently chosen: iforrr aeyl; C't-€3pal.kyi, 2- to 6-r.oernbered hetefdtdkyl. aryl 5- or b-raeS|jdfedshgtCifj^i, Cs-C» SpSloalkyl add 5- to 8-membered heterocydoaikyl; Cy is chosen from cycioalkyi, heterocydoaikyl, aryl, and heteroaryl, wherein the cycioalkyi, heteroeycioalkyl, aryl or heieroaryl is optionally substituted with 1 ~ 6 substituents independently chosen from substituted or «nsubsiittfted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyi, haloalkyl,, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycioalkyi, substituted or unsubstitufed heteroeycioalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryi, CN, halogen, 0RSi, SRs~, NRS2R5i, C(Q)R34, C(0)NR52R53, 0C(0)NR52R53, C{0)0R52, NR55C(0)R.54, NR55C(0)0R52, NR55C(0)NR52RS3, NR55C(S)NR52R53, NR5SS(0)2R54, S(0)2NR52R53, S(0)R54 and StPkR , wherein R , R·'* and R" are independently chosen from H, acyl, Ci-Q-alkyl, 2~ so h-membered heteroalkyl, aryl. 5- or b-reernheroo hetero&amp;ryl, CVO, cycioalkyi and 3· to 8~np»bere| heteroeycioalkyl, wherein K52 and R53, together will the nitrogen atom to which the)· are bound aresopti©nslly joked to form a 5- to 7-membered:hderocydi® ring; and Roi is independently chosen from acyl, Cj-Ce-aikyl} 2- to 6-rnernbered heteroalkyl, aryl, 5- or 6-membercd heteroaryl, Cj-Cs cycioalkyi and 3- to 8-membered heterocydoaikyl, 10018] The present disclosure else provides for a use of a compound in an in viva assay irseaMidnir kina.se activity, said compound having a structure according to Formula (I);

(I) or a salt or so]vats thereof wherein ring A is S~mcmbc?cd heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted, with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl haloalkyl, heteroalkyl, Ci-Cur cyeloalkyl, 3» to 8-membered heterocydoalkyl, aryl, 5- or 6-mem.bered heteroaryl, CN, halogen, OR12, SRLl MRi2R13, C(0)Ri4, C(0)NR12R13, OC(0)NR12RL?, C(0)0R12, NRwC(0)R.M, NR1SC{0)0R12, NR15C(0)NR12Ri3, NR15C(S)NRi2Ri3, NR!5S(0)2R34, 8(0)ίΝΚ1ζΚ13, S(0)R14 and S(0)2R14, wherein R12. R13 and RJ3 are independently chosen from H, acyl, Ci-Cd-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C3 cycloalkyl and 3- to 8-membered heterocydoalkyl, or R12 and R"\ together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and Rf4 is chosen from acyl, Ci-CValkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-mem.bered heteroaryl, Cs-Cg cycioalkyl and 3- to 8-membe.red beterocyeioalkyi;Ca and C!> are carbon atoms, which ate adjacent to each other and are part of ring A; Z is 5- or 6-membered heteroaryliR3 is chosen from I I, acvl, Ci-Cg alkyl, atid Cj-Cs cycloalkyl; W is chosen from C3-C4 alkylene, wherein the alkylene is optionally substituted with 1-4 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, Cj-Cs-cyeloalkyl, 3- to 8-membered heterocydoalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR42, SR4! NR^R4! CfOlR"3, C<0)NR42R43, 0C(0)NR42R·3, €(0)0R42, NR45C(0)R44, NR4iC(0)OR42, NR45C(0)NR42R42, NR45C(S)NR42R43, NR45S(0>Ri4s S(0)iNR42R43, S(O)R44, and S(0)?R44, wherein R42, R43 and R45 are members independently chosen from 11, acyl, Ci- G;-aifcyl 2- to ό-membercd hcieroaikyl, aryl, 5- or fomemhercd heteroaiyl QrC* cycloaikyl and 3- to S-mcmbcred heterocyeloalkyl, wherein R42 and R4:!, together with the nitrogen atom to winch they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; an R44 is independently chosen from acyl, Ci-Cg-aikyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-Cg cycloaikyl and 3- to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein tire cycloaikyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 - 6 substituents independently chosen from substituted or unsubstiluled alkyl, substituted or unsubstituted alkenyl substituted or unsubstituted alkynyl, haksaikyl, substituted or unsubstituted heteroalkyl. substituted or unsubstitutod cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituled heteroaiyl CN. halogen, OR52, SR>2, NRS2R5', C(Q)RM, C(0)NRsR53,0C(0)NR52R53, C(OPRa, NR5SC(0)R54, NR“C(0)0R52, NRSSC( 0)NRs?R53, NR55€(S)NR52R^, NRmS(0)2RS4, SCO^NR5 V\ S(0)R54 and S^OjiR54» wherein R52, R53 and R55 are independently chosen from M, acyl, Ci-Ce-aU^d, 2~ to 6-memb-ered heterdalkyl aryl, 5- or ό-membercd heteroaryl CVCh cycloaikyl add 3- to 8-membered hererocycloaIkyl, wherein R^and R53, together with the nitrogen atom to which they: aresboimd are optionally joined to form a 5-to 7-membered heterocyclic ring; and R5" is indcpcodenliy chosen frbfo acyl, CHValkyl, 2- to 6-meaihefo| heteroalkyi, aryl, 5- or 6-membered heteroaiyl, CVCs cycloaikyl and 3- to 8-memhered heterocycloalkyl 0QH9j The present disclosure further provides for an in vitro method fol measuring pbosphorylated kinase substrate comprising: (t) creating a mixture comprising a kinase and a compound having a structure according to Formula (I):

or a sate:©rsolvate thereof, wherein ring Am S-mem^s^i teei-oaryi comprising a sulfur atom, wherein the heteroaryi is optionally substituted with. 1 or 2 substituents independently chosen front alkvi, alkenyl, alkynyl, haloalkyl, heteroalkyl, Ch-Cjo-cycioalkyl, 3- to 8-membered heterocycloalkyl, aiyl, 5- or ό-membered heteroaryl, CN, halogen, OR12, SR12, NR%13, C(0)R34, C(G)NR12R!3S 0C(0)NRl2R°s C(0)0Rli, NRl5C(0)R14 NR35C(0)GR!2, NR15C(0)NR,2Ri!!, NR,5C(S)NR,2R‘\ NR^SCO^R14, SfO'bNR^R13, S(0)R14 and S(0)2Ri4, wherein R12 R13 an.dR15 are independently chosen from H, aevi, Ci-Cg-alkyl, 2- to 6-membered heteroalkyl, ary], 5- or 6-membered heteroaryl, C3 -Cs cycioalkyl and 3- to 8-membered heterocycloalkyl, or R12 and R3| together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and R14 is chosen from acyl, Q-Ce-alicyi, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryi, Cs-Cg cycioalkyl and 3- to 8-membered heterocycloalkyl; Ca and Cb are carbon atoms, which are adjacent to each other and are part of ring A; Z is 5- or 6-m ern bered h eteroary 1; and (ii) when ring A is thiasde, then Z h no; berszoimidazole; R5 is chosen from H, acyl; CrCg alkyl, and C-rCf; cycioalkyl; W is chosen froth C1-C4 ai.kybne, wherein the alkylehe is optionally substituted with 1 - 4 substituents independently chosen from alkyl, alkenyl, alkynyl haloalkyl. heteroalkyl Cj-Cg-syeloalkyl:, 3- to 8-merobered heterocyclcaikyi, atyh 5- or 6-ntembered heteroaryi, CN, halogen, OR42, SR.42, NR42R4\ CfOjR44, C(0)NR42R4\0C<0)NR42R43, C{0)0R42, N^4SC(fM ", NR::'QO)OR42, NR4iC<0)NR42R4\ NR4i'C(S)NR4V:\ NR45S(OhR44, S(0)2NlC"R“y S(0)R44, aad wherein R43, R4j and R** are members independently chobdfr from acyl, Ci-C^-alkyl, 2- to 6-membered heteroalkyl aryl, 5-or 6-membered heteroaryl, Cj-Cg cycioalkyl and 3- to 8-membered heterocycloalkyl, wherein R4" and R4l together with tire nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R44 is independently chosen from acyl, Ci-Ce-alkyL 2- to 6-membered heteroaikyi, arvl, 5- or 6-membered heteroaryi, C^-Cg cycioalkyl and 3- to 8-membered heterocycloalkyl; €y is chosen from cycioalkyl, heterocycloalkyl, aryl, and heteroaryi, wherein the cycioalkyl, heterocycloalkyl, aryl or heteroaryi is optionally substituted with 1 - 6 substituents independently chosen, from substituted or unsubstituted alkyl, substituted or unsubstiiuted alkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted or rinsubstituted heteroalkyi, substituted or unsubstituted cycloalkyl, substituted or un substituted heterocycloalkyl, substituted or unsubsiituted and, substituted or unsubstituted heteroaiyl, CN, halogen, OR52, SR52, NRS2R5?, CfOjR54, C(0)NR%s\ 0C(0)NR52RS3, Cf0)OR32, >JR55C(0)R^, bm:35C(O)0RS2s MR55(^i^«%s, mssC(S)NR%53, m^SCOJjR54, S(0)2NR52RS3, S(0)R- and KO)#M; w%il R®> Rss and Rss are independently chosen from B. acyl, C--0,-alkyl, 2- to b-mcmbered heteroalkyi, aryl. 5--or dAncmbered heteroaryi,, C3-C3 cycloalkyl and 3- to 8-mernbered heteiocyeloalkyl, wherein BP2 and R5<, together with the nitrogen atom to which they arc bound arc optionally joined to form a 5- to 7-rnembered heteroeyeiicidng; andR54 is ffid^endcntly chosen from acyl, Cj-Q-alkyl, 2- to 6-membered hcteroaiky!, aryl, 5- or 6~mernbcred heteroaryi, C?.~C* cycloalkyl and 3- to 8-membered heieroeycioalkyl; (ii) adding a kinase substrate andsMfRor a derivative thereof to the mixture; and; (1M) measuring an amount of phosphoiylated kinase substrate, in one example, the method further comprises measuring phosphoiylated kinase substrate, such as phospho-cJun, [ti020] The present invention also provides for an in vitro method comprising contacting a cell with a compound having a structure according to Formula (I):

01 or a stilt ox solvate thereofpwhstem ring A is 5-membereti heteroaryi comprising a sulfur atom, wherein the heteroaryi is optionally substituted with 1 or 2 substituents mdepeadealy chosen Horn alkyl alkenyl, alkynyl, haloalkyl, heteroalkyl. QrCtr cycloalkyl, B- to 8-m.embered he·erocycloalky 1, ary 1, 5~ or ti-memhered heteroaryi, CN, halogen, OR12, SR12, NR^Ri3, C(0}R^, CiO}KR%;?. OGOINR^R12, f(Op“, NRi:SG|0||.!4, NR’-C(0}0R;2, NRlst(0)NR12Ri3, NRi5C(S)NRJ2R13, NRI5S{0)2R.Hs ΗίΌ)ίΝΕ!'Κ.:\ S(0)Ri4 and SfOl>RSi, wherein R:i2, Ru and R55 are independently chosen from H, acyl, Ci-Cg-alkyl, 2- to 6-rnembered heteroalkyi, aryl, 5- or h-i-icmbcrc-d heleroaryi, €·>~€κ cycioaikyl and 3- to 8-membered Ireterocyefoalkyl, or R^uod R;\ together with the nitrogen atom to which they are bound form a 5~ to 7~membered heterocydie ring; and R:< is chosen fremsaeyk Ci-Cg-sllspi; 2- to 6*s&amp;embered heteroalkyl, aryl, 5~ or 6-mcmbered heteroaiyl, CyCs cycioaikyl and 3- to 8-raembered heteroeycloalkyl; C* and Cb are carbon atoms, which are adjacent to each, other and are part of ring A; Z is 5- or 6-membered heteroaryl; R5 is chosen from H, acyl, Ci-Q alkyl, and Cj-Ce cycioaikyl; W is chosen from Cj-Cj alkylene, wherein the alkylene is optionally substituted with .1 ~ 4 substituents independently chosen from alkyl, alkenyl, alkynyi, haioaikyl, heteroalkyl, Ci-C&amp;-cycioaikyl, 3- to 8-membered hetemeyeloalkyl, aryl, 5- or b-meinbered heteroaryl, CN, halogen, OR42, SR42, NR/'R'1’, C(O)R44, C(0)NR42R43, 0C{0)NR42R4% C(0)0R42, NR45C(G)R*\ NR45C(0)0R42, NR45C(0)NR42R43, NR4SC(S)NR42R43, NR45S(G}2R44, S(0)2NR42R43, S(0)R44, and S(0)jR44, wherein R42, R43 arid R45 are members independently chosen from H, acyl, CV-Cs-alkyl, 2- to 6-niembcred heteroalkyl, aryl, 5- or d-membered heterearyl, C3-C3 cycioaikyl and 3- to 8-membeccd heteroeydoalkyl, wherein R4': and R4\ together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-mernbered heterocyclic ring; and R44 is independently chosen from acyl, Cj-Craikyl, 2- to 6-raembered heterealkyl, aryl, 5- or bsmembered heteroaryi, Cj-Cg eyeksalky! and 3~ to 8-membered heteroeycloalkyl; Cy is chosen from cyclonlkyi, heteroeycloalkyl, atyk and heteroaryl, wherein ire cycioaikyl, heteroeycloalkyl, aryl or heieroary! is optionally substituted wife 1 - 6 substituents independentiy chosen from substituted or nnsnbstitnted alkyl, substituted or unsubStitbted alkenyl, .vebsutuied or unsubsd toted alkynyi, haioaikyl, substituted or unsubstinueo heteroalkyl, substituted or imsufcstiluted cycioaikyl, substituted or unsubstitoted heteroeycloalkyl, substituted or unsubstitntsd:sryl, substituted or unsubstituted heteroaryl. CN. halogen, OR32, SR3'1, Nlk''R5:', C(0)Rv';, c(0)nr52rS3, ociOjNRT; c(0)0r“ nrsscyo>r54, m55ao)OR53, m%P)MR%53, NRiSC(SjNR?2R'\ NRf JS(0)2R:'4, S(G>2NRi2R” S(0)R54 and S(0)2R''4, wherein R52, R*3 and R3*1 are independeiiy chosen from H, acyl, Ci-CWalkyi, 2- to 6-membered heteroalkyl, aryl, 5~ or 6-rnembered heteroaryi; cycioaikyl and 3- to h-membered heteroeycloalkyl, wherein R52 and together with the nitrogen atom to which they are bound are optionally joined to form a 5~ to 7-membered heterocyclic ring; aadlfc5® is itdepemdently chosen from acyl, Ct-Q-alkylg dN ίο fkmembered heteroalkyl, aryl, 5- or 6-metnbered heteroaryi, CrCK cvcloalkyl and 3- to 8-membered heterocyclealkyl. In one example, the method farther comprises measuring phosphorylated kinase substrate, such as pbospho-eJun.

DETAILED DESCRIPTION OF THE DISCLOSURE

Definitions 10021) The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims Throughout ifbe specification and tire appended claim®:, a given, formula or name shall encompass all isomers thereof, such as stereoisomers, geometrical isomers,optical isomers, tautomers, and mixtures thereof where such isomers exist, as ‘.veil is phannacentically acceptable salts and solvates thereof, such as hydrates.

[0022] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound” includes a mixture of two or more compounds. It should also he noted that the term “or" is generally employed in its sense including “and/or' unless the content clearly dictates otherwise. 18023] Where multiple substituents arc indicated as being attached to a structure, those substituents arc independently chosen. For example "ring A is optionally substituted with. 1,2 or 3 % poups’’ indicates that ring A is substituted with 1, 2 oc TRq gpups, wherem the R*, groups are independently chosen (i.e., can be the same or different).

[0024] Compounds were named using Autonom 2Θ00 4.01.305, which is available from Beilstein Information Systems, Inc, Englewood, Colorado; ChemDrsw v.10.0, (available from Catnbridgcsofi at 100 Cambridge Park Drive, Cambridge, MA 02.140), or ACD Name pro, which is available from Advanced Chemistry Development, Inc,, at 110 Yonge Street, 14th floor, Toronto, Ontario, Canada M5c 1T4. Alternatively, the names were generated based os thee 1UPA.C rules or were derived from names originally generated using the aioreme n dotted nomenclature programs. A person of skill id tide art will appreciate that chemical names for lauuwneric forms of the torrent compounds will vary slightly, but will nevertheless describe the saam compound, Far example, the names N-(2~{3-methyj~iH-l,2,4-triazoi-5-yl)t,biophert~3“yiV2~(naphthalen-1 -y])acotamide and N-(2~(3~methyl-4H-l,2,4-tri;rrol-3-'yi)iliiophen-3--y]}-2~(naphthalen- l-yi)acetaimde describe two tautomeric forms of the same compound.

[0025] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents, which would result from writing the structure from right to left. For example, “-€Η·?0-“ is intended to also recite “-OCH2-“.

[0026] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the number of carbon atoms designated (e.g,, C].~Cjo means due to ten carbon atoms). Typically, an alkyl group will have from 1 to 24 carbon atoms, for example having from 1 to 10 carbon atoms, from 1 to 8 carbon atoms or from I to 6 carbon atoms. A “lower alkyl” group id sin alkyl group having from 1 to 4 carbon atoms. The term “alkyl-includes di- arid multivalent radicals. For example, the term “alkyl” includes “aikylene” wherever appropriate, e.g., whemthe formula mdfoatesthai the alkyl group is divalent or when substituents are joined id form a ring. Examples of alkyl radicals include, but are not limited so. methyl, ethyl, «-propyl, Ao-propyl, ««butyl. terrtbutyi hw-bulyi. .vw;-bui>4, as well as homologs and isomers of. for example, «-pentyl. «-hexyl, «-hsplyl and «-octyl.

[0Θ27] Thederin “alkylere” by itself of as part of another substitu&amp;it means a divalent (drradleai) alky! group? w he~r in alkyl is defined herein. “Alkylenc” Is exemplified, but not limited, by -TTfiCHAJiATir· Typically, an “alkyfone” group will have from 1 to M carbon atoms, for example, having 10 or fewer carbon atoms (e.g,,: 1 to 8 or 1 to 6 carbon atoms). A “lower alky lone” group is an alkylene group ha ving from 1 to 4 carbon atoms.

[OHS] The term “alkenyl” by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having from 2 to 24 carbon atoms and at least oncidouble;bond, a typical alkenyl group has from 2 to 10 carbon atoms andat least one double bond. In one embodiment, alkenyl groups have from 2 to 8 canton atoms or from 2 to 6 carbon atoms and from 1 to 3 double bonds, Exemplary alkenyl groups include vinyl, 2-propenyi, l-but-3-enyi, erolyl, 2-(butad'ieayi), 2,4-pentadienyl, 3-(j yi-pentadienyl}, drisopcmcnyi, l-pcnt-3-enyl. i -hes-5-enyl and the like, HHWb>] The term ka1kynyi>! by itself or as part of another substuaeru refers to a straight or branched chain, unsaturaied or fxd.psnsaturated hydrocarbon radical having from 2 to 24 carbon atoms and at least one triple bond. A typical “aifeynyf group has from 2 to 10 carbon atoms ami at least one triple bond. In one aspect of the disdosure, alkynyl groups have from 1 to 6 carbon aforns and at least one triple bond. Exemplary aikynyl groups meltute pmp-Uynyl. pep2*piyl (i.e., propargvl), ethynyl and 3-butynyl. |M30] The terms "alkoxy." ’’alkylamino” and "alkyhhio” (or thioaikoxy) are used in their conventional sense, and refer to alkyl groups that are attached to the remainder of the molecule via on oxygen atom, an amino group, or a sulfur atom, respectively.

[0031 ] The term 'lieteroalkyl,” by itsellor in combination with another term, means a stable, straight or branched chain hydrocarbon radical consisting of the staled number of carbon atoms (e.g,, Ca-Cio, or C-j-Cg) and at least one heteroatom chosen , e.g., from N, O, S, Si, B and F (in one embodiment, N, O and S), wherein the nitrogen, sulfur and phosphoms atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. I’he heteroatom(s) is/are placed at any interior position of the heteroalkyl group. Examples of heteroalkyl groups include, but are not limited to, “CHb-CHh-O-OHu -CHi-CHr-Mf-CHa, ~ee2-CH;-N((T-ir)-Cm, -CHi-S-OI2-CH?, -€HrCH;.~SiOKTk, -CHrCHr-StOlrCH.,, -CH=6H-0-CH3> -CHi-SiiCHj),, -CH2-CH-N-OCH3, and CH-QT-N(CH3)-ClHi. Up to two heteroatoms can be consecutive, snob:as, for example,: -Qiii-ISIH-OCH;? and OIvdT-SifCH;)?. Similarly, the form '‘heicroalkylene*' by itself Or as part of another substituent means a dlvalcm radical derived from heteroalkyl, as exemplified, but not limned by, CMgsCHr S~€H;47H>·· and CH2-£--CHrCHrNH<;.H;>-, Typically, a bercroulkyl group will have from 3 to 24 atoms (carbon and heteroatoms, excluding hydrogen).(3- to 24-rnemhcred heteroalkyl), In another example, the heteroalkyl group has a tolabof 3 to 10 atoms (3- to 10-memhered heteroalkyl) or from 3; toJlstoms (3- to I-me^berei:feema]kyl|:, The term “heteroaisyi” includes ‘dhrteroalkylerip wherever appropriate, i,g., when the formula indicates that die heteroalkyl group is divalent or when substituents are joined to form a ring.

[0(02] The tern “cyeloslkyF by itself or in combination with other terras, ref resents a saturated os- unsaturated, non-aromatic earlxtcyclic radical having from 3 to 24 carbon atoms, for example, having front 3 to 12 cariboo atoms {e.g* (ib-C* eycloailyl or Cs-Ce eyeioaifcyl). Examples of cycloalfcyl include, hut are not limited to, eyelopropyk cyclobutyl, cyclopentyl, cyclohexyl. cyclohcptyl l-^llohe^ipyl, 3-<^||ohex^yl cyelohsptyl and the like. The term “cycloaikyPiahso includes bridged, polycyclic (e.g., Mcyclic) structures, such as norbomyl, adamantyl and bicyol©[2.2.1 jhepfyi. The “Cyeioalkyr’ group can be fused li at Hast ope (g,g,, 1 to 3} pther ring chosen from aryl [e.g,, phenyl), hoteroaryi (c.g.. pyridyl) and non-aromatic (e.g... carbocyclk or heterocyclic) rings. When the “cycloalkyl” group includes a fused aryl, heteroaryl or heterocyclic ring, then the “cycloaikyl” group is attached to die remainder of the molecule via the earbocyclie ring. ]0033j The term Ateieiocycioalk;, Γ, “heterocyclicf “luneroeyde", or “heterocyciyf', by itself or in combination with other terms, represents a carbocyeiic. nou-arornahi: ring (c.g., 3- to 8-membeicd ring and tor example, 4~, 5-, 6- or 7-membcred ring) conlaining at least one and up to 5 heteroatorM chosen1 from, e.g,, N, O, S, Si, B arid1 P {tor example, hi, O and S), wherein the mlruger·, sulfur apd phosphorus atoms are optionally oxidised, and the nitrogen atom(s) are optionally quatemized (e.g,, from 1 to 4 heteroaioms chosen from nitrogen, oxygen and sulfur), or a fused ring system of 4~ to 8-membered rings, containing at least one and up to 10 heteroatoms (e.g., from 1 to 5 heteroatoms chosen from N, 0 and S) in stable combinations known to those of skill in the art. Exemplary hetcroeycloalkyi groups include a fused phenyl ring. When the “heterocyclic” group includes a fused aryl, hctcroaryl or cycloalkyl ring, then the “heterocyclic” group is attached to the remainder of the molecule via a heterocycle. A heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Exemplary heterocycloalkyi or heterocyclic groups of the present disclosure include morpholinvl, thiomorpholinyl, thiomotphoiinyl. S-oxidc·, thiomorpholinyl S.S-dkoride, piperazinyi, homopiperazinyl, pyrrolidinyl, pyrroiinyl. imidazoiMinyL tetoahydrop^&amp;nyl, piperidinyl, tetrahydrofuranyl, tetrahydrothieayi, ffpsridmyl, bomopiperidinyll, hoinomorpholinyl, hornothiomorpholinyi, komoihiomorpholinyl S,S~dioxide, oxazolidinouyl, dihydropyrazolyh dihydrcpyrrolyi, dihydropyrazolyl, dihydropyridyl, dihydropyrimidiny!, dihydrafuryl, dihydropyranvl, tetrahydroihieny! S-oxide, tettahydro-hienyl S,S~dioxide, homothiomorpholinyl S-oxide, 1-(J,2,5,6-tetrahydropyridyi), 1-piperidinyl, 2~piperidinyl, 3-pipcridmyl, 4-morpholinyl, 3-morpholinyl, totrahydrofuran-2~yl, tetrahydrofuran-3-yl, tetrahydrolkien-2-yi, iefrahydrothiert-3-yL I-piperazmyL 2-piperazinyi, and the like.

[0034] By “aryl" is meant a 5-, 6- or 7-membered, aromatic carbocyclic group having a single ring (e.g., phenyl) or being fused to other aromatic or non-aromatic rings (e.g., from 1 to 3 other rings). When the “aryl” group includes a non-aromatic ring (such as in 1,2,3,4-"tetraliydn>naphthyi) or heteroaryl group then the “aryl” group is linked to the remainder of the molecule via an aryl ring (e.g., a phenyl ring). 'Tire aryl group is optionally substituted (e.g., with 1 to 5 substituents described herein). In one example, the aryl group has from 6 to 10 carbon atoms. Non-limiting examples of aryl groups include phenyl, 1-naphthyl, 2-naphthyl, qinoline, indanyl, indenyl, dihydronaphlhyL fluorenyl, tetralinyl, beazo[d][! ,3]dioxolyl or 6,7,8,9-tetrahydro-5H-heaz»[a]cyclohsptenyl, la one embodiment, the aryl group is chosen from phenyl, henzo[d][K3]dioxoIy1 and naphthyl The aryl group, in yet another embodiment, is phenyl, [0035] The term “arylalkyl” is meant to include those radicals in which an aryl group or heteroaryl group is attached to an alkyl group to create the radicals -alkyl-aryl and -alkyl-heteroaryl, wherein alkyl, aryl and heteroaryl are defined herein. Exemplary “arylalkyl” groups include benzyl, phencthyl, pyridylmetkyl and the like.

[SG36] By '’aryloxy’' is meant the group -O-aryi, where aryl is as defused herein. In one example* the ary! portion of the aryloxy group is phenyl or naphthyl. The aryl portion of the aryfesxy groups in one embod iment is phenyl f003?| The term “heteroaiyl” or “heteroaromatic'’ refers to a polyunsaturated, 5-, 6* or 7- membered aromatic moiety containing at least one heieroatom (e.g., 1 to 5 heteroatoms, such as 1-3 heteroatoms) chosen from M, 0, $, Si and B (for example, N, 0 and S), wherein the nitrogen and sulfur atoms arc optionally oxidized, and the nitrogen alom(s) are optionally quatemized, The “heteroaryl” group can he a single ring or he fused to other aryl, heteroaryl, cycloalkyl or heteroeycioalkyl rings (e.g., from 1 to 3 other rings). When the “heteroaryf5 group includes a fused aryl, eycloatkyl or hetirocyeioalkyl ring, then the ‘IsctcroaryP group is attached to the remainder pf the molecule via the heteroaryl ring. A beieroaryl group can he attached to the remainder of the molecule through a carbon·· or heteroaiom. In one example, die heteroaryl gsoup has from. 4 :·:> 10 carbon atoms and from 1 to 5 heteroaiorns chosen from O. S and N. Non-ismiling examples of hetcroa-yl groups include pyridyl, pyrimidmyl, quiaoUnyl, benzothienyl, iMoIyl, mdoHayh ptyidaz-nyh pyrazinyl, Lsoindoiyl, isoqulnolyk OuinacdsnyL qumoxaliny;.. phthaiazinyl, imidazolyl, isoxazoiyl, pyrazoiyl, oxazolyi, diiazolyi, imiolizinyi, isdazrsiyl, berszoihiazoiyl. henzirnidazoiy!, benzefrimoyi. feranyl, thienyl, pyrrolyl, oxadlazolyh thidiMzolyl, trihxolyh tetriiZdM, isethiazolyl, naphthyridinyl, isochromanyl, chromanyi, tetrahydroisoqtbnolmyl, isoindolinyl, IsobenzotetmhydrofuranyL isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, bemzodioxoiyi, triazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, dibydrobenzisoxazinyl, benzisoxazinyl, beuzoxazinyl, dihydrobenzisothiazinyi, benzopyranyl, benzothiopyranyl, chromonyi, chroman.on.yl, pyridyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinoimonyi, dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindotinonyl, benzodioxanyl, benzoxazolinonyi, pyrrolyl N-oxide, pyrimidinyi N-oxide, pyridasdnyi N-oxide, pyrazinyl N-oxide, quinolmyl N-oxide, indolyl N-oxide, indolinyl N-oxide. isoquinolyl N-oxide, quinazoliny! N-oxide, qumoxaliny] N-oxide, phthakzinyl N-oxide, imidazolyl N-oxide, isoxazoiyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, beazothkzolyl N-oxide, benzimidazolyi N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, letrazolyl N-oxide, benzodiiopyraayl S-oxide, benzoibiopyranyl S.S-dioxide. Exemplary heteroaryl groups include imidazolyl, pyrazolyl, thiadiazolyl, triazolyl, isoxazoiyl, isothiazolvl, imidazolyl, th.iazol.yi, oxadiazolyl, and pyridyl. Other exemplary heteroasyl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyixoiyl, 3-pyrazolyl, 2-imidazolyi, 4-imidazolyl, pyrazmyl, 2~oxazolyl, 4-oxazolyl. 2-phenyl~4~ox&amp;zolyl, >oxa;mIyi, Sdsoxasolyl, 4~isoxaeolyl, Skoxurolyi. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-foryi, driuryl, 2~tbicn.yl, 3-thienyl, 2-pyridyl, 3» pyridyl, pyridin-4-yl, 2-pyrimidyl, 4-pyrinudyI, rVoemothiazolyl, purinyl, 2» beimmidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinoiyl, 2-quinoxalinyl, 5-quinoxalinyI, 3-quinolyL and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are chosen from the group of aceepiable ary! group substituents described below.

[00311 For Brevity, the term Maryi” when -r-eJ in. combination with other terms ie.g., aryloxv, arybbioxy. aryialkyl s indndes both aryl and heteroaryi rings a» defined above.

[0039] Each of the above terms (e.g,, '“alkyl", “cycloalkyr, “beteroalkyP, heterocycloalkyf \ “aryl” and “heteroaryl”) are meant to include both substituted and unsubstitated fotffis of the indicated radical. The term “substituted" for each type of radical is explained below. When a compound of the present disclosure includes more than one substituent, then each of the substituents is independently chosen.

[tMMfo The term “substituted” in connection with alkvl. alkenyl, alkynyl, cycloaliyl, heieroalkyl and heterocydoalkyl rads'cals {including those groups referred to as alkyiene, hoioroaikyiene, hetcronlkenyl, oyeloalkenyt, hetoioeyefoafoenyhirndsthe like) refers to one or more substituents, wherein each substituent is independently chosen from, but not limbed % 3- tp ib-membered heforoalkyb Cs-Cjescyeloalkyl, 3* to '10* mesnbered heteroeycloalkyi aryl, hetctoaryl, -(JR3, -SRs, :::0, :::>R(3R\ ~NR.aRb, ~ halogen, -SiRltTlV -OC(G)Rs, -C(0)Rs, -C(0)GRa, -C(G)NRaRb, -0C(0)NR*Rb, * NRaC(0)Re, -NReC{0)NR*Rb, -NR'C^NR^ -NRcC(0)0Ra, -NReC(NR*Rb):"NRd, -· S{0)R°, -S{0)2r, ~S(0)2NRaRb, -NRCS(G)2RS, -CN and -NO*. Ra, Rb, Rc, Rd an.d R* each independently refor to hydrogen, €;-€;>« alkyl (e.g,, C3-C10 alkyl or C: -Cf, alkyl). €<.·· €;:(·· cycloalkyl, C* -€;>< heteroalkyl (e.g , C·. -Ck> heteroalkyl or C; -G. heteroalky I). th-Ck heteroeycloalkyi aryl, heteroaryl, arylaikyl and hetcroaryl&amp;lkyl, wherein, in one embodiment. R° is not hydrogen. When two of the above R groups (e.g.. Ra add Rb) are attached to the same nitrogen atom, they can fee combined with she nitrogen atom to form a 5", ό~, or Itoiembered ring. For example, -N'R,:Rb is meant ίο include pyrroHdiriyl N-alkyl-piperidinyl and morphoiinyi. {00411 The tens “substituted” m connection with aryi and heteroaryl groups, refers to one or more substituents, wherein each substituent is independently chosen from, but not limited to, alky! (e,g.> C1-C24 alkyl, C-.-Cis alkyl or Ci-Cs alkyl), cycloalky! (e.g., C3-C10 cycloalkyl, or C.vC$ cycloalkyl), alkenyl (e.g., CK'io alkenyl or CrQ alkenyl), alkynyl (e.g., Ci-Cm alkynyl or Ci-Cf, alkynyl), heteroalkyl (e.g., 3- to 10-membered heteroalkyi), heterocycloalkyl (e.g., Cj-Cs heterocycloalkyl), aryl, heteroaryl, -R®, -OR) -SR8, =0, =NR®, -N-OR®, -NR*Rb, -halogen, -SiR’R.'R*, -0C(0)Ra, -C(0)Re, -C(0)0Ra, -C(Q)NR.*Rb, -QC(Q)NR*Rb, -NRcC(0)Re, -NRcC(0)NR*Rb, -NR"C(S)NRaRb, »NReC(0)0R®, -NRcC(NR*RVNRd, -S(0)Re, -S(0)2Re, -S(0)aNR*R*, -NRcS(0)2Rai:^..... CN, -NO2, "N3, -CH(Ph)2, iluoro(Cj~C.'i)aIkoxys and %oro(Ci -Crialkyl, in a number ranging from zero to the total number of open, valences on the aromatic rmg system, wherein R®, R\ R", R1 and R'; each independently refer to hydrogen, €rCm alkyl (e.g., CrCjo alkyl or 0:-0¾ alkyl), C«-£'u> cyeloaikyl, heteroalky! (e.g., C3-C10 helerosliyl or €ri€g hetorbuikyf), Cj-fho hetmocyeloalkyl, aryl, heteroaryl, arplkfl and hgteroarykilkyl, wlrerein, in one embodiment, R* is not hydrogen. When lm> R groups (e.g., Ra and R*) aroadachedto the same nitrogen atom, they can be combined with die nitrogen atom to form a 5-, 6-, or 7-merobered ring. For example, -NR‘R~ is meant to include pyrrolidinyi, N-nll^'i-piperidinyl and morpholinyl.

[0042] The term “substituted” is comeetton with: aryl and heferoaiyf groups also refers to one or more fused ring(s), to fli two hydrogen atoms on adjacent atoms of the aryl or heteroaryl ring are optionally replaced with a substituent of the formula -T-C(0)-(CR.Rv)^~U“, wherein T and U are independently -NR-, »0», -CRR’- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the hydrogen atoms on adjacent atoms of tire aryl or heteroaryl ring can optionally be replaced with a substituen t of the formula -A-(€H2)r“B--, wherein A and B are independently -CRR''-. -0-, -NR-, -S(Q)-, -S(0)jNR’- or a single bond, and r is an integer from 1 to 4. One of the single bonds of the ring so formed can optionally be replaced wife a double bond. Alternatively, two of the hydrogen atoms on adjacent atoms of the ary! or heteroaryl ring can optionally be replaced with, a substituent of the formula ~(CRR’)s-X~(€Ri,R”,)d-* where s and <1 are independently integers from § to 3, and Xw-0)-, -Hi’-, -S-, -8(0)-, -8(0)2-, or -§(0)>ΝίΓ-, wherein the substituents R, R’, R” and R,8> in each of the formulas above are independently chosen from hydrogen and (Cj ~Q)aikyl.

[0043] l.’he terms “halo” or “halogen,” by themselves or as part of another substituent, mean at least one of fluorine, chlorine, bromine and iodine.

[0044] By “haloalkyi" is meant an alkyl radical, wherein alkvl is as defined above and wherein at least one hydrogen atom is replaced by a halogen atom. The term “haloalkyi ” is meant to include monohaloalkyl and poTyhaloalfcyl, For example, the term. “halo(Cj-Chalky!” is mean to include, but not limited to, chlorometbyl, 3 -bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 J,l~trifluoroetby.l and4~chlorobutyl, 3-bromopropyl.

[0045] As used herein, the term "acyl" describes the group -€(G)Re, wherein R° is chosen from hydrogen, Ci-Qt* alkyl (e.g., Cj-Cta alkyl or Cj-C$ alkyl), Ci-Cm alkenyl (e.g., CrCio alkenyl or Ct-Q alkenyl), C1-C24 alkynyi (e.g., Cj-Cki alkynvi or Ci-Cjj alkynyi), tV-Cjo eycioaikyl, C1-C24 heteroalkyl (e.g., Cj-Cio heteroalkyl or Ci-C« heteroalkyl), C3-C10 heterocycioalkyl, aryl, heleroaryl, aryltdkyl and heteroarylalkyl. in one embodiment. R" is not hydrogen, 10046] By “alkanoyi” is meant an acyl radical -C(Q)-Alk-. wherein Aik is an alkyl radical as defined herein. Examples of alkanoyi include acetyl, propionyl, butyryi isobutyryl, valeryl, isovaleryl, 2~methyl~butyryL 2,2-dimethylpropiony.l, hexanoyl, heptanoyl, oeianoyl and the like, [05147] As used herein, the term "heteroaiom” includes oxygen (O), nitrogen (N), sulfur (S), silicon (Si), boron (B) and phosphorus (P). In one embodiment, heteroatoms are 0, S and N.

[O048J By “oxo” is meant the group ~0.

[0049] The symbol "R” is a general abbreviation that represents a substituent group as described herein. Exemplary substituent groups include alkyl alkenyl, alkynyi, cycloalkyl, heteroalkyl, aryl, heleroaryl and heterocycloaIky 1 group, each as defined herein.

[0Θ5Θ] As used herein, the term "aromatic ring” or “non-aromatic ring” is consistent with the definition commonly used in the art. For example, aromatic rings include phenyl and pyridyl. Non-aromatic rings include cvdohexanes.

[0051] As used herein, the term "fused ring system” means at least two rings, wherein each ring has at least 2 atoms in. common with another ring. “Fused ring systems can include aromatic as well as non-aromatic rings. Examples of “fused ring systems” are naphthalenes, indoles, quinolines, ehromenes and the like. Likewise, the term "fused ring” referes to a ring that has at least two atoms in common with the ring to which it is fused.

[0052] The phrase "therapeutically effective amount" as used herein means that amount of a compound. material, or composition of the present disclosure, which is effective for producing a: desired therapeutic effect, at a reasonable benefWrisk ratio applicable to any medical treatment. For example, a Nhcrapcuticalfy effective amount"' is an amount effective to reduce or lessen at least one symptom pf ife ij&amp;sass or condition being treated or to reduce or delay onset of one or more clinical markers or symptoms associated with the disease or condition, or to modify or reverse the disease process.

[01)53] The terms “treatment” or "treating·’ when referring to a disease or condition, means producing a desired therapeutic effect. Exemplary therapeutic efleets include delaying onset or reducing at least one symptom associated with the disease, positively affecting (e.g. reducing or delaying onset) a clinical marker associated with the disease and slowing or reversing diseasesprogression.

[0054] The term "nhnrmaceur ical !y acceptable:' refers to those properties an|/or substances that are acceptable to a patient (e.g., human patient) Irotn § toxicological and/or safely point of view.

[0055] The term "pharmaceutically acceptable salts" means salts of the compounds of the present disclosure, which may be prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities (e.g., -COOH group), base addition salts can be obtained by contacting the compound (e.g., neutral form of such compound) with a sufficient amount of the desired base, cither neat or in &amp; suitable inert itoivent. Examples of pharmaceutically acceptable base addition salts include lithium, sodium, potassium, calcium, ammonium, organic ammo^-magnesium and aluminum-salts and the like. When commands of the present-disclosure contain, relatively basic functionalities (e.g., amines), acid addition salts can be obtained, e.g,, by contacting the compound (e.g., neutral form of such compound) with a sufficien t amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable add addition .salts include those derived from inorganic acids like hydrochloric, hydrobrornic. nitric, carbonic, monohydnogencarbonic, phosphoric, diphosphoric, monohydrogenphosphoric, dibydrogenphosphoric, sulfuric, monohydrogemuifuric, hydriodic and the like, as well as the salts derived from relatively nontoxic organic acids like formic, acetic, propionic, isobulyric, malic, maleic, malonic, benzoic, succinic, suberic, fumade, lactic, mandeiic, phthalic, benzenesul&amp;nie, p-tolylsul ionic,: citric, tartaric, methanesulibnic, 2 bydroxyethyhsulfonic, salicylic, stearic and the like. Also included arc salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galaetuaoric acids and the like (see, for example, Rerge ex a!., Journal qf Phannd&amp;eutica! Science- 1977, 66: 1-19). Certain specific compounds of the present disclosure contam both, basic and acidic, functionalities that sallow the compounds to be conversed into eh her base or acid addition salts. 10056] The neutral forms of the coo-pounds can be regenerated, for example, by contacting the salt with a base or add and isolating the parent compound in the conventional manner: The parent form of the compound can differ from the various salt forms in certain physical properties, such m solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0057] When a subsit meet includes a negatively charged oxygen atom *O", e.g., in S‘-CO0“, then the formula is meant to optionally include a proton or an organic or inorganic cationic counterion (e.g., Nat). In one example, the resulting salt form of the compound is pharmaceutically acceptable. Further, when a compound of the present disclosure includes an acidic group, such as a carboxylic add group, e.g., written as the substi tuent “-COOH”, “-COiH” or “-C(0)2H”, then the formula is meant to optionally include the corresponding “de-protonated'’ form of that acidic group» e.g., “-COO'4', "J-CO{“ or ““CiO’h"44, respectively. {0058| In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Non-limiting examples of ''pharmaceutically acceptable derivative” c«r “prod-rug” include pharmaceutically acceptable esters, phosphate esters or sulfonate esters thereof as well as other derivatives of a compound of this present disclosure which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this present disclosure. In one embodiment, derivatives or prodmgs are those that increase the bioavailability of . the compounds of this present disclosure when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood stream) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

[005$] Prodrugs mehxde 1 variety of esters (ie«, carboxylic aeid ester). Ester groups, which are suitable as prodrug groups are generally known in the art and include bcnxyloxy, di(tfrQ)a!kykminocdhyk3xy, acetoxymethyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyl, 5~methyl-2-oxr>1.3-dioxol-4-yl methyl, and (€·--CVtaikoxv users, optionally substituted by N-morphoimo and andde-fbiming groups such as di(C]-€e)alky]amino. For example, ester prodrug groups include Ci-G, aikoxy esters. ΤΙΐοΜ .skilled in the art will rbifognize various synthetic methodologies that may be employed to form pharmaceutically aceeptabiefiodrugs of the compounds of the present disclosure (e.g., via esterification of a carboxylic aeid group).

[$060] in ah. exemplary embodiment, the prodrug is statable for treatment /prevention of those diseases and conditions that require -he drug molecule to cross the blood feraia feamer. In one embodiment, the prodrug enters the brain, where it is converted mid the active forth of the drug molecule. 10 another example, a prodfug is used to enable aa active drug molecule to reach the inside of the eye after topical application of the prodrug to the eye. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly con verted to th e compounds of the present disclosure when placed in a transdemial patch reservoir with a suitable enzyme or chemical reagent.

[0061] Certain compounds of the present disclosure can exist in unsolvated, forms as well as solvated forms, including hydrated terms. In general, the solvated forms are equivalent to unsolvated forms and1 are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms ("polymorphs"'}, in general, ail physical forms are of use in the methods contemplated by the present disclosure and are intended to be within the scope of the present Ikslosure. ‘‘Compound or a pharmaceutically acceptable salt, hydrate, polymorph or solvate of a compound’I intends the inclusive meaning of "and/or”, in that materials meeting more than one of the stated criteria are included, e.g., a material that, is both a salt and a solvate is encompassed.

[0062] Ha* compounds of the present disclosure cart contain unnatural proportions of atomic Isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ("4H), iodine-125 (ii5l) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Compounds described herein, in which one or more of the hydrogen atoms are replaced with another stable isotope of hydrogen (i.e., deuterium) or a radioardive isotope the,, tritium), are part of this disclosure.

Compositions Including Stereoisomem ||ίΙ6|] Compounds of the present disclosure can esriit in particular geometric or steieoixorneric forms, The present disclosure contemplates all such compounds, including eis- and iranr-issmers, (-)- and (T^pjantiomers:, diastoreemets, (0)rihdniers, (L)-isomers, the racemic mixtures thereof and other mixtures thereof, such as enantiomerically or diastereomerieally enriched mixtures^ as falling within dm scope of the present disclosure. Additional asymmetric carbon atoms cm be present in a substituent such as an aikyl group, /ϋ such isomers, as well as mixtures thereofoare intended to be included in this disclosure. When the compounds described herein contain olefimc double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both. 1 and Z geometric isomers, likewise, ^tautomeric forms and miinres of tautomers are included.

[I|64] Optically active (R}~ and (S)risomers and d and / isomers can be pirated Using chiral synthons or chiral reagents, or resolved using conventional techniques. Resolution of the racemates can be accomplished, tor example, by conventional methods such as crystallisation in the presence of a resolving agent; chromatography, using, for example a chiral HMC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereoraers via chromatography, and removing the resolving agent to generate the original compound in enantiomerieally enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound. If, for instance, a particular enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomerie mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomerie salts can be formed with an. appropriate optically active acid or base, followed by resolution of the diastereomeis thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomeis is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e,g.5 formation of carbamates from amines).

[0065] As used herein, the term “chiral” “cnantiomcricaily enriched” or "diastereomericaily enriched” refers to a compound having an enantiomeric excess (ee) or a diastereomerie excess (dc) of greater than, about 50%, for example, greater than about 70%, such as greater than about 90%. In one embodiment, the compositions have higher than about 90% enantiomeric or diastereomerie excess, c.g., those compositions will greater than about 95%, greater than about 97% and |ptelnta 99% ee or de, [(MMS6J The terms “enantiomeric excess” and “diastereomerie excess” are used to their conventional sense. impounds with a single stereocanter are referred to m being present in “ehahnbmeric those with at least two storeocenters are referred to as being present in “diastereomerie excess”. The value ofee will be a number from 0 to 100, zero being meernie and 100 being enanriomeriealJy pare. For example, a 90% ee reflects the presence of 95% of one enan tiomer and 5% of toe other(s) in the material in question. {0067] Hence, in one embodiment, the disclosure provides a composition in cluding a first stereoisomer and at least one additional stereoisomer of a compound of the present disclosure. The first stereoisomer can he present in a diastereomerie or enantiomeric excess of at least about $0%, such as at least about 90%, and for example, at least about 95%. In another embodiment, the first stereoisomer ϋ present in a diastereomerie or enaatiomerie excess of atieast about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%. in yet another embodiment, the compounds of the present disclosure is enantiomericaiiy or diastereomerically pure (diastereomerie or enantiomeric excess is about 100%). Enantiomeric or diastereomerie excess can. be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers. In an exemplary embodiment, enantiomeric or diastereomerie excess is determined relative to all other delectable stereoisomers, which arc present in the mixture. Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC.

[00681 The term “JNK-mediated condition”, “c-Jun N-terminal kinase mediated disorder” or any other variation thereof, as used herein means any disease or other condition in which INK is known to play a role, or a disease state that is associated with elevated activity or expression of INK. For example, a “JNK-mediated condition” may be relieved by inhibiting JNK. activity. Such conditions include, without limitation, inflij.tnma.tory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, cancer, infectious diseases., neurodegeoeradvc diseases, allergies, reperfusion/ischeiriia in stroke, hear! attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation, ansi conditions associated with prostaglandin endoperoxtdase synthase-2, [0069] The term “neurological disorder” refers to any undesirable condition of the central or peripheral nervous system of a mammal. The term “neurological disorder” includes neurodcgenerative diseases (e.g,, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), neurcpsychiatrie diseases (e,g. schizophrenia and anxieties, such as general anxiety disorder). Exemplary neurological disorders include MLS (cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e.g, spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g, AIDS, encephalopathies), epilepsy, benign forgetfulness, closed head injury, sleep disorders, depression (e.g., bipolar disorder), dementias, movement disorders, psychoses, alcoholism, post-traumatic stress disorder and the like. “Necrological disorder5 ' also includes any undesirable condition associated with the disorder. For instance, a method of treating a neurodegenerative disorder includes methods of treating loss of memory· and/or loss of cognition associated with a nenrodegenerative diseeder. Such method would also include treating or preventing loss of neuronal function characteristic of iibifodegeUBthiiyo disorder. 1007ft] The term ‘inourodegencrative diseases” includes any disease or condition characterized by problems with movements, such as ataxia, and conditions affecting cognitive abilities (e.g., memory) as well as conditions generally related to all types of dementia. <£Nenrodegenerative diseases" may be associated with impairment or loss of cognitive abilities, potential loss of cognitive abilities and/or impairment or loss of brain cells. Exemplary “neurodegenerative diseases” include Alzheimer’s disease (AD), diffuse Lewy body type of Alzheimer’s disease, Parkinson’s disease, Down syndrome, dementia, mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), traumatic brain injuries, ischemia, stroke, cerebral ischemic brain damage, ischemic or hemorrhaging stroke, multi-infarct dementia, hereditary cerebral hemorrhage with amyloidosis of the dutch-type, cerebral amyloid angiopathy (including single and recurrent lobar hemorrhages), neurodegeneration induced by viral infection (e.g. AIDS, encephalopathies) and other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy and dementia associated with cortical basal degeneration, epilepsy, seizures, and Huntington’s disease.

[0071] ’Tain” is an unpleasant sensory and emotional experience. Pain classifications have been based on duration, etiology or pathophysiology, mechanism, intensity, and symptoms. The term :"para" as used herein refers to all categories of pain, including pain that is described in terras of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of a injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g,, mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g,, inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain (see, e.g., Harrison’s Principles of Internal Medicine, pp. 93-98 (Wilson et al,, eds., 12th ed. 1991); Williams etaL>J. of Med. Ckem. 42; 1481-1485 (1999), herein each incorporated by reference in their entirety), “Pain” is also meant to include mixed etiology pain, dual mechanism pain, alkxiynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.

Compositions 10972] In various aspects, the present disclosure provides a compound having a structure according to Formula (I);

(I) or a sal* or solvate thereof |P$3f la Formula (I|, ring A is chosen from substituted or ansuhstituted awl Cfcg,, p!iga^i|:arid substituted or ^substituted hsteroaryl In one example, ring A is a 5~ membered heteroarornatie ring. In one example, the 5-membered heteroarornatie ring eornpripig from 1 to 3 hetematpms chosen from O. S and N (e.g,, thiophene, thiazole, or oxaaole^ In another example, ring A is a 5-membered heteroaroimtie ring containing at least one sulfur atom (e,g., thiophene, tbiarote). In another example, ring A is a 6-membered. heteroarornatie ring, In otrg esgpipie, the ό-rnembered heteroarornatie ring comprises I» 1 to 4 heteroatoms chosen from 0, S and N (e.g., pyridyl or pyrimidyl). The above 6-niemhered heteroaroinatie ring is opionaily substituted with from 1 to 3 substituents, and the above 5~mcmbered heteroaromatie ring is optionally substituted with I 0f:i sasbtiluents, wherein each substitnent s independently chosen from substituted Of imsubsiituted alkyl |e.g,s C i -Co~al kyl), substituted or unsub,si link'd alkenyl (e.g., Cj-C^-aikenyli. substimred or unsubstituted alkynyl (e.g., Ci --C'-i-aikyiiy 1), haioalkyi (e.g., CisCg-haloaikyi), substituted or unsuhstsfuted lie-croalkyi (e.g., 2- to 6-merobcred hctcroalkyl}. substituted or uusubstitured cyeloalky] io.g., €rCs<yeloaikyi), substituted or unsubstituted heterocyeloalkyl (e.g., 3- to h^nembersd heterocyeloalkyl), substituted or unsubstituted aryl (e g., phenyl), substituted or uosubstinned hetcroafyl (e.g., 5- or 6-membered hetcroaiyl), CN, halogen. OR*3, SRiJ, NRURL\ C(0)Ri'a, tY0)NR:?Ri;\ OC(0)MRI2Ri3, C;0)0Rs:) NRua.O>Rt4, NRiSC(0,!0R!f NR'-CfOlNR^R*·5. NRi5C(S)MR%B, NR^SCO^R5", S«ri2NR:>Ri:\ S(0)Ri4 and SK>kR:4, wherom R12, R™ and R1* are independently chosen fromff, acyl, if "Cf-liikyl, 2- to b^pemberc'd heteroalkyl» aryl, 5- or 6-membered heteroatyl» C3-C* cycloalkyf and 3- to 8-membered heterocyeloalkyl, wherein Ri2 and R1J, together with, the nitrogen atom to which they are bound are optionally joined io form a 5- to 7-memhered heterocyclic ring. R54 is independently chosen from acyl, Ci-Cg-aLkyl, 2- to 6-rnembered hcteroalkyl, aiyi, 5- or 6» membered heteroaryl, Cf-Cs cycloalkyl and 3- to 8-membered heterocyeloalkyl.

[Θ9741 In Formula (I), Ca and €b are carbon atoms, which are adjacent to each other and are both part of ring A. j(>075j In Formula (i\ Z is a 5- or d-membercd heteroaroma tie ring (e.g., triazoie, oxazole, oxadiazole, imidazole, tetnizoie, pyrazole, pyridine, pyrazine and the like). Exemplary Z groups are described herein below.

[0076] In one example, when ring A is thiophene, then Z is not a ihiazole-2~yI or bcnzo[iijthiazoi~2~yl. In another example, when ring A is thiophene, then Z is not ] /7-ben2©[</]iimdazoie-2-yi. In yet another example, when ring A is thiophene, then Z is not methyl or ethyl-substituted thiazole. In another example, when ring A is thiophene, then Z is not substituted (e.g., alkyl-substituted) or unsubstituted thtazoles and substituted or unsubstituted benzothiazoles. In another example, when ring A is thiophene, then Z is not substituted or misubstituted benzimidazoles. In a further example, when ring A is thiazole, then Z is not substituted or unsubstituted benzimidazoles. In yet another example, when ring A is thiazole, then Z is not li?-benzo[</]imidazole-2-yl.

[0077] .....In one example, when A is thiophene, then Z is not:

[0078] In another example, when A is thiophene, then Z is not:

[0(179] In a Pother example, when A is thiophene, the». 2 is not:

[0080] In another example, when A is thiophene or thiazole, then Z Is not:

[®0|lj In one example,; when ring A is thiophene, then 2 is other than oxadiazoie. in another example, when ring A is thiophene, then Z is other than substituted (e.g,, phenyl-substituted) oxadiazoie. In yet another example, when ring A is thiophene, then Z is other than oxadiazoie substituted with phenyl or substituted phenyl. In yet another example, when ring A is thiophene, then Z is other than oxadiazoie, wherein the oxadiazoie is substituted with a phenyl, 4~methy!~phenyl, or a 4~ethyl~ phenyl group, in another example, when ring A Is methyl- or ethyl-substituted thiophene, then Z is other than oxadiazoie.

[00S2] In another example, when ring A is thiophene, then Z is other than pyriimdinone. In another example, when ring A is thiophene, then Z is other than substituted pymnidmone (e.g., pyrimidinone substituted with at least one of hydroxy, earboxy or hydroxy-methylene).

[0$83] In Formula (I), R5 is chosen from H, substituted, or unsubstituted alkyl (e.g., C)-CV. alkyl), substituted or unsubstituted Cj-Ce cycloalkyi and acyl (e.g., acetyl).

[0084] In Formula (I), W is chosen from substituted or unsubstituted alkylene (e.g., substituted or unsubstituted Ci-Cio aikylene). In one example, W is CrCio alkylene optionally substituted with from 1 to 6 substituents chosen from R3ti and Ru defined as hereinbelow for Formulas (X) and (XI) in another example, W is straight chain aikylene rtpesented by the formula-4PR10R3:)h-, wbereins Is chosen from Ϊ to 10 and R30 and R.n are defined as hereinbeiow for Formulae (X) and (XI). In yet another example, W is a street carbon chain represented by (CM-)*--, wherein a is from 1 toM) (e.g., n is chosen from from 1 to 3 or n is 1 or 2). la another example W is C1-C4 alkylene optionally substituted with fixup 1 to 4 substituents chosen from R30 anl; Rn as defined herein. In a farther example, W is substituted or unsubstituted methylene, e.g., ~ CRlfrRn -, wherein Ri0 and Ru are defined as hereinbeiow for Formulae (X) and (XI). In a further example, W is methylene, optionally substituted with one or two substituents chosen from Ci-Cs alkyl, Cy-Cg cycloaikyl, Γ·-€δ alkoxy, CM and halogen (e.g.. F, Cl or Br). In a one example, W is unsubstituied methylene {-CH?-).

[0085] Cy in Formula (I) represents a ring or fused ring system. In one example, €y is chosen from Substituted or unsubstituted cycloaikyl (e.g,, substitutes or unsubslhited Q-Cs cycloaikyl),.substituted oii^^tbstit^dibetesocycWfeyl (e.g., substituted or unsofestiruted 3- to 8-membsr^ feeieroeycioaikyl), substituted or unsnbsimned ary! (e.g., phenyl), substituted or unsubstituied beteroaryl (e.g., pyridyi) and a fused ring system:. Exemplary Cy are described hemribdow.

[0086] in one example, ting Z in Formula (i) is a 5-membered heieroaromatic ring and the compound of the present disclosure has a structure according to Formula (II):

(II) or a salt or solvate thereof, wherein A, C*, Cb, R5, W and Cy are defined as for Formula (Γ), above.

[0087] In Formula (O), Vs Is chosen front M, O and Si Y2, Wi and ¥4 are independently chosen from S, Ο, N, NR3 and CR4. In one example, at least one ofY1 and Y:? is N. Each R3 and each R4 is independently chosen from H, substituted or unsubstituied alky! (e.g., Cj-Q-alkyl), substituted or unsubstituted alkenyl (e.g., C--CV alkenyl), substituted or unsubstituied alkynyl (e.g., Ci-Ce-alkynyl), haloaikyl (e.g., Ci-Q-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 6-mernbered heteroalky l), substituted or unsubstituied cycloaikyl (e.g., CVCg-cycloalkyl), substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-ra.embered heterocycloaikyl), substituted or unsubstituied aryl (e.g., phenyl), substituted or unsubstituied heteroarvl (e.g., 5- or 6~ mernfeered heicroatyl), CM, halogen, OR17, SR17, MRI?R1S, C(0)R1S, C(0)NRnR18, 0C(0)NR,7R!8, C(0)0E/7, NR^C^R**, NR20C(O)OR175 NR20C(O)NRi7R5a, NiPC(S)NR:7R,s( NR20S(O)3R:9s S(0)JNHWs, Sp|R;9 and S(<%R-, R17,

Rfa and R20 are independentiy chosen from H, acyl, C--Co-alkyl, 2~ to b-mcmbered heteroalky], aryl, 5- or 6-membered hetemaryl, C3-C3 cvcloaikyl and 3- to 8-membered heterocyeloalkyl, wherein R17 and Ri a, together with the nitrogen atom to which they are hound are optionally joined to form a 5- to 7~memhered heterocyclic ring. Ri9 is independently chosen from acyl. C.-Cs-alkyl, 2- to fomembered heteroalkyl, aryl (e.g., phenyl), 5- or 6-membered heteroaryl, C3-C5 cycloalkyl and 3- to 8-membered heterocyeloalkyl, In one example, each R* is independently chosen from H, alkyl (e.g,, Cj-Ce-aikyl), alkenyl (e.g., Ci-Cd-alkenyl), alkynyl (e.g., CVQrttlkynyl), haloalkyl (e.g., Cj-C'6-haloalky]), heterocyeloalkyl (e.g., 3- to 8-membered heterocyeloalkyl), cycloalkyl (e.g., Cj-Cg-cvcloaikyi), aryl (e.g., phenyl) and heteroaryf. In another example, each R" is independently chosen from H, alkyl (e.g., CrCs-alkyf), alkenyl (e.g., C--Ο,·-alkenyl), alkynyl (e,g.> Ci-Cg-alkynyi), haloalkyl (e.g., Cj-Q-haloalkyl), heterocyeloalkyl (e.g,, 3-to 8-membered heterocyeloalkyl), cycloalkyl (e.g., Cj-Ce-cycloalkyl), aryl (e.g., phenyl), heteroaryl, CN, haiogeli. ©R‘SR1' and NR17R‘®, wtoam R17 and R18 are defined as above.: [0088] Alternatively, any of the RJ subspuents and/or R4 substituents, together with the atoms n> which they are attached^ forts a > to ?-membercd ring. For example, if two of Y'\ Y . and Y4 are NR", then the two R' groups may form a 5- to 7-rnembered ring, in another embodiment, if two of Y2, YJ, and Y4 arc CR4. then the two R4 groups may form asfo to 7-membered ring* In yet another embodiment, if one of Y*, Y3, and Y4 is NR* and a second ofYb Y\ and Y4 is CR4, then the R’ and R4 groups may form a 5~ to 7-mernbered ring.

[0089] lr= another example, in. Fonnuaf (1), Y! is N. in a further example, Y1 is N hhd Y2, Y3 and Y4 form a imx.ole, thi&amp;mie, oxayole, oxadiazole, imidazole, pyrazole or tefrazole ring:, in yet another example, Y4 is N md Y2, Y3 and Y4 form a maze l e ring.

[00901 *R one example, in Fotritiia (FT)» when Y3 and Y4 are both CR.4 and Y1 is 'N, then Y2 is other than S, In another example, when YJ and Y4 arc .bath CR4 and Y2 is N, then Y: is other than S. fit a further example, when A is thiophene, then the moiety:

is notihiaxalei In a further exmuple, when. A is thiophene, then the above moiety is .not beozotbiazoie. In a further example, when A is thiophene, then the above moiety is not benzimidazole. In a further example, when Λ is thiazele, then ihesmoieiy is other than benzimidazole. In a further example, when A is thiophene or thiazole, then the above moiety is not thiazoic-2-yl, benz»[d3thiazol-2~y! or i//d;LUizo[djimidazole~2-y1, 10991] In another example, in Formula (.II), when. Yfis NR.', then R,! is H, In another example, in Formula (11), when Y2 is CR4, then R‘! is H, [0092) In another example, in Formula (II), W is sulxsii luted or uusubstituted methylene. In a further example, W is -CH*-. In another example, each R° is H. In yet another example, each if is chosen from H and methyl. In a. further example, in Formula (II), R" is IF in another example, in Formula (II), W Is methylene and R.5 is H.

Rluu A

[0093] In one example, in .Formula (I) and Formula (.11), ring A is a is membered heteroaromatic ring, in another example, in Formula (I) and Formula (II), ring A is a 6- membered aromatic or heteroaromatsc ring. Bxemplaty rings for A include phenyl, pyridine, thiophene, thiazole and oxaxofe. in a one example, in Formula (I) or (11), ring A. is chosen from thiophene and thiazole. in another example, in Formula (i) or (II), ring A is chosen from thiophene and thiazole, wherein the thiophene is optionally suhstituted with km 2 substituents and the ddazole is opriosaily substituted with 1 substituent wherein each substituent is indepcndenfly chosen from ('h-Ct alkyl (e,g., methyl, ethyl, tip-propyl, (erRhutyl), Ci-Cg eyeloulikyi (ζφ, cyelopropyl), C-mlCi haloalkyl (e.g., CFs, CHF2, CFRF, CHjCfh), halogen (e.g., F, Cl. Br) and CN. In another example, ring A is thiophene or thiazole, Y1 is N and Y2, Y5 and Y* form a triazole ring.

[0094] In yet another example, ring A is a 5-menxbered heteroaromatic ring and the compounds of Formula (II) have a structure according to Formula (Illft) or Formula (mb):

(I list)

(nib) or a salt or solvate thereof, wherein Z. R\ W, Cy, Y5, Y2, Y* and Y4 are defined as for Formula (f) and Formula (IT), above. i00951 In. formula (ilia) and (Hlb), X1, X2 and X3 areikdependently chosen from S, G, N, NR: and CM2, With foe proviso that at least one of Xs, X2 and X'1 is other than CRf R* is chosen from IL substituted or unsubstituted alkyl, (e.g., Ci-Cg-alkyl), substituted or unsubsiiiuted alkenyl (e.g., Cf-Cg-alkenyl), substituted or unsubstituted alkyuyl (e.g., Cj-Ce-alkynyl), haloalkyl (e.g., Ci-CVhaloalkyl), substituted or unsubstituted cycloalkyl (e.g,, Cj-Ce-cycloaikyl), substituted or unsubstituted heteroeycloalkyl (e.g., 3- to 8-membered heieroeycloalkyl), substituted or unsubstituted aryl (e.g,. phenyl), substituted or unsubstituted heteroaryl (e.g., pyridyi). In one example, R1 is chosen from H, substituted or unsubstituted Ci-Ce alkyl (e.g., methyl or ethyl) and Cj-Cj haloalkyl.

[0096] M Formula (Ilia) and ("flib), ©sch is ktoependendy chosen from aryl group subsumenis as defined heroin, 1¾ one example, each R"’ is independently chosen from H. substituted or un-sub,'.tinned alkyl (e.g., Ci-<Valkyi i substituted or unsubstitutod alkenyl (e.g., Ci-C«-alkenyl), substituted or unsubstituted alkyrtyl (e.g., Ci-Q-alkynyl), haloalkyi (e.g,, Ci-Cs-haloaikyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 6-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., CrCfi-cycloalkyl), substituted or unsubstituted hetemcyeloalkyl (e.g., 3- to 8-membered heterocycloalkyl), substituted or unsubstituted aryl (e.g,, phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or 6-membered heteroaryl), CN, halogen, OR*2, SR22, MR22Rm, C(0)R24, C<0)NR22R23, OCCOJNR^R23, €(0)0R22, NR2SC(0)R24, NR“C(0)0R:??'5 NR25C(0)NR22R235 NR2sC(S)NR22R2--, NR2iS(G)2R34, S(0)2MR22R2-\ S(0)R24 and SCORR24, wherein R22, R2a and R*5 are independently chosen from H, acyl, Cj-Ce-alkyl, 2- to 6'iTictnbcred heteroaikyl, aryl, 5- or b -rnembered heteroaryl CVCg cvdoalkyl and 3- to B-membered heterocyeloaikyl. wherein Ri ?and Ri?) together with the rmrogen atom to which they are bound are optionally joined to form a 5~ to 7-mcmbcred heterocyclic ring, R34 is independently chosen from acyl, Ci-CR-alkyi, 2- to 6-membered heteroaikyl, aryl, 5- or 6-metnbered heteroaryl. Cj-Cs cydoalkyl and 3- to 8-mcmbc-rsd hetetoeycioalkyl in one example, each R? is uincpendehtly chosen from H, Cj -€4 alkyl (e.g,, methyl, ethyl, iso-propyl, tez-r-butylh C3~C£, eyctoalky! (e.g., eydopropyl), Cj-Ch haloalkyi (e.g., CF), CHFj, CHjF, Cl hCF?>, halogen (e.g., F, Cl Rr) and CN, [0(197] In a further example, the compounds of the present disclosure have a structure according to Formula (IV), Formula (V), Formula. (VI) or Formula (VII):

(IV);

(V);

(VI);

(S II) or a salt or solvate thereof, wherein Cy, W, R', Y1, Y2, Y3 and Y4 are defined as hereinabove in. Formulae (I), (II) and (HI), respectively, [IMS9S] In Formulae (IV) to (VII), R'; and R2a are each defined as R2 in Formula (Ilia) and (Ilib). In one example, R2 and R2* are independently chosen from B, C1-C4 alkyl (e,g., methyl, ethyl, fro-propyl, ierf-butyi), CrC* cycloalkyi (e.g., eyeiopropyl), Q-C4 baloalkyi (e.g., CF3, CHF2, CH2F, CH2CF3), halogen (e.g., F, Cl. Fir) and CN. In another example, R2 and Q.la are bpthkk In yet another example, at least one or R? and R~* Is halogen (e.g., F\ Cl, Br). In a further example, at least one of R‘ and Rf ' is CN. In another example, at least one ofR* and is methyl.

[0099] In one embodiment, ring Z is chosen from 5-menibered and 6-membered heteroaromatic rings. Exemplary 6-memfaered heteroaromaiic rings for Z include pyridines and pyrazines. In vitro biological activity of the compounds of the present disclosure is generally higher when ring Z is connected to ring A via a carbon atom of ring Z (as shown above in Formulae II-VII) as opposed to being connected via a nitrogen atom of ring Z. Hence, in one example, ring Z is connected to the remainder of fee molecule via a carbon atom. 1091081 In vitro biological activity of a compound of the present disclosure is generally higher when Z does not include a substituent (e.g., a methyl, group) at the atom, which is immediately adjacent to the ring connection connecting rings Z and A. Hence, in another example, when Y2 is NR'}, then RJ is H. In another example, when Y* is €R4., then R.4 is H.

[00101] Exemplary .>xnembered heteroaromatic rings for Z in Formula (I) or (mb) or the moiety;

in Formulae (II), (Ilia) and (IV) to (VII) include triazoles (e.g., 1,2,3-triazoles or 1,2,4-triazolcs), oxazolcs, isoxazoles, thiazolcs, isothiazoles, totrazolcs, oxadiazolcs (e.g,, 1,2,4-oxadiazoles or 1,3,4-oxadiazoles), thiadiazoles (e.g., 1,2,4-thiadiazoles or 1,3,4-driadi azotes), pyrazoles, imidazoles and istrazoles. In another example, ring Z has a structure, which is chosen from:

wteeiis Y5 js chosen finom 0,1 and NR?, wherein Rhisdefiiredas litails (II), abo^. In one example, each Rt is independently chosen frost 1¼ Ci-Q- alfeyl:J, alkenyl (e.g., CrCe-alkehyl), alkynyl (e.g., CrCft-alkvnyl), Mbalkyl (e.g., Ct-Ce-haloalkyli,: beleroeyeloalkyl (e>g^ 3- to S^isetsbered heieT^yctealkyll, eyeloalkyl (e,g,, Ci'Cs-eycloaikyl), aryl (e.g., phenyl) and hetevoatyi. in another example, R"4 in the above structures 1¾ chosen iron· H, €>C< alkyl (e.g., methyl) and CyC; haloaikyl. 180ΙΘ2] In the above structures, R4 and R'13 are independently chosen and are each defined as R4 in Formula'(H), above. In one example, R4 and R4e are independently chosen from H, alkyl (e.g,, Cj-Gg-aikyl), alkenyl (e.g., Ci-Q-alkenyl), alkynyl (e.g,, €r Oralkyny'·), haloaikyl (e.g,, ('':-€y halos!ky;), heterocyeloalkyi (c-.g,, .3-- to 8~membered heteroeycIoaIky 1), cycloalkyl (c g., Cj-Cts-eycloalkyl), aryl (e.gM phenyl), heteroaryl, CN, halogen,: OR57, SR1' and NR!7R; <, wherein R17 and RiS are defined as above. In another example^ R4 and R’3 in the above structures are independently chosen from H, substituted or uosubsimhod CVO alkyl (e.g., methyl), C>C&amp; oyeloalRyi (e.g., cyclopropyl} and. hiR^R1^, In another example, R4* in the above ihruefiuos is H. In yet another example in the above stmotsresi R4 is li. in yet another example R*iin the ak>vs structees is II. In a thither exaaf te in the ahove strnctures, R?, R1 and R4* are each H. (001031 ^teastively, any of the R:’ stfestitnents andfor E4 substituents^ together with the atoms to which they are attached, form a 5- to 7-mernbcred ring. Per exmnple, if two of Y”, Y*, and Y4 are NR'\ then the two R? groups, may form a 5- to 7- tneaibercd ring. la another cmbodunexii, it'two of Y‘:, Y\ arid Y" are CR4S then the two R4 groups may form a 5- to 7-membered ring. In yet another embodiment, if one of YY YJ, and Y4 is NR3 and a second of Y2, YJ, and Y4 is CR“, then the R.3 and R.4 groups may form, a 5- to 7>membered ring, [001 (14] In one examples, ring Z in Fortrnila (!) or (TTIh) or ihe moiety:

in any of the above formulae and embodiments, is chose® from:

|0δ105] or a ianfemersotmixture of tautomers thereof, wherein. R4, R4* and R'! ate d|Shed as hereinabove, i« one example, R4,il** and R' are independently chosen from H, substituted or unsubstituted alkyl, subsutiued ox uosubsututed heteroaikyl substituted or unsubstituted cycloaikyl, substituted or unsubstituted heteroeycloalJkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryi, OR1? and NR17Ri8, wherein R1 ’ and R:* are independently chosen from H, substituted or unsubstituted alkyl, substituted or imsubstituted heteroaikyl, substituted or unsubstituted and. substituted or unsubstituted heteroaryl, substituted or imsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and wherein R1' and RlS, together with the nitrogen, atom to which they are attached, are optionally joined to form a 5- to 7-membered ring, in the above structures, at: least two of R3, R4 and R4a, R17 and R18, together with the atoms to which they are attached, are optionally joined to form a 5- to 7~memhsred ring. For example, one of R3, R4 and R4a and one of R1' and RIS, together with the atoms to winch they are attached, are optionally joined to form a 5~ to 7-membered ring. In another example, R3 and R4 or R'3 and R4\ together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring. In one embodiment, in any of the above structures, R3 is H.

[00106] M bite embodiment, in the above structures, R4'1 is 11, In another embodiment, in the above structures, R4 is H, methyl, cyeiopropyl or amino. In yet arbiter embodiment, in the above sttueiums, R4® (when present) is M and R4 is S, in yet another embodiment, in the above structures, R4a (when present) is F! and R4 is methyl.

In a farther embp&amp;tnent, :fcsteabovei«tni«hires, R*6 (phen present) is K and W is cyeiopropyl. {00107] In one example, Z hi Formula (T) or (HIb) or the moiety:

i| any of the above formulae and embodiments, is chosen from:

or a tautomer or mixture of tautomers thereof. 100108( its one embodiment, Z in Formula (1} or (Mb) or any of the formulae above is a triazole. In one example according to this embodiment, Z has the formula:

wherein R R1' and R1* are defined as herein above, in one example, in the above structure, R" and one of R! and R/*, together with the atoms to which, they are attached, are optionally joined to form a > to 7~tnembered ring. In another example, in the above structure, R' is H, [001091 In another example, 2 in Formula (I) is a iriazole and the compounds of the present disclosure have a structure according to Formula (Villa), Formula (Villb) or Formula (VIIIc):

(Villa)

(vuib)

CVIIIe) or a tautomer, mixture df tautomers, salt or solvate thereof. 100110] In Formulae (Villa), (Vlllfe) and (YUIe), nog A. €?, €b, R'\ R4, R5, W atvd Cv are defined as hereinabove. In one example, R4 is H, In another example, R4 is methyl I?': Formula (Vfflb), R3 and 1:“, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-memhered ring.

[601Π1 In one example, in Formula (Villa), ring A is chosen from thiophenes and thiazoles. In a further example, the compounds of the present disclosure have a structure according to one of Formula (IVa), Formula (Va), Formula (Via) and Formula (Vila):

(Va);

(Via); and

(Vila) or a taulornci, mixture of tautomers, salt or solvate thereof, wherein Gy, W, R4 aad R"' are defined as for Portnois (i). above. R“ and R":l are defined as in Formulae 0 V) to (VIT) hereinabove, hr one example. R“ is H or methyl {001121 Exemplary 6-membered heteroaromatie rings for Z„ e.g.s in Formula (I) and Formula (Rib),, include pyridine*. pyrarises, pyrimidines, pyrKURaes and sriaaineg (e.g., 1RJ-tri&amp;sdnes; i ,2,4~timzines m 1,3,5-triasdaes). in one examples 7. in Formula 0} or (Bib) has as8tn3ciuK5} which is chosen from;

wherein π is ail integer chosen from 0 to 4, m is an integer chosen from 0 to 3 and o 04 an integer chosen from 0 to 2, Each R:<5 is independently chosen from H, substituted or msuhstitoted alkyl (e g, Crfspalbyl), substituted or unsuhstituted alkenyl {e.g , Ci-Gs-dlkeayl), stibstitiiled or unsubstituted alkynyl (e.g., €:-€(;-alkynyf}, haloalky! (e.g., Cj-Ce-haloalkylj, substituted or unsubstituted heteroaikyl (e.g., 2- to 6-membe^d heteroalfef), substituted or unsubstituted cydoalkyl (e.g,, Cj-CVcyrioalkyl), substituted or uiSUbsiituteti hiiisreeycloaifcyl (e.g., 3~ to B-mcmbcrcd hefcrocydoalkyl), substituted or unsubsuhited aryl (e.g., phenyl), substituted: or unsubstituted hcteroaryl (e.g,, 5- or 6-membered heteroaryl), CN, halogen, OR3?aUSR3\ NR3V\ C(0)R* ®©pr¥3: OCiC))KR5iR·5·’, Of))OR32, NRi;:C(0)R'4, KRi:C(0;0R?''. NRi5C(0}NRaR33; NR3SC(S)NR32R33, NR3SSCO)2R34, S(0)2NR32R33, S(0)R34 and S(0)?R34, wherein R32, R·’·"1 and RJ'S are independently chosen from H, acyl, Cj-CVaikyl, 2- to 6-membered heteroaikyl, arvl, 5- or 6-menabered heteroaryl, C'rCs cydoalkyl and 3- to 8-membered heterocycloalkyl, wherein R32 and R33, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring, R34 Is independently chosen from acyl, Ci-Cc-alkyl, 2- to 6-membered heteroaikyl, aryl, 5- or 6-membered heteroaryl, CVC« cycloalkyl and 3- to 8-membered hctcrocydoalkyl..

Adjacent. RiiJ, together with the carbon atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring. ΓΟΟΙ131 In another example, Z. is a fu»ed ring system, which includes si least die of the above 5- or 6-membered rings. In one example, Z is chosen from benzo- or pyrido-imidazole, benzo- or pyriclo-oxazoie, benzo- or pyrido-tMazole, benzo- or pyrido-isoxazole and benzo- or pyrido-isothiaaole.

[ΘΘ Ι14] In one example, when ring A is thiophene, then Z is other than ox ad i azoic-. In another example, when, ring A Is thiophene, died Z is other than substituted (e.g., phenyl-substituted) oxadlazole. In yet spoiler example, when ring A is tbiopiacne, then 2 is other than oxadiazoie substituted with phenyl or substituted phenyl In yet another example, when ring A Is thiophene, then Z is other than oxadiazoie, wherein the oxadlazple is substituted with a phenyl, 4-methyl-phenyl, or a4-»ethyl-pbenyl group. In another example, when ring A is methyl- or eihyi-substmsted tluophene, then Z is other than oxadiazoie.

[04115] In another example, when ring A is thiophene, then Z is other than pyrirnidinone, In another example, when ring A is thiophene, then Z is other than substituted pyritnidinone (e.g., pyrimidinone substituted with at least one of hydroxy, carboxy or hydroxy-methylene)

W

[00116] In another exaEmpie accordiigg to tidy of the above embodiments of Formulae (!) to (IX), W is straight chain alkyknc represented by ~{CR.i(5Ru)i,-, wherein n is chosen from ί to 10 and Rf0 and R{ 1 are defined as hereinbdow for Formulae (X) and (XI). In another example, W is straight chain alkylene represented by -(CH^)»-, wherein n is chosen from 1 to 10. In one embodiment n is 1 or 2. In yet another example according to any of the abo ve embodimen ts of Formula (I) to (IX), W is unsubstituted methylene (-CH?.--). (80117] The present disclosure further provides a compound, having a structure according to Formula (X) or Formula (XT):

{X):

(XI) or a salt or solvate thereof! wherein 2, R/' and Cy are defined as for Formula (Γ) above. ^00118] la Formula (X) and Formula (XI), X! and W are independently chosen from M and CR'·, R‘ and R** arc each independently defined as Rl in Formula (Ilia) and Formula (Ulb). In one example, R2and R2* are independently chosen from H, substituted or unsubstituted Γι-€·ο alkyl, substituted or μη-subsf.ltuied 3- tp FO-raerabeced heipoalkyl substituted or m-substituted Cj-Cs cyeloa&amp;yl, substituted or unsubsfituted 3:- to 8-mernbered beterocycloalkyl substituted or unsubstituted aryl (e.g., phenyl), substituted^ imsubstituted heteroasyt (e.g., pyridyi), CN and halogen. In another example, R’ and Br® are independently chosen from H, C1-C4 alkyl (e.g.. methyl ethyl, iso-pspyi, terf-huiyl), C3-C* cycloalkyl (e.g., cyclopropyl), Ci-Ch haloalkyl (e.g., CF*, CHF2, CFfcF, CH2CF3), halogen (e.g.. F. Cl or Br) and CN, In one example. TV and R/S are independently chosen from II, methyl, halogen and Col [00119J I® Formula (X) and Formula (XI), R10 and R11 are independently chosen from H, substituted or unsubstituted alkyl (e.g., Cj-Ce-alkyl), substituted or unsubstituted alkenyl (e.g., Cj-C^-alkenyl), substituted or unsnhstituted alkynyl (e.g., €,-Cs-alkymyl), haloalkyl (e.g., Cj-Cg-haloalkyl), suisstituted or unsubstituted heteroalkyl (erg., 2- to fimiembered heteroalkyl), substituted or uosufestituted cyetealkyl (eig,, Cs-C#* cycloalkyl), substituted or unsufestituted heterocycloalkyi (e.g„, 3- to 8-membered heterocycloalkyi),, substituted or uasubstituted and. (e.g„ phenyl), substituted or unsubstituted heteroaiyl (e,g., 5- or 6-membered lieteroaiyl), CN, halogen, OR42, SR42, NRV, CXOtER C(G)Mr;2R4?, 0€(0)NR42R3C(0)Oir·’, NR4iC<0)R4\ bl-CCOPf82, NR45C{0)NR42R43, NR45C(S)NR42R4'\ NR45S(0)2R4‘\ SCOfcNiV, 8(0)1(44 and 8(0}dT4. wherein 1Γ2, R’* and R~' ate independently chosen from H, acyl, Ci-€f>-aikyl, 2- to 6-tnembered freteroaLkyL aryl, 5- or 6~membered heteroaryl, CVC* cycjdajkyl and 3» to 8-membercd heterocycloalkyi, wherein R'*2 and R43, together with the nitrogen atom to which they are bound are optionally: joined to form a 5- to 7-membcred heterocyclic ring, R"' is independen dy chosen froth acyl, CrC^-alkyL 2- to 6-membered heteroaiky], aryl, 5~ or 6-room.hered heteroaryls: Cr€a cydoatkyl and 3- to 8-membercd bcterocycloalkyl. In one example, Rlu and R’1 are both H.

[0(1120] In Formula (X) and Formula (XI), Z is chosen from those Z-gronps described hereto, above. In one example, Z. in Formula (X) or Formula (XI) is chosen from;

wherein n, m. o, Yj, R”, K*, and Ri6 are defined as hereinabove. In another example, Z in Formula is a rriazole.

Substituent R5 |00i21] In any of the embodiments of Formula (I) to (XI ), R5 is defined as tor Formula (Ϊ). In one example, according to any of die above embodiments of Formulae (I) to (XI), RJ is H or Ca-CF, alkyl. In another example, according to any of the above embodiments of Formulae (!) to (XI), Rr is |L it another example according to any of the above emfeodimentssof :Fortnute (I)sto (Mi), R5 is II ami W is .methylene [00122] In one example, the compounds of the present disclosure have a sRuehire according to Formula (XXI), Formula (XIII), Formula (XIV) or Formula (XV):

(Mil)

(XIV)

[00123] of ’λ tautomer, mixture of tautomers* salt or solvate thereof, wherein Cy and R” arc defined as for Formula (!) hereinabove. R.^ and Rf* are defined as for Formulae (IV) to < Vi!) hereinabove. In one example iu the above structure». R' and R** (when present) are independently chosen from H, halogen (e.g., F, Cl, Br), methyl and halogen-substituted methyl (e.g., CF_* or CHF>), Isa another example, R4 m H or methyl, in yet another example, R' and R2* (when present) are independently H, halogeg (e.g., F, CL Br) or halogen-substituted mctliyL and R4 is H or methyl;

Ring Cy (0M24J Cy in any of the embodiments of Formula (I) to (XV) represents a ring or a fused ring system, In one example according to any of the above embodiments of Formula (I) to (XV), Cy is chosen from substituted or unsubstituted CYC 12 cycloalkyi (e.g,, substituted or unsubstituted cyclopentanc, cyclohexane, norbomane or adamantane), substituted or unsubstituted 3- to 12-membered heterocycloalkyl (e.g,, substituted or unsubstituted niorpholino), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl), substituted or unsubstituted heieroaiyl (e.g., substituted or unsubstituted jjyridyl, substituted or npsubstiiuted quinoline, substituted or unsubstituted isoquinoine, substituted or urssubstiiutsd quinoxaMnSi substituted or unsvrbstituted quinaEoiine) and other frised ring systems (e.g,, substituted or un&amp;ubatttuicd 3,4-ditlxydroqi·) nolin-2-one, and substituted or unsuhsthuted 3db4ilpil^lslN^phthyrid|^2s^e). in one example, each of the abo ve cysfealkyL hetemqpioalkyl, aryl or heteroaryl groups is optionally substituted with from 1 to 8 R2C groups, wherein each R?'° is independently chosen from substituted or imsuixstibumd Ayl (e*gi, Cj-Cr,-alkyl), substituted or unsubstituted;alkenyl (e.g., Ci-Cs-alkenyl)., sufestimted or unsubstituted aifcyny! (e;p, Ct-Cfi-alkynyl), haloalkyl (e.g., halbaikyl), siibkHtiked or uMUbStituted heteroaikyi (e.g., 2- to ό-membered heteroalkyl), substituted or unsubstituted cycloalkyl (e.g., (YCYcycloalkyl), substituted or unsubstituted heterocyeloaikyi (e.g,, 3- to 8-membered heterocyeloaikyi), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroarvl (e.g., 5- or 6~ membered heteroaryl), CN, halogen, ORixs SR52, NR52R53, C(())R;,'i, C(Q)NRi2Rs'\ 0C(0)NR52R53, C(0)GR52, NR55C(0)Rs \ NR55€(Q)OR52, NRi5C(0)NRaR53, NR55C(S)NRS2R53, NR^SCO^R54, S(0)2NR52R5\ S(0)R54 and SfO^R54, wherein R52, R“3 and R55 are independently chosen from Ff, acyl, Ci-CYalkyl, 2~ to 6~tiiembered heteroaikyi, aryl, 5- or 6--membered heteroarvl, CrCs cycloalkyi and 3- to 8-membered heterocyeloaikyi, wherein R'2 and R53, together with the nitrogen atom to which they are bound are optionally joined to form a 5· to 7-membereti heterocyclic rings F/4 is independently chosen from acyl, Cf-CiralkyL 2- to 6~mcmbered heteraahkyl, aryl, 5- or 6-msmfeered beteroaryi, CVCs cycloalkyl and 3- to 8-rnembered heterocycloalkyi.

Jpi! 251 In one example, Cy in any of the above embodiments of Formula (I) to (XV) has a structure chosen Sot:

wherein q is an integer chosen front 0 to 5, r is an integer chosen fksnO to 4, s is an integer chosen from 0 to 0, t is an integer chosen from 0 to 8 and each is independently defined as dbovc. M least two R2**, together with the atoms to wffeieli they are attached, are optionally joined to form a 5- to 7-racmbcied ring. In one example, two R20, together with the atoms to which they are attached, are joined to form a 5- or 6-membered, aromatic (e.g.. phenyl) or heteroaromatic (e.g., pyndyl, pyriraidyi. pyraryl, thienyl or pyrazolc) ring. 100127] In a further example. Cy in any of the above embodiments of Formula (I) to (XV) is 4-substituted or 3-substituted phenyl or pyridyl. For example, Cy has a structure chosen from:

wherein u is an integer chosen from 0 to 4 and v is an integer chosen, from 0 to 3. R40 is defined as herein above. In one example, R20 in the above structures is OR53, wherein R3' is dsf.ned as herein above. In one example, R '1 is chosen from substituted or unsubstituted alkyl (e.g., Cj-Cg alkyl). In one embodiment, R;,J in the above structures is chosen from methoxy and ethoxy. Each R20* in the above structures is independently chosen horn R20 groups as defined herein above. In one example, the integer u or the integer v are 0 and R20* in the above structures is absent.

[00128] In a fiat her example, Cy hi any of tiie above embodiments of Fonnuio {;) ao (XV) is chosen from.:

wherein R2i) and R2ai are defined as herein above. R20 and R20as together with the atom to which they are attached, are option ally joined to form a 5- to 7-membered ring, §§1291 In yet another example, Cy in any of the above embodiments of Formyl» (I) to (XV) is chosen from:

HKilSOj wherein v is an integer chosen from 0 to 3:, w is an integer chosen from 0 to 2, x is an integer ©hoses, from 0 to 4S and y is an integer ©hOsen fr®n 0 to 2, labi R.20* in the above structures is independently chosen and is defined as herein, above. In one example, each R20* in the above structures is absent, Y6, Y7, Y8 and. Yy are independently chosen from N and CR20bs wherein each Ri0b is independently chosen from H and R20 as defined herein above. In one example, Y6, Y7, Yg and Y9 are chosen from N and CH, Y10 is a chosen from O and S. In another example, Y50 is S.

[ΘΘ1311 irt a further example, Cy in any of the above embodiments of Formula (I) to (XV) is chosen from:

wherein v\ x. R^”"' and jR"'*' arc dciinod as. herein above. The integer z is chosen front 0 to 4 and the integer a is chosen from 0 to 3. in one example in the above structures R~;)a is absent... In another example,, each Κ'“Λ> in the above structures is 11 In yet another example in the above struct urea, each U2u* is absent and each R20b is H.

Vitro Actmti.es [00132J Certain compounds of the present disclosure exhibit various in vitro biological activities as demonstrated, e,g., in Example 14 and Figure 1, For example, certain compounds of the present disclosure exhibit inhibitory activity against iun N* temutial kinases (JNMs), In vltiri assays for the determination of JN|l activities are known in the art and exemplary assay formats are described herein (see e.g., Example 14). Many compounds of the present disclosure ate especially active against MK3 (e.g.. μΙΜΟ or cJNK3) but may also inhibit JNK1 arid JMK2. (001.331 in one example, the compounds of the present disclosure may be inhibitors of ajNK.3 will su IC50 of less than about 50 μΜ, less than about 40 μΜ, less than about130 μΜ, less than about 20 μΜ or less than about 10 μΜ. in another example, the compounds of the present disclosure may exhibit inhibitory activity against ajNbJ with an 1C?o of less than about 9 μΜ, less than about 8 μΜ, less than about 7 μΜ, less than about; 6 μΜ, less titan about 5 μΜ, lessithan about 4 μΜ, less than about 3: μΜ, less than about 2 μΜ, or less than about 1 μΜ. In yet another example, the compounds of the ppsent disclosure may exhibit inhibitory activity against a3NK3 with an 10^ of less than about 0.9 μΜ, less than about 0.8 μΜ, less titan about 0.7 μΜ, less than about 0.6; μΜ, less than about 0,5 μΜ, less than about 0.4 μΜ, less than about 0.3 μΜ, less than about 0.2 μΜ. For example, the cOUtpounds of the present disclosure may exhibit inhibitory activity against aJNK3 with m IC$o of less than about 0.1 μΜ (100 nM). In another example, the compounds of the present disclosure may exhibit inhibitory activity ugphst a JNK3 with an IC50 of less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM or less than about 20 nM. In another example, the compounds of the present disclosure may exhibit inhibitory activity against aJNK3 with an IC50 of less than about 10 nM.

[00134] Certain compounds of the present disclosure do not only exhibit inhibitory acti vity against INK, but at the same time have little or no inhibitory activity against certain other members of the MAP kinase family of proteins. For example, certain compounds of the present disclosure are active against aJNK3 and show little or

BpfeybitoiypAvity against p38 and^rlMAPK. ίο® the purposeof this application the selectivity of the instant compounds for INK over other kinases is expressed in a ratio of IC50 values. Those can be determined using assays known in the art or those described herein (see e.g.. Example 14).

[ooiiii Certain compounds of the present disclosure am characterized by tie following inhibitory acti vities involving a3NK3 and p38. In one example, the ratio of 1C» (aJNK3)/ 1C» (p38) is less than about 1, less than about 0.9, less than about 0.8, less than about 0,7, less than about 0,6, less than about 0.5, less than about 0,4, less than about 0.3, less than about 0.2 or less than about 0.1. In another example, the ratio of f€$o (aJNKjy IC50 (p38) is less than about 0.09, less than about 0.08, less than about 0.07, less than about 0.06, less than about 0.05, less than about 0.04, less than about 0.03, less than about 0.02 or less than about 0.01. In a further example, the ratio of ICso (aJNK3)/ ICso (p38) is less than about 0,009, less than about 0,008, less than about 0.007, less than about 0.001¾ less than about 0.005, less than about 0.004, less than about 0.003, less Aan about 0.002 or less Ann about 0.001. In vet another example, the ratio of IC5.3 (aJNK3)/ ICco (p38) is less Aan about 0.0009, loss than about 0,0008, less than about 0.0007, less than about 0.0006, less Aan about 0.0005¾ less than about 0.0004, less than about 0.0003, less than about 0.0002 or less than about 0:0001. P0I361 Certain compounds of the present disclosure are characterised by the following inhibitory activities involving a* and MM.. In one example, Ae ratio of IC50 (aJNK3)/ IC50 (MAPK) is less than about 1, less Ann about 0.9, less Aan about 0:1, less than about. 0.7, less than about 0.6, less than, about 0.5, less than about 0.4, less than about 0.3, less than about 0.2 or less Aan about 0,1. In another example, Ae ratio of IC50 (ad.NK3)/ IC50 (MAPK) is less than about 0.09, less than about 0.08, less than about 0.07, less Aan about 0.06, less Aan about 0.05, less Aan about 0.O4, less Aan about 0;03, less than about 0.02 or loss than, about 0=01. In a further example, Ae ratio of iCjo (aJNK.3)/ lib (MAPK) is less than about 0.009, less than about 0.008, less than about 0.007, less than about 0:006, less than about 0.005, less than about 0.004, less Aan about 0,003, less than about 0.002 or legs Aan about 0.001. In yet another example, the ratio of IC50 (aJNK3)/ ICso (MAPK) is less than about 0.0009, less than about 0.0008, less Aan about U.OOOfϊ less than about 0.0006. less than about 0.0005, less than about 0.0004, less than: about 0.0003, less than about 0.0002 or less than about OiOOOl. |d0137| Certain compounds of the present disdosure are eharaeterized by fee following inhibitory activities involving aJNK3, p38 and MAPK. In one example, the ratio ofICso (aJNK3)/ TCso (MAPK) and the ratio of fC5C· (aJNK3)/ ICso (p38) is each less than about 1, less than about 0.9, less than about 0.8, less than about 0.7, less than about 0.6, less than about 0.5, less than about 0.4, less than about 0.3, less than about 0.2 or less than about 0.1. In another example, the ratio of ICso (aJNOV ICso (MAPK) and the ratio of ICjo (aJNKB)/' ICso (p38) is each less than about 0.09, less than about 0.08, less than about 0.07, less than about 0.06, less than about 0.05, less than about 0.04, less than about 0,03, less than about 0.02 or less than about 0.01. In a further example, the ratio of ICso (aJNK3)/ ICso (MAPK) and the ratio of ICso (aJNK3)/ ICso (p38) is each less than about 0.009, less than about 0.008, less than about 0.007, less than about 0.006, less than about 0.005, less than about 0.004, less than about 0.003, less than about 0.002 or less than about 0,001, In yet another example, the ratio of ICso (aJNK3)/ ICso (MAPK) and the ratio of ICso (aJNK3)/ ICso (p38) is each less than about 0.0009, less than about 0.0008, less than about 0.0007, less than about 0.0006, less than about 0.0005, less than about 0.0004, less than about 0.0003, less than about 0,0002 or less than about 0.0001.

[00138] Exemplary compounds of the present disclosure and t heir in vitro biological activities are listed in Table 1, below. ICso values in Table 1 were determined \;sing the procedures c·'' Exam Pe 14.

Mitel

In Vitro Biological Activities

(+++) < 0.1 uM

(•H) ICs9 0.1 μΜ - 10 ,uM (+) ϊΟ.ΐο > 10 μΜ (-) Activity below level of detection in assay used (10¾ >50 μΜ)

ImVivo Activities [0(1139] Certain compounds of the present disclosure exhibit m vivo biological activities, such as the inhibition of exeitotoxic ceil death. An in vivo model, which can be used to assess the potential in vivo beneficial effect of the compounds of the present disclosure is described in Example 15. Exeitotoxic cell death can be induced experimentally by the administration ofkainic acid. Peripheral injection ofkainic acid resul ts in the degeneration of neurons in the hippocampus. Mice lackin g the Jnk3 gene are resistant to kainie acid-induced upregulation of phosphoryiated e-jun (p-ejun) and hippocampal neuronal apotosis (.see e.g., Yang D,D, et al., Nature 1997, 389: 865-870). Phosphoryiated c-jun in wildtype mice is upregulated after kainie acid administration and demonstrate that this upregulation is inhibited by certain compounds of the present disclosure.

Certain compounds of the present disclosure are characterised by the following in vivo biological activities involving the concentration of p-ejun in the brain tissue (e.g., hippocampus) of a test animal (e.g., rodent, such as mice. rat. rabbit and the like) after treatment of the test animal with an excitatory amino acid or analog thereof (e.g,, kainie acid). In one example, administration of a compound of the present disclosure to a test animal (e.g., at a dose of at least about 100, 200 or 300mg/kg), results in. a reduction of kainie acid-induced n-ejun concentration in the brain tissue of the test animal by at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%. at least about 7%, at least about 8%, at least about 9% or at least about 10% relative to the p-ejun concentration found in brain tissue of a comparable, un treated (vehicle treated) test animal. In another example, adrahustration of a compound of the present disclosure to a test animal (e.g., al a dose of at least about 100.. 200 or 300mg/kg), results in a reduction of kainie acid-itufoeedp^Mn concentration in the brain tissue of the test animal by at least about 11 %, at least about 12%, at least about 13%, at least about 14%, at least about 1.5%, at least about 16%, at least about 17%, at least about 18%, at least about; 19% or at least about 20%, relative to the p-ejun concentration found in brain tissue of a comparable, untreated ( vehicle treated) test animal In yet another example, administration of a compound of the present disclosure to a test animal (e,g.s at a dose of at least about 100,200 or 300mg'kg), results in a reduction of kainie acid-induced p-ejun concentration in the brain tissue of the test animal by at least about 21%, at least about 22%, at least about 23%, at least about 24%, at least about 25%, at least about 26%, at least about 27%, at least about 28%, at least about 29% or at least about 30% relative to the p-ejun concentration found in brain tissue of a comparable, untreated (vehicle treated) test animal. In a further example, administration of a compound of the present disclosure to a test animal at a dose of at least about (100, 200 or 300mg/kg), result s in a red uction of kainie acid-induced p-ejun concentration in the brain tissue of d ie test «Banal by at les# about 31%, at llast about 32%, at least about 33%, at least about 34%, at least about 35%, at least about 36%, at least about 37%, at least about 38%, at least about 39% or at least, about 40% relative to the p-ejun conception found in brain tissue of a comparable, untreated (vehicle treated) test animal. In yet another example, administration, of a compound of the present disclosure to a test animal (e.g.. at a dose of at least about 100, 200 or 300 mg/kg), results in a reduction of kmnic acid-i nduced p-ejun concentration in the brain tissue of the test animal by at least about 41%, at least about 42%, at least about 43%, at least about 44%, at least about 45%, at least about 46%, at least about 47%, at least about 48%, at least about 49% or at least about: 50% relative to ihe p-cjnn concentration found in brain tissue of a comparable, untreated (vehicle treated) test animal. In yet another example, administration of a compound of the present disclosure to a test animal (e.g., at a dose of at least about 300mg/kg), results in a reduction ofk&amp;inic acid-induced p-ejun concentration in the brain tissue of the test animal by at least about 51%, at least about 52%, at least about 53%, at least about 54%, at least about 55%, at least about 56%, at least about 57%, at least about 58%, at least about 59% or at least about 60% relative to the p-ejun concentration found in brain tissue of a comparable, untreated ( vehicle treated) test animal.

Synthesis of Compounds [80141] The compounds of the present disclosure can be prepared using methods known in the art of organic synthesis and those described herein (see, c,g., Examples 1 to 13). The starting materials aifo various intermediates may be obtained from commercial sources, prepared from commercially available compounds, and/or prepared using known synthetic methods. For example, the compounds of the present disclosure, as well as all intermediates, can he synthesized by known processes using either solution or solid phase techniques; Exemplary procedures for peparing; compounds of the present disclosure arc outlined m the following schemes. pii42] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired ructions. Suitable protecting groups for various fimstionai groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P.G. M. Wuis, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York,1 999, and references cited therein.

[00141] In one example, the compounds of the present disclosure arc prepared using a procedure outlined in Scheme la, below:

Scheme la

[00144} I» Scheme la, Cy and W ace defined as herein above. Xs and XX are independently chosen from CR2, S and N with the proviso that at least one of X3 and X.’ is S. R·4 is defined as herein above. R* is chosen from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or imsubstituted heierocydoalkyl, substituted or imsubstituted aryl and substituted or unsubstituted heteroatyl. In one example, Ra in Scheme la is Ci-G; alkyl (e.g., methyl or ethyl). The moiety -C(0)E of compound It represents a carboxylic acid gpoup (in which. E is 01% an adM cfilbridd (in which E is €1) or aft aetivg|ed ester, such as a ISi^iydrpsysuccmimide ester (NHl<<esterh i. carbodliuiide, a trsazolol and the like, The activated ester is optionally formed in situ from the corresponding acid, in wbkh E is OH. In one example, compound ill is formed by contacting compound I and compound 0 (w herein E is OH) in the presence of a coupling reagent and optionally an organic base, such as an amine (e.g., dnsepmpyicthyi amine, DIPEA), Coupling reagents suitable for amide bond formation ate Mown te those of skill in the art and include dicyclohcxylcarboddmide fDCC% dhsuprsfylcarbodiimide (131C), 1-hydroxybcnzu-triazole (1ΊΟΒΤ), l-hyditoxy-?-»;®)··' benzoin azole tj-iOAt), 6-ohlcHx>-I-hydroxybenzotriasolc (Cl-HOBT), 1-ethyl-3-(3!-dirnetltyiamiR.opmpyl)carbodiirn.ide (EDC), N-[(1H- benzotriazol-l-y1Xdimd.hyiamino)methyienej-bl»mdhylmethaiiamii3ium hexafluorophospbate M-oxide (HE s U), N-[idtmethylamuio)-1 IT 1 ,2,3*tnazolo(_4,5-bjpyridine-l -ylmethlenoj-N-meth.ylxnethanammi'um hexaflmraphosphate (HATH), beazotriazol.-l~vi-N”Oxy·· lm(pynrolidino)phospbonium hexailuorophosphate (PyBOP) and combinations thereof Alternatively, POO; and a base (e.g,, pyridine) can he used to Form an amide bond. jf'MIMSf Afur coupling, the ester group sf compound III cart be converted to a. hetero-aromatic group Z. bxemplmy groip 1 are described herein above. Schemes 2 to h Outline ilk' ‘iu'ion or vau"k·* . A "civ'e of \hi . m ., *· ,u w;ti smirecsaic that the conversion shown m Schemes 2 to 8 are exemplary and that compound*, which include other Z groups can he synthesized 'using known methodologies and methods modified from those presented.

[00146] In one example, Z can fee covalently linked to the core moiety via an aryl-aryl cross coupling reaction, such as a Suzuki or Stilie-type reaction. An exemplary reaction is outlined in Scheme lb, below.

Scheme 11>

[00147] In Scheme 1 b, Z, X!, X3 and R“ are as defined as herein above (see, e,g.s Scheme la). X is halogen (e.g., Cl, Br or I). Y is a leaving group suitable for a cross-coupling reaction. In one cxamtple, Y is a leaving group suitable for a Si file-type cross-coupling reaction, e,g,, a tiialiiyktaniiyi (e.g., trifeuiylstarurelfe In another example, Y is a leaving group suitable for a Suzukhtype cross-eouplmg reatA®, e.g., a boronic add |tbtp, It is well Within the capbilliics of a skilled person to select a suitable catalyst. Typically, the cross-coupling reaction wall be pal&amp;dium-catalyzed. However, other transition metal catalysts can also he used. In one eMmple, the catalyst is a palladium phosphide, sup as tnphenyl phosphine, PdCPPhg)^ In anoiter sample, the catalyst is a coppeWfessel: catalyst,; The reducing agent can be any reagent suitable for tire reduction ofe. nitro group to an amino group. Exemplary reagents include hydrogen in combination with a metal catalyst, such as palladium on carbon (Pd/C); and tin(O) reagents, such as SnCfi.

[0Θ148] In Scheme lb. the nitro analog is first coupled to Z, followed fey reduction of the nitro group to an amino group. The resulting amine can then be coupled to a suitable carboxylic acid derivative, e.g., as outlined in Scherbo lb. lo another example, the coupling reaction is performed after the amide has been formed as outlined in Scheme lcs below,

Scheme Is

[0ΘΙ49} lit Scheme le, Z, Y. X1, X', R2, X and the catalyst arc defined as herein above (see. c.g., Scheme lb), [06150] In another example, the compounds of the present disclosure are prepared according to a procedure outlined in Scheme id, below:

Scheme id

[60151] In Scheme Id, R\ XJ and X3 are defined as herein above and X is a leatoug group, such as halogen £e.g,, Gl, Br, If, tosylate, mesylate and the like. Ring® represents any heterocyclic or ireiemarornatie ring, (e.g., imidazole, pyrazole). Ring ® can optionally be part of a larger ring system (e.g., indolyi). Is Scheme Id, compound Olh is readied with compound 1¾¾ e,g., by healing t|e components in a suitable solvent, such as aeetonMie, to afford compound ¥b, 'I'he niiro group of Gompound Vb can then be reduced to an amino group, e.g, , using a metal reducing agent, sueh as iion (Fe) or zinc io afford confound VIb. Compound VIb can be further converted to a compound of the present disclosure by means of coupling with a suitable carboxylic acid or acid derivative, similarly to toe reaction outlined in Scheme la.

[00152 j Imanoiher example, tbs compounds of the present disclosure include a triazoie moiety as the ring 7.- and arc prepared using a procedure outlined in Schemes 2a or 2b, below.

Schema 2s

100153] In Scheme 2a, the ester III is first converted ίο the hydride V (e,g„ using a lvydm?.me), which Is further reacted with an iraidamide (c.g., acetimidamide or propionmridamide) in the presence of a base in order to give the triazoic VII. In Scheme 2a, X1, X3, Rb R'1, Cy and W are dedmed as heroin above, in one esample, R4 is chosen ffpm substitute! or nnsubstitiited ail(y^:Sub^tu£ed:,oi:sn^^toed aryl, substituted or unsubstituted heteroaryl and amino (gig., alkyl-aminoV When R4 is amino, the imidamide reatigfnt VI of Scheme 2a can be a guanidine. In. Scheme 2a, X3 and X3 are independently chosen from Cl3, S and N, with the proviso that at least one of X1 and X3 is S. R"4 is dsSued as herein above.

[00151] Alternatively, the eatboxylic acid Mia can be converted to a primary amide, which is then, reacted with hydrazine to form a iriazole, e.g., as outlined in Scheme 2b, below:

Steheme.2.b

lii Scheme 2b, X , X ,. cy and W eto d.cimed rs herein above.

Oxadlazolc [00155} in anomer example, the compounds of the present disclosure include an oxadiazoie moiety as the ring Z. Such compounds can be prepared using procedures outlined nr Schemes 3a to 3e, below,

Scheme 3a

[091561 la Scheme 3a, X1, X3, Pd, Cy and W are defined as herein above. In Scheme 3a, the hydraadde V is reacted with trialkoxy-methane (e,g., iriethoxymethane) to form the 1,3,4-oxadiazote analog VIIL

[0015/J Aiicmabvdy, the carboxylic add Ilia can be reacted with s?> acyl hydrazide to prepare a substituted 1,3,4-oxadiazole analog Villa as outlined in Scheme 3b, below.

Scheme 3b

|0815||; In Scheme 3b, X1, X'\ R2, Cy and W are defined as herein above. Alternatively, the unsubstituted oxadiazole (R’! - H in Formula Villa) can be prepared by reacting the above carboxylic acid with isocyanoiinino-triphenyi-phosphorane.

Scheme 3e

[801591 In Scheme 3c, X'\ R\ Cy and W are defined as herein, above.

In Scheme 3c, the ester ΙΪΙ is reacted with a hydroxyi.rflidami.de XX je.g., {£)-N’-hydmxyaeetmfidMm^ form the l ,2,4~oxadiazoie analog X.

Scheme 3d

[OOMOl In Scheme 3d, X1, XJ, R2,Cy and W am defined as herein above. In Scheme 3d, the carboxy lic acid Ilia, which can optionally be prepared through saponification of ester HI, is first converted to the primary amide XI (c.g ,, using ammonium hydroxide and a catalytic amount of ammonium chloride) and then further converted to the i;2,4-oxadiazole analog XII, e.g., by means of AW-dimethylformamide dimethyl acetal (DMF-DMA) followed by hydioxylamine.

Scheme 3e

100161) In Scheme 3e, the nitrile IIIc, Is first converted to the corresponding iimdarnide (e.g,, us|ng hydroxyiamine), w|ieh is further rcaeted with an aeid chloride (®ϊ§μ acetyl chloride) to give an oxadiazole. In Scheme 3e, XJ, R2, #, Cy and Ware defined m herein above. "In one example,# is CrCi alkyl (e.§., methyl).

Oxagole/Tfaiasiole )00161) In yet Mother example, the compounds Of the present disclosure include an oxazole or a thiazole moiety as the ring Z and are prepared using a procedure outlined in Scheme 4, below,

Scheme 4

)00l6lj;: In Scheme 4, X', X"5, #, R“, iC\ Cy, W and E arc defined as herein abovm Oig., for Scheme la. X is halogen (e.g., Cl, Br or I). M one example, X is Cl or Br. Y2 is clbsla frcOn © and $· ;Thf catalyst can be any transition metal catalyst sttitahb for a. Suik-iypc reactions in one example, the catalyst in Scheme 4 is &amp; palladium catalyst, such as &amp; palIadm^;|iios|iiine, e.g. pa!ladrjm(0)teirakistripihe»tylphosphine, Pd(PPh3),, [001641 In Scheme 4, the nitre analog XiH is first covalently baked to the oxazolc or ihiazoie XIV, The nitro group oil he resulting cross-coupled product XV is reduced ίο an amino group using an appropriate reducing agent, such as hydrogen in combination with a metal catalyst, stick as Pd/C. The reduced analog XVI can then be coupled to an appropriate carboxylic acid analog, e.g„ compound 11, e.g., as outlined in Scheme la, to produce the desired oxazole or thiazole, [00165] A person of ordinary skill in the aft will appreciate that compound XIV in Scheme 4 can be replaced with another oxazole, thiazole, isoxazoic or issthiazole derivative to produce the corresponding products. Exemplary reagents are;

wherein P.“ is defined as hereinabove and Y2 is O or S. imidazole [001.661 In a further example, the compounds of the present disclosure include an imidazole moiety as the ring Z and are prepared using a related procedure outlined in Scheme 5, below.

?kbeme S

[001.67] In Scheme 5, X'1, X3, R2, R3, R\ Cy, W and E are defined as herein above (see, e.g., Scheme la). X is halogen (e.g., Cl, Br or I). In one example, X is Cl or Br. The catalyst can be any transition metal catalyst suitable for a Stilie-type reaction. In one example, the catalyst in Scheme 5 is a palladium catalyst, such as a palladium phosphine, e.g. Pd(PPh3«. 100168] A person of ordinary skill in the art will appreciate that compound; XVU in Scheme 5 can be replaced with another imidazole derivative to produce the corresponding product. An exemplary reagent is:

wherein ΚΛ R4 and R,,a are defined as hereinabove [00169] Alternatively, in Schemes 4 and 5, the coupling reaction with the imidazole, thiazole, oxazole and the like is performed, subsequent to the amide formation, starting with compound XX. An exemplary coupling reaction is outlined below.

Tetraaolo [001701 Jn another example, thesepounds oithe present disclosure include λ tetrazofe moiety as the ring Z. Me teitazole moiety trim be prepared loom the corresponding nitrile through reaction with an aside-·trialkylstannaac. An exemplary px>c®dure is outlined in Scheme 6, below. For ©cample, the nitrile XXI is reacted with azidotributyistannane (BioSnN.}) to form the tetrazoie XXII, The teiramlc hydrogen cars be replaced with another substituent an alkyl group) by contacting the tetrazolc with an electrophile and, optionally, an organic or inorganic base (c.g., carbonate or mieihylamine). Exemplary electrophiles include ]g-Rw whemtt I.4 is defined as herei® above and X is a leaving group, such as halogen: (e.g„ Cl, Br, I), In one example, X-R4 is a halogerfesubstituted alkyl or hcteroslfeyl reagents (e.g., MM).

Ssteii

[Oh17!) In Scheme 6, Xs, X \ R2, R4, Cy and W are defined as herein above (sec, c.g., Scheme la). R is alky! (e g., Ci-Cjo alkyl). A person of skill in the aft will appreciate that the teiraxole moiety can alternatively he formed prior to amide formation (e.g,, garting with an appropriate eyaao nitro analog).

Fvrazole [Willi In another exarnpi e, the compounds of the present disclosure include a ppazste moiety as the ifeg Ϊ, and can be prepared using a procedures outlined in Scheme 7, below.

Scheme 7

[##173] In Scheme 7, X:, Xy P/\ R

'. R''\, Cy and W am defined as herein above (see, e.gu, Scheme la). In one example, R4 is H or methyl In Scheme 7. the aeeiyl analog XX iV is first converted to the dirncthyiamino aetyloyl analog XXV, which is then converted to the pyrazole XXV! by reaction with a hy Jrazide. A. person of skill in the art will appreciate that the pyrazole moiety can alternatively be formed prior to amide formation, »17! in another example, the pyrazole moiety can be coupled to the remainder of the molecule via a nitrogen atom, e|g., m outlined in Scheme 7b.

Sfita£Zb

[(10173] In Scheme 7b, Χ’,Χ*, Β/\ R" and B4° are defined as herein abow (see, e.g., Scheme la).

[00176] In another example, the compounds of the presen t disclosure iasisde a 6-membered heteroaromatie ring, such as a pyridine or pyrazine moiety as the ring 2. Such molecules can be prepared using a procedure outlined in Schemes 8a or 8b, below.

Scheme 8a

[00.177] In Scheme 8a, Ys is N or CE4, X5, X3, R2, R4, R* Cy, W and the catalyst are defined as herein above (see, e,g.s Scheme la and Scheme ll). In one example, the catalyst is a palladium phosphine, e.g., Pd(PPh3><.

[00178] Alternatively, the pyridine or pyrazine moiety can be coupled prior to amide formation starting from the nifro analog XIII as outlined in Scheme 8b, below.

Scheme 8b iwi /»| in scheme bb, Υ" is N or

CR\ X:\ X", ti\ K\ R.4*, % W and the catalyst are defined as herein above (see, e.g., Scheme la and Scheme lb). In one example, the catalyst is a pallMum phosphine, e.g., Pd(PPh3)4,

Synthesis of Substituted Thiophene Analogy fSOl SOI In one example, the compounds of the present disclosure include a substituted thiophene ring. For example, in Formulae (II) to (XV), R2 and/or R2* is other than H. Halogen-substituted analogs may be prepared using the procedure outlined in Scheme 9.

Scheme 9 ^wawwwwwwwwv

[00181] In Scheme 9, Rb is a ring arid X is a halogen (eq|, Br or llib In one example, X in Scheme 9 is Br. in another example, Rb is chosen ®m simMtated or unst&amp;stifoted eycloally/l, substituted or uusubstituted heieroeyeleaikyb substituted or unsifostifoted aryl and substituted or unsofestiftited heteroaryl. For example®®? is 9B~ fluorene. in Scheme 9. the iso thiocyanate Χ.ΧΥΠ is eyclized with the chloro beta-ketocster XX Vi 11 in the presence of a base to give the carbamate XXIX, Deproteetion of the amino group (e.g., nsrng rnorpholine to remove ftnorene protecting groups a®ids the halogenated thiophene ester XXX. I. Compound ΧΧΜΪ can be further converted to an. amide by coupling to an appropriate carboxylic acid, similarly to the reaction outlined in Scheme I.

[091821 Alternatively the halogen can be replaced with; another moiety (e.g., cither before deproteetion of the amino group, or after coupling of the amine with an appropriate carboxylic acid to form an amide). In one example, the halogen X (e.g., Br) in Scheme 9, can be replaced with a trifluoro-methyl (-CF^) group, c.g., using CF3-CO2-Cul or methyl 2,2-difiuoro-2*(fluorosnIfonyl)acetate/CuL In another example, halogen X is replaced with halogen X* or CN, eg., utilizing Sandmeyer or Sandmeyer-type reactions. For example, Br can be replaced with CL using a reagent including CuCS (CuCl/DMF) or with CN using a reagent including CuCN (e.g., CuCN/DMF), The substitution of one halogen for another can be performed at different stages of the synthesis. For example, compound XXXI in Scheme 9 can first be converted to an amide and foe resulting analog can be subjected to halogen exchange. Subsequently the ester moiety can be converted to an heteroaryl group (e.g., a triazole moiety), e.g., using the methods described herein, [08183] Analogs including an alkyl group as R2 can be prepared using appropriate starting materials such as methyl-2-amino-4~tiiethyl-3-tiiiophene carboxyiate, which is eemmereially available (etg., Oakwood, Fluorochem):

Pharmaceutical Clomposltioas |00||4] She disclosure further provides pharmaceutics! compositions including a compound of the present disclosure, e.g., those of formulae (i) to (XV) (or any: embodiment thereof), and at least one pharmaceutically acceptable earner. The term ’‘pharmaceutically acceptable carrier” means all pharmaceutically acceptable ingredients known to those of skill in the art, which are typically considered non-active ingredients. The term “'pharmaceutically acceptable carrier” includes solvents, solid or liquid diluents, vehicles, adjuvants, excipients, glidants, binders, granulating agents, dispersing agents, suspending agents, wetting agents, lubricating agents, disintegrants, solubilizers, stabilizers, emulsifiers, fillers, preservatives (e,g,s antioxidants), flavoring agents, sweetening agents, thickening agents, buffering agents, coloring agents and the like, as well as any mixtures thereof. Exemplary carriers (ie„ excipients) are described In, e.g.„ Handbook oj Pharmaceutical Manufacturing Formulations, Volumes .1-6, Mazi, S&amp;rfaraz Taylor &amp; Brands Group 2605, which is mlbipd^d:::her#a by reference in its entirety. A pharmaceutical composition of the present disclosure may include one or more compounds of the present disclosure in association with, ow or more pharmaceuticafly acceptable carrier and optionally other active ingredients, f#8X85J The compounds of the present disclosure may be administered orally, topically, paremcrailv, by inhalation or spray or fecially in dosage unit formulations containing at least one phqrtpacsutically acceptable carrier. The team "parenterai” as used herein includes percutaneous, subcutaneous, intravascular {s.g., inttnVendtii), intramuscular, or intrathecal injection br infusion techniques and the like, fie pharmaceutical compositions containing compounds of the present disclosure may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

[00186} Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents chosen from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture wish non-toxic phanmacemidaily acceptable excipients that are statable for the manufacture of tablets. These excipients may be for example, inert diluents, snob as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agems, for example, cqp starch, or aigbiie acid; bhtdiig agents. for example starch, gelatin or acaei% and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uneoated or they may be coated by known techniques. M some cases such coalings may be prepared; by known tpbi|iques to delay disSgegraifon and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyeeryl Mahbsteriie or gUceryi diitearate may be employed. formulations for oral use may also be presented as hard gelatin capsules, wherein the active Ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example f damn oil, liquid paraffin or olive oil. Formuteiioas for oral use may also be presented as lozenges.

[OllSSj Aqueous suspensions contain the active materials in admixture with excipients suitable for the manu&amp;ctme of aqueous pspensfom Stick excipients are suspending agents, for example sodium earboxymethyleefiulose, methyteelluiose, hydronropy i -methylcel I ulose, sodium alginate, polyvinyipyrro; idone, gum tragacanth and gum acacia; dispersing of wetting agents may be a naturally-occurring phosphatide; for: example, Itidtluh, or condensation products of an aikylenc oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadeeaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatly acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyi p-hydroxybeszoatc, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin, [0O189| Oily suspensions may be formula,ted. by suspending the active ingredients in a vegetable oil, for example aracliis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin, The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[00190] Dispersible powders and granules siniable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with, a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present, 190191] Phanrnaceutical compositions of the present disclosure may also be in. the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these, Suitable emulsifying agents may be naturally-occuning gums, for example gum acacia or gum tragaeanth, naimaliy-oceurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. 100102] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to rim known art using those suitable dispersing or wett ing agents and suspending agents that have been mentioned above, fhei^et^iMjectaMsrpt'iepar^e^ mm also be a sterile injectable solution or suspension in a norotoxie parentally acceptable diluent or solvent, for example as a solution m 1 s3~butiiiiediol. Among the acceptable vehicles and solvents that «Say be employed are water. Ringer's solution and isotonic sodium chloride solution In addition, sterile, fixed oils are com-erUfon ally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation, of in] eetables.

[00193 f The compounds of the present disclosure may a lso be administered in the form of suppositories, e.g., for rectal admin^iration of the drug. These compositions can be prepared by mixing the drug with a suitable rson--irotating esdplent that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa burter and polyethylene glycols.

[00194] Compounds of the present disclosure may be administered parenterally in a sterile medium. The compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the -vehicle, la one embodiment adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved is the vehicle.

[08195] For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are applied, for example, as a topical gel, spray, ointment or cream, or as a scleral suppository, containing the active ingredients in a total amount of for example, 0.075 to 30% w/w, 0.2 to 20% w/w or such as 0,4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base, [8819b j Alternatively the active ingredients may be formulated in a cream w ith an oil-invwaier cream base . If desired, the aqaeons phase of the cream base may include, fer example at least 36% w/w of a polyhydrie alcohol such m propylene glycol, butane-1,3-diol, mannitol, glycerol, polyethylene glycol and mixtures thereof The topical formulation may desirably include a compound, which enhances absorption or penetration of the active Ingredient through the skin or other affected areas. Examples of sniff derma] penemfoon enhancers include·dimethylsulfoxidc and related analogs. The compounds of this present disclosure can also fee administered by a iransdefmal device.

In one embodiment, topical administration will be accomplished using a patch either of the reservoir and porous membrane lype or of a solid matrix variety, in either ease, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agpt ;$ absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of raicrocapsuies, the encapsulating agent may also function as the membrane. The traasdertnal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this present disclosure may be constituted, tern known inpedients in a known manner. While tire phase may comprise merely an emulsifier, it may comprise a mixture of at least one emul-.dmr with a fat or oil or will? both a fat and m oil. In one embodiment, a hydrophilic emulsifier;is included together with a lipophilic emulsifier, which acts as a stabilizer. The phase may, for e>;arnpie,ioc!mie both an oil and a fat. Together, the emulsifferfs) with or without stabilizers) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily, dispersed phase of the cream, formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation, of the present disclosure include Tween 60, Span 80, cetostearyl alcohol, myristy! alcohol, glyceryl monostearate, and sodium iauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream may, for example, be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alky] esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl paknitaie, butyl stearate, 2-ethylhexyf palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on. the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

[001971 Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, esps^&amp;Uy an aqueous solvent for the active ingredients. The anti-inflammatory active, ingredients may, for example, be present in such formulations in a concentration of 0.5 to 20%, such a* 0.5 to 10%, for example about. 1.5% w/w. For therapeutic purposes, Ihc active compounds of the present disclosure are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, po.iyYin.yipjOToUd.otie, and/or polyvinyl alcohol, and then tabieted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared ifom sterile powders or granules having one or more of the carriers or diluent&amp;uneutioned tor use in the fornmlations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycpl, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, beusyl alcohol, «sodium chloride, and/or various buffers, ©ther adjuvants and modes of administration afe well and widely known in the pharmaceutical art. | ¢101981 Dosage levels of the order of from about 0.005 mg to about 80 mg per kilopM of body weight per day are useful in the treatment of the diseases and conditions described herein (e.g., about SJl mgto ibout:5.6 g per human patient per day, based on an average adult person weight of 70 kg). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may, for example, be applied as a topical preparation of compounds of this present disclosure on the affected area one to lour times a day.

[00199] Ponsmlations suitable for inhalation or insufflation include solutions: and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures there f, and powders. The liquid or solid compositions may contain suitable pharmaceutical ly acceptable excipients as describe above. The compositions may be administered by oral or nasal respiratory route for fecal or systemic effect Compositions may be nebulized by use of inert gases or vaporised., and breathed directly from the nebulizing/vaporiciric device or the neblilmtig device may be attached to a faceruask tent or intermittent positive pressum-br eathing machine.

[00200] It will be understood, however, that the specific dose level for any particular patient, will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease u ndergoing therapy:.

[00201] For adminisirktibu to dtim-human animals, the exposition may also he added to the animal feed or drinking water. It may be convenient to formulate the animal feed sad drinking water compositions so that foe animal takes in a therapedtieally appropriate quantity of the composition along with its diet. It may also he convenient to present the composition as a premix for addition to the feed or drinking water.

Methods [00202] Over-acrivation of INK. is believ ed to be an important mechanism in autoimmune, inflammatory, metabolic, neurological diseases as well as cancer and pain. Certain compounds of the present disclosure exhibit inhibitory activity against INK (c.g., JNK1, JNK2 and JNK3). Kinase activity can be determined using a kinase assay, which typically employs a kinase substrate and a phosphate group donor, such as ATP (or a derivative thereof). Exemplar/ kinase substrates for various kinases are described in Example 14. The kinase catalyzes the transfer of a phosphate group from the phosphate group donor (e.g.s ATP) unto the substrate forming a covalent bond. Certain compounds of the present disclosure can inhibit the activity of the kinase, slowing the above described reaction and resulting in a smaller number of phosphate groups being transferred. Electee, the current disclosure provides a. method (i.e., an in vitro assay) that includes: (i) contacting a compound of the present disclosure with a kinase (e,g.s JNK, p3S, MAPK and the like) thereby forming a mixture. The method may further include (ii) contacting the mixture with a kinase substrate (e.g., peptide substrate) and ATP (or a derivative thereof), thereby forming an amount 6f phosphoryiated kinase substrate. The method cun further include tin) measuring tbs amount of phosphoryiated kinase substrate. The amount ofphosphorylated substrate may be accomplished using st detection reagent. Suitable detection reagents can include a metal reagent, su|h asta lanthanoid (e.g.. Eu~63) a radioactive probe, a labeled (e.g., iuoresccntly labelled) antibody and combinations thereof. In one example, the assay Is a fluorescence resonance energy ransfer (FRET) assay (1^ TR-FRET). Examples of such assaya-am: described in Example 14. In another embodiment, compounds of the present disclosure; is used as;a;referenoe standard to determine the in vitro activity of other compounds in a kinase assay as described above. In another example, the ctu^f>euad% disclosure is used in an in vitro assay for identifying candidate compounds that are capable of inhibiting JNK.

[00203] Over-activ ation of INK is believed to be an importan i meehanism in autoimmune, inflammatory, metabolic, neurological; diseases as web as cancer and pain. Hence, compounds and compositions of the present disclosure may be useful in the treatment and/or prevention of c-Jurs N~tcrrom;;l kinase mediated disorders, such as autoimmune disorders, mflarnffiatory disorders, metabolic disorders, neurological diseases, pain and cancer.

[00204] One member of the JN K family, Jrsk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system. Thus, the compounds of the present disclosure may be useful for the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and other diseases and conditions characterized, by neuronal cell death, such as stroke. An in vivo model, which can be used to assess the potential in vivo beneficial effect of the compounds of the present disclosure, is described in Example 15.

[(10205] Excitotoxic cell death can be induced experimentally by the administration of kainic add, a potent agonist of the kainate class of glutamate receptors.

Peripheral injection of kainic acid results in recurrent seizures and degeneration of select populations of neurons in the hippocampus. Activation ofjnk is observed after kainic acid treatment in vivo (see, e.g., Jeon S. H. et al, Experimental and Molecular Medicine 2000, 32(4): 227-230 and Kim Y.-H. etal, Molecules and Cells 2001. 11(2): 144-150). Mice lacking the Jnk3 gene are resistant to kainic acid-induced upregulation of phosphorylated c-jun (p-cjun.) and hippocampal neuronal apotosis (see e.g., Yang D.D. et ah, Nature 1997, 389: 865-870), Pliosphoryiated c-jun in wildtype mice is upregulated after kainic acid administration and demonstrate that this upregulation is inhibited by compounds of the present disclosure.

[0112061 The disclosure provides a method for reducing the upregulation of pliosphoryiated c-jun (e.g,, which is induced by an excitatory amino add or an analog thereof), in the braiu of a test animal, such as a rodent (e.g., mice, rat, rabbit and the like). The method includes administering to the test animal a compound or composition of the present disclosure. The method can further include administering to the test animal an excitatory amino acid, such as kainic add. The method can further include measuring the amount of phosphorylated c-jun in the brain, (e.g., hippocampus) of the test animal [002071 In one example, the disclosure provides a method of treating a disease. The method includes administering to a mammalian subject (e.g., human) in need thereof a therapeutically effective amount of a compound or salt of the present disclosure, for example those according to any one of Formulae I to XV (or any embodiment thereof), or a composition comprising such compounds or salts, [00208] In one example, the disease is a neurodegenerative disease. In another example, the disease is an infectious disease (e.g., sepsis, septic shock and Shigellosis).

In yet another example, the disease is an autoimmune disease. In a further example, the disease is a destructive bone disorder, such as osteoporosis, osteoarthritis and multiple myeloma-related bone disorders.

[00209] Neurodegenerative diseases which may be treated by the compounds of this disclosure include, but are not limited to Alzheimer’s disease (AD), diffuse Lewy body type of Alzheimer’s disease, Parkinson’s disease, Down syndrome, dementia, mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS)„ traumatic brain injuries, cerebral Acheron. brain damage, ischemic or hemoithagifg stroke, multitiMirot dementia, hereditary cerebral hemorrhage with amyloidosis of the dutch-type, cerebral amyloid angiopathy (including single and recurrent lobar hemorrhages), neurodegeneration induced by viral infection {e.g. AIDS; encephalopathies) and other degenerative dementias, including dementias of mixed vascular and degenerative ongia, dementia associated with Parkinson’s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration,

Netirodegenerati ·. e diseases also: includes epilepsy, seizures, neuroriegeocrative diseasc caused by traumatic injury, isehemialroperfusion in stroke, cerebral ischemias, acute hypoxia and ischemia or glutamate neurotoxicity. In a one example, the neuKviegener&amp;iive disease is Arzheimer’s disease or diffuse Lewy body type of Air!;d;ner ’$ disease. In one example, the neiaodegeoerativo disease which can be treated using the compounds of tills disclosure is Alzheimer’s disease. The treatments# Alzheimer’s disease (AD) cap include methods of treating a patient who has AD, mellmds of preventing a patient from getting AD, methods of preventing or delaying fie onset of AD; e.g., delaying or proven ring the progression from MO to AD. In another example, the neurodegenerative disease is diffuse Lewy body type of Alzheimer’s disease. In yet another example, the disease is mild cognitive impairment (MCI).

[IHK2103 In another embodiment, the disclosure provides a method of treating a disease chosen from epilepsy, seizures, Huntington’s disease, multiple sclerosis, cancer, age-related macular degeneration, diabetic retinopathy and retinal npurodegeneratlon related to glaucoma or ocular trauma, the method comprising administering to a mammalian subject (e.g., a human subject) in need thereof a pharmaceutically effective amount of a compound or salt of any one of Formulae I to XV (or an embodiment thereof) or a pharmaceutical composition comprising at least one compound of Formulae I to XV (or an embodiment thereof). Other diseases, which may be treated using the compounds of the present disclosure include alcoholism, Alexander's disease, Alper's disease, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), prion diseases, bovine spongiform encephalopathy (BSE), Cauavan disease, cerebral palsy, Cockayne syndrome, corticobasa! degeneration, Creutzfeldt-Jakob disease, ifontotempm-al lobar degeneration, Huntington’s disease, HIV-associated dementia, Kennedy's disease, Krabbe’s disease, Lewy body dementia., neuroborreliosis, Maehado-Joseph disease (e.g., spinocerebellar ataxiatype 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann Pick disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, progressive supranuclear palsy, Return's disease, Sandhoffs disease, Schilder's disease, subacute combined degeneration of spinal cord secondary to pernicious anaemia, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszcwski disease and tabes dorsalis.

[80211] Autoimmune diseases which may be treated or prevented by the compounds of this present disclosure include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, tlu*omboeytoperna, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis and graft versus host disease (GVKD), The compounds and compositions of the present disclosure may also be useful to treat pathologic immune responses such as that caused by T ceil activation and thrombm-i nduced platelet aggregation.

[002li] Additional specific conditions or diseases that may be treated with the compounds or compositions of the present disclosure include, without limitation, myocardial ischemia., ischemia/reperfusion in heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, hepatic ischemia, fiver disease, congestive heart failure, thrombin induced platelet aggregation, endotoxemia and/or toxic shock syndrome, and conditions associated with prostaglandin endoperoxidase synthase-2.

[00213] in other embodiments, the specific conditions or diseases that may be treated wills the compounds or compositions of the present disclosure include, without limitation, angiogenic disorders, including solid tumors, liquid tumors, tumor metastasis, ocular neovasculiaaiion, infantile haemangiomas. Proliferative diseases which may be treated or prevented by the compounds of this disclosure include, but are not limited to, a®ie myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Ki|5osi's sarcoma, multiple myeloma and HTLV-1 mediated fttmorigenesis. 100214] Other specific conditions or diseases that may be heated with the compounds or compositions of the present disclosure include, without limitation, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis., systemic lupus oythematosis, scleroderma, chronic thyroiditis, Grave's disease, diabetes, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft versus host disease (GVHD), inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter’s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterised by massive neutrophil infiltration, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary' infkmmatoxy disease, silicosis, pulmonary sarcossosis, bone resorption disease, allograft rejections, fever sad myalgias due to infection, cachexia secondary to infection, meloid formation, sear tissue fermation, ulcerative eolitisypyresis, iutiuenza, osteoporosis, osteoairirSis add multiple myeloma-related bone disorder, [011215] In addi tion, .INK inhibitors of the instant disclosure may be capable of inhibiting the expression of inducible pto-inflammatory proteins. Therefore, other "JNK-mediated conditions” which may be treated by the compounds of this disclosure include edema, analgesia, fever and pain, such as neuromuscular pain, migrains, cancer pain, dental pain and arthritis pain. |IM)2I6J In addition to the compounds of this disclosure, pharmaceutically acceptable derivatives or prodrugs of the compounds of this disclosure may also be employed in expositions to treat or prevent tbs above-sidentifisd disorders.

[0d21T] The disclosures in this document of all articles and r eferences, including patents, are incorporated herein by reference in their entirety.

[Ο0ΐϊΙ| tie instant disclosure is illustrated furibp· by the following examples, which are not to be construed as limiting the present disclosure in scope or spirit to the specific procedures described in them. Analogous structures and alternMive synthetic routes within the scope of the present disclosure will be apparent to those skilled in the art,

EXAMPLES

[00219] Reagents and solvents obtained from commercial suppliers were used without further purification unless otherwise stated. Thin layer chromatography was performed on precoated 0,25 mm silica gel plates (E. Merck, silica gel 60, F254). Visualization was achieved using UV illumination or staining with phosphomoiybdic acid, ninhydrin or other common staining reagents. Flash ekomatography was performed using either a Biotage Flash 40 system and prepacked silica gel columns or hand packed columns (E. Merck silica gel 60,230-400 mesh). Preparatory HPLC was performed on a Vartan Preps tar high performance liquid chromatograph. Ή and I3C NMR spectra were recorded at 300 MHz and 75 MHz, respectively, on a Varian Gemini or Broker Avance spectrometer. Chemical shifts are reported in parts per million (ppm) down field relative to tetramethylsilane (TMS) or to proton resonances resulting from incomplete deuteration of the NMR solvent (S scale). Mass spectra were recorded on an Agilent series 1100 mass spectrometer connected to an Agilent series 1100 HPLC, [0Θ228] Compound purity was typically determined by HPLC/MS analysis using a variety of analytical methods. Exemplary methods arc described below.

[1] ~ 20% [B]; 80% [A] to 70% [B]: 30% [A] gradient in 1.75 min, then hold, at 2 mL/min, where [ A]=0.1 % trifluoroacetic acid in water; [B]=0.1 % trifluoroacetic acid in acetonitrile on a Phenomencx Luna Cl 8 (2) 4,6 m«m X 30 cm column, 3 micron packing, 210 run detection, at 35 °C.

[2] = 50% [B]: 50% [A] to 95% [B]: 5% [A] gradient in 2,5 min, then hold, at 2 mL/min, where [A]=0J% trifluoroacetic acid is water; [0)=43.1% trifluoroacetic acid in aeetomtrie on a Phenoaieocx Luoa Cl 8 (2) 4.6 mm X 30 cm column, 3 micron packing, 2.10 am detection, at 35 °G.

[3] = 5% [8]: 95% [A] to 20% [B]: 80% [A] gradient in 2.5 mini then hold, at 2 mUimd. where [A.]=0,1% trifluoroacetic acid in water; [B]:-0,1% trifluoroacetic acid in acetonitrile on a Phenomenex Lana Cl8 (2) 4.6 mm X 30 cm column, Smiiot®»paeSling, 210 nm detection, at 35 °C.

[4] - 20% [Bj: 80% [A] to 70% [B]: 30% [A] gradient in 2.33 min, then hold., at J.5 mL/min, where [A]-0.1% trifluoroacetic acid in water; trifluoroacetic acid in acetonitrile on a Phenomenex Luna 08 (2) 4.6 mm X 30 cm column, 3 micron packing, 210 nm detection, at 35 °C.

[5] = 50% [B j; 50% [A] to 95% j Bj: 5% [A] gradient in 3,33 nun, then: hold, at 1,5 mL/min, where [A]=0,1% trifluoroacetic acid in water; trifluoroacetic acid in acetonitrile on a Phedomensk Lima C18 (2) 4.6 ritih X 30 cm column, 3 micron packing, 210 nm detection, at 3.5 [6] - 1% §B|; 95% [A] to 20% pij: 80% [A] gradient in 3,33 min, then hold, at 1.5 mL/min; where (Aj~0.1% trifluoroacetic acid in water; [B]H}.1% trifluoroacetic acid a acetonitrile on a Phenomenex Luna Cl 8 ||) 4.6 mm X 30 cm column, 3 micron packing, 210 nm detection, at 35 °C. |7] “ 205¾ [Bj: 80% [A] to 7054 [Bj: 30% [A] gradient in 10.0 min, then hold, at i.5 mL''min, where [A]=0.1% trifluoroacetic acid in water; [B]=0.1% trifluoroacetic acid in acetonitrile on a Phenomenex Luna CIS (2) 4.6 mm X 3 cm column, 3 micron packing, 210 nm detection, at 35 *C. PI = *0% [i|j: 90% [A] to 40% j Bj: 60% [Aj gradient in 10*0 min, then hold, at 1.5 mL/min, where [A]:::Q. 1 % trifluoroacetic acid in water; [Bj=0.i% tnfluoroaeetic acid id acetonitrile on a Phenomenex Luna €18 (2) 4.6 mm X 3 cm column, 3 micron packing, 230 nm detection, at 35 °€.

[11 =23% [BJ: 77% [A] to 30% [B j: 70% [Aj gradient in 15.0 min, then hold, at 1.0 mL/min, where [A] 0.1% trifluordaeetic acid in water; [B]=0.i% trifluoroacetic acid in aeemratrilfe on a ils^ex SB-pherat ¢318 2.1 mat X 5 cm column, 5 micron packing, 210 nm detection, at 30 °C.

[10] = 50% (Bf: 50% [A] to 95% (BJ: 5% [A] gradient in 10.0 min, tlsn hold, at 1.5 mL/min, where [A]-0J % trifluoroacetic acid in water; [Bj=0.1% trifluoroacetic acid in acetonitrile a Phenomenex Luna €18 (2) #.6 mm X 3 cm eofipin, 3 micron packing, 210 nm detection, at 35 ,;'C.

[.11] -§% [B|: 95% [A] to 20% [B]: 80% [A] gradient in 10.0 mih, then hold, at 1.5 mL/min, where [A]=Q.1% triftuoroacetic add in water; [B]=0.1% trifluoroacetic acid in acetonitrile &amp; Pheuomenex Luna C i 8 (2) 4.6 mm .X 3 cm column, 3 micron packing; 210 am detection, at 35 °€, [12] = 30% [B]:70% [A] to 60%[B]:40%[A] gradient in 30 minfthen hold, at 16 mL/min, where [A]=0.1% trifluoroacetic acid in water; [B]= 0..1% trifluoroacetic acid in acetonitrile on a Phenomenex synergi Hydro-RP 2 X 25 cm column, 4.0 micron pacing,

210 ilrii detection, at 3 5 XT

[13] = 10% |BJ: 90% [A] to 40% [B]; 60% [AJ gpadientin lO.O miu, then hold, at 1.5 mL/min, where [A.]=0.1% trifluoroacetic acid in water; [B];::6.1% trifluoroacetic acid in acetonitrile a Phenomena* Synergi Polar-RP 4.6 mm X 5 cm cohrmn, 2d micron packing, 210 run detection, at 35 °€.

General Procedures;

Protocol A

[00221] 7¾ a solution of the cathoxylic acidfe.g,, 1.00 mmol) and the amine (e.g , 1,00 mmol) in pyridine (e.g., 0,5 M) at about 0 °€ was added phosphorus oxychloride (POLL, e.g., 1.1 mmol) and the resulting .solution -was stirred at about G W for about 30 minutes, Water was added to the reaction mixture and the resulting solution was diluted (e.g., with methylene chloride). The mixture was washed with: saturated aqueous NaRCO? and the aqueous phase was separated and extracted with methylene chloride. The combined organic phases were dried (e.g, NavSCL), filtered, concentrated under vacuum and the residue was optionally purified (e.g,, silica gel column chromatography and/or preps?%; i ve HPLC).

PmtUCOi Β [00222] [OWl] To a solution oftbe carboxylic acid (e-g* 1.00 mmol) and the amine (e.g., 1.00 mmol s ip methylene chloride (0.3 M) was added 1-( 3* dimethylaminopropyll-S-ethylcarhodiimide hydrochloride (EDCI, e.g., 1.20 mmol) and 1 -hydroxybenzotriazole (HOBt, e.g., 0.10 mmol). The reaction mixture was stirred at room temperature for about 18 h and was subsequently washed with 1 N aqueous HCi and saturated NaRCCX The organic phase was separated, dried (NajSO i), filtered, concentrated under vacuum and the residue was optionally purified (e.g,. silica gel column chromatography),

Protocol C

[©§223] The carboxamide (e.g,, 1.00 mmol) was dissolved in dimethyObrmamide dimethylacetal (DMP-DMA, e.g.. 10.0 mmol? and the riisnltiilg solution was heated to about 110 “C for about 30 minutes. The solution was concentrated under vacuum and the residue was dissolved in acetic acid (e.g., 0.5 M). Hydrazine monohydrate (e.g., 1.10 mmol) was added to the solution and the mixture was heated to about 90 CC for about 30 minutes. The reaction mixture was concentrated under vacuum and the residue was optionally purified (e.g., by preparative HPLC).

Protocol I> [00224] Ί he carboxamide (1.00 mmol) was dissolved in dimothyiacctamide dimethylacetal (DMA-DMA, 10.0 mmol) and the resulting solution was heated to 110 °C for 30 minutes. The solution was concentrated under vacuum and the residue was dissolved in acetic acid (0.5 M). Hydrazine monohydrate (1.10 mmol) was added to the solution and the mixture was heated to 90 °C for 30 minutes. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC.

ProtocolE

[§0221] The chlorothiophcne (e.g., 1.00 mmol), stannanc (c..g., 1.00 mmol), and Pd(PPh3)4 (e.g., 0.1 mmol) were dissolved in DMF (e.g., 0.5 M) and the reaction vessel was evacuated and purged with nitrogen three times. The reaction mixture was heated to about 95 °C for about 18 h and the resulting solution was cooled to room temperature and diluted with E%0. The solution was washed with brine and the organic phase was separated, dried (NazSO-s), filtered, concentrated under vacumn#diptiihailY purified (e„g.f silica ge! column chromatography}.

Protocol F \ 00226} The nurothiophens and 10°<> palladium;» carbon in ethyl scel&amp;re (e.g., 3 mL) was shaken under a hydrogen atmosphere (e.g., 40 psi) for about 2 h. The resulting suspension was filtered through a pad of diaijomaccous earth and the filtrate was concentrated under vacuum.

Protocol G

[0(1.227! CuCl (e.g., S mmol) was added to a solution of ihs brsmothiophene (e.g., 1 mmol) in Hf (e.gi, 0.3 M) andthe resulting suspehriion was placed into a heated oil bath (e.g., 140 °C). The mixture was stirred for about 15 minutes and then removed from the oil bath. The resulting solution was diluted with Et-jQ and washed with brine. The organic phase was separated, dried (Na2S04), filtered, concentrated under vacuum and optionally purified (e.g., silica gel column chromatography).

Protocol If [00228] Ammonium chloride (e.g., 0.05 rnxnol) was added to a solution of the methyl ester (e.g., 1 mmol) in concentrated aqueous ammonium hydroxide (e.g., 0.3 M) in a glass pressure tube. The tube was sealed and the reaction mixture was placed in a heated oil bath (e.g., 90 °C). After stirring for about 2 h the reaction was cooled to room, temperature and diluted with water. The resulting solution was extracted with ethyl acetate and the organic phases were combined, dried (Na2S04), filtered, concentrated under vacuum and optionally purified (e.g., silica gel column chromatography).

Protocol I

[0022P] DMF-DMA (e.g.. 1.00 mmol) was added to a solution of the carboxamide (e.g., 1.00 mmol) in methylene chloride (e.g., 0.2 M) and the resulting .solution was stirred at room temperature for about 30 minutes. The solution was concentrated under vacuum and the residue was dissolved in acetic acid (e.g., 0.5 M).

Hydrazine rnonohydrate (e.gM 1.10 mmol) was added to the seiutiod aid the tiixture was stirred at room temperature for about 5 minutes. The reaction mixture was concentrated under vacuum and the residue was optionally purified (e„g.s preparative HPLC).

ProtocolJ

[00230] DMF-DMA (e.g., 2.00 mmol) was added to a solution of the carimxamide (e;g., 1.0© mmol) in methylene chloride (e.g., 0.2 M) and the resulting solution was fprred at room temperature for about 30 minutes. The solution: was coventrated under vacuum and the residue was dissolved in aeefic&amp;cid (e.g·, 0.5 M). Metbylhydramne (e.g., 2;0 nundi) was added to the seiitidn and the mixture was sirred at room temperature for about 5 minutes. The reaetiou mixture was concentrated under vacuum and the residue was optionally purified (e.g., preparative HPLC).

Protocol JK

[00231] Sodium hydride (e.g., 2 mmol) was added to a solution of the lactam (e.g., 1 mmol) in DMF (e.g., 0.2 M) at about 0 °C. The resulting suspension was stirred for about 15 minutes after which methyl 2-hromoaceiaie (e.g., 1.2 mmol) was added. The reaction mixture was stirred at room temperature for about 1 h and was then diluted (e.g., with E1?0). The solution, was washed with brine and the organic phase was separated, dried (e.g., Na^SCti), filtered, concentrated under vacuum and purified (e.g., silica gel column).

ProtocolL

[00232] To a solution of the carboxylic acid (e.g., 1.00 mmol) and the amine (e.g., 1,00 mmol) in DMF (e.g., 0.3 M) was added EDO (e.g., 3.5 mmol), DMA? (e.g., 0.5 mmol) and HGBt (e.g,, 0.5 mmol). The reaction mixture was stirred at room temperature for about 8 h and was subsequently diluted (e.g., with ethyl acetate) and washed with brine. The organic phase was separated, dried (e.g., Na2S04), filtered, concentrated under vacuum and the residue was purified (e.g., silica gel column and/or preparative HPLC).

ProtocolM

[00233j The aryi halide (e,g., LOO mmol), triethykmine (e.g., 2.00 mmol) and Ρ(ο-Το1)ι (e.g., 0,30 mmol) were dissolved in acetonitrile (e.g., 0.5 M) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 •minutes. Ethyl acrylate (e.g,, 1.25 mmol) and palladium acetate (e.g., 0.10 mmol) were added to the reaction mixture and the tube was sealed and placed into an oil bath preheated to about 120 °C for about 18 h. The resulting solution was concentrated under vacuum and purified (e.g., silica gel column).

Protocol N (812341 (00811 Sodium stboxide (e.g.. 4 mmol of a 21% solution in ethanol) was added to a solution of the acrylate (e.g,, LOO mmol) in ethanol (e.g., 0.5 M) and the resulting solution was heated to about 60CC for about 2 h. The reaction mixture was diluted (e.g,, with ethyl acetate) and washed with brine. The organic phase was separated, dried (e.g,, hkjSO-i). filtered, concentrated under vacuum and the residue was purified (e.g., silica gel column).

Synthesis of Various Intermediate: 2-(6-Fluoroqismolte-S-yl)acetiC add and 2-{6~£l«areqyin0Hn-7-yl)a€eiie acid Protocol O: [002351 To a solution of o-fluoro benzoic acid (30,0 g, G.19moL in cone, sulfuric acid (50 mL) and water (10 mL) was added dropwise a solution of firming nitric acid (10 mL) in water (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The resulting precipitate was filtered off and washed with cold water, dried in vacuum to give 2”(2-fl.uoro-5-mtrophenyl)aeetic acid as a white solid (35.2 g, 91%).

[0G236J To a suspension of 2-(2-fluoro-5-nitrophenyl)acetic acid (15.0 g, 75.3mmol) in ethanol (8QQmL), THF (400mL), and water (2Q0mL) was added ammonium chloride (4.46 g, 83.4rmno!) and ferrous powder (25,04 g, 405.4mmol). The resulting mixture was heated at 80 °C for 1 hr and the progress of the reaction was monitored by TLC. Upon complete consumption of starting material, the reaction mixture was filtered off while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (20OmL) and washed with water (3 x lOGmL). The combined organic layer was washed with brine, dried dtter Na2SCi4 and evaporated under vacuqm 1» afford 2~(5-a:nino-2-i|noropbeny3)aeede acid as a grey solid which was used for the next step without ftirther puriffearion (6.13 g, 48%).

[002371 To a solution of 2-(5~amina-2-fhu>ropkenyl)aeetic acid (6.13 g. 36.2mmoi) in ethanol (!5mL) was added cone, sulfuric acid (2mL) dropwise. The reaction mixture was stirred under M2 at 80 ®C for Ihr. After the reaction mixture was cooled to RT and neutralized with aqueous Na?.CO? to pH 7-8, the aqueous solution was extracted with ethyl acetate (3 x lOOmL). Hie combined organic layer was washed with brine, dried over Na2SC>4 and evaporated under vacuum to afford ethyl 2-(5-amino-2~ fluorophenyl)aeetate as a yellow oil which was used for the next step without further purification (6.13 g, 95%).

[00238] To a mixture of ethyl 2-(5~amino-2~fSuoropheuyl)acetate (3.7 g, 18.8mmol), glycerol (6.92 g, 75.2mmol), nitrobenzene (4.63 g, 37.6mmol) and ferrous sulfate (j .06 g, 3.76mmol) was added cone, sulfuric add (4.5tnL) dropwise. The reaction mixture was heated at 120 °C for 15hr. After cooled to RT, the reaction mixture was diluted with ethanol (20mL), and 2N aq. NaOH was introduced to adjust pH about 13,

The resulting mixture was stirred at RT for Ihr, Then the reaction was neutralized with aq, HC1 and filtered, and the dark brown precipitate was washed with methanol. The combined filtrate was concentrated to dryness in vacuum. The resulting residue was washed adequately with methanol and the combined filtrate was concentrated to dryness to give crude product, which was isolated by flash column chromatography to give 2-(6-:fiuoroquinolin-5~y!lacehc acid and 2-(tPfliioroquiiioji»-7-y!)aceilc acid (1.7 g, 44%), LC-M$ (0JS1TFA): [MTl]+201,1. 1H-NMR (DM5G~d6, 400MHz): 512,66 (brs, 1H), 8.90 (rn, 10),:8.36: (m, !H), 8.04(0),111( 7,76 (m, IH), 7.56 (m, 1H? 3.88(s, 20). 2-{8-FluoroqumeMn-5-yi)aeet!e acid [00239] The title compound (1,2g) was prepared from p-fiuorobenzoic acid (10.1 g, 65.5mmril§ aeodrding to Ftetocp ©, above. LCMS (0.05%TFA): [Mr 1]^2|6.0, ft-I-NMR (CD3OD, 400 MHz): δ 8.91 (d, ]H, 3===2.8 Hz), 8.58 (d, ill, J===-6.8Hz), 7,68 (tp, IH), 7.53 (m, IH), 7.50 (m, IH), 4.12 (s, 2H). 2~(8%TriIluoromethyi)qam0Mn-5”yi)a€etIe add [06248] To a solution of 1, 4-dibromo-2-mtrobcnzene (5 g, 17.8rnmd| in N-tneihylpymolidinonc (4teL) were added methyl diit»ro(fliiorosulfonyl)aeetate (4.5ml., 35.6mmol) and copperfl) iodide. The mixture was heated at 80 CC overnight, decolorized with activated charcoal, diluted with brine and extracted with ethyl acetate (3X30mL), The combined extracts was dried over MgSO^, concentrated in vacuum and purified by fash chromatography (0-1 OGpercent ethyl acetate in petroleum) to give 4-bromo-2-nitro-1 -(trifl.uoromethyl)benzene (4, .1 g, 85%) as a yellow oil, [68241] To a suspension of·443renip-lmitro~l~(trifluoromerhyi)benzene (4.0 g, l:4t9mmol) in ethanol (230mL), THF (85ml.), and water (40mL) was added ammonium chloride (1.0 g, Ib.Kmmol) and tenons powder (5.06 g, 90nimol). Tire resulting mixture was heated at 80 "’€ for .1 hr and the progress of the reaction was monitored by TLC. Upon complete consumption of stating:material, foe reaction mixture was filtered oft while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (lOGmL) and washed with water (3 x 50mL). The combined organic layer was washed with brine, dried over Na^SO* and evaporated under vacuum to afford 5-bromo-2-(trifluorom.ethyl)aniline as a solid (3,2g, 90%), [80242] To a mixture of 5 -bromo-2-(tiitluoromethyl)amline (3,0g, 12.6mmol), glycerol (4.64g, SO.Omrnoi), and ferrous sulfate (0.56 g, 2,0mrnoi) was added cone, sulfuric add (2.2mL) dropwise. The reaction mixture was heated at 120 °C for 4hr. After cooled to RT, the reaction was diluted with ethyl acetate (150ml,), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over NajSO^s and evaporated to give the crude product, which was purified with flash column chromatography to gi ve 5-brom0-8-(irifluorometkyl)quinoline (1.2g, 48%).

[88243] 5-Bromo-8-(trifluoromethyl)quinolme (l.Og, 3.6mmol) was subjected to protocol P to give teri-butyl 2-(8-(irifiuoromethyl)quinolln.~5-yl)acetate (450mg, 40%).

[08244] To a solution of tcrt-butyl 2-(8“(trifluotomethyi)quinolin-5-yl)acctatc (400mg, 1.28mmol) in DCM (5mL) was added TFA (1 OrnL) dropwise. The reaction was stirred at room temperature overnight. After the1 reaction was complete, the solvent was removed and the residue was purified (silica gel chromatography) to give the final product 2-(8-(trifluoromethy{)quinoHn”5-yI)acetic acid (180mg, 54%), LC-MS (0.05%TFA): [M+ljf 256.1. Ή-NMR (DMSO-d.6, 400MHz): δ 12.70 (s, 1H), 9.Q7(m, 1H), 8.56 (m, 1H), 8.15 (d, 1H), 7.74(m,M), 7.68(m, 1H), 4.23(s, 2H). !3C-NMR (DMSO-d6,100MHz): 8171.9, 151.0,144.0, 138.3,133.5,127.87,127.83,127.78, 125.3,123.1, 122.2, 37.7. 2-(Isoq8ilnoilii-4-yl)acetlc add :::f|8245|: 5i2gpf 2¾ powder was put into a 25GmL of three- neck flask under N?. protection, and then 0.5mL of TMSCI being dissolved in 20mL of dry THF was injected into the flask. The suspension mixture was stirred at room temperature for 20 minutes, and then 6mL of text-butyl 2-bromoacetate in 50mL of dry THF was dropped into the flask for about 30 minutes at 25-40 °C, After the addition was complete, the reaction mixture was stirred at 40 °C for another 30 minutes.

[002461 4~8ro?ncisoqumoime (2.0g, 9.7mraol) was subjected to protocol P to give a residue which was purified with silica gel chromatography to give tert-butyl 2-{isoquinolin~4~yi}ac<statc (1.9g. 81%).

[00247] To a solution of tert-buty! 2~(isoquinohri'4~yl)aceiate (1.8g, 7.4mmol) in DCM (I OmL) was added TFA (1 OmL) dropwise, The reaction was stirred at room temperature overnight. After the reaction completed, the solvent was evaporated and the residue was neutralized with aqueous ammonia to pH 3-4, then the precipitate was filtered, washed with water and ether, and the ether extract was collected to give the title compound(!.3g, 93%)LC-MS(0.05%TFA): [M+lf 188,1. lB~NMR (DMSCM6, 40GM!Iz): 69.39 (s, 1H), 8.48 (s, Iff, 8.24 (d. 1H, J=6.4Hz), 7.93 (t, 1H), 7.79 (m, !H), 4.11 (s, 2H). 2-(Ise<|Minohn"8-yl)acetsc add [iH>248j 2-bromoben2.aidchyde (18.4g, 0. lmol) and 2,2-dimeltexyethanaminc (11.55g, 0.11 mol) in 200mL of toluene was heated to reflux for 4hr, The reaction mixture was evaporated under vacuum to give an oil of 2-biomo~N-(2,2-dimcthyoxyethylidenelaniline which was used for the next step without purification. The oil was dropped into 50mL of concentrated H2SO4 and the mixture was heated to 130-140 °C for 30mins, then the reaction mixture was poured into 50QmL if ice-water and adjust to pH-8 with 5N sodium hydroxide solution. The aqueous solution was extracted with DCM (2S0mLX5) and washed with water (3 * SQxxiL). The combined organic layer was washed with brine, dried over NajSOi and the solvent was evaporated under vacuum.

The crude solid was purified with silica gel to give 8-bn>moisoquinoHne (2.2g, two steps 10.6%).

ProtocolP

[00249] To a suspension, of 8-bromoisoquinoiine (2,Gg, 9,7mmol)f Q-phos (68mg„ Q.096mmol) and Fd(dba)j (132mg, 0.14mrnol) in dry THF (30mL) was added 40mL of (2-tcri-bidoxy-2-oxGelhyl)2rinc(II) bromide solution under N2 protection. The resulting mixture was heated at 80 **C overnight. The solvent was evaporated under vacuum and the crude residue was diluted with ethyl acetate (lOOmL) and washed with water (3 x SOmL). The combined organic layer was washed with brine, dried over Na2Si>4 and the solvent was evaporated under vacuum to give a residue which was purified with silica gel chromatography to give ten-butyl 2-(isoquinolin-8-yl)acetate (1-8¾ 78%).

[00250] To a solution of tert-butyi 2~(isoqu mohn-B-yDacetate (.1.8g) in DCM (IGmL) was added TFA ( 1 OraL j dropwise. 'The reaction was stirred at room temperature oviMight After the reaction was complete, the solvent wf removed to give a residue which was adjusted to pH 3-4 with aqueous ammonia The precipitate was filtered off and washed with water, The final product was purified (silica gei couiunm chromatography) to afford 2-(isoquinoiixi-8-yl)aceiic acid as a solid (1.2g, 87%). LC-MS (0.05%TFA): [M+lf 188.1,3H-NMR(DMSO-d6,400MHz): 813,0 (bra, 1H), 9.65(8,1H), 8,61(d, 1¾ Ρ4.8ΙΙ/Λ 8.16 (d, 1H, T· 4.Site), 8.05 (|,: 1H, J-6.8i-te},7.92 (t, 1H), 7.72 (d, lH.T-6.xl te), 4.29 (s, 2H). 2-(Qnlnolk8-8-yS)aeetic add

1002511 The title compound (278mg> was prepared from 8-bromoquinoline pi0g, 14.5mmol) according to pr^ocol P above. MiMS (0.05%TM); [MH-lf 188. L (CD>OD, 4m MHz): δ 9.01((1,1¾ 3===3.6Hz), 8.72(4 I IT, J«6.4Hz), 8.06 id, ΪΗ, J-6.SHz)s ?.87 (4 1 Η, .1-5.6Hz),7.77 (m, 2H), 4,31 (s, 2H).

Preparation ©f 2~(beHzo[dithfa£oI~7~y!)aceiie add [08252] To a solution of 6-niirobemzothiazole (3.8 g, 0,02mol) in 40 ml 2N HC1 was added SnC1.2(15.9 g, 0.06ηκ>1), and the mixture was stirred at room temperature overnight. The reaction mixture was treated with concentrated NH4OH to pH 11 and extracted with, ethyl acetate (3 x 150ml). The combined organic phase was concentrated under reduced pressure. The residue was purified (silica gel chromatography) to give benzojdJthiazo 1 ~6~amine (3g, 72%).

[6ft253S To a solution of be®2:o(d}thia5S6!-6-amine (.100 jpg, OJImmoi) ip 6 ml CHCi/, was added Br? (42 mg, 0.27ramol) in CHO.; (;0ml) drop-wise about 15 mini The mixture was concentrated under reduced pressure, and the residue was crystallized from D€M:'.Vie(3H (5:1) to give 7-brGmohenzo[djtMazol-6-anune (80mg, 80%). 10(1254] To a solution of brotnobenso[d]th!azol--6-arni7ie (30 mg, 0.1 Jmmol) was added 50% H&amp;SCfci (38 mg, 0.39mmbl), and then NaNOs (18 mg, 0.26r»moi) was added to the mixture at 0-5 eG. The reaction mixture was stirred about 15 min at th5 °C, 50% fl3pOa (17 mg, 0.26mmol) was added. The mixture was stirred at room iemperafure overnighh quenched writ aq.NaHO@3 soiiihbh, extracted with ethyl acetate, The combined organic layer was concentrated under vacuum to give a residue which was purified with chromatography (ethyl aeetate/petroleum. ether-0.06} to give 7~ bmmob<mzo[d]thiaz:oie (10 mg, 30%). |0§255| The title compound (20 mg) was prepared from 7-br«8tobenzo[d]thiazole according to protocol P. LCMS (0.05%TFA): [M l·]]” 194.1. ^fi* NJi! (fDCU, 400MHz): 59.05 (s, 1H), 8.10(4 HI, 3===6,8Βζ), 7.53 (m, Hi), 7,39 (d, M, mmz), 3.96(s, 211). 4“ΒΓ(ηηο-3-(42Α.1,2,4-ΐΓΐ®ζοΤ3-ν1)ι.|ιΙορΐ5Μ~2~®5ηΙη® [00256] 2-AmiuotMqphenc-3-carboniiriic (2.75 g, 22.1 mmol) in formic acid (15 ml) and concentrated sulfuric add (1 ml) was heated in a microwave for 15 min at 10G°C. The solution was dilated with water, filtered^ and ih| filtrated was concentrated under reduced pressure to yield thiene[2,3~djpyrinuditH*(4 * Λ-ene as a purple fftai Method [Ί5] retention time 2.09 nun by HPi.C (M+ 153), [092S7] 'Hueno[2,3-djpyrunidm~4i3J9V one, sodium acetate (20.92 g. 255 mmol), and bromine (3.0 ml, 58.2 mmol) in glacial acetic add (100 ml) was stirred for 24 h, A second portion of bromine (10 ml, 194 mmol) was added and the heterogeneous mixture heated to reflux for 3 h, then cooled to ambient temperature. The mixture was diluted with saturated aqueous sodium sulfite and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 99:1 ;G. 1,49:1:0.1, 24:1:0.1, and 23:2:0.2 methylene chioride:methauol:coneentrated ammonium hydroxide as the eluant to afford 1.96 g (29% yield over two steps) of 5,6-dibromothieno[2,3~ tfjpyrimidin-4{3//}-one as a yellow solid. Method [8] retention time 6.19 min by HPLC (M+ 309, 311, and 313). 100258] Zipc dust (2 ΐ 0 mg, 3.21 mmol) was added to a solution of 5,6-di^tru>thienoPi3-d3pyriniidmM(3i9)-®ffie (910 mg, 2.94 mmol) in glacial acetic acid (8 ml) and water (2 ml). After stirring for 4 h, a second portion of zinc dust (214 mg, 3.2? rnmoi) was added and; the heterogeneous mixture was placed info a preheated oil bath at 60fl€. The heterogeneous mixture became a clem· solution if 30 min. The solufon was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated tmdersreduced pressure to afford 5-bTOmoth!eno[2s3-d]p>'rimidin.-4(3f9)-onc as a white solid. Method [8] retention time 2.68 min by HPLC (M+ 231 and 233).

[90259] S-Bromothieno^jS-dlpyrimidin-diSi·/)'0^ ^ phosphorus(V) oxychloride (10 ml) was heated in a microwave at 100°C for 30 min. The solution was concentrated under reduced pressure to yield 5-bromo-4-chlorothieno[2,3“i/]pyriniidine. Method [8] retention time 8.72 min by HPLC (Mt 249, 251, and 253) major peak intensities.

[09260] 5-Broirto-4-chlorothieno[2,3”i/]pyrimfdine and hydrazine monofaydrate (2 ml, 41.2 mmol) in absolute ethanol (10 ml) was heated to 75°C. After stirring for 1 h, insolation was eonceatrsted to.yieW5^bronJO-4"hydiaziaylthicaK>[23“flQpyfinjid«ne.

Method [8] retention time 0.80 mm by HPLC (M+ 245 and 247).

[00261] 5-bromo^hydrazmyfthi^of23^pyr«nidme and triethylorthoformate (40 mi) in ethanol (TO mi) was placed into a preheated oil bath at 100¾ for 24 h. The SOkiion was concentrated and the residue was flash ehrorntograph®! with 9: i, 4:1, and 7d> methyleneeMoidde:ethy3 acetate as the eihant to afford 578 iig (38% yield, over 4 steps) of PbromofhkTKi|3,2-^jri,2,4]triazolo[43-c]p>Titr;.idmc as a yellow solid. Method M retention time 4.17 min by HPLC (M+ i§5 and 257); [00262] 9-Btomothieno[3,2"e]ri;7,4]triazokt[43"dpyrirnidine (551 mg, 2slS mpo|) and .^manhylcthiine-1,2-diamine (I ml, 11.3 mmol) ·'?· methanol (20 ml) was placed into a pehea ted oil bath at 60¾. .Mter stiriisg: Sir 15 man, the solution was diluted with sMUated ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 525 rag (99% yield) of 4-bro:mo-3-(4/7-1,2,4-triazo]~3~ yI)thiophen-2-antine as a brown solid. Method [8] retention time 2.25 min by HPLC (M-t-245 and 247).

Example I lynthesis of Thiophene Triazoles ILL Synthesis of .ri'-(2-(f//-1,2,4~4riai5oi»5-yl)thiopben-'3~yl)-2'rinffiphthalen-l- yi)acetamlde (1)

hhh 3~^{N^&amp;tkalm-l^^ceiamMi!)ikiopkene^mmhmyimmMi [00263] Methyl 3 (2-(naphfhalcn-i~yl)acetamido)thiophene-2H:arboxylate (210 mg, 0.645 mmol) was dissolved in THF/J 1-0 (2.5 rn.L, 4/Ί, v/v). Sodium hydroxide (129: mg, 3.22 mmol) wax added and the reachon mixture was stirred at 50 °C tor 20 h. The resniting solution; was aeidiied With 10% aqueous HC1 and extracted with ethyl acetate.

The organic phase was separated, dried JptoSCH). filtered and concentrated under vacuum to give 3-{2-(napbihaien.-l-yi)acetamido}thiophene-2~carboxyiic acid. Retention time - 1.962 min, method [1], MS(ESI) 312 J (M+H). 1,1.2. 3~(2~(Naphthelen~l~yi)ucetamMe)thiophme~2-<;arhoxamide £00264] 3-(2-(Naphthaleii-l-yl)aceiaJT).ido)thlophene-2-carboxylic acid (151 mg, 0.485 mmol) was dissolved in thienyl chloride (2 mL) and the resulting solution was stirred at 60 °C for 30 minutes. The resulting solution was concentrated under vacuum and the residue was dissolved in acetonitrile (2 mL), Concentrated aqueous ammonium hydroxide (2 mL) was added to the resulting solution and the mixture was stirred at room temperature for 2 h. The solution was concentrated to 1 mL, diluted with ethyl acetate and washed with brine. The organic phase was separated and dried (iNazSO*), filtered, concentrated under vacuum, and the residue was purified on a silica gel column (eluant hexane/ethyl acetate, 8/2 to 1/1) to give 3-{2-(naphthalen~1 -yl)acetamido)thiophene-2~ carboxamide (81 mg, 0.26 mmol, 54%). Retention time (min) = 4.917, method [7], MS (ESI) 311.1 (M+H). {§0265J The tile compound was prepared from 3-(2-( naphthaien- i -yl )ac.etarnido)ih!ophcne~2-carboxarnidc (104 mg, 0.335 mmol) according to protocol C. Method [7] retention time (min) +5,105, MS(ESI) 335.1 (M+H)·: ;H NMR (300 MHz, CDCU) δ 10.43 (s, 1H), 8.15 <d,./ = 5.4 Hz, IB), 8.05-8.08 (ro, 1H)« 7.90-7.94 (to, IB), 7,80 (¾ HI), 7,29-7,60 (m, 4H)t 7.27 (s, IB), 4,32 (s, 2H). 1.2. Synthesis of Ai-(2-(3"meftyi-lfl“i,2,4-iria2;ol"5-yl)fhiophen-3-3'1)-2- (napMhaleu-l-yfiaeetauikle (2) |00266j The title compound was prepared from 3-{2-(naphthaler!~l-yl)acetamido)thiophene-2-carboxamide (72 mg, 0.23 mmol) according to protocol D. Retention time (min) = 4.939, method [7], MS(ESI) 349.0 (M+H); 'll 74MR (300 MHz, CDCI3) δ 10.32 (s, 1H), 8.16 (d, J-5.5 Hz, 1H), 8.08-8.1 i (m, 1H), 7.87-7.92 (m,2H), 7.52-7.61 (m, 4H), 7.24 (d, 5.5 Hz, 1H), 4.28 (s, 2H), 2.32 (s, 3H). :1.3, iSyssthesis of N~(2-{ 1,3~d methyl- I//-1,2,4»4rja»;ol~S~y^iiiopisejj

CnapJsthaleM-l~yl)ac£t&amp;mide (3) 10267] The title compound was prepared from 3-(2-(rtaphih?Jeo- I -y!)aseta8^ide!iduopf3sne-2-sa.rboxami^ (71 mg, 0.22 mmol) using protocol D except that methyl hydrazine was used instead of hydrazine. The etude product was purified by preparative HPLC to give A^2~(3~mei!3yi-ji/-K2:^^^ol~5'-yl:)fhiophen~3~yl>-2~ (nafshihalen-l -yi)asgteKHde.&amp;efentio#time (thin)» 6.636, method [7], MS(ESf) 363.1 (M+H); Ή NMR (300 MHz, CD6¾) I 11.20: (s, IH), 8:,30 (d. ^ 5.5 Hz, 1H), 8.12 (d, J = 8.2 Hz, ΪΗ), 7.85-7.91 (m, 2H), 7.48-7.62 (to, 4H), 7.40 (d,/= 5.5 Hz, IH), 4,27 (s, 2H), 3.96 (s, 3H), 2. i 9 (s. 3H). 1,4. Sys5theslscifA-(2-(l-methyM//-l,2,4-friazol-5-yl)fhiop1ien-3-yl)-2- (uaptithaless-1 -y I)acetami de (4) I0026S] The title compound w'as prepared from 3~(2-(naphthalen-“l -yl)acetamido)ihiophene-2-carbox8mide (104 mg, 0.335 rnmo!) according to protocol C except that methyl hydrazine was used instead of hydrazine. The reaction mixture was purified by preparative HPLC to give ^<2-{d-methyl-1.ff-l,2,4-triazol-5-yi)thiophen-3-yl)-2-(naphtha1en-1 -yl)acetamide. Retention time (min) = 6.494, method [7], MS(ESI) 349.1 (M+H); lHNMR (300 MHz, CDCI3) δ 11.26 (s, IH), S.30 (d, J -- 5,5 Hz, IH), 7.88-8.06 (m, 3H), 7.42-7.59 (m, 5H), 7.41 (d, J = 5.5 Hz, IH), 4.30 (s, 2H), 3.98 (s, 3H).

Synthesis of2-(4-Methosyphenyl)-.'V-(2-<3-meihyi-lJ¥~l,2,4-trlaz«1~S~yI)t1ilophen-3·-y1)aeefamMe (5)

L5.L Methyl $~(2~(4-meiMxyykmyl)metaMi4@$kiepkt!m-’2mm&amp;8xyl8te 19269] The ti tle compound was prepared from 2- (4-xr!ethoxyy>hcQyi)ace'ic acid (3,18 g, 19.2 mmol) and methyl 3~aminothiophone-2-airb0xyiiUe (3.02 g, 19.2 mmol) according to protocol B, Retention time (min) ~ 2 14 3. method [1 ], MS{£ST) 306,1 (M+H). 23,2. 3-{2-(4^etkoxyphe.Hyl)acsimMd0)tM(>pkem-2~c8rb8xyH€udd [0027Θ] Methyl 3-(2~(4-methaxyphenyl)acetomido)thiGphene--2-earhoxyIate (5.7g, IS.7 mmol) was dissolved in THF/H20 (40 mL, 4/1, v/v). Sodium hydroxide (2.24 g, 56.1 mmol) was added and the reaction mixture was stirred at 60 °C for 8 h. The resulting solution was acidified with 10% aqueous HQ and extracted with ethyl acetate. The organic phase was separated, dried (NajSt^), filtered and concentrated under vacuum to give 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-caihoxyiic acid. Retention time (min) = 1.678, method [1], MS(ESI) 292,1 (M+H). 2,53. 3-(2-{4-Methoxyphenyi}aceismide)thmpherte~2-carboxiimide [00271] The title compound was prepared from 3-(2-(4-methoxyphcnyi)acetamido)-thiophcns-2-earboxyik acid (1.51 g, 4,95 mmol) according to protocol B (504 mg, 1.73 mmol, 35%), Retention time (rain) ::: 1.446, method [1], MS(.ES1) 329.1 (M+H). 13.4, 2-{4-Meihoxypkenyi)-N-{2-(3-meihy!-lE~li23"^^Z8l3~}'iHhmpkm-3~ yl)acetamide 100272] The title compound was prepared from 3-(2-(4-meihoxyphenyl)aeetiBriido)-thiophcne~2-carbt>xamide (204 mg, 0.703 mmol) according to protocol D. Retention time (min) = 3.893, method [7], MS(ESJ) 329.1 (M+Ή); lH NMR (300 MHz, CDCt) δ .10.33 (s, 1H), 8.10 (d, ./== 5.4 Hz, 1H), 7.27-7.33 (m, 3H), 6.90 (d, ,/=== 9.2 Hz, 2H). 3.81 (s, 3H), 3.71 (s, 2H), 2.54 (s, 3H). 1.6. Synthesis of ,(Y-(2d3-melhyi~l!/-l,2,4~iriazGi-5-yl)ihlophen-3-y!>-?^ (qmrudm~5~yl)acetamMe (6) [00273] The title compound can be made from 3-(2-(qumoiin-5-yl)acctamido)thiophene-2-carhoxatriide (see Example 1.27.1, below) using protocol D. 1.7. Synthesis of ^-(2-(1^-1,2,4-irIazoS-5-yl)tlilophen-3-yl)-2"(4' metboxyphenyl)aceiamlde (7) [00274) The title compound was prepared front 3-(2-(4--m^oxyphe^l)iie^tmdo)>tM£^ene-2-Ktaiboxarnide (Exatopfe * -5:.3., 271 mgs 0.933 mmolf according to protocol C. Retention time (min) =>= 3.754, method [7¾ MSpSl) 315.1 (M+H); Ή NMR (300 MHz, CDCb) S 10.48 (s, 1H), 8.12-8.16 (m, 2H), 7.28-7.33 (m, 3H), 6.97 {d, ./= 8.3 Hz, 2H), 3.87 (s, 3H), 3.79 (s, 2H), 1.8. Synthesis of <¥-(2“(li?-l,2;,4-TrIazol~l“yI)tMophea~3~yi)^-{4“ meihGxyphenyl)&amp;eetamide (8)

/.8./. l-Q-Nkr^dimphen-l-ylhlB-i^l-trittzeie 1092751 1//-1,2,4-triazole (582 mg, 8.43 mmol), 2-ehloro-3-mtoihiophene (1,15 g, 7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolved in DM.F (30 ruL). The resulting solution was stirred at 90 °C for 2 h, after which the reaction mixture was cooled to room temperature and diluted with EtaO. The solution was washed with brine and the organic phase was separated, dried (Na2S04), filtered, concentrated under vacuum to give l-(3-nitrothiophen-2-yl)-l//-l,2,4-triazoie. Retention time (min) = 1.073, method [1], MS(ESI) 197.0 (M+H). 1.8,2* 2-(1114s2J~Trfaml~l~yi}tkmphen~3-mHne [00276] A mixture of 1 -(3-nitrothiophcn-2-yl)-1//-1 ^2,4-triazole (462 mg, 2.35 mmol), iron (1.31 g, 23.5 mmol) and ammonium chloride (163 mg, 3.06 mmol) in water (5 ml,) was stirred at 100 °C for 18 b. The resulting suspension was filtered through a pad of diatomaceous earth and the filtrate was basified with aqueous NaOH. The aqueous solution was extracted with methylene chloride and the organic phase was separated, dried (Na^SQ^). filtered and concentrated under vacuum to give 2-(1//-1,2,4-triazol-l-yi)thiophen-3-amme (314 mg, 1.89 mmol, 80%). Retention time (min) = 0.454, method [1], MS(ESI) 167.0 (M+H). AO. N-(2^1H4,2,4-Trieyol4-y'l)thwphm-3-yi)-2-(4-methoocypk4myi)eeetamide [00277] The title compound was prepared from 2-{4-methoxyphenyl)acetic acid (233 mg, 1.41 mmol) and 2-( 17/- 1 ,2,44ri&amp;zoi- 1 -yl)tkiophen~3~amine (234 mg, 1,41 mmol) according to protocol 8. Retention time (mils) = 2.847, method f 7], MS(ESl) 315.2 (M+H); lH NMR (300 MHz, CDCI3) δ 9.27 (s, 1H), 8.31 (s, 1H), 7.99 (d, J - 5.3 Hz, 1H), 7.83 (s, 1H), 7.22 (d, /= 8.1 Hz, 2H), 7,09 (d, /= 5.3 Hz, 1H), 6.94 (d, / = 8.1 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 2H). 1.9. Synthesis of 2-(4-metliosyphenyl>-iV~(4-meihyK1-(3“ineihyl-l/]i”l,2,4-trla2ol-5-yl)thtophen-2-yi)acetaQilde(9)

L 9. L 2-Q~(4~Meth&amp;xyphen}4)acetamUi&amp;)~4~methfUhk>phe.ne~3~carbox^mide [00278] The title compound was prepared from 2~(4-medioxyphcnyi)acetic add (1,21 g, 7,22 mmol) and 2-ainino-4-methy-lthioph.ene-3-carboxamide (1.12 g, 7.22 mmol) according to protocol B. Retention time (min) ~ 1.903, method [1], MS(ES1) 305.0 (M+H). L9.2, 2-(4~Methaxyphmyi)--N'-(4-metkyl-3~(3“metkyi-!H-l,2,4-tritiz0i-5-yi}ihk^phen~2~)fl}m;etamMe [00279] The title compound was prepared from 2-(2-(4-inciho:typhenyi)acetamido)-.4“meihylthippheiie-3-carbnmmid8:(604 mg. 1.98 mmol) according to protocol D. Retention time (min) = 4.530, method [7], MS(ESI) 343.1 (M+H); JH NMR (300 MHz, CDCt>) δ 11.95 (s. Ill), 7.33 (tfc/= 9.1 Hz, 2H), 6.95 (d,../ - 9.1 Hz, 2H), 6.52 (s, 1H), 3.83 (s, 3H), 3.82 (s, 2H), 2.49 <s, 3H), 2.34 (s, 3H). 1.10. Synthesis of A' (2-(2/7-1,2,3-tiiszol-2~yl)tfeiophen-3-yI.H-(4-methoxyphenyllacetamsde (10)

L2&amp;.L 2~(3-Nitmthi&amp;phen-2~}2)~2H~I,2,3-tr$&amp;z®k (00280] A solution of 1,2,3-triazole (430 mg, 6.23 mmol), 2~chloro-3-nitrothiophene (1.02 g, 6,23 mmol) and potassium t-butoxide (838 mg, 7,48mmol) i@; DMF (20 mL) was stirred at 90 °C for 4 h, after which the reaction mixture was cooled to room temperature and diluted with EfeO. The solution was washed with brine and the organic phase was separated, dried (Na2S€>4), filtered, concentrated under vacuum and purified by silica gel column chromatography (eluant hexane/ethyi acetate, 8/2 to 1/1) to give a 1:1 mixture of2-(3-mtrothiophen~2~yl}-2i7-L2,3-iriazoieand l~{3-nitrothiophcn.-2-yl)-!//-l,2,3-tri8zole (1.08 g, 5,55 mol, 89%). Retention time (rpm) ~ 1.2S6and 1,70.1,:: method [1], MS(ESl) 197.0 (M+H). 1.2 ύ, 2. 2-(222-2,2,3- Triaz&amp;l~2~yi)thiopkeit-3-amme [00281] The title compound was prepared front 2-(3-mtrothiophen-2~yI)“2H-1,2,3-triazole and 1 -(3-nitrothiophen-2-y 1)-1 //--l ,2,3 -triazole (514 mg, 2.61 mmol) according to protocol F to give a 1/1 mixture of2-(222-1,2,3-iriazol-2-yl)thiophen-3-amine and l~(l/f-l,2,3-triazol-2-yf)thiophen.-3-amine (431 mg, 2.61 mmol, quantitative). Retention time (min) 0.581 and 1.035, method [1], MS(ESI) 167.0 (M+H). 2.2 0,3. N~(2~(2E-2,2,3~T?iaz®l-2~yi)thu3pken-3-fl)-2-(4~metk&amp;xy'phett$t)-&amp;mMmide [M282J The title compound was prepared from (2i(4-fficihoxyphei^?l)acetic acid (i,11 g, 7.22tnrnoi) and. a 1:1 ntixtureof 2-(2663,2»3-triazol^-yl|poopbeo-3“aFri> tie and 1 -(1//-1,2,3-triazol-2-y!)thiophen-3-amine (431 mg, 2.61 mmol) according to protocol B to gi ve N-(2-(2H~ i ,2.3-triazoS -2->yl)th iophcn-3-y 1)-2-(4-ffiethoxyphenytiacm&amp;n^ time (thin) = 5:712, method [7], MSfESlS 315.0 (M+H); Tl NMR (300 MHz, CiM%) 6 9*99 (s, 1H), 8*06 (d, */= 6*4 Hz, 1M), 7.67 (s, 2H), 7.28-7.31 (m, 2H), 7.02 (d, J = 5.7 Hz, 1H), 6.98 (d, J = 9.1 Hz, 21¾ 3.88 (s, 3H), 3.76 i, 2H). LI 1. Synthesis of /¥~(2~(3~€ydopropyi-Ι/M,Ld-miassoI-S-y I)t Issophen-Ly))-2-(4-aieffeosvpSieBy1)aceiai3aide (11)

I, //,/. N~(2~(Hydmziae(mrh&amp;nyi)thkipken~3~yi}~2~{4~meiimxyphenyi)~ acetamide [002S3J Hydrazine monohydrate (0.825 mL, 17,1 mmol) was added to a solution of methyl 3~(2~(4-methoxyphenyI)acetamido)thiopliene-2-carhoxyIate (3.48 g, II. 4 mmol) in ethanol (40 mL) and the resulting solution was .stirred at room temperature for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2S0.4)s filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/elhyl acetate, 1/1 to 1/9) to give if-(2-(hydra2ine-carbonyl)thioplien-3-yl)-2~i4-methoxyphenyl)acetam.ide (1,71 g, 5.60 mmol, 49%). Retention time (min) = 1.300, method, [1], MS(ESi) 306.0 (M+H). /,//,2 Ν^3-ΟοΙορΜρ^ί-1Η-Ι,2^-«Ηαζο^^αιίίφΗβ»-3~^2-(4- m ethf!xyphenyi)sceiamide [002841 A mixture of A^2-(hydrazineearbonyi}ihiophen~3~y]:)-2-(4-mcihoxyphcnyl)acctainidc (101 mg, 0.30 mmol), cyclopnopylcarbamidinc hydrochloride (47 trig, 0.39 mmol s and sodium, mcf.boxide (39 trig, 0.72 mmol) in ethanol (3 ml.) was stirred: at 120 s€ for 17 h. The mixture was dinned with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na^SCfi), filtered, concentrated under vacuum and purified by preparative HPLC to give Ar42-(3-cyclopropyM./-/·1 ..2,4.tri;!:aol-5-yi)&amp;iopfeeu-3--yi)~2'-(4--methoxyphenyl)aeetamide. MeteBtiea time (min) = 5.578, method [7], MS(ESi) 354.43 (M l-H); iHNIiR (3Q0 MHz, CDCi.) δ 10.48 (s, 1H), 8.11 (dL J= 5.6 Hz, 1H), 7.25-7.32 (m, 3H), 6.94 (d, Jrnm Hz, 2H), M§ (s?;3H), 3.74 {% 2H), 1 98-2:03 (m, 1H), 1.07-1.17 sm,4H). f0028S| The following compounds were synthesized fiomlV-(2-|hydrazin«?carbonyl)~thioph||-3“yl)-2~(4~methoxyphenyl)aeetiimide (Example 1.11.1) lad the appropriate amidine using the procedure described above in Exatnpte 1.11.2: 1.12. A'-(2“(3~Etlsyl~l/f-l,254~iriai:ol~S~y!)iMopiieis»3-yl)"2-(4“ ?n eitsaryph eny 8}«etamsde (12) [0028# Ihopionimidamide hydrochloride was used!. RHMrion huts (min) 4.4|4, method [7], MS(F.SI) 343.1 (M+H); lH NMl (300 MHz, CH03) 110.54 (s, 1H), 8.14 (¢1,./ - 5.4 Hz, 1H), 7.24-7.34 (:mf. 3H), 6:92 (d,,/- S3 Hz. 2H), 3.84 (s, 3H), 336 (s, 2H), 2.79 (i],,/- 73 Hz, 2H), 136 (t, 7 - 7.8 ?;:+ 31?) 1.13. A-i2-(3~teri~Bi5tyl-y7~i,2,4-trlazo?»S»yI)thioi>hen~3~yl).244. methoxyphenyi)acei amide (13) [00287J Pivafhnidami.de hydrochloride was used. Retention time (min) ::: 6,103, method j/7], MS(ESI) 37.1.1 (M+H); ]H NMR (300 MHz, CDCU) δ 10.76 (s, 1H), 8,05 (d, J 5.6 Hz, 1H), 7.26-7.31 (m, 3H), 6.88 (d,J- 8.8 Hz, 2H), 3.76 (s, 3H), 3.75 (s, 2H), 1.44 (s. 9H). 1.14. 2-(4-Methox5phenyl)-,iV-(2-(3“(tetra!iydrofnran-2-yI)-l/f-l,2,4-irlazol~5-yl)tMophei^3-yl)a£Ctaniide (14) [00288] Tstrahydrofuran-2-c.arboximidamide acetate was used. Retention time (min) - 4.585, method [7], MS(ESI) 385.1 (M+H); *H NMR (300 MHz, CDCI3) δ 10.37 (s, 1H), 8.14 (d,./- 5.4 Hz, JH), 7.25-7.32 (m, 3H), 6.94 (d, J= 8.8 Hz, 2B), 5.08 (dd, J = 7.6, 5.8 Hz, 1H), 3.96-4.09 (n>, 2H), 3.84 (s, 3H), 3.80 (s, 2H), 2.43-2.45 (m, 1H), 1.95-2.10 (m,3H). LI 6. 2“(4-Methexypbenyl>4¥-(2~(3"{i:rIfiaortimeifeyl)"i^'-lj2,4-triazol-5-yi)f.hiepben-3-yl)fteetanide (15) [00289] 2,2,2-Trifluoroacetimidamide was used. Retention time (min) = 6,744, method [7], MS(ESl) 383,1 (M+H); JH NMR (300 MHz, CDCI3) δ 10.38 (s, 1H), 8.11 (d, 5.4 Hz, 1H), 7.28-7.34 (m, fi), 6.90 (d,,/- 8;8 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 2H), L16, Synthesis ofA"(4-snefliy!-3-.(i/]f-l,2,4-trk^ol-5-yI)!lifephes-2-yl)-2-(2--®i:o- 3,4-dihydroqsJta?>Iiii~l(2fl)~yl)acetaffilde (16)

1J6J 4-Me&amp;yi-2-(2-(2^xe-3,4-dihy<iroqmMim~2(2H)~yi)ace&amp;mi40)- thmph^m-S-mrb&amp;x&amp;mide f00290J 4-Methyi-2-(2~(2-oxo-3,4-dihydroquinolin-l (2/7)-yl)acetamido)thiophene-3-carix>xamide was prepared from 2-(2-oxo-3,4-diliydroquinolm-1(2/i)~yi)aeetic acid (0.49 g, 2,38 mmol) and 2-amino-4~ methylthiophen.e-3-caiboxainide (0.37 g, 2.38 mmof) according to protocol B Retention time (min) === 3,405, method [1], MS(ESi) 344.0 (M-f-H). 1.16.2. N~(4~Metkyi~3~(lM~1^2f4-4riaz&amp;i-S~yl)thi&amp;phm~2-yl)~2~{2~0xi}~3,4~ dshydmqmmiiin~l(2H)~yi)aceiamide [002911 /v-(4-Methy 3 -3 -(1 //-1 ,2,4~triazol-5 -y l)thi ophen-2-y!)~2-(2-ox©~3,4~ diliydroquinolin-I(2i7)~yi)aeetamide was prepared from 4-meihyl-2-(2-<2-oxo-3}4-dihydi»qijinolra-1(2ir)~yi)acetainido}thiopheae-3“Carboxamide (107 mg, 0.315 mmol) according to protocol C. Retention time (min) = 4.052, method [7], MS(ESI) 368.1 (M+H); JH NMR (300 MHz, CDCi3) δ 12.40 (s, 1H), 7,95 (s, 1H), 7.21-7,28 (m, 2H), 6.99-7.08 (m, 2Hi, 6.56 (s, IB), 4.91 (s, 2H), 3,09 (dd,,/= 8,2, 6 Hz, 2H), 2.91 (dd, J = 8.2, 6 Hz, 2H), 2.51 (s, 3H). 1.17. Symhmk of A-(4-Methyl~3~(3-rosthyl-lfl»l,2,44rkKofr5~yl)t1ii0plmn-2-yI)- 2~(2~o;ro-3,4-dlh vdroqu imdin-1 (2//)»y!)aeetamlde (17)

1.17.1 Methyl 4-metkyl-2-(2-(2^x&amp;~3,4~iiihydr&amp;qmmlm~l (2H)~ )l}meimiide)ihhphette~3<ii?bi!xyl&amp;ie [00292] The title compound was prepared from 2-(2-oxo-3,4-dihydroqumolin~ l(2fi)-yl)acetic acid (0,43 g, 2.09 mmol) and methyl 2-amino~4-metbyIihiophene-3~ carboxylate (0,358 g, 2,09 mmol) according to protocol B Retention time (mm) = 6,895, method [7], MS(ESI) 359,1 (M+R). dihydmquimim-2{211}~yi)acetamide [00293] Hydrazine mormhydmie (0.059 mi., 1.23 mmol) was added to a solution of methyl 4-metliyh2~(2~(2"Oxd-’3i4-dihydroquinoiin-l(2if)-yl)aceiamido)ihk^hene“3-carb0xyiate (22] nig. Q^lfimmol) in ethanol (2 ml,) and the resulting solution was stirred at 50 °C for 24 h. The Mxbm was diluted with W&amp;c and extracted with ethyl, acetate. The organic phase was separated, dried (KajSQri, filtered, concentrated under vacuum to give Ar-(3-(hydrazinecarhonyl)-4-meihyltMophert-2~yl)-2” (2roxO“3,4-dihydroquinoiixi-l(2/f)-yi)acetainide (174 mg, 0.485 mmol, 79%). Retention time (min) 1.435, method jfl], MS(£SJ) 359.1 (M+H). 1.17.3. N~{4~Metkyl-$-{3~methyl~lM»l,2,4-tnaz0l-$~yl}thi&amp;pheM~2~yi}~2~{2~oxi!-3,4-dihydr(>quimUit~i{2M}~yl)aceta.mi(le [00294] The title compound was prepared from acetimidamide hydrochloride (55 mg, 0.590 mmol) and AM;3-(hydrazinecarhonyl)~4~methylthiophen-2-yl)-2-(2~oxo- 3.4- dihydroqumolin-l(2i7)-y])acetantide (141 mg, 0.393 mmol) according to the procedure of Example 1.11.¾ above. Retention time (min) ~ 4.106, method [7], MS(ESI) 382.1 (M+H); lH NMR (300 .MHz, CBCh) δ 12.07 (s, 1H), 7.23-7.31 (ffi, 2H), 7.05- 7.23 (m, 2H), 6.57 (s, 1H), 4.86 (s, 2H), 3.02-3.07 (m, 2H), 2.84-2.87 {m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.18. Synthesis of 2-i4-methoxyphenyl)-A-(2-(3~(pyrldhs-4-yl)-li/--1,2,4~-triar:ol--5-yl)4hlopheB-3-yl)acetamide (18) [00295] The title compound was prepared from pyridine-4-carboxintidamide hydrochloride( 157 mg, 1,00 mmol) and A-(2-(hydrazinecarbonyl)thiophen-3-yI)-2-(4-rag&amp;oxyphmyl)acetamide pxample 1,11.1,, 204 mg, 0.668 mmol t according io the procedure described in Example 1,11.2,, above. Retention tins (min) “ '2,51 f, method [7| MipSlJ 392.1 (M+H); lH NMR(300 Mffe, DMSG-40 g 10.52 (s, ffl), 8,87(1, ,/- 4.5 Hz, 2H), 8,08-8,16(m,2H), 7.94 (d J=5.0Hz, 1H), 7.67-7.70 (m, 1H), 7.31 (d5./= 5.6 Hz, 2H), 7.88 (d,y= 8.6 Hz, 2H), 3.88 (s, 2H), 3.67 (s, 3H). 1.19, Synthesis of AH2^]-amtno~l.ff4,2,4-iriaxol-5~yl}ihioph£K~3~yI)“2-{4" methoxyphenyS)»cetamide (19) [00296] The title compound was prepared from A-(2-(hydraziiiecarbosyl)tiiiopheii-3-ylV2~(4-methoxypheriyI)aeet:ainide (Example 1.11,1,, 152 mg, 0,497 mmol) and S-methyiisothioiaonium sulfate (276 mg, 0.995 mmol) according to the procedure described in Example 1.11,2 except that sodium hydroxide was used (rather than sodium methoxidc). Retention time (min) = 2.324, method [7]. MS(ESI) 330.0 (M+H); lH NMR (300 MHz, CDC13) 6 9,95 (s, 1H)S 8.07 (d,5.7 11¾ 1H), 7,26- 7.29 (m, 3H), 6.94 (d, J= 7,9 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H). 1.20. Synthesis of A/-(4-chIoro~3-(1H-l,2,4-trlazol~5-yl)thloplsen-2-yi>-2~(2-(ixo- 3,4-dihydroqninolin-l(2fl)-yl)aceiasnide (20)

1S<U. Mgik$l:4^mmti~242~{2^M&amp;3^-dik0m)qumtttm-H2Hfc y!)mekumdo)ihk»pkene~3‘-carhexyiaie [00297] The title compouitd #a%pr|pared from 2-(2-oxo-3,4~dihydroqukoiin-l(|H)-yl)acetic acid (447 mg, 2.18 mmol) and methyl 2*-«nino-445romothfephene-3“ carboxylate (516 mg, 2.18 mmol) acasrding to protocol A. Retention time (min) =- 2.51¾ method [1], MS{£ST) 423.0 (M+H). 1.20.2, Methyl 4~chiom~2~(2~(2~oxo~3}4~dihydr&amp;qmmUn~l(2H)-yl)&amp;cet®mid&amp;)thi®pkem-3~CM?hoxyl@£e [0(1298] The title compound was prepared from methyl 4-bxomo-2-(2-(2~oxo~ 3,4-dihydroqiuTio1in"l{2i:-/)~yi)ace4amido)thiophene-3~carlx)xyiate (148 mgs 0.35 mmol) aceotding to protocol G. Retention time (min) ~ 2.540, method [1], MS(ES1) 379.0 (M/H), 1.20.3, 4-Ch!®r®-2~(2~(2~&amp;x(>-3s4~dikydroqm»o£m~l(2fl)~yl)ai:etemid0}~ thi^hem~3~mrhmamide [00299] The title compound was prepared from methyl d-ehloro^^-CZ^xo-3,4~dihydroquinoi3n^l (2l^^l)acetarttido)thiopherie-3-earbo?iyl:ate (254 mg, 0.67 mmol) according to protocol H. Reterdion time (min) = 2:(14, method [1], M|(ESJ) 3Ms0 (M-rH). 1.20.4, N~{4~Chl&amp;r&amp;-$-(lH-l,2,4~t?wzoi-5-yl)thkiphe}i-2-yi)-2-{2-8X8~3i4-dihydr®qmm!m~l(2H}-fi)aceSumide [00300] The title compound was prepared from 4~chloro-2-(2-(2-oxo~3,4-dihydmqiimolis~l(2//)''yl)acetamido)thiopheae-3"carboxamide (218 mg, 0.601 mmol) according to protocol C. Retention time (min) - 4.171., method [7], MS(.ESI) 388.0 (M+H); lH NMR (300 MHz, CDCU) δ 7.85 (s, 1H), 7.21-7.30 (m, 2H), 7.07 (dd,/ = 7,4, 7.3 Hz, 1H), 6.94 (d5 /- 8.3 Hz, IB), 6.83 (s, 1H), 4.93 (s, 2H), 3.09-3.14 (m, 2H), 2.89-2.94 (m, 2H). 1.21. Synthesis of A'~(3-(lH-l^,4-tTlazoh5~yl)tl-iiopl5ee~2-yl)~2~(2-oso-3,4-dihydroquinolin-1 (21/i-yl)aeetamlde (21)

[00301] A-(3-(117~I.s2,4-Tria2;o!-5-yl)thiophen-2-yI)-2-(2-oxo-3,4“ dihydroqiimoim-l(2i7)-yi)acetamide was isolated during the purification of iV-(4~ehloro- 3-(l//-l32.4-triazc4-S-yf)thiophen-2-yl}~2~(2-oxo-3>4-dihydroqumolin-l(2?/)- yl)acetamide (1.20.4.. The des-chiorothiophene was likely formed during the conversion oi 4-feronK}^0^PsP^^~3,4*dihydi^quit»iin-ip^^yI)acetarfii^3)tiiiophe}ie“3-carboxyiate to methyl 4^chioro-2<2K2Hixo-3,4^iihydroquinolin--l(2/0--yi}acelamido)tfiiopherie-3-carboxy'iaie. Retention time (min) = 3.2%, method [7], MS(ESI) 354.0 (M+H); iH NMR (300 MHz, CDC13) 6 7.99 (s, 1H), 7.23-7.29 (m, 3H), 7.06-730 (m, 2H), 6.88 (d, J- 6.3 Hz, 1H), 4.92 (s, 2H), 3.07-3.10 (m, 2H), 2.92-2.95 (in, 2H). 1.22. Synthesis of Ar-(4-clsl0re-3-(lfl-l,2,4-triazoI-5-yl)thiophen-2-yl>-2- (isscgsin 0lin-5-y!)aeetamicie (22)

L 22.1 Methyl 4~bromi}~2~(2~(isoqum&amp;ltn~S~yl)acetBmM&amp;}thmpheiie~3~C'arbi)xyliite [00302) The tide compound was prepared from 2-(isoquinolin-5-yl)acetic acid (427 mg, 2.18 mmol) and methyl 2~&amp;minG-4-bromothiophme-3-cart>oxylate (514 mg, 2.18 ramuf) according to ptRncol A. Retention time (min) == 1.634, method [1], MS(Eit) 405.0 (M+H). 1.22.2 Methyl 4~chbro~2~(2~a§0qum&amp;im~5~yl}meiimtidG)thmpkme~3~mrhoxykite [09303) The title compound was prepared from methyl 4-htOmo-2-(2-(isoqumo3in-5~yl)acctamido)thiophcne-3-carboxylate (124 mg, 0.306 mmol) according to pmtoosl ii. Retention time (min) = 1,609, method [1), MS(ESl) 361.0 (M i ll). 1.2223. 4^hhr^~(Mls0qummMn~S^llmemmM03thi^km^mtrboxamMe [00304] The title compound was prepared from methyl 4»ckbiO-2-(2-(isoquirioiin-5~y 1 tacetanndo)ihiophcne-3-carlx)xylatc (110 mg. 0.306 mmol.) according to protocol H. Retention tim&amp;:(mm) -= 1.139, method [1], MS(ESl) 346,0 (MTH). ySJ&amp;cetemiile [0®30Sj The tills compound was prepared from 4--eMoro-2-(2-(isoquittoIin-5-yi)acetamido)thiophene~3~earboxamide (104 rag, 0.306 mmol) according to protocol C. Retention time (min) = 1.570, method [7], MS(ESI) 370.1 (M+H); *Η NMR (300 MHz, CDjOD) δ 9.62 (s, 1H), 8.57 (d, J - 6.1 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.35 (d, J = 6.1 Hz, 1H), 8.18 (d, J- 7.0 Hz, 1H), 8.09 (bs, 1H), 8.00 (dd, J= 8.4, 7.3, 1H), 6.95 (s, 1H), 4.51 (s, 2H). 1.23, Synthesis ofiV-(4"eltloro-3-(lH-l,294-tr!azo1~5~yl)thtophen-2“¥l)~2“(i|nlnoiln-

1.23.1. Methyl 4~hmnw~2~{2~{qumoim~S~yi)u€etamM(i}thiophene~3~ceirboxylMte [00306] Methyl 4~bromo-2-(2-(qirinolin-5-yl)acetamtdo)tliiophene"3~ earboxylate was prepared firo 2-(qumoiin-5-yl)aeetic acid (427 mg, 2.18 mmol) and methyl 2-amino-4-bromothiophe3i©-3-carbox>'late (514 mg, 2.18 mmol) according to protocol A. Retention time (min) = 1.660, method [1], MS(ESI) 405.0 (M+H). 1.23.2. Methyl 4~<:hlim>~2-(2-(qitinoim~5~yl}&amp;cet<mi<i0)thiopkme~3~earbox)?late [0Θ307] Methyl 4-chlorO"2-(2-(quino1in-5-yl)acetamido)thiophetie~3-carboxyiate was prepared from methyl 4-bromo~2 -(2 ~(q uinolin-5 -yl)acetamido)tliiophene-3~earboxylate (350 mg, 0.86 mmol) according to protocol G. Retention time (min) = 1.629, method [1], MS(ESI) 361.0 (M+H). L 23.3. 4~CMoro~2-(2^quinolm-5-yt)acetamide)thi0pkem-3-eerh&amp;xiimide [06308] 4-Chloro-2-(2-(quinolin-5-yl)acetamido)thiophene-3“Catrboxamidewas prepared from methyl 4-ehloro-2~(2-<quinolin-5-yl)acc4amido)tMophene-3-car1boxylate (.151 mg, 0.418 mmol) according to protocol H. Retention time (min) == 1.151, method [1], MS(ESI) 346.0 (M-H). 4. N-(4~Chloro~3~(l H-1,2,4^ffizoi~5~yi)thi&amp;phen-2-yi}~2~(quinoRn-$-yl)acetamide [60309] A?“(4-Ch1ofo-i-(lH-1^,4-triaz»I>5-y1)thiophen-2“y!)-2-(qijitioHn-5- yllaeetamide was prepared from 4-cWoro~2-(2-(qumolm-5-yl)acetemMo)tfuGpiiene“3-carboxamide (78 mg, 0.225 mmol) according to protocol I Retention time (min) = 1.429, method [7], MS(ESI) 370.0 (M-H); *H NMR (300 MHz, CD3OD) 8 9.15-9.19 (m, 2H)} 8.26 (d.,/- 8,3 Hz, 1H), 8.11-8.17 (m, 2H), 7.95-8.01 (m, 2H), 6.95 (s, 1H), 4.57 (s, 2B). 1,24, Synthesis of h!-{2-{lEA A4-iirlaz®l-5-yl)thlopheii~3-yI)-2-(2,3-dUsydrobenzo[bj il,4Jd!oxln-6-yt)acela™ide (24)

L 24.1. 3~{2~{2^-Bikydr(&amp;enzftib]lIA$dmxin-f}-)4}®i;£t&amp;mi4o)ihiophi!rie~2" carboxamide [00310] The title compound was prepared from 2-(2,3-dihydrobenzo[b][l,4]dioxin-6-yI)acetic acid (450 mg) and 2~am.inothiophen.e-3-carboxamide (345 mg) according to protocol B, The crude product mixture was taken directly to the next reaction without ftrther purification. Method[1). MSfESI) 319.2 fM+H], R etention time - 1,496 min, 1.24.2. N~{2~.{iH~l,2f4~Trmz&amp;i~5~yi)thiophers~3-yi)-2~{2,3-dikydrobmzo!b][l,4]dmxin~ 6~yl)aeemmide |00311 j The title compound was prepared from 3-(2-(2,3-dihydrobenzo[/)][l,4]didxin^6-p)acetamido)t|ippheifiei2-c0sd>oxamide according to pnstocol C. The crude product was purified via preparative HPTC to give 6/42-( Uf-l,234-triazol-5-yl)thiophen-3^1)-2-(2t3^dihydrdbeira|[h][;l,4]dioxi!~6--yl)acetamide; Method[7], MS(ESI) 343.0 [M+H], Retention time = 3.39 mis- {H~NMR (300 MHz, CDCH] δ 10&amp;1 (¾ 1M), 8,21 (s, 1H), 8.11 (d,J= 5.5 Hz, Hl)i 7M - 7.26 (m, 1H| 7.31 (d, J - 5.5 Hz, IB), 6.93 - 6.83 (m, 2H), 4.27 (s, 4H), 3.73 (s, 2H). liili SyrathesigiDf (4 - sxs e £ hy 1-3 - CI //-1,2^frfa2ol-5-y!)f hlopfiett-2~yi}-2·· iqulnoIfa-5-y!)aeetaml£ta (25)

k25J, 4-Me&amp;$l~2~(2~{quiMUn~5~yt)Metemido)ikiophene~}-carboximlde> 108312j The title compound was prepared from 2-(qumoI in-5 -y I )acetie aei d and 3-amiao^-ii«fihLyhhiophcnC”2--ca)rboxarnidc using protocol B. Method [1 1, MS(ESI) 326.0 {Vf-hH], Retention time =1 0.767 min. 1,25,2. N~(4~Methyi~3-{lH-lf2s,4~trmz(}l~§~}i)tkmphem~2~yl)~2~{quimim-’5-yl)metmu4e [083131 The title compound was prepared from 4-methyl-2-{2~(quinolin-5-yl)acetamido)thiophene-3-earboxamide using protocol C. The crude product was purified via preparative HPLC to give N-(4~mcthyi~3-(lH-1,2,4-triazoI-5-yl)thiophen-2-y 1)-2-iquiito]m-5-y])aeetamide. Method[7], MS(ES1) 350.1 [M+H], Retention, time ~ 1.43 min; T-I-NMR ¢300 MHz, CDClj) 611.16 (s, 1H), 9.02 (d, /= 4.94 Hz, 1H), 8.96 (d, /- 8.2 Hz, I B), 8.6 (d, /- 8.2 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.92 (s, 1H), 7.90- 7.84 (m, 2H), 6.51 (s, 1H), 4.45 (s, 2H), 2.44 (s, 3H). 1.26, Synthesis of 2-(2,3-dihydrobenzo [ftj [ 1,4] dfox isi-6-y])~Ji\~(2-(3-methyl-1 H-t ,2,4-Mazol-5~yl)tMopheu-3~yI)steefamide (26) j 003141 The title compound was prepared: from :2-(2-(2,3-

dihydrohenzo[h|p ,4jdtoxm-6-yl)aoctarnido>ihiophene-3-carboxarnide using protocol D except that the DMF was also used in the DMA-DMA step with heating to 95°C (rather than 1 Iptgj and the hydrazine step wasbeated at 9S°€ (ratherthan 90PC), 1¾ product was purified via preparative WLC to give 2-(2,3-dihydrofien^[b] [l,4|dioxm-6-y i)-N~(2- (3-methyRlHils2,4-tm2ol-5~^l|thippfen-3-yl)acetaruii[e; Melhodj/j, MS(E|l) 357.1 [MrH], Retention time - 3.56 min; *H-M MR (300 MHz, CDCH) δ 10.33 (s, 1H), 8.06 (d, /- 5.5 Hz, 1H), 7.29 (d, /-5.5 Hz, 1H), 7.27 - 7.26 (m, Hi), 6.88 - 6M (m, 1H), 6.84 - 6.82 (m, 1H), 4.22 (s, 4H), 3.70((¾ 2H). 2.S1 (s, 3H). 1*27. Synthesis of yi)&amp;eetamide (27)

i«3isj The title compound was prepared, fipp 2-(quin0lin~5~yI)aeeiie seid aad 3 -;:aniiierbiO}?l'icne"2·carboxamide using protocol B. Method! 1], MS(ESl) 312,1 [M+H], Retention rime~ 0.35 \ mm, 1.27,2. N-(2-Uffl-l,2,4~Trwz0i-5-yi)tM@pheM~3-yi)-2-{qumolm-~5-yl)(icetiimide 1003161 This compound was made from 2-(2-( quinol.m-5-yl)acs^amido)ihiopherse~3-carhoxaimde using protocol C and was purified via preparative HPLC, Method[9], MS(ESI) 336..0 [M+H], rt = 6.526 min; ‘H-NMR (300 MHz, CDCL) δ 9.30 (s, 1H), 9.05 (d, J= 8,24 Hz, 1H), 8.98 (d,/= 4.95 Hz, 1H), 8.63 <d, 8.8 Hz, IH), 8.20 - 8.15 (m, 1H), 8.06 (ss 1H), 8.04 ($, 11% 7.99 - 7.91 (m, 3H), 4.47 (s, 2H). 1.28. Synthesis of A^4~mefrhyI”3~(3“methy|-llT-l^54.triazffil~5-y|)thiQphen~2~yl)“ 2-{<3ulnoiiH-S~yi)acetaiiside (28) [00317] This compound was made from 4-methyl-2-(2-(quinolin-5-yJ)«c^«da)4hioptene-3-ewb<M^mide using pmoeoi D. The pHhct was purified via preparative 1« to give ,2,4^iazoh5-yl)inophen-2-yl)- 2-(qipsp|in-5^yi)aeetamide. Method [91 MS(ESI) 364.1 [MH% Retention time - 8,72 min; H*MMR (300 MHz, EDCfii) § 10.76 (s, H% 9,04 (s, lf% 9.0 fd, J-~ 3,85 Hz, 1H|, 8,61 (d,7- 8.8 Hz, 11% 8.14 (<id, J- 8.8, 7.7 Hz, 1ί·% /.94 ~ 7.89 (rn, 2H), 6.49 (s, 21% 4.46 (s, 2i% 2,4:1 (s, 3H), 2.40 (s, 3H) 1.29. Synthesis of A'-(4-methyi--3-(lif-l^54-trtazoI-S-yi)thlophea-2-yl)-2-(qmsoxalhs-5-yl)aeemmi<le (29)

L29J, Tert-butyl 1003181 rl|e title compound was prepared 5·bromoquinoxaHue (500 mg, 1,0 ecj) according to protocol O to give tort-butyl 2-(quM6xdin-5-yi)acetate. Method [1 ], MSsESI) 245.1 [M-'-H], Retention time 2.305 πώχ. L29J, 4~Meik\2~2-(2-{qHimmaiix~S~)i}m;etmndi^hi^hem-3<Mrhe>x&amp;mde [00319] To a sttrrmj mixture oftert-hutyl 2-(qninoxalmrS-yI)acetate (200 mg) in i iOAc (5 mL) was added 6\ HCf (5 ml..-). The reaction mixture was warmed to 80 °C for 2hi The crude product .mixture was cotKcmrafdd jMdgf reduced pressure to give 2-(quinoxalm^S-yOacetic add, which was used in lie next readier: without further purification. Method] 1], M5(£Sf) 189.0 PvHHj, Retention time - 0.722 min [00320| The lit]e compound was prepared from 2-(quinoxalin-5-yl)acetie acid and 2-amino-4-rnethyIthiopl;ene-3“Carf>exanude using protocol B Method] I ], MS(F.SI) 327,0 [M-i-R], Retention time = 1.644 min. OR 5, N~{4-Methyl~32lH~l22,4~iriazM--5-}2)thi^kett~2~yl}~2-{qm?wxxUn~5~ yfyacetamide 10032! I This analog was prepared from 4-mdhyl-2-(2-(qeitioxalin-5·-yi)acetatnido)ihiophene-3'Carboxaimde using protocol C. Method]?], MS(ESI) 351.1 [M+H], Retention time = 3.36 min. !H-KMR (300 MHz, CDCfi) S 11.84 (s, 1H)S 8.90 -- 8.87 (in, 2H), 8.21 - 8.18 (m, 1H), 7.93 - 7,85(m, 211), 7.73 (s, 1H), 6.52 (s, 111), 4.56 (s, 2H), 2.45 (s, 3H). 1.30, Synthesis of A^4»methyk1-(3~methyl-11/-1,2,4~frkge!-5-yI)ihii}piseM-2-y!)~ 2-{quiaoxa!iK-5-y1)aeetaaii(Ie (30) [00322] This analog was made from 4-methyi~2“(2-(quinoxalin-5-yl)acetamido)thiophene-3-caiboxamide using protocol D except that the DMF was also used in the DMA-DMA step with heating to 95%: (rather than 1 fO°C) and the hydrazine step was heated at 95°C (rather tkm 90°C). Method[7], MS(ESI') 365.1 [M+H],

Retention time - 3.58 min; ‘H-NMR (300 MHz, CDC13) 6 U.9 (s, 1H), 8.87 (s, 2H), 8.17 - 8.34 (m, 1H), 7.92 - 7.83 (m, 2I-I), 6.50 (s, 1H), 4.53 (s, 211), 2.45 (s, 3H), 2.30 (s, 3H). h3L Synthesis of .¥-{4^metiyyi-3<H/4i2i44riagol.5*yI)thiophen~2~yi>2-(4-(3- (plperldin~l~yI)propoxy)phenyl)aeetantlde(31)

L 3 L1- Methyl 2~(4~0-{piperidin~l~yi)pmp03iy)phenyi)metate [003231 1) To a stirring mixture of methyl 2-(4-hydioxyphenyl)acetate (Ig) in acetonitrile (12 mL, 0.5M) was added bromo-3-cWoropropane (911 mg), K2C03 (2.4 g), The reaction mixture was heated to 100 °C for 2h, then quenched with water and extracted with EtOAe. The organic layers were dried over MgSG4, filtered and concentrated. The crude product was used without further purification Ir the next reaction step. Method[ 1 ], MS(ES1) 243.0 [M+H], Retention time == 2.50 min.

[Θ9324] 2) To a stirring mixture of crude methyl 2-(4-(3-chloropropoxy)phenyl)acetate in acetonitrile (17 mL, 0.35 M) was added K.T (192 mg), piperidine (1.5 g). and K2CO3 (2.4 g). The reaction mixture was heated to 100 °C for 2h.

It was then quenched with water and extracted with EtOAc. The organic layers were dried oyer MgSG*, filtered, and concentrated. The crude product was taken directly so ihe next reaction. Method[lj, MS(1SI) 292;1 li^ndon time - 1.330 min 131.2. 2°'{4"{3~iPipendmr2~jr'i}pmpmg)phenyi)®mtic odd [0(13251 To a stirring mixture of methyl 2-(4-(3-(piperidin-1 -yi)propexy)phenyI)aceiate (370 mg) in HO Ac (5 ml.) was added 6N HO (10 mL). The reaction mixture wp wanned to 80 °C for 2h. The crude product mixture was concentrated under reduced pressure and directly taken to the next reaction without farther purification. Method] 1], MS(ESI) 278.1 [M+H], Retention time = 0.666 min. 1.313. 4~Methyi~2~(2~(4-(3~(p^erMn-l~yi)pr&amp;p0xy)phmyl)~&amp;cemmid&amp;)tki&amp;phme~3~ carboxamide

100326] Tod stirring mixture of 2-(4-(3-{pipcridin-1-yUpropoxy)pbeny!}acetic aci| (80| mg) In DMF/DCM (6 mL, 1:1) was added triethykmine (1.2 niL), OMAR (Ι8Θ mg), 2^mixio^-nK;thy]thiopheit^-3-caihoxainide (440 mg), arid EDC! (Ϊ.1 g). He reaction mixture was stirred at rt overnight, quenched with saturated NallCOs solution and extracted with. EtOAc. The organic layers were dried over MgSCfi, filtered, and concentrated under reduced pressure, The crude product was purified via preparative HPLC to give 4-methyi-2-(2-(4-(3-(piperidin-l-yl)propoxy)phenyl)acetamido)ihiophene-3-carboxamide. Method[7], MS(ESI) 416.2 [M-HH], Retention time ~ 2. 254 min. I. 31.4. N~{4~Methyl~3diH.-l>2,4~trmzoi~5~yl)thkiphcM-2-yi)~2~(4~($-{psp!?ndm~l~ yi)pr&amp;paxv)phenyl)acetamide [00327] This compound was prepared from ~m.ethyi-2--(2- (4-(3-(piperidinri -yi)propoxy)phenyl)-aceiamido)ihiopheue-3”Carboxamide using Protocol C. The crude product was purified via preparative HP'LC to give N-(4-methyl-3-(l II-1,2,4vtriazoi-5-yl)Aioph@n-2^1)^2>T4 <3^(piperidin»3 -yl)propoxy)phcnyl}aeetamide. Method]?], MS(ESi) 440..2 [M+H], Retention time = 2.86.5 min; (300 MHzs CDCI3) δ;

II. 64 (s, IH), 7.96 (s, IB), 7.3.1 (a, IH), 7.29 - 7.20 (m, MI), 6.91 (d, J= 8.2 Hz, 2H)r 6.50(s, IH) 4.16 -4.12 (m. 2H), 3.81 (s, 2H), 3.69 - 3.65 p,2H), 3.42-3.1! (m, 3H), 2.78 - 2.60 p, 2H), 2.43 (x, 3H), 2.33 - 2.i9(m, 2H), 2.(1: 1,9i (m, 4H), i .50 - 1.42 MMI m2. Synthesis of ,V-<4-mcthyi-3-(3HmethyI~l//-1,2,4~trizol~S-yI)fWophen-2f l£ 2"(4-(3~(plperidisii-l“yI)propo^y)plieKyl)acetai5side (32) [00328] This compound was prepared from 4-meihyl-2-(2-(4 -(3-(piperidin« I ~ yi)propoxy)phenyi)aceiamido)ihiopheoe-3-carhoxamide (Example 1.31.3) using Protocol D. Mctfaod[?j, MS(ESI) 454,2 [M+H], Retention time - 2,857 min; Ή-NMR (300 MHz, CDO;,) δ 11.35 (s, 1H), 7.28 - 6.92 (in, 2H), 6.87 (d, J = 8.8 Hzs 2H), 6.50 (s, 1H), 4.11 - 4.08 (τη, 2H), 3.78 (s, 2H), 3.72 - 3.68 (τη, 2H), 3.35 - 3.20 (m, 2H), 2.75 - 2.61 Jg 2H), 2.45 (s, 6H), 2.30 - 2.21 (m, 2H), 2.02 - 1.91 (m, 5H), 1.50 - 1.42 (m, 1H). 1,33. Synthesis of 2-(4-(2-(lif-lmida^ol-l-yl)®tliijsy)phesiyi)--7V“(4~nieth¥l-3'(lif" lJ54-triazol-5~yI)ehiophen-2.yl)aeetamide (33)

7. 32 λ Methyi 2-(4-(2-(1 [10329] To § stirapg mixture of the methyl 2-(4~h¥droxypheuyl:)acetate (1.4 g, 1 IQ) and 2-(1 B-imidazoi-! -y!)ethanof (1.0 g) m TMF (0.5 ml., 0.5 M) at 0 °C was added FRh? p.9 g). To this mixhife was added dtopwise 1ED (2.2 ri*L) over 10 min The reaction mixture was wanned to ambient temperature overnight. A normal aqueous workup with water and Et®Ac was hollowed. The organ® layers were dried over filtered, Md concentrated under reduced pressure, 'Me etude product was purified via silica gel chromatography to give methyl 2-(4-(2-(1 H-Umdazol-l-yl)ethoxy)phenyl)acetate. Method[l], MS(ESI) 261.1, Retention time = 0.782 min. /.33.2, 2-(4-(2-(1 H-lmdlazd- / -yfyedwxyjpkenyijmeHc add [00330] To a stirring mixt ure of 2-(4-(2-( I H-imidazol-1-yl)ethoxy)phenyl)acetate (240 mg) in THF/water (3.3 mL, 10:1) was added fine powder KOH (77 mg). The reaction mixture was .stirred at ri overnight. The crude product mixture was acidified with 1.0 M HQ and diluted with EtOAc. A nonnal aqueous workup with EtOAc was followed. The organic layers were dried over MgSQj, filtered, and concentrated under reduce pressure. The crude acid was taken directly to the next reaction without further ρurif cation, Method[l}. MS(ESI) 247.1, Rot-Cation time - U.323 1333. 2-(2-(4~(2~(lM-Imidaz&amp;i-l-yi)^h&amp;xy}pkemi)&amp;cefamido)-4-methyltkiophem~3-carboxamide 100331] This compound was prepared from 2-(4"(2«(lH~imidazol-l-yl)ethoxy)phenyl)acetic acid and 2~ammo-4~methy!thiQphene-3-ear1roxar'nide using protocol B except that triethylamine was also added. The crude product was purified via silica gd column chromatography. Mcthodf 1], MS(ESI) 385.1, Retention time = 1.254 min.. 133.4. 2-(4-(2-(3H-Smidaz&amp;i-i~yt)eth&amp;xy)phenyi)-N-(4~methyl~3~(lH~ls2}4-triazol-S-yi)ihhphen-2-yi)acetamide {00332] The title compound wasproj^d from 2-(2-(4-(2-( 1 H-imidazol-1 -yl)e^S^)phenyl)acetan^)-4rit^yltMef^^^^dtoK»ide using protocol C. Methed{7], MS(EI) 409.1 pMff, Retention tine - 2.352 min; lH-NMR (300 MHz, CDiOD) δ 9 08 (s, llli. 8.24 (b s, Ui), 7.79 (t,/= 1.65 Hz, Iff), 7.62 (t,J= 1.65 Hz, 1H), 7.36 - 7.33 (m, 2H)S 7,02 - 7,0 (m, 2H), 6.62 (s5 1H), 4.72 (t, /= 4.94 Hz, 2H), 4.45 - 4.42 cm, 2H)S 3.80 (s, 2H>, 2.48 (s 314). ! .34. Synthesis of AL(4-Bromo~3-(li7-l?2j4-triazoI-5~yl)'t.hiophi.;s5-2-yl)-2- (i mq srin odn-S-y!)aeetamidc (34)

1.34.3. Methyl 2-ammo-4-bmmothwphene~3~carh{K‘iyiase [Θ0333] Methyl 2-(((9H-fluorcn--9-yJ)meih03Ey)earbpnylaniino)*4» hromothiophcne-3 -carisoxykte (1 g) Wiss.stirred ro DGsMAnorpholine (12 «$,, 1:1) at rt until all tire ester was consumed. I. he crude rhixrure was concentrated under reduced pressure. The residue was dissolved in ethyl ether. The white solid was. removed. The mother liquid was concentrated under reduced pressure and a 1:1 mixture of ethyl ether/pentane (20 mL) was added. Ass additions] white solid was removed. The organic layer was concentrated under reduced pressure and the crude mixture was placed under higi vac,arms to remove the excess of morpholine The crude amine was taken directly to the next reaction step without further purification. Method[l], MS(ESl) 235.9 [M+H], Retention time = 1.919 min. 1,34,2, Methyl 4~briim&amp;~2~(2~(is&amp;qmiwiin-S-yl)seetamM&amp;)tkmphem~3~£arb&amp;xylute [00334] This compound was prepared from methyl 2-amino-4-bromothiophene-3-carboxyfate and 2~(isoquitioliQ-5-yi)acetic acid using protocol A. Mcthod[l], MS(ESi) 404.9 [M+H], Retention time = 1.678 min. L 34,3. 4-Brmmh-2-(2~(is&amp;quimiUn~5~yi)metumM&amp;)thmphem~3~carb&amp;x&amp;mide [00335] The title compound was prepared from methyl 4-bromo-2-(2~ (isoqumolin-5-yI)acetamido)thiophsne-3-carboxyiate using protocol H. The crude product was purified by preparative HPLC, Method!!], MS(ESI) 389.9, Retention time ::: 1.166 min. 1,34,4, N-(4-Er<mo~3~{Ul~lf2!l4~triazol''3-yi}(hi&amp;phefi-2~yl)~2~{isoqumi?lm~S~ fijaeefamide [00336] The title compound was prepared from 4-bromo~2~(2-(isoquinoHn-5-yl)aeetamido)thiophene-3-cai'boxamide (28 mg) using protocol C and was purified by preparative HPLC. Method]?], MS(ESI) 413.9 [M+H], Retention time = 1.50 min; !H-NMR (300 MHz, CD3OD) S 9.72 (b s, 1H), 8.60 (b s, 1H), 8.48 (d,J= 7,7 Hz, 2H), 8.24 (d, J= 6.6 Hz, 2H), 8.09 - 8.04 (m, ill), 7.11 (s, 1H), 4.55 (ft, 2H). US. Synthesis of j¥-(4~Rroma~3-(lff~l,2s4-trla2ol-S“yl)thiophen“2-yi)-2-(q ninoIin-S-yilacetamlde (3 S)

L3:\ h Methyl 4^wmo-2-{2-(qumelin-$-$)(ieetamitl&amp;)ikiopheite~3-eai'hexylaie [00337] This compound was prepared from methyl 2~ammo~4~bromothiopheae-3-carboxylate and 2-(quino1in-5-y1)acetic acid using protocol A. Method]!], MS(ES3) 405,0 [MAH], Retention time = 1.650 min 335.2. 4-Erome~2~(2-(qmn&amp;lm~S-yi)acetumido)thiopkeite^3~cm'boxamide [00338] This compound was synthesized from methyl 4-l>romO”2"(2-(quinoiin-5-yl)acetajnido)thiophene-3-carboxylatc using protocol H. Method] 1], MS(ES1) 390.0 [M+H], Retention time = 1,174 min. L353. N-(4~Bmm&amp;3~{JII333~triuzel3-yl)m&amp;phe^2~}^3-(qiiimmn3-yl)%eeteumide [00339] This analog was made from 4-bromo-2-(2-(quinolin-5-yi)acetamido)thiophene-3-carboxamide using protocol C. The crude product was purified via prep. HPLC to give N<4-konK>-3<lHM^^tiia2»l-5-yl)thiqjhen-2-yi)-2-(quinolin-5-yl)acetamide. Method[9], MS{ESI}413.9 [M tH], Retention time = 9.42 mitt; 'H-MMR (300 MHz, CD3OD) δ 9.15 - 9.14 (m, 1H), 9.12 (s, 1H), 8.25 - 8.21 (m, 2H), 8,16-8.10 (m, IB),8.0-7.97 (m, 111), 7.96-7.94 (m, lH),7.10(s, 1H),4.56 (s,2H). 1,36. SyntltosfrofA'A4~Bromo-3Ti«~l.,2,4^ria2ohSwi)ti5lsphen-2--yl)-2--i2-iJs.o- 3,4-di foyd r β<ρ 1 η ο i in~1 (2Z/)-y l)acetami de (3g)

UU. 4-^^2-(2-0^-3,4^ [0034») This compound was prepared from raetbyl 44,^-2-(2.(2-0^.3,4-dihydroquioolin-1(2H}-yl)acetamidi>)thiopiieae,2.carboxjfjatellsjflgpf(>^coj^j

Method] 1], MS(BSt) 407.9 [M-fH], Retention ^ ^ 2 043 min 1.36.2. ^»^3·<ΙΗ-ΐα^ί«>,Ι^^ρΗ^νίμ^^}4_ {£hy&amp;8qumaMn-.i@M}*$}mmamide [00341J This analog was synthesized from 4~bromo~2~(2~(2-oxo-3,4-dihydroqumQjin~l(2H)~yl)aeetamido)tblophene J~carboxamide using protocol C. Method{7], MS(EST) 432.0 {M+H]s Retention time - 4.311 min; 'H-NMR (300 MHz, CBaOj i 7.89 (b s, 1H)> 7 JO -7.26 (m, 3H), 7.09 - 7.04 gm 1H), 6.95 - 6.93 (m, 2¾ 4.92 (s, 21% 3.11 - 3.07 (in, 1¾ 193 - 2.88 (m, gH). L37, Synthesis ofiV-(4-Cyano~3rii^-l?2,4-irMzol~5~yI)th!ophen~2~yl)-2-(isocphsiOsn-S-ygacetaroide (37)

U37M Methyl 4~e}wrni~2~{2~(imquinsiMn~^l)ammmid®)thmpkms-‘3'· cmboxyiate

Protocol ¥; f60342] 1¾ a stirring mixture of methyl 44m>tr>o~2-(2-(isoquim>Sin-5'-yl)acraamidG)thiophene-3-carboxylate ('00 rag) in DMT -:0.5 roL) was added CuCN (150 mg). The resulting mixture was heated to 106 overnight. The reaction mixture was cooled to rwm temperature. To this mixture was added a 16% ΝΪ ?401-f solution and ethyl ether. The crude mixture was stirred at rt for 1 h. A normal aqueous workup with ethyl ether was followed. The organic layers were dried over MgSQ4, filtered and concentrated under reduce pressure. The crude product mixture was purified by silica gel column chromatography to give methyl 4~cyano-2-(2-(isoquinoIin-5-yi)acetamido)th«ophene-3“ carhoxylate. Method[l], MS(ESI) 352,0 [M+H], Retention time ::: 1.343 min. 2.3 7,2, 4~Cym(}-2~{2-{isoqmm}Un~S~yi}&amp;€etimMo}thiophme~3~carb0X4imide [ΘΘ343] This compound was prepared from methyl 4~cyanO“2-(2-(isoqui»olin-5-y1)acetamido>thiophene-3-earboxylate using protocol If Method[l], MS(ESI) 337.0 [M+H], Retention time = 0.673 min. 07.3, N-(4~Cyme»-3~(lH-I3,4-4riawl~5~yl)thwphen-2-yl)~2~(iseqmmHn-5-yfyaceiamide I00344J The title compound was prepared from 4-cyano~2-(2~(isoqiunolin-5-yl)acetamido)thioplj.ene-3--carix)xamide (15 mg) according to protocol C except that DCM was added to the DMF-DMA step and refluxed while the hydrazine step was heated at 90°C (rather than 95°C). The product was purified via prep, HPLC to give N-(4-cyaiiO"3~(IH-L2)4~triazol~5-yi)thiophen-2-yi)-2“(isoqinnoim”5~yl)acetamide, Method[7], MS(ESI) 361.1 [M+H], rt - 1.273 min; XH-NMR(300 MHz, CD3OD) δ 9.62 (b s , iH), 8.60 - 8.57 (m, 1H), 8.44 - 8.37 (m, 2H), 8.34 (s, 1H), 8.29 - 8.20 (m, 1H), 8.04 - 8,0 (m. IK), 7.86 (s, IH), 4,56 (s, 2H). 1.38. Synthesis of iV-(4“Cyano-3"(liT"l,2,4-triMOl-5~yl)thiopbeH"2-yI)-2“(2“OXO- 3,4-dihydroqulnolln-l(2£f)~yl)aceiamide (38)

1383, Mw8^&amp;tq?mm>2^2-J2mxm3,4-dihy<imquimfa-l(2H^ }4}meMmM&amp;}ilmiphene-3-ci(rhox}4aie [003451 This compound was prepared from methyl 4-hromo-2-(2-(2-oxo-3,4-dihydioquinolin-1 (2H)-yi)acctamido)thiophcnc-3-carboxylatc using protocol Y. Method]!], MS(ESi) 370.0 [M+H], Retention, time ~ 2.237 min. 138.2, 4-Cysm~2~(2-(2~&amp;xo-3t4-dthydroq«iRoUn~l(2E}~yi)acetemMo)thiophme~3~ carboxamide [00346J Tins compound was prepared from methyl 4-cy8no-2-(2-(2-oxo-354-dihydroquinolin-l(2H)*yl)acetaxnido)thiopheiie-3-carboxy1ate using protocol H, Method[l], MS(ESI) 355.0 [M+H], Retention time ~ 3.392 min. 1.383, N~{4-Cy^no,3^{?H3J,4~tHaz(^3~y()fhhpheii~2-yi}~2-‘i2-‘Oxe~3f 4~ dihydroqmmUn~l(2H)-yi)aceUmide [00347] This analog was synthesized from 4-cyano-2-(2-(2-oxo~3,4-dihydroqumolia-l{2H)-yl)aeetamido)thiophen<>-3-carfeo>:amide using protocol €, The crude product wad purified via preparative HPLC to give N-(4-eyana-3-(IH-1,2.4-iriazoh 5-yI}thiophen-2-yi)-2-(2»oxu-3,4-dihydroqumolm-1 (2B)-yl )aeetarnide. Method[7j, MS(ESI) 379.1 [M-ff], Retention time - 3.91 min; "M-NMR (300 MHz, CDCIS) S: 12.34 (s, IH), 8.13 (s5 IB), 7.62 (s, ill), 7.28 - 7.10 (m, 2H), 7.06 - 7.01 (m, IH), 6.94 (¾ /·· 7.7 Hz, IH), 4.92 {s, 2H), 3.12 - 3.06 (m, 2H), 2,91 - 2.86 (m, 2H). 1.39. Synthesis of .¥-(2-(3~methyM/f4,2>44ria2;Ql“5“y1)thiophen^-yl)-2-(4-(2“ oxopy rroildia-1 -y1)ptsenyl)aeetamlde (39)

/, 39. /. 3-3344ed0pkmyl}meiamid0)ikiophette*2*earb0xamide |®0348j lids compound was prepared from 2~(4-iodophenyl}acerie acid and 3~ annhiotfiio]iItene-2-earbox&amp;mide using protocol B. Mct.hod[1], MS(ESI) 387.0, Retention lime1.777 min. 1,393, 3~(2~{4~{3~Ox^pyrir0iMin-l-yS)pkmyi)iu:eMmiiiit}^hi(/phene~2~c«rb&amp;xsmide [00349] To a stirring mixture of 3-(2 -(4-iodophenyl)aeetamido)thiophcne-2-carboxamide (300 mg) in dioxanc (2 mL) at rt was added Cul (103 mg), K2C(6 (325 mg), pyrrolidm-2-one (80 mg), and rao-dimedhyicyclohexane4,2-diamine (92 mg). The resulting mixture was heated to 90 °C overnight. The crude product mixture was diluted with saturated NaHCOa solution and extracted with EtOAc. The organic layers were dried over MgSO,;, filtered, and concentrated under reduced pressure. The product was purified via silica gel chromatography to give 2-(2-(4-(2-oxopyrrolidnt-1 -yd)phemyl)acetamido)ihiophene-3-carboxamide. Method[i], MS(ESI) 344,1. Retention riroe-:: 1.476 min. 1.39,3, N-(2-(3-methyi~lIi~I,2,4~triaz0!-5-yi}tki0phen~3~yi)~2-f4-f2-0xepyrmiidin~l~ yl)phenyi)m:etamide [00350j T|j$ analog was prepared from 3-s(2~(4-(2-oxopyrrolidin-1 ~yl)pheny 1)-aectaroido}thiophene-2-carboxamde using protocol C. Method[7], MS(ESI) 382.1 [M i H|, Retention tiile - 3.46 9% iH-NMR (360: MHz, (Ml) 6 10,02 (s, 1H), 8.13 (d, ./ = 5.5 Hz, 11¾ 7.46 - 7.38 (m, 4M), 7.30 (d, Jw 5.5 Hz, 1H), 3R7 ··· 3.93 (m, 2H), 3.87 (s, 2H), 2.78 - 2.72 (m, 2¾ 2,52 (s, 3H), 2.40- 2.25 (m, 2H). 1 <40. Synthesis of A"(4“inethyl~3-(5-mefhyI-4//-l ,2,4-trkzol-3- yI)thiophen-2"yl)~2-<4“(pyri£SiK”4-yl)phenyl)aeetasiiMe (40)

1.4$, L 2~(2~{4~lodGphmy^acemmM0}~4~meikyUhkiphme-'3~f:Mrbmaitride [00351] To asolution of 2ranajiio--4-medrylihif^hene-3^earfeoxaixiide (1 g, t5.4mmo.i) and T^-iodopheoyRaceMe acid (1.83g, 7.0mffibl) M methflMe chloride (lOrnL) was added Hunig’s base (i.e., N5N-diisopropylethykmine) (3.1 mL, Ifermol) and IMTU (2.66g^ 7.0inmel), The heterogeneoua was Miii»d fisr 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the biphasie mixture was extracted with additional methylene chloride. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to provide a pale brown solid. LCMS method [2]: rt = 2,02 min; M+Na 423.0, Material was used without further purification, ϊ.4ϋ,2< 2~(4-l8dophetiyi)-N-{4-metkyi~3~(5"Metkyi-41i-I,2>4~trwmi~3-yi)fkkipkeM-2-yljitcetamsde [00352] The title compound was prepared from 2-(2-(4-iodophenyl)acetaroido)- 4-methylthiophene“3-earhoxasnide <277mg, 0.69mmol) using protocol D and was purified by column chromatography using 3%MeO.H/xnethylene chloride (140mg, 46% yield). Method [1]: rt = 2.11 min; MH+ 438.9. 1,4@, 3. N~(4-Metkyi-3-{5-metkyl-4H-lf2>4-triaz&amp;l-3-yl)thi0phen-2-yl)~2~{4-(pyndin-4-yl)phenyi}acetamide [¢0353] [0083] A 30mL reaction vial was charged with 2-(4-iodophenyI)- N-(4-meihyi»3-(5-methyJ-4H-] ,2,4-triazoI-3-yl)thiophen-2~y!)ac«tamide (140mg, 0.32mmol), pyridin-4-ylbaronic acid (60mgs 0.48mrool), sodium bicarbonate (lOOmg, .1,2mmol), DME (2mL), and water (2mL). The heterogeneous mixture was stirred vigorously under a scream of nitrogen tor 5 minutes before Pd(PPh3>f was added and the vial was sealed under its Teflon cap. The reaction mixture was heated to 90 °C for 3.25 h before being transferred to a microwave vial and being microwaved to 150 °C for 5 minutes. The reaction mix was concentrated under reduced pressure and the residue was partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride, The organic solution was washed with brine and dried over sodium sulfate.

The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (3.5%MeOH/methyfene chloride) Yield: lO.Orng (8%). Method [1]: rt - 1.136 min: MH-f 390.2. ‘H-NMR (300MHz, CD3OD) 5 8.71 (d, /=6.3 Hz, 1H), 8.60 (dd, J= 4.6,1.6 Hz, 2H), 7.84 (d, ./=8.0 Hz, 2B), 7,77 (dd, /-=4,6, 1.6 Hz, 2H), 7.57 (d, /=8.2 Hz, 2H), 6.58 (s, 1H), 3.94 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H). 1.41. Synthesis of /9~(4~eyasi©-3-(4//~l,2,4-triszol~3-y!)thi©pheii-2-3d>-2-(qnin4>lin- S-ylJaeetaoilde (41)

1.41.1. Methyl 4^mm&amp;-2~(2#(ij[mmtiw$~yf)aceteMiii&amp;}t&amp;i0ftme~$^rhw$liite [00354| The title compound Was prepared from methyl 2-ahdnp-4-broinothiopfiene-S-cilbQ^ylate {o60mgj 2.8mmolj and 2-squinoim4>-yI)aeetic acid using protocol A. 560mg (49% yield). Method [1]: rt = 1,666 min; MH+ 405/407. L 41.2, Methyl 4~qym0~2~(2-(qumoim~S~yi}uceiamido)ihi&amp;pheite~3~cath0xyiate [00355] A 20mL microwave vessel was charged with methyl 4-bromo-2-(2~ (quinoIin-5-yi)acetaimdo)thiophene-3-carboxyiate(560mg, 1.38mmoI)> CuCM (540mg, 6mmoi), DMF (8mL), and (lR,2R)-N1,N2~dimethylcyciohexatie-l,2-diamine (3O0uL). The reaction mixture was flushed with nitrogen and sealed under a teflon cap before being heated to 150 °C using microwave radiation for 0.5h. The reaction mixture was concentrated under reduced pressure to give an oil that was partitioned between an organic layer of 10% iPrOH/eMorofomi and an aqueous layer saturated with sodium bicarbonate, The heterogeneous organic layer was filtered and concentrated under reduced pressure to give a green oil. The crude product was purified fey column chromatography with 6£fe7©% ethyl acetate / hexanes, Yield: 40m| (8%). Method [1 ]: rt - 1,401 thin; MB- 352.0. 1.41.3. 4-C.yane-2-{2-(qMneUn~$~yl}<icetmiiii0)fhiopkene-3-carb&amp;xami{lg [06356] The title compound was prepared from methyl 4-cyano~2“(2-(qumolin~ 5-yI)aceiamido)tluophene~3-carboxyiate using protocol H (Bmg, 80% yield), Method [1] : rt = 0.665 tnin; MH+ 337.0. 1.41.4. (Z)~4~€yam-N~{(dmeihylamimf}methylene)-2~{2-(qulmUn~S-yl)iieet(mido)-tklophem-B-carboxamide [00357] The title compound was prepared from 4-cyano-2-(2»(quinolin-5-yl)acetemido)thiophene-3carboxamide (37mg, O.llmmol) according to protocol C and was use! without fo^rer purificatfon. Method [1]: rt::: 1.291 min; MH+ 392,1. L41,5< 0aMtemide [tM535S| i'o a mixture &amp;f 47cy*ao-N-((dimetliylainiaQi)imithyIsii.e)^siS·- (quinolin~5-yi)ac^amido)toiophene-3<arboxamide (0,1 Imrnol) in HOAc (2mL) was added hydrazine (19uL of 65% aqueous solution). The reaction mixture was heated to 8? °C for 12 hours and was then cooled to 23 °C and concentrated. The residue was taken up in a 10% isopropanoi/chioroform solution and washed with a saturated, aqueous solution of sodium bicarbonate. The organic solution was dried over sodium sulfate and concemrated to give a solid,: which was purified by column chromatography (using 5 to 10% methanol / methylene chloride) and prep-HPLC (5-40% MeCM gradient). Snugs (13% ibr thefkud 2 steps), Method [8] : tt “ 8.1 min; Mf!+ 361.1. ^-NMR (dlMlMMz, <HCi3) δ 8.86::(¾ l:H), 8.48 11¾ 8.14 (d,MH.SHz, 1H), 7.85 (to, 211), W9 (d, J-6.6Hz, Ilf), 7.54 (m, 2¾ 4 J4 0,¾3.30 (S, 3H). 33€-blMR (fSMHz, I}MS£>-4) δ 168.7, 158.9, 158.4, 149.5,139.5, 132.3, 131.3, 181.2, 130.,5, 127.9, 127.2, 122.3, 118.3, 1.15.7, 112.5, 105.7, 105.6, [003591 Compounds of Examples 1.42 through 1.48, below, were synthesized by activation of the corresponding carboxylic acids and condensation with 4-bromo-3-(4H"l52,4-lriazoi-3-yl)thioph.en-2-amine. which was prepared according to the scheme, below,

1,42. 7V-(4“Brfimo-3~(l/#-l,2,4-t5'ia2oh5~yl)tMophen-2-yl)-2-(2~oxo-7- (fttifl uorom et hy l)qu S nolin-- 1 (2/9>-y!)ncetxmiide

[00360] Retention time {min) - 5.456, method {?], MS(£$0 497.9 (M+H); ‘H 'NMR (300 MHz, CD»OD) 5 7.92 id, J- 9.8 Hz, 1H), 7.79 (d, J ~ 8.2 Hz, 1H), 7.73 (s, •1H), 7.52-7.55 (m, 21-1), 6.96-7.01, (m, 2H), 5,34 (s, 2H). L43, Λ-(4-Βηϊοκ}-3-(ϋ7-1?2,4-(τΜ^ο1~5->Ί){1ϊΙηρ1ϊ£!η~2^·Ι)-2-(6-ί1«©Γ(5-2-οχ«ί-3?4-

[003611 Method! ?], MS(E$i) 450.0 [M+H], Retention time - 4,428 min; Ή-NMR (300 MHz, CDCiO § 7,80 (s, 1H), 7.28 (s, IB), 7,10 - 7.0 (m, 2H), 6.94 (s, ifl), 4,86 (d, J = 3.84 Hz, 2H), 3.12 -3.06 (m, 2H), 2,86 - 2.81 (m, 2H). 1.44, A-(4-Bnimn-3-(li7-l,2,4~triaxii!-5-yS)thtop!sen~2~jI)-2-(7-ilporo-'2-oxnqMS5tnMn-l(21f)-yl)iie£tomIde

[00362] Method[7], MS(ES1) 448.0 [M 44], Retention time = 4.417 min; !H- NMR (300 MHz, CDCI?) δ 7.86 (d, J - 8,9 Hz, 1H), 7.70 (s, 1H), 7.66- 7.60 (m, M), 7.04 - 6.90 (τη, 2H), 6.95 (s, iH), 6,85 (d, 9.34 Hz, ΪΗ), 5.26 (s, 2H). 1.45. A;-(4-Bromo~3”(l /7-1 ?2,4~trSazoI-5-ji)thk)phen~2-yl)-2-(7-els1or©'-2“i>so-3,4-

[00363] Mc«hod[7], MS(FSJ) 466.0 [M4H], Retention time =· 5,594 min; ;H-N'MR (300 MHz. CDCI>) δ 7.93 (,s 1H). 7.17 (d, J - 7.7 Hz, 111), 7.04 (dd: J = 8.24,1.65

Hz, m, 6.98 ts, IH), 6.94 (d. j - 1.65 Hz, IH), 4.88 (s, 2H), 3.08 3.03 (m, 2H), 2.93 : 2.85 (m, 2H). 1,46. A^4-Bromo-3-(!.if.lj2,4.triaz©I-5“yI)thIophen-2-yl)-2»(6,7-dllliBoro-2-

[00364) .Method[71, MS(ESS) 465.9 [M-HI], Relent bn time == 4.5.16 min; ’Ή-NMR (300 MHz, CDC13) § 8.58 (b s, IH), 8.07 (d, 5 - 9.8 Hz, IH), 8.02 (dd, J == 10.44, 8.8 Hz, IH), 7,91 - 7.84 (m, IH), 7.33 (s, IH), 6.79 (d, 3 = 9.9 Hz, IH), 5.27 (s, 2H). L47, Ai-(4-Br©rs5o~3~(.liM52,4-irk^(ikS~yI)tSif®p.hess-2-yi)~2~(2-osi>-6- (trlfl5sstrosisethyl)i| omolm-1 (2J9)-yl)acetamlde

[0036?! Method[73, MS(ESI) 497.9 [M+H], Retention 'dine ::: 5,696 min; Ή-NMR (300 MHz, CDCb) δ 12.87 (b s, IH), 7.92 (d, J = 6.6 Hz, i H), 7,73 (s, ] H), 7.77 (d, J = 8.24 Hz, IH). 7.73 (s, .IH), 7.42 (d, J == 9.34 Hz, IH), 6.98 (d, J ::: 9.9 Hz, IH). 6.95 (s,lH), 5.33 (s, 2H). 1.48. A;-(4-Bromi>-3-(lI?~l,234-triazol~S-yl)t!iiophe85-2»Yl)-2"(6‘~il8ior©-2» oxoq(ilnoliK"1(2//)“yl)aeeianiide

[003661 Method[7], MS(ESI) 448.0 [M+H], Retention rime == 4.347 min; SH-NMR (300 MHz, CDClj) δ 7.82 (d, J = 9.9 Hz, IH), 7.68 (s, IH), 7.37 7.33 (m, IH), 7.28 (s, IH), 7.26 - 7.23 (m, IH), 6.95- 6.92 (m, 2H), 5.30 (s, 2H). 1.49; Synthesis of «^MK|ridiiS“l(2M)~yl)fficetamtie

lijiJll, Methyl 2-(2~&amp;XQ-l,6-mphthyridm~l{2H)-yl)acetate [00367] The title compound was prepared from 1,6~naphthyridin--2( 1 N)~onc according to protocol TL Retention time (min) - 0.949, method [3], MS(ESI) 219.1 (M+H). h 49,2, 2{20xo~ 1,6-mpktkyridin-l (2H)~yi)aceiic acid [90368] To a solution of methyl 2-(2-oxo-l }6-naphthyridin-l(2ff)-yl)acetate (1,51 g, 6.92 mmol) in TUP (10 mi.) was added sodium hydroxide (4 mL of a 3 N aqueous solution, i 3.8fnrnol) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was diluted with ethyl acetate and washed with water. The aqueous phase was separated, adjusted to pi i 2 With aqueous HC! and extracted with ethyl acetate. The organic phase was separated, dried (NaaSCT.), filtered and concentrated under vacuum to give 2-(2-oxo- ί ,6-napbthyridin-1 (2//)-yl}acctic acid, Retention time (min) - 0.368, method [3], MSfESI) 205.0 (M+H). 1.493* N-(4~Br0m»-3’-(lII-lf2y4’4riaz0l~5~yl)thiepkeH-2-yi)~2"(2~oxif~l:i6-mphfhyridm~l(2H)-yi)acetamide [00369] The title compound was prepared from .2-(2-oxo-l,6-naphth.yridin-1 (2i/)-yI)aeetic acid (62 mg, 0.306 mmol) and 4-bromo-3-(liT-l,2,4-triazoI.-5-y!)thiophen-2~amiue (25 mg, 0.101 mmol) according to Protocol L. Retention time (min) - 1.258, method [7], MS(ESI) 431.0 (M+H); lH NMR (300 MHz, CD3OD) δ 9.10 (s, IH), 8i65 (d, J* 6.5 IH); 833 (s, IH), 8.23 (d, ,/=== 93 Hz, 1«), 7.75% ,/== 6.5 Ha, Mi), 7.15 (s, IH), 7.01 % ,/=== 9.7 Hz, IH), 5.39 (s, 2H). 1.50. Synthesis of j¥-i4-bromO“3-(IH-l,2s4-triazoi“S-y!)fhlophen"2-yl)-2~(2-oxo- 1,5-siapli thyridin- i(2H>-yl)acetamid.e

L 50. L Methyl 2-(2-&amp;x&amp;-l,5~mphihyridm~I(2ff)~yl)ace&amp;ite [00370! 1. 5-naphthyridto ~2 (1 //)-one (2.05 g, 14.0 mmol) was treated with lithium hexamethyldisilazide instead of sodium hydride according to protocol K to give methyl 242-oxoH,5~naphth}uidm-lf2/f>yl)acetate (224 mg). Retention time (min) - 2.084, method [3], MS(ESI) 219.0 (M+H), 7.5ft 2, 2-(2-Ox0~lt 5-nqphtkyrMw~ I (2M)~yi)acetic acid [00371] To a solution of methyl 2-(2~oxo-l ,5"naphthyridinH(2j7)-yl)acetate (0.205 g, 0.939 mmol) in THF(5 mL) was added sodium hydroxide (0.939 ml. of a 3 N aqueous solution, 2.818 mmol) and the reaction mixture was stirred at 70 CC for 0.5 h. The resulting .solution was concentrated under vacuum and co-evaporated from toluene to give 2-(2-oxo-l»5-naphthyridin.-l(2if)-yl)acetic add. Retention time (min) = 1.033, method [3], MS(ESI) 205.1 (M+H). 1.503. N-{4-BFom&amp;-3~(lH~l!2,4-tH&amp;zM-5-yi)tki&amp;phen-2-yl)-2-(2-&amp;x&amp;-l,5~ mphthyridm-l (2H)~yl)aseiamde [00372] The title compound was prepared from 2-(2-oxo-i ,5-naphthyridin·-If2/f)~yl)acetic· acid (42 mg, 0.204 mmol) and 4-brom0-3-(I/f-l,2,4~triazol--5-yi)thiophen-2'amine (25 mg; 0.101 mmol) according to protocol A. Retention time (min) = 2.295, method [7], MS(ESI) 431.0 (1¾ NMR (300 MHz, 00.00) 5 8.57 (<M, J - 4,6. 1,7 Hz, 1H), 8.16 (d, J = 9,9 Hz, 1H), 8.11 (s, 111), 7.98 (d,7== 9.1 Hz, ill), 7.62 (dd, J- 8 8, 5.1 Hz, 1H), 7.01 (d, J= 4.3 Η|, 1H), 7.05 (s, IH), 5.33 (s, 2H). ¢1.51. Synthesis of A^^hromo-S-CUi-RS^inaitol-S-ylRhiOphen-S-yiTi-Q-oso-y^-dfh yd ro-1 < 6~na ph thyri &amp;i n~l(2H)-yl)acei amid e

hSld, 2~{2^x0~$i4^ihydra*l,6maphikytiMn~l(21I)-yl}metk 'tmM

[00373] A .suspension of' 2-(2-oxo-1,6- naphthyridin- 3 i2/4}-yl)aceuc acid (150 mg, 0.734 mtsoi) and Pd/C (20 mg) ip methanol was shaken under a 40 psi atmosphere of H2 for 18 h. The suspension was filtered through Petite and thesfiltrate was concentrated under t?aenmnte give 2-proxo-3i4-dihydPo-ls64;iaphthpidiii"l(2if)-yf|aeetie acid. Retention time (pin) = 0,343, method |3j, MS(ESi) 207.1 (M+H). 1.51.2. N~{4~.Bmm&amp;~3~(lM~l,2,4-in(izol~5~yi)thk>phen~2-yi}~2~(2~ex&amp;~3>4~dihydro-l}6~ mphtkyridin-l{2H)~yl}iiC8i&amp;mide [0®374| The tide compound was prepared from 2-(2-oxo-3,4-dihydro~1,6-naphthyridin-l (2W)-yl)acetic acid (40 mg, 0.195 mmol) and 4-hrom0-3-(l/7~ls2,4-tria2o]-5-yi)thiophexi"2-amine (24 mg, 0.0979 mmol) according to protocol A. Retention time (min) - 8.108, method [6], MS(ESI) 433.0 (M+H); lH NMR (300 MHz, CEfeOD) δ 8.63-8.48 (m, 3H), 7.51 (d, 6.8 Hz, Iff), 7.16 1H), 5.08 (s, 2H) 3.29-3:.25 (ra, 214), 2.98- 2.93 (m. 2H). 1.52. Synthesis of Ar-(4-brnro0-3-(1 II~!,2,4-ir.iazol»5-yI)thiophen-2-yi)-2-(2-sxo~ 3,4~dihydro-l,5-naphthyriclin-l(2H)-yI)acgiamIde

L SZ /. 2-(2~0m)3,4^h0m~l3^hhphthyridm 1 (21f)~yl)acetic #i?p [00375] 2-(2-0^0-1,5-naphthy ridin-1 (2//}-yl)acetie acid (90 mg, 0,441 tamo!) was treated according to Example 1.51,.1 t© give 2^2<>xo-3,4KiL^di»-l l(2/0-yi)acetic acid, Retention time (min) = 0.262, method [3], MS(ESI) 207,0 (M+H). LS2.2. ;V-(4-Brom«>"3»(l/l"l,2;4-trIax0l--5»yl)thioi>hen~2“yt)-2"(2-osO“34-tlihydro·' 1.5- sapliitiyrlilia~l(2i/)-yl)aceiamide [00376) i¥"(4-Bromo~3-(l.ff-l,2,4~triazol-5-yi)tbiophcn-2-yi)"2"(2-oxo~3,4~ dihydro-1 ,S-aaphthyndm-l (2i?)-yl)acetamide was prepared from 2-(2-oxo-3s4-dihydro- 1.5- naphthyridm- I(2//)-yl)acciic acid (42 trig, 0.203 mmol) and 4-bromo-3-(li7~l52,4“ triazol~5-yl)thiophen-2-arnine (25 mg, 0.102 mmol) according to protocol A. Retention time (min) - 1.274, method [7], MS(ESI) 433.0 (M+H); lH NMR(300 MHz, CD3OD) δ 8.35 (s, 1H), 8,23 (d, /= 4.5 Hz, 1H), 7,65 (d, J = 9.2 Hz, 1H), 7,45 (dd, /- 9.2, 4.5 Hz, !H| 7.12 (s, If), 4.9:1 (s, 2Hj 3.34-3.33 (ra 2H), 2.98-2:.93 (m, 2H). 1,53- Synthess of A?-(4-i>roi»o-3-(1//-.1 j2»4-lftazol-5-yi)thsop0e!t~2-yI)-2-<2~o.so~7- (iYiBmmm&amp;ih oxyiqulneiln-l(2//)-yi)aeetasnliie

7« 55. L Ethyl 3-{2~ammo~4-{triJium&amp;methoxy)phmtyl)acryieie [00377] The title compound was prepared from 2-bromo~5~ (Mfiuoromethoxy)aailine according to protocol M, Retention time (min) = 2.693, method [1], MS(ESI) 276.1 (M+H). 1.53.2. ?"{TriftuwometkiKtY)quimUn~2{iITH}m [0S378] 7“(TrifiuoromethoxyK|uinoliii-2(j.H)-onc was prepared from ethyl 3-(2-^ino-44()tifl«ororhip©xy)pbonyi)acrylate according to protocol N* Retention time |ηίη) - 1J03, method [1], MSfBSI) 230.1 (M+H). LS33. Methyl 2~(2~ox&amp;~7~{trifluori)meihoxy)qumfflm-I(2H)~yl)«€eMe 10O379J The Mile compound was prepared from 7~(trifluoromethoxy)quinolin~ 2(l//)-one according to protocol K. Retention time (min) - 2,226,.method [1), MS(ESi) 302.0 (M-H-i). 1.53,4. 2~(2~Oxo-7-(trifiuoromei:he3^)qmmtUn~2(iM)-yi)aceUcmdd [00380] Methyl 2~(2--oxo--7-(trifluoromethoxy)qumolin-l(2if)-yl)acetste (0.49 g, 1.62 mmol) was dissolved in IMF (4 raL). Sodium hydroxide (1.08 mL of a 3 N aqueous solution, 3,25 mmol): wax added and the reaction, mixture was stirred 60 °C for 2 b, The resulting solution was diluted with ethyl acetate add washed1 with water, The aqueous phase Wgs separated, adjusted to pH 2 wish aqueous HQ and extracted with ethyl acetate. The organic phase was separated, dried (N&amp;.2SO.-.)s filtered and concentrated under vacuum to give 2~(2-exo-7-{i«S«©»fflethoxy)qumQlm-I(2H)--yl)aeetIc acid. Retention time (mm) ··· i 75, methpl [1¾ MS(ESI) 288,1 (MuTl). /,53,5. N^{4~Brmn0~S"{iH^lf2,4~irsazf>i~S~ylithsi}phm--2'):i)-2~(2~mi>~7~ {iriflmnmeth0xy)quimtm-l(2il)-yl)ai'etamide [0038! ] The dtic compound was prepared trom 2-(2"Oxo-7·· (tiafinoromeihoxy)qiunoliUil(2i7)^yl)ai^liC add (79 mg, 0.275 mmol) and 4-bromo-3-(17/-1,2j4~tnazol-S-y])thiophpn-'2-amine (35 rag, 0.137 mmol) aeecrfhg to protocol A, Retention time: (min) = 6.037, method |7]yMS(ESI) 514.0 JM NMR (300 MHz, GH3OH)6 8.15 (s, IH), 8.11 §, J-9.9 Hz, Mf, 7.88 (47 = 9.1¾ IH), 7.4Us, IH), 7.26 (m, 3H), 7.10 (s, IH), 6.81 (d, J-9,9 Hz, IH), 5.31 (s, 2H), ί .54 Synthds of ,;V-(4-l)r<>mo-3-(l/7~l,2,4-trsazoR5-yl)thlo|>heu-2-y!)-2~i?-ey?auO" 2~exoqu laoli n-1 (2^)-yl)aestamlde

1, 54<L Methyl 2~(7~bmm&amp;M.~oxoqmmlm~l{2H}‘-y!){iicetate [003$2j The title compound was prepared flora 7·^ρ*@^ι«ηοΗιι-2{ IHy-omi according to protocol K. Rdention time (mis): = 1.89, method [1], M 8(1585) 296.0 (M+H), L 542. Methyl 2-{7^me’^m&amp;qmmhm~l(2By-yl)^etsite [00383( CuCN (0.211 g, 2.36 mmol) and PdiMhih (0.136 g, 0.118 mmol) were added to a solution of methyl 2~(?4iromO“2"Oxoqidsoiis-l(2i/)-yl)ac«igtc (1.35 g, 1.18 mmol) in ilMF (1 rnL) in a screw cap vial. The vial was sealed and placed into a oil bath at 120 °C and the reaction mixture was stirred tor 18 h. The resuiting mixture was diluted with Et?0 and washed with brine. The organic phase was separated, dried (NajS©*), filtered^ concentrate «rider vacuust and tire residue was prided on a silica gel ebhitih to give mdhyi 2^7^ano-2<>xo|pihcia~l(2Kl~yl)aceiate (0.204 g, 71%). Retention time (min) ·= i .464, method f 1], MS(ESI) 243.1 (M; H). f§0384| Trimethyl tin hydroxide (0,388 g, 2.14 mmol) was added to a solution of methyl 2-(7seyanO"2-ox0qninolirt-l(2fi)-yl)aeetate (0.104 g, 0.429 nurse!) in 1,2-diehloroeihsne (5 mli) and the resulting suspension was sirred at reflux fdr 4 L The reaction mixture was diluted with dic'h 1 ororoet bane and washed with IN aqueous HCl Filtration of the organic phase provided 87 rag (89%)of2- (7-cya!io-2 -oxoquinoiin-1 (2/:/)~yi)aeetic add.. Retention time (min)::: 0.987, method [1J, MS(ESI) 229.1 (Μ i f Ϊ) I, 54,4, Ν^4~ί&amp;θΜθ-3^1ΗΜ£,4-*Ηαζ0ΐ~$-$1)&amp;^ρΗ6ΐΐΓ2·$1)~2-(?-€$αηο-2- ox&amp;qmnolm-l(2H}~yl)ucetmnMe (98385! ;V~(4-Brorno-3-( 1M-1,2 s4~triazol-5 -yl)ibiophen--2~yl)*2 -(7-cyano-2-oxoqdnoiin- 1 (2/f }*y !)a<mtantidc was prepared from 2-(7-eyariO-2-oxoqainolin-i(2f0-y1)acetic acid (65 mg, 0.286 mmol) and 4-|imi®“3-(ljRI>2,44riazol-5-yi)tliiophen-2-amine (21 mg, 0 143 msrml) aecordingsto protocol A. Retention time (tnin) = 4.143, method [7], MSpSi) 454.9 (MW); ‘Η NMR (300 MHz, DMSO-4) δ 12.18 (s, 1H>, 8.56 (s. 1H), 8.24 (s, 1H). 8.16 fd,/- 9.0 Hz, 1H), 8.01 (d, / = 8.0 Hz, 111), 7.70 (0..,/ 8.01 Hz, III), 7.28 is, 1H), 6.90 (d, /- 9.0 Hz, 111), 5.31 (s, 2H). LSS. Synthesis of jV-^-bromo-S-Cl/J-l^dHriazol-S-yRthiopheo-l-yipj-ilsoqofnoI!n-8-yl)acetarnide [003861 ,¥-(4-Bromo--3-( 1 Η-1,2,4-triazo1-5-yi)thiophCTi-2-y3)-2-(fsoqumoitn-8-yl)acetamide was prepared from 2~(isoqoinolin~8-yl)acetie add (53 mg, 0,286 mmol) and 4-bromQ-3-(l /7-i}2,4-triazoi“5-yl)tfriophen-2~ami!ie (35 mg, 0.143 mmol) according to protocol A. Retention time (min)::: 1.769, method [7], MS(ESI) 414,0 (M+H); SH NMR (300 MHz, CD3OD) δ 9.84 (bs, 1H), 8.55 (bs, 1H), 8.41 (4/=6.0 Hz, IH), 8.26-8.23 (m, 2H), 8.18 (dd, J~ 8.1, 7.2 Hz, IB), 7.99 (d,/“ 4.0 Hz, 1H), 7,09 (s, IH), 4.61 (s, 2H). 141. iSynthesIssOf A~(4~l)rcfmn-3-(iii“14'4'4rkzoI-S-y!}ihiop|iesi-2-yl)-2-(6- fliioroqiiino!ln~5-yl)aeetamide [09387] V-(4-bromo-5 -(j H~ 1,2,4-triazol-5~yl)thioplHni-2-y'i)~2"i;6-fluoroquh.oUn-5-\ .jaeei&amp;mide was prepared from 2~(6-fiuoroqi.iinolin-5-yl)aeei!e acid (42 mg, 0.203 mmoi) and 4-bromo-3-(l /7-1,2.4-tri;cro!~5-ylHhiopher;'2-an)ine (25 mg, 0.102 mmol) according to protocol A. Retention time (min) = 2.499, method {?], MS(ESl) 432.0 (M;i K); lK NMR (300 MHz, CDgH©) § 8.99 (dd, /= 4.2, 1.1 Hz, 1H), 8.86 (d, / = 7.9 Hz, 1H), 8.23 (dd, /= 8.9, 4.5 Hz, 1H), 8.08 (s, HI), 7.85 (dd, J= 9.4,9.2 Hz, IH), 7.81 (dd,/ = 9.2,4.5 Hz, 1H), 7.07 (¾ IH), 4M (s, 2H). 1.57 Synthesis of i¥~(4~bromo~3~(Iif~lf2s4~iriazoI"5~yI)ililopheri-2~yl)»2-(6-fi nortK|niaolin-7-yl)aeetamide [00388] Afc(4^romo-3K177-l,2,4^azoi-5-yl)lMdpen-2-yi)-2-(6^ fluordqdMdim-7->d)acdtamide was prepared from 2-(6-4luomqumpim4->d)aeetic acid (42 rag, 0,203 mmol) and 4-frromo4--( MIA ,2,4-isazol-S-yi)tyophem2~am^ (25 mg, 0,102 mmol) according to protocol A, Retention time (min) = 2.338, methbd [7], MSfESI) 432.0 (mm NMR (300 MHz, CD3OD) 8 9.02 (d, J 4.2 Hz, HI), 8,73 (d, J = 84 Hz, IH), 8,24(4/= 7.2 Hz, 1H), 7.93 (s, 1H),7.88 (4/= 10.0 Hz, IB), 7.82 (M,J~ 9.0,4.2 Hz, IH| 7.09 (s, IH), 4.42 (s, 2H). 1.58. Synthesis of A'-(4~Bromo-3“(l//"i ,2,4”triazol-5-yl)tliiophen-2-yl)-2-(2'0zo-7“ (triflnorornethyl)-1,6"naphtliyr!din-l(2H)-yl)aeetamld e

L 58.L 5~hide~2~(iHfiuoroiftetk¥{}pyrkU&amp;~4~i)l [00389| Iodine (8.16 g, 32,1 mmol) was added in five portions to a .solution of 2^trifluoromdhyl)pyridirM!-ol (5 g. 30.65 mmol) mid K:CQ< (4.66 g, 33.7 mmol) in methanol (34 mL) at# “C and the resulting mixture was stirred at room, temperature for 20 In. The solution wus washed wi^satoiediatpcousssedium. sulfite then acetic act'd (10 mL) was added and the solution was extracted with ethyl acetate, dried (NasSOi), filtered, concentrated trader vacuum and the residue was purified on a silica gel column to give 5riodo42-(trif;irommet%i)pyiidin--4-ol (5,1 g, 57%). Retenfi0niitn®:(pla) = 1.761, method [1], MS(ESI) 290.9 (M+H). 1,58,2. 4"€hfaro-S4odo~2~ft?iflmri>meth}4)pyridme [09390] A solution of 5riodo--2-(-rifruoromet!v/l^yridiT:.-4-oi (4.8 g, 16,6 mmol) in POQI3 (SOimT·) was heated to 100VC for 30 minutes. The resulting solution was eoseentrated under vacuum and the residue was neuanligsd by the addition of ice and aqueous potassium carbonate. The spjutfott was extracted with ethyl acetate, dried (NajSOi), filtered and: concentrated under vacuum to gi ve 4 ~ch !oro-5-iodo-2-(tn fl uo romei by I )pv riditsc. Retention time (min) - 2.594, method j1 ], MS(F.SI) 307.9 (M+H), 1*5$3.

[06391] Concentrated, aqueous ammonium hydroxide CilmL) was aided to a solution of4-cbforo^5-iodi>'2-(ti'ifiuoromethyl)pyridine(4Jl g, 13.3 mmol) in DMSO in a glass pressure tube. The tube was sealed and placed in an oil bath pre-heated to 110 °C for 48 h. The resulting solution was diluted with brine, extracted with ethyl acetate, dried (NaaSOa), filtered and concentrated under vacuum to give 5-iodo-2- (iiiiuoiOmcthyl)pyridm-4-amiae. Retention time (min) " 1.584, method [.1), MS(ESI) 289.0 (M+H), L 58,4, Ethyl 3-{4~umino-8-{tdfiu&amp;romet.h}4)pyridm~S-yl)acfyMte [003921 Ethyl 3 -{4-anvino-6-(trif3uoromcthyl)j:(yridin--3-y!)acry[atc was prepared front 54odo-2-(tn41am-Qfi®ethyl^pmdin-4--aiiiiae aeeordiBg to protocol M. Retention rime (mis) - 1.064, method [1], MS(ESI) 215.1 (M+H). 158.5. 7^7^m}wmsth}i)~}}6-.naphthyridm-2{2H}~&amp;tu; [Θ03931 7--fFHEi:oromethyl)-1.6-naphthy«diri-2(!i|/-one was prepared iron) ethyl 3-(4 •anano-6-([rifluororfietby{)pyridine-3-yl)aetytete according to protocol N. Retention time (min) = 1.064, method [if, MS(ESI) 215.1 (M-H). 1,58. &amp; Methyl 2~(2~m&amp;~ 7~(ts ifliiflr&amp;Metky2)~lfl^mphikyridi%~lf22l)-yl)eceUitfe [00394) Methyl 2-{2~oxo~7-(trit]uoromethy;)- 3,0-naphthyrsdirs~l(2H}-y i jaeetate was prepared from 7-(trifluoromethyl)-l,6-imphthyridin-2(lii)-one according to Protocol K. Retention time (mis) ~ 1,621, method [1], MS(ESI) 287.1 (M-HH).

2.58.7. 2"{2~Om-7~(iFffimrmneihyiylf6~naphthytiim~l(22$}-yl)ttc&amp;tic acM

[00395 j Methyl 2-(2-oxo-7~(tritliiorotnethyS)-i ,6-naphthyfidin~l (2H)-yl)acetate (0.O69 g, 0.1O mmol) was treated according to Example 1.53.4 to give 2-(2-om-7-(trifli!oromcthy!)-ls6-naphfhyridis-l(2i7)-yi)acetic acid. Retention time (min) - 1.081 s method [I], MS(ESi) 273.1 (M+H). 2.58.8. N-{4~Bmm&amp;-3-(2H~2j,2>4-f?iaz@t~5~yi)thk}pken-2~y2)"2-(2~GXit- 7-(trftlwremeihyl)-l,(hmphthyriditi~i(2H)~yl)acetmtMe [00396) The...title compound was prepared from 1,6--naph0iytidin-1 (2fi)-yl)acetic acid (55 mg, 0.203 mmol) and 4%omo-3-(li/-ls254-triazoI-5-yl)thiophen-2-amin.e (25 mg, :0.102 mmol) according to protocol A. Retention time (min)- 4.565, method [7], MS(ESf)499.0 (M+H); 'h NMR ¢300 MHz, CD.OD) δ 9.06 (:% 1H). 8.31 (s, 111),8.24 (d. /- 9.4 Hz, 1H), 7.94 (s, 1H), f. 14 (s, 1¾ 6.99 (4 9.4 Hz, It), 5.39 (s, 2M). .1 ,59« Synthesis of A?-(4-bs’onio-3-i 1.^-1,2544na?.oi~5-yi)tiiiophe?i“2--vi)-2-(5- osopyrtotoIo[L5-aJpyrfmtdin^{5/?^yS)seeiam!te

1.ML Pymz(ile[l,5~s]pyrmidin~5(4Jilhsne

(06397] 1 ,3-Dimcthyi uracil (3.15 g, 22,5 mmol) and sodium ettexide (23 mL of a 21 % solution in ethanol) were added to a solution of li/-pyrazol~5--amme (1.7 g, 20.4 tamo;) m ethanof (50 ml). The respiting mixture was tested to 60 °C for 2 h and was then cooled to room temperature. The pale brown, solid was isolated fey filtration to give pyrazcdof i,5-a]p>Titr:idin-5(4A0-onc (1.6 gf 58%). Retention time (min) ^ 0.810, method [3], MS(ESl) 136.1 (M+H).

[00398| Methyl 2-(5-oxopyrazo 1 o[ 1,5»a]pyrimidinM{5/7)»yl)aeetate was prepared lorn pyrazolef l,5-ajpynmidin-S(4iT)-»one according to Protocol IL Retention time (min) = 1.951, method [3], MSpSI) 208.1 (MW). 1.59.S, i^-Smpyrmot5m$pyrmidm^0H}^$imMe acid [00399] Methyl 2-(5«oxdpyras>lo[l ,5“4]pyTimiditi-4(5.S|-yi)aeetaie (0.26 g, 1J5 mttel) was treated aecoriing to Example 1.54,3 to give 2-(5-oxoppmH>tep,5-a]pyriniidin-4(5.ir)-yi)acelic acid. Retention time (min) = 1.00, method [3], MS(ESI) 194,1 (M+H). a]pyHmidm~4(SE)-}i)acemmMe [00400] The title compound was prepared from 2~(5-oxopyrazolo[ 1. ,5-a]pyrin)idin-4(5/7)-yl)acetic acid (39 mg, 0.203 mmol) and 4-bromo-3~( 1//-1,2,4-triazol-5”yl)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (mitt) - 2.45.1, method [7], MS(ESI) 420,0 (M+H); !HNMR (300 MHz, CDClf) d 8.28 (d,/= 8.5 Hz, 10), 7,83 (s, IH), 7.77 (d./=2.6 Hi IH), 6.971, 11).615 (1:-/-1.9 0¾ IH), 5.94 (4 J = 2.6 Hz, IH), 4.98 $s, 2H). 2.60. Synthesis! of 2-(2-ox<>-li6»itapliiliyrIdiJS”ii2ii>'yl)"A‘-(2»(tMazol-4~ yI)ihiophera~3~yJ)aeetamide S00401J The title compound was prepared from 2-{2-«xg·- 1,6-naphthyridin~ l(2//)-yl)acetic acid (83 mg, 0.307 mmol) and 3-( I //- 1,2,4-to4reol~5-y1}thiophen-2-amine (28 mg, 0.154 mippl) according to protocol A. Retention time (mis) ~ 1460. method [7], MS(ES1) 3694 (.M+H); }H NMR (300 MHz, €M53OH) δ 9,09 (s, 1H). 8.89 (4-/- 2.3 Hz, I H), 8:62 (d,./- 6,6 Hz, 11), 8.23 (4/ -9,7 Hz, il l), 7.81-7.76 (m, 22¾ 7-63 (d, J= 2.3 Hz, Hli 7.35 (4./- 5.5 Hz. IH), 7.01 (4/ - 9.0 Hz, IH), 5.30 (s, 2H). 1.61. Synthesis of A-(4-bpipP“3'-(llf-M54-iria®&amp;l-i-yi)il}|opbea»2»-yi>-2-42-»xs^4-(triiluorooietliy?)-l55--ijapi4l3}Tidlo-l(2//)-yi;iai;etamlde

2.62. i, l-Mdo-fe-itrifluomMethyllpyriim-S-aMme [00402] Iodine (7.83 g, 30,84 mmol) and silver sulfate (9.6 g, 3984 mmol) were added to a solution of 6~(ttiflnoreffieftyl)p>m4m^3»amine (5 g, 30.84 mmol) in ethanol (209 ml) arid the rtisuitiig siispenpjpn was stirred at room temperature for 18 h, PP solution was filtered and the filtrate was concentrated under vacuum The residue was rfedissolved in methylene chloride and washed with aqueous NaOH (1 N), dried (Na^SO-t), filtered and concentrated under vacuum to give 2~iodo-6-(trifluoronrethyl)pyridin-3-amine. feention time (min) =- 2.136^ method [1], MS(ESi) 289.01 (M+-H). L 61.2. Ethyi 3^~ammi-6-(tiriftmzi)metkyi)pyridm~2~yi)m;iylui£ [O04O3| Ethyl 3-(3-am.ino-6-(trif],uoromethyI)pyridm-2~yl)aciylate was prepared from 2-iodo-6-(iriiluorometliyl)pyrid.in-3-amine according to protocol M. Retention time (min) = 2.350, method [1], MS(ESi) 261.1 (M-t-H). 6~fTriflmmwiethyl}-IS~naphihyridin"2{lB)~one [08404! 6~(Trifluiirom.etby 1)-1,5-naphtb>tod!«"2< li¥)~one prepared from ethyl 3-(3-arniriO"6~(trinuoi»meiW)pyddiT5~l^|a^tete aeerting p5 pretoeol Retention time (min) = 1.401, method [I], MS(ESI) 215.0 (M+H), L61.4. Methyl 2-(2^xo~6-{iHfimmMethyl}-l,5~n&amp;pktk$ridm~l(2E)-yi)aceiate [00485] Methyl 2-(2-oxO"6-(irifluoromethyl)-1,5-naphthyridin-l (2//)-yI)aeetaie was prepared from 6-(trifluoromeibyl)- i ,5-iiaphthyridin-2( I //R).ne according to Protocol K. Retention time (min) = 1.822, method [I], MS(ESI) 287.1 (M+H). L61.5. 2~{2~Oxo~6~{tH0uer0methfi)~l,5-n&amp;phihywidm-l(21f}~yl}aceSicsd4 [00406] Methyl 2~(2~oxo-0~(iri ilworomcthyl)-1,5-naphthyridin-1 (2H)-y l)acetate (0.15 g, 0.524 mmol) was treated according to Ex. 1.53.4 to give 2-(2-οχο-·ό-(iriiSorometpi)-! ,5^ap|dhyr£||p-l (2/^ryl)acetic acid. Retention time (min) ::: 1.535, method [1], MS(ES1) 27M (M+H), 1.61. &amp; N~{4~Br0mo-5~{lH~l!2i4-trmz8t-$~yi)tkhiphen~2-yii}-2-{2~0x0~6~ {trifluor()methyi)~l!S-naphikyri.dm~i(2H)-yi}metsmuie [00407] The title compound wax prepared from 2-(2-oxo~6"(trifluoromethyr>-l,5“naphthyriiiin--l(2.H)-yl)acetic acid (66 mg, 0,245 mmol) and 4-bromo-3-(\H~ 1,2,4-triazol-5-yl)thioplicn~2-amine (30 rng, 0.122 mmoi) according to protocol A. Retention time (min) = 5.195, method [7], MS(ESI) 499.0 (M+H); *H NMR (300 MHz, CD3OD) δ 8,26-8,21 (m, 3H), 7.96 (d, J= 8.9 Hz, IH), 7.17-7.13 (m,: 2H), 5.37 (s, 2H). 1.62. Synthesis of Ar-(4~bromo~3-(lii-l,2}4“iriazol-5-yl)thiophea"2~yl)~2~(5“Oxo-2~ (tdnaoromethyl)pyrazoio[ 1 ,§~a] pyrlmidfn-4(5/^-yI)aeetamide

L62J. 2~(Fnftu&amp;t&amp;ffiefhyi)pymx&amp;l8iI,5^JpyrimiMn-5{4H)-om [00408] 3-(Trifliwromethy 1)-1 //-pyrazol-|~amine (4.8 g, 31,7 mmol) tsiass subjseted ίο the potocei i® Example 1.5¾ 1 to give 2^^fluoK»»eihyi)pymzok>[l,5-a]pymmdin-5(4ff)~0;ne. Retention time (min)----- 1.220« method [1], MS(ESI) 204.0 (M+H). 1,62J, Methyl 2~(5^xo-2-(ffifluarGmethyl)p}razBUttl,5-a]pyrimi4in-4(5H)-yl}aeetate [0O4O9J Methyl 2~(5-oxo-2-(trifluoromethy f )pyrazolo[ 1,5-a]pyrimidirs-4(5//)~ yDaeetate was prepared from 2-(trif]uoromethyS}pyrazo!o[L,5~a]pyrmiidim5(4i/)-one according to protocol K, Retention time (min) - 1.846, method [1], MS(ESI) 276.0 (M+H). i« 62,3, 2-(5-Ox&amp;-2-{t^Meromeikyi)pymzoioiif 5~ejpyrimidm~4f$H)~y!}acetk acid [004.10] Methyl 2-t5roxo-2-(trifluoronietiiyl)pyrazol®[ 1,5-ajpyrimidirs-4(3/7V yl)aeetaie 60. J 29 gs 0.469 mmol) was subjected to the conditions in Example 1.54.3 to give 2^(Sto%o^2-(tdidorornethyI}pyraKoto[l55-a]pyrimidin~4(560-yl)a^tic aeid.

Retention time (min) -1.448, method [1], MS(ESl) 262.2 (M+H). L6M. ft-(4-3mm&amp;-3~(lHA,&amp;4-MazM-5-yl)thwphen-2-yi)-2-^Hmi-2r [004111 The title compound was prepared from 2-(5-oxo-2-(triiIaon>inethyl^pyra2oio{l,5-a]p>?rim.idin -4(5/f5“yl)aeetic acid (63 mg, 0.244 mmol) and 4-hrorrK>~3~(1i7~l?2,4^roarol-5--yr)thiophen--2-antine (30 mg; 0.122 mmol) according to protocol A. Retention time (min) - 4.975, method [7], MS(ESI) 488,0 (M+H); lH NMR (300 MHz, DMSO-<4) δ 8.79 (d, /- 7.4 .Hz, 1H), 8.61 (bs, 1H), 7.32 (s, JH), 6.96 (s, 1H), 6.45 (d, J - 7.4 Hz, 1H), 5.01 (s, 2H). 1.63. Sysifisesis of /y~#~brppp-3^i|-mdihyl-li/~r,2,4^i3^*#"3-yS)ihloftheB-2*fI)“2~ (2-oso-3,4-dlfeyi|ro-l ,S-«isphthyridli?“1 (26^~yl)aeetaffilde

[00412]; Sodium hydride (4.2 mg of a 60% dispersion in mineral oil,; 0.107 mmol) was added to a solution of A“(4 -faronio-3-( 1 //- i ,2.4-rriazo!-3-ylhhiophea·2·}:1)··2-|2ro^>-3,4-£ihydro-l,5'naphto>nidm*l(2ii/)”y0^6siaxmde (31 mg, 0.0715 rantol) in DMF (0. ] ml-) si 0 °C. The suspension was stirred for 5 minute* after which iodomdhane (12 mg, 0.058 mmol) was added. The reaction, mixture was stirred at room temperature for 20 minutes then diluted with water, extracted with ethyl acetate, dried (Na2SO<), filtered, concentrated under vacuum and purified by preparative HPLC to give iV~(4-bromo-3-(l-meihyl-W-L2,4-iri&amp;zGi-3-yl)ihiophen~2-yl)-2~(2-Gxo-3,4-d.ihydro~L5~naphthyridin~ 1 (2fl)~yl)acctatnidc. Retention time (min) = 1.740, method [7], MS(ESI) 447.0 (M+H); *H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 8.33 (d, J= 5.2 Hz, 1H), 7,85 (bs, ΪΗ), 7.61 (bs, ffl), 7.11 (s, 1H), 4.94 (s,2H), 4,02 (s, 3H), 3.41-3.36 (m> 2H), 3.01-2J7 (¾ 2H), 1.64, Synthesis of ^(4^hlorn^-(IiPI,^4~trSz©RS^phi0p|^s.2.y|-2~(5-©xopyrazolop,5'a]|>>Timidin"4(5f/{-'yi)acetsi,iiikie (004.13] The title compound was prepared from 2-(5-oxopyras5olo[ 1,5-ajpyrimidin~4(5//)>yl)acetxc acid (94 mg, 0.488 mmol) and 4-chioro-3»(i//-l,2,4-triazol-5-yl)thiophen“2-aintne (49 mg, 0.244 mmol) according to protocol A, Retention time (min) - 2.161, method [7], MS(ESI) 376.0 (M+H); !H NMR (300 MHz, CDCH) 8 8.31 (d,7« 8.1 Hz, 1H), 7.83 (s, 111), 7.76 (s, 1H), 6.85 (s, 1H), 6.27 (d, J = 8,1 Hz, 1H), 5.94 (s, 1H), 4.98 (s, 2H). L65, SyntSiesisof JV“(4”€hlor®-3~(l-msthyI“iHr-l,2,4-fr1azoI-3-yl)thiophen'2~yl)-2"(S-oxopyrazolo(l,5-a|pyHmidin-4(5H>-yI)aeetamide [00414] Todomethane (36 mg, 0.255 mmol) and K2C03 (44 mg, 0.319 mmol) were added to a solution of ,¥-(4-chloro-3-(l/f-l,2s4-tri.azol-3-yl)thi<^phea--2-yl)-2-(5-oxopyrazoioP ,5~a]p>n-imidin-4(5//)-yl)acetamide (80 mg, 0.212 mmol) in BMP (1 mL),Ihe reaction mixture was stirred at room temperature for 30 minutes and was subsequently diluted with ethyl acetate and washed with brine. The organic phase was dried (Na^SCfi), filtered, concentrated under vacuum and purified by preparati ve HPLC to give A-(4~chloro“3”( i -methyl-i HA ,2,4-triazol-3-yl)thiophen-2-yi}-2-(5-oxopyrazo1o[],5-a]pyrimidin~4(5H)-yi)acetamide. Retention time (min) - 3.00, method [7], MS(ESI) 390.1 (M+H); ‘H NMR (300 MHz, CD-.C1) δ 8.25 (d, 7-8.2 Hz, 1H), 7.90 (s, 1H), 7.76 (d, 7 = 2,1 Hz, 1H), 6,79 (s, 1H), 6.22 (d,7 = 8.2 Hz, 1H), 5.97 (d,./- 2.1 Hz, 1H), 5.36 (s, 2H), 3.99 (s, 3H). 1.66. Synthesis 0fiV^(4-Chl®r6-3-(|-ineU5y1~iB-l32J-ti|a^i--3-yi)iii®phM-2-yi)" 2-(2-oxo-6-{l.rsflM0ro0}etlsyl)~l,5»iiaphtfiyridm"K2iif)"yI)acetamMe

The title compound was prepared froth :ft^4^cMdro~3»( \ H~ I ,2,4-t r f a zoi-3-y 1 )r'r;i ophen-2-yl)~2-(2 -oxo -6-(1 ri iluoromethy (}~ i ,5 -naphthyr i dm-1 (2.//)-yl)aeetamide (51 mg, 0.1.12 mmol) using the conditions in Example 1.65, and was purified by preparative HPLC. Retention time (min) - 5.927, method [7], MS(ESI) 469.1 (M+H); lH NMR (300 MHz, DMSCW6) δ 8.51 (s, 1H), 8.31 (d, /= 8.9 Hz, 1H), 8.20 (d, /- 9,8 Hz, 1H), 8.10 (d, /= 8.9 Hz, 1H), 7.18 (s, 1H), 7.13 (d, /= 9.8 Hz, 1H), 5.35 (s, 2H), 3.92 is, 3H). 1.67. SyiithesisofA'-(4-«htoro~3"(l/i-l,2s4-tsiazoI-3-yI)tlsiopheE"2"yl)-2--(2“OsO“6” {trillu«iromethyI)-l,5-naphthyrldin-l(2^)-yl)aeetamide [00416] The title compound was prepared from 2-(2“Oxo-6"(trifluorornethyl)-L5-naphth>'ridin-l(2iyhyl)aeetic acid (160 mg, 0.588 mmol) and 4-chioiO-3-(lH-l,2,4~ triazol-3-yl)thiophen-2-amine (59 mg, 0.294) mmol) according to protocol A. Retention time (min) = 5.046, method [7], MS(ESI) 455.1 (M+H); Ή NMR (300 MHz, DMSCKA) 5 8,62 (s, 1H), 8,30 (d, /= 8.9 Hz, HI), 8.21 (d, /= 9.8 Hz, 1H), 8.09 (d,/= 8.9 Hz, 1H), 7.20 (s, 1H), 7.13 (d, / = 9.8 Hz, 1H), 5.36 (s, 2H). 1.68. Synthesis of N-(4-brom©~3-(lH-4,234"triazol-3"yl)thiopheo~2~yl)-2-(3-ftuoroquinolIn-O-y^acetamfde

1,68.1. 3-Flitemqmmdme {004171 /ferf-butylnitrite (4.6 ml, 38,7 mmol) was added dropwi.se over 15 min to a solution oiqutnoJin-3-aminc (4.61 g, 32.0 mmol) and boror/riiluoride-erherate (6 ml, 47.3 mmol) in dichlorobenzene (100 ml). The solution was heated to 100"C. After stirring isr for 1 h, the solution was cooled to ambient temperature and the dicblorobemmne was decanted lea ving 3-tluoroqiiinoline as a black residue. Method [8] retention time 3.28 min by HPLC (M+ 148). A 68.2. 3-Fimm»~8~mtroquimMm and 4~fluom-5~mir&amp;quinsUm [0(1418] A solution of 3:1 concentrated sulfuric arAi.'.·concentrated nitric acid ¢12 ml) was added dropwisc to 3-fluoroquinol i;sc 03.0-1 g. 88.6 mmol.) in concentrated sulfuric acid (100 mi) at 0V€. After stirring for 2 h, the solution was made alkaline with 10 N d|. Ma@M arid extracted with diethyl ether. The combined organic extracts were dried oyer magnesium sulfate, filtered, and concentrated under reduced pressure to yield 3-fluoro-8 -nitroqumoline and 3~fluorm5'-nitioquinoline as a yellow solid. Method [7] Attention tone 3.30 and 3.92 miri fy HPLL (M+ 193) and (ML 193).

[00419] 3-F!woro-8-nitroqumo3me, 3 -fluoro-T-nitroquinoline, and tin(II)cMoride-dihydrate (68.23 g, 302 mmol) in ethyl acetate (200 ml) was placed into a preheated oil bath at 60l'C, After heating for 4 h, the solution was cooled to ambient temperature, diluted with 3 N aq. NaOH, and filtered through a pad of celite. The filtrate was extracted with ethyl acetate, the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 19:1, 9:1,17:3,4:1, 3:1,7:3, and 3:2 hexane:ethy! acetate as the eluant to afford 2.14 g (11% yield over two steps) 3-fluoroquinoiin-8-amiue and 7.02 g (37% yield over two steps) of 3-fiuoroquin.o!iii'5~amme. Method [6] retention time 1.57 and 4.02 nun by HPLC (Mf 163) and (M+ 163). L 68.4. 8-Er&amp;mo~3~flmmqmmdme [00420] 3-FIuoroquirtolΐn-8-a.minc (900 rug, 5.55 mind) was added to teri~ butyftritrite (1.3 mi, 10.9 mmol) and cupric bromide (1.37 g, 6.13 mmol) in acetonitrile (30 ml). The heterogenous mixture was heated to 70‘’C. After stirring tor 18 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was puiified by flash chromatography (hexahteethyl acetate) to afford 568 mg: (45% yield) of 8"bromo-3-fluon>qumolme, Method [7] retention time 4.76 min by HPLC (M+ 226 and 228). 1.65.5. 2-0~Fimr&amp;gukmlm~8~yi)iicetic acid {»4211 The title compound was prepared from 8-bromo-3*ffooroquino!ine (568 mg, 2.11 mmol) and 0.5 M (2~rt^bu?oxy-2-oxoctbyl)zinc(I]) chloride according to Protocol F, accept that the ester was1 converted to the acid using NaOH and MeGH ip diOxane. Me shod [7] retention time 2.39 min by HPLC (M----206). L 68.6, N~(4~Brmm!-3-{l H~ l,2,4~iin^^3"yl)thiophsm~2~yl)~2~0'$mrequimim-8-yi)acetumMe I »422] 4-Bromo-3-i4i7-1 s2:j4-triazol-3:<-yl)fMoplteri-2‘amino (17 mg. 69.4s imiol), 2<3“tiumoquinolin^8-yl)scetie acid hydrogen, chloride (22 mg, 91 0 nmol}, 2~ chioro- 1 -melhylpyridiitifflP: Iodide (101 mg, 395 urns!) and tri.ethykrome (0 Jim!) in methylene chloride (1 ml) was heated to reflux. Alter stirring for 1 h the solution was concentrated and the residue was purified by HPLC to yield A?»{4--bromo-3 -(1 //-1,2,4-!riazoh3-yf}th!ophcn-'2‘yl)-2-(3-fluoroqu!nolm-8"yl)acetamidc. Method [7] retention time 5.67 min by HPLC (Mf 432 and 434) and (M4Na 454 and 456). fH NMM (360 MHz, CDClj) δ 12.25 (vS? 1H), 8.83 (d, J-3.3 Hz, ill), 7.87 (m, 2H), 7 80 (d, J-6,0 Hz, 1H), 7.73 (s, Hi), 7,66 (t, 3-7.8¾ IB)* 6.90(s, iH), 6.70 (broad s, 2H), 456 is, 2H). 1,69. Synthesis ofAH4“bronK>3%lAH,2,4-triaz0l-3~yl)tirio|foen-2yy!)-2M3·-Buor©qumoMm5~y!)acetaimi«fe

[00423] TKf tile eong^pd was prepared by converting 3-Iuor0qsinoiin-5-amine (850 mg, 5.24 mmol) into 2-(3-fluoroquinolin-5”yi}aeetic acid hydrogen chloride (76 mg, 315 umol) and reaction with 4~btomo-3-(47/--l,2,4~triasol~3-yl)thiophen~2-amine (34 mg, 139 umol) as outlined in Example 1.68., above. Method [8] retention time 2.46 min by HPLC (M i 206). hi MMR (300 MHz, CfX'U) δ 12 JS (s, I.HL BM id, JH2.7 Hz, IK), 8.26 id, j-8.7 Hz, \H), Mt7 |dd. J-9.3 and. 2.7 Hz, I H i, 7.83 <m, 1H), 7.74 (&amp; .1-6.9 Hz, 1 Hi, 7.59 (&amp;, Mi), 6.93 (s, IS), 4.33 §, 2H). 1.70, Synthesis of Ai'-{4-br0mo-3-(lHr~l,2,4"trk2ol--3-yl)tbl9p!ien“2“y!)“2-(3~ (tdflTOromethyl)qulne?ln~3-yi)acetamMe

1.7&amp;M 3-kid&amp;qmmMne [00424] 3-Bro mo quinoline (64.00 g. 308 mmol). NJf~ dimcttiylcthylcnediamine (13.5 ml, 127 mmol), cuprous iodide (12.00 g, 63.0 mmol) and sodium iodide (.112 g, 747 mmol) in dioxane (300 ml) was placed into a preheated oil bath at 100°C. After stirring for 18 h, the heterogeneous mixture was diluted water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with methylene chloride as the eluant to afford 68.47 g (87% yield) of 3-iodoqumoline as a yellow solid. Method [8] retention time 6.47 min by HPLC (M+-256). 1.70.2. 3~{THfluoromeihyi)qmmime |O041|j 3-Iodoquiaoline <13.65 g, 53.5 mmol), cuprois iodide pi .12¾ 111 nrnio%: potassium fluoride (7.11 122 mmol), and methyl 2--ch!oro-2!2-difluoro.%cel«ie (23 mi, 216 mmol) in dsrnethyiforamide (200 mis was placed into a preheated oil bath at: 120*0. 4ier stirring fer 6 h, the solution was diluted water and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, add concentrated under reduced pressure. Tire residue was flash chromatographed with 99:1, 4|:l, 24:1,23:2, 9:1» and 4:1 tocane;ethyl acetate as the eluant to afford 3.89 § (37% yield) of 3~(trifluoromclhyi)quinolinc. Method [7] retention time 4,67 min by HPLC (M+ 198). L 70.3, 8-Bmm&amp;~3-(i^mr0meihyi)qifmoUm and S-bramo-3-(trifluoromethytjquinoline [00426] 3“(Trifluororncthyl)qiiiit3ol3ne (7.00 g, 35.5 mmol) and N-bromosuceinirnide (9.00 g, 50.6 mmol) in concentrated sulfuric acid (50 ml) was heated to 50°C. After stirring for 1.5 h, the solution was cooled to ambient temperature, diluted with, saturated aq. sodium sulfite, made alkaline with 3 N aq. sodium hydroxide, and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 99:1, 49:1, 24:1, and 23:2 hexane:ethyl acetate as the eluant to afford 4.55 g of impure 8-bronio~3-{triffnoromeihyi}qinnolme and 3.89 g (37% yield) of 5-bromo~3-(trifliioromethyl)quinoliiie. Method [8] Retention time 6.75 and 7.47 min by HPLC (M+=276 and 278) and (M+=2?6 and 278). L 70,4. 2-(3-(7?ipmpameth)i)qnimlm-5~yi)®eedc acid [00427J T he title compound was prepared from 5»bromo-3-(triiluoromethy! jquino!ine (3.59 g, 13.0 mmol) according to the procedures oulinei m Protocol P. Method [7] retention time 2.80 min by HPLC (M3s=2Sri).

Mm, N-{4~hr0m&amp;-3-{IH~l,2f4-trktzel-3~yi}thiephefi~2~yi)~2~i3- [0042-8] The title compound was prepared from 4-bronrso-3-(4/7-1,2,4-triazol-3-yl)thiophen-2-amine (56 mg, 228 umoi) and 2-(3-trifluoiOmethyiqumolin-5-yl)acetic acid hydpgen chloride (200 mg, 784 nmol): aeeording to the procedures outlined in Example 1.6&amp;6., above. Method [7] retention time 5.93 min by HPLC (M3-482 and 484) ««4? (M+*ia 504 and 506). Ή NMR (300 MHz, CDC13) δ 12.45 (&amp;, ΤΗ), 9.23 (s, 1H), M4 (s, 1H), 8.37 (d, MU Hz, 1H), 8.03 (m, TO), 7.85 (d, «.9 m, HI), 7.74 (s, IH), 0.95 (s, 1H), 4.38 (s, 20).

Synthesis ofjM-(4-hriimo~3-(lif~l,2,4-trlazoi~3~yi)tlslophea-2^yl)-2-(3-(trl!1noronieihyl)i|iil5iollS“8-yi)aeetansIde

1.71.1. 2~0-{lr^mmmet^§qiiimim~S~yi)aceiic mmd f60429| The title compound was synthesized from 2-?«r.f-butoxy-2-oxoethyi)zine{ii;< chloride and 8 -bromO"3-(trifSuoK)rnethy1 }qui«ol me (4.55 g) according to |frotodol P. Method [7] retention time 3.78 min by HPLC (M+ 256). L 71.2, N~{4~br&amp;m{i~3~{lM~lf2s 4~trmzol~3~yi)thmp hm-2~}l)~2-(3~ 0ifimmmeihyi)quimdm-4~yl}(ieetmnMe 1004301 The title compound was synthesized from 4-6031110-3-(4//-1,2,4~tri azoI -3-yf)thioplien~2~amme (40 mg, 163 nmol) and 2-(3-tluoroquinolin-8-yI)acetic acid hydrogen chloride (284 mg, 1,1! mmol) according to the procedure outlined, in Example 1.68,. above. Method [7] retention time 7.10 min by HPLC (M+ 482 and 484) and (M+Na 504 and 506). Ή NMR (300 MHz, DMSO-40 5 11.80 (s, 1H), 9.20 (d, J=2.7 Hz, IE), 9.01 (s, 1H), 8.39 (broad s, !H), 8.25 (d, J=8.1 Hz, IE), 8.08 (d, 1=-6.6 Hz. 1H), 7.79 (t, 1=7.2 Hz, IB), 7.21 (s, 1H), 4.38 (s, 2H). 1.72. Sy re thesis of ,¥-(4-chSoro-3-(3~isopropyl-lf:/-l,2,4-tnazoi-S-yS)thiophe?i~2- ylb-S-CS-oxo-J^-dlhydr o-l .,5~n aphthyridin-1 (2^)-yl)acetamIde

L 72ilt S~Chiem~4~hydrazwyHkien(.>f 2s3~djpyHmiiime [064311 5-Chlhre-4-chlorothiexsipj-djpyrimsfee (1.38 $ 6.73 mmol) and hydrazine monohydrate (5.0 ml, 103 mmol) in. absolute ethanol (20 mi) were heated at 75V'C, Mm stirring frfr 24 h. the solution wa|s concentrated to yield 5*ehlor0-4-hydmzin\'lihieffo(l#-^pyHisidme, Method [6] Retention time 035 min by HPLC (M«Q1 |sd 103)- 1,72,2, 9~Chh>ro~3~ist}prop}4thim&amp;[3f2-eMli2f4]iriazoio[4,3~cjpynmidme [00432] 5-CbIoro-4-hydrazinylthien0[2,3-d)pyrimidine and 1,1,.1 -triethosy-2-methylpropane (10 mi) in ethanol (10 ml) were heated at 100°C for 2 h. The solution was concentrated and the residue was flash chromtographed with 9:1,4:1, 7:3, and 3:2 hexaneteihyi acetate as the eluant to afford 300 mg (24% yield over 2 steps) of 9-ehloro-3-isopropylthieno[33-e][133]triazolo[43^]pyTimidm.e as a brown solid. Method [8] Retention time 4.62 min by HPLC (Mt-253 and 255), 1.723, 4~€hforo~3-(34$oprepyl-lH-lJ,4-iriazei-5~yi)thiephen~2-amme [00433] 9~chloro~3 -isopropylthieno[3,2-e] [ 1,2,4jt.riazokt[4,3-c] pyrimidine (300 mg, 1.19 mmol) and Af-methylethane-l ,2-diamine (0.50 ml, 5.67 mmol) in methanol (10 ml) was placed into a preheated oil bath at 6Q°C, After stirring for 15 min, the solution was diluted with saturated ammonium chloride and extracted with methylene chloride.

The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 4-ch loro-333 - isopropyl-1 Η-1,2,44riazo1-5-yl)thiophen-2-amine. Method [7] Retention time 1.39 min by HPLC (M+=243 and. 245), 1,72,4. N-(4-chioro-3-{3~isopropyt~lH-l£,4-tn®%8l-5~yl}thiophen~2-yi)-2-(2-oxo-3,4-dihydro-1, S-naphihyridin-l (2H)~yl)&amp;c®tmnide [00434] The title compound was prepared from 4-chloro-3-(3 -isopropyl-1 H~ l,2s4~tiiazoi"5-yl)thiophen-2-amine (117 mg, 482 nmol) and 2-(2-oxo-3,4-dihydra-l,5-naphthyridin-1 (2fl)-yl)acetic acid (155 mg, 752 umol) using protocol A and was purified by HPLC to yield ,¥-(4-chloro-3-(3-isopropyl- l77- ls2,4-triazol-5-yl)thiophen-2~yi)-2~(2~ oxo-3,·4“dihydro-l,S-naphthyridhr-l(2J7)-yi)aeetamide. Method [7] Retention time 0.35 min by HPLC (M+=431 and 433) and <M+Na=453 and 455). ’H NMR ¢300 MHz, DMSO-ifc) δ 12.28 (s, 1H), 8.30 (d, >5.1 Hz, IH), 7.76 (d, J==8.7 Hz, 1H), 7.51 (m, IE), 7.16 (d, >1.8 Hz, 1H), 4.89 (s, 2H) 3.17 (m, 2H), 2,98 (m, 1H), 2.81 (m, 2H), 1.28 (d, >7.2 Hz, 6H). : L73. Synthesis of AL(4^hloro~3--(3-ethy5“l&amp;1^^4-trMzol-5“^|tbihphes#-]i)-: 2-{2-oxo~3i>4--dihydyo-l}5''naphthyTldio»i(2/^)-yi)acei.aiSiii!e

2,73J. 9~Chkm>~3~efkyitkie.tsv[3< [¢¢4351 5~Chkux>A-hydrazmy]thietto[2,3~2]pyrimidinc and 1,1,1-tric-thoxypropam· (5 ml) m ethanes 0 mb was placed into a preheated oil bath at HXT'C for 2 h. The solution was concentrated and the residue was Bash chrosnsograpbed with 9:1,4:1, 7:3. and 3:2 hexanerethyl acetate as the eluant to afford 20 mg of 9-chioro-3-ethyit.hk-no[3,2-e][l,2,4]t.riasoio[4t3-c]pyrsmidinc, Method [8] Retention time 6.31 min by HPLC (M+:::239 and 241). 2.73.2. 4~Ckhrtf-,3-0~etk}>f.-lH~2>2r4~$?taz&amp;i"5\vl}fk&amp;pheft-2*-ismiiw [09436] 9-Chloro-3 -ethyl tliienoi 3,2-e][ 1 ,2,4]tri&amp;zoio[4,3<]pyrimidme (20 mg, 83.8 umol) and i^Me%deifidtto-]^“d%tiihe (#.05 ml, 5.67 nmol) in methanol (2 ml) was placed into a preheated oil hath, at 60°C, After stirring for 15 min, the solution was diluted with saturated mmmmm chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 18 mg (94ie yield) of 4-chloro-3-( 3-ethyl-1 //-1,2,4-ma2ol^-yl)tfeiophen-2-amine as a brown solid. Method [8] Retention time 2.63 min by HPLC (hi t- 229 and 231). 1.73.3. N~{4~chierO"3"(3~eth}2~lE-100~irMzo’!~5~$4)tkhphm--2~}'i}~2~(2~exi)~3,4~ dihyd?»~iJ~mphihyndm~l{2H)~)i}iweismide [¢¢437) The title compound ’was prepared from 4-cHoro-3-(3-e:hyi-12/- i ,2,4-triazol-5-yl)thiophen-2-ainine (18 mg, 78.7 nmol) and2~(2~Qxo~3,4-dihydfo~],5~ naphthyridm-l(2H)-yi)acetic acid (20 mg, 97.0 nmol) using protocol A. The residue was purified by HPLC to yield Af-(4-ehloa5~3“(3-ethyi-12/~l,2,4-triasol-5-yi)thiophen~2-yl)-2-(2-oxo-3s4~dihydrO"l,5-naphihyridiEi-l(2i2)-yl)aeetamide. Method [8] Retention time 4,47 min by J-1PLC (Mr-417 and 419) and (M+Na-439 and 441). JHNMR (300 MHz, CDCIs) δ 839 (dd, 3=5.4 and 1.2 Hz, 1H), 7.67 (dd, 3=8.1 and 1.2 Hz, 1H|, 7.49 (dd, 3=8.1 and 5.4 Hz, 1H), 6.85 (s, 1H), 4.93 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.84 (q, 3=7.8 Hz, 20), 1.39 (t, 3=7.8 Hz, 3.B), I.74i Synthesis ©f,¥-(4~dshnm-3-(3~irietKp-l//~i,2,4-irfazol-5~yi)ihi8phen-2- vI)~2-(2-o x©~3,4~dihydr ©-1,S-n a ph f hv ridisi-l (2/f)“yl)acetam ide 1.74.1. 9~(M0m*3^etbykMem®$$~e$ili2^trmz&amp;fo[4i3^pyriMMme [00438} 5sChloro~4~hydrazinyhMe©0[2;3-i/]pyrimidin© and 2,1,1- trielhoxycthaoe (10 ml ) in ethanol (10 nil) was placed into a preheated oil hath at 100°C for 2 h. The solution was con.emtailed and the residue was flash chromtographed with 9;1. 4:1, 7.3, and 3:2 hexaneiethyl acetate as the eluant to afford 92 mg of 9-chioro~3~ mcfh.ylihierso[3,2-e][ 1,2,4]tria?xtio[4,3<Jpynin«#ne whilsrpinfesoid. Method [7] Retention time 3.77 mm by HPLC (M-R-225 and 227). 1.74.2. 4~€hhm}~3"{3-Meihyi-Hi-lr2,4-4rmzoi-5-yl)tki0pken-2-amine [00439] 9-Chloro~3-methylthieno[3,2-e;][ 1,2,4}triazolo[ 4,3-e]pyrimi dine (82 mg, 365 imiol) and A-methyl ethane-! ,2-diarnine (0.30 ml, 3.40 mmol) in methanol (2 ml) was placed into a preheated oil bath at 60°C. After stirring for 15 min, the solution was diluted with saturated ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 69 mg (88% yield) of 4-chloro-3-(3-methyl~ j//~l,2,4-iriazol-5~yl)thiophen-2-amine as a yellow solid.Method [1] Retention time 0.61 min by HPLC (M+=215 and 217). dik?dm~L5~mphihyridin~i(2Hh)lh€etemide [00440] The title compound was prepared from 4-chioro-3-(3-methy 1 -1//-1 ££-triazo i - 5 - y i Rhiophen-2-aimnc· (69 mg. 111 umol) and 2-· 2·oxo-3,4-d:hydro-1,5-nuphihy ridin-1 (lUyylydC^tic acid (82 rug, 397 umol) using protocol A. The residue was purified by HPLC. Method PJ Retention time 3.40 min by HPLC (M i ===403 and 405) and (MTNa~4:25 and 427). lH NMR (300 MHz, CDCL) 6 8.39 (d, J-5.4 Hz, 1H), 7.67 |d, 1=8.4 Hz, 1H), 7.49 <dd, J=f.4 and 5.4 Hz, IH). 6.86 (s, IH), 5.46 (broad s, 2H), 4.95 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.50 (s, 3H). 1.75. Synthesis oiiV-(4"diloro-3~(1/i'li2i4-trl^>l~3~yI)ifeIophen-2~yl)~2-(2-«xi5-4~ (trlfluoromethy])quinoIln~l(2//)~yl)acetftmide [00441] The title compound was prepared from 4-chIoro-3~(l #-1. s;2»4-triazol-3-yl)thiophen-2~aminc (502 mg, 2.50 mmol) and 2-(2-oxo~6-(trif].uoromethyl)qitinolin-1 (2H)~yi)acetic acid (675 mg, 2.49 mmol) using protocol A (626 mg, 55% yield). Method [7] Retention time 5.59 min by HPLC (M+=4S4 and 456) and (M+Na=476 and 478). lH NMR (300 MHz, DMSO-de) δ 12.23 (s, 1H), 8.38 (broad s, 1H), 8.27 (s, 1H), 8.22 (d, JM9.3 Hz, 1H), 7,89 (d, JM9.3 Hz, 1H), 7.70 (d, 3=9.3, IH), 7.17 (s, 1H), 6.87 (d, 1=9.9 Hz, IH), 5.31 (s, 2H). 1.76. Synthesis of.'V-(4ehliiro-3-(l-i3"(dlBJetlsylamlno)propyI>-li/-l>2>4-triazol“3-yl)thk>phen-2»vl)-2“(2-oxo-6'(irif1uoremethyl)qwlnollii"I(2t7)-yl)acetaniide 100442] Dusopropy) azodicarboxyiate (0.30 ml, 1.52: mmol) was added dropwiseto a yl)-2~(2“Oxo-6-(1rifi«orometiiyl)quinoIinn{2H)-yi)acetamide (111 mg,245 nmol), polymer supported tnphenyiphosphine (500 mg, 1.50 mmol), and 3~ (dimeihylrainojpropan-l-ol (300 tap 2M mmol) in tetmhydroftiran (5 mi) at 0°€.

Alter stirring for 2 h, the heterogeneous mixture whs filtered through a pad of cente and concentrated under reduced pressure. The residue was pur .'tied by HPLC to yield /7-(4-::chloro~3~( I "(3-(dinietbyiamino)propyl)·-1 //- i ,2,4-tHazo:M3-yl)thiophen-2-yl)^2-(2-oXo~6~ (tri.fluoiomethyl)quinolm-1 (2jf/>-y0acetamide. Method [7] Retention time 4.33 min by HPLC (M+=539 and 54.1). Ή NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.52 (s, IH), 8.29 (s, IH), 8.22 (d, J=9.6 Hz, IH), 7.92 (d, 3=8.7 Hz, HI), 7.72 (d, 3=8.7, IH), 7.18 (&amp;, IH), 6.87 (d, .1=9,6 Hz, IH), 5.32 (s, 2H), 4.31 ft, J-6.6 Hz, 2H), 3.09 (13=6.6 Hz, 2H). 2.75 (s, 6H), 2.17 (m, 2H). L77. Synthesis of /V-(4-cSiloro-3~(i-(2-(dimetliylamino)etbyl)-lif-l^,4-trlazol“ 3-yl)thlophen-2-yi)-2-(2-oxo-6~<trUluoroniet!iyl)quinolin~l(2B)-yl)acetnmide [00443J The title compound was prepared from A’-fd-ehloro-S -(1 H~ 1,2,4-iriazol-3-yi)thiophen~2~yI)-2"(2'Oxo-6-(ti’ifluoromethyl)quinoIm-l(2H,)-yl)acetamide (125 mg, 275 umol) and 2~(dimethylamino)ethanol (311 mg, 3.49 mmol) using the procedures described in Example 1.76 except that the reaction was run at 60°C (rather than CFC). The residue was purified by HPLC to yield A?-(4-ehloro~3-(l -(2-(dimethyi ammo)ethyl)- \H~ 1,2,44riazol-3 -y I)thiopheii-2-yl)-2-(2-oxo-6-(irifiuorom.ethyl)qumolm-l(2i:i)~yl)acetaiiiide, Method [7] Retention time 4.40 min by HPLC (M+=525 and 527) and (M+Na=547 and 549). JH NMR (300 MHz, DMSG-rig) δ 8.41 (s, 1H), 8.28 (s, IK), 8.22 (d, 3=9.3 Hz, 1H), 7,90 (d, 3=8.7 Hz, 1H), 7.72 (d, 1=-8.7, 1H), 7.16 (s, 1H), 6.87 (d, J=9 3 Hz, iiH, 532 (s, 2H), 4.28 if 5-6.0 Hz, 2H), 2,64 (t, 3-6.0 Hz, 2H), 2.15 (s. 6H). 1.78. Synthesis of jV-(-4-chlori>-3-(l“(3“(4-metbylplperazm-i-yl)propyi>-l//-l,2,4~triazol-3~yl)tlilophen-2-yl)~2~(2-oxo~6~(irifliioromeihyl)qtiljiolin-l(2^)-yl)aeetamide [00444] The title compound was prepared from JV-(4-chloro-3-( 1//-1,2.4-tnazol'3-y])thiophen-2-yI)-2-(2-oxo-6-(trifluoromelhyl)qninolin-l(2/:/)-yl)acetamide (108 mg, 248 umol) and 3-(4-meihylpiperazin-l~yl)propan-l-ol (350 mg, 2.21 mmol) using die procedures described in Example 1.76. HPLC purification gave JV-(4-cMorO“3-(l-(3-(4~meihyipiperazin-l-yl)propyl)-lff-l,2,4-triazol--3“yi)th8ophcG-2-yl)-2-(2-oxo-6-(trifluoromethyi)qumoiin-l(2//>-yl)acetairiide. Method [7] retention time 4.27 min by HPLC (M+=594 and 596). *H NMR (300 MHz, DMSO-ifc) S 12.13 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.22 (d, 3=9.9 Hz, 1H), 7.92 (d, 1=7.2 Hz, 1H), 7.72 (d, 3-8.7 Hz, 1.H), 7.17 (s, 1H), 6.87 (d, 3-9,3 Hz, 1H), 5,32 (s, 2H), 4.25 (t, 3=6.6 Hz, 2H), 2.95 (broad m, 10H), 2.73 (s,3H), 1.97 (m, 2H). 1.79. Synthesis of.;¥-(4-chtoro-3-(l“(3--morptinliuopropyl)-i/i'~i,2,4-4rIazoi3-yl)tbiuphen~2~yl)-2-(2-oxo-6“(tr!flHoromethyl>qnlnolin-l(2/f>"yl)acetem]iie {80445] The title compound was prepared from jV-(4-cliloro-3-(i//-l,2,4-triazol-3 -yl)ihiophen-2 -y!)-2-(2 - oxo-6-(trifluoromethyl)quinolm-1 (2if )-vi)acetamide (110 mg, 242 umol) and 3-morphoiinopropan-l-ol (350 mg, 2.41 mmol) using the procedure described in Example 1.76. HPLC purification gave ;V-(4-chloro-3-(I~(3~ moipho]inopropyl)-l//-!,2,4-iriazoi-3-yl)thiophen-2*yl)-2-(2-oxo-6-(trifiuoromethyi}quinolin-l(2i7)-yi)acetamide. Method [7] Retention time 4.58 mis by HPLC (M+-581 and 583) and (M+Na-603 and 605). !HNMR (300 MHz, DMSOdfe) δ 12.10 (s, 114), 8.47 (s, 1H1 8.26 (s, 1H), 8.20 (d, 3=9.3 Hz, 1H), 7.91 (d, J-7.2 Hz, JH), 7.70 (d, 3=9,3 Hz, 1H), 7..16 (s, 1H), 6.86 (d, 3=9.3 Hz, 114), 5.30 (s, 2H), 4.30 (i, 3=7.2 Hz, 2H), 3.20 (broad m, 1GH), 1.20 (m, 2H). 1,8®, Synthesis idhiY‘-(4-'Chloro-3“(l-'(3~(p}.TroIidm--l'yl)prs)pyI)~1J/-'l,2,4-· tri5Kol-3*¥l)th8opheii“2-yl)~2-(2-oso-6-(iriflnor®metiiyl)i|uinoiiii“l(2//)-yI)a€e<aiMide [08446] The title compound was prepared from ,V~(4-cMoro~3-{ I Η-1,2,4-mazol-3-yi)thiophen-2-yl)-2-'(2~oxo-6-({rLfluorome(liyI)q-umoiiii-l(2H)-yl)acetamide (110 mg, 242 unto!) and 3-(pyrrolidin-l -y!)propan-l-ol (325 mg, 2.52 mmol) using the procedures described in Example 1.76. HPLC purification gave iV-<4-chloro-3-(l-{3-(pyrroUdim 1 -y i)ptopy 1)^ 127- ] ,2,4-tfi szol -3 -y I )th iophen-2 -y i )-2-(2~oxo-6-(trifluompietltyiKiuinolin -1 i2/7)-yliaeetamsdc. Method [71 Retentioa time 4.65 fflis by HPLC (Mi "565 and 567). 'H NMR (300 MHz, DMSO-do) § 12.10 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.21 (d, 3=9.3 Hz, 1¾ 7.91 (d, 1=9.3 Hz, 1¾ 7.78 (d, 3=9.3 Hz, 1H), 7.17 (s, 1¾ 6.86 (d, m3 Hz, 1H), 5.31 (s, 2H)„ 4.31 (i, 3-6.6 Hz, 2H), 3.20 (broad m, 6H), 2.18 (m, 211), 1,99 (m, 2H), 1.83 (m, 2H). 1-81. Synthesis of 2-(6-brom®-2-oxoquiisoliij-l(2H>yl)-N-(4-brons«>3~(lH-i^,4-tHazoi“3'-yl)thtophesw2~yl)acetam8de

J.8LL mM P8447] 6-Brompqpnolin-2(17i)-csrfe::(5:,03::g, 22.5 mmol) was subjected to protocol K with ethyl bromoaeetate instead of Methyl bromdacetato to ailord 6.96 g (100% yield) of ethyl 2-(:6Φτοιηο*·2-οχο(|ΐιΐηο1)η* 1 (2/D~yl)e£@tate es a white solid.

Me-hod [7] Retention time 4.79 min by HPLC <M+=310 and 312;):;aad (M4Ha=332 and 334), The acetate (3.18 mg, 1 ,03 mmol) was subjected to the protocol in Example 1.53,4 to afford 228 mg (83% yield) of 2-(6-b«>nK>-2-oxoqumolm-l(2i/)-yl)acetic acid as a white solid. Method [8] Retention time 4.79 min by HPLC (M+=282 and 282) and (M+Na=304 and 306). 1.81.2. 2~(&amp;Bromo-2~ax&amp;quimHn~l(2Ii)-yi)-N-{4-&amp;r<>me-3-(lH-l,2t4-tirm&amp;l~3- yi}ikmphen~2~}4h&amp;£imii4g [00448] The title compound was prepared from 4-0ΓαΐΉθ-3-(1//~1,2,44Γΐ3ζο1-3-y].)thiophen-2-amine (55 mg, 224 nmol) and 2-(6-bromo-2-oxoquinoh'n~l(2//)-yl)acetic acid (85 mg, 301 umol) according to protocol A, HPLC purification gave 2~(6-bromo-2-oxoquiitolin-l(2ii?)-yl)-iV-(4-btonK>-3-(l/r--1^,4-triai»l-3-^)Uriopto-2-yl)a<»tatnide. Method [7] retention time 5,41 min by HPLC (Μτ=508, 510, and 512). Ή NMR (300 MHz, CDC13) δ 7.80 (τη, 2H), 7.70 is, 1H), 7.63 (dd, 3=9.0 arid 2.4 Hz, 1H), 7.19 (d, .1=9.0 Hz, 1H), 6.94 (m, 2H), 5,31 (s, 2H). 1.82. Synthesis of 2-(6-hroEiiO-2-oxo{|nlnolm-l(2ifLy0“^'""(4-€li!or'o-3~(ii/- l,2,4-triazol~3~yI)th?opheu~2-yI)£ce4ainaide [00449] The title compound was prepared from 4-chloro-3-(i//-l,2,4-triazol-3-yl)thiophen-2~amine (115 mg, 573 umol) and 2-(6-bromo-2-oxoquinolin-l(2jf/)-yi)acelie acid (135 mg, 479 umol) according to protocol A. HPLC purification gave 2-(6-bromo- 2-oxoquiuoiin-l(2i/)-yl)-iV:-(4-chloro-3-(li/-l,2,4-triazo]~3~yi)t.hiophen-2-yl)acetamide. Method [7] Retention time 5.30 min by HPLC (M+^464,466, and 468) are the major peak intensities. Ή NMR (300 MHz, CDCls) δ 7.80 (m, 2H), 7.70 (s, 1H), 7.64 (dd, 3=9.0 and 2.4 Hz, 1H), 7.19 (d, 3=9.0 Hz, 1H), 6.94 (d, 3=9.3 Hz, IB), 6.82 (s, 1H), 5.30 (s, 2H).

Synthesis ofA-(4-hromo-3-(l//~I,2;4-triazol~3-yl)thTophen-2-yl)-2-(6-€yatTO-2-oxoquinolio-1 (2J9)~yl)aeeiansid£

L83.L £fkyi. 2~{6~cym&amp;~2~i)xoq(iin&amp;iin-l(2H)~yi)aceMe (0S450) Ethyl 2-(6-brorm?~2~oxoquiEoiiri-i(2i/)'yl)aceMe (2,37 g, 7.64 nmrql)mprous cyanide· (8.87 g, ΨΜ mmol), and ielrakis(tiipheny3phosphine)pa(ladiiini(0) (3.50 g, 3.03 mmol) m dimerhyiforamlde (100 ml) was placed into a preheated oil bath at 140°C. After stirring lor 24 h, the solution was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 9:1,4:1, 7:3, and 3:2 methylene eWorideretbyl acetate as the eluant to afford 0.74 g (38% yield) of ethyl 2<6-cyano-2~ oxoquinolin-1 (2//)-yl)aceiate. Method [7] retention time 2,87 min by HPLC (M-f 257).

£83.2. 2-{6~€ymo~2~&amp;x&amp;qumoliit-2(2M}~}'i)aceiie acM 100451} Ethyl 2-(6--cyanO”2-oxoquinoIm~ l(2//)-yr)acetate was subjected to the protocol in Example 1.53.4 to afford SSfl mg (83% yield) of 2-(6-cyaoo-2”Oxoqwinolin-l(2//)-yi)aeetic acid as a yellow solid. Method [7] retention time 2,44 min by HPLC (M+ 229). L 833. N-(43im}m!~3~(rH-$33~iPi&amp;Zfk~3-yi}thiepken~2~yl}-2-i6~iy{imi~2~· ox{fqmmfm~l{2H}~yi)ucetimii4e [60452] The title compound was prepared from 4-bromo-3-(l//-1,2,4-triazoI-3-yl)thiophen-2-amine (253 mg, 1,03 nunol) and 2-(6-eyano~2~oxoquinolin-l(2i/)-yl)acetic add (325 mg, 1.42 mmol) according to protocol A. HPLC purification gave JV'-(4“bromo~ 3-(1//-1,2,4-mazol--3~yi}thiophen-2-yi)~2-(6-cyano~2-oxoquinolin-,l(2.7/)-yi)acetaniide. Method [7] Retention time 4.00 min by HPLC (M+-455 and 457). Ή NMR (300 MHz, DMSCMs) δ 8.42 (broad s. 111), 8.37 (s, 1H), 8.13 (d, j=9,9 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.70 (d, 1=9.0 Hz, Hi), 7.27 (s, 1H), 6.87 (d, 1=9.3 Hz, 1H), 5.30 (s, 2H). 1.84. Synthesis of ,M^4~ehtaro~3~{l//-1,2,4~triazf>l-3“y?)thiophen”2-yl)-2-(6~ cyaso-2-oxoqnlsolm-l(2//)-yl)acetaiJiM£ 100453] The title compound was prepared from 4-chloro-3~(l //-1,2,4-lriazoi-3-y{)tMopfaen~2-amine (215 mg, 1,07 mtnoi) and 2«(6-eyano-2-oxoquinolm-l(2fl)-yl)ac-ctic acid (325 mg, 1.42 mmol) using protocol A. HPLC purification gave iV-(4-chloro-3-(1//- 1,2.4-triazoi'•3-yl)thiopheii”2-yI)-2-(6-cyaQO-2-oxoquii!olm-1 (2//)-yl)aceiamide. Method [7] Retention time 3.83 min by HPLC (M4=411 and 413). 3HNMR (300 MHz, DMSO-d6) 6 8.37 (s, 2H), 8.13 (d, 1=9.9 Hz, ΓΗ), 7.98 (d, 3=8.7 Hz, 1H), 7.70 (d, J=9.3 Hz, IH), 7.17 (s, 1H), 6.86 (d, 1=-9.9 Hz, 1H), 5.3.1 (s, 2H). 1.85. Synthesis of N-(4-f}romG-3-(47/--l,2,44rk«oh3~>1)thiophen~2-yl)”2-· (isoq uli5oiln~4-yl)aeetaBiide [00454J To a solution of 4-bromo-3-(4H-1 ^,4-triazol-3-yl)thioph.©t"2-amme (50mg, 0.2mrnol) and 2-(isoquinolin-4-yl)acetic acid (56mg, OJntmol) in methylene chloride (2mL) were added Hunig’s base (i.e., N-N-diisopropylethylatnine) (7luL, 0.4mmo1) and HBTU (133mg, OJSmmol), The heterogeneous reaction mixture was homogenous after 3h. The reaction was quenched with, saturated aqueous ammonium chloride and the aqueous was extracted with methylene chloride. The organic phase was washed with brine and dried over sodium sulfate. The resulting solution was concentrated to provide a pale red solid, which was purified by column chromatography using 3.5% Με0Η/€Η2Ο2. LCMS: retention rime 1.955 min using analytical method [7] with an M-f-Na of 414.0. 19,0 mg (15% yield): white solid. 'H-NMR (300MHz, CDCla) δ 9.34 (s, IB), 8.66 (s,lH), 8.07 (d, /=8.01-¾ ΪΗ), 8.01 (d, /=8.0¾ IH), 7.75 (m, 1H), 7.65 (tn. 2H), 6.88 (d, /=0.5¾ IH), 4.30 (s, 2H). ,3C-NMR (75MHz, CDC13) δ 168.3, 153.2,144.8,142,8, 135.0,131.5, 1.28.7,128.4,127.8,123.5, 122.9,116.2,104.7, 38.7. 1.86. Synthesis of AT-(4-t>mno~3-(4f/'1,2,4~tdazol-3--yl)thiupheu-2-yI>-2-(3,3- difluorO”2-oxo3ndoilii“l~yl)aeetiimide

L86.L 33^ijhi(mnnd0iin-2~(>m> [08455] A 1 OOmL reaction flask was charged with indofine-2,3-dione (0,88g, b.Ormnol), DCM (40mL) was added, followed by OAST (2.4g, 15.0mmol). The reaction was stirred for J 6h before being quenched by the additioup 2foL MpH. fbe organic reaction mixture was rinsed with water and the organic layer was dried over sodium sulfate. The solution was concentrated under reduced pressure to give 3,3-difluoroindo1in-2~one (1 .Og, 98%). LC-MS of this crude showed the desired m/z of 170.0 at a method [1] retention time of 1.673min in. L36,2, tert-Buty'i 2-(3f3~difimm-2~&amp;xom4&amp;im~l~}i)aceiaie [08456J The title compound was prepared from 3,3 -difiuoroindo ! i n-2-one using protocol K except using iert-butyi 2-bromoacctate to give crude test-butyl 2-(3.3-difluoro-2-oxomdolm-l -yl)acetate as a yellow oil. LCMS method [1] showed an M-f- Na peak of 306.1 with a retention time of 2.502min. 1.86.3. 2~{3f3~Difiimro-2~i}xomUoUn~!~}4)metic acid [00457] A 30mL reaction vial was charged with tert-buty! 2-(3,3-difluoro-2-oxoindolin-1 -yl)acstatc (275mg, lmmo!) as a yellow oil, DCM (3tnL) was added, followed by an equal volume of formic acid. The reaction was stirred for 16h, The reaction mixture 'was concentrated under reduced pressure to give 2-(3,3-difIuoxo~2-oxoindolin-1 -yl)acetie add as a yellow solid. The desired M+H (228) was observed in the LCMS using the method [1 ] with a retention time of 1,652mm. 1.86.4. N~{4~Bromo-3~{4M~l>2i4-triazei-3-yl)tkfaphen~2-yi)~2-(3,3~difiu&amp;r&amp;-2·· 0xmndaUn~l~yi}ucittemide [00458] The title compound was prepared from 2-(3,3-difluoro-2-oxoindo1m-l-yl)acetic acid (50mg, 0.22mmol)s 4-hmmo-3-(4H-l,2,4-tria2»l-3-yl)thiophen.-2-amitte (45mg, 0. ISrmnol) using protocol A, HP1.C purif!|atfon gave N-(4 -bromo-.s-Cdl ;· 1,2,-4-triq^l-3-yi)thiifohen-2-ylM-(3,3sdifoioro~2~C!xoindolm-l-yl)3eetarnide (12mg) as a white solid (m/z 454;0, retention 0f£;6iNhiia in [71), ‘H-INMR (300MHz, CD€h>) 6 13.1 is, Hi}, 7.82 (s,iH).7,70 (dd, ,/-7.5, 1 5Bz, ill), 7.50 (td, ,/-7.9, 1.2Hz, 1H), 6.99 (s, 1H), 6.92 (d, ./-7.9Mz< 1H), 4.71 (s, 2H). 1.87, Synthesis of A?“(4~hrom©-3~(4/f-l .2J4-trIaxel-3“yl)thiophesj~2~yl>-2-(7- (frifSiioroKiethyl)qfonolia-S-y!)aeeiamlde and A;~(4-hromO”3”(4//-.1,2,4-trlazol-3-yI)tMoplmn~2-yl)-2“(5-(tr!JluofomethyI}qmn©lm~7~yi)acetamfde

L 87.1, 7-Bmffi®~S~{tnpuarmmtkyi)qwmime and 5-brom&amp;-7·· (iti^dnremetkyijqmndMne [004S9] 3^amO"3KtriS«orom.e&amp;yl)afflitoe (11,7 g, 48.S mmol) was tiien up in glycerol ψΜ ml.) aad cone, H2SCL1 (13 ritL). Nitrobenzene (5# #1?) and FeS04*7H?.0 (800 rag, 2.88 mmol) were added, and. the mixture was slowly w armed to 130 “C lor 4 b Isolation led to a 3:2 mixture of regioisomer*, which was used without further purification in the^subsequent reaction. HPLC method [4|, retention time 2.53 and 2,59 min; MS(ESi) 278 J (MH+ ,SiBr). 1. 8 7.2, tert-Butyl 2-(5-(Mflmromeihyl)qumoUn- 7-yl)acefate and tert-butyl 2-(7-(Mfinoremethyi)qmmdm-S-yi)ac-ci&amp;t&amp; [00460^ The title compounds were prepared front 7-bromo-5-(triilueromet.hyljquirtoiirie and 5-bmmO“7-(trifl.ooromethyi)qumo3me (550 mg, 2,0 mmol) using protocol P, Flash cinematography (10-30% EtOAc/hexanes elution) afforded the product as a brown oil (400 mg, 64%). HPLC method [7], retention time 5.61 and 5,74 min; MS(ESI) 312,0 (MH+). 2,873, 2~(5-(Trifiuartmetkyi}qmmUn~7-yl}ueetic acid and 2-(7-{mfimramc1hyl}quinoiin-Syl)meik add [0046! j A mixture of tort-butyl 2-(5~(trii1uoromethy])quinolin-7-y1)aceiate and tert-butyl 2-(7-(rrifliioromethyS)quinolm“5-yl)aeetate (400 mg, 1.3 mmol) was dissolved in glacial AcOH (8 mL) and 6 N HC1 (8 rnL), The mixture was heated to 70 °C for 1 h, then 80 °C for an additional hr. The reaction mixture was concentrated in vacuo to afford the crude title compounds, which were used without further purification. HPLC method [4], retention time 1.29 min; MS(ESI) 256.0 (MH+). 1.87,4, N-(4~Br0mn-3-(4M~l)2>4-trtaz&amp;i-3-yl}tkiephen~2~yl}-2-(?- (frijiaanmelhyljqnimdm-S-yijacctamide and i\~(4-hmm0-3-{42i-I,2*4-iriaz(fi-3- yl)tMophen-2-yl}-2~(5~(frifIustmiethyl}qmmim-7~yi}ac£iamide 190462] 2^5“(^ifiuoi®ffiS^>']}qui:io!i3i-7-yl)acetie acid and the mixture of 2-(7-(iritli^T^rri^ih^rI)£|«iftpli!Br|t~yI)aceii© acid (28,3 mg. Oil 1 mmol) and 4-hromo-3-(4H-1 ,2,4-triazo!-3-yi)ihK>pher:· 2-amine (23 mg, 0,094 mmol.) Were treated according to protocol. A. The erode product mixture was purified by HPLC to afford A;~(4-bmmo~3-(4//-.1 >2f4-tria.zol-3-yl)thiophen--2-yI)-2"(5-(triiluoromethyl)qumolm-7-y1)acetamide and 7V'-(4~brom.o--3-(4//-J;,2J4--triazok3~y[)ih!ophen--2-yI)--2-(7'-(triili}oromethyijquinolin"5-yl)aeetamide. LCMS method [13], retention time (tnin)10.100 and 10.386; MS(ES1) 482.0 (MH-t, 7i>Br); JHNMR (300 MHz, CD3OD) δ 9.01 (dd, ./-4.3, 1.6 Hz, 1H), 8.62 (d, /= 8.4 Hz, IH), 8.41 (s, 1H), 7.98 (s, 1H), 7.70 (dd,/== 8.7, 4.3 Hz, IB), 4.30 (&amp;, 2H). 1.88. Synthesis of AH4~hromo-3-f4JM,2,4-triaz©k1~y!)ihiophets~2-yl>-2-(2“ (trlflaoromeihyl)<|uiiiolfsi-7~yl)aoetaffliide

li 88, L tert-Butyi 2-0~{t^u&amp;r&amp;me^t}qumo(m~ 7-yl)memte. 100463:] The title compound was prepared from 7-bro?no-2-(i^fiimromethyl)qnmoiine (IMlor, H. and Schiosser, hi Tetrahedron 1996, 52: 4637-4644) (45 nig, 0.163 mmo!) using protocol P and was purified by flash chromatography (10-3031 EtQAe/hexaaes elution) to afforded aferawa oil. HPLC method [S], retention time 1.875 min; .MS(HSI) 312.0 (MH :). 1*8$2. 2^2~{TT$u&amp;mme$ty$qnm&amp;im*7^i}mmie mid [00464] tert-Butyl 2^(2Afrifinoroinethyi)nuin.oli'n-7-y!)i,-.ecsatv was dissolved in glacial AcOH (0.8 mL) and 61¾ HC1 (0-8 naL) and heated to 80 7C lor 2 hr. He reaction mixture was concentrated in vacuo to afford the crude product, which was used Without further purification. HPLC method [4], retention time - 1.874 min; MS(ESl) 256.1 (MH+). L88J. N~(4-Bmm(i-3~{4E-l,2,4-trmz®i-3--yi)tkmpkefi~2~yl}-2~(2~ {iripm?oMeih}4)quinolm~7~yl)amiamhie [00465) The title compound was synthesized via protocol B from 2-(2-(trifiuoromet hvl)quinolin-?-yl)acetic acid and 4-brorao-3-(4H-l,2,4-triazol-3-y])ihiophen~2~amine, using HO At instead of HOBt HPLC purification afforded the product as a white solid, HPLC method [7], retention time 8.68 min; MS(ESI) 484.2 (MHr, 83 Br); *H NMR (300 MHz. CD3OD) δ 8.76 (d, J = 9.5 Hz, 1H), 8.25 (d, /- 9.0 m 1H&amp; 7M (dd,/= 8.7,7.3 Hz, 1H); 7.92-T81 gm, 1¾. f, 11-6.97 (m, Hi), 4.45 (|, 2fl). 1.89. Synthesis of AH4-eyantKl"{IH-i ,2j4-iTiazol-3-yl)thlophen~2~yl)-2~(2~i)s©“ 3,4-dlhy firo-1,5-naph thy r idi n-1 (2 //}~yl)aee tamide

L 89, /, ThiemP, 2-ejflJ, 4Jttiazelo{ls $"C]pyrimMine-9<itrbemtrUe [00466) 9"Broniothieno[3.2»e][l;,2.4]triazolo[l>5-cjpyrimidine (1.16 g, 4.55 mmol) was dissolved in DMF (23 mL), and eopper(i) cyanide (817 mg, 9.1 mmol) was added. This mixture was heated to 150 °C for 23 h, whereupon the reaction mixture was concentrated muter reduced pressure, and the residue purified by flash chromatography, LCMS method [4], retention time - 0.890 min; MS(ESI) 202,0 (MH+); !H NMR (300 MHz, C1.X.1,} S 9.36 (s, 1H), 8.57 (s, 1H), 8,32 (s, 1H). 7.89.2, 5~A 1,2,4-triaz@i~3~yl)thiaphem-3~atrbmitriig )00467) Thieno[3,2-e][],2,4]triazato[d,5-c]pyriimdme~9-carhonitriie (251 mg, 1.25 mmol) was dissolved in MeOH (6,2 mL), and Ny -meth yi ethane -1,2-d i amine (0.22 mL, 2.5 mmol) was added. This was heated to 60 CC for 20 min, then immediately cooled in an ice bath, Saturated NH4G (30 mL) was added, then the aqueous mixture was extracted with 10% iPrOH/CHClj (3x). The organic layers were combined, dried (MgSCL), filtered and concentrated under reduced pressure to give the titled compound as a single peak on LC/MS: method [4), retention time =- 0.658 min;. MS(ESi) 192.0 (MHt). h 89,3. N~{4~fAmiii~3~{iH~L2f4~mazel"3~)3Hhkipken~2~yiy2~(2~i!XO~3i4--dihyiirii-L5-‘ mphfhyridm~$ (2E)-yl)mefmiM$ [00468] The title compound was synthesized according to protocol A from 3-amina-4-{4n-!,2,4~triazoI“3-yrjthiophone-3~carhonifrije (69 mg, 0:,364 rotnei) and2-(2-oxo-3,4-dihydro-1 <5 •naphibyrniin-· 1 (21)· y l}acetic add hydrochloride (89 mg, 0.36? mmol). MPLC puriicafan afforded desired product as a white solid. LCMS method [11], retention time ~ 6.22 min; :MS(EST) 380.1 (ΜΗ·.··): Ή NMR (300 MHz, CD,()D) 6 8,52 is, Hi), 8.38 (d, /- 5.2 Hz, 11), 7.81 (s, 11), 7.82 id,./- 8.4 Hz, 11), 7.55 (dd, /-8 4, 5.3 Hz, iH), 5.01 (s, 21), 3.37 it, 7- 7.6 Hz, 21), 2.99 (I, J - 7.6 Hz, 21) 1.90*. Synthesis df./^C4-i^aRO“|^0-meihyI-lJf~lJli4-irlszoI‘“3~yl)tlssoph:gn-2--yl>· |-0»o«^3,4-diltydpo-l jS-itaplithyrfd!ts*l (21)-yl)a®etamlde [:09469] N-(4~cyano-3-(10-1,2,4riria&amp;Sf -3-yl)tliiopheii'-2-yi)-2-(2~oxo-3,4-dihydrO"i,5-naphihyridin-l(2H)-yl)acetainide (180 mg, 0,475 mmol) was dissolved in MeOH/CffeCls (1:1, 4 niL total), and TMSCHN2 (Aldrich, 2.0 M in diethyl ether, 8 mL, 16 .mmol) was added at it. This was stirred for 4 h, whereupon the reaction mixture was concentrated under reduced pressure. The crude residue was purified by HPLC to give a white solid as a trifluoroacetie acid salt: method [11], retention time = 7.56 min; MSfESI) 394.2 (MH+); XH NMR (300 MHz, CD3OD) 8.41 (s, 1H), 8.25 (d,/- 5.0 Hz, 1H), 7.87 (s, .11), 7.72 (d, J- 8.7 Hz, 1H), 7.52-7.42 (m, 1H), 4.98 (&amp;, 2H), 3.97 (s, 3H), 3.40-3,20 (m, 2H), 2.96 (t, / = 8.3 Hz, 21). 1.91. Synthesis ufA!-(4“ehl©ro-3-(l“methyl-ii/~l,2,4-trlazsJ-3-yJ)thiopheu-2~ y^-lril^oso-S^rdlhydrn-ljS^uphlhyrlilii-lCt^^acetuihlde

2.91. L 4~CMa?o~3~i42$~ [004791 This compound was made via a sequence analogous to the synthesis of 4-6»Μο-3^4Η^1,2,4-Μ4ζο1-3^Ι)έ&amp;ϊρρ&amp;6^2'Ρ§ηη: method [11]* retention time = 3.73 mm; MS(ESI) 201.0 (MH+, aSli| ΊΪ NMR (300 MHz. OM$0-/>)o 13.68 (hr s, 1H), 8.35 (br s, 1H), 7,14 (hr s, 2H)S 6.48 (s, 1H). 1912, N~(4~Cki0ro~3~{lH~li2,4-fri®z&amp;i~3-yl}thiopken~2-yi}-2-{2~&amp;x®-3>4-iUhydm-l>5~ nmphthyddm-l{2H)~yi}aeetmdite [00471 ] The titled compound was synthesized from. 4-chloro-3-(4H-1,2,4-triazoi-3-yl)t.hiophen-2~art!me and 2~(2-oxo-3,4-dihydro-I ,5-naphihyridin- l(2H)-y!)acetic acid via protocol A. LCMS method [4], retention time === 1.035; MS(ES1) 389,1 (MH+, ?sCii. 1.9L3, N~(4-Ckl&amp;m-3~{i-ffleihyi~lH~iJf4-trmz0i~3-yi)tki0phen~2~y!)-2~(2~i?x0~3>4·· dihydm~l,S~mphihymim~l(2H}-yl}&amp;eemmide [00472] The titled compound was synthesized from N-(4-chIoro~3-( 1H-1,2,4-iriazol-3-yl)thiophen-2-yi)~2-(2-oxo-3>4-diliydro-l,5~naphthyridin-1(2H)-yl)aoetamide and TMSCHNj, HF'LC purification afforded a white solid. LCMS method [11], retention time = 7.322 min; MS(ESl) 403.2 (MH+, 35C1); JH NMR (300 MHz, CD3OD) δ 8.43 (s, 1H)S 8.29 (d, /= 5.3 Ηζ,ΙΗ), 7.85 (d,/ = 8.0 Hz, 1H), 7.59 (t,J= 7.1 Hz, 1H), 6.94 (s, 1H), 4.98 (s, 2H), 3.98 (s, 3H), 3,36 (t, / === 7.5 Hz, 2H), 2.97 (dd, /= 8.2, 6.3 Hz, 2H). 1.92. Synthesis of A'-(4-i>mmo-3-(lI/-! ,2,4-trlazoT5-y|)thiophen~2~yl>'2- (quisolm'S-l)aeetxmide 100473] To a mixture of 2-(quinohn-8-yl}aeetie acid (35.6 mg, 0.19 mmol) and 4-bromo-3-(lif-1,2,4-triazol-5-yJ)thiophen-2-amine (27.6 mg, 0.11 mmol) in methylene chloride (1.0 ml.) and triethylannne (0.1 rnL) was added 2-chioro-i - methylpyrk! irduoi iodide (46.5 mg, 0.18 mmol) at it. After stirring lor ] 5 min, the reaction mixture was concentrated under reduced pressure. Purification fey flash chromatography (silica, 40:60 ethyl acetate/hexane) gave .¥-(5-brorno-3-(li:/-L2,4-triazol-5-yi)ihiophen~2-yl)-2-(qtiinolin~8ft)aoefamide (12 mgs, 26%). The desinsd ptridgpt was submitted to prep HPI.C for further purification. Retention time (min) = 3.486, method [7], MS(ISI) 415.9 (M+H). !HNMR (CDCI?) &amp; 12,42 (s, 111),9.09(4..7=- 1.7 Hz. 1H), 8.40 (d,/- 8.5 Hz, IB), 7.96 i<lJ 8.6 Hz, 1H), 7.89 (d,/- 8.6 Hz. IH), 7,73 (s, 1H), 7.71 (d,J- 8,0¾ 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.58 (d, /= 4,5 Hz, 1H), 6,86(s, 1H), 4.62 (s, W). IM, Synthesis of 2'{hen2iiii<flihiaKOi-7-yI}^'-(4iIjrortto~3'C1Jf"l,2l!4~irisx;oi~Sr yi)tfel©pliesi~2-yi)aeeiamsde [00474] The title compound was prepared from 2“(benzo[rf]thia7o1-7*y1)acetic add (25,5 mg, 0,13 mmol) and 4~bn>mo~3-(l//-l,2,4-lTiazol-5-y])thiopheii-2-iam«3e (22.3 mg, 0.093 mmol) according to protocol A, The crude product was purified by prep HPLC. LCMS Retention time (min) = 4,075, method [7], MS(ESi) 421.9 (M+H). JH NMR (CDC!3) 6 12.39 (s,.lH), 9.02 (s, 1H), 8.22, (d, 6.6 Hz, 1H), 7.65-7.61 (m, 1 IT), 7.54 (&amp;, 1H), 7.55-7.49 (m, IH), 6,90 (s, 1H), 4.19 (s, 2H). 1.94, Synthesis of ,\-(4~hromo-3'‘(l/f”l;>2,4-i:riazof--5'-yl)fhIophen-2-yI>-2-(7-HnoroqsiInoIIii~5-yI)aceianiide 1.94J. mm] To a mixture oi his(dibeszyhdeneacetone)dipalladtom (0 Ji g, 0.22 mmol), 9,9-dimethyi-4,5-bis(dipheny[phosph5ne)>,antbcne (0.13, 0.22 mmol) and cesium carbonate (5.0 g, 13.41 mmol) under λ% gas was added acetamide (0.90,14.73 mmol). ],3 dibrorno-5-iluorobensen€ (2.8 g, 10.83 mmol) and dioxanc (22 mL). The reaction mixture was heated at 80°€ overnight and concentrated under reduced pressure. Purification by flagl chromatography (silicas 50:50 ethyl aeeMe/hexane) gave N~(3-bromo-5-flL;orophenyl)aecta05ide(3.5J g, quantitative). Retention time (min) ··· 1,945, ^method [4], MS(ESi) 232.0 (M+H). 1.94,2. 3-Bmmo-5~flmroaniMm hydrochloride [00476] To a solution of A-'^-bnomo-5-(1uo»Bpbenyi)ace4arriide (3.5 g, 15.13 mmole) M absolute ethanol (40 tnL) was atled HO (30 mL of a 11% aqueous solution). The reaction mixture was stirred while refluxing is an oil bath set at 110°C overnight,

Cone hydrochloric acid (5 mL) was added and stirred for an additional 5h prior to eonttonimtffig mider mduoe prepare. The resulting S-brnmo-S-fluoroaisiline hydrochloride (2.9 g, 85 % yield) was used in the next1 reaction without hither purification. Retention time (rum) = 2.077, method [4], MSpSl) 192.0 (M+H). 1.94Λ S-Bromfh7~ftuoroquimtme and 7~hromo-S-fimroqmmiine [01)-477] To 34umno-5-iiuoroaniime hydrochloride (2.9 g, 12.89 mmol) was added glycerol (1,9 ml,, 25,99 mmol): nitrobenzene (1.3 mL), sulfuric acid {3,5 mL) arid iron (H) sulfate hepiahydrate (0.23 g, 0.82 mmol). The reaction mixture wax placed in an oil bath set at 80 :'C and stirred overnight follo wed by hasiflcatioo with 12N NaOl f and extraction with dieMoromsthanc. The organic phase was collected, dried (sodium sulfate), filtered and eoncehiraied under reduced pressure. Purificationfey flash chromatography (silica, 50::50 ethyl aeetate/hexane) gave 5 -brome···?··iluoro qulnoliiκ· add 7ftramQ*5-fiuoroquinoline (1.03 g, 30%) Retention. rime (min) ·;: 1 877 and 1 967. method [4], MS(ESi) 227 9 $f+H). 1.94,4. iert-Butyt 2~(7-ftmroqumeUn~5~yt)ucetate md tert-Butyi 2-{5-flwroquinoUn-7-yi)&amp;cesMe [00478] The title compounds were prepared from d-bromo-T-fluoroquinoline and 7-bro.mo-5-fluoroquiru>line (1.0 g, 4.356 mmol) using protocol P. Ratification by flash chromatography (silica, 30:70 ethyl aeetate/hexane) gave a mixture of reiV-butyl 2-(7-iluoroquH'!olin-5-yi {aceiaic and .'v/t-buty! 2-(5-0uoroquinolin· 7-yl[acetate (0.500 g, 42%) Retention time (min) - 1.559 and 1.725, method [% MS(EST) 262.1 (M+H). L94.S. 2^0~FimmqMm&amp;Mn~S-y§aced(’ add [00479] To a elution of ter^butyl 2~(7~flubroquinoMn-5'-yl}acetaie and tw$-bntyi 2-(5^fiu6mqulndlm"7-yl)neeitlte (0.50 g, I „91 mmol) in acetic acid (5 ml.) was added 4M hydrochloric acid in I .d-dioxano (10 mL). The reaction mixture was heated in an oil baft set at 60712 jmder condenser with 5¾ (g) inlet overnight. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica, 60:40 ethyl acetate/hexane followed by 20:80 methanol/dichlotomethane). Further purification and separation by prep HPLC yielded the single regio-isomer 2-(7-iluoroqiiinolHi-5-yl)acetic acid (0.025g. 6%). Retention time (min) - 0,337, method [4], MS(ESI) 206.1 (M+H). 1,94.6. N~{4~Bmm&amp;~3-(lH~lf2,4‘tna70i~5~yi}ihiaphen~2-yi)~2~{7~fluar&amp;qumoim-§~ yijacet&amp;mide [Θ048Θ1 The title compound was prepared from 2-(7-fiuoroquinolin~5-yl)aceiic acid (0.025 g, 0.122 mmol) and 4~bromo~3~(iHn,2,4-mazol-5~yl)thiophen~2~y]~amine (0,20 g, 0,083 mmol) according to protocol A, The desired product was submitted to prep HPLC for farther purification. Retention time (min) - 2.33, method [7], MS(ESI) 434.0 (M+H). NMR (CDCla) δ 11.79 (s, IB), 8.94 (d, J-4.0Hz, 1H), 8.54(d,/= 8.1 Hz, 1H) 8.38 (s, 1H broad), 7.80 (d,/= 10.1 Hz, IB), 7.70 (d,/= 10.1 Hz, 1H), 7.59-7.55 (m 1H), 7.:22 (s, Hi), 4.47 (s, 2H). J .95. Synthesis of A-(4-eyano~3-C I HA ,234mzokl - yS)thi0phen~2-y?)-2-(2-im;~ 6-(trifSssoromethyi)q!iinsIta~l(2ii)-yl)aeetamide

2.95,L 5-Mtro~4~{2H~lf2f3~itmzoi~l~yi)thi{tphem~5~mrb0niirUe and 5-mtro~4~ (2H~2f2f3~trmzoi~2~yi)iki&amp;phem~3~cm'bimiiriie (004811 A mixture of 44jromo-5-nitiOthiophetie-3-carborsiiri!e (0.53 g, 2,26 mmol), 177-1,2,3-triazoie (20 pL, 0,35 mmol) and sodium bicarbonate (0.050g, 0.60 mmol) in DMF (0.6 ml.) were stirred in an oil bath set at 1 10*C under condenser with N2 (g) inlet for 2h. The reaction mixture was quenched with H20 and extracted with ethyl acetate. The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acetate/hexane) gave the regie-isomer of each nitro intermediate (0,138 g and 0.11%, 61% of 1:1 mixture), detention time (min) =- 1.260 and 1.692, method pj, MS(ESl) 222.0 (M+H). L95,2. 5-Amimi-4-{f2I»lJ^4n£Ztd~l~}4pMophem~3~mrbmifriie 100481} 5^amino-4-(;l//-l,23 4riazol-l-yl)thiopb.ene-3-ear'bonitrilc was prepared from 5-niiro-4-(iif'-l,2!3-hiazol“.l-y!)thiophene-3~caritonitrile (0.12 g, 0,52 mmol) according to protocol P. Retention rims (mis) = Μ i 4,:meiftod [4], ϋΙ(Ε|3): 192.0 (M+H). L9S3, N~{4~Cyim&amp;~$~(jtH~i,2f3-iriazot~I-yi)tkwphen-2~yi)-2-(2~exa~6~ [00483] The title compound was prepared from 2-(2-oxo-6-(trifluoroineihyl)qiauolin--l(2//)-yl)acetic add (0.072 g, 0.27 mmol) and 5-amino-4-(l/7- 1,2,3 -triazol- 1 yl)ihiophene-3‘Ciirbou?irile (0.025 g, 0.13 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS retention time (min) - 5.505, method [7], MS(ESI) 445.1 (M+H). 'H NMR (CDQ3) 6 11.17 (s, 1H), 8.41 (s, IH), 7.91-7.87 (m, 3H), 7.79 (0,,/-9.0 Hz, IH), 7.67 (s, JH), 7.48 <d, /= 9S Hz, 1H), 5.26 i s. 2H). L96. Synthesis of i¥-(4~cyaeO"3-{2^-1,233-triaxol-2-yl)thiophea-2~yI>-2'-(2~ox©~ 6-(tdflaoromethyI)qii!Kolm-l(2H)-yl)aeetaiBld«

li96,L 5~Amin0~4~(2H~l}2J-$r!Ciz&amp;l~2~yi}tkhph(me~3"m?bi)mfrile [004841 5~ami'uo-4-(2f/~i, 2534riazo]:42-yl)thiophene-3-carbemtr:ie was prepared ffcsm 5-mtro-4-(2^-1 A3-tria2»J-2-yi)th{ophcTie--3-carb0nimIc (0.11 g, 0,62 mmole) according to protocol P. Retention time (min) = 1.304, method |4| MSpSI) 1924 ΡΛ). L 96,Z N-(4~Cymo-3~(2H~lt2t 3-triazol~2-yi)thwphen-2-yl)~2~{2-@xi}~6~ {i?iflmromethyi}qmmim~l{2H}~yi)metamide [00485] iV-(4-eyano--3-(2ii-I s2, 3~iriazol-2-yi)tbi0pheii-2--yi)~2-(2-oxo-6-(lrifluoK)inethyl)quiiiolin-1 (2#)-yl)acetaude was prepared from 2-(2-oxo-6-(ttifi uoromeihyi)qumoiin-1 (2//)~yi)acetic acid (0.15 g, 0.56 mmol) and 5~armno-4-(2i7-j,2,3~triazol-2~yl)thiophetie-3-carbomtrilc (0,070 g, 0.37 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min) = 6.5, method [7], MS(ESI) 467.1 (M+Na). 1H NMR (CDC1.3) 511.50 (s, 1.H), 7.93-7.85 (m, 4H), 7.83 (s, 1H), 7.64 (s, i H), 7.60 (d, J = 8.5 Hz, IH). 6.95 <d, /- 0.7 Hz, .1H), 5.29(s. 2H). 1%, ^Synthesis of Jrom®4-(2£M ,2,3-ti*ii»i.2-yI)thiophen-2-yl>.2-(2-oxa- 6"<trii1soromethyl)qiifeoliK-i(2fl)-yl)aceisi!3[ii£le

1,973, 2~i4"BP(iMM"2™m£$‘&amp;thi(}phett~3~yi}~2M-l,2)3~tHaz<tl<} I0O486J A mistisre of 3,4HForomo-2-mirothiophenc (1.5 g, 5.23 mmol), IH~ 1,253~iriasoie (0-30 mi.., 5.18 rarnoi) and potassium bicarhonale (0.54 g, 5 36 mmol) in DA# (13 xnL) were stirred: mm oil bMh set a: HO C wider condenser wife. N2 (g) inlet fi>r Ih. Hie retuTibii haixture was quenched with ||§ and extracted wife ethyl acetate.

The organic phase was.eoleeted, dried (sodiumsnlfitte), filtered and concentrated under reduced pesetas. Parification by iasfe chiematd|rap% {silica, 30:70 ethyl acetal e.'ttexarie) gave the regio-isofnei'nitro intermediate of interest (0.518g, 36%). Retention tine (min) =1.950, method [4], MS(ESl) 276J CM-fH). L97.2* [I0417J 4 mistae of 2^^ttto^2^iirothiopfeen"3-yl)^l-L2,34rlazo]e (0.59 g, 2. .15 mmol); iron powder ¢0.75 g, 13:38 mmol), glacial acetic add (8.4 ml.) and H;0 (1.2 ffiL) was heated in an oil bath set at WC under condenser wit 1¾ (g) Met tor Ih. i^rifi cation fey flash chromatography (silica, 40:60 ethyl acecate/hcxane) gave 4.bromo-3-(M^l523rtria^l-2^1)thioptene-2%inihe (0.35 g, 66%).Reiemiojs time (min) ==1.540, method 14], MS(ESI) 246.9 (M Hi). 1,973, N~{4~Bromi)-3~(2H-l,2t3~tfiuz8i~2~yi)tkmphen~2~yi}-2-{2~oxo~6~ (trifimnmethyi)qumoUn~l{2}i)-yi)ucetamide (90488J The title compound was prepared from 2-(2~oxo-6-(trifiuoromethyl)quinolin-I(2i7)-yI)acetie acid (0.31 g, 1.14 mmol) and 4-bronio-3-(2//~ 1,2,3-triazol-2>yl)tliiophene”2-ai3iKie (0.35 g, 1.42 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min) = 6.9, method [?| MS(ESI) 498.0 p+H), Ή NMR (CDCfe) δ 10.56 ($, IH), 7J0~ 7.89 in*, 2H), 7.86 (s, 1H), 7.83 (d,/ - 8.9 Hz, IE), 7,66 (<!,./ = 8.9 Hz, 1H), 6.97 (&amp;, 1H), 6.92 (d,,/- 8.9 Hz, 2H), 5.16 (s, 2H). 1.98. Synthesis yl)- 2~(2-0xe-i ,5-iiaphtiiyridiii-1 (2i9)~yl)aceiaasitle

1.M1, Μ^<Μί&amp;Τ4ΐ>^ίΜ^2^ίί^ί-3^0ίί^Η^2^)^^^Ι^- ^0ρΜί^ΜίΜ^1(2Μ^ξ)^^ί&amp;ΜΜέ:: I69489J The title compound was prepared from 2··(2-οχο-1 sSraaphthyridia.-l(2i/)-yi)icetic acid (0,13 g, 0J2 xnmoi) and 4“eWom~3-(lli"l,2,4-tria^l-3~yl)tliii)pheri~ famine (9.22 g, 1.12 mmol) according to protocol A and purified by prep KBPLC. Retention time (min) = 1.010, me shod [4], MSfESI) 389.0 (M-H). mphtk$ridin-l(2H)~yl}aceiamtde

[00490] To a solution of iV-(4-chloro-3-(IH~1,2,4-triasol>3-yl)thiophen*2"yl>2-(2-oxo-l ,5Hnaphthyridin-l (2fl)-yi)acetarrHde (0.047,0.12 mmol) in DMF (0.4 mL) was added potassium carbonate (0.041 g, 0.30 mmol) and iodomethane (17 uL, 0.27 mmol). After 2 h the reaction mixture was partitioned between H2O and ethyl acetate, The organic phase was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product was submitted to prep HPLC for further purification. Retention time (min) = 4.407, method [8], MS(ESI) 403.i NMR (CDCIP δ 12.40 (s. IHp 8.32 (d,./- 5.1 Bz, 1H), 8.07 (s, 1H),7 56 <d, J= 8.1 Hz, 1H) 7.41 (d, J- 5.1 Hz. 1M), 7.39 (d, J -5.1 Hz, 1H)6.81 (s, m),4.89(s, 2H), 4.02(8, 3H), 3.47-3.42 (m, ZH), 5.03-2.98 (m, 2H).

Synthesis ofA^(4~broni©-3-(lff-j,254“trl8ZOi-S-yI)thin|>ben~2~yip2-(8·· iluoroHoquinolin-fv-yriacetamlde

JjtSiL S~Bmmo~8~aiireisoqumoiim fW«| KINO* {5.1g, SGmmoi) was suspended io sulfuric acid (40mL) and chilled to 0 °C. S-bromoisoqumoline (4g, 19J2mmol) was added slowly over the course of 20 minutes. The yellow, heterogeneous solution was brought to pH 8 by slow addition of ammonium hydroxide. Yellow solid was filtered off and recrystaSHzed from methanol to give 7.5g of S-hromo-S-uitroisoqninoline. LCMS showed an m/z of253.0/255.0 with a retention time of 1.797mins method [1], i. 99,2, S-Bremoisequimim-S-amme [00492] A 3-neck flask was charged with S-bromo-S-nitroisoqumoline (4g, 15.8mmol) and dissolved in MeOH (50mL). A condenser was affixed and the mixture was heated to 100 °C. Aqueous (26mL) solution of ammonium chloride (4.12g, 79mmoI) was added slowly, followed by iron powder (3g, 53.7mmol). The heterogeneous mixture was stirred at 100 i;C for 3h. LCMS confirmed complete reduction to the amine. The mixture was filtered and the solution was concentrated under reduced pressure to give a brown solid as crude product (2.4g, 68%). LCMS showed an m/z of225,0/223.0 with a retention time of 0.767mm, method [1]. 1,993. S-Bromo^fluoreisoquimime [00493] To a solution of 8”anu|o-5-brqmdisoquinoiine in 48% HSF4 (36mL) at 0 CC was slowly added an aqueous: (10mL) solution ofNaNCL (172rngs Umrrsol). The reaction mis sure was stirred at 0 °£' for !h and1 was then concentrated under reduced pressure to give a dark residue. The dark residue was heated to 150 °C for 16h, The resulting dark pil was cooled to 23 *€, quenched with ammonium hydroxide and extracted w ith DCM. The organic solution was concentrated and the resuJlng dark solid was rccrystaHired from EtOAc/TlexaneS;. The desired product (lOOtng) was in the mother liquor while the by-product was filtered away as a solid. LCMS showed an m/'z of 228.0/226.0 with a retention time of 1.318msn. method [l]. L99A, 2-(8~Plmrmsaquim4m~5~yl)ac&amp;tk: mid [60494] A 30mL reaction vial was flame dried and charged with isopropylamine (0.67mf. A .Bromo!) in toluene (3mL), The solution was chilled to 0 °C before a L5M solution of nSuLi (4;8mmoL 3,2ml..·) was added. Pdjfdb&amp;h catalyst (lS4mg, 0.2umlel) w$i added, followed by ligand 2,-(dicycphexyIpho,spkmo)-M>M-· dimcthyiblph<m>4-2-$mae (I60mg. 0.4mmol), and t-butyiacetuic (464m g, 4mmoi). After 1 Spain, a toluene (3tnL) solution of S-bromo-S-fliioroisoquinoHne (2O0mg, 0.9mmol) was added. The reaction was shirred for 16h while warming to 23 °C. The crude mixture was purified by coluro.n chrormttography (3% MeOH/DCM) to give tert-butyl 2-(8-fluorolsoqumoliri -S-yilacctatc (140rog( l..C'MS showed an rn/z of 262.1 with a resention time of 1.469miit, method [1], [0(1495] To a solution of the above ester (200mg) in DCM (2rnL) was added formic acid (3mL). The reaction was sealed with a Teflon cap aai heater to 50 °C for 16h. The solvent was removed and the crude product was used without further purification. LCMS showed an m/z of 206.1 with a retention time of 0.43Train, method m 199,5, N~(4-Brem&amp;~B~(lH-If2s4-4rmzoi-5-yi)thhphen~2-yi)~2~(8~flmroisoqmmlm~5~ yimeetmude [60496] The title compound was prepared from 2-(8-flitoroisoquinolm-5-y!)aceite acid and 4-brom.o-3-(lf/-l!2!4-iriazo1-5“yl)thiophen~2-amffle using protocol B. Retention time (min) = 1.987, method [7], MS(ESf) 432.0 (M+H); lE NMR (300 MHz, CBjOD) δ 9.74 (s, 1H), 8.66 (d, ,/ = 6.6 Hz; 1H), 8.30 (d, ,/= 6.1 Hz, 1H), 8,20 (b s, 1H), 8.1 (dd, / = 8.24, 5.5 Hz, 1H), 7.67 (dd, /= 9.9, 7.7 Hz, 1H), 7.1 (s, 1H), 4.46 (s, 2H).

Synthesis of/V~(4~hromG-3-(l/f-i,2v4-trlazeS-5--yl)tMophen“2“yl)~2-(2-05e-6-(iriOuoromctlsi>sy)quinoll!i--l(2i/>-yi)acetamMe

ΐ,Ιίβ&amp;Λ (E)-Eihyi 3-{2~amim~5--(t?ifimrvtmih0xy}pht*mi}ttc?ylaSe [004971 To a mixture of 2 bronKv-4-(tr;t1uorometlK>xy)araiine Π .00 mmol), tricthylarnine (I .§ mmol·} and F(o-toi)3 (0.40 mmol) in DMF (0.5 M) ir; a glass pressure tube under nitrogen gas were added ethyl aery lure (1.0 mmol) and palladium acetate (0.20 mmol). The tube was sealed and heated lo 120 °C for 1B h. The resulting solution was concentrated under vacuum and punned by column chromatography. Retention time (miii) - 2.467. method [ i ]. MS(ESI) 276.1 (M-4-1). /../00,2 6~{Tt^uarimefhaxpqmmdm"2(!H)~i)ae [00498] To a stirring mixture of (E)-ethyl 3-(2-ammo-5" (trifluoromethoxy)phettyl)acrylate (2,2 mmol) in 4N HC1 in dioxane (25 mL) was added concentrated HC1 (2 mL). The resulting mixture was warmed to 100 °C overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHC03 solution until pH > 7. The product was extracted with EtOAc and used without further purification. Retention time (min) ~ l .804, method [1 ], MS(ESI) 230.1 (M+H). LNJ&amp;.S. Methyl 2-{2-ox&amp;~6-(trifiiwmmethoxy)qmnolm~l {2H)-y!)meMie [00499] Methyl 2-(2-oxo~6"(trifluoromethoxy)quinoliu-l (2H)-yi)acelaie was prepared from 6~(tritluoromethoxy)qumolin-2(lH)"One according to Protocol K.

Retention time (min) - 2.083, method [1], MS(ESI) 302.1 (M+H). L1&amp;&amp;.4. 2~(2-Oxo~6~{iHfiuor&amp;Meth(rxy)qmmlm-l(2H}-yt)ai:eMc add [00508] To a stirring solution of methyl 2~(2-oxo-6-(tiifluoromethoxy)quino!iri-l(2H)-y!)acetate (1.2 mmol) in THF/water (2:.1) was added LiOH. H20 (8,1 mmol). The resulting mixture was stirred overnight. The crude product mixture was slowly acidified with IN HO solution and then extracted with EtOAc. The organic phase was separated, dried (MgSCL), filtered and concentrated under vacuum to give 2~(2--oxo-6- (^flKommetbi>xy)q«iHQliii^l(2Ei)-y!)a^c acid; Retention time (mrti| ~ 1.783, method [1¾ MS(ES1) 288.1 (M+H). 1.160»$. N-{4-Br0mQ-3~(lH~li2>4-Mez0i-5-yl}iM&amp;pken~2~yl}~2~(2~i}x®~6~ {iriflmmmeih&amp;xy)qstmoUn~I{2H)~yi)metamMe [90501 | The title compound was prepared from 2-(2-oxo~6~ (trifluoromethoxy)qdnoIin-'i (2H)-yl)acetic acid (40 mg, 0.14 mmol) and 4-bromo-3-(l H~ L2s4-triazol“5-yI)thiophen~2~amine (28 mg, 0.11 mmol) according to protocol A. Retention time (min) = 6.06, method [7], MS(ESI) 514.0 (M+H); lH NMR (300 MHz, CD3C1) 6 7.85 (d, J- 9,35 Hz, 1H), 7.73 (s, 1H), 7,50 (s, 1H), 7.44 - 7.41 (in, 1H), 7.35 - 7.33 (m, 1H), 6.97 (d, J= 9.9 Hz, 1H), 6.95 (s, 1H), 5,31 (s, 2H). 1.101. Synthesis i>f.¥-(5-chtorO“3->(l//"l,254~trsazoI-5-yl)thiophea~2-yl)~2~(2~oso~6~ (trtflu4>rnmcihyl)qumolto4(2/i)»yl)acetamide

£161.1. 8~Chiewthiemf3,2-ejflf2f4]irias(>loi4y3-i:fpyrimidirte [00502] To a stirring mixture of thie?K>[ .T2-c][1,2i4]rr!a2t4o| 4.3-c]pyrimidin.e (123 mg, 0.7 mmol) in HOAe (1 mL) was added NCS (200 mg, 1.5 mmol), Pd{QAc)2 (48 mg, 0.21 mmol). The reaction mixture was stirred at 120 “€ overnight. The reaction was neutralized with a saturated NaHCO* solution and extracted with DCM. This product was purified via an isco column to give 8~ehlorothiGuo[3,2re][l,2,4]triazolo[4,3-e]p>Timidine as the major product. Retention time (min) - 1.663, method [1], MS(ESI) 211.0 (M+H). L161.2, 5-€Moro~$-(4H-lf2,4-trmwt-3~ytythiopheti~2-imme [00503] To a stirring mixture of 8--chlorothieno[3>2-e][l,2,4]triazoioi4,3-cjpyrimidine (60 mg, 0.285 mmol) in MeOH (10 mL) was added N-methylethyl 1,2-diamine (106 mg, 1.4 mmol). The resulting mixture was warmed to 60 °C for 1 hr. The reaction mixture, was cooled to rt and then diluted with DCM. This mixture was then wasted several times with a saturated NFLiCI solution. The organic layer was dried over MgSOj, filtered, and concentrated under reduced pressure to give 5~cWoro-3-(4H-l,2s4-triazol-3-yi)thiophsa-2~amine. This amine was taken directly to the next coupling reaction without further purification. Retention time (min) ::: 1.227, method (1], MS(ESI) 201.1 (M+H). 1.101.3. N~{5~ckkmi-3~{lH~l,2,4-triszifi-S~yi)ikhpheM~2~yi}~2~(2--exo~6~ (trifl.uoromeihyi)quimUn~l(2M)-yi)ucel«mide iliSidj The title compound was synthesized from 2~(2~ttxO'6-(trifiuommedtyl)quinoljn-l(2H)-yl)^cSic acid and 5Η?Μοϋ&amp;-3^(4Μ^1 ,2,4-tria^E^-yl)thiophfn-2-amine according to protocol A, Retention time (min) = 6.178, method [7], MS(ESI) 454.1 }; Ή NMR (300 MHz, CD3€I) S 11.93 (b s, IB), 8.0 (s, HI), 7.92 - 7.86 (m, 2H), 7.84 - 7,81 (m, 1H), 7.58 id../-8.8 Hz, 1H), 7.17 (s, JH), 6.97 (d, J ------ 9.34 Hz, 1H), 5.30 (s, 2H). 1.102, Synthesis of A'-(4-hrom0-3-(1 H- 1,2,4-tria2ol-5-y!)thio|ihen-2-yl)-2~(2"OxO”5- (trltlut>rometh}1)quinolin“li2/f)“yl)ucetanride

1.102.1- [00505] The aryl halide (2,1 mmol) and P(PPh).} (0.82 mmol) were dissolved in triethylamine (3.15 mmol) in a glass pressure tube and nitrogen gas was bubbled through the solution vie a gas dispersion tube for 10 minutes. Ethyl acrylate (2.3 nnnol) and palladium acetate (0.41 mmo!) were added to the reaction mixture and the tube was sealed arid placed into an oil bath pre-heated to 120 CC for 18 h. The resulting solution was concenrrated undcr vacuum and purified via an iseo column. Retention rime (nun) = 2.416, method [1], MS(BSI) 260.1 (M+H). 1102.2. 5^'Trifiueremethyi)quimUn~2(lH}~mte [00506( To it stirring mixture of (E)-eihyj 3-(2'«nino-6-(trifluoromethyl)phenyl)acrylate in 4N HC1 in dioxane (25 mL) was added concentrated HC1 (2 mL), The resulting mixture was wanned to '100 °C overnight. The reaction mixture was cooled to rt and dies slowly quenched with a cold saturated NaHCO? solution until pH > 7, A normal aqueous extraction with EtOAc was followed. The muds mixture was taken directly to the next reaction without further purification. Retention lime (min) = 1.892, method [11, M8(ESI) 214.0 (M+H). 1.102.3, Methyl 2-(2-9xG~§~{trijJm&amp;r&amp;meihyl)qmmstm~S(2H}~yi)sceMie [00507( Methyl 2-(2-oxo-5-(trifiuoromethyI)qiiinoiin-1 (2H)-yl)aeetate was prepared from 5-(trifli{oromethoxy)quiiioIiii-2(lH)~one (T. Sakamoto, Y. Kondo, H, Yamanaka, Chem. Phar, Bull., 33, .1985,4764) according to protocol K. Retention time (min) = 2.02, method [1], MS(ESI) 286.1 (M+H). To a stirring solution of the acetate §},33 mmol) in lH|7water (10; 1) was added MOH-HaO (2.33 mmol). The resulting mixture was stirred owrnight. The etude product, mixture #Ss slowly acidified with 1H MCI solution and then extracted with pOAc. The organic phase was separated, dried (MgS04), filtered* and concentrated under vacuum to give 2-(2~oxO”5" (Miluoromethoxy)qumoliml(2i-l)^yl)acetic acid. Retention time (min) - 1.710, method [VI M|pSI) 272.1 (M-: H). 1.102.4, N-(4-hroMO-3^1H-lJ^-&amp;kzol~5-yf)thi0phen-2-yl)~2-(2-0xe-S·· [00508] The title compound was synthesized from 2-(2-oxo-5-(triflitetemethoxy)qxiiitolin-1 (2B)-yl)acetic acid and 4-hromp-3-(\H-1 ,2,4-tria2oi-5-yl)thiophep-2-amine according to protocol A. Retention time (min) = 5.810, method [7|, MS(ESI) 498.0 (M-H). lB NMR (300 MHz, €!>.€[) δ 8.30 - 8.23 (m, 1H),7.67 (s, :H), 7.65 - 7.62 (m, \ H), 7.63 is, 1H), 7.57 - 7.53 (m, 1H), 7.05 (d, J= 9.9 Fk, 1H), 6 95 (s, 1H), 5.37 (s, 2H), 003. Synthesis of (V-(4-brorao-3-(lJS'-i,2s4”tria5Koi-5-yi)flilophen-2-yl)-2-(2-oxo-6- (irlf!tsoromefl5yl)-3,4“dihydr0qsilnolin-l(2/2)-yl)acetnmlde

1.103. !. 2~(2~Oxo~6~it^mr&amp;metkfi)~3,4~dih}'dmqmm»Ua~!(2H)~yl)aeeiic acid [00509] To a stirring mixture of 2-(2K}xo~6~(iriflimromethyl)qihnoiin~1 (2H)-yl)aeetic acid in Pd/C was added MeOH, The reaction mixture was placed under an atmosphere of hydrogen (balloon) for several hours, The product mixture was filtered through a plug of celite. The plug was washed several times with EiOAc. The mixture was concentrated under reduced pressure and the crude amine was taken directly to the next reaction without further purification, Retention time (min)= 1.841, method [1], MS(ES1) 274.1 (M-fH). L 103.2. N-(4-bromo~3~(lH~i!2>4~iriaz0(~S~yi)ikmpken~2~yi)~2~{2~dXii~6~ (Mfiu&amp;rmmthyl)~3,4-{Mhy(ir&amp;qutmMn~l(2E)-yl)aeetamMe [03510] The title compound was synthesized from 2-(2~oxo~6~(tri&amp;oromeihyi)- 3,4-dihydroquinolin-1 (2H)-y1)acctie acid and 4“bromo-3-( Iff-1,2,4~triazol-5-yi)ttoophcn-2-amine according to protocol A. Retention time (min) = 6.373, method [7], MS(ESi) 500.0 (M+H); Ή NMR (300 MHz, CD3C1) δ 7.90 (s, 1H), 7.50 (s5 1H), 7.48 (d, /- 6.6 Hz, 1H), 7.03 (d, J - 9.34,1H), 6.90 (s, 1H), 4.92 (s, 21i), 3.20 - 3.14 (m, 2H), 2.93 ·· 2.90 (m, 2H). 1.104. Synthesis of J¥-(4“bromO"3»(lff"i!2,4~triazol~S"yl)thsophen~2-yl)-2"(6“ ethynyi-2-oxoqolno!ljni-l(2£f)~yl)acetamlde

i. 104.1.

[00511] Methyl 2^-bromc^2^xoqoinefinripH)~yl)acetate (0.67 sufiol), CM (0.67 mmol) and PdCizCPPb})? (0-40 mmol) were dissolved in trieihylatnme (3 rnL) in a glass pressure tube and nitrogen gas was bubbled through the solution, via a gas d^persion tithe for 5 minutes. Bthynyltrkndthylsiiane (3.5 mmo# was added to the reaction mixture and the tube was sealed and placed into an oil hath preheated to 80-CC for 8 h. The resulting solution was concentrated under vacuum and purified via an iseo column. Retention time (min) = 2.759, method [1], MS(ESI) 314.1 (M+H), LI04,2. 2-(6-£tkyn}i-2~oxoqmim}im~l(2H)-y()aaetic mid {005121 Methyl 2~(2roxo4S-((trimeihylsilyl)ethynyi)quinolin-1 {2li)-yl)acetate (0.128 mmol) was subjected to the protocol in Example 1.53.4, except with LiOH-EfeO instead of NaOH. Retention time (min) ~ 1.435, method [1 j, MS(ESI) 228.1 (M+H). ox&amp;quimim~i(2H}-y!)aceiiimide 1085131 The tile compound was synthesized from 2-(6--ethynyl-2-oxoqni«olia-l(2H)#yl)aeetie add and ani 4-hroiTiO“3^1#^l,2J4-triazoM-yl)thlophei5-2-aiT;ine according td protocol A. Retention time (Pitt) = 6.563, method [7], MS(ESS) 454.0 (M+H); XE NMR (300 MHz, DMSO-4) 3 8*51 (s, 1H), 8.07 (d* ./= 9*35 Hz, 1H), 8.01 · * 7.97 (m, 1H), 7 68 - 7.63 (rn, 1H), 7.50 id, J-8.80 Hz, 1H), 730 (s, 1H), 6,80 (d,/ 9.9 Hz, 1 FI), 537 (s, 2H), 4.23 §, 1H). 1 JOS. Synthesis of /V-(4“bromO“3*(1H~l,2i4-tiiazol”S-yl)if8iophen~2~yl)-2~(6~ methyIimidazoi2}1“h]tMaz0l"3-yi)acetamIde [00514] The title compound was synthesized from 2--{ 0-H3eihy!imidazo[2s 1 ~ b]thiazol»3-yl)accrie acid and 4~bromo-3~(lH-ls2}4-triazoi-5-y])ihiophen~2~amine according to protocol A. Retention time (min) = 8.520, method [6], MS(ESI) 423.0 (M+H); lE NMR (300 MHz, CD3C1) S 8.12 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.0 (s, 1H), 4.15 (s, 21:1), 2.50 (s,3H). 1J06. Synthesis of N“(44>romo~3~(Iif~l,3,4“iriszoi“5~yl)tMophen~2~yi)~2" (imidazo ] 1,2-aJ py ridiu“5-yl)aeet&amp;mide

Λmi-Butyl 2~{{mM4iz&amp;iL2^pyridin~5-yl}ac(rtaie 1'OOSlSi The title compound was prepared from 5-hrorammidazo[l 52~8|pyridMe (1.0 g) according to protocol Pi The crude product rpixtisre was purrfied via normal phase chromatography to give· ten-butyl 2-(i;rudaao[J J-alpyrihiin-S-ynacetam Methodjf 1 j. MS(EST) 233.1 fM >H], Retention time - 0.951 min. 1J&amp;6.2, ?-{Imidazofl,2--ii/p}ridm~5~)i}aa^cacid F00516] To a stirring mixture of tert-butyl 2-(imida2x>[l,2-a]pyridin-5-yf)acetate (200 mg) in HOAc (5 mL) was added 6N HC1 (5 mL). The reaction mixture was warmed to 80 "’C for 2 h. The crude product mixture was concentrated under reduced pressure and directly taken to the next reaction without further purification. Method[l], MS(EST) 177.1 [M+Hj, Retention time::: 0.303 min. Ι.ΐθά.3. N-(4-Brt?m{?~3~(JII~l,2!,4~tri(iml-5~yi)tkwpken~2-yi)~2-(ifflidaz®fli2~®jpyti(iw- S-yl)acetamide [0Θ5171 N-(4-bromo-3-(lH-l ,2,4-triazol-5"yl)thiopben~2~yl)'-2-(iimdazo[l ,2~ a]pyridin-5-yl)acetamide was synthesized from 2-(imidazo[ 1 ,2-a]pyridin-S-yi)acetic acid and 4-brorno~3--(l Η-1,2,4-triazo; -5-yl)thiophe.n-2»ami no according to protocol A. Retention time (min) - 7.958, method [6], MS(ESi) 403.0 (M+H); }H NMR (300 MHz, CDsOD) δ 8.46 (b s, 1M), 8.3S (d, Jm.::2.2 Hz, 114), 8.12 (d, J- 21 m, 1H), 8.08 - 7.96 (in, 214), 7.58 id, J = 7.2 !Iz, IB), 7.16 §* 10),4.64 (s, 2H), I..107. Synthesis of AT-(4-bronu>~3-{l/f-l^!,4-triazol-5-yi)thiophen-2-yl)~2-<7-fluoro- 2-osi>-g-(trli1uoromethyl)qulnolIn~l(2ff)-yl)a£etainid£

1. 2 ¢7../, 2~Brmw~5^m}ro^~{Mfimremeihy2)amii?ie [005t8| Ίο a stirii«| mixlie bf3-flUoro^kifiuoromefoyl)annme (1.5 $m. DCM (12 mi.) at room temperature was added dropwi.se· a solution of MBS fi .5 g) in DCM (24 mL) over 15 min. The reaction mixture was stirred at rt for 1.5 fa. The product mixture was concentrated under reduced pressure to one half of its original volumn. The white solid was filtered off and the crude product mixture was further purified via column chromatography. Retention time (min) = 2.490, method [1J, MS(ESI) 257.9 (M+H). L 107.2. (E)~£tkyl 3-{2^mm&amp;-4^mmt~5~ftrifimr&amp;metkyl)pheii.yl)acrylat.e [¢0519] 2~Bromo-5"fluoro-4-(tritluoromethyl)anifine (0.97 mmol) and P(o~toi)3 (0.40 mmol) were dissolved in methyl am me (2.0 ml.) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 minutes. Ethyl acrylate (1.0 mmol) and palladium acetate (0.20 mmol) were added to the reaction mixture and the tube was sealed and placed into an oil bath preheated to 85 °€- for 18 k The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min) ~ 2.504, method [.1 ], MS(ESI) 278.0 (M+H). 1.107.3. 7~Fiuom~6~{t?i£tte?omeih}l}qukwim~2(iB)~&amp;m [00520] To a stirring mixture of (E)-ethyi 3~(2-amino~4-fluoro~5-(trif1uoromeihyl)pfaenyl)acrylate in 4N HC1 in dioxsne (10 mL) was added concentrated HC1 (2 mL), The resulting mixture was warmed to 100 c'€ overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCGb solution until pH > 7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time (min) = 1.887, method [1], MS(ESI) 232.0 (M+H). L107.4. Methyl 2-{7"fhi&amp;m~2~(m0-4>--(Mjhwn>meihyl)quinolm~2{2M)~yi)acelMte [00521] The title compound was prepared from 7-fihoro-6-(tnfiuoromethyi)qumolin-2( 1H t one (T. Sakamoto, Y. Kondo, H, Yam&amp;naka, Chinn.

Phan Bull., 33, 1985,4764) according to protocol Eh Retention ilrne (min) = 2,224, method [I], MS(ESi) 304.0 (M+H). 1.107.5 2~{7~Fimm}~2-oxo~6-{iriflum0methyi)qmneUn~l(2H)~ft)metic sdd :p§22| To a sHtring solution of melhy! methyl 2-(?-fiuoro-2~oxo-6-(irefiuorornethyi)qusrsolin-1(2HVy I)acetate (0.59 mmol) in THF/waier (5:1) was added L1.OH.H2O (3.0 mmol). The resulting mixture was stirred overnight. The crude product mixture was slowly acidified with IN HC1 solution and then extracted with EtOAc. The organic phase was separated, dried (MgSO*), filtered, and concentrated under vacuum to give 2“(7-fiuoro-2~oxO”6-(lrifluoromethyi)quinoiin“l(2H)~yI)acetic acid. Retention time (min) - 1.90, method [1], MS(ES1) 290.1 (M+H). 1.107.6 N»(4-Br&amp;ffi&amp;~3~{IH~l)2,4~trwz®i-5-yi)tki&amp;pheH-2-y$)-2-{7-Jimr0~2~0xo~6- [005231 N-(4-hromo-3-(lH-i,2f4-tria2ol-5-y3)thiophen»2”yi)-2~(7~fluoro~2~oxO" 6^trifluoromethyl)quinoIin-l(2H)-yl)acetamide was synthesized from 2-(7-iluoro~2"Oxo- 6-{triiluoromethyl)qmnolin-l (2H)~yl)acctic add and 4-bromo-3-(i//-.l,2}4~ttiazol-S-yl)dtiophen-2-amine according to protocol A. Retention time (min):::: 6.276, method [7], MS(ESi) 516.0 (M+H); lH NMR (300 MHz, DMSO-ufe) δ 8,54 (b s, 1H), 8.37 (d, J = 8.24 Hz, JH), 8.20 (d, J= 9,34 Hz, 1H), 7.89 (d, J= 13.72 Hz, 1H), 7.31 (s, 1H), 6,81 (d, ,/- 9.34 Hz, 1H), 5.28 (s, 2H). 1,108. Synthesis of A~f4~bromo-3-( 1 Η-1 ?2,4~triaK0l"5"yI)thlaphen~2~yi)"2-(6- fln§roisoi|oinoiin-S-yl)acetamic!e

L168.1 5~Brrtmo--6-fiuoroh&amp;qimwttms [005241 To a stirring mixture of 6-fiuomisequinoime in lijSO,, (5 ml) at 0 °C was added solid NBS (1.5 fiQ) slowly over 5 min. The reaction mixture was reacted at 0 X: for 1 h. To this reaction mixture was added NBS (0.5 JEQ). The cold bath ’was then removed. The reaction mixture was reacted until all the starting material was consumed. To fitia reaction mixture was neutralized with a cold solution of MatOB (5N) unfit thepfl of this mixture >10. The white solid was filtered off and dissolved in DCM and washed with a solution of Na®H (IN). The organic layer was dried over MgSGti, filtered, and coaceMmtedmder-reduced pressure. Πιο crude product was purified via a column to g)vf J^bromo-fi-fiuoroisoqumolme, Retention time (min) = 2,BIO, method [3], MS (ESI) 226.0 (M+H). LI98.2, t&amp;rt-Butyi 2~(6~flu&amp;misoqmmim-5~yi)acetme [00525] The title compound was prepared from 5-bromo~6-iluoroisoquinoiine (290 mg) using protocol P. The crude product was purified via normal phase chromatography to gi ve tert-hutyl 2-(6-fluoroi.soqumoiin-5-yl)acetate, Method]!], MS(ESI) 262.1 [M+H], Retention time1.503 min. 1.198,3 2-{6~Fim)mm}qmmdm~5~yi}{iceUc acid [00526] To a stirring mixture tert-hutyl 2-(6rilnoiOisoqai;U.>iin-5-y'l)acctaic (150 mg) in HOAc (5 fflL) was added 6N MCI (5 ml.). The reaction mixture was warmed to 100 °C for 3 h. The crude product mixture was concentrated under reduced pressure and directly taken to the next reaction without further purification. Method[l]s MS(ESI) 206.1 [M+Hjs Retention time - 0,313 min, 1.1&amp;8.4* N~(4~Br&amp;mo~3-(IE~i,2,4~triaz,ol~S~yi)tkhphm~2~yi)~2-(6-0Meroisaqmmlm~S-yijacetamide [00527] N-(4~bromO"3“(lH“l,2,4-triazol-5-y!)thiophen-2-yl)~2“(6- fluoroisoquinoiin-5-yl)acetamide was prepared from 2-(0-fiuoroisoquinolin-5~yi)acetie add and 4-bromo-3-(1 /7-1,2,4-tria;ro!-5~y3)ihi0phen-2--amine according to protocol A. Retention time (min) = 1.901, method [7], M8(ESi) 432.0 (M+H); lH NMR (300 MHz, DMSO-rfe) , 11.96 (b s, 1H), 9.58 (s, 1H), 8.64 (d, J= 6.05 Hz, SB), 8,46 - 8,41 (m, 1H), B.24 (ds Jm 6.05 Hz 1«), 7,84 (t,./- 9.34 Hz, 1H>, 7.27 fs, III), 4.46 (s, 2Ht.

Example 2

Thiophene Thiazeie Analogs 2J. Synthesis of|”<Isoqwini}iin-5-yi>-A?"i2~(4~mei.ljiyIthia2oi~2»yI)thIophen 3-yl)aeetamldd (42)

2, LI 4~Methyi~2~(3~mt?i>thi{fpkeji”2-yi)thmz8ie [00528] 4-Melhyl~2~(3"iiitrothiopheH"2«yI)thiazole was prepared from 2-ehloro~ 3-mtrothiophene (219 mg, 1,34 mmol) and4-methyi-2-(tribuiylsiamyi)thjazole (520 mg, 1.34 mmol) according to protocol E. Retention time (min) = 2.462, method [1], MS(ESI) 227,0 (M+H), 2. /,2, 2-{4-Methylihmz&amp;i~2~fl)tkiophen~3~amme 100529] 2-(4-Methylthiazol~2~yl)thiophen-3-amiiie was prepared from 4-methyl-2-(3-nitrothiophen-2-y1)thiazole (69 mg, 0.305 mmol) according to protocol F. Retention time (min) = 1.828, method [I], MS(ESI) 197.0 (M+H), 2.L3, 2~{heqiiimtiin~5-}i}"ft"i2-{4-meikyitkiazjiti~2~yi}fMepkm~3~y$}acetttmide [00530] 2~(Jsoquinolin-5-yl)~A"(2-(4~methyithiazol"2“yl)thiophen-3-yl)acetamide was prepared from 2~(isoquinolin~5-yl)acetic acid (63 mg, 0.341 mmol) and 2-(4~methy!thiazol~2-yl)thiophen-3-amine (67 mg. 0.341 mmol) according to protocol A. Retention time (min) = 3.130, method [7], MS(ESI) 366.0 (M+H); !H NMR (300 MHz, CDC13) 6 11.55 (s, 1H), 9,64 (s, 1H), 8.60 (d,/= 6.8 Hz, 1H), 8.39 (d, ./-6.6 Hz, 1H), 8.20 (d, /- 8.4 Hz, 1H), 8.05-8.08 (m, 2H), 7.88-7.91 (m, 1H), 7,24 (d, J - 5.5 Hz, 1H), 6.74 (s, 1H), 4.31 (s, 2H), 2.45 (s, 3H). 3.2. :Syhthesls of^(%s^|Qinolin-5-yl)>lV>(2-(titiazol>4>’yl)thioplten>3>yl)iscetainide ¢41)

2.2. 1. 4-{3-Niir&amp;thi0phen~2~yi)ihkm^· [00531] 4~(3-NitrotMophen-2-yl)thiazG]e was prepared from 4-(tribetylsiannyi)thiazole (0.5 j g, 1.31 mmol) and 2~eMoro~3-mtroihiophmc (0.21 g, 1.31 Diffioi) according to protocol E. Retention time (min) " 2.012, method [I ], MS(£S1.) 212.9 (M+H). 2.2.2. 2~{Tkmwi~4~yl)thiopkm~3~amme |8ϋ3Ι| 2^hiai»l^yl.}thiopjhen-3"ararae was prepared from 4-(3-nitrothiophen-2-yl)thiazolc (151 mg, 0,828 mmol)) apeordijg to protocol f . Retaptfpa time (min) == 0.544, method [1], MS(ESi) 183.0 (M+H). 2.2.3. 2r(l$WHW0tt-5~yl)-N~{2~{thiaz&amp;l-4-yt)thiophea-3-yl)acetami(ie [00533] 2.-(isoqmnolin-5-yl)-jy~(2~(thiazoi-4-yl)thiopheii-3-yl)aceiamide was prepared from 2-(isoquinolin-5~yl)aeetic acid (120 mg, 0.641 mmol) and 2-(thiazol-4-yl)thiophen-3“amine (117 mg, 0.641 mmol) according to protocol A, Retention time (min) - 2.147, method [7], MS(ESI) 352.0 (M+H); *H NMR (300 MHz, CDCi3) δ 10.99 (s, 1H), 9.63 (s, 1H), 8.59 (d, J= 5.9 Hz, 1H), 8.43 (d,./ = 1.6 Hz, 1H), 8.23-8.42 (m, 2H), 8.04-8.08 (m, 2H), 7.90 (dd,./ = 8.1, 7.2 Hz, 1H), 7.18-7.23 (m, 2H), 4.31 (s, 2H). 2.3. Synthesis of 2-(2-Ox0-3,4-dih¥dro-l,6~naphihyrldln~l (2H)-yl)-A'-(2-(thlazol-4-yl)thlophen-3-yl)aee4ainlde(44)

23, L MeMif!2~(2~ex<i~3,4-dihydr(>~l/^miphthyridm~l{2Hyyi)^ceiate [00534] The title compound was prepared from 3,4-dihydm-1 ,?S-msphihyridm-2{l//)-onc (0.84 g, 5,67 mmo!) using protocol K to give -methyl 2-(2 -oxo-3,4«d:hydro-l»6-na.phthyridin-l(2H)-yl)acetate. Retention time (min) = 0.341, method [1], MS(ESI) 221.0 (M+H). 23.2, 2-(2~Oxo~3i4~di^ydro~J>6~naphthyridin.-l(2li)~yi)uc^iC acid 100535] Aqueous IN HCI (2 mL) was added to ^solution of methyl 2-(2-oxo» 3,4-dih.ydro-I ,6~naphihyridm·1 (2//)-y[)acetate ¢1.24 g, 5J7 mmol) m acetic acid (5 mL) and the resnltffig mixture was heated to 60 °C for 4 h. The solution was concentrated under vacuum to giye 2^241i@^3i4^ydK^ls6^pMiyadm-1 (2//)-yl)a«eiic add. RetentioUita(mm) * 0.27¾ method [1 ], MS(ESl) 207.0 &amp;3&amp;. 2-{2~Oxo333iihydm-2f6-mphthyridm-l{2H)~yi}~N~{2~{tkwztd-4-y$)thwphm~· 3»yi}&amp;eetmnide |'0(IS36| The title compound was prepared from 2-(2-oxo~354-dihydiO-l,6-naphthyridin-I(2//)-yl)acetic acid (65 mg, 0.32 mmol) and 2-{thiazol-4-yi)tbiophen-3-amine (57 mg, 0.32 mmol) according to protocoi A. Retention time (min) = 1.471, method [7], MS(ESI) 371.1 (M+H); *H NMR (300 MHz, CDCI3) δ 11.48 (s, IH), 8.87 (d, J- 1.8 Hz, IH), 8.48-8,76 (m, 1H), 7.99(4 5.4 Hz, IH), 7.37(4,/=1.8¾ 1H), 7.27-2.28 (m, 2H), 7.23 (d,J~ 5.4 Hz, IB), 4.91 (s, 2H), 3.20-3.25 (m, 2H), 2.96-3.01 (m, 2H). 2.4. Synthesis of 2-(2-»xo-3,4~d!hydriMpimolln~l(2/7)~yl)-jV-(2-(thi8zoi-4-yl)thiophen”3-yI)acetamlde (45) [00537J Theiitte compound was prepared from 2-(2-oxo-3,4-4hpl3^UmoIin-l(2H}-yi)aeetic add (88 mg, 0.43 mmol) and 2-(thiazoi4-y1)thiophen-3-arnine (79 mg, 0.43 mmpl) according to protocol A- Rctenhbp time (min) = 5,703, method [ 7], MS(ES7) 370.0 (Mi H); lH KViR (300 MHz, CDCIrJS H.2(s, 1H), 8.49 94·/= 2.7 Hz, IH),8.L3 (4 “ 5.4 Hz. IH). 7.19-7.25 (m, 4H), 7.02-7.08 (m, 2H), 4.81 (s, 2H),3.05-3.09 (m, 1Ι|1Ιΐ85-2.8|:|η5 2H>. 2,5, Synthesis of 2“(isoqaint?Un--5"y!VAf-( 2-{2-metho.mhi&amp;zaI~4 s I)thiophen~3~ yl)sseeiaKii«!e (46)

2, xL 2~Methoxy-4-{3-mtr®thwphm~2~pl)tkiaz&amp;ie [06538] 2~Meihoxy-4-(3miirothiophen--2-yi)thiazGle was prepared from 2-meihoxy~4-{tributyIstannyl)liaa2;ole (1,0 g, 2,47 mmol) and 2-cfiloro~3"Hitrofhiopiione (0.404 g, 2.47 mmol) according to protocol E, Retention time (min) = 2.516, method [1], MS(ESI) 242,9 (M+H). 2,5.2, 2-(2-Meihoxytkm’mt-4-yl)thiopken~3~&amp;mme [Θ0539] 2-(2Rvfstbx)x>thiaroi"4yi)tb!opb.eii-3-arnme was prepared from 2-methoxy-4-(3mitrotMophen~2~yi)lhiazole (209 mg, 0.862 mmol) according to protocol F. Retention time (min) = 1.17, method [1], MS(ESl) 213.0 (M+H). 2.5. A 2-(Imqmtf®iin~$-yl)~N~{2-(2-methoxyihiaz&amp;i~4~yl)tkk*pkeM-3-yi)acei&amp;miie [00540] The title compound was prepared from 2-(isoquinolin~5~yl)acetic acid (72 mg, 0.36 mmol) and 2-(2-mcthoxylMazol-4yl)iMophcn-3-amine (78 mg, 0,36 mmol) according to protocol A, Retention time (min) = 3.237, method [7], MS(ESI) 382,0 (M+H); lH NMR (300 MHz, CDCfr) 8 10.99 (s, 1H), 9.69 (s, 1H), 8.60 (d, J= 6.5 Hz, !H), 8,39 (d, /= 6.5 Hz, IB), 8,23 (d,/ = 8,4 Hz, 1H), 8.06 (d, /= 7.3 Hz, 1H), 7.96 (d, /=5.5 Hz, 1H), 7.89 (dd,/= 8.4, 7.3,1H), 7.35 (d,/= 5.5, 1H), 6.70(¾ IB), 4:,26(¾ 2H), 4.17 (s, 3H). 2.6. Synthesis of A?~(2~(2»ehtarothiazol‘4“y1)tMophen-3yyl)42"{l§oquInelm-5" yQacetanride (47)

2. 6. 1. 2~€hloro~4-0~mtrQtlmphen~2-yl)ikiazfHe 108541] A solution of 2-'methoxy“443-nittot!iiophen-2“y[}ihiazo!e (403 rog, 1.66 mmol) in POCi? (2 mL) was heated at 60 °C for ! b then to 100 °C for a farther 2 h. The resulting solution was cooled to room temperature and diluted with cold %G then saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride add the combined organic phases were dried f^SCM, llisred ami concetrtrated under vacuum to give 2><Mo^^3-mtrodnaphcn>2%y!)ddazok. detention time (imtym 2.550, method [1], MS(ESI) 246.9 (M+H). 2.6.2. 2-(2-Chforothiaz&amp;l-4-yl)iklophm~3~aMine [08542| 2~(2~Chlorothiazo!-4-yi)thiophen-3~armne was prepared from 2-chloro- 4-(3"mtiothiophen-2-yi)thiazole (307 mg, 1.24 mmol) according to protocol F, Retention time (min) - 1.579, method [1], MS(ESI) 216.9 (M+H). 2.6.3. N-(2-(2-ehioroihMZ0l-4-yl)thi0pken~3-yt)-2~(i$oquin0Htt~5~yi)acetamide [00543] The title compound was prepared from 2-(is0qmnolm-5-yl)aeetic acid (218 mg, 1.11 mmol) and. 2-(2-chi orothiazol-4-yl)thiophen~3-amme (241 mg, 1.11 mmol) according to protocol A. Retention time (min) ~ 3.049. method [7], MS(ESI) 385.89 (M+H); (H NMR (300 MHz, CD,OD) δ 9.54 (s, 1H), 8.56 (d, / = 6.4 Hz,1H), 8.39 (d, J - m Hz, 1H), 8.31 (d8.1 Hz, 1H), 8.16 (di; J= 6.8 Hz, 1H| 7.94 (dd,/ = 8.1, 7.1 Hz, 111), 7.73 (4/= 5.5 Hz, Hi), 7,45 (s, 1H), 7.37 (4/ = 5.5 Hz, 1M), 4.39 (s, 2H), 2.7; Synthesis of 2^Ι^ι^ηοΒη-5^Ι>Ν^2~(«ϋ>^3^2^)ΐ||^|^3···^|ι«^8ΒΒΐιΐ6 m

2.7J. 2#^hz^2^)th^keH-}^amine [00544} 2-(3“Njiioihiopiico~2-yl)thia2:oie was synthesized from 2~ch!oro-3-nitrothkrphcnc according to protocol E except that 24inbuiy;siannyl)duazole whs used. Method];! ], MS(ESI) 212.9 [M+Mf, Retention tint® «2,163 min. 2-n hiazoi-2-yi)tWe||ien-3~atMhe was synthesiaed from 2^-iit«yihtophen»2-yl)thiazole according to protocol F. Method[1 ], MS(ESI) ill [Mh-H], teteauon time = 1.718 min. 2.7.2. 2~(ls&amp;qum&amp;Un-S~yi)~N~(2-(ikm^i~2~y'i)thiophm~5~yi)aceiimide [00S45J [0004] The title compound was prepared from 2--(thiazol-2- yl)thiophen~3-amine and 2-(isoqumQiin-5-yl)aeetie acid according to protocol A. Preparative HPLC gave 2^isoqvunolin-5-yl)-N-(2-(thiazol-2-yl)diiophen-3-yl>ceta£nide. Method[7], MS(ESl) 352.1 [M+HJ, Retention time - 2.59 min; JH-NMR (300 MHz, (»3)611.32(8,1H); 8i26 (d, J= 8;2 Mr, IB), 8ΗΘ- S;09(m 111), 8.07 (a, 1H), 7.94 (t,/= 7.7 Hz, 1H), 7.35 (d,./- 3.3 Hz, HI), 7.31 - 7.24 (¾ 4H), 7.1|(d, J- 3.3 Hz, l%4.33(s,IH). 2.8. Svfithesisof2-(isoqnmi>lin-5-y!)~AK2~(S-raethylthi3izol-2y!)tl3lyphen-3-yS)acetamide (49)

2.8.1. 2~^MethyMMau^2^i)thmphemB~amin€ 1005461 This amine was prepared ibom 2-eh3oro-3-nitrothiophene using protocols E and F. Methodf 1 j, MS(ESI) 227.0 [MtH}, Retention time - 2.538 min. 2.8.2. 2~(i$equim)im-$~yl)-N42-{5-metkyItkwz®i-2~yi)tk^km~S-}i}aeeiimiide 100547) The title compound was prepared from 2 fl>!oquir!o!ir!-5-yl}acedc acid am 2-(5-methyithia2:ol~2-y}.>thiophen«3“amine using Protocol A:. Method;'?], M8{EST> 366,01Μ·:·Η ], Reteniion time =3.157 min, !B-NMR (300 MHz, CDCR) δ !! ,24 (s, IK;, 9.67 (s, Ml), 8 J7 (d, J- 6:6 m, 1H), 8.30 (d, 6ift, Ml),; 8.26 (§, /= 8.24 Ife, 1H), 8.08 - 8.04 (m, 2H), 7.96 - 7.9! (ms 1H), 7.20 (d,J - 5.5 Hz, 1;H), 6.97 (d,/= 1.1 Hz, Ml), 4.31 (s. 2H), 2.43 (4/- U Hz, 3H). 2,9, Synthesis of 2-(4-(3"(piperklio-HyI)propos:y)plii;oj4)~A-(2-( y!}thlophen-3-yl)scef amide (50)

2.9.1. 2~{Thiazai-4-yi)thii?phefi~3-((mme [O0548] This amine was prepared from 2-ehl oro-3 -ni UoiMophene using Protocols E and F except that 4-(tribut>'istannyi)thiazole was used. Metbodp ], MS(ESI) 183.0 [M+H], Retention time = 0.518 min. 2.9.2. 2~(4~(3~(Piperi$n-2-tf)prop&amp;x})pkmyi}~N^2~{ihiag&amp;!~4~yi)thwpkm-3-yi)o£etamide [Θ0549] The title compound was prepared from 2~(thiazol-4-yl)thiophen-3-amiae and 2-(4A3^lperyin-l-yl)propoxy)pheiiyMacetic acid using prxitecol X* Method[7], MS(ESi;) 442.1 [M+H], Retention tkmm 3.586 rain; ®Cti 5 10.8 (s, Iff, 8.54 - 8.53 (m, IH), 8.13 - 841 (m, 1H), 7.33 7.30 (m, 2H), 7.25 ~ 7.17 £m, 21¾ 6.# (4 /= 1« Hz, 2H), 4*08 (1,/-4.95 Hz, 2H), 3,74 (m, 31% 3.28 ~ 3:21 (m, 2H); 2.72 - 2*61 (at, 2H), 2.40 - 2.20 (m, 6H), 2*05 - 1.91 (in, 31f. 2. Ml %stthesisof/V-(3-(fesnzo[d]thiazol”2~yl)-4-methyltliiophen~2-yl>-2·· (isoq5iincilln~5~yl)aeetnmlcle (51) [00550] The title compound was prepared from 2-(isoqnitiolin~5~yl)acetic acid and 3"(benzo| d]th?a:Oi-2-yl)“4~n).ethyWiiophen-2~aminc using Protocol B except that tifothyiamine wasMso ^Meds MS(ESfj4lii0 fM+H| Retention time = 2,86 min; }H-NMR (300 MHz, CDCI3) 5 9.40 (s, 1H), 8.57 (d. J= 6.04 Hz, 1H), 8,10 - 8.07 (m, 2H), 8.0 (d, /= 6.6 Hz, 1H), 7.90 ~ 7.88 (m, 1H), 7.83 - 7.77 (m, 1H), 7.71 - 7.68 (m, 1H), 7.55 - 7.51 (m, 1H), 7.42 - 7.37 (m, 1H), 6.56 (s, 1H), 4.39 (s, 20), 2.56 (s, 3ΙΪ). 2,11, Synthesis of Ar-(4-eyano-3-(thla®ol~2-yl)iljlophea“2“yl)~2-(2“OXO“6~ (trifisorooi®ithyl)i}ii5noliii-l(2//>-yI)aeetamiile

2i 2 711. (E)~Etky$ $-(2-mii&amp;t&amp;-5~(tnftuoromeikyl)phmyl)ecryiate (005611 To s mixftife Of 2-bromo-4*(trif!uoKHnethyl)aniliE)c (5g, 20.83 mmol), trieihylamifle (4.4 mL, 31 ,| mmol) and Pio-tol); ¢2.5 g. 8.33 (nmol) in DMF (42 mL, 0.5 M) in a glass pressure tube under nitrogen gas were added ethyl acrylate (2.3 g, 23 mmol!) and palladium acetate (940 mg, 4.167 inmol). The tube was scaled and heated to 3 20 °C for 18 h. 'The resulting solution was concentrated under vacuum and purified by column diron&amp;tography. Retention time(min) = 2.532, method [1], MS(ESi) 260.1 (M4-H). 2„ IL 2. 6~{lnfiiiort}miithyl)qmn{dm~2(Hl}~me |(H)S52) To a stirring mixture of (EVeihyl 3“(2-amihp-5-(trifluorometh>d)p&amp;eny!)acrylate (4g, 15,4 mmol) in 4N HCI in dioxane (20 mL) was added concentrated HCI (3 mL). 'The resulting mixture was warmed to 100 °C overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated MaHCOa solution until pH > 7. A norma] aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time(min) - 1.849, method [1 ], MS(ESl) 214.0 (M+H). 2.21.X Ethyl 2-{2~!)X£-&amp;-fiE0m)r&amp;methyt)qmmiin-l(2E)~yl)acetute [00553] To a stirring mixture of the above crude 6-(trifluoromethy3)quinolin-2(lH)~one in DMF/THF (0,5 M, 1:1) at rt was addedNaH portionwise (1.2 g, 30.88 mmoi|o¥sr 15 min, file reaction mixture was stirred at it for additional 20 min before a solution of bromo methyl acetate (4.73 g, 30.88 mmol) in T1IF was added. 'The resulting mixture was stirred at rt until the starting material was consumed. The mixture was slowly quenched with brine and extracted1 withEtOAc, The crude product mixtfre was purified by column chromatography (3.6 g„ 82% in two stepsl &amp;etentfon time (min) 2.04¾ method [i], MSpS® 286^ (M+H). 2.1L 4, 2~{2~Ox(}~6~{tnfluor0methyi)qmmim~4{2M)-yi}acetic acid [00554] To a sStirring solution of methyl 2~(2~oxo*6-(trifluoromcthyi)qninolffl~ 1 (2H)-yl)aeetate (4,8 g, 16.8 mmol) in THF/water (25 mL/5 mL, 5:1) was added LiOH-HfeO (3.52 g, 84.2 mmol). The resulting mixture was stirred overnight. The crude mixture w'as slowly acidified with IN HC1 and then extracted with EtOAc. The organic phase was dried (MgSGy), filtered and concentrated under vacuum to give 2-(2-oxo~6~ (irifluoromeihyl)quinolin-l(2H)-yl)acetic acid (4.3 g). Retention time (min) = 3.005, method [7], MS(ESI) 272.1 (M+H). 2,1L S. $-Nit?o~4~(ihimtd~2~yi)thksphgm-3‘-mrbtmiirile [00555] A mixture of 4-bmnTO-5mitrothiophene-3'-carbonitrile (0.5g, 2 Jmmol), 2d’tributylstaunyl)tMazole (1.2g, 3,2mmol), dioxane (3.5mL), and tetrakis(tripiienylphosphine)pailadinm(0) (0.23g, 0.21mmol) was heated by microwave to 130 °C for 30 min under nitrogen. The reaction mix was concentrated under reduced pressure, and the resulting dark oil was purified by column chromatography using a mobile phase of 20% EtOAc/hexanes to give 5-mtro-4^(ihiazol~2-yl)thiophene-3-carboaitrik (180mg) as an oil. LCM5 of this material revealed an m/z of 238:0 with a retention lime of 1.807min method [1] 2, lh ft 5-Amino~4-(ihM%ol~2-yt)thi&amp;pheiie~3"Cefb&amp;nitriie [00550] A 30mL reaction vial wm ehaj^dd with 5~nitro~4-(thiaK>l-2-y llthiophene- j'-carbonil fiie (180mg, 0.76mmol) and AcOIi (3mL·). A spatula tip of iron dust was added and the reaction via) was heated to 6@ °€ for 20min. The reaction mixtare was cooled to 23 °C and parfifiondd between methylene chloride and sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated to give 5-amhio-4-{thiii2c-i-2 yl}fhiopbcne- 3-carbonitri]e as a red solid. LCMS showed an Wz 01208.0 with a retfeatim time of 2.0f6min using method [1|, 2» M 7. M~(4~Cym&amp;~3^him&amp;l~2-)4)ikmpiim~2-}ti)~2-(3~i}M~6-(ttipsmremethyl}qmm}Un~l(2H)~y4)meiamide [¢0557] [Θ005] The title compound was prepared from 5-ammo-4-(thiazol· 2-yl)thiophene-3-carbonitrile (271 mg, lmmol) and 2-(2~oxo~6~(trifluoroniethyl)qi:ii-ti>im·-l(2H)-yl)acedc acid (0.76mmoi) according to protocol A. Tire crude product was purified by column chromatography (35%EtOAc/hcxa©es) and HFLC to give N-{4-cyano-3~ {thiazol-2”yl}ihiophen.-2-y?}-2-(2~oxO"6-(trii']uoroniahyl)quinohn-l(2H)”yl)acetaovidc (24.mg) as a white solid with an m/z of 46.1.1 and retention of 7.348min using the [7] LCMS method, 'H-NMR (300MHz, CDCh) δ 13.21 (s, 1H), 7.93 (m, 2H), 7.86 (dd, ,/=8.9,1.8Hz, 1H), 7.58 (s, 1H), 7.54 (d,J=3.4Hzs 1H), 7.46 (4^8.8¾ 1.H), 7.31 (d, ,/-3.3Hz, 1H), 7.00 (d, /=9.61-¾ IE), 535 (s, 2H). ,3C-NMR (75MHz, CDCh) δ 165.3, 161.7.161.0, 140.8, 140.0,139.9, 129,4, 128.0, 126.5, 122.7, 120.4,117.8, 115.9,115.0, 114.7, 106.0, 46.3. 2.. 12. Synthesis of A-{4~eyaK#-3~(tyazoi-2-yi>tIriophen-2-5l)~2-(2-0:xG~3,4-dihjdro-1 A-naphthyridhs-i (2/#)~yl)acetasi8ide

[00558] The title compound was prepared from 5-amino-4-(d}iazol>2· idPriopherte-BaKH^EmMIe (6lmg, 0.32mxnoi) and 2-(2-oxo-3i4-dihydro“1.5~ !3aphthyridm^l(2MHyl)aeetic acid (10Omg, 0.48mmoi) according to protocol A. The crude product mm phified by column eluf tnatography (2%methano3Anethyi®ie chloride) and $P$£ to give 14-(4-eyauOi3-(thia2ol-2-yl)thtopheii-2-yl)-2-(2-oxo-354-dihyd«)-l,5-oapbthyridk-l(2H)-yl)acetamide (5.4mg s as a white solid. LCMS m/z 396. L method [7] retention time 2,611mm. Ή-NMR (300MHz, CDCfr) δ 8.39 (d, JM.lHz, 1H), 7.76 (4 •M.3SZ, 2Η), 7.62s|| 1 .Η), 7.58 (d, 7.4Hz, 1H), 7.44 p, 2H), 3.46 §, ,/-7. ίHz. 2Π), 3,02 (i, J:::7,2Hz, 2H),

Synthesis ofJV^4>bromo>3-(th!aasol>2-yl)thtoph«n-2~g||H2^-oi!^3^Mihyi|:i|!hl^ n&amp;phihyrklks-1 {2H}~yl)%cMmnkh

2.133. 2~{4’Β?θ&amp;β~2~ηϊί?#ί&amp;ΗψΗβΗ~3-}ϊ}ίΜαζ{?ί# [00559J A mixture of 3.4-djbrorno-2mikoiha^h€ae (242mgf G.SSmmof), 2-(mhiiityistp.nnyl)thiazole (3I5mg, 0,84mraol), Pd/Ph??)*. catalyst (194mg, O.ITmmol) and dioxane (0.9mL) was heated in the microwave to 130 °C for 25min. The reaction mixture was diluted with EtOAc and filtered to remove solids. The remaining organic solution was washed with saturated, aqueous solutions of sodium bicarbonate and salt before drying over sodium sulfate. The organic was concentrated under reduced pressure to give a dark oil The crude product was purified by column chromatography (30%EtOAc/hexanes) to give 2-c4-bromo-2-m'trothiophen"3-yi)thiazole (210mg). LCMS m/z of289,1 /291.1 with a retention time of 2.043mm on the [1 ] method. 2.23.2. 4-Bmm&amp;-3‘(thwz@l-2~}2)ihk*phen~2~amme 100560] The title compound was prepard from 2-(4-bromo-2-nitrothiophen-3-yl)thiazole (120rags 0.4] mmol) according to the procedures of Example 2.11,6 to give 4~ bronio-3“(thia^ol-2~yl)thiophen-2-amine as a dark residue (90mg). LCMS m/z of 260.9/292.9 with a retention time of 6.0O3min in the [7] method. 2.133. N-{4-Er0mo-3~{tkmzoi~2~yi}thmphen~2-yl)~2~(2~ox0~3f4~dihydr0~ltS~ m4phthyrsiim3(2H}--y!}m^amide [00561] The title compound was prepared from 4-bromo-3-(thiazol~2-yl)thiophcn-2-amine (90mg, 0.35mmol) and 2^2^xo«3,4-dihydro-l ,5-n^hthyridin-l{2H)-yi)aeetic acid (lOSmg, 0.52mmol) according to protocol A. The crude product was purified by HPLC to give .Y-(4-bromO“3-(thiazol-2-yl)thbphen--2-yi)~2-(2Hjxo-3s4-dihydrO“lJ5-‘naphtiiyridin~l(2/?)~yi)acetamide (24mg) as a white solid. LCMS miz 449.0/451.0 and retention of 4.019min using method [7]. Ή-NMR (300 MHz, CDO3) 6 8.39 (d, /-5.2Hz, 1H), 7:76 (d, J-3,3Hz; IB), 7.70 (d, J=8,3Hzs 1II), 7.51 (dd, /=8.4,5.3Hz, 1H), 7.34 (d, /-3.4, 1H), 6.94 (s, J.H), 4.09 (s, 2H), 3,49 (t, /-7.2Hz, 2H), 3,00 (t, /=7.2Ηζ, 2H). 2.14. Synthesis 0f N-{4~ch lere-JTlhi azo b2-yl)thiophen-2«yl}~2-(2-oxo~3,4« difiydro~l,5~usp!itliyrldis-l(2//)~yl)aeetafflicle

ZMJi 2~(4~€hlorm^mitfothiophm^3~yl)tkmmte |00562| A mixture of 2/'i-bromo-2-«iUx>thiophen~3~y])thiazok· (J20mg, O.dltfflaal). CuCI (240mg) in dioxane (l.SpL) and 5 drops of DMF was heated to 110 °G fbr Ih by microways. The reaction mixtum was dihttsd with EtOAc and washed with saturated^ aqueous sodium bicarbonate and brine before drying ovSt sodium sulfate. It was concentrated under reduced pressure to give 2-(4-di3croJimiirothiophen-3~ jd^thiamie as a yellow residue (lOOmg), TCMS m/z of 246.9/249.6 with a retention time of 3.994min on the [7] method. 2,14.2« 4~€kUmi~3~(thmzol-2-pi)ikfaphen~2~®ffiim I00S631 The title compound was prepared from 2-(4-ehIoro”2-nitr-oihiophen“3-yisihnmole (100mg, Q.4romoi) according to the procedures of |xample2.l 1.6 to give 4-chioro-3-(tltiazol-2-yi)thiophen- 2 amiue as a dark residue (90mg). LC'MS m/z of 217.0/218.9 with a retention time of2.426τηίπ in the [1] method. 2.14.2« N-{4~Chhro~S~{thim.(4 2-\4)tkif.}phim--2~yl}~2~{2~(>x()~3f4~iikpdm-i>S-mpk^yriifm~l(2II)~)4}ecei(imiiL· {00564] The title compound was prepared from 4-cMoro-3-ahiaaol~2-yl)thiopheiw2~amine (O.dmMei) and 2 ·{ 2-oxo-3,4-dihydro- {J-naphlhyridin-1 (2H)~ yl)acetie acid {16Smg, 0s8tnmol) according to protocol A, The erode product was purified by column chromatography (4% methanoL'methylene chloride) and HPLC to af&amp;rdN-(4-chloro-3-(thiazol-2-yi)t3iiopheQ-2-yl)-2-(2-oxo-3,4-dihydro-l,5-naphihyridin-1 (2H)-yi)acetamide (2,lmg) as a white solid. LCMS w/z of 405.1/407.1 and retention of 3.670mk using the [7} LCMS method. lH-NMR (300MHz, CDC13) δ 8.36 (d, /-4.9Hz, IH}, 7,71 (d,>3.4Hz, 1H), 7.57 (d5 >8.1Hz, IH), 7.42 (dd,/=8.1,5.1Hz, 1H), 7.36 (d, >3.4,1H), 6.82 (s, 1H), 4.92 (s, 2H), 3.44 (t,>7.1Hz, 2H), 3.01 (t, >7.1 Hz, 2H). 2.15, Synthesis ofiV-(4-ehlorO”3~(thiazoI-2-yl)thiophen-2-yl)-2-(8-(trlfl«oronieihyl)q«inoHii-5“yI)aceteinltle [00565] The title compound was prepared from 4-chIorO“3-(lH~l,2,4-triazol-5-yl)thiopltp^-sp|pe (150mg, |.75ρϊοιοΙ) an! 2-(8-(triflui^in^hyi)qmBolm''5~yl)aeete acid (148mg, 0„58mmol) according to protocol A. The crude product was purified by column chromatography (35%EtOAc/hexanes) to give N-(4-cMoro-3~(thiazoi-2-yl)thiopheo-2-yi)-2-(8-(trif!uoromethy1)quir5oSin-5-yl)aeetarm'de (35mg) as awhile solid. LCMS m/z of 438.1/440.1 and retention of 5.789mln using the [7] LCMS method, lB-NMR (300MHz, DMSO-d6) δ 9.06 (dd, >4.2,1.6Hz, 1H), 8.64 (dd,>8.7,1.6Hz, 1H), 8,26(0,/=7.6¾ IfI), 7.83 (d,>7.5Hz, 1H), 7,72 (dd,>8.6,4.2Hz, IH), 7.13 (s, 1H| 4.56 (s, 2H). 2.16. Synthesis of A-(4-cyano-3~(tlsiaz®l-4-yl)thsophen-2-yI)-2-(2-oxo-6-(trl0uoromcilsyl)qninolin~1(2ff)-yl}acetamsde

[00566] A Microwave via! equipped with a stir bar was added 4 brorno-5-mtrothiophene-3~carhonitrile (0.15 g, 0.66 mmole) and tetraMs(triphenyIphosphme)palladium (0) (0.077 g, 0.066 mmol) and then purged with. N? (g) inlei prior in addition of 4~(trihiiiyistannyi)thiazoie (0.42 g, 1,13 mmol), dioxane (1.2 mL) and few drops of DMF. The reaction mixture was heated at 110“C for 30 min and then, concentrated under reduced pessure. Purification by flash elnottiatogrnphy hn’Hea. 50:50 erhyi acetate/hexane) gave 5-nitro4-(tiM,azol4”>d)thiophene^|-carbonitrile (71 mgs. 45%) Retention time (min) =1.656. method [4], MS(ESI) 238.0 (Mr-H). &amp; /41 S"amm0~4/ihmze<L4~} hthioph^fi'-S’-carbiwiMJe Protocol Os |00567] To a solution of 5mirio-4-(thiaz0i-4-yi)thiophene~3~Garbonitrile (0.07lg, 0.31 mmol) in ethyl acetate (3 ml.) -was added tin (II) chloride dihydrate (0,29 gs 1.27 mmol). The reaction mixture was heated in an oil bath set at 70'C under condenser. After 20 min. the mixture was cooled to RT and concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-amino-4-(thiazol-4-yl)thiophene-3-carboniirtle (24 mgs. 38%) Retention time (min) =1.837* method [4], MS(ESI) 208.0 (M+H). 2.16.3. N~{4-Cymw~3~(ihiMZ8i~4~y!)tkwphen~2~yl)~2~(2~ox&amp;-'&amp;~ (tHfiM&amp;?0metkyl)qmmim-l{2H)yi)eeetamMe (00568] The title compound was prepared from 2-(2~om~6~ (trifluorometfey{)quinohn-1(2i/)-yl)acetic add (0.047g, 0.17 mmol) and 5-ammo-4~ (thiazol -4-y I)ihiophene-3-carbonitri!e (0.024g, 0.12 mmol) according to protocol A, The desired product was submitted to prep HPLC for further purification. Retention time (min) - 7.57, method [7],MS(ESI) 461.1 (M+H). 3ii NMR (CDCb) 6 12.73 (s, 1H), 8.60 (d, /-2.4 Hz, 1H), 8.14 (d,/=2.4 Hz, 1H), 7.92-7.89 (m, 2H), 7.89 (d, J = 9.3 Hz, 1H), 7.59 (s, 1H), 7.48 (d, /= 8.9 Hz, 1H), 6.96 (d, /= 9,3 Hz, 1H), 5.30 (s, 2H). 2.17, Synthesis of A-(4-cyano-3-(ililazuT5“y!)thlophen-2~yl)-2»(2-oxo-6- (trlllu®romethyl)quInolln-I(2ii)-yl)aeet&amp;nilde

Protocol Η; [00569] A microwave viai equipped with a stir bar was added 4-bromo-5-oit^ptMapheiie--2iCartenitnie (0.24 g, US mmole) and tetrald^ttifteimyifiii6s|^ine)pall®di^ (0) (0.14 g, 0.12 mmol), copper iodide (0 02b g, 0.15 rnmol) and then, purged with Nj (g) inlet prior to addition of 5-(tributyl;siannvf)fMazole 0).63 g, 1:.:67 rnmoi). dioxane (2.3 mL) and few drops of DMF.. The reaction mixture was heated at 110'C for 30 min and then cones?·trated under reduced pressure. Purifkatiori by flash chromatography (silica,, 40:60 ethyl acetate/hexane) gave 5mitrrv4-(&amp;la^.ol-5~yi)thiopheiiei3-carb(>mtriie (153 mgs, 61%) Retention time (min) --1.715, method [4], MS(ESI) 238.0 (M-f-Hj. 2, i 7.2, 5-Aminv~4~ftkiazid~S-yl)tkkipkem~3~carhmM?ile [00570] 5-Ammo~4-(thia2oi-5-yl)tfaiophene-3-carbonitrife was prepared from 5-mtro-4-(thiazoI-5"yl)ihiophcne-3“Carbonitrile (0.15 g. 0.65 mmol) according to protocol Q. Retention time (min) = 1,520, method [7], MS(ESI) 208.0 (M+H), 2,17,3, N-(4-Cymo~3~{ihmz0l~5-yi)tkfaphm--2-yih2~l2~t)xo~&amp;~ (tHpmmmetk}4)qmmiin~l(2M)~yi)met€smide [00571] The title compound was prepared from 2-(2-oxo~6--(trifluoromethyi)qnmolin-l(2//)-yl)acetic acid (0,047 g} 0.17 mmol) and 5-amino-4-· (thiazol“5-yi)thiopheHe-3-carboniiri.lc (0.055, 0.26 mmol) according to protocol A, The crude product was purified by prep HPLC. Retention time (min) = 5.989, method [7 j, MS(ESl) 46 U (M-H). jH NlR (CDCfe) δ 9.95 (s, 1H), 7.91-7,85 (m, 4H) 7.78(¾ J -8,7 Hz, 111), 7.63 (s, Hi), 6.84 (d, J~ 8.7 Hz, 1H), 5.06 {>. 2H). 2,18. Synthesis of A'-(3-il)enzo[r7|thtezol-2-yl)-4-tsyanothioph©n-2»yl)-2-(2-oxo-l,5“isaphthyridi«“l{2.H)~yI)aeetamidg

2J8.L $-Nitm~4~ffiem&amp;fd]thw%el~2-y!)ihiepkem~3"earbomtrile [ΘΘ572] 5-nitro-4~(benzo [t/jthiazol-2-yl)t.h iopliexie-3 -carbon itrile was prepared from d-bromo-5*nitrothiopheoe-3"Carbomtrile (0.16 g, 0.67 mmol) and 2-(tributyist3nnyl)benzo[/jiMazoIe (0,45 g, 1,07 mmol) according to protocol R. Retention time (mm) = 0.381, method [4], MS(ESI) 288.0 (M+H). 2.18.2, S~Ammo-4~(benzo^djthmzol~2~yi)ihiopke}te~3~carb&amp;nitnie [00573] 5-amino-4-(bcnzo[i/]thiazol”2~yi)tJiiopliene-3'Carbonitrilc was prepared from 5-nitro-4-(benzo[i/]thiazol-2-yl)iMophene-3-carbonitriie (0.27 g, 0.92 mmol) according to protocol Q. Retention time (min) = 2.579 method [4], MS(ESI) 258.0 (M+H). 2.18.3. N~(3~(bemo[djikiaz&amp;i~2~yl)~4~cyat!i}tki0phgii~2-yl/~2~(2~t)X0~l>S~napktk}iri{im~ 1 (2Ii}~yi}ucelMmMe [00574] The title compound was prepared from 2~(2~oxo-l,5~naphthyridin-l(2fl)-yl)acetic acid (0.040 g, 0.19 mmol) and 5-ammo-4-(bermo[d]lhiazol~2“ yl)thiophene-3"Carbomtri.le (0.073 g, 0.28 mmol) according to protocol A, The crude product was purified by prep HPLC, LCMS retention time (min) = 5.122, method [12], MS(ESI) 446.1 (M+H). 5H NMR (CDCb) δ 13,38 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.99(d, J = 7.5 Hz, 1H), 7.94 (d, J~ 15 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J - 8.4 Hz, 1H), 7.54 (d, J- 8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7,35-7.30 fm, 1H), 4.95 (s, 2H), 3.33-3.28 (m, 2H), 2.99-2.94 (m, 2H). 2.19. Synthesis of 2-(2-oio~6~(trilliiorometbyJ)qutaiiMn-l(2if)-yl)-A-(2-(thiazQi-4~yi)thioph®n-3-yl)acetamMe [0O57|] The title cpn^piptd was prepared Ip 2-(thiaz©l”4-yi)^iophen-3-amine and 2-(2'~i3xo-6~(triiiiiororiicthyi)quiEioliEi-l(2i:/)-yl)acetic acid according to protocol A. Retention time (min) = 6,485, method1 [7], MS(.HSI) 436.1 (M+H)· NMR (300 MHz, CHpi) δ 11.32 (s, VH), 8.51 (d, J- 1,5 Hz, 1H), 8.04 (d, J - 5.5 Hz, 1H), 7.92 (d, /- 10,211¾ !H), 7.90 (s, Mi), 7.80 (d. /- 8.9 Hz, 1H), 7.30 (d, /- 8,9 Hz, M), 7.22 (dii Jm 1.4 m 1H), 7.20 (d,J= 5,5 Hz, 1H), 7.03 (d, J = 9.7 Hz, 1H), 5.23 (s, 2H).

Example 3

iWkWkWkWAMA^NWVWVU

Synthesis of Thiophene Oxazoles 3.1. Syoileslsi of 2K4~meMs«^vphe]3¥l)-vV^P-ps;ajioI-2~|ipisiephes5-3~yi)aceian}Ide (52)

3.1.2, [00576J 2-(3-nitrothiophen-2-yl)oxazole was prepared from 2~ <tributyistannyl)oxazo1e (0.94 g, 2.62 mmol) and 2-elrloro-3rnitmthioplieiie (0.429 g* 2.62 mmol) aa»Mingto protocol E. Retention ttoe (min) = 1.794, method [1), MSffiSI) 197.0 (M+H). 5.1,2 2^Oxaz0i-2~yl}tkwphex-3~amme [.00577] 2-(Oxazol”2~yl)thiophen-3-a.mine was prepared from 2-(3-nxtrotMophen-2-yl)oxazole (250 mg, 1.27 mmol)) according to protocol F. Retention time (min) = 1.388, method [1], MS(ESl) 167.0 (M+H). 3.1.3. 2~(4~Mgt,h0xyphenyi)~N~(2~’(exaz&amp;i~2~}4)thhphen~3~yi}metamMe [005781 2~(4”methosyphen.yi)-JV'-(2-(oxazoi'-2-yl)thioph.en-3~yl)acetamide was prepared from 2-(4-mcthoxyphenyl)acetic acid 64 mg, 0.385 mmol) and 2-(oxazol--2-· yl)thiophen-3-amme (64 mg, 0.385 mmol) according to protocol A. Retention time (rain) = 6.845, method [7], MS(ESI) 315.1 (M+H); 3H NMR (300 MHz, CDClj) δ 10.59 (s, 1H), 8.17 (d, J= 5.2 Hz, 1H), 7.52 (s, 1H), 7.28-7.37 (m, 3H):; 6,94-6.99 (m, 3H), 3.83 (s, 3H), 3.66 (s, 2H). 3.2. Synthesis of 2~(isoqntaollsi-5-yi)-Ar“(2”(osazol“2-yl)thioplien-3-yl)acetaraMlc (53) [00579J 2-(lsoqumolin-5-yl)-A-(2-(oxazol-2-yl)thiophen-3-yi)a.cetamide was prepared from 2-(isoqumolm~5-yl)acetic acid (48 mg, 0.246 mmol) and 2-(oxazol-2-yl)thiophen~3-amme (41 mg, 0.246 mmol) according to protocol A. Retention time (min) « 2.206, method [7], MS(ESl) 336.1 (M+H); *H NMR (300 MHz, CDCi.,) 6 10.79 :(8, IH}* Ml (s, IH), J = 6.5 Hz, IH), 8.36 m -J - 6.5 Hz, Hi), m8 (ti, J - 8.2 Hz,

Hi), 8.@P8.13 (m, 2¾ 7.95 (d<| &amp;3, 7.3 1¾ IB), 7.55 (s, IH), 7.36 (4./=5.3 Hz, IH),6.95 (s, IH), 4.36 (s, 2H). 3.3. Synthesis ofA~{4~hroiBO“3"(oxazol-2”yl)thiopheiS“2-yi)“2“{2“OXii”3,4" dihydrO“l,S-RaphthyridiiS-l(2/#)~yl)fflc«tffiiSiid£

5.3, /, 2^4-Bromm2-nitwtteophm-3-yt)oxaz0le 190586] A mixture of 3,4~dibramo-2mUrothiophene (0.166 mg, 0,581 mmol), (67 mg, 0.0581 mpm!) and 2-|y^iylslmmyl)oxa®ie ¢256 mg|0.698 mmol) in I3MF (1.1 mL) was evacuated and pinned with nitrogen three times. The reaction mixture was heated to 90 °C for 18 h |§d iM5iesi|lng solution was booled to reomtemperature and dilated withEtjCh "ike solution was washed with brine and the organic- phase was separated, dried (Ma2SO<j), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/etbyi acetate, 20/1 to 1/1, v/v) to give 2-(4~bromo-2-mtioihiopben-3-yl)oxazole (107 mg, 67%). Retention time (min):::: .1,948, method [1], MS(ESI) 2?4.9 (M-H). 5.3.2, 4-Bmmo-3^oxazol~2~yi)tk&amp;>phm~2-entme [00581] The title compound was prepared from 2 -(4-bromo-2-nitrothiophen-3 -yl)oxazole (224 mg, 0.8.14 mmol) using the procedures of Example 2.11.6 to give 4~ bromo-3-(oxazol-2-yl)thiophen--2-amine which was used without further purification. Retention time (min) = 2.131, method [1), MS(ESl) 244,9 (M+H). 3.3.3. N-(4-Br&amp;mo~3~(i*X£iz&amp;i-2~yi)ihM)pken-2~}4}~2~{2-&amp;xa~3}4-dihydr0-lt5-Maphihyndin~l(2H)~yl)m:etamhie [00582] The title compound was prepared from 2--(2-oxo~3,4-dihyd.ro- ί .5-naphthyridin-l(2//)-yl)acetic acid (85 mg, 0.416 mmol) and 4-bromo-.>-/oxazol-2» yl)thiophen--2-amme (51 mg, 0.208) mmol) according to protocol A, Retention time (min) “ 3,245, method [7], MS(ESI) 433.0 (Mill); Ή NMR (300 MHz, CDCh) S 8.39 (dd, J = 5.1,1.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d, 7.0 Hz, 1H), 7.45 (dd, J= 8.4, 5.5 Hz, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 4.93 (s, 2H), 3.51-3.46 (m, 2H), 3.05-3.00 (m, 2H). 3.4, Synthesis of N“<4-cyafie“3H>xaz9l-2-yi}iMophen~2~yl)-2-{2~«x©-6-(frifluoromethyl)quinel!n~l(2H)~y1)&amp;cetamide

3.4, h 5~Nitm-4-{exizz*d~2~yl}fkiophem~S-vwbmmrUe P0g§3] The above tided compound (34 mg, 18%) was synthesized from 4-bromo-5-mtrotliiophene-3-carbonitriie (203 mg, 0,87 mmol) and 2-tributylstannyloxazole (0.27 ml,, .1.29 mmol), tetrakisiiriphenylphosphine}palladium(0) (103 mg, 0.089 mmol) and copper(I) iodide (16 mg, 0.084 mmol) according to methods described herein. LCMS method [4], retention time = 1.62 min; MS(ESI) 222.0 (MH+). 3.4,2. 5~Amwo~4~(oxaz&amp;l-2-yl)tkiephene-3-carhonitrUe [00S84] The title compound was prepared from 5 -nkro-4- (oxazol -2-yl)thiophene~3-carbonitrile (34 mg, 0.15 mmol) using protocol Q, Flash chromatography (EtOAc/hexanes elution) gave desired product (20.8 mg, 71%); Rf= 0.84 (60% ElflAc/hexaneSj silie^; method (4], retention time - 1.673 min; MS(ESi) 192.0 (MH+). 3.43. N~{4~Cyumi3~{<fxazoi3~yi)ihi&amp;phen~2~yi}~2~(2~exo~6~ itrlflmmmtetkyi)quin&amp;Un-l(2E}~yi)acetumide

IfMISSil The title compound was synthesized from 5-ap^o-4~(pxazofrl~ yi)tbmphene~3rearbonitrile (21 mg, 0.11 mmol) and 2-{2-ox.o~6·· f n ifbioroniethyllquinoiin-1 (2H)-y!)acetic acid (30 mg, 0.11 mmol) according to protocol A. The product was purified by HPLC. LCMS method [7], retention time ^ 6,70 min; MSfESlJ m0'(MHT); 'HI4m(3i@i^^C^d^l9(dpf-MiHz,^,7.95- 7.80(m, 31\s, 7.85 (4,/ 1.8 Hz, I R\ 7.08 id,./ === 0.8 Hz, ΪH)„ 6.90 (d,J™ 9.6 Hz, ΪΗ), 5.45 «s, 211).

Siiffiiki

Synthesis of Thiophene Qxadlazeles 4.1. Synthesis of 2-{4-methoxypheny1)¥9~(3~f5-methyI-ls2,4-oxadia£©!“3~ yi)thiephen-2-yi)acetamide (54)

4. Li, [00586] ^3^anojMcfto«|-yl)-^4^e^^ypfe6syl)aeetatmie! was prepared from 2-(4-methDxyphenyl)acetic acid (1.37 g, 8.29 mmol) and :2~ airuQothiophene~3~carbonirrile (1.03 g, 8.29 mmol) according to protocol B. Retention time (min) = 2.150, method [1], MSfiESI) 273.0 (M+H). 4. /, 2 N~{3~(N,~Hydmxymrb&amp;mim$d^yi)ihi&amp;pheM~2-yi}~2-‘(4-mei}mxyphenyi)~ acetamide [005871 To a solution οίΛ;Μ3~ον3ηοΐ1ηορΗδΓ:-2··νΐν2-{4-· Tnethoxyphenyl)aeetand|e (234 mg, 0.859 mmol) in a mixture of ethanol (5 ml), methylene chloride (0.5 mL) and hiethylamine (202 μ!.., 1.46 mmol) was added hydroxylamine hydrochloride (90 mg, 1.29 mmol). The resulting solution was stirred at room temperature for 18 h and was subsequently diluted with saturated aqueous .sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO.ii), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 7/3 to 2/8) to give <V-(3~(,¥~hydri>xyearbamiEnidoyi)thiophen~2"yl)-2-(4-methoxyphienyl)acetamide. Retention time (min) «= 1.161, method [1], MS(ESI) 306,1 (M+H). 4,13. 2~{4~Meth&amp;xyphenyi)~N~(3-(S~methyi-lJf4-axadmzM~3~yi}ihiopken~2- ylkiceiamidg [00588) To a solution of/v'-(3"(A*4iydroxycmhamirnidoyl)thiophen-2--yi)-2--(4-:'i»ethoxypheny!)-acertamisle (104 mg, 0.341 mmol) in acetonitrile (2 tnDwas added DIPEA.,(127 mg, 0.987 mmol) and acetyl chloride (48 gL, 0.681 mmol). The resulting solution was stirred at 60 -C for 18 h and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. Tie organic phases were combined, dried (Na?.SO·*}, filtered, concentrated under vacuum and purified by preparative HPLC to give 2~(4-niethoxyphenyI)-.'V-(3~(5--meilsyl-i ,2./1-oxadiazol~3~ yl)thiophen-2-y!)acet:amide. Retention tin*® (min) ^ 6.733, method [?)? MSpSI) 330.1 (M+flg lH NMR (300 MHz, CDClj) 8 10.63 (s, 111), 7,30-7.35 (m. 3H), 7.00 (d, J- 9.2 m 2H>:6,89 (d, J~ 6.2 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 2fi), 2 J0(s, 3H). 4.2. Synthesis ofAi-(2-(0,4-osadki50l-2-y1>tMepheB-3-y!)-2"(napl8ihalen-l~ yl)acelam!de (35) [0§589] Isa solution of (isoeyanotmino)triphenyiphosphorane (978 trsg, 3.24 mmol) in anhydrous CH2CI2 (30 mL) w# added dropwise a solution of 3-{2-(naphthaien~ l-^)aeqtarm<to)duophene-2"CarlBxyiie add (340 mg, 1.09 mmol) in anhydrous €H2€% (27 mL), The resulting mixture was stirred at room temperature under nitrogen overbig|ii and evaporated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acctate/hexane) gave ^'iS-ifi-Td-oxadiasoi-S-yfithiophen-S-yl)··?· (naphthalen-1 -yls&amp;eetam:dc (45mg, 12%), Method [7] m/35 357.9 (Mt-'Na); retention time - 5.019. ’H-'NMR (CDO3) S 8.18 (d,.7 - 1,1 Hz, 1H), 8.16 (d,./- 1.4 Hz, 1H), 8.05 (d, J =··= 8.3 Hz, 1H), 7.88 (d, J= 8.0 Hz, 2H), 7.61-7.41 (in, 5H). 4 27 (s, 2H). 4.3. Synthesis of 2-(4-imuh0xyphmyI)%A{2^5-meilyvTi4M~es&amp;dtexid-2·-yI)thiopheu~3-yl)sectamide (56)

*MJ. Metkii 3~t2~f4~metkmyphenyi}acetamid&amp;}thi&amp;phmg~2~€arh(Ksryfei? [00590) The title compound was prepared from 4-methoxyphenyl acetic acid (6,65 g, 40.2 mmol) and rnethyi“3-amino-2-thiophene caiboxylate (6.30 g. 40.08 mmol) using protocolA to afford rhe coupled intermedia!» (7.40g, ff|ethod [7] m/z 306:.0 (M+H); retention time-5.907. (CDCI3)δ 10sl4 (broad s, 1¾ 8.07 (d, Jte=53

HaplH), 7M0,J= 5<MH 722 (d, /-8.3 Hz, 2H,), 6.88 id, J === 8.3 Hz, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.65 (s, 2H). 4.3.2. 3^2^4~Methoxyphmyi}metamid0)thwphme~2-earboxylicad<t [©©591] A 3M lithium hydroxide solution (80 mL) was added to methyl-3-{2-(4-mcthoxypheuyl)aceiamido}&amp;iophene~2-earboxylate (7.30 g, 23.91 mmol) dissolved in methanol. The reaction mixture was refluxed for 2 h, cooled to room temperature and then partitioned between ethyl acetate and H20. The aqueous layer with acidified with cone HC1, filtered and washed with H20. The precipitate that formed was collected by filtration (8.55¾ quantitative) and used in. the next step without further purification. Method [7] mlz 291.9 (M+H); retention time = 3.827. ^-NMR (CD3OD) 6 8.0 (d, J-5,3 Hz, ill), 7.61 (d,./=+5,3 Hz, 1H), 7.26(6,./-83 Hz, 2H), 6.91 <d,/=8.3 Hz,2Hh 3.76 (s, 3H), 3.70 (s, 2H), 43.3, N-{2~{2~Aeefylkydrazmecerbonyl}ihiephen-3-yi)~2-(4~methoxyphenyl)-acetamide 100592] The title compound was prepared from 3-(2-(4-meihoxypheoyl)aceramido)-Mophene3)toarboxyhc acid (500 mg, 1.72 mmol) and acetylhydrazide (1.0 g, 13.50 mmol) according to protocol B to give N-(2-(2~ acetyiliydrazinecarbonyl)ijiopl6n-3ryl>'2-#^atothoxyphenyl)acetnsmdewhich was used without hnther purification (300 mg; 50%). Method [4] m/z 370.0 (MWa); retention time = 1.186. 43.4. 2~{4~Meih8xyphenyl)-N-{2-f5-tftetkyl~13,4-8xadiazol~2~yi}ikiephgn-3-yijacetamide |00593] To a solution of A7-(2-(2-acetylh.ydrazinecarbonyl)thiophen-3-yi)-2-(4-· methoxyphenyl)acetamide (300 mg, 0.86 mmol) in anh. acetonitrile (6 mL) was added di i sop ropy lc thy f amine (0.8 mL, 4.84 mmol) and triphenylphosphine (396 mg, 1.51 mmol). After 5 min, hexachioroethane (292 mg, 1.23 mmol) was added to the reaction mixture and then stirred at room temperature overnight under N2(g) inlet. The reaction mixture was evaporated under reduced pressure, partitioned between ethyl acetate and H20, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40:60 ethyl aeetaie/hexane) gave 2-(4-methoxyphenyi)-Af~(2--(5--methyl~.l}3,4”Oxadiar:ol"2-yl)tliiopben“3-yl}acetamide (25 mg, 9%). See James, C.A, et aL, Tet. Lett. 47 (2006) 511-514. Method [7] m/z 330.0 (M+H); retention time = 4.805. 3H-NMR (CDCij) 8 10.15 (broad s, 1H), 8.18 (d,./- 5.4 Hz. 1H), 7.43 (d, J= 5.4 Hz, 1H), 7,31 (d,J-7.6Hz,2H), 6.92 (d,/= 7.6 Hz, 2H),3.81 (s, 3H), 3.75 (s, 2H), 2.75 (s, 3H). 4.4. Synthesis of.¥-{2-{5"S§opr©pyI-1,3,4~oxadiaxol':2-yl)thtophen-3-yl)-2”(4» methoxyphenyi^cetamide (ST)

ueetumiie {00594] .¥4'2-(2-isGhutysy]hydrazinecHrbony])ihiophen"3''yi)-2-(4-methoj;ypbeuyl)acetemide (443 mg, 34%) was prepared from 3-(2-(4-methoxyphonyl)aeetarnido)lMophene-2~carboxylic acid and isobotytohydrazine according to essentially the satoC:procedure as described above in Example 4.3.3. and was puri fied by flash column chromatography (silica, 50:50 ethyl acetate/hexane).

Method [4] miz 398.0 (M+Na); retention, time = 1.453. 4.4,2. N-(2~(5~!$&amp;pmpyl-I,3,4-oxaditmi~2-yt)thi9pkm-3-yl)-2-{4-methoxyphenyi)~ acetamide iOOS9S| AH2-(5-isopropyl-.1,3,4-oxadiazol-2-yl)thiopiien-3-yi)-2-(4-methoxyphenyl)acetamide (339 mgs, 81%) was prepared from N-(2-(2-isobutyrylhydra2inecarbonyl)thiophen.»3-yl)"2-(4-methoxyphenyl)acetamide according to essentially the same procedure as described for Example 4.3.4 and was purified by flash column chromatography (silica, 50:50 ethyl acetate/hexane). Method [7] m/z 358.0 (M-l-H); retention time = 6,683, Vi-NMfr (€D€13) δ 10.21 (broad s. 11¾ 8.15 (d, J-S.2 Hi?) 1H), 7.40 (d, J= 5.1 Hz> 1H), 7.29 (d, 8.2 Hz, iH), 6.89 (d,J= 8.2 Hz. 2H>, 3::.:79 (s, 3M), 3.71 (s, 21-1), 3.24-324 (m, 2:1).1,42 (s, 3H). 1.40 (s, 3H;·. 4,5, Synthesis of AH2-(5-meth3d-is3,4-0:£adl&amp;zcl~2~yI)thtoph£n-3-y][)~2~ {mphthsle?ii~!~yl)a€etaimde (58)

4Mli N-(2-(2-Acetylhydriszinecarbonyl)tkwphen~3~yi}~2~(tiapkthaten~]~yl)(scet&amp;mUte [00596] The title compound was prepared from 3-( 2~(naphthaiene-· 1 -yI)acetamido)thiophene-2-carfeoxy3ie add (321 rng, 1.03 mmol) and methyl keto hydrazine (609 mg, 8.22 mmol) using protocol B to give the desired 272-(2-aceiylhydrazineciirbom>i)thiophen-3-yl)-2-(naphthaien - l-yi)acetamide, which was used without further purification (250 mg, 66%). 4.5,2. N~{2~{$-Methyi~l,3f4~&amp;xadiaz&amp;i~2~yl)thi&amp;pkeM-3-)>i}-2-{naphtka!m-l~ yljacetamide [00597] #-(2-(5 -methyl -1,3,4-oxadiazol -2-yl)thiophen-3 -y l)-2-(napht3iaien-1 -yl)acetamide (105 mgs, 44%) was prepared from #-(2-(2- acetyIhydrazinecarbony[)thiophen-3~yl)~2-(naphthalen-1 -yi)acetarmde (250 mg, 0.68 mmol) according to essentially the same prodecure as described in Example 4.3.4.. Method [7] miz 371.9 (M+Na); retention time = 6.243. *H-NMR (CDCla) δ 10,0¾ (¾ IH), 8.12 (d, J= 5.4 Hz, IH), 8.03 (4./- 8.1 Hz, 11¾ 7.83 (d,J-8.1 Hz, 2H), 7.57-7.40 (m, 4H), 7.33 (45=5.4 Hz, IH), 4.21 (s, 2H), 2.45 (s, 3H). 4,6. Synthesis of #-(4-m ethyl-3-(3-osethyl-1s2,4~ex&amp;diaz©^5-yl)tMophen-2-y:l)~2~ (nnphtlialeK-l-yl)aeetaaside(59)

£ &amp; Λ Methyl [00598] The title compound was prepared from 2-(naphthalen-1 -yl)aceiic acid (1¾ &amp;, 54 tiitnol) atid methyl 2-ammo-4-mcd)ylthiophene-3-carboxyIaic (9.2 g, 54 tppc»l) according ίο protocol A (15,4 g, 85%) as a white solid. lH NMR (CDQs) 31.1 »0 (ss 1H), 8.05-7.85 (m, 3H), 7.63-7.50 (no, 4B), 6.36 (s, 1H), 4.29 (s, 2H), 3,57 (s, 3H), 2.28 (s, 3H); ,3CNMR(CDCi3) £168.3, 165A 149.3, 135.0, 134.0,132,1,129.8,128.9, 128.6, 127.0, 126.2, 125.7, 123.7,112.9,112.2, 51.1, 41.9, 17.7; MH+ 340. 4.42. N^4~methyl-3-0-meikyl-i:!2,4~oxi!iiiwzt>l‘5~yi)ihmphen-2-yl)~2'-{Mepktkuhm~i-yOacetumide [00599] Sodium hydride (60% dispersion in mineral oil, 106 mg, 2.65 mmol) was added to a solution of acetamide oxime (218 mg, 2.94 mmol) in dry' THF (5 ml.) at rt. Methyl 4-methyi-2-(2-(naphthrien-1 -yi)acetamidQ)thiophene-3-earboxyIate (Aldrich, 500 mg, 1.47 mmol) was added, and the reaction mixture was allowed to stir over 3 days, The mixture was concentrated under reduced pressure, then partitioned between ethyl acetate and water. The organic layer was separated, and washed with saturated. INaCi solution, The organic layer was dried (MgSO^), filtered and concentrated. The residue was purified by flash chromatography (EtO Ac/hexanes elution), and then triturated from acetonitrile to afford the desired product (58 mg) as a white solid. Method [7]: rt = 9.42 min; ’B NMR (CDCR) £1 1.3 (s, 1H), 8.02-7.89 (m, 3H), 7.63-7.50 (m, 4H), 6.48 (s, 1H), 4.35 (s, 2H), 2.42 (s, 3H), 2.08 (s, 3H); l3C NMR (CDCI3) »5172.1, .168.9,165.2, 146.4.134.0. 133.4.132.4.129.4.129.1.129.0.128.8.127.2.126.4.125.7.123.7.134.0, 106.9,42.1, 16.9,11.4; MH+364.1. 47. Synthesis of A-(4-methyl-3~(3“methyI-l ,2,4~©.iadlagol"5-yl)thiophen“2-yl)-2» (4"{pyrsdm-4-y!)piseny!)acetaffiide (66)

4. 7. L Methyl 2-{2~(4~m^i^hmy§m0t0mid^r4^e^yliM!!^kme3^&amp;rimjg?ittte [00600] The Otic compound was synthesized in 87% yield according to protocol A from 24440dopltenyi)acetic acid and methyl 2^mino^-Hied5fii3iophene«-3*> carboxylate. n€ NMR (CDp3) <5167.5, 166.6, 149.8, 138,1,1341,133.1,131.4,113,0, 112.3, 93.2, 50, 43.3,17.8; MH+ 416,#; 4.7,2, Meikyt 4~meihyi-2~(2~(4-{pyridm-4~yl)phenyl)iiceSitmsds}}thmphem~3~ carboxylate [00601 ] Methyl 2-{2-(4-iodophenyl)acetaTnido)-4-methylthiophene-3-carboxylaie (420.4 mg, 1.01 mmol), 4-pyridylborcnic acid (Aldrich, 167 mg, 1.36 mmol), teirakis(triphenyiphosphins)paikdium(0) (123 mg, 0.11 mmol), and potassium carbonate (565 mg, 4,1 mmol) were combined in DME (2 mL) and water (1 ml.,) in a sealed tube, and heated to 80 °C over 17 L The reaction mixture was cooled to rt, then partitioned between EtOAc and water, The organic layer was separated, washed (brine), dried (NajSO-t), filtered and concentrated under reduced pressure. Flash chromatography (EtOAc/hexanes) afforded the titled compound. 1HNMR (CDCfe) £11,3 (s, 1H), 8.67 (dd,./ = 4.7,1.4 Η, 2H), 7.67 (d, J= 8.2 Hz, 2H), 7.60-7.40 (m, 4H), 6.38 (s, 1H), 3.88 (s, 2H), 3.80 (s, 3H). 2,33 (s, 3H); 13CNMR (CD€1:<) £167.7, 166,6,150.3,149.9, 147.8, 137Λ 134.8,134.6,130.3,127.7, 121.5,113.0, 112.3, 51.5,43.5, 17.8; MH+ 367.1. 4.73. N^4-metkyl3-(3^etkyl-lJJ^xadkwl-5-yr)tMepken-2-yl)~2^4-4pyri0m~4- yijpheityD&amp;ammkh?

[00602] Acetamide oxime (66 mg, 0.89 mmol) was taken up in dry THF (1 mL) at rt, and sodium hydride (60% dispersion in mineral oil, 55 mg, 1.4 mmol) was added. After hydrogen evolution ceased, methyl 4-methyi~2"(2-(4-(pyridin-4-y[}pheHy1)acetamido>0u0phene-3~earboxyla.te (82 mg, 0.22 mmol) was added in one portion. The reaction 'was stirred at rt for 90 min, then at 50 9C for 21 h. The mixture was concentrated under reduced pressure, then partitioned between ethyl acetate and water. The organic layer was separated, and washed with saturated NaCl solution. The organic layer was dried (MgSCu), filtered and concentrated. HPLC purification of the crude residue afforded the title compound as a trifiuoroacetk acid salt, Ή NMR (CDCI3) S 11.6 (s, 1H), 8.86 (dd, /=5.3,1.4 Η, 2H), 7.94 (dd,/= 5.3,1.4 Η, 2H), 7.77 (d,/= 8.2 Bz, 2H), 7.61 :(4/= 8.2 Hz, II), 6.54 (s, 1H), 3.99 (s5 2H), 2.51 (s, 3H), 2.34 (s, 3H); MH+ 497.1. 4.8. Synthesis of N^2~{3-m&amp;thy§"l,2Λ-ύJiiιάL·mή~5~yl)thMψhm~3~yl}~2~ (naphthaSen-l-yilacetamlde (61)

4.8, L 100603] Methyl 3“(2~(o:sphtl®len-l -y!)acetamido)tlridphene-2-carboxylate was prepared from methyl 3-aminothiophene*2"Cafboxylate (4 30 g, 27.3 mmol) and 2-(naphthalen-l-yl)acetic acid (3.10 g. 27.3 mmol) according to protocol A. Retention time (min) = 8.738, method [7], MS(ESI) 326.1 (M+H). 4,8.2. N-(2~(3-Methy!~l,2f4-0xadiazeI-5”yl)tki&amp;pkm~3~yl)~2~{itephthelm-l~ }4}memmMe 100604] Sodium hydride (60% dispersion, 15 mg, 0.39 mmol) was added to a solution of acetamide oxime (29 mg, 0.39 mmol) in THF (1 mL). The resulting mixture w'as stirred at room temperature for 10 minutes after which a solution of methyl 3-(2-{naphihalen~l-yl)acetamido)tlriopherse-2--carhoxylate (107 mg, 0.33 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 1 h and was subsequently diluted with ethyl acetate (10 ml.). The resulting solution was washed with brine (5 mL) and the

organic phase was then dried (NfazSO*), -filtered and concentrated under vacuum. The residue was dissolved in THF (1 mL) and HC1 (i mL of a 10% aqueous solution) was added. The mixture was stirred for 20 minutes after which ethyl acetate (10 mL) was added: The resulting solution was washed with brine (5 mL) and the organic phase whs men dried (Na2SO.iL filtered, concentrate under vacuum. and tie residue was purified by preparative HPLC to give ΛΗ2··(3-methyl-1 ,2,4^03iadia^Gi-5«yl)thiophen^3»yl)“2-(naphthalen-1 -yljaeetamide. Retention time (min)9.533, method [7], MS(ESf) 350.1 fM+H). XH NMR (300 MHz, CDCh) δ 10.10 (s, IB), 8,26 id,./- 5.4 Hz, !M)y8.03 (d, J 9.3 Hz, 211), 7.59-7.49 (m, 5H), 4.2? (s, 2H), 2.14 (s, 30).

Synthesis of iV-(3-(l,2,4-ovadiazi>J-3»yi)i:hiophen-2-71)-2-(6,T-dilluuro-l-ttxoqusnciiin' l(2//)“y!)acetamiile

4.9. L j!fl60S] 4-chloi^ien®PP-d)pyrimiiiH;e (340 rug, 1.99 rmml% hydtbxylatrsine^ hydrogen chloride (550 mg, 7.91 mmol), and diisopropylethylamioe (1 ml) in absolute ethanol (5 ml) was placed into a preheated oil bath at ?5°C. After stirring for 6 h, the solution was concentrated raider reduced pressure.

[00606] A&amp;(thicnoP,3«dipyrimidm-^4^y1)hydM3xytamine and inethylorfhoformale (10 ml) in ethanol (10 mi) was placed into a preheated oil bath at 100°C for 4 h. The solution was concentrated to yield (Jspsthy i N-3 - (1.2 id-oxadiazolrS -yl.)thiophen--2-yIformimidatc. Method F8j retention time 4,08 min by HPLC (Μ4---22Ί), 4.93. 3-(ϊ,23-Οχαά!Άζϋ^~γΙ}έΗίορ$ϊ€κ~2-αηιϊηβ |0®607] (E)-Ethyi A-3-(l}2s4-oxadiazol“3-yl)thioplier!-2-yIfornhmidaie (82 mg, 365 umol) and .V-mel.hylethane-1,2-diamine (0.30 ml, 3,40 mmol) in methanol (2 ml) was jiacediinto a preheated oil bath at 60*€. Alter stirring for 15 nun, the solution was concentrated under reduced pressure and. the -eM-iue was flash ehromotraphed wiih 9:1, 4:1, 7:3, and 3:2 hexaneiethyi acetate as the eluant to afford 18 mg (5.4¾ yield over three steps) of 3-(1 ^,4^xadia^l-3-yl)tfMophen-2-attnjine, Method [6] retention time 4.08 min by HPLC (Mt 168). *Η NMR (300 MHz, CDCfe) δ 8.70 (s, 1H), 7.22 (d, J-5.4 Hz, 1H), 6.45 (d, .1-5.4 Hz, 1H). 4.9,4. N-(3-(lt2,4-oxMiaz0l~3~}4)thwphm-2-yt)-2~{6, 7-difluarO"2~axoquinottn- 1 (2H}~yi}acetmmde [00608] The title compound was prepared from 3-(1,2,4-oxadiazol-3-yl)thiophen-2~amiue (18 mg, 108 umol) and 2~(0J-difiuoro-2-oxoquinolin-1(2//) yl)acetic acid (32 mg, 134 umol) using protocol A. The crude product was purified by HPLC to yield jV-(3-(1 ,2,4-oxadiazol-3-yl)tinophen-2-yl>2-(6,7-difluon>-2-oxoquinol«i-i(2/7Vyi)8cetamMe. Method. [7] retentionstime 5.34 min by HPLC (MT~389) and (M-tNa=4J1). hlNMR (300 MM, CBC|) δ 11.06 (s, IB), 8.69 (s, Ilf, 7.74 (d, J=9.9 Hz, l PI), 7.42 (m. 2H), 7.35 (m, Iff, 6.98 (d, 1=5.4 Hz, IB), 6.86 id, >9.3 Hz, 1H), 5.22 (s, 2H).

Example 5

Synthesis ofTMazole Triazoles S.l. Syntheses of lV-<4'-'(l//”i,2,4-iriaa;ol-S-yl)thSazoi-S~yl)”2-(lsoqoiooSt.n-S-yfacetamide (62)

5..LI. Methyl 5~(dipkenyiMetk}4emaniim)thimole-4-c8rboxyl&amp;i£

[00609] A mixture of methyl S-bromothkzole-d-carboxylaie (3.51 g, 15.8 mmolY, idiphenylmethamrmnc (4.0 ml, 23,9 mmol), cesium carbonate (10.98 g, 33.7 mmol). P<b(dba).rCTiCl·; (876 mg, 957 umoi), and f S-bis(dipheuyiphosphino)~9i|-d-nictbylxatnhene (Xantphox, 1 67 g, 2.89 mmol) in toluene (30 ml) was heated at 80 "C for 18 h. The heterogeneous mixture was directly flash chromatographed with 9:1,4:1, 7:3, 3:2 and 1:1 hexane: ethyl acetate as the eluant to yield 4.30 g (84% yield) of methyl 5“(diphenylrnethylen.eamino)thiazole-4“carboxylate as a yellow oil. Retention time (min) = 6.41, method [7], MS(ESl) 323.0 (M+H). 5.1.2 Methyl 5-atnimthmzele-4-carhexyi&amp;ie 100610] A queous 3 N HC1 (1 m'L) was added to a solution of methy l 5-(diphenyhneihyleneamino)thiazQle-4-carboxyIate (1.22g, 3.81 mmol) in THF (5 raL), The reaction mixture was stirred for 1 h and the white solid which had formed was isolated by filtration to give methyl 5-aimnotMatrole-4-carboxylate (0.527 g, 2.72 mmol, 71%). Retention time (min) = 0.422, method [7], MS(ESI) 159.0 (M+H). 5.13, Methyl 5-(2-(hvqMiwHn-5~yi)eeetemid&amp;}ihiazele-4-earbexylate [006111 Methyl 5-(2-(isoqumolin-5-yl)acetamido)thiazole~4-carboxykte was prepared from methyl 5 aminothiazole-4-carboxykte (0.132 g, 0.834 mmol) and 2-(isoqnmolin-5-yl)aeeiic acid (0.163 g, 0.834 mmol) according to protocol A. Retention time (min) = 2.400, method [3], MS(ESI) 328.0 (Μ+Ή). 5.1.2 S-{2-(lsoqum&amp;lin3-yl)&amp;eetemide)thiaziite-4~earb0xamide [ 006!. 2] [0006] 5 -(2-(isoquinoHn-5 ~y l)ac etamido)thi azote-4-carhox am i de was prepared from methyl 5»(2-(isoquinolin-5“yl)aeetamido)thiaxole-4-carboxykte (210 mg, 0.64 mmol) according to protocol H. Retention time (min) ::: 2.507, method [3], MS(ESl) 313.0 (M+H). 533, N-0-(lH~lf23-trmzol-5-yl)ihiazel~5-yl)-2-(isequin&amp;im3~yi}aceMmide [00613] .¥-(4-( Iff-1,2,4~triazol"5-yl)thiazol“5“yl)-2“(isoqninoim-5-yl)acetara:ide was prepared from 5-(2-(isoquinGlin-5-yi)acetamido)tMazole-4-carboxamide (124 mg, 0.396 mmol) according to protocol 1. Retention time (min) = 4.890, method [8], MS(ESI) 337.1 (M+H); XHKMR(300 MHz, CD3OD) 5 9.75 (s, IB), 8.45-8.59 (m, 4H), 8.29-8.31 (m, 1H), 8.05-8.14 (m, 2B), 4.63 (s, 2H). 5.2. Synthesis of 2-(lsoquinolin-5-yl)~.¥~(4-(l-methyI-l^r-l^,4-tr!azol-5- yl)thlazol-§-yl)acetamide (63) [ΘΘ614| 2-(Isoquinoiin-5-yl)-.(V-{4-{]-methyl-1//-1,2#4-iriazol-5-yl)thia2oi--5-yl)acetamide was prepared from 5-{2-(Isoqumolin-5-yl)acetamido)thiazoie-4-carboxamide (Example 5,1.4., 197 mg, 0.631 mmol) according to protocol J. Retention time (min) - 1.196, method [7], MS(ESl) 351.1 (M+H); 5HNMR (300 MHz, CDjOD) § 9.75 (s, 11¾ 8,45-8 60 (ro, 41 f). 8.28 (d J= 7.6 Hz, ill),:8,07 (dd. J = 8.8, IS Hz, 1H), 7.73 (s, 1H), :4.61 (s, 2H), 4.27 (:,, 3H).

luimM

SynthesisiOf 2-(2^yryyl)“3*(l~napMhytaeetylahino)ttsieplserse (64)

6./. 2~J{)d{f-3-fisr^huioxycnr^ony^mmn}ihhphefi<' 1006151 A vial was charged with 199 mg (L0 mmol) 3 butoxycarbonylamino.ahiophece, 164 mg (2.0 mmol) NaOAe. 4,0 ml.. HOAc, and a stir bar. The mixture was stirred at room temperature, giving a homogeneous solution “A” A second vial was charged with 162 mg (1,0 mmol) iodine moiiocftloride and 2.0 mL glacial acetic add. The second mixture was swirled at room temperature. This second homogeneous solution '''8s’ was added to .solution *'’A” d top wise over three minutes, A White solid begp to precipitate immediately. After the addition, the mixture was allowed to stand overnight, at which time the white solid had separated from the brown .supernatant. With Stirring, 290 uL sat: Na,>$>C.h/H?0 was added, decolorizing the mixture from brown to yellow, 10 ml. water was added, and then the mixture was evaporated, affording a semi-solid light brown residue The residue was partitioned between EtOAc sad Ff ?Ot and the separated EtOAe phase was washed (sat. MaHCOj. then sat, NaCi).

The EtOAc phase was filtered, ami concentrated to give 262 mg (81%) of the title compound as light brown crystals. Ή NMR (COCK, 300 MHz) § 7.49 (hs, 1H), 7.45 (d, J - m m 1¾ 6.50 f§, Iff, 1.S4 (s, 9H). Method [5]: rt - L40 e; mfz - 269.9 (MH+ minus isobutylene). 6,2, 2~(2-P\TUyiht~{l~ft8pfofhyi&amp;£etyiamme}tkiti>phem

[ΘΘ616] A vial was charged with 255 mg (0.783 mmol) 2’-iodo-3-(iert-bMoxycarlx)ny!ithind)--thiofheries 467 mg (1.27 οιπη|Ι) l-(trihuiylstanny^yridin^ 18 mg (0.015 mmol) Pd(PPh5)4, and 2 mL toluene. The vial was flushed with nitrogen. The vial was shaken at 95 C for 24 h. The cooled vial was opened, and TLC indicated consumption, of 2do#>>3^r^butoxycafiiaylaip]|!>^tiophfie and formation of a complex product mixture. The toluene was evaporated, and the residue was treated with 3 mL CF3CO2H. After 5 h at rt, the ClfoCCTH was evaporated, and the residue was partitioned between 1 M H2S% and toluene. The aqueous phase was made basic by adding solid MailCsCis» and then the mixture was extracted with EtOAc. Evaporation of the EtOAc extracts provided 75 mg of a 2:1 mixture of 2~(2Tsyridihyl)-3-ah«n^ and 2^1"noiitsothiophene-2-yl)-3-aminothiophene, as determined by HPL£MS;.

[01)617] The title compound was prepared from the above mixture and 1-naphthylacetjc acid (230 mg, 1.23 mmol) according to protocol A The residue was purified by flash chromatography using EtOAe/hexanes on silica gel, affording 40 mg (15%) of the title compound as a white solid. !li NMR (C3DCU, 300 MHz I δ 11.92 (Is, 1H), 8.26 id, J - 5.4, 1 l-i), 8.08 (dd$ J = 1.8 Hz, 111), 7.93*7.88 (m, 211), 7.59- 7.46 (m, 6H), 7.27 (d|J«8 1H2,ΪΗ), 7.20 (d, J = 6,3 Hz, Hi), 6.84 (dd, J “ 4.8 Bz, J - 7.2 Hz, 1H), 4.24 (s, 2H). UC NMR (CIXH, 75 MHz) 8 153.5, 147.1, 138.3, 136.7, 134.0, .132.6, 130.9, 128.9, 128.6,128.4, 126.8,126.1, 125.6, 124.4,124.1,123.9,12Θ.1, 119.8,116.9, 43.2. Method [5]: rt === 1.67 min; MH+ 345,2,

EmmsMI

Synthesis of Thiophene Pyr&amp;goles 7,1. Synthesis of N"(2"iliI-p5T;imM~yiHhfo$ihm~3-yl)™2~i4«mgthmypkmyih aeetomMe ;(6§)

[09618} T^tassiaKi^i-biitoxide (2.28 gj 20^3 mmol) and i/f-pyrazole (2.02 g, 29.7 mmo!) m BMP (59 si) was sited fbr 30 ». 2~dh1oro~3“ffittothiopMefie ($.56 g, 15.6 mmol) was added and the solution was placed info a preheated oil bath at 100°C. After stirring for i h, the sotorion was diluted with brine and extracted with diethyl ether. The combined organic extracts were dried over magnesiuM sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1,7:3, 3:2. and 1:1 hexane’efhyi acetate as ib eluant to yiddimpure 1-(3-muothiophen-'2-yl)-ll/-pyrazoie. Method [1] Retention time 1.32 min by HPLC (MH+ 196). 7, h 2. 2-{lIf~iymzi}I~f~}'i}thiopkett-3"Simme [00619] The title compound was prepared from 1 -(3 -aitrothiophcn-2-yl)-1H-pyrazole using protocol Q to yield impure 2-(]7/-pyrazol“1“yl)thiophen-3~amine. Method [3] Retention time 1.55 min by HPLC (MH+ 166). 7.1,3. N~(2-{lB~Pymz0i~l~yl)thwphen-3-yi)~2-{4~Metk8XfpkeHyl}&amp;ceiaMi4e {00620] The title compound was prepared from 2-( 1 id- pyrazo 1-1 -yl)thiophen-3-amine and 2-(4~methoxyphenyl)acetie acid using protocol B. The solution was directly purified by HPLC to yield M(2-(l//-pyrasoi-1 -yl)thiophen-3-yl)-2-(4-methoxyphenyDacetanride, Method [7] Retention time 5,22 min by HPLC (MR 314). *H NMR. (300 MHz, CDC13) δ 9.94 (broad s, 1H), 8,00 (d, j =5.7 Hz, 1H), 7,61 (d, .1-2.7 Hz, 1H), 7.39 (d, J-1,8 Hz, l H), 7.27 (m, 2H), 6.94 (m, 3H), 6.35 (t, J-2.4 Hz, 1H), 3.87 (s. 3H), 3.71 (s^H). 7.2. Synthesis of 2H4-st*eth©xyphenyl}-A"(2~<4~mcthy1~Lff-pyra£0!" 1 -yl)thfopfreiKl~yl)acetaml(le (66)

72. i. 4-Metk}i-f~(3~nifrothi0pke?i~2-yi)~fH-pymz0te 166611] Potas;>;urn rtr/fimtoxkie (2.78: g, 24.8 mmol) and 4m>ethyMi/'pyrazole (3.0 mi g. 37.3 mmol) in DMF (50 nit) was stirred for 30 min. 2-chloro-3mii.rothiophene (3,08 gs S 8.7 mmol) was added and the solution was placed into a preheated oil bath at 100'€. After stirring for 1 h, the solution was diluted with brine- and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, 3:2, and 1:1 hexane:ethy! acetate as the eluant to yield 4-njethyH-(3-nitrothiophen-2-yi)-li7"pyrazole. Method [1] Retention time 1,80 min by HPLC (MH+ 21:6),. 7.2.2. 2^4-Methyl-lH-pymzoi~l~yt)tkwphen-3-amme 160622] 4-Methyi-1 A3mhroihiophcn-2*y IV l /Apyrazoic was treated with protocol Q to yield impure 2-(4-methyl··: //-pyrazol-1 ••yl)thiophen-3-anunc. Method [3J Retention time 2.6! min by HPLC (Hit 180), 7.2.3. 2-{4-Meth&amp;xypheisyi)~N~{2~{4~methyi~lH-pymz^i~l-’}i)thmpkm~3- yljacemmidg [0O62JJ The title compound was prepared from 2-(4-mefhyi-!H-pyrazol-l-yi)tbiophen~3-amine and 2-(4-methoxyphenyl)acelic add using protocol B and purified by HPLC. Method [7] Retention time 6.16 min by HPLC (MH+ 328). Ή NMK (300 MHz, CDCli) 6 9.93 (broad s} 1H), 7.97 (d, 1-6.0 Hz, IBs, 7.38 (s, 1H), 7.19 (s, IIif 7 27 (d, i~8.7 Hz, 211), 6.96 (d, 1-8.7 H|, 2H), 6.90 (d, >6.0 Hz, 1H), 3.87 («, ||| 3.70 (s, 2H)f 2.11 (s, 3H). 7.3o (67)

Z3e&amp; (EpN^2^3-(i>inmkylomim)actyloyt}ihi0pkeH-}-yl)~2~(napkdtalen-l- yttscdmude f00624j A solution of'M^|"aeeiySthiophe{i-3~yI)"2-(rtaphil3aSen“lsyi)aeetaTTiide (165 mg, 0,53 mmol.) iο N,Λ-dimerhy I ibrmamide dimethyl acetal (0.2 rnL, i ,50 mmol) was heated at 80 ,:'C for 2 h. The reaction mixture was partitioned between ethyl acetate and ffeO. The organic layer was washed with Ηϊ% dried (sodium sulfate), Steed and concentrated under reduced pressure to give the desired N»p-(3-(dimethylamino)acryloyl)thiophCT~3~yl)-2-(naphfhale«-l-yl)acetamide (I85 mg, 95%) which was used without further purification. Method [4] ns/z 387.0 (M+Ma); rt = 2,199 min, 7.3.2 N~(2~{1 H-P)ria&amp;i^yi)lhk>phsn~3~yih2~{miphthsisn~i-‘yi)aceirmide 100625] To a solution of(^)-,¥-(2-’(3-(dimethyIamino)acr>doyl)thiopheEC'3 yl)-2«(naphthalen-l-yl)acetamide (185 mg, 0.51 mmol) in abs. ethanol (2 ml.) was added hydrazine hydrate (G„2mi, 4,11 mmol) and acetic acid (0.5 niL, 8,73 mmol). The reaction mixture was stirred at room temperature o vernight under N?. (g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O, The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure, The precipitate that formed was washed with methanol and collected filtration to afford iV-(2~(l//»pyrazoi“3~yi)thiophcn-3~yi)-2-(Haphthalcn~]-yl)acetanude (50 mg, 30%). Method [7] m/z 334.0 (M+H); retention time = 5.887. iH-NMR (DMSO-dg) δ 12,92 (broad s, 1H), 10.37 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.92 (d, J= 6,9 Hz, 2H), 7,86 (d,./- 7,7 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J - 5.3 Hz, 1H), 7.61-7.47 (m, 4H), 7.36 (d,./- 5.3 Hz, IH), 6,36 (d, J-2.4 Hz, !H), 4,19 (s, 2H). 7,4, Synthesis ©f N-(2~( t~meihyI~l^r-pyraz©l'3-yi)thiophen-3-yl)"2-(itaphthalen-l~yl)acetamide (68) [09626] To a solution of (£)-iV-(2^3-(dimetiiylamino)aciyloyi)thiophen-3-yl3-2~(naphthalen-l~yi)acetamide (Example 73.1,, 143 mg, 0.39 mmol) in abs. ethanol (2 mL) was added methyl hydrazine (0.2 mL, 3.80 mmol) and acetic acid (0,5 mL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under Ni(g) miet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and HjO. The organic layer was dried (sodium sulfate), filtered and soueontmted under reduced pressure. Shnificatidn hy flash cdfusm chromatography (silica, 19:1(5 ethyl ^gt^e/hexane) yielded Mi(2-(l-metliyi~lli^yrazoi-3-yl)ihiophen^3-yi)r2~(naphAalenil~yfiaciemmide (27 mgs, 20%); Method [7Jm/z 348J (M-H-l); retention lime - 5,328. tH-NMR (CDC1>) | 7.96 (d,/- 5.2 Hz, II), 7.94-7.91 (m, 1H), 7.86 id, J- 7.8 Hz, 1H), 7.56-7.53: (m, 2H), 7.41 (d, J“ 7J Hz, Hi), 7.36 (d, ./=9.1 Hz, 5 H). 7.32 (dsJ-6.2 H2S 1H), 7.15 (s, 1H), 7,09 (d,,/- 1.9 Hz, 1H), 5.17 (d, J= 1,9 Hz, 1H), 4.13 (s, 2H). 3,45 (s, 3H). 7.5. Synthesis ofA-(2-(5-methyi-li¥~pyrazi>l~3~yI)thk>phen~3~yl)-2-(i5apht!ialon-I-yfiacetaralde (i>9)

7.5. L (E)~N~(2~(3-{Dm.ethyiamm0)hut--2--enuyi)ikii}phen~3--}'02~(nspkikiikn~I·.

[0(1627] A solution of 'N~(2-aceEyltliiophen-3-yi)-2-(naphthaleii-l-yi)acelarnide ¢197 mg, 0.64 mmol) in A^V-dimethylacetamide dimethyl acetal (0,3 mL, 2.05 mmol) was heated at 80 °C for 2 h. Tire reaction mixture was partitioned between ethyl acetate and HiO. The organic layer was washed with 11--0. dried (sodium sulfate), filtered and concentrated to give tire desired //-(2~(3-idimethylanimo)bui-2"enoyi)ihtophen~3-yl)-2-(naphthaien-i -yl)acetamide (139 mg, 58%) which was used without further purification., 7.5.2. N~{2~0nie(hyil.71-pyrm,&amp;l~i~yl)thkiphim~3~yl)~2~{naphthslen--l~yi}acf;mntide [0(1628) To a solution of (E)-Ar-(2-(3-(diinethylaniiiio)but-2-cnoyl)thiophc.n-3~ yi)-2-inaphihaleii- l-yi)acetamide (139 mg, 0.37 mmol) in abs, ethanol (2 mL) was added hydmzineshydrate (1 ml,:62,91 rnmoi) and acetic add (0,5 roL, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under N2 (g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate andThO, The organic layer was dried (sodium sulfite), filtered and concentrated under reduced pressure, f unification fey fi&amp;h column chromatography (silica, 20:80 ethyl acetaie/hexatie) yielded :VT2-(5“mcfhyi·· l:JTspyraml~3~yI)thiophen-3-yl)~2"(uaplnhalm-l-yilacctamide (20 mgs, 16%), Method (?) ηχ/ζ 348,1 (Mt-Na); retention tithe = 6.791, hR-i|iR (COCi) δ 10,28 (bread $,1¾ 8M7 ld,J=5J Hz, 2H), 7.91 (d, /= 4i3 Hz, 2¾ 7.33 (d, ,/= 3.8 Hz, 2H), 7.53 (s, ;H>, 7,50 (d, ,/ = 4.5 Hz, 2H), 7.08 (d,./- 5.2¾¾ iH), 5,88 (s, 1H), 4.23 (s, 2H), 2,19 (s, 3H).

Example 8

Thiophene Tetrazofi Analogs 8.1. Synthesis of 3-(3-(2//--t&amp;trazol--3-yI)tltiriphen--2--yl)-2--(4--rnetlicsyphenyl)~ acetamide (70)

8.1.1, 2~{4~Μ0(Ηθ)φρΗ0ίφΙ)~Ν~Ο~(4"^$^^ίΗ~ργ?αζ0ΐ~1^ί)$ΗωρΗ€η~3~$)&amp;;€έβΜΪΜ [00629( The (Me compound was synthesized from 2~(4rEpefhexyphenyi)aeetic acid and l-^rmsodiiophen&amp;o-carbonifriieusing protocol B. The crude product was purified using normal phase chromatography with 9:1,4:1,7:3, and 3:2 hexaneiethyl acetate as the eluant to yield jV-(3~cyanothtophen-2-yi)-2-(4-methoxyphenyl)itoeiamide. Method [1] Retention time 1.81 min by HPLC (MH+ 307). S. 1,2, N- (3-(211- Tetmz&amp;i-5-yii)tki&amp;phei?i-2-yi)-2~(4~Meiho.xypheftyi)-8€efiiMide [00630) AL(3“Cyanothiophen-2~yI)-2-(4-methoxyphenyI)acetamide (285 mg.

1.05 mmol), and azidotributylstannane (614 mg , 1.85 mmol) in toluene (10 mi) was placed into a preheated oil hath at 100°C. After stirring for 6 b. The solution was concentrated and directly purified by HPLC to yield Af~(3"(2//-tetr8Zol-5-yi)thiophen-2« yl)-2"(4-methoxyphenyi)acetamide. Method [7] Retention time 4.92 min by HPLC (MH+ 316¾. 'B NMR (300 MHz, DMSO) 5 11.05 (s. Hi), 7.37 (4 1=6.0 Hz, 1H), 7.30 (d, 1=8.4 Hz, 2H), 7.23 (d, 1=6.0 Hz, 1H), 6.94 (d, 1=8.4 Hz, 2H), 3.88 (s, 2H), 3.76 (a, 3H> 8.2. Synthesis of 2T4~iiieih©x>phenyi)7¥4M2"methyl42H"ie!:Fit2G!-5-yI)ihiophen-2-yI)aceta!nide (71) [006311 lodomethane (0.20 ml, 3.21 mmol) was added to a heterogeneous mixufe afA?-(3-(2i7-teirazol*5-yI)thiophen-2-yi)-2-(4~methoxyplieuyl)acetatiiide (Example 8,1., 620 mg, 1,97 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in DMF (10 ml). After stirring for 72 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated unde!· reduced pressure. The residue was directly purified by HPLC to yield 2-(4-metboxyplienyl)-Ar-(3‘(2-niethyl*2i;/-tetrazol-5-yi)thbphen42-yi)acemrnidc Method [7] Retention time 6.03 min by HPJ.C (MH+ 330). ίΠ NMR (300 MHz, 030 3 5 10.59 (s, 1H), 7.34 (d, 1=6.0 Hz, 1H), 7.33 |§ J=8 7 Hz, 2H), 7.00 (41=8:,7 Hz, 2H), 6.91 (41=6.0 Hz, 111), 4,28 (¾ 3¾ 3.89 (s, 3H), 3.86 (,s, 2H). 8.3. Synthesis ofJV-(3-(2”(meihi>xyiJiethyl)-2/f~tetr«ol-S~yl)tSilopheii-2-yi)-2“(4“ m ethoxyphenyI)acetamlde (72) [00632] Chloromethyl methyl ether (0.20 ml, 2.63 mmol) was added to a heterogeneous mixture of N-{3-(2/7- tetrazol -5~yl)thfophen-2-y!) -2-(4-methoxyphenyRacetemide (Example 8.1,, 580 mg, 1.84 mmol) and potassium carbonate (1.36 g, 9,84 mmol) in DMF (10 ml). After stirring For 72 h, the solution wras diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure, The residue was directly purified by HPLC? tp yield A-(3^2^merhoxymcthyl)-2E?-tetrazoi-5-yihhk>phe5i72-y!)-2-(4-methoxypIienyl)-acct&amp;ir:!dc. Method [7j Retention time 6.60 mm by HPLC (Milt 360). *H NMR (300 MHz, CDCfe) δ 10.58 (s, ill), 7.47(d, 1==5,7 Hz, 1H), 7.33 (41-8.4 Hz, 2H), 7.00 (d, 1=8,4 Hz, 2H), 6.93 (d, 1===5.7 Hz, ΓΗ), 5.77 is, 2H), 3.87 (ss 3H), 3.86 (s, 2H), 3.37 (s, 3H). 8.4 Synthesis of/V-(3"<l-(iBethosymeihyi>-iH”ieir«xol-S-yI)th1ophen-2-y!)-2-(4“ metisoxyph enyl)acetam ill e (72a)

[00633] The title compound was isolated during the purification ofiV-(3-(2-(methoxymcthyI>-2H-tetmzol-5-yl)thiophca-2--yi)-2-(4Hmell)oxyphi».yl)acetamide, above. Method [7] Retention time 6.60 min by HPLC (MH+ 666).

ExaraaSe 9

Synthesis of Thiophene Imidazoles 9.1. Synthesis of ^2-{i-methyl-lll"is5sldazol“2~yi)thlophen-3-yl)-2-(naphilia!eii-l-yl)acetainide (73)

9, L1, 24Nephihelen~l~y!}-N-{thu)phen-3-yf}8eenimdi' 160634] 2-(naphthalen~] -y l)aeetami<k (!4.00 g, 75.6 mmol)*: ddodothiophene (1015 g, 48.3 mmol), irar^A,2diaminocydohexane ( 3.0 ml, 25.0 mmol), cuprous iodide (1.97 g, 10,3 mmol), and potassium carbonate (13.66 g, 98.8 mmol) in dioxane (50 ml) was placed into a preheated oil bath at 95°C. After stirring for i 8 h, the heterogenous mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 19:1,9:1,17:3, and 4:1 methylene chkdde:ethy1 acetate as the eluant to yield 12.26 g (95% yield) of 2-(naphthalen~l'yl)-Ar-(thiophen-3-yl)acetamide as a brown solid. Method [7] Retention time 2.07 min by HPLC (MH+ 268). 9. L 2, N-(2-2&amp;dothi&amp;phm~‘S~yi}~2~(n&amp;phtheim~] ~yl)avetamMe [00635] 2-(naphthakn-l~yI)-Af-(thioplien-3-yI)acetaxnide (7,50 g, 28.1 mmol) and N-iodosuccintmide (7,12 g, 31.6 mmol) in acetonitrile (100 ml) was placed into a preheated oil bath at 75¾. After stirring for 18 h, the solution was concentrated under reduced pressure. The residue was flash chromatographed with 99:1,49:1, 24:1, and 23:2 methylene chioride:ethyl acetate as the eluant to yield impure 7v-(2-iodoth:ophen-3-yl)~2-(naphthalen-l-yl)acetamide. Method [1] Retention time 2,32 min by HPLC (MH+ 394)1 9.1.3. N-(2~{l~Meihyl~lH~imM&amp;zol~2~yi)ihiephe/t~3~yi)~2~(iiaphthaleiP-l~ jijaceiamide [00636] This molecule was synthesized from N-(2-iodothiophen-3-yi)-2-(naphthalen-1 -yl)acetamide and l-tn,ethyl-2“(tributylstannyl)-lH»imidazole according to protocol E. The residue was directly purified by HPLC to yield Λτ-(2-(1-πΐ6ί1ιγ1“ϋϊ" imidazol-2-yl)thiophen-3-yf)-2-(naphthalen-l-yl)acetamide. Method [7] Retention time 3.4.1 min by HPLC (MH+ 348). NMR (300 MHz, CDCL) δ 10.27 (s, 1H), 7.87 (m. 3H), 7,51 (m, 6H), 6.91 (d, J=L5 hz, 1H), 6.82 (d, J===l.5 Hz, IB), 4.15 (s, 3H), 3.68 (s, 2H). 9.2, Synthesis of 2"(4~i!iet!ioxyplteityl)~j¥~(2-{.i-roethyl"1 M-imidawM-yl)thioplsen-3"yl)aeetamide (74)

9.2.1.

[00637J 3 M Ethyl magnesium bromide in THF (11.0 ml, 33.0 mmol) was added drispwise to a solution of 4-iode-: - methyl -1 /f-imidazole :5.61 g, 27.0 mmol) Itt THF (50 ml) at -78°C. After stirring for 2 fa, tributyltk chloride (M ml, 29J mmol) was added, After stirring for an additional 2 b. the solution Was concentrated under reduced pressure. The residue was flash chromatographed (hexane:ethyl acetate) to yield 1-

methyM^tributyhte^l)-li?-in}ida2iolc. Method [7] Rgtenfion time 7,34 min by HPLC (MH+ 373). 9.2,2. l-Methyl-4-(3~nitri>ihi0phen-2-yi)3H~imidazole [i!063SJ The title compound was prepared from 2~ehloro~3~mtathiophcne (2.57 g, 15.7 mmol) and I-methyl-4-(tributylstaimy 1)-liT-imidazole (8,64 g, 23.3 mmol) using protocol E except tire reaction was heated to 90°C (rather than 95°C) and was purified by flash dnomatogpphy (hexanpieihyl acetate). Method [1] Retention time 0.57 min by HPLC (MH+ 210).

[00639] 1 -methy 1-4-(3--utrothlophen-2~y 1)-1 //-imidazole was reduced according to protocol P to yield 2-( 1 -meShy 1 -1 H-hnidazoi-4-y 1 jthiophen-3-amine.

Method [6] Retention time 0.35 min by HPLC (MH+ 180), 9,2,4, 2^'4~Meih&amp;x}iphenyi)~N~(2~(I~meihyi~lH~midsz^i~4~yi)thmpken~3~ jijaeefamide 100640] The title compound was prepared from 2-( 1 -methyl*· IHdmidazol-d-yl)thiophen-3-amine and 2-(4-methoxyphenyl)aeetic acid using protocol B and was purified by HPLC. Method [8] Retention time 3.55 min by HPLC (MH+ 328). 3H NMR (300 MHz, DMSO) δ 1037 (s, 1H), 8.33 (s, 1H), 7.48 (3m, H), 7.26 (d, 3=8.4 Hz, 2H)> 6.92 (d, 3=8.4 Hz, 2H), (s, ό.Η), 3,60 (s, 2H). 9,3, Synthesis of ,V"(2-T1//“teidnzol-4-yi)thlopIieffi-3“y%2-(4“methoxy|iheayi)" acetamide (75)

9,33, 4-{THbutyist{mnyi)~l3ntyi~ni-4midezoie |0064i] 3 M Ethyl magnesium bromide in THF (5.0 ml, 15.0 mmol) was added dropwise to a solution of 4-iodo-l-trityj · I/f-iHajdazole (4,44 g, 10.2 mmol) in THF (100 ml) at -78°C After stirring for 2 h, tributyitin chloride (5,0 nil, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was concentrated under reduced pressure. The residue 'was flash chromatographed with .19:1, 9:1, 17:3, and 4:1 hexane:ethyl acetate as the eluant to yield 7.72 g of impure 4-(tributylstaimyl)-i-tri1yl-l//-imidazole as a yellow .solid. Method [7] Retention time 10.89 min by HPLC (MH+ 60! }. 9.3.2, 4-(3-Niirethiophm~2~yi}~l~irityi~lE-imidazoie 1006421 The title compound was prepared f|bm 2-chloro~3-mtiothiophene artl

4-(tributyjsiaunyl)-i drityl-lJMmida^le accordi^g tolhotoeolE. Yield: 2s43 g (56% over 2 steps from 4-iods<-l“txityl-i //-imidazole) of 4-(3-nitrotiviophen-2~yl)·- l-trityl- IH~ imidazole as a greenish-yellow solid. Method [7j Retention time 9.92 min by HPLC (M+Na=460). 93,3, 2~(3 T)rity!~lIl~!midaz&amp;l-4-yi)thtophm~3~amme [006431 The title compound was prepared from 4-(3-nitrothiophen-2-y 1)-1-trityl-l H-imidazole using protocol F (1.27 g, 95% yield) as a red viscous liquid. Method [7] Retention time 5.51 min by HPLC (MLNa—43G). 9.: 3.4. 2-{4-Met.h&amp;xyphenyi}~N-{2-{l 4riiyi~lH~miS&amp;z0l-4~yl)tMopken~3~yi)acemmide [00644] [0007] The title compound was prepared from 2-{1~ΐηίγΜΗ-irmdazol~4~yI)tMopheii~3-amme and 2-t’4~methoxyfphenyl)acetic acid using protocol B (561 trig, 59%) as a brown solid. Method |7] Retention time 9.46 min hv HPLC (MHi-556), 9,3.5. N-(2~{lH-imidazol-4"yl}thkipken-3-yi)~2~{4~mgthoxyphenyi}®cetamide [00645] 2-(4-Methoxyphenyl)~iY-(2-(i-trityl-lH-imida2ol-4~y!)thiop3ien-3-yliacctamidc (561 mg, 1.01 mmol) in TFA (10 ml) was stirred for 1 h. The solution was concentrated under reduced pressure and the residue was directly purified by HPLC to yield /7-(2-( li7-imidazol-4-yl)thiophen-3-y!)-2-44-methoxypherfyl)acetaniide. Method [8] Retention time 3.37 min by HPLC (MH+ 314). {H NMR (300 MHz, DMSO) δ 10,28 (s, 1H), 8.60 (s, 1H), 7.59 (s, IH), 7.53 (d, J=5.7 Hz, 1H), 7,49 (d, J-5.7 Hz, 1H), 7.23 (d, 1-8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 3.73 (s, 3H). 9.4. Synthesis of<¥-(2-(iff-imidazol“4”y!)tliioplieii-3-yI>"2“(2“OxO”3i4“ difeydroq«tsso1isj~.t(2/i)~yl)acetaisilcte (76)

8 4,1. 2~{2~Oxo~3>4~dikydr&amp;qxi?!<}lm~l(21$)^§-N-(2-{2~iriiyi-llfcMM8z&amp;i--&amp;-yi)1k&amp;phex-3-yl)acet8mide [006461 The title compound was prepared from 2-(! -trityl- IHrimidazoM-yljdnopherKhsmLse and 2-(2-oxo-3.4-dshydroq\ii«ofii:vl(2l-:!)-yriacet.!C acid «.sing protocol B (269 nig. 32%). Method [7] Retention time 9.32 min by HPLC (MH+ 593). yijacetimide [00647J The title compound was prepared from 2-(2~oxO”3,4-diiiydroqumolin“ l(2/f)-yl)-jV-(2 -(1- trityl-li7-imidazol-4-yl)tbiophen-3-yl)acetamide (269 mg, 452 umol) as described in Example 9.3.5. and was purified by HPLC. Method [8] Retention time 3.74 min by HPLC (MH+ 353). !H NMR (300 MHz, DMSO) 8 10.58 (s, 1H), 8.52 (s, HI), 7.65 (| IH), 7.54 (s, 2H), 7:22 (m, 2H), 6.99 (p, 2H), 4.68 §, 2H), 2.95 (m, 2H), 2.66 (m, 2H). 9.5. Synthesis of 2»(4-metfaoxypfaenyI)7V-(2-(2-4®ethyMHTmMa^M~ y!)th 8©phen-3-yf)aeet»Biide (77)

9.5. L 2~Metkyi^-(tnlmtyistiin^i)~ I-drityl-IH^idaz/ote |00648| 3 M Ethyl magnesium bromide in THF (6.0 ml, 18.0 mmol) was added dropwise to a solution of 44odo--2-metbyl-l~irilyl-l//-iraidiizoie (5.30 g, 11.8 mmol) in THF (100 ml) af ~WC. After stirring |br 2 h, tribuiyUin chloride (3.0 ml, 18.4 mmol) was added, After stirring for an additional 2 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated ondeii reduced pressure to yield 8.49 g of impure 2--methyl*4^tributylstannyl)-1/'/“imidazole as a orange liquid. Method }71 Retention time .11.32 min. by HPLC (MH+ 615). 9.5.2, 2~Metkyl~4~{3~miri}tkiophen"2--yt)--i-trityl-lH4midaz&amp;le [00649J The ti tie compound was prepared from 2~methyi~4~(iributylstannyl)-1 -trityl-lH-imidazoIe and 2-ch1oro-3-nitrDthiophenc using protocol E (3.43 g, 76% over 2 steps). Method [7] Retention time 8.87 min by HPLC (M+Na-474), 9.5.3, 2~(2~Methyi~$~irityi~IH~midez&amp;$-4~yi)tkk)phen~3~umme [00650] The title compound was prepared from 2-methyi-4-(3-nitroihiophen-2-yl)-l -trityl-lH-imidazole using protocol F (1.33 g, 100% yield). Method [7] Retention time 5.42 min by HPLC (M-HNa=444). 9.5.4, 2~{4~Meiho:%yphenyl}~N42~{2-meihyl-i~trti)2~lM4mid{iziii~4~}4}thhipken-3-yi)mceinmide.

[00651J The title compound was prepared from 2-(2-methy3-l -trityl-1 H-imidazoM~yl)thiophe«~3~arame and 2-(4-methoxyphenyi}aeetic add using protocol B (540 mg, 57%), Method [7] Retention time 7.42 min by HPLC (MH+ 570). 9,5. J. 2~(4~Meih&amp;xyphenyl)~N~{2~(2~metkyi-lM-imiduzot-4~yi)tMophen~3- yijaceiiimide 1006521 2-(4-metlioxyphenyl)-A'"(2~(2~methyl-1 -trityj- lii-iMdtizoM-yt)thiophen-3-y!)acctaimde (540 rag, 948 mmol) in TFA (1| ml| was siirred for 1 h. The solution was soneesRatcd under reduced pressure and the residue was directly purified by HPLC to yield 2~(4-mefboxypheoy!)"AM2"(2-mcthyl-1 //-imidazoS~4-y! }thiophen-3-y|)acetamide. Method [8] Retention time 3.52 min by HPLC (MH+ 328). ’H NMR (300 MHz, DMSO) ft 10.02 (s, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.40 (d, J =5.4 Hz, 1H), 7.23 (d, 3-8.7 Hz, 2H), 6.89 (A, >-8.9 Hz, 2H), 3.73 (s, 3H). &amp;&amp; Synthesis ©f^(2^^ffieifeyl~t^!midazol"4-yl)tMopheii^~|i)-2-{2~e3Efp3, dihydroqalnii!ln~l{2S>-yI)aceiamide (78)

$h$$roquinoim~.l (2H}~yi}acetmdde [00653! The tide compound was prepared ftorn 2-(2-®*eHy!~.l -trityl-lH- imidaaoMrylhluophen·3-amino and 2-(2-ax0-3,4-dihydroqu media-1(2H)-yl)aeetic acid using protocol B (123 jag). Method [7] Retention tiros 7,33 min by HPLC (MH-r 609), &amp;&amp;&amp; Md2~(2-Msihyi~lH~imidazo^yl)ihiophm^~yi^{2--om-3f4*-dU^dnb· qmnoUit~l(2M)~yl}acetumidii [Θ0654J iV-(2~(2“Siethyl-1 -trityl-1 /f~imidazoi“4”y3}thiophea-3~yl)”2~(2~oxa-3.4-dihydmqumoi;;:·· ] (27/)-yl)acetaunde (125 mg, 205 mmol) in TFA (5 ml) was stirred for 1 h. The solution was concentrated under reduced pressure and the residue was directly purified by HPLC to yield Λ-(2-(2-methyl-lT/-imidazo3-4"yl)thiophen~3~yI)-2~(2~oxo-3,4-dihydroquinolin-l(2£Q-yl)acetamide. Method [8] Retention time 4.05 min by HPLC (MH+ 367). !H NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 7.57 (m, 2H), 7.43 (d, JN4.8 Hz, 2H), 7.22 (m, 2H), 6.99 (m, 2H), 4.68 (s, 2H), 2.92 (m, 2H), 2.59 (m, 2H), 2.46 <s, 3H). %!f· Synthesis ofi^{2-(L®4mMaz0l“l~yJ)lhtephen*3^ip*(n&amp;phlM£m-l~ y!)aeetamide (79)

9.7.L J~0Mtmthi0phen~2~)4}-IM~mM(iZ&amp;le [3MM5§| Insidaxole (860 mg, 12,63 mmol) was added 10 a solution of2-chlon>3-ititro-ihiophcne (lg, 6,10 mmol) in abs. ethanol (20:mL). The reaction mixture was heated to reflux in a sealed tube for 3 days and then concentrated under reduced pressure. Purification by flash chromatography (silica, 25:75 ethyl/hexaae) gave 1-(3-nitrot.biophen-2-yl)-l//rimida2ole (540 mg, 45%), See Erker, T, I et al, «/. Heterocylk. Chem. 39 (2002) 857-861. Method [3] mix 195.9 (M+H); retention time « 0.615. 9,7,2, 2-(lH-imidazel~l~yl)thiopkm~3-mnme [00656] The title compound was prepared from 1 -(3-nitrothiophen-2-yi)-l//~ imidazole (540 mg, 2376 mmol) using the procedures of Example 1.97.2 (431 mg, 94%) and was used without further purification. Method [4] m/z 1:66:.0 (M+H); retention time = 0,227.

[08657] To a mixture of 1-naphthyl acetic add and 2-(lif-imidazoi-!-yi)tiiiophen-3-amine in anhydrous CH2CI2 was added 0~(7-azabenzotriazol-1 -yl)-.tV,iMA(Af-tetramethyi uranium hexafinompho^hato and ^methymo^holiae. A small amount of BMP was added to help starting material reagents go into s^iitidri. The reaction retire was stirred overnight under M2 (g) inlet and evaporated under reduced pressure. The resulting residue was purified by flash eotarnn ehrarnatagraphy (silica, 10:90 methanol/methyicne chloride) to aiford iV-(2-(li7~imida:n>i”l-yl)ihiopheii-3 -yi)2-(n£gpha|eii~l-yl)acetamide (209 mg, |3%), The dpaSed product was purified by preparative 1:1 PLC. Method [8] m/z 334.1 (M+H); retention time -- 4,885. ’H--NMR (CD3OD) δ 8.83 (s,.lH), 7.89-7.80 (m, 2H), 7.77 (d,J = 7.8 Hz, 1H), 7.51 (d,./-6.3 Hz, 211), 7.48-7.32 (m, 511),7.17 (d, J - 6.3 Hz, 2H), 4.08 (s, 2H). 9,8, Synthesis of of 2-(4-snethoxyphenyI)-/Y”(2-<4~i«etliyl-t//-lmidazoI~1~ yi)thiopheH-3--yI)aceifiwside (80)

'9.8.1. 100658] 4-methyf- 1 -{3~niifoduophon-2-yi}~l /^imidazole was prepared from 2-chioro-3-nitrothiophene and 4>mcthy MH-inudazole according to tile procedure described m Example 9.7.1., #ove. Purification by %§i column chromatography (silica, 40:60 ethyl aeetate/hexane) gave ttesitfo intermediate (1.26 g, 49%). (CDCij) δ 7.67 &amp;1H), 7.59 (d,,/ 6.1 Hz, IH), 7.19 (d,J= 6.1 Hz, 1H), 6.89 (s, 1H), 2.27 (s, 3H). 9.8.2. 2-{4~Metkyi~2H~imMez&amp;$~l-}i)thwpke!t-3-afflme [00659] 2-(4-methy{-l.i9-imida2»M-y.l)thiophen-3-amine was prepared from 4-methyl-1 -(3-nitrothiophen-2-yi)~1 H-imidazole according to the procedure described in Example 9.7,2., above. The amine intermediate (1.52 g, quantitative) was used without further purification , Method [4] m/z 180.1 (M+H); retention time ~ 0.236. 9.8.3. 2-(4-Methoxypkenyi}-N~{2~f4-methyl-2H4mMuz»i~^~ji)ikiepken-3·· yl)acetami4s [00660] 2-(4-methoxyphenyi)-i¥~(2~(4-methyHiT-imidazoH-y!)tMophen~3~ yl)acetamide was prepared from 2~(4-methoxyphenyl)acetie add and 2-(4-methyl-1H-iroidaz»l-l-yl)thiophen-3-anniie according to the procedure described in Example 9.7.3., above. Purification by flash column chromatography afforded the final product (silica, 75:25 ethyl aceiate/hexane) (77 mg, 6%). Method [7] m/z 328.0 (M+H); retention time = 1.001. !H-NMR (CDCb) δ 8.00. (broad s, 1H), 7.77 (d, /= 6.4 Hz, 1H), 7.16 (s, 1H), 7.13 id,/= 8.7 Hz, 2H), 6.85 (d,/= 8.7 Hz, 2H), 6.50 |s, 1H), 3.81 (s, 3H), 3.65 (s, 2Γ1). 2.15 id, /=0.9 Hz, 2H),

Thiophene Pyraztae Analogs 10.1, Synthesis of 2d4~methoxypiseay])-A^-{pyraziiu2~yi}thiophen-3~ yljacetarmde (81)

[Ift66f| The title compound was prepared. From 2-(tnbuiylslannyi)pyraKitie and 2-eMoro3mittothk>phene using protocol E and was pufifled by flash chromatograpy (hesane:ediyl acetate), Method [7] Retention time 238 mm by HPLC (MH+ 208), 1 Θ. 1,2, 2~{?ymzm~2~)'i)thh»pke*i"3-®mim (00662] The title compound was prepared from 2-(3-nitrothiophen-2-yl)pyrazine using protocol F. Method [8] Retention time 2.17 min by HPLC (MH+ 178). 1 ¢, 2.3, 2~{4~Meik()x\phmyi}~N-{2~(p}ruziw-2-x4)tkwphm~3"yi}aceMmide )00663] The title compound was prepared from 2-(pyrazin-2-yl)thiopheii"3“ amine and 2-{4-methoxyphenyl)acet!c acid according to protocol B and was purified by HPLC. Method [7] Retention time 5.91 min by HPLC (MH-r 326). NMR (300 MHz, DMSO) δ s ¢11.02, ill), 8.81 (d, 1=0.9 Hz, 1H), 8.45 (d, 1-2.7 Hz, 1H), 8.26 (m, 1H), 7.92 (d 3=5.4 Hz, 1H), 7.74 (d 3=5.4 Hz, 1H), 7.33 (d 8.7 Hz, 2H), 6.99 (d, J=8,7 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H). 10,2, Synthesis of ,¥»(4-cyano~3-(pyrazln-2-yl)thlophen~2~yI)-2-(quinoMu'-5» yl)aeetamide

Μ 2d. 4-Br0mo-5-nitrothwphMe~3~c8rh0mtrHe [0Θ664] The title compound (2,8 g, 71 %) was prepared from 4-broirtolliiopliene-3-earbonitrile (2,9 g, 15.5 mmol) according to the procedure described in U.S, Patent Application Publication 20080214528 (p. 25), Rf= 0.48 (20% EtOAc/hexanes; silica); !H NMR (300 MHz, CDCh) 8 8.12 (s, 1H). 10.2.2. S-Nltm~4~(pym^n^yl)ihiophene-3~cerbmUrile [80665) To a solution of 445romG~5mitrottue'phene-Tmarbomiriic (312 mg, .1.34 mmol) in dioxaiic (4 mL) was added teP^is(triphe-iyipbospMiie)palladiutri(()} (154 mg; 0.133 mmol) and tnbutylstarmylpyrazine (794 mg, 2.15 mmol). This was healed by microwave irradiation io 140°€ for 30 min. The reaction mixture was concentrated trader reduced pressure, and the residue purified by flash chromatography to afford -be idled compound (166 mg, 53%}: !*= 0.33 (20% EtOAe/hcxanes; silica); HPLC method [4], retention time - 1.45 min: MS(ESI) 233.0 (MH+). .M 2 3i S~A mimfddp}^szi^~2~yidkkiphgrse~3~i!atbimiiriie [00666] To 5~miro4-(pyrazth-2-y[)thiopherie~3^cafl>otiitri!e (166 mg, 0.72 mmol) in cone HO (3 mL) at it w as added tin(ll) chloride (327 mg, 17 mmol). This was sited at m for 2 h, whereupon the reaction mixture was basiHed with aqueous NaOH and extracted With EfOAc, The combined organic extracts were dried (Ν^δΟ.*), filtered and concentrated to give a brown oil (31 mg, 21%), HPLC method [4], retention time ~ 1.458 min; MS(ESl) 203.1 (MH+). 16.2.4, N-i4~Cyam-3-(pyruzki~2~yl)thkipken~2~yl)~2-{qmmUn-S-^i}metamlde [80667] The title compound was synthesized from 5-amino-4-(pyrazm-2-yi)thiophenc-3 earbomtrile (30.5 mg, 0,15 mmol) and 2-(quinolin~5~yl)aoetic acid hydrochloride (36 mg, 0.16 mmol) according to protocol A. The product was purified by HPLC method [4|, retention time == 1.393 ms; MS(M) 372,1 (MBf); XM NMR (300 MHz, CB|DD) δ 9.30 (4 / = 1.5 Hz, !H), 9,06 (dd, /= 4|, 1.3 H|, TH), 8.99 (d, /= 8.5 Hz, 1H), 8i51 (4 J- M Hz, 1H), 8.29 <4/= 1 «9 Hz, 1HX 420 (4/ = M Hz, 1H), 8.09 (dd, /= 46,7.1 Hz, 1H), 7.95 (s, 1H), 7.93 (4 /= 6:7 Hz, 1H), 7,86 (dd, J= 8,6,4.9 Hz, 1H), 4.55 (s, 2H).

Example 11

Synthesis of 2-(lsoquiiiolIn-S-yI>-IV~(4~{pyrszta~2~yI)tMa2ol-5-yl)aeetiimide (82)

ILL iert-Bttiyl 4-brofmHkiaio(-5~ykarham«fe [00:668|: To a solution of ien-baiy; thiazo1~S~yicarbamate (WO 2007/0?] 955) (607 mg, 3,0 mmol) in chloroform (50 mL) was added Λ-brotnosuccinajide (542 mg, 3-04 mmol) at 0 °C. After 1 h, reaction was quenched by addition of saturated NaHCOa solution (50 mL·), The layers:were separated, and the mixture extracted with CHOU (3 x 50 fiiL), The combined organic extracts were dried (MgSO-Os filtered and smneentrated. SH NMR (CDCh) £8.37 (d, J - 0.6 Hz, 1¾ 7,05 (hr s, 1H), 1.55 (s, 9H| MH+ 278.¾ 11,2 teri-Butyi 4-(pyrazm~2~yi)ihmz&amp;l-S-yi€arbamute

imm] a mixture of reri-buiyl 44)rQmothiazol-5-yicarbamate (420 mg, 1.5 mmol), teti^is(triphenylp|pspMne)palladhim(0) (170 mg, 0,15 mmol) and &amp;fri|utyL stamsylpyrazine (930 mg, M mmol) in anhydrous dioxaae (4 mis) was heated to 14Θ °C in a microwave reactor for 2 h. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes) t© give the desired produet (26# mg, 62%), lHNMR (®C13) £11.10 (s, 1H), 9.47 (d, ./= 1.4 Hz, 18), 8.52 (t, J*2.0 Hz, IK), 8.45 (d, J= 2.7 Hz, 18), 8.40 (s, 1H), 1.58 (s, 9H); ΜΙΉ 279,0. 11.3. 2-(faaqwnGMti~5-yi)-N-{4-(pymuit~2-yl}thiazfil~5~yl)aceMmide |00>670] To a solution of #m~butyl 4-(p>Tazin-2-yi)thia.7oi-5-yiearbamate (260 mg, 0,94 mmol) in CH2CI2 (1 ml.) at 0 °C was added trifluoroaceuc acid (i mL) and the mixture was allowed to warm to it over 1 h. The solvent was removed in vacuo add the crude product was used without further purification.

[006711 The crude 4-(pyrazin-2-yi)thiazol-5-am«ne was coupled with 2-(isoquinolin~5~yl)acetic acid hydrochloride using procedure A and was purified by ΗΡ1.Γ purified to afford desired material as a whits trifluoroacetic acid salt (107 mg). Method [8]: rt === 3.71 min; *H NMR (CDClri S 12.16 (s, 1H), 9.80 is, 3 H), 9.48 (d, J -·· 12 Hz, 1H), 8.64 (d,./ === 6.4 1¾ 1H), 8.47 (s, 1H), 8.45 (d, 7=== 2.7 Hz. = H), 8.39 (d,7- 8.5 Hz, i H).. 8.31 (d, 7==== 6.5 Hz, 1H),8.I5 (d, ./- 7.2 Hz, 1H), 8.10-7.98 (m, 2H)S 4.45 (s, 2H); MH+ 348.0.

SyutlH=sis #j¥-(4?4,-bithiiizol-5-yl)-2-(lsoqiiiuolln-S“y!)acetariiIde (83)

1ZL tert-iButyl 4,4 !-biihiazol~5~yicarbamate [00672] A mixture of Aft-butyl d-bromothiazol-S-ylearbamate (590 mg, 2.1 mmol), teirakis(tripheuyiphosphine)palladium(0) (240 mg, 0,21 mmol) and 4-tribiitylsiannylthiazole (1.18 g, 3.2 mmol) in anhydrous dioxane (5 ml) was heated to 140 °C in a microwave reactor for 1 h. 'Hie reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAc/hexanes elution) to give the desired product (420 rng, 71%). MH+ 283.9.

[60673] Conversion of tert-Butyl 4,4’-biihiazt>i-5-yk-arbaixiaie to the above titled cotopttind was performed according tp the procedure detailed for the synthesis of 2-(isontomtiin-S->yf)~N~(4-(p5fiazim2-yl)ihkzoi-5-yl)aeetarnide. Method (4): rt == 1.22 min; JH MMR (74-MeOD) S9 73 (s, 1H), 8.79 (d, 7== 2.0 Hz, Ifi), 8.63-8.45 (m, 4H),

MO (d,J~ 1.1¾ 1¾ 8.09 (i, /- 7.8 Hz, 1H), 7.86 (d, /- 2.0 Hz, 1H), 4.58 (s, 2H); MHf 353. L

Ei«s>Is 13

Synthesis of 2"(4~methox¥piieiiyi)»A,-(2"(2-o50oxaxoiliiiii-3“yl)yitophen~3- yljacetamide (84)

'13,1. 3~f3--Nitr&amp;t/ii8pkm»2^l)exffwiidm~2kme [00674] Potassium /er/-butoxide (1J6 g* 16.6 mmol) and oxazolidin-2-one (1.90 g, 21.8 mmol) in DMF (50 ml) was stirred for 30 min, 2rehloro-3mitrothiophene (1.64 g, 10.0 mmol) was added and after 1 h, the solution was placed into a preheated oil bath at 100°C. After stirring for 1 h, the solution was diluted with brine and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 9:1,4:1,7:3, 3:2, and 1:1 bexaneteibyS acetate as the eluant to yield impure 3^3mittotMppheu-2"yl)oxazolidm-2<ine. Method [3 j Retention time 2 JO rhin by HPLC (MH+ 215) and (M-i-Na-237). 13.2. 3-0-A mimiihiophen-l-y!) oxazoUdin-l-om 1006751 The title compound was prepared from 3-(3-niirothiophen~2~ yl)oxazolidin-2-one according to the procedures of Example 1.97.2. Method [7] Retention rime 0.85 .min by HPLC (MH+ 185). 133. 2~0-Meth&amp;xyphenyi)~N~{2~(2~0xmxazolidm~3-}>l)tki{)phen~3~yi}metamide 108676] The title compound was prepared from 3-(3-aminothiophen-2--y!)oxazolidin-2~ons and 2“(4-meihoxyphenyl)acetic acid (510 mg, 3.06 mmol) using protocol B. The crude product was purified by HPLC. Method [7] Retention time 2.95 min by HPLC (MH+ 333), lH NMR (300 MHz, CDCl,) δ 8.14 (broad s, 1H), 7.39 (d, JH|,7 Hzs 1H)S 7.27 (d, J-9.G Hz, 2H), 7.06 (df j -5.7 Hz, 1 Hi. 6.92 (d, .1-9.0 Hz, 2H); 4.47 (m, 2HX 3.89 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H),

Example 14

Determination of Kinase Activities

Abbreviations

Muwmnnmwn\TO\\w»Ke [99677} [9008] DTI: DL-dithiothreitoi; DM50: dimethyl sulfoxide; BSA" bovine serum albumin; ATP: adenosine triphosphate; MAPK: mitogen-activated protein kinase; EDTA: ethyienediaminetetraacetic acid; HEPES: (4~(2-hydroxyeth.yl)-i-piperaztneethan esu 1 fonic acid).

Materials EPIW-1

Biotin-Jun-Jun 50mer {BlOT!N-I..C-Asn~Pro-Lys-iIe-LeU”Lys-Gin-Ser~Met-'rhr-I.eu-Asn-Leai-Ala-Asp-Pro-Vaui-Giy-Ser-Lett-Lys-Pro-His-Lea-Aig-Aia-Lys-Asii-Ser-Asp-

Leu-Leu-Thr-Ser-Pro-Asp-Val-Gly-Leu-Leu-I/ys-Leia-Aia-Ssr-Prc-Glu-Arg-Ghi-Arg-

Leu-OH) E-PIG-1

Biotin-ELK.-] 45mer (BlOTIN-LC-Pro-Gln-Lys-Gly-Arg-Lys-Pro-Arg-Asp-LeiJ-Glu-

Leu-Pro-Lcu-Ser-PrO'-Ser-Leu-Lea-Giy-Gly-Pro-Giy-Fro-giii-Thr-Leu-Ser-Pro-ne-Aia-

Pro-Arg-Scr-Pro-Ala-Lys-Leu-Ser-Phe-Gln-Phe-Pro-Ser-Ser-OH) EPIG-2

Biotin-ATF-2 35mer(BIOTIN-LC-Leu-Ala-Val-His-LyS”His-Lys-His-Glu-Met-r.rhr-l^u-

LyLS-Phe-Giy-PsO-Ala-yArg-Asu-.Asp-Ser-Val-Iie-Val-Ala-Asp-Gln-Tkr-Pro-Tbr-Pro-Thr-A rg-Ph e-Leu-0 H) aP383 (Upstate Biotech); aP385 (Cell Signaling Technology); SA-XL (High grade XL665~eonjugaied streptavidin SA-Xlent, CIS Bio International); Eu-ELKL-l-Ab (Fhospho- ELK-1antibody from Cell Signaling Technology labeled by Perkin Elmer with Lance En Wf 024); Eu-ATF-2-Ab (Phospho»ATF-2 antibody from Cell Signaling Technology labeled by Perkin Elmer with Lance Eu W.1024); Eu-Ser-63-Ab (Phospho-c-

Jun (Ser63) II antibody irons ( Vi) Signaling Technology labeled by Perkin Elmer with: Lance Eu W'1024); Eu-Ser-73-Ab (Phospho-e-Jun (Ser73) II antibody from Cell Signaling Technology labeled by Perkin Elmer with Lance Eu W1024); Eu~ELK~l~Ab (Phospho- ELK-1 antibody from Cell Signaling Technology labeled by Perkin Elmer with Lance Eu W1024); aJNKl/SAPKlc, aJNK2/SAPKla, aJNK3/SAPKlb, uJNKl/SAPKle, uJNK2/SAPKla, uJNK3/SAPKlb, MKK4/SKK1 active, MKK7M active, uMAPK2/Etk2, MEK.1 (active), ιφ38α/8ΑΡΚ2α and MKK6/SK&amp;3 (active) from Upstate Cell Signaling Solutions; K252a (A.G, Scientific); 506126 (Calbiochem).

Re&amp;settts Α\\\\\\ν«ί(Λ\\\\ν«»9 [00678J Reagents were prepared and stored as specified below. JNK buffer stock solution: 27 rsiVI BEPES (free acid), 1 mM MgCI;:, pH 7,0, prepared by media kitchen and stored at 4°C. ?Tk.' !<' .•‘5."'pjy; 50 mM HEPES, 0.1% BSA, 400mM NaCl, stored at 4°C.

0.5 M EDTA 0.5 M EDTA in DI water, stored at RT.

ImM. ATP

275.6 mg of ATP (MW 551.2) were dissolved in 500 mL D'i I'LO and stored at -2DCC 14,L Active MAFK TR-FRET Assay Procedure (1) Assay buffer #1 was prepared (JNK buffer stock solution, 0.0025% Tween, ImM DTT). (2) Assay buffer #2 was prepared (assay buffer #1,0.025% BSA), (3) Test compound solution preparation: 5X compound solution was prepared using assay buffer #1 with. 5% DMSO. The compound solution (lOplAyell) was added to a 384-well plate. (4) aMAPK preparation: aMAPK stock (iOOuf/ftti) was thawed from -80°C on ice, and aMAPK (10ng/2GpM).5ng/p.l) solution using assay buffer #2 was prepared. The aMAPK solution (2θμ1Λνοί1) was added to the plate. The plate was shaken and the enzyme was incubated with the compound at RT for 10 min. (5) ATP/substrate solution preparation: ATP and substrate stocks were thawed on ice. 2.5X ATP/substrate (75μΜ ATP/50nM ELK-1) was prepared using assay buffer#!. The ATP/substrate (20pl/wetl) was added to the plate. The plate was shaken and incubated at 30°C for Ihr. (6) EDTA preparation: 30rnM EDTA was prepared using 0.5M EDTA stock and assay buffer #1. The EDTA (Ιθμΐ/well) was added to the plate to quench the enzyme reaction; and the plate was shaken well. (7) Detection reagent preparation: £u-ELK-l-Ab and SA-.XJL stocks were thawed on fee. 4X Eu- Anii-ELK ·! /S A-Xl (2nM Eu-Ants-ELK-1/ 9.4nM SA-XL) using INK detection buffer was prepared. The 4X Eu-Anti-ELK-! /$A-XL solution (20pL wei!) was added to the plate. The plate was shaken and metibared at RT for Ihr before reading the plate on LJL using ratiomeiric method named HTRF. $4.2. Activep38 TR-FRET Assay

Procedures (1) Assay buffer #1 with ΘϊΘ025% Tween and ImM DTT was prepared using JNK buffer stock solution, (2) Assay buffer #2 with 0.025% BSA was prepared using the assay buffer #1. (3) Test compound solution preparation: 5X compound solution was prepared using assay buffer #1 with 5% DMSO. The compound solution (ΙΟμΙ/weil) was alied to a 38Jrwel! piate (Coming, Cat No. 3614); (4) aP38 preparation: aP3B stock (lOOug-'m·) at -80¾ was thawed on ice and a F3S (30ng/20pJ-1,5sig/pl) solution using assay buffer #2 was prepared. The P38 solution COgi/wcll) was added to the plate. The plate was shaken aid the enzyme was incubated with compound at RT for 10 min. (5) ATP/substrate solution, preparation: ATP and subsiiaie stocks wsrelhawed on ice. 2.5X ATP/substrate (75μΜ ATP/50nM ATF-2) was prepared using assay buffer #1, The ΑΤΡ/subsiraie (20jd/well) was added to the plate, the plate was shaken, and the plate was incubate at 30°C for Ihr. (6) EDTA preparation: 30mM EDTA was prepared using 0.5M EDTA stock and assay buffer #i„ The EDTA (IQpl/weil) was added to the plate to quench the enzyme reaction and the plate was shaken well. (7) Detection reagent preparation: Eu-Anti~ATF~2 and SA-XL stocks were thawed on ice. 4X Eu-Anti-ATE-2/SA-XL (2nM Eu-AstbATP-2 / 9,4nM SA-XL) whs prepared rising JNK detection buffer. The Eu-Anti-ATF-2/SA-XL solution |20,ul/weii) was added to the plate. The plate was shaken and incubated at ST for Ihr before reading the plats on LJL using raiiometric method named HTRF. M,1 Active JNK 1,2 md 3 TR-FRET Assay (1) Assay buffer #1 with 0.0025% Tween and 1 mM DT'f was prepared using JNK buffer stock solution. (2) Assay buffer #2 with 0.025% BSA was prepared using the assay buffer #1. (3) Test compound solution preparation: 5X compound solution was prepared using assay buffer #5 with. 5% DMSO. The compound solution (1 Onl/well'; was added to a 3 84-well plate (Coming, Cat No. 3054), (4) aJNKI, 2 or 3 preparation: aJNK stock (lG0ug/ml) at-80°C was thawed on ice and an aXNK (Lbng/'ml) elution was prepared using assay buffer #2. The aJNK solution (20pl/welf) was added to die plate and the plate was shaken. The enzyme was incubated; with the compound at RT for .10 min. (5) ATP/sabstrate solxdion preparation: ATP and substrate stocks were thawed on ice, 2.5X ATP/sisbstrate (e.g., 25μΜ or 2,5 mM ATP/50nM EPIW-1) was prepared using: assay buffer #1. The: ATP/substrate (2 Of Ewell) #is added fo the plate and die plate was shaken The plate was incubated at RT tor 15mln. Note; In an exemplary assay, the final ATP concentration was about 1 mM. (|| EDTA preparation: 30mM EDTA was prepared using 0.5M EDTA stock and assay buffer #1. The EDTA (ΙΟμί/well) was added to the plate to quench the enzyme reaction and the plate was shaken well (7) Detection reagent preparation: Eu~63 and SA-XL stocks were thawed on fee. 4X Eu-63/SA~XL (2nM Ell-63 / 9.4nM SA-XL) was prepared using JNK detection buffer. The Eu-63/SA-XL solution (20pl/well) was added to the plate and the plate was shaken. The plate was incubated at RT for Ihr before reading the plate on IJL using mtiometric method named HTRF. 14,4. Coupled JNK 1,2 md 3 TR-FBET Assay

Procedures (1) Asmg buffer With 0.0025% TWsen, C|01% 33|A, and ImM DTT was papered using INK buffer stock solution, (2) Test compound solution preparation: 5X compound solution, including EDTA background, was prepared using assay buffer with 5% DMSO. The compound solution (ΙΟμΙ/well) was added to a 384-well plate (Coming, Cat No. 3654), (3) uJNKl,2, or 3 activation reaction preparation: «JNK activation solution was prepared using assay buffer (l,6ng/ml MKK.4, 1.6ng/ml MKK7, 16ng/mi uJNK, and 20uM ATP final). The uJNK activation solution (35,«l/well) was added to the plate, the plate was shaken, and the reaction mixture was incubated with compound at 30°C for 60 min. (4) c-Jim substrate solution preparation: 50«M EPiW-1, c-Juu peptide, was prepared using assay buffer (15nM final), The EPIW-1 solution (15 μΙ/well) was added to the plate, the plate was shaken and incubated at 30'C for ¢30 min. (5) EDTA preparation: 30.mM EDTA was prepared using 0.5M EDTA stock anl assay buffer. The EDTA (3 ΟμΙ/weO) was added to the plate to quench the enzyme reaction and the plate was shaken well. (6) s Detection reagent preparation: Eu-73 and SA-XL stocks were thawed on ice. 4X Eu-73/SA-XL (2nM Eu-73 / 9.4oM SA-XL) were prepared using JNK detection buffer. The Eu-73/SA-XL solution (20μ1Λνε11) was added to the plate. The plate was shaken and incubated at RT ibr lbr before rea<hng the plate oksLJL using rahomeine method named HTRF. 14.5, Coupled MA PK2/£rk2 TR-FRET Assay

Procedures (1) Assay buffer with 0,0025% Tween, 0,01 % BSA, and ImM DTT was prepared using INK buffer stock solution, (2) 'J est, compound solution preparation: 5X compound solution, including EDTA baekgtmmd, was prepared using assay buffer with 5% DMSQ. The compound--solution (IQui/well) was added to a 384-well plate (Coming, Cat No. 3654). (3) uMAPKd:kk2 activation reaction preparation: uMA$iK activation solution was prepared using assay buffer (16ng/mi MEK1, I60ng/rnl uMAPK2/Erk2, and 60uM ATP tine!) The uMAPK activation solution (35pl/well) was added to the plate. The plate was shaken and the reaction mixture was incubated with compound at 3QC'C for 60 min, (4) ELK-1 substrate solution preparation: 50nM ELK-1 peptide was prepared using assay buffer (15nM final). The ELK-1 peptide solution (ISgbwell) was added to the plate. The plate was shaken and incubated at 30°C for 60 min, (5) EDTA preparation: 3GmM EDTA was prepared using 0.5M EDTA stock and assay-buffer. The EDTA (ΙΟμΙ/well) was added to the plate to quench the enzyme reaction and the plate was shaken well (6) Detection reagent preparation: Eu-E.LK.-1 .-Ah and SA-XL stocks were thawed m ice. 4X Eu-Auti-ELK-l/SA-XL (2nM Eu-An.ti-ELK-1/ 9.4nM SA-XL) was prepared using JNK detection buffer. The Eu-Anti-ELK- 1/SA-XL solution (20pl/well) was added to the plate. The plate was shaken and incubated at RT for 60min. before reading the plate on LJL using ratiometrie method named HIRE, 14.6. Coupledp38a'$A?K2a TR-FRET Assay

Procedures ||) Assay buffer with 0.0025% Tween, 0.01% BSA, and ImM DTT was prepared using INK buffer stock solution. (I) Test compound solution preparation: 5X confound solution, including EDTA background, was prepared using assay buffer with 5% DMSO. The compound solution (1 ΟμΙ/welf) was added to a 384-well plate (Coming, Cat No, 3654). (3) up38ia/SAPK2a activation reaction plptti; fp38a acfiyitfen solution was prepared using assay buffer (dSng/ml MKK6,480sgknl up38a and 6§oM ATP final). The up38a activation sOlidioh (35pl/wdi) was added to the plate. The plate was shakop and the reaction mixture was incubated with compound at 3G°C for 60 min. (4) ATF-2 substrate solution preparation: 50nM ATF-2 peptide was prepared using assay buffer (15nM final), The AI'F-2 peptide solution (15,ui/wei)} was added to the plate, the plate -was shaken, and the plate was incubate at 30°€ for 60 min. (5) EDTA preparation: 30rnM EDTA was prepared using 0.5M EDTA stock and assay buffer. The EDTA (ΙΟμΙ/wdi) was added to the plate to quench the enzyme reaction and the plate was shaken well. (6) Detection reagent preparation; Eu-Anti-ATF-2 and SA-XL stocks were thawed on ice. 4X Eu-Anti~A.TF-2/SA-XL (2nM Eu-Anti-ATF-2 / 9.4nM SA-XL) was prepared using JNK detection buffer. The Eu -Anti -A TF-2/S A~XL solution (2001/%¾] 1) was added to the plate. The plate was shaken and incubated at RT for 1 hr before reading the plate on IJL using rationictric method named HTRF.

Eiamolfc 15

Inhibition of Kalnk Acid Induced Thospte^Jo» Sppltte in Mice Hippocampi 110679] Excitoteie cell death can be induced experimentally by the administration of kairtic acid, a potent agonist of the kainate class of glutamate receptors. Peripheral injection, of kainic acid results in recurrent seianes and degeneration of select populations of neurons in the hippocampus. Activation of jnk is observed after kainic acid treatment in viva (see, e.g,, Jeon S. H. el a/., Experimental ami Molecular Medicine 2000, 31(4): 227-230 and KimY.-l. ei aL· Maiemles am£elfc2mL 11(2): M4-I50). Mice lacking the Jnk3 gene are resistant to kainic acid induced uprcgulation of phosphorylatcd c-jun (p-ejun) and hippocampal neuropil apotosis (see e.g., Yang D.D, et ah, Nature 1997, 389: 865*870). Pbosphoryiaicd c-jaa in wildiype mice is upregulafsd after kainie acid administration and haveilemonstratsd that this upregulation is inhibited by certain compounds of the present disclosure.

Methods [Wmi Females FVB/N mice (Taeonic) were treated by oral gavage (PO) with one 300 il|/kg dose QfN^chloro~3-(lH-l4»4"tr%zol-5"yl)thiophen-2-y1)-2-i jsoquiin>lin~5~y Oaeotemi.de or vehicle (0.9% saline) at a 5 ml/kg dose volume, Control animals" were dosed with vehicle. Thirty Jimmies Idler animals were treated intcrperitoneajly with 25 mg/kg of kainie acid or saline at a 10 ml/kg dose volume. Kainie acid was formulated in 0.9% saline. Four hours after kainie acid administration animals were euthanized by carbon dioxide and wen.' tr&amp;nscardially perfused with 0.9% saline. Brains were removed, and separated into left and right hemispheres. The hippoeampus was dissected from the right hemisphere, frozen on dry ice and kept at -80 °C until used for quantitation of p-ejnn levels,

[00681 ] Freweighed hippocampus tissues were homogenized in cold cell extraction buffer (CEB) containing 1% Triton X I00. 0.1% SDS, 0.5% deoxycholate, 20mM Na,P;;07! 2 ml Xa.VC),, ft, 1% SOS and protease inhibitors (FI, 2 rog/mL aproiinih and i mg/raL ieupeptin) §t a ratio o|9:l CEB to wet tissue weight Homogenized samples: were; analyzed using PathScan Phospho-e-Jun (Ser63) Sandwich ELISA Kit ΙΪ from Cell Signaling Technology. Samples were diluted 1:10 in sample diluent provided in the kit. An 8-poin· standard curve was prepared by diluting a 10 ng/mL phos-e-Jun standard 1 ;3 in 1:0% CEB/P1 in sample diluent. Samples and standards were added at 100 μΐ per well to preweiied EIJSA plaics which contain a phos-c-jun(ser63)-speciflc rabbit monoclonal capture antibody and incubated overnight at 4 °C. The plate was then allowed to warm to room temperature and washed three times using TBS+0.05% Tween 20 (TTBS), To each well were added 100 pL of a mouse monoclonal c-Jim detection antibody and the plate was incubated at 37 °C for 1 hour. The plate was washed three times in TTBS, then 300 ^iL per well of an anti-mouse IgG HRP-Hnked antibody was added. The plate was incubated at 37 °C for 30 minutes and was then washed three times in TTBS, To each well were added 100 pL of TMB substrate and the plate was incubated for 10 minutes at 37 °C. Then stop solution was added, The colorimetric reaction was read using a Molecular Devices Spectramax plate reader and sample data was calculated from the standard curve fit to a 4-parameter function.

Easts! is P0682J Treatment with 300 mg&amp;g of N-(4-cMom>i3-{ WT Ji4-fria^>l"5-yl)thiophen'2-yi)~2“(isoq'uinoliffi-5-ylpoetasjiide resulted in a staistieally significant ftppaired t-test) 51fo reduction ofps^jun in the Mppoeampus of F¥B mice 4 hours after treatment with ka inie acid. The results are sunnrtartzed iff Table % below. mm* N~(4-ehloro-3-{HI“l,2,4-trla2o!--S-yl)thiophen-2-yl)-2-(i«'iqniueiiis~S-yl)acetamidc Inhibits Kalnic Add Induced Phospho-cJnn Upregnlstion in Mice

Claims (17)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-

1. A compound having a structure according to Formula (I):

(»). or a salt or solvate thereof; wherein ring A is 5-membered heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, Cs-Cio-cycloaikyi, 3-to 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR12, SR12, NR12R13, C(0)R14, C(0)NR12R13, OC(0)NR12R13, C(0)OR12, NR15C(0)R14, NR15C(0)0R12, NR15C(0)NR12R13, fs|R16C(SpR12Ri3s MR15SP)2R14, S(0)2NR12R13, S(0)R14 and S.(Q)zR14. wherein R12, R13 and R15 are independently chosen from H, acyl, Ci-Ce-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-Cs cycloalkyl and 3- to 8-membered heterocycfoalkyl, or R12and R13, together with the nitrogen atom to which they are bound form a 5-to 7-membered heterocyclic ring; and R14 is chosen from acyl. Ci-Ce-aiky!, 2-- to 6-membered heteroalkyL aryl, 5- or 6~membered heteroaryl. Cs-Cg cycloalkyl and 3-to 8-membered heterocycloalkyl; Ca and Cb are carbon atoms, which are adjacent to each other and are past of ring A; Z is triazole optionally substituted with alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, -R3, -OR®, -SR3, =0, =NRa, =N-GRa, ~NRaRb, -halogen, ~SiRaRbRc, ~0C{0)Ra, -C(0)Re, -C(0)GRa, -C{0)NRaRb, -0G(0)NRaRb, -NR°C(0)Re, -NRcC(0)NRaRb, ~NRcC(S)NRaRb, -MRcC{G)ORa, -NRcC(NRaRb)=NRd, -S(0)Re, -S(0)zRe, ~S(0)2NRaRb, -NRcS(0)2Ra, -CN, -NCte, -Ns, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, where when two R groups are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 8-, or 7-membered ring; wherein Ra, Rb, Rc, Rd and Re each independently hydrogen, C1-C24 alkyl, C3-C10 cycloalkyl, G1-G24 heteroalkyl, C3-C10 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and wherein where two R groups are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 8-, or 7-membered ring, Rs is chosen from H, acyl, substituted or unsubstituted Ci-Ge alkyl, and C3-C6 cycloalkyl; W is chosen from C1-C4 aikylene, wherein the alkylene is optionally substituted with 1 - 4 substituents independently chosen from alkyl, alkenyl, alkynyl, haloaikyL heteroalky!, C3~Cs~cycioalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5~ or 6-membered heteroaryl, CN, halogen, OR42, SR42, NR42R43, C(0)R44, C{0)NR42R43, 0C(0)NR42R43, C{0)0R42, NR4SC{0)R44, NR45C(0)0R42, NR45C{0)NR42R43, NR45C(S)NR42R43 NR45S(0)2R44, S(0)2NR42R43, S(0)R44, and S(0)2R44, wherein R42, R43 and R45 are members independently chesen from H, acyl, Ci-Cs-a!kyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R42 and R43, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring;and R44 is independently chosen from acyl, Ci-Ce-alkyl, 2- to 6.-membered heteroalkyl, aryl, 5- or 6-membered heteroaryi, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyl, heterocycloalkyl, aryl; and heteroaryi, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryi is optionally substituted with 1 - 6 substituents independently chosen from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryi, CN, halogen, OR52, SR52, NR^R53, C(G)R54, C(0)NR52R53, 0C(0)NR52R53, C(0)GR52, NR55C(Q)R54, NR65C(0)GR52, NR55C(0)NR52R53, NR55C{S)NR52R53, NR55SiO)2R54, S(0)2NR52R53r S(0)R54 and S(0)2R54! wherein R52, R53 and R55 are independently chosen from H, acyl, Ci-C&amp;-alkyl, 2- to 8-membered heteroalky], aryl, 5- or 6-membered heteroaryl, Cs-Ce. cycloaikyl and 3- to 8-membered heterocycioalkyl, wherein R52 and R53, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; R54 is independently chosen from acyl, Ci-Ce-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-Cg cydoalkyl and 3~ to 8-membered heterocycloalkyl; the optional substituents of the alkyl, alkenyl, alkynyl, heteroalkyl, cycloaikyl, and heterocycioalkyl groups of Cy include one or more substituents independently chosen from 3- to 10-membered heteroalkyl, C3-C10 cycloaikyl, 3- to 10-membered heterocycioalkyl, aryl, heteroaryl, -ORa, -SRa, =0, =NRa, =N-ORa, -NRaRb, -halogen, -SiRaRbRc, ~0C(0)Ra, ~C(0)Re, -C(0)GRa, -C(0)NRaRb, -OC(0)NRaRb, -NRcC(0)Re, -NRcC(0)NRaRb, -NR°C(S)NRaRb, -NRcC(0)0Ra, -NRGC(NRaRb)=NRd, -S(0)Re, -S{0)2Rss -S{0)2NRaRb, -NRcS(0)2Ra, -CN, -NO2, wherein Ra, Rb, R°, Rd, and Re are each independently hydrogen, Ci~C24 alkyl, C3-C10 cycloaikyl, C1-C24 heteroalkyi, Ga-C-io heterocycioalkyl, aryl, heteroasyl, arylaikyl, and heteroarylalkyl, and when two R groups are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5~, 6-, or 7-membered ring; and the optional substituents of the aryl and heteroaryl groups of Cy are independently chosen from alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, -Ra, -OR8, -SRa, =0, ~NRa, =N-ORa, -NRaRb, -halogen, -SiRaRbRc, -0C(0)Ra, ~C(0)Re, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, * NRcC(0)Re, -NRcC(0)NR8Rb, -NRcC(S)NRaRb, -NRcC(0)0Ra, > NRcC(NRaRb}=NRd, -S(0)Re, -S(0)2Re, -S(0)2NRaRb, -NRcS(0)2Ra, -CN, -NO2, -Ns, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci- Chalky!, in a number from one to the total number of open valences on the aromatic ring system, wherein Ra, rcs ancj j^e are independently hydrogen, C1-C24 alkyl, C3-C10 cycloalkyl, C1-C24 heteroalkyl, C3-C10 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, and when two R groups are attached to the same nitrogen atom, they can he combined with the nitrogen atom to form a 5-, 8-, or 7-membered ring; wherein the aryl groups are chosen fem 5-, 6- or 7Hmernbered, aromatic carbocyclic group having a single ring or being fused to other aromatic or non-aromatic rings; and wherein the heteroaryl groups are chosen from polyunsaturated, 5-, 6- or 7-membered irpmatic rti

ty containing at least one heteroatom chosen from N, O, S, Si and B, wherein the nitrogen and sulphur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quarternized, and wherein the heteroaryl groups can be a single ring or be fused to other aryl, heteroaryl, cycloalkyl or heterocycloalkyl rings.

2. The compound of claim 1, wherein the compound ha** a structure according to Formula (IV), Formula (V), Formula (VI) or Formula (VII):

(IV) ;

(V) ;

iVh: or

(VII) or a salt or solvate thereof, wherein R2 and R-s5 are independently chosen from H, Ci-ChalkyI, C1-C4-alkenyl, Ci-C4-alkynyl, Ci-C4-haloalkyl, 2-ίο 4-membered heteroalkyl, Ca-Ce-cycloalkyl, 3- to 8-membered heterocycloalkyl, CN, and halogen; wherein the moiety

is

wherein R4 is chosen from H, C1-C4 alkvl, Ci~C4 alkenyl, Ci-C4 alkyoy C1-C4 haloalkyl, Cs-Ce cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, 5- or 8-membered heteroaryl, CN, halogen, OR17, SR17 and NR17R18, wherein R17 and R18 are independently chosen from H, acyl Ci-Ce-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-Ce cycloalkyl and 3~ to 8-membered heterocycloaikyl, wherein R17and R18, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring.

3. The compound of c aim 2, wherein ring A is chosen from thiophene and thiazole, wherein the thiophene or the thiazofe is optionally substituted with 1 or 2 substituents chosen from Ci~C4-aikyl, Ci-C4-alkenyl, Ci-C4-alkynyl, C1-C4-haloalkyl, 2- to 4-membered heteroalkyl, Ca-Ce-cycioalkyl, 3- to 6-membered heterocycloalkyl, CM, and halogen.

4. The compound of claim 2, wherein the compound has a structure according to Formula (IVa), Formula (Va), Formula (Via) or Formula (Vila):

(IVa);

(Va);

(Via); and

(Vila) or a sail or solvate thereof, wherein R4 is chosen from H, methyl, and cyclopropyl,

5. The compound of claim 1, wherein W is methylene (-CH2-).

6. The compound of claim 1, wherein R5 is H.

7. The compound of claim 1, wherein Cy is chosen from phenyl, naphthyl, quinoline, isoquinoline, quinoxaline, quinazoline, quinQlin-2-Qne, 3,4-dihydroquinolin-2-one, 3,4-dihydro-1,5-naphthyridin-2-one, and 3,4-dihydro-1,8-naphthyridin-2-one, each optionally substituted with 1 · 8 substituents independently chosen from Ci-Ce-alkyl, Ci-Ce-alkenyi, Ci-Ce-alkynyl, Ci-Ce-haloaikyl, 2~ to 6-membered heteroalkyl, Cs-Ce-cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, 5~ or 6-membered heteroaryl, CN, halogen, OR52, SR52, NR52R53, C(0)R54, C(0)MR52R53, 0C{0)NR52R53, C(0)0R62, nr55c(0)r54s NR55C(0)0R52, NR55C{0)NR52R53, NR55C(S)NR52R53, NR55S(0)2R54, S(0)2NR52R53, S(0)R54 and S(0)2R54,......

8. The compound of claim 7, wherein Cy is optionally substituted quinoline.

9. The compound of claim 7, wherein Cy is optionally substituted isoquinoline.

10. The compound of eilim 7, wherein Gy is optionally substituted quihplin-2-one.

11. The compound of claim 10, wherein the Cy is quinolin-2-one substituted with at ieast one Ci-Cs-haloaikyL

12. The compound of claim 7, wherein Cy is optionally substituted 3,4-dihydro-1,6-naphthyridin-2~one.

13. The compound of claim 7, wherein Cy is optionally substituted 31 dihydro-1,5-naphthyridin-2-one.

14. The compound of claim 13, wherein Cy is unsubstituted 3,4-dshydro- 1,5-naphthyridin-2-one.

15. The compound of claim 1, which Is N-(4-hromo~3-(1 H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2Hoxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide.

16. The compound of claim 1, which is N-(4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide.

17. The compound of claim 1., wherein Cy is selected from the group consisting of:

wherein: R20a and R20b are each independently chosen from Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkynyl, Ci-Ce-haloalkyl, 2~ ίο 6-membered heteroalkyl, C3-Ce-cycloalkyl, 3- to 8-membered heteracycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR52, SR52, NR52R53, C{0)R54, C(0)NR52R53, 0C(0)NR52R53, C(0)QR52s NR55C{0)R54, NR55C(0)0R52, NR5SC{0)NR52R53, NR55C(S)NR52R53, NR55S{0)2R54, S(0)2NR52R53, S(0)R54 and S{0)aR54 v is an integer from 0 to 3; x is an integer from 0 to 4; z is an integer from 0 to 4; and a is an integer from 0 to 3. Dated this 23rd day of May 2016 Imago Pharmaceutical loo. Patent Attorneys for the Applicant PETER MAXWELL AND ASSOCIATES