AU2015215863C1 - 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 HIE DISCLOSURE

[091 ] This application claims priority from U.S. Provisional 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, die disclos ures each of which are incorporated herein by reference in their entirety.

[082] The present disclosure relates to inhibitors of c-Jun N-terminal kinases (JNKs). Hie 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. I'tMBJ 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 regulated kinases (ERKs), the p38 MAP kinases and the c-Jun N-temu’naJ kinases (JNKs), MAP kinases (MAPKs) are serme/threoniue kinases and are acti vated by a variety of signals including growth factors, cytokines, IjV radiation, and stress-inducing agents, MAPKs phosphoryiate various substrates including transcription factors, which in turn regulate the expression of specific genes, [004] Members of the JNK family are activated by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IX.—1 beta), as well as by environmental stress, including UV irradiation, hypoxia, and osmotic shock (see, e.g,, Minden ei al., Bïochemica el Biopkysica Acta 1997, 1333:F85-F104). Three distinct JNK genes, jnkl,jnk2 and jnk3 were identified and at least ten different splicing isofonns exist m mammalian colls (see, e.g., iJupta αί,, LIvtBU J, j.996s 15:2760-2770). |005j Down-stream substrates of JNKs include transcription factors c-Jun, ATF-2, Elkl, p53 and a cell death domain protein (DENN) (see, e.g., Zhang et aL Proc.

Mad. Acad. Sci. USA 1998, 95:2586-2591). Each INK isofbrm binds to these substrates with different affinities, suggesting a regulation of signaling pathways by substrate specificity in vivo (Gupta et aL, supra).

[806] 3NK$ have been implicated in mediaiiag a number of physiological responses and disorders including cellular-response 10 cancer, ilmmm in-induced platelet aggregation, irmnunodcficicney disorders, autoimmune diseases, ceü death, allergies, osteoporosis and heart disease. The therapeutic targets related to activation of the JNK pathway include chronic myelogenous leukemia (CML), rheumatoid arthritis, asthma, osteoarthritis, ischemia, various careers and neurodegenerauve diseases.

[CKiTjj Several reports have detailed the importance of INK activation associated with liver disease or episodes ofhepatlc ischemia (see, e.g., Nat. Genet. 1999, 21:326-329; FEBS Lm. 1997, 420:201-204; J. Clin, invest. 1998, 102:1942-1950; Hepatology .1998,28:1022-1030). A role for JNK in cardiovascular disease such as myocardial infarction or congestive heart failure has also been reported (see, e.g., Circ. Res. 1998, 83:167-178; Circulation 1998, 97:1731-7). The JNK cascade also plays a role in T-cel! activation, including activation of the 11,-.2 promoter (see, e.g,. J. Immunol. 1999, 162:3176-87; Eur. J. Immunol. 1998, 28:3867-77; J Exp. Med. 1997), A rede for j \ K activation in various forms of cancer has also been established. For example, eonstitutively activated JNK. is associated with HTLV-1 mediated tumorigenesis (Oncogene 1996, 13:135-42), JNK may play a role in Kaposi's sarcoma (KS) because it is thought that the proliferative effects ofbFGF and OSM on KS ceils are mediated by their activation of the JNK signaling pathway (see e.g., J. Clin. Invest. 1997. 99:1798804). Other proliferative effects of certain cytokines implicated in KS proliferation, such as vascular endothelial growth factor (VEGF), JL-6 and TNF alpha, may also be mediated by JNK, In addition, regulation of the e-jun gene in p2.10 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, 922450-60).

[008] While JNK.1 and JNK2 are widely expressed in a variety of tissues, JNK3 is selecti vely expressed in the brain and, to a lesser extent, in the heart and testis (see, e.g,, Gupta et a!., supra; Mohit etal.s Neuron 1995, 14:67-78; Martin et at, Brain Res. Mol Brain. Res. 1996, 35:47-57). JNK3 has been linked to neuronal apoptosis induced by kainie acid, indicating a role of JNK is the pathogenesis of glutamate neurotoxicity. In the adult human brain, JNK3 expression is localized to a subpopulation oipyrainidal neurons ία she CA I, CA4 and subiculum regions of the hippocampus and layers 3 and 5 of the neocortcx (Mohit etal·. supra). The CAI neurons of patients with acute hypoxia showed, strong nuclear JNK3 -immunorcacti vity compared So minimal, diffuse cytoplasmic staining of the hippocampal neurons from brain tissues of normal patients (Zhang ei at., supra). Thus, JNK3 appears to be involved in hypoxic and ischemic damage of CAI neurons in the hippocampus.

[009] Disruption of the JNK3 gene caused resistance of mice to the excitotoxic glutamate receptor agonist kainie 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).

[0Θ1Θ] In addition, JNK3 eo-loealizes immunochemically with neurons vulnerable in Alzheimer's disease (Mohit etal., supra). Based on these findings, INK. signalling, especially that of JlSKA has been implicated in the areas of apoptosis-driven nemo 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.

[§@111 Drug molecules that inhibit MAPKs, such as p38 are known (see, e.g., WO 98/27098 and WO 95/31451). However, inhibitors that are selective for JNKs versus other members of the MAPK family are rare (see, e.g., U.S. Patent Application Publication 20080033022). There is art unmet medical need for die development of potent, JNK specific inhibitors that are useful in treating the various conditions associated with JNK activation.

SUMMARY OF THE DISCLOSURE

[0012] In various aspects, the present disclosure provides for a compound having a structure a coot ding to Formula (I):

0) or a salt or solvate thereof, wherein ring A is 5-inemhered heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyt, haloalkyl, heteroalkyi, Cs-Cjo-eycloalkyl, 3~ to 8-mcmbcred hetexocycloalkyl, aryl, 5- or 6-mcmbcrcd heteroaryl, CM, halogen, ORi2, SRi2, 'NR12R°, C(0)R54, C(G)NR13R3i, 0C(O)NRiSR13, C(0)0R12, NR35C(0)Ri4, NRlsC(0)0Ria, NRiSC(0)NRi2R15, NRi5C(S)NRi2R13, MRlsS(0}:>RH, S(Q)2NR3iR!1 S(0)R14 and S(Ü)2Ri4, wherein R52, R.!j and R15 are independently chosen from B, c.eyi, Ci-Q-alkyL, 2- to 6-mcmbcred heteroalkyi, aryl, 5- or 6-mcmbcred heteroaryl, Cs-Cg cycloalkyl and 3- to 8-membered heterocycloalkyl, or R32and RDf together with the nitrogen atom to which they are bound form a 3- to 7-membered heterocyclic ring; and R14 is chosen from acyl, Q-Cl-alkyl, 2- to b-memhered heteroalkyl, aryl, 5- or ό-membered heteroaryl, Cg-Cg cydoalkyl and 3 to 8·membered heterocycloalkyl; C1 and Cb axe carbon atoms, which are adjacent to each other and are pari of ring A; Z is 5- or 6-membered heteroaryl, with the proviso that (!) when ring A is thiophene, then Z is not a heteroaryl chosen from benzoinudazole, thiazole, and benzothiazole; (it) when ring A is thiazole, then Z is not benzoimidazole; (in) when ring A is thiophene, then Z is not substituted oxadiazole; and (iv) when ring A is thiophene, then Z is not pymmdinone; R5 is chosen from H, acyl Ci-Cs alkyl and CyC6 cycioaikyl; W is chosen from Ci-Ca alkyiene, wherein the alkylene is optionally substituted with 1 -4 substituents independently chosen from alkyl alkenyl, alkynyi, haloalkyl, heteroalkyl, CrCVcyeloalhyi, 3- to 8-membered heterocycloalkyl aryl, 5- or 6-membered heteroaryl, CM. halogen, OR42, SR42, NR :;R CiO)R;H C(0)NR'i2R4\ OC(ö}NR42R4'-\ C(G)OR42, NR45C(0)R44, NR45C(Ö)ÖR42, NR4SC(0)NR42R”u? NR45C(S)NR42R4:i NR4ïS(O)2R44, S(0)2NR'u'R4'\ SCOfR44, and S(0)2R44, wherein R4-4, R"3 and R4j are members independently chosen from H, acyl, CVCe-alkyl, 2- to 6-membered heleroalkyl aryl, 5-or 6-membered heteroaryl, CyCs cycioaikyi and 3- to 8-membeied heterocycloalkyl, wherein R4^ and R4', together with the nitrogen atom to which they are bound are optionally joined to form a 5~ to 7-raembered heterocyclic ring; ami R44 is independently chosen front acyl, C] -CValkyk 2- to 6-membered hercroalkyl. aryl, 5- or 6-membered heteroaiyl, Q-Cg cycioaikyi and 3- to 8-membered beterocycioaikyl; Cv is chosen from cydoalkyl, heterocydoalkyl, aryl, and hetefoaryL wherem the cycioaikyi, heterocydoalkyl, aryl or heteroaiyl is optionally substituted with 1 - 6 substiiueuts independently chosen from substituted or unsubstitnied alkyl, substituted or unsubsiituted alkenyl, substituted orunsubstituted alkynyi, haioalkyl, substituted or unsubstituted heterouikyi, substituted or unsubstiiuted cycioaikyi, substituted or imsubsthuted heterocydoalkyl, substituted or onsubstituted aryl, substituted or unsubstituted, hetemaryl, CK halogen, OR52. SR52, NRS2R* C(0)R54, C(0)NRS2RS?, 0C(0)MR52R5i, C(0)ORi2, NR-;:C(OjR;-\ NR-'-CiO)ORr?, NRS5C(0)NR52RS·5, NRS5C(S)NR52R5i, NR^SjOjzR"4, SiObNR'^R·'1, SiO;R “ and SfOjjR'4, wherein Rj2, R53 and R53 are independently chosen, from H, acyl. Ci-Cs-alkyl, 2- to 6-membered heteroalkyl, and, 5-or g-mernbered heteroaiyl, Cj-Cg cycloalkyl and 3- to 8-membered heterocydoalkyl, wherein Rs* and RSl, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membercd heterocyclic ring; and R'4 is independently chosen from acyl, Ci-*Volkyi, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, CVCg cycioaikyi and 3- to 8-m.embered heterocyctoalkyi. The present disclosure further provides for a pharmaceutical composition comprising a compound according to Formula (I) and a pharmaceutically acceptable carrier, [Ö1113J The present disclosure also provides for compound having a structure according to Formula (VIII);

(¥111) or a tautomer, mixture of tautomers, salt or solvate thereof, wherein ring A is 5» or 6~ membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-3 substituents independently chosen, from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyi, Ci-Cjo-cycloalkyi, 3« to 8-membered heterocycloalkyl, aryl, 5~ or 6-membered heteroaryl, CN, halogen, OR1". SRNR12Ri3, C(p)R54, C{0)NRi2RL\ 0C(0)NR12R13, CiOiüR12, NR3'CiO}R:\ NR-500;QRs\NR1sOD)NR! ’R% NRi3C(S)NRi2Ri3t NRi5S(0’hR14, S(0)2NR%S3, S{0)R44 and S(0)2R3\ wherein R12, R° and R15 are independently chosen from H. acvh Cj-Cs-alkyl, 2- to 6-memhercd heteroalkyi. aryl, 5-or 6-membered heteroaryl, Ca-C» cycloalkyl and 3- to 8-membered heterocycloalkyl, or R]' and Ri3, together with the nitrogen atom to which they are bound term a 3- to 7-memhered heterocyclic ring; and R'4 is chosen from acyl, Cj-Q-alfcyl. 2- to ó-membsred heteroalkyi, aryl, 5- or 6-membered heteroaryl, Cs-Cs cycloalkyl and 3» to 8-membered heteroeyeloalky); 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, Ct-G alkyl, C1-C4 alkenyl, Cs-G alkynyl, C1-C4 haloalkyl, C3-C0 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl, and 5- or 6-membered heteroaryl, CN, halogen, OR;?, SR:7 and NRi7R18, wherein R3/ and R38 are independently chosen from H, acyl, Q-Q-alkyl, 2- to 6~membered heteroalkyi, aryl, 5- or 6-membered heteroaryl, CrCg cycloalkyl and 3- to 8-membered heterocycloalkyl, or Ri7 and R3®, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; R: is chosen, from H, acyl, Ci~ G alkyl, and C3-G cycloalkyl; W is chosen from C1-C4 alkyiene, wherein the alkyl one is optionally substituted with from 1 to 4 substituents chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyi, Cj-Cö-cycioalkyl, 3- to 8-m.em.hered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR42, SR42, NR42R43, C(0)R*s, C(0)NR42R4_\ OC(0)NR4V3, C(0)0R42, NR45C(0)R44, NR45C(0)ÜR42, NR45€(Ct)NR'l2R43, NR45C(S)NR42R43, 'NR45S(0)2R44, S(0;hNR42R43, S(0)R44> and S(0)2R445 wherein R42, R43 and R44 are independently chosen from H, acyl, Ci-CValkyl, 2- to 6-m.embered heteroalkyl, aryl, 5~ or 6-membered heteroaryl, Cj-Cg cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R4'1 and R43, together with the nitrogen atom to which they arc bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R44 is independently chosen from acyl-, Cj-CValkyi, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl Cs-Cs cycloalkyl and 3- to 8-membered heterocydoalkyl; Cy is chosen from cycioalkyi, heterocycioalkyl, aryl, and heteroaryl, wherein the cycloalkyl» heterocycioalkyl, aryl or heteroaryl is optionally substituted with 1 - 6 substituents independently chosen from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aikynyl haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycioalkyi, substituted or unsubstituted heterocycioalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, CN, halogen, OR52, SR52, NR52R53, C(0)R34, C(0)NRS2R53, 0C(0)NR52R53, C(0)0R52, NR55C(0)R54, NRS5C(0)0R52, NR53C(0)NRS2R53s NR55C(S)NRS2Rs'\ NR15S{0)2R54, S(0)2NR52R53, S(0)RS4 and S(0)2R34, wherein RS2, R* and R35 are independently chosen from H, acyl, Cj-Qralkyl, 2- to 6-membered heteroalkyl, aryl, 5-or 6-membered heteroaryl, Cj-Cs cycioalkyi and 3- to 8-membered heterocycioalkyl, wherein R42 and R42, together with die 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-CValkyi, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl,, Q-C* cycioalkyi and 3- to 8-membered heterocycioalkyl The present disclosure further provides for a pharmaceutical composition comprising a compound according to Formula (VIII) and a pliarmaceutically acceptable carrier, (60141 The present disclosure further provides for a compound having a structure according to Formula (X) or Formula (XT); (X)

(XI) or a salt or solvate thereof, wherein X1 is chosen from N and CR28; R2 and R2a are independently chosen from H, Ci-Cj-alkyi, CVib-alkenyL Ci-Q-alkynyl., C1-C4-haloalkyl, 2- to 4-membered heteroaikyl, C.rCfi~eycioaikyl, 3- to 6-membered heteroeycloaikyi, CN, and halogen; Ri0 and Rsi are independently chosen from H, Ct-CV alkyi, Ci-C<5-aikenyl, Q-Cs-alkynyl, Ct-Ge-haloalkyi, 2- to 6-mem.bered heteroaikyl, C3-Gs-cycloaJkyl, 3- to 8-membered heteroeycloaikyi, aryl, 5- or 6-membered heteroaryi, CN, halogen, OR42, SR42, NR42R13, C(0)R44, C(0)'NR42R43, 0C(0)NR42R43, C(0}0R42, NR45€(0)R44, NR4SC{0)OR42s NR43C(0)NR4aR4\ NR43C(S)NR4?-R4ï, NR^siOHR44, S(0)2NR42R43, S(0)R4" and S{0)2R44, wherein R42, R4j and R"’’ are independently chosen from H, acyl, Ci-Qs-aikyl, 2- to 6-membered heteroaikyl, aryl, 5- or 6-membered heteroaryi, C3-C3 cyeloalkyl and 3- to 8-membered heteroeycloaikyi, or R42 and R43, together with the nitrogen atom to which they are bonnd form a 5- to 7-membered heterocyclic ring; and R44 is chosen from acyl, CpQ-aikyl, 2- to 6-membered heteroaikyl, aryl, 5- or 6-membered heteroaryi, Cj-Cg cyeloalkyl an.d 3- to 8-membered heteroeycloaikyi; R-’ is chosen from H and substituted or unsubstituted Ci-Ce alkyl; Cy is chosen from cyeloalkyl, heteroeycloaikyi aryl, and heteroaryi, wherein the cyeloalkyl, heteroeycloaikyi, aryl or heteroaryi is optionally substituted with from 1 to 6 substituents independently chosen from Ci-Cg-alkyl, Ci-Cs-aikenyl, Ci-Ce-alkyuyl, Cj-Ce-haioalkyl, 2- to 6-membered heteroaikyl O-Circycloalkyl. 3-ίο S-merobered hereroc-yclcaikyi, aryl, 5- or 6-membered heteroaryl, CN, halogen, OR52, SR52, NS1'^3, C(0)R54. C(0)Ml52R5-\ 0C(0)NRS2R3\ CiO)OR-'% NR55C(0)R·54, MR55C(0)C>R52, NR55C(0)NRï2Rs\ .NfiS5C(Si.NR";:K.53,NR55S(0)2R54, S(0)2NR52R53, S(0)R54 and S(0>2R'45 wherein R’2, R" and Rss are independently chosen from H, acyl, Ci-Cvalkyl, 2- to ó~memhered heteroalkyl, aryl, 5- or 6-mesribered heteroaryl, C?~C* cycloalkyi and 3- to 8-memhered hetenocycioaikyi, wherein R^and R", together with the nitrogen atom to which they are hound are optionally joined to toon a 5- to 7~membemd heterocyclic ring; and R>4 is independently chosen from acyl, Cj-O-alkyl, 2- to 6-membered beteroalkyl, aryl, 5- or 6-membered hetenoaryl, Ci-Cg cycloalkyi and 3- to 8-membered heteroeycloalkyl; and Z is chosen from:

and wherein Y·’ is chosen from O, S and NR\ wherein R3 is chosen from H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, 3~ to 8-membered heierocycloalkyl, aryl, and 5- or 6- membered heteroaryl; and R\ K4a and R16 are independently chosen from H, alkyl, alkenyl, alkynyl, haloalkyl, cycioaikyl, 3- to 8-menibered hefemcycloalkyl, aryl, 5- or 6--membered hctcroaryl, CM, halogen, OR17, SR1' and NR.1 "'R18, wherein Ri? and R18 are independently chosen from H, acyl, Ci-Q-alkyl, 2- to 6-membered heteroalkyl, aryl, 5-or 6-membered heteroaryl, Cs-Cs cycioaikyl and 3~ to 8-membered hdexocycloalkyl, or R3' and R18, together with the nitrogen atom to which they are bound form, a 5« to 7-membered heterocyclic ring, or two of R4, K'1a and R3, together with the atoms to which, they are attached, form a 5- to 7-xnembered ring, or adjacent R3'"’ groups, together with the carbon atoms to which they are 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 (XT)and a pharmaceutically acceptable carrier.

[0015] The present disclosure also provides for a method of treating a neurodegenerative disease comprising administering to a mammalian subject in need thereof a pharmaceutically effective amount of a compound having a structure according to Formula (I);

¢1) or a salt or solvate thereof, wherein ring Λ is 3-inembered heteroaryi comprising a sulfur atom, wherein the heteroaryl is optionally substituted with. 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroaikyl, Cs-Cjr cycloalkyl, 3- to B-membered heterocycloalkyi, aryl, 5~ or 6-membered heteroaryi, CN, halogen, OR12, SR12, NRi2R13, C(0)R14, C(0)NR12R33, 0C(0)NRl2RB, C(0)0Ri2, NRi3C(0)R34, NR33C(0)0R12, NR1sC(0)NR%b NRbC(S)NR12Rb NR15S(0)2R14, S(0)2NR3/'Ri3, S(0)R14 and S(Q)2R14, wherein R12, R° and RB are independently chosen from H, acyl, Ci~C.Val.kyl, 2- to 6-mcmbercd heteroaikyl, aryl, 5- or 6-mcmhered heferoaryl, Cfr-Cs cycioalkyl and 3~ to B-membered heterocycloalkyl, or R12 and Rïj, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and R14 is chosen from acyl, Cj-C*-aikyi, 2- to 6~membered heteroaikyl, aryl, 5~ or 6-membered heteroaryl, Cj-Cg cycioalkyl and 3- to 8-membered heterocycloalkyl; Ca and €fc are carbon atoms, which are adjacent to each, other and are part of ring A; Z is 5- or 6-membered heieroaryl; R3 is chosen from H, acyl, Cj-Cs alkyl, and C3-Cs cycioalkyl; W is chosen from. Cs-Cb alkylene, wherein the aikyiene is optionally substituted with 1 - 4 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroaikyl, CY-Cd-eycIoalkyi, 3- to 8-membered heterocycloalkyi, aryl, 5- or 6-membered heteroaryi, CN, halogen, OR42, SR42, NR42R43, €{0)R44, C(0)NR42R4-\ 0C(0)NR42R43, C(0)0R42, NR45C(0)R44, NR4SC(0)0R42, NR43C(0)Mt42R43, NR43C(S)NR42R4\ NR4\S(0)7R44, S(0)7NR42R43, S(0)R44; and S(0)iR44, wherein R*“, R4i and R45 are members independently chosen from H, acyl, Ci~ Cs-alkyl, 2- to 6-membered heteroaikyl, aryl, 5- or 6-membered heteroaryi, CVCs cycioalkyl and 3- to B-membered heterocycloalkyi, 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, Cj-Ce-alkyl, 2- to 6~ metabersd heteroalkyl, aryl, 5- or 6-membored hefcroaryl, th-Ch cycloalkyl and 3- to 8~ raemhered heterocycioalkyl; Cy is chosen from cyeloalkyl, heterocycioalkyl,. aryl, and heteroaryl, wherein the cyeloalkyl, heterocycioalkyl, aiyi or heteroaryl is optionally substituted with 1 - 6 substituents independently chosen from substituted or imsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyi, haloalkyl, substituted or unsubsiitnled heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitiited heterocycioalkyl, substituted or unsubstitiited aryl, substituted or unsubstituted heteroaryl, CM, halogen, OR52, SR5"', NR52RS3, (XO)R54, C«)>NR,:1C\ 0C(0)NRS2R33, C(0)0R5\ NR55C(0)R34, MR5ïC(Ü)ÜR32s NR5SC(0)NRS2RS3, NR55C(S)NR52Ri3, NR53S(0>2R54, S(0)2NR52R53, S(0)R54 and S(0)2Rj". wherein R32, R53 and R55 are independently chosen from II, acyl, Ci-Cg-alkyl, 2- to 6-xnembered keteroalkyi, aryl, 5- or 6-rnernbered heteroaryl, C.;-Cs cycloalkyl and 3- to 8-membered heterocycioalkyl, wherein RS2 and Rs3, 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, Ci-Ce-alkyi, 2- to 6-membcred heteroalkyl, aryl, 5~ or 6-membered heteroaryl, Cj-Cg cyeloalkyl and 3- to 8-membered heterocycioalkyl.

[Sill 6] The present disclcKsufe also provides for a method of reducing p-ejnn 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):

O) or a sail or solvate thereof, wherein ring A is f-membered heteroaryl comprising a sulfur atom., wherein the heteroaryi is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkeoyi, alkynyi, haloalkyl, betefoalkyl, C?.TVr· cycloalkyl 3- to 8-membered heterocycloaikyl aryl 5- or ό-memhered heteroaryl, CN, halogen, OR52, SR52, NR,aR13, CtO)R14, C(OiNR12R!:\ 0C(0}NRS2R!3, CCO)OR17, NRiSCYO)R1\ NR35C(0)0R12, NRtsC(0)NF "“I * NR<sC(S)NRK>R5;, NR,5S(0)2R54, S<0)2NRi2Rld, S(0)Ri4 and 8(0)?Ε14, wherein RJ% R1' and R35 are independently chosen from H, acyl, Cj-Ce-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-menibered heteroaryl, Cl~Cs cycloalkyl and 3- to 8~membered heterocycloaikyl or R:J and R33s together with the nitrogen atom to which they are bound form a S- to 7-membered heterocyclic ring; and R14 is chosen from acyl. C>.-€«-aikyi, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroatyl, Cs-Cs cycloalkyl and 3- to 8-memhered heterocycloaikyl; Ca and Cb are carbon atoms, which are adjacent to each other and are part of ring A; Z is 5- or 6-membered heteioaryl; R5 is chosen from H, acyl, Cj-Cg alkyl, and Q.-C* cycloalkyl; W is chosen from CrQ alkylene, wherein the alkylene is optionally substituted with 1 - 4 substituents Independently chosen from alky!, alkenyl, alkynyl, hafoalkyi, .heteroalkyl, Cs-Ce-cycloalkyl, 3- to 8-mcmbercd heterocycloaikyl aryl, 5- or 6-membered heteroaryh CN, halogen, OR42, SR43, NR42R4*4, CföjR44, C(0)NR'%43, 0C(0)NR4iR4\ C(0)0R42, NR4SC(0)R44j NR45C(Ö)ÖR''2, NR45C(0)NR42R4;\ NR,jC(S)NR”/R43, NR4SS(0>2R44, S(0)?NR42R41 S(0)R4-, and SCOfeR44, wherein R.4\ R43 and R45 are members independently chosen from H, acyl Cr Cg-aikyl, 2- to 6-membered h.efe.ioalkyi, aryl, 5- or 6-membered heteioaryl C^-Cg cycloalkyl and 3- to 8-membered heterocycloaikyl wherein R4^ and R/ \ together with the nitrogen atom to which they arc bound arc optionally joined to form a 5~ to 7-membered heterocyclic ring; and R4* is independently chosen from acyl, Cf-Cl-alkyl, 2- to 6-membered heteroalkyl aryl, 5- or ó-xnembered heteroaryl Cj-C$ cycloalkyl and 3- to 8-membered heterocycloaikyl; €y is chosen from, cycloalkyl, heterocycloaikyl, aryl, and heteroaryl wherein the cydoalkyl, heterocycloaikyl, ary! or heteroaryl is optionally substituted with 1-6 substituents independently chosen from subriiiuled or unsubstituted alkyl substituted or unsubstituted alkenyl, substituted or uasubstituied alkynyl haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstiiuted cycloaiiyl substituted or imsubsuiuied heterocycloaikyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroatyl, CN, halogen, OR52, SR52, NRi2R:'3, C(0)R54, C(0)NR52R53, OC(0)NRS3R53s C(0)0R52, NR5SC{0)R54, NRssC(0)QR52, NR55C(0)NR52R53, m5SC(S)NR52R53, NRS5S(0)2R54,SiO^NR^R53, S(0)R54 and S(0)2R , wherein R , R" and R',J are independently chosen from H, acyl, Cj-Cs-alJkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cj-Cs cycloalkyl and 3- to 8-merabered heterocvcloalkyl, wherein R52 and Rs-’, 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, Ct-Cg-alkyl, 2~ to 6-membered heteroalkyl, aryl, 5- or 6-merobered heteroaryl, Cs-Ca cycloalkyl and 3- to 8-membered beterocycloalkyl.

jj#017J In addition, the present disclosure provides for use of a compound in an in vitro assay measuring kinase acrivuy, sa-d compound having a structure according to Formula (1): (I) or a salt or solvate thereof, wherein ring A is 5-membered heteroaryl comprising a sulfer atom, wherein the heteroaryl is optionally substituted with. 1 or 3 substituents independently chosen from alkyl, alkenyl, alkynyi, haloalkyl, heteroalkyl, CV-Cio-cycloalkyl, 3- to 8-membered beterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CJNf, halogen, OR12, SR52, NRl2RL\ C(0)R14, C(0)NR12RB 0C(0)NR12R13, C(0)0R12, NRlsC(0)Ri4, NRi5C(0)0R32, NRi5C(0)NR,2RB NRi5C(S)NRI?R!3, NRlsS(O)2R54, S(0)2NR12R13, S(0)Rl4 and S(0)iRH, wherein Rt2, RB and R15 are independently chosen from ;?, acyl, Cj-CValkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-m.embered heteroaryl, Cj-Cg cycloalkyl and 3» to 8-membered beterocycloalkyl, or R32 and RB, together with the nitrogen atom, to which they are bound form a 5- to 7-membered heterocyclic ring; and Rf'*‘ is chosen from acyl, Ci-C«-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-Cg cycloalkyl and 3- to 8-membered heierocycdoalkyl; C® and Cb are carbon atones, which are adjacent to each other and are part of ring A; Z is 5-- or 6-meinbered heteroaryi; R5 is chosen from H, acyl, Ci-Ce alkyl, and C.rCfi cycioalkyi; W is chosen from Cs-C* alkylene, wherein the alkylene is optionally substituted with 1 - 4 substituents independently chosen from alkyl, alkenyl, aikynyl, haksalkyl, heteroalkyl, C H-VcydoaJkyl. 3- to 8-membered heterocycloalkyl, aryl, 5- or 6-mcmbc-red heteroaryi, CN, halogen, OR4~, SR42, NR42R4'\ €(0)Κ44, C(0)NR42R4-\ OC(O)KR-s-R4j, CfOlOR43, NR4iC(0)R44. NR4SC{0)OR42, NR45C(0)NR42R43, NR45C(S}NR42R43, NR45S(0)jR44, S(0)2NR42R43s S(0)R44, and S(O}aR44, wherein R42, R45 and R45 are members independently chosen from H, acyl, Ci-Cg-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cj-Cs cycioalkyi 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-CVaUeyl, 2-- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryi, CV-Cs cvcloalkyl and 3-- to 8--membered heterocycloalkyl; Cy is chosen from cycioalkyi, heterocycloalkyl, aryl, and heteroaryi, wherein the cycioalkyi, heterocycloalkyl, aryl or heteroaryi is optionally substituted with 1-6 substituents independently chosen from substituted or onsubsdtuted alkyl, substituted or unsubstituted alkenyl, substituted or unsufestituted aikynyl. haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycioalkyi, substituted or imsubstituied heterocycloalkyl, substituted or unaubstimted ary], substituted or unsubstituted heteroaryi, CN, halogen, OR;,J\ SRs~, NRS2R5i, €(0)R34, CCO)NR52RS3f 0C(0)NRS2R53, C(Oj(}Rsh NRssC(0)R54, NR5ïC(0)0RS2, NR5SC(0)NR52RS3, NR55C(S)NR52R53, NR5SS(0)2R54, S(0)2NR52R53s S(0)R54 and S(O)2R"4, wherein R52, R-'3 and R55 are independently chosen from H, acyl, Ci-CValkyL, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membcred heteroaryi, C3-C3 cycioalkyi and 3- to 8-membered heterocycloalkyl, wherein K“2 and R53, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring; and R'"1 is independently chosen from acyl, Cj-CValkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryi, CVCs cycioalkyi and 3- to 8-memhered heterocycloalkyl, (0018] The present disclosure also provides for« use of a compound is mi in vivo assay measuring kina.se activity, said compound having a structure according to Formula (I);

0) or a salt or solvate thereof, wherein ring A is 5-menibered micro ary] comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl haloalkyl, heteroalky], Cj-Cur cycloalkyl, 3» to 8-membered heterocycloalkyl, aryl, 5- or 6-mero.bered heteroaryl, CN, halogen, OR12, SR12, MRi2R13, C(0)Ri4, C(0)NR12R13, OC(0)NR12R3\ C(0)0Ri2, NR15C(0)RH, NR;5C(0)0R12, NR15C(0)NR12R1y NRlsC(S)NRi2R13, ΝΚί58(0)2Κ34, SiO^NR^R13, S(0)R14 and S(0)?.R14, wherein R12, R.13 and RiS are independently chosen from H, acvl, Crd-alkyl, 2- to 6-membered heteroa.ikyl, aryl, 5- or 6-membered heteroary!, C3-C3 cycloalkyl and 3- to 8-membered heterocycioaikyl, or R.l2and R‘3, 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-Q-alkyl, 2- to 6-membexed heteroalkyl aryl, 5- or 6-membered heteroaryl, C3-C3 cycloalkyl and 3- to 8-membered heterocycloalkyUC* 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 II, acyl, Crd alkyl, and Cj-C$ 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-CVcyeloalkyl, 3- to 8-membered heterocycioaikyl, aryl, 5- or 6-membered heteroaryi, CN, halogen, OR42, SR4! NR4*R43, C(0)R"4, C(0)NR42R®, 0C(0)NR42R43s C(0)0R42, NR45C(0)R44, NR4SC(0)0R42, NR45C(0)NR42R43, NR4SC(S)NR42R43, Mfr'SCOlR'kS(0)?NR42R43, S(O)R44, and SiOjjR44, wherein R42, R"3 and R',J are members independently chosen from H, acyl, Ci-

Qs-alkyl, 2- to 6-membered heteroaikyi, aryl, 5- or ö-memhered heteroaxyi, Ca-C* cycloalkyi and 3- to 8-membered heterocycloalkyl, wherein R42 and R43, together with the nitrogen alom to which they are bound are optionally joined to form, a 5- to 7~membered heterocyclic ring; an R44 is independently chosen from acyl, Cj-Ce-aikyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-Cg cycloalkyi and 3- to 8-membered heterocycloalkyl; Cy is chosen from cycloalkyi, heteroeycloaikyl, aryl, and heteroaryl, wherein the cycloalkyi, heterocycloalkyl, aryl or heteroaryl is optionally substituted with. 1 - 6 substituents independently chosen from substituted or nnsnbstituted alkyl, substituted or unsubstituied alkenyl, substituted or unsubstituted alkynyl, haioaikyl, substituted or imsubstituted heteroalkyl. substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituied aryl, substituted or unsubstituied keteroaryl, CN, halogeu, OR52, SRs2, NRS2R.5i, €(0)Ri4, C(0)NRsR53, 0C(0)NR52RS3s C(0)0Ra, NRssC(0)R54, NRS5C(0)0R52, NR5SC(ö)NR53R53, NR53C(S)NRi2R5\ NRs-S(0)>R54. Scoort53, S(0)R54 and S(0)2R'‘4, wherein RS2, R53 and R55 are independently chosen from H, acyl, Ci-Cg-alkyl, 2~ to 6-membered heteroaikyi, and, 5- or 6-membered heteroaryl, Ch-Cg cycloalkyi and 3- to 8-membered heterocycloalkyl, wherein R52and Rs% together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring: and R5"1 is independently ehosen from acyl, C.-Cg-aikyi, 2- to 6-membered heteroaikyi, aryl, 5- or 6-membered heteroaryl, CVCg cycloalkyi and 3- to 8-membered heterocycloalkyl, fOOI9] The present disclosure further provides for an in vitro me If sod for measuring phnsphoryiated kinase sobsunte comprising; (i) creating a mixture comprising a kinase and a compound having a structure according to Formula (I):

(1) or a salt or solvate thereof, wherein ring A is 5-memberod heteroaryl comprising a sulfur atom, wherein the heteroaryl is optionally substituted with 1 or 2 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, C3-C30-e}rcloalkyl, 3- to 8-membered heterocycloaiky!, aryl, 5- or ό-membered heteroaryl, CN, halogen, OR12, SR12, NR12R13, C(0)R34, C(0)NR12Ros 0C(0)NRl2R°s C(0)0Ri ?, NRI5C(0)Rh, NR13€(0)0R!2, NRisC(0)NR,2R13, NR,sC(S)NR12Ri3} m;5S(0)2R34, SfO^NR^R13, S(0)R14 and S(0);?Ri4, wherein R12 R13 andR1*' are independently chosen from H, acyl, Ci-Ce-alkyl, 2- to 6-membered hetemaikyl, aryl, 5- or 6-memhered heteroaryl, C3-Cs cycioalkyi and 3- to 8-membered heterocycloalkyl, or R12 and R33, together with the nitrogen atom to which they are bound form a 5- to 7-membered heterocyclic ring; and R!4 is chosen from acyl, Q-Cb-aikyl, 2- to 6-membered heteroalkyi, aryl, 5- or 6-membered heteroatyl, C3-C3 cycioalkyi and 3- to 8-membered heterocycloalkyi; C1 and Cb are carbon atoms, which are adjacent to each other and are part of ring A; Z is 5- or 6-mernhered heteroatyl; and (ii) when ring A is thiazole, then Z k not benzimidazole; R5 is chosen from H, acyl, Cr€s alkyl, and Cs-Cg cycioalkyi; W is chosen from C1-C4 alkybne, wherein the aikylene is optionally substituted with 1 - 4 substituents independently chosen from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, Cj-Cercycloalkyi 3- to 8-membered heterocycloalkyi,, and, 5- or 6-membered heteroaryl, CN, halogen, OR42, SR42, NR42R43, €(0)R44, C(0)NR42R43, 0C(0)NR42R43, C(0}0R4V NR4SC(0)R44, NR45C(0)0R42, NR45C(0)NR42R43, NR4?;CfS)NR42R4'\ NR45S(OkR44, SiOhNR^R*'3, S(())R44, and S(O^R"·’, wherein R4i, RAi and R45 are members independently chosen from H, acyl, Ci-Ce-aikyl, 2- to 6-membered .heteroalkyi, aryl, 5-or 6-membered heteroatyl, Cj-Cg cycioalkyi and 3- to 8-membered heterocycloalkyi, wherein R4' and R4", 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 heteroalkyi, aryl, 5- or 6-membered heteroaryl, C3-Cg cycioalkyi and 3- to 8-membered heterocycloalkyi; €y is chosen from cycioalkyi, heterocycloalkyi, aryl, and heteroaryl, wherein the cycioalkyi, heterocycloalkyi, aryl or heteroaryl 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 heteroeycloalkyl, substituted or unsubsiituted aryl, substituted or unsubstituted heteroaryl, CNS halogen, OR52, SR52, NRS2R53, €(0)R54, C(0)NRi2R53,0C{0)NR52RB, C{0)0R52, NRSSC(0)R54, NR55C(0)0R52, NR55C(0)NR52R53, NR5SC(S)NRS2R53, NR'''"S(0£>R'!,\ S(0):NR^R"''\ S(0)R“ï and S(ObRj4, wherein R’f R'x" sod R" are independently chosen from H, acyl Ci-Ce-alkyl, 2- to 6-membered heteroalkyl, aryl 5-or ό-membered heteroaryi, C3-C3 cycloalkyl and 3- to 8-membered heteroeycloalkyl, wherein Rs2 and R5i, together with the nitrogen atom to which they arc bound are optionally joined to form a 5- to 7-merabered heterocyclic ring; andRs“ is independently chosen from acyl. Cs-Q-aihyL 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl CVCg cycloalkyl and 3- to 8-membcred heteroeycloalkyl (ii) adding a kinase substrate and ATP or a derivative thereof to the mixture; and (hi) measuring an amount of phosphorylated kinase substrate. In one example, the method further comprises measuring phosphoiyiated kinase substrate, such as phospho-c Jun, [002b] 'The present invention also provides for an in vitro method comprising contacting a cell with a compound having a structure according to Formula (I):

0) or a salt or solvate thereof, wherein ring A is 5-membered heteroaryl comprising a sulfur atom, wherein the heteroary! is optionally substituted with 1 or 2 substituents Independently chosen from alkyl, alkenyl, alkynyl, haloaikyi, heteroalkyl, Cs-Cjo-cycloalkyl, 3- to 8-tnembered heteroeycloalkyl, aryl, 5- or 6-merahercd heteroary!, CN, halogen, OR12, SR12, NR32RU, C(Ö)R14, C(0)NR12R13, OCiO).NR12R13, C(0)0R12, NRiSC(OjR14, NRi5C(0)0R12, NRlsC(0)NRi2Ri3, NRi5C(S)NRJ2R13, ml5$(0)2}iiA, S(0)2NR12Ri3, S(Q)Rl4 and S(0)?R3ii, wherein R.i2, Ru and R35 are independently chosen from H, acyl, Ci-Cg-alkyl, 2- ίο 6-membered b.eleroatkyl, aryl, 5- or 6~membercd heteroaryl, C.wCs cycioalkyl and 3- to 8-membered heteroeycloalkyl» or R^and R13* together with the nitrogen atom to which they are bound form a 5~ to T-membored heterocyclic ring; and R: * is chosen from. acyl Ci-Cg-aikyl, 2- to 6-rneiisberod heteroalkyi, aryl, 5- or 6-membered heteroaryl, C3-Cs cycioalkyl and 3- to 8-membered heteroeycloalkyl; C* and Ctj are carbon atoms, which are adjacent to each other and are part of ring A; Z is 3- or 6-membered heteroaryl; RJ is chosen from H, acyl, Ci-C6 alkyl, and Cb-Cc cycioalkyl; W is chosen from Ci-Cs alkylene, wherein the alkyiene is optionally substituted with .1 - 4 substituents independently chosen from alkyl, alkenyl, a.Jkymd, haioalkyl, heteroalkyi, Cj-CV-cycloaikyl, 3- to 8-membered heteroeycloalkyl, aryl, 5* or 6-membered heteroaryl, CN, halogen, OR47', SR42, NR4“R4j, C{0)R44, C(0)NR42R43, 0C(0)NR%43, C(0)0R42, NR4SC(0)R44, NR45C(0)0R42, NR45C(0)NR42R4i, NR4SC(S)NR42R43, NR45S(0>2R44s S(0)2NR42R43, S(0).R44, and S((3);R44s wherein R42, R43 arid R45 are members independently chosen from H, acyl, CV CValkyl, 2- to 6-mernbered heteroalkyi, aryl, 5- or 6-membered heteroaryl, Cg-Cg cycioalkyl and 3- to 8-membered heierocycioalkyi, wherein R4"· and R45, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7~membe.red heterocyclic ring; and R44 is independently chosen from acyl, Ci-Ce-alkyl, 2- to 6-memhered heteroalkyi, aryl, 5- or 6-membered heteroaryl, Cj-Cg cycioalkyl and 3- to 8-membered heierocycioalkyi: Cy is chosen from cycioalkyl, heierocycioalkyi, aryl, and heteroaryl, wherein tire cycioalkyl, heteroeycloalkyl, aryl or heteroaryl is optionaily substituted with 1 - 6 substituents independently chosen from substituted or unsubstituted alkyl, substituted or unsubsfi sided alkenyl, substituted or un&amp;ubsritutcd alkynyi, haioalkyl, substituted or unsubstituted heteroalkyi , substituted or unsubstituted cycioalkyl, substituted or unsubstituted heteroeycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, CN, halogen, OR32, SR52, NRS2R53, C(0)R'vf C(0)NR52Rss, 0C(0)NRS2R" C(O)0Rs% NRSSC(0)RS4, NR55C(0)0R52, NR‘;5C(0}NR52R53, NRiSCfS)NR32RB, NR55SiO}2R'4, S{0},NR-’R55, S(0)R54 and S(C>kR'\ wherein R52, R33 and R3j are independently chosen from II, acyl, Ci-C*-«lkyl, 2- to 6-membered heteroalkyi, aryl, 5- or 6-membered heteroaryl, C3-C3 cycioalkyl and 3- to b-membered heteroeycloalkyl, wherein R52and R33, together with the nitrogen atom to which they are hound are opt ionaiiy joined to form a 5- to 7-juembcred heterocyclic ring; andR'vi is independently chosen from acyl, Ci-C«-aikyi, 2“ to 6-memhered heteroalkyi, aryl, 5- or 6-membered heteroaryl, C.rC8 cveloalkyl and 3~ to B-rnentbered heterocycloalkyl. In one example, the method further comprises measuring phosphorylated kinase substrate, such as phospho-eJun.

DETAILED DESCRIPTION OF THE DISCLOSURE

Definitions |0Q21] The definitions and explanations below are for the terms as used throughoutthis entire document including both the specification, and the claims. Throughout the specification and the appended claims, 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 well as pharmaceutically 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.

[0023] Where multiple substituents are indicated as being attached to a structure, those substituents are independently chosen. For example "ring A is optionally substituted with .1,2 or 3 Re groups" indicates that ring A is substituted with 1, 2 or 3 Ra groups, wherein the R*, groups are independently chosen (i.e., can be the same or different)., [0024] Compounds were named using Autonom 2ÖÖÖ 4.01.305, which is available from Beilstein Information Systems, Inc, Englewood, Colorado; OiemDraw v.10,0, (available from Cambridgesoft at. 1ÖÖ Cambridge Park Drive, Cambridge, MA 02.140), or ACD 'Name pro, which is available from Advanced Chemistry Development, Inc., at 11(5 Yonge Street, 14th floor, Toronto, Ontario, Canada M5c 1T4. Alternatively, the names were generated based on the 1UPAC rules or were deri ved from names originally generated using the aforementioned nomenclature programs, A. person of skill in the art will appreciate that chemical names for tautomeric forms of the current compounds will vary slightly, but will nevertheless describe the same compound. For example, the names N-(2-^3-methy].~lH-l,2,4-triazol-$-yI)tbi0phen“3-y3)~2~{naph:thaien- 1-y1)acetamide and N-(2~(5-me&amp;yl-4H-l,2,4-tria^I-3-yl)thiophen-3-yl)-2-(naph.thaien·· l-yl)acetamide describe two tautomeric forms of the same compound. 18025] 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 trim right to left. For example, “-CHhQ-*4 is intended to also recite “-OCHjr*.

[00.26] The tern “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., Cj-Cje means one 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 is an alkyl group having from 1 to 4 carbon atoms. The term “alkyl” includes di- and multivalent radicals. For example, the team “alkyl” includes “alkylene” wherever appropriate, e.g., when the formula indicates that the alkyl group is divalent or when substituents are joined to form a ring. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, «-propyl, iso-propyl, «-butyl, tert-butyi, wo-butyl, ms-butyl, as well as homologs and isomers of, for example, «-pentyl, «-hexyl, a-heptyf and «-octyl, [0027] The term “alkylene” by itself or as pars of another substituent meatus a d*valent (diradka!) alkyl group, wherein alkyl is defined herein. “Alkylene” is exemplified, but not limited, by -CH2CH2CI AC1 !>··. 'Typically, art “alkylene” group will have from 1 to 24 carbon atoms, for example, having 10 or fewer carbon atoms (e.g., 1 to 8 or 1 to 6 carbon atoms). A “lower alkylene” group is an alkylene group having from .1 to 4 carbon atoms.

[0028] The term “alkenyl” by itself or as parr of another substituent refers to a straight or branched chain hydrocarbon radical having from 2 to 24 carbon atoms and at least one double bond, A typical alkenyl group has from 2 to 10 carbon atoms and at least one double bond. In one embodiment, alkenyl groups have from 2 to 8 carbon, atoms or from 2 to 6 carbon atoms and from 1 to 3 double bonds. Exemplary alkenyl groups include vinyl, 2-propenyl, i-but-3-enyi, eroiyl, 2-(butadkmyi), 2,4-pentadienyi, 3-(Ed-pentadienyl), 2~isopentenyls l-pent-3-enyi, i-hex-Sronyi and tire like. jTH)29J The term “alkynyl” by itself or as part of another Msbrtlt cent refers to a straight or branched chain., unsaturated or polyunsaturated hydrocarbon radical having from 2 to 24 carbon atoms and at least one triple bond. A typical “alkynyl” group has from 2 to 10 carbon atoms and at least one triple bond. In one aspect of the disclosure, alkynyl groups have from 2 to 6 carbon atoms and at least one triple bond. Exemplary alkynyl groups include prop-l-ynyL prop-2-yny! (i.e., propargvl), ethynyl and 3-butynyl.

[0030} The terms "alkoxy," "alkylammo” and "alkylthio” (or thloalkoxyl are used in their conventional sense, and refer to alkyl groups that are attached to the remainder of the molecule via an oxygen atom, an amino group, or a suifur alom, respectively.

[0031 j T he term “heteroalkyl,” by Itself or in coxabmation with another teim, means a stable, straight or branched chain hydrocarbon radical consisting of the staled number of carbon atoms (e.g,, Cz-Cjo, or C-i-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, sul fur and phosphorus atoms are optionally oxidized, and the nitrogen atomfs) are optionally quatemized. Ihe heieroatom(s) is/are placed at any interior position of the heteroalkyi group. Examples of heteroalkyl groups include, but are not limited to, «CH2-CH2-Ö-CH3, -CHi-CHj-MH-CH», CHrCHj-Nfairi-CHu -Cl-fi-S-C lirCi3?, -CH2-CHrS(0}-CI-T?, -CB.;--CBj -S{O VC Hi. -CH=CH-0-€H3> -CH*-Si(CHj)»( *€H:*CH-N-OCH3, and Ο.ΐ-€1·1··.Ν(0Ηϊ)··ίΉ.·8. Up to two heteroatoms can be consecutive, such as, for example, CHrMI-OCI-E, and - CHi-O-SifCBf).?, Similarly, the term “heteroalkylene” fey itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, ~CH2~CII:~S~CEfr~CB>- and - CH vS-CH2“CHrNH-CH2-v Typically, a heferoaikyl group will have from 3 to 3d atoms (carbon and beioroatoms, excluding hydrogen) (3- to 24-memhered beteroaikyl). In another example, the heteroalkyl group has a total of 3 to 10 atoms (3- to lO-membered heteroalkyl) or from 3 ίο 8 atoms (3- to 8-merofeered .heteroalkyl.), The term “heteroaikyi” includes “heteroalkylene” wherever appropriate, e.g., when the formula indicates that the heteroalkyi group is divalent or when substituents are joined to form a ring, [0932] The term “cyeioalfcyF by itself or in combination with other terms, represents a saturated orunsaluxaled, non-aromatic carbocyclic radical having from 3 to 24 carbon atoms, for example, having from 3 to 12 carbon atoms (e.g., Cy-C* cycloaikyi or Cs-Ce cycloaikyi). Examples of cycloalkyl include, but are not limited to, eydopropyl, eyclobutyl, cyclopentyl, cydohexyl, cycloheptyl, l-eyclohexenyl, 3-eycloh.sxeoyl, cycloheptyl and the like. The term “cycloalkvr also includes bridged, polycyclic (e.g., bicyclic) structures, such as norbomvi, adannmtyi and bicyclo[2,2.1 jhepfyi. The “cycloalkyl” group can be fused to at least one (e.g., 1 to 3} other ring chosen from aryl (e.g,, phenyl), heteroaryl (e.g., pyridyi) and non-aromatic (e.g., carbocyclic- or heterocyclic) rings. When the “cycloaikyi” group includes a fused aryl, heteroaryl or heterocyclic ring, then the “cycloaikyi” group is attached to tire remainder of the molecule via the carbocyclic ring.

[0033] The term “hctciocycloalkyl”, “heterocyclic”, “heterocycle", or “hcterocyciyl", by stseifor in combination with other terms, represents a carbocyclic, non-aromatic ring (e.g., 3- to 8-memtaercd ring and for example, 4-, 5-, 6- or 7-mcmbcrod ring} containing at least one and up to 5 heteroatoms chosen from, e.g,, N, Ö, S, Si, B and P (for example, N, Ö and S), wherein the nitrogen, sulfur and phosphorus atoms are optionally oxidised, and the nitrogen atom(s) are optionally quatemixed (e.g,, from 1 to 4 heteroatoms 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, O and S) in stable combinations known, to those of skill in the art, Exemplary heterocycloalkyl groups include a fused phenyl ring. When the “heterocyclic” group includes a fused aryl, hctcroaryl or cycloaikyi 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 heterocycloalkvl or heterocyclic groups of the present disclosure include morpholinyl, thiomoipholinyi, thlomorpholinyl. S-oxidc, thiomorpholinyl S,S-dioxide, piperazinyi, homopiperazinyl, pyrrol!dlnyl, pyrroiinyl, ksidazolidmyh tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothieayl, p-pendinyl, homopiperKHuyl, homomorphoimyl, homothsornospholinyi, hornothiomotpholinyi S,S~dioxide, oxazoüdinonyl, dihydropyrazoiyl, dihydropynolyL dihydropyraxolyL dihydropyridyl, dihydröpyrimidinyl, dihydrofuiyl, dihydropyranyl, tetrahydrothienyl S-oxide, ielrahydroiMenyl S,S~dk>xide, hotrtóhiomorphoKayl S-oxide, I-{J,2,5,6-ietrah.ydropyridyl}, I-piperidinyl, 2~piperidmyS, 3-pipendmyl, 4-morphölinyl, 3~ morpholinyl, tetrahydrof«ran-2-yI, tetrahydrofiuuni-3-yl, tetrahydröthieu-2-yi, tetrahydrothiea~3-y!.f l-piperazinyl, 2-piperazinyi, and. the like, [00341 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-tetrahydi'onaphthyi) or heteroaiyi group then the “aryl” group is linked to the remainder of the molecule via an aryl ring (e.g., a phenyl ring). The ary! 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, dihydronaphthyl, fluorenyl, tetralinvl, baazo[dj[1,3]dk>xoly! or 6,7,8,9~tetrahydro-5H~ henro[a]cyeloheptenyL In one embodiment, the aryl group is chosen from phenyl, henzo[d][l ,3]dioxoiy1 and naphthyl. The aryl group, in yet another embodiment, is phenyl, [0035] The term “arylalkyi” is meant to include those radicals in which an. aiyl group or heteroaryl group is attached to an alkyl group to create the radicals -alkyl-aryl and -alkyi-heteioaryl, wherein alkyl, aryl and heteroaryl are defined herein. Exemplary “arylalkyl” groups include benzyl, phenetliyl, pyridylmethyl and the like, 1103d] By ?iaryk5xy’' is meant the group -O-aryl, where aryl is as defined herein. In one example, the aryl portion of the aryloxv group is phenyl or naphthyl. The aryl portion of the aryioxy group, in one embodiment, is phenyl. {00371 The term, “beteroaryΓ or ‘'heteroaromaiic'1 refers to a polyunsaturated, 5-, 6- or 7-membered aromatic mo-cry containing at least one heteroatom (e.g.. 1 to 5 heteroatoms, such as 1-3 heteroatoms) chosen froni N, O, S, Si and B (for example, N, O anti S), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. The “heteroaryl” group can he a single ring or he fused to other aryl, heteroaiyl, eyeioalkyl or heteroeycloalkyl rings (e,g., from 1 to 3 other rings). When the “heteroaryt” group includes a fused aryl, eye balky! or heteroeycloalkyl ring, then the- ‘lictcroarvl” group is attached to the remainder of the molecule via the heteroarvl ring, A heteroaryl group can be attached to the remainder of the molecule through a carbon- or heteroatom. in one example, the heteroaryl group has from. 4 to 10 carbon atoms and from 1 to 5 heteroatoms chosen from O, S and N. Nonlimiting examples of heteroaiyl groups include pyridyl, pyrimidinyl, qumaiinyl, benzothienyl, indolyL mdotinyh pryidazinyl, pyrazlnyl, isoindolyl, isoquinolyl, mnnuzoimyi, qui'ooxaljnyL phthalazinyl, imidazolyl, isoxazoiy!, pyrazolyl, oxazolyi thiazolyi, indolmoyi, mdazoiyl. benzothiazoiyl, benzimid&amp;zoiyl, henzofuranyl, ruraiiyl, thienyl, pyrrolyl, oxadiazolyl, thiadlazolyl, triazolyl, tetrazolyl, isothiazoivl, naphlliyridinyl, isochromanyi, chromanyl, tetraliydroisoqulnolinyl, isoindolinyl, IsobenzotetrahydroiuranyL isobenzotetrahydrothienyi, isobenzotfrienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuranyl, benzotetrahydrathienyl, purinyl, benzodioxoiyi, triazmyl, pteridinyl, bsnzothiazolyi, imidazopyrtdyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyk dihydrobenzisothiazinyl, feenzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridyl-N-oxide, teirahydroquioolinyS, dihydroquinoiinyl, dihydroquinolinonyl dihydroisoqumolinonyl, dihydrocoumarinyl, dihydroisocoumarinyi, isomdolinoayl, benzodioxanyl, benzoxazolinonyi, pyrrolyl N-oxide, pyrimidinyl N-oxtde, pyridazinvl N-oxide, pyrazlnyl N-oxide, quinolmyl N-oxide, indolyl N-oxide, indolinyl N-oxide. isoquinolyl N-oxide, quinazolinyl N-oxide, qumoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyi N-oxide, oxazolyl N-oxlde, thiazolyl. N-oxide, indoiizinyl N-oxide, indazolyl N-oxide, henzothiazolyl N-oxide, benzimldazolyi N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazoly! N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S,S-dioxide. Exemplary heteroaiyl groups include imidazolyl, pyrazolyl, thiadiazoly!, triazolyl, isoxazolyi, isothiazoivl, imidazolyl, thiazolyi, oxadiazolyl, and pytidyl. Other exemplary heteroaiyl groups include 1-pyrrolyl 2-pyrroiyl. 3-pyrroiyl, 3-pyrazolyl, 2-imidazolyi, 4-imidazolyl, pyrazmyl, 2~oxazolyl, 4-oxaxoiyl, 2-phenyl~4~oxazo]yI, 5-oxaKoIyl, 3~isoxas»lyL 4-Isoxaz®iy!, 5-isoxazolyL 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyi, 3-thienyi, 2-pyridyl, 3» pyridyl, pyridm-4-yl, 2-pyrintidyl, 4-pyrknidyl, 5-benzothiazoiyi, purinyi, 2-benzdmidazoiyl, 5-indolyl, 1-isoquinolyl, 5-isoquinoiyl, 2-quinoxalinyl, 5-quinoxaIin.yl, 3-quinolvL and 6-qumolyl, Substituents for each of the abo ve noted aryl and heteroaryl ring systems arc chosen from the group of acceptable ary! group substituents described below.

[0038j For brevity, the term “aryl” when used in combination with other terms (e.g., aryloxy, aiylthioxy, arylalkyi 1 includes both aryl and heteroaryl rings as defined above, [0039} Each of the above terms {e.g., “alkyl”, “cyetealkyr, “heferoalkyF, heterocycloalkyP, “aryl” and “heteroaryl”) are meant to include both substituted and vousuivxbuned forms oft.be indicated radical. The term “substituted” for each type of radical is explained below. When a compound of ihe present disclosure mdudes more than one substituent, then each of the substituents is independently chosen.

[0040] The term “substituted” in connection with alkyl, alkenyl, alkvnyl, cycloalkyl, heteroaikyl and heterocyeloalkyl radicals (including those groups referred to as aikyiene, hetcroalkyiene, hctcro&amp;lkcnyl, cycloalkenyl, heterocydoalkeayi, and the like) refers to one or more substituents, wherein each substituent is independently chosen from, but not i i mi led to, 3- to 10-xnembercd bereroaikyl, CVCJ;; cycloalkyl, 3* to 1G~ membered heteroeydoalkyl, aryl, heteroaryl, -OR3, -SR*, -(), :::fel~ORa, -NRaRb, -halogen, -SiRlFRb -0C(0)R*, -C(0)Re, -C(0)0Ra, -C(0)NRaRb, -GC(0)NR*Rb, -NRaC(0)Rs, -NRcC(0)NR*Rb, ~NRsC(S}NR:!Rb, -NR’C(0)0Ra# -NRT{NR3R*>N'Rd. -S(0)Rc, -S(0)2R0, -S(0)jNR*Rb, -NRcS{0)2Rs, -CN and -N02. Ra, Rb, Rc, RJ and Re each independently refer to hydrogen, €,-€2.4 alkyl (e.g., Ci-Cio alkyl or Ci-Cg alkyl), Cj~ Ci.fi cycloalkyl, C1-C24 heteroalkyl (e.g., Ci-Cio heteroalkyi or CrQs heteroaikyl), C3-Q0 heteroeydoalkyl, aryl, heteroatyl, atylalkyl and hetero&amp;ry.klkyi, wherein, in. one embodiment, R.° is not hydrogen. When two of the above R groups (e.g.. R* and Rb) are attached to the same nitrogen atom, they can fee combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR*Rb is meant to include pytTolidmvl, N-alkyl-piperidinyl and morpholsnyl.

[00411 The term, “substituted” m convection with aryl and heteroaryl groups, refers to one or more substituents, wherein each substituent is independently chosen from, but not limited to, alkyl (e.g., Ch-C^ alkyl, C;-C!0 alkyl or Cj-Q alkyl), cyel.oaI.kyl (e,g., Cj-Cjo cveloalkyl, or Cj-Cg cycloalkyl), alkenyl (e.g,, Ci-Cjo alkenyl or Ci-C* alkenyl), alkynyl (e.g., Ci-Cic alkynyi or Ct-C* alkynyi), heteroalkyl (e.g., 3- to 10-membered heteroalkyl), heterocycloalkyl (e.g., Cj-C» heterocycloalkyl), aryl, heteroaxyl, ~R\ -OR) -SR8, =0, =NR*, =N-QR®, -NR*Rb, -halogen, -SiR*^*, -0C(0)Ra, -C(0)Re, -C(0)0R\ -€(0).N.R*Rb, -0C(0)NRÏRfc, -NRcC(0)Re, ~NRcC(0)NRaRb, -NRcC(S)NR*Rb, -NRcC(0)0R*f -NRcC(NR*Rb)~NRd, -S(0)Re, -S(0)2Re, -S(0)2NR*Rb, -NRcS(0)2Ra; -CN, -N02, "N3, -CH(Ph)2, iluoroCCj-C.-ijalkoxy, and fluoroCCi-C^alkyl, in a number ranging from zero to the total number of open valences on the aroma- ie ring system, wherein R* Rb, Rs, R* and Re each independently refer to hydrogen, CrC24 alkyl (e.g,, Cj-Cie alkyl or CrC6 alkyl), C3-C10 cycloalkyl, Cj-C24 heteroalkyl (e.g,, CyCio heteroalny; or Ci-C« hetoroalKyl}. Ch-Cjo hsieiocycloalkyl, aryl, hctcroaryi, arylalkyl and hctcroarylalkyl, wherein, in one embodiment, R* is not hydrogen. Whet; two R groups (e.g., R" and R“) are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-memhered ring. For example, -NR ‘Rb js mean; to include pyrrolidinyi, N-alkyl-piperidluyl and motpholinyl. {11042] The term “substituted” in connection with aryl and hctcroaryi groups also refers to one or more fused rmg(s), in which two hydrogen atoms on adjacent atoms of the aryl or heteroaryl ring are optionally replaced with a substituent of the formula -T-C(0)-(CRR’)^-U-, wherein T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the hydrogen atoms on adjacent atoms of the aryl or hctcroaryi ring can optionally be replaced with a substituent of the formula --A-(CH2)i“B-, wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(0)-, -8(0)?-, -S(0)2NR5- 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 with a double bond. Alternatively, two of the hydrogen atoms on adjacent atoms of the aryl or hctcroaryi ring can optionally be replaced with, a substituent of the formula ~(CRR’)s-X-(€R,5R”’)d~* where s and d are independently integers from 0 to 3, and X is -0-, -NR’··, -S-, -8(0)-,-8(0)2-, or -S(0)2NR’-, wherein the substituents R, R’, R” and R’5’ in each of the formulas above are independently chosen from hydrogen and (Ci-C^alkyl.

[0ft43j The terms “halo” or “halogen,” by themselves or as part of another substituent, mean at least one of fluorine, chlorine, bromine and iodine.

[M44] By “haloalkyi" is meant: an alkyl radical, wherein alkyl is as defined above and wherein at least one hydrogen atom is replaced by a halogen atom. The term “haloalkyi ” Is meant to include monohaloalky} and polyhaloaikyl For example, the term. “kalo(C 3-Chalky!” is mean to include, but not limited to, c-hiorom.eth.yl, 1 -bromoethyl, fluoromethyi, di fluoromethyi, trifluoromethyl, 1,1,1-trifluoroethyi and 4-chIorobutyl, 3-bromopropyl, [0045] As used herein, the term, ’’acyl" describes the group ~C(0)Re, wherein R* is chosen from hydrogen, Ci-Ca* alkyl (e.g,, Cj-Cuj alkyl or CVQs alkyl), Ci-Qm alkenyl (e.g., Ct-Cio alkenyl or Ct-Q alkenyl), C1-C24 alkynyi (e.g., Cj-Cio alkynyi or Ci-Có alkynyi), C3-C10 cycloalkyi, C1-C24 heteroalkyl (e.g., CVCio heteroalkyl or Ci-Ce beteroaikyl), C3-C10 heterocycloalkyl, aryl, heleroaryl, axylalkyl and heteroarylalkyi. In. one embodiment, R" is not hydrogen, [0046) By “aikanoyl" is meant an acyl radical -C(Ö)-Aik-, wherein Aik is m alkyl radical as defined herein. Examples of alkanoyl include acetyl, propionyl, biUyryl, isobntyryl, valeryl, Isovaleryi, 2~methyi~butyryl,2,2-dimethylpropionyi, hexanoyl, heptanoyl, ocianoyl and the like, [05147] As used herein, the term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S), silicon (Si), boron (B) and phosphorus (P). In one embodiment, heteroatoms are O, S and N.

[SM148J By “oxo" is meant the group ~0.

[11049] The symbol "R” is a general abbreviation that represents a substituent group as described herein. Exemplary substituent groups include alkyl, alkenyl, alkynyi, cycloalkyi, heteroalkyl, aiyi, heteroaryl and heterocycloalkyl groups, each as defined herein.

[0950] As used herein, the terra "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 incin.de cvelohexanes.

[00511 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, chromenes and the like. Likewise, the term "fused ring” refercs to a ting that has at least (wo atoms in common with the ring so 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 benefii/risk ratio applicable to any medical treatment. For example, a ‘therapeutically effective amount” is an amount effective to reduce or lessen, at least one symptom of the disease 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.

[0053] The terms “treatment” or "treating” when referring to a disease or condition, means producing a desired therapeutic effect. Exemplary therapeutic effects include delaying onset or reducing at least one symptom associated with the disease, positively affecting (e g., reducing or delaying onset) a clmitvd marker associated wuh the disease and slowing or reversing disease progression.

[0054] The term "pharmaceutically acceptable” refers to those properties and/or substances that are acceptable to a patient (e.g., human patient) from a toxicological aad/or safety 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., -COÖH 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, either neat or in &amp; suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include lithium, sodium, potassium,, calcium, ammonium, organic amino, magnesium and aluminum salts and the like. When compounds 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 sufficient amount of the desired add, either neat or in a suitable inert solvent Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobrontic, nitric, carbonic, monohydrogencarbonic, phosphoric, diphosphoric, monohydrogenpbosphoric, dibydrogenphosphoric, sulfuric, monohydrogeasulfuric, 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, furaarie, lactic, mandelic, phthaiic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, 2 -hydroxyethylsulfonic, salicylic, stearic and the like. Also ind tided are salts of amino adds such as arginate and the like, and salts of organic adds like glucuronic or galactunoric ac ids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science, 1977, 66: 1 -.19). Certain specific compounds of the present disclosure contain both, basic and acidic, functionalities that allow the compounds to be converted into either base or acid addition salts.

[0Θ56] The neutral forms of the compounds can be regenerated, tor 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 as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[Θ1157| When a substituent includes a negatively charged oxygen atom “O', e.g., in “-COO'“, 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 acid group, e.g., written as the substituent “-COOH”, “-COzH” or then the formula is meant to optionally include die corresponding “dc-protonaled” form of (hat acidic group» e.g., “-COO'4', CQ{“ or 1£“C(Q)ri‘, respectively.

[0t)5§l 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 feat readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Non-limiting examples of "pharmaeaifically acceptable derivative” or “piodrug" include pharmaceutically acceptable esters, phosphate esters or sulfonate esters thereof as well as other derivatives of &amp; 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 prodrugs are those that increase the bioavailahility 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.

[0059} Prodrugs include a variety of esters (i.e., carboxylic acid ester). Ester groups, which are suitable as prodrug groups are generally known in the art and include bcnzyloxy, di(€i~€6)dky3aminod;hy!.oxyt acctoxymcihyl, pivaloyloxymethyl, phthalidoyl, ethoxycarbonyloxyethyh 5-raethyl~2-oxo-l ,3-dioxol-4-yl methyl, and (C··· Cö)alkoxy esers, optionally substituted byN-moiphoiino and amide-forming groups such as di(C]-Cö)aiky]amino. For example, ester prodrug groups include Ci-Cg alkoxy esters. Those skilled in the art will recognize various synthetic methodologies that may be employed to form pharmaceutically acceptable prodrugs of the compounds of the present disclosure (e.g., via esterification of a carboxylic acid group).

[6060] in an exemplary embodiment, fee prodrug is suitable for treatment /prevention of those diseases and conditions; that require fee drug molecule to cross the blood brain barrier. In one embodiment, fee prodrug enters the brain, where it is converted into the active form of the drug molecule. In another example, a prodrug is used to enable an active drug molecule to reach the inside of the eye after topical application of the prodrug to the eye. Additionally, prodiugs 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 transdema! patch, reservoir with, a suitable enzyme or chemical reagent. ÏÖ061] Certain compounds of tire present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general., the solvated forms are equivalent to unsol vated forms and 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, all physical forms arc of use in the methods contemplated by d ie present disclosure and are intended to be within the scope of the present disclosure. "Compound or a pharmaceutically acceptable salt, hydrate, polymorph or solvate of a compound” 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.

[0962] The compounds of tbc present disclos ure can contain unnatural proportions of atomic isotopes at one or more of th e atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium f'H), iodine-125 (ii5I) 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 wife another stable isotope of hydrogen (i.e., deuterium) or a radioactive isotope, (i.e., tritium), are part of this disclosure.

[0063] Compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and /mas-isomers, (-)- arid (+)-enantiomer8, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof and other mixtures feereof, such as enantiomericaliy or diastereomerically enriched mixtures, as falling within the scope of the present disclosure. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All .such isomers, as well us mixtures thereof are intended to be included in this disclosure. When the compounds described herein contain olefinie double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers, likewise, all tautomeric forms and mixtures of tautomers are included.

[01164] Optically active (R}~ and (5)~isomers and d and / isomers can be prepared using chiral synthous or chiral reagents, or resolved using conventional techniques. Resolution of the racemates can be accomplished, for example, by conventional methods such us crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPf .C column; or derivariring the racemic mixture with a resolving reagent to generate dlasiereomers, separating the dhistcreomers via chromatography, and removing the revolving agent to generate the original compound in enantiomerieally enriched form. Any of the above procedures can be repeated io 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 diastereomeric 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, diastereomeric 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 dtastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0065] As used herein, the term “chiral” “enantiomerieally enriched” or “diastereomericaily enriched” refers to a compound having an enantiomeric excess (ee) or a diastereomeric excess (tie) of greater than abou t 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 diastereomeric excess, c.g., those compositions with greater titan about 95%. greater than about 97% and greater than about 99% ee or de, [0O66J The terras “enantiomeric excess” and “diastereorneric excess” are used in their conventional sense. Compounds with a single stereocenter are referred to as being present in “enantiomeric excess”, those with at least two stereocenters are referred to as being present in “diastereorneric excess”. The value of ee will be a number from 0 to 100, zero being racemic and 100 being enantioTnerically pure. For example, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.

[Θ067] 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 diastereorneric or enantiomeric excess of at least about 80%, such as at least about 90%, and for example, at least about 95%. In another embodiment, the first, stereoisomer is present in a diastereomerie or enantiomeric excess of at least about 96%, at least about 979», 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 diastereomerieally pure (diastereorneric or enantiomeric excess is about 100%). Enantiomeric or diastereorneric 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 diastereorneric excess is determined relative to all other detectable 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.

[O068J The term “JNK-rnediated 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, inflammatory diseases, autoimmune diseases, destructive hone disorders, proliferative disorders, cancer, infectious diseases, neurodegenerative diseases, allergies, reperiiasbn/Lschexnia In stroke, heart attacks, angiogenic disorders, orgart hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase 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 neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), neuropsyeMatric 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 epiiecticus, contusive injuries (eg. spinal cord injury and head injury), viral infection induced neurodegeneration, (e.g, AIDS, encephalopathies), epilepsy, benign forgetfulness, closed bead injury, sleep disorders, depression (e.g,, bipolar disorder), dementias, movement disorders, psychoses, alcoholism, post-traumatic stress disorder and the like. “Neurological disorder” also includes any undesirable condition associated with die 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 neurodegenerative disorder. Such method would also include treating or preventing loss of neuronal fandioti characteristic of neurodegenerative disorder.

[0070] The term “neurodegenerative 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. “Neurodegenerative 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 Lewv 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. 10071] “Pain” is an unpleasant sensory and emotional experience. Pain classifications have been based on duration, etiology or pathophysiology, mechanism, intensity, and symptoms. The term "pain." 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 ah, eds., 12th ed. 1991); Williams et ai.t J. of Med. Chem. 42:1481-1485 (1999), herein each incorporated by reference in their entirety), “Pain” is also meant to include mixed etiology pain, dual mechanism pain, allodynia, causalgia, central pain, hyperesthesia, hyperpathk, dysesthesia, and hyperalgesia.

CeamesitioMS

[0972] In various aspects, the present disclosure provides a. compound having a structure according to Formula (I):

(I) or a salt or solvate thereof. |ÖÖ73 | In Formula (I), ring A is chosen from substituted or un substituted aryl (e.g., phenyl) and substituted or unsubstituted heteroaryl, in. one example, ring A is a 5-membered heteroaromatte ring. In one example, the 5-membered beteroaromatic ring comprising from ! to 3 heteroatoms chosen from O, S andN (e.g., thiophene, thiazole, or oxazole), In another example, ring A is a 5-membercd heteroaromatie ring containing at least one sulfur atom (e.g., thiophene, thiazole). in another example, ring A is a 6-membered heteroaromatie ring. In one example, the 6-mcrnbcred hoierosromatic ring eompnscs bum 1 to 4 heteroatoms chosen from O, S andN (e.g,, pyridyi orpyrimidyl). The above 6-memhered heteroaromatie ring is optionally substituted with from I to 3 substituents, and the above 5-raembcred heteroaromatie ring is optionally substituted with I or 2 susbtiluents, wherein each substituent is independently chosen from substituted or unsubstituted alkyl (e.g,, Ci-Ce-alkyl), subsist ek'd or unsubstituted alkenyl (e.g., C;~Cs-alkenyI)s substituted or unsub,stilyted alfcynyl (e.g., Ci-C$-aikyoyl), haioalkyl (e.g., CrQ-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 6-membered heteroalky.l}, substituted or uusubstituied cycloaiky; (e.g., €3-¾-cycloaiky I), substituted or unsubstuuted heterocycloalkyl (e.g., 3- to 8-memberedheterocycloalkyl), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or 6-membercd betoroaryl), CN, halogen, OR12, SR52, NR!2R13, C(0)R"\ (;<0}NR%13, 0C(0)MR,2Ri?, C(0)0Ri:; NR15C(0)RH, NR55C(0)0R12, NR1SC(0)NR12R13, NR55C(S}NR%s:\ NRi5S(0;feR!d, S(0)2NRpR<34 S(0)Rm and S(0)2Ri4, wherein R12, R13 and R1* are independently chosen from H, acyl, Ci-C^-alkyl, 2- to 6-membcred heteroalkyl, aryl, 5- or 6-membcred heteroaryl, Cj-Cg cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein Ri2 and R1J, together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ting. R54 is independently chosen from acyl, Ci-Cg-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6» membered heteroaryl, Cb-Cs cycloalkyl and 3- to 8-membered heterocycloalkyl. 10974J In Formula (I), C* and Cb are carbon atoms, which are adjacent to each other and are both pan of ring A. j(>075j in Formula (i\ Z is a 5- or O-menxbercd hcteroaroma tie ring (e.g., triszoie, oxazoie, oxadiazole, imidazole, ietiuzole, pyrazofe, pyridine, pyra?.ine and the like), Exemplary'' Z groups are described herein below.

[ΘΘ76] In. one example, when ring A is thiophene, then Z is not a tlüazole-2-yi or benzo[d]thiazol"2~yl. in another example, when ring A is thiophene, then Z is not 1H-benzc[d]imidazoie--2-yL In yet another example, when ring A is thiophene, then Z is not methyl or ethyl-substituted thiazoie. In another example, when ring A is thiophene, then Z is not substituted (e.g., alkyl-substitnted) or ^substituted thiazoles and substituted or unsubstituted benzothiazoles. In another example, when ring A is thiophene, then Z is not substituted or unsubstituted benzimidazoles. In a further example, when ring A is thiazoie, then Z is not substituted or unsubsfituted benzimidazoles. In yet another example, when ring A is thiazoie, then Z is not liAbenzoli^imidazole-S-yt.

[0(177] In one example, when A is thiophene, then Z Is not:

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

|00?9j In a further example, when A is thiophene, (hen Z is not:

[0980] In another example, when A is thiophene or thiazoie, then Z Is not:

[0881] In one example, when ring A is thiophene, then Z is other than oxadiazole, 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 oxadiazole substituted with phenyl or substituted phenyl. In yet another example, when ring A is thiophene, then Z is other than oxadiazole, wherein the oxadiazole is substituted with a phenyl, 4~metliyl~phenyl, or a 4~ethyl~ phenyl group. In another example, when ring A is methyl- or ethyl-substituted thiophene, then Z is other than oxadiazole.

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

[0083] In Formula (I), R5 is chosen from H, substituted or unsubstituted alkyl (e.g,, Ci-Cs alkyl), substituted or unsubstituted Ca-Cfi eycloalJkyi and acyl (e.g., acetyl).

[0084] In Formula (I), W is chosen from substituted or unsubstituted alkylene (e.g., substituted or unsubstituted Q-Cio alkylene). In one example, W is C1-C10 alkylene optionally substituted with from 1. to 6 substituents chosen from R3ti and Ru defined as herdnbelow for Formulae (X) and (XI). In another example, W is straight chain alkylene represented by the formula -(CRt0R3 wherein n is chosen from 1 to 10 and Riu and R31 are defined as hereinbelow for Formulae (X) and (XI). In yet another example, W is a straight carbon chain represented by (CH2)n--, wherein n is from 1 to 10 (e.g., n is chosen from from 1 to 3 or n is 1 or 2). In another example W is C1-C4 alkylene optionally substituted with from 1 to 4 subsbiuenis chosen front R30 and Rn as defined herein. In a. farther example, W is substituted or unsubstituted methylene, e.g., -CRlwRli-~, wherein Ri0 and Ru are defined as hereinbelow for Forandae (X) and (XI). In a further example, W is methylene, optionally substituted with one or two substituents chosen from ί.-r-CV. alkyl, C3-CJ0 cycloalkyl, C;-f &amp; aJkoxy, CN sod halogen (e.g., F, Cl or

Br). In a one example, W is unsubstituied methylene (-CH?--).

[Θ885] Cy in Formula ¢1) represents a ring or fused ring system. In one example, Cy is chosen from substituted or ««substituted cydoaikyi (e.g., substituted or unsubstituted CyCg cydoaikyi), substituted or unsubstituted heteroeycioalkyl (e.g., substituted or unsubstituied 3- to 8~membered heteroeycioalkyl), substituted or unsubstituted aryl (e.g., phenyl 5. substituted or unsubstituted heteroaryl (e.g., pyridyl) and a fused ring system. Exemplary Cy are described hereinbelow.

[00861 In one example, ring Z in Formula (I) is a 5-membemd heisroaromatic nng and the compound of the present disclosure has a structure according to Formula (O):

(II) or a sail or .solvate thereof, wnercta A.. C*, Cb, R'. W and Cy are defined us tor Formula (I), above. J0087J In Formula (II), Y: is chosen from N, O and S. Y2, Y3 and Y4 are independently chosen from S» O, N, NR3 and CR4. In one example, at least one of Y3 and Y * is N. Each R3 and each R4 is independently chosen from. H, substituted or unsubstituted alkyl (e.g., Cj-Q-alkyl), substituted or unsubstituted alkenyl (e.g.. C.-CV alkenyl), substituted or unsubstituied alkynyl (e.g,, Ci-Cg-alkynyl), baioalkyl (e.g., CfrCg-haloalkyi), substituted or ««substituted heteroalkyl (e.g., 2- to 6-membered heteroalkyl), substituted or unsubstituied cydoaikyi (e.g., Cj-Cg-cycloaikyl), substituted or unsubstituied heteroeycioalkyl (e.g,, 3- to 8-membered heteroeycioalkyl), substituted or unsubstituied aryl (e.g., phenyl), subsliiuted or unsubstituied heteroaryl (e.g., 5- or 6-membered heteroaiyl), CN, halogen, OR17, SR17, NRJ7Rls, C(0)R1S, C(0)MRl7R'8, OC(ö)NR17R!8, C(ö)OR‘7, NR2üC(0)Rlst, NR20C(O)OR175 .NR20C(O)NRI7R38} NR-f,OSWR17RIS, NR*:'S<Ö)2Ri9, S(0)»NR,7R18, S(0)R'<:' and S(0)>R55, wherein R17, R"* and R“° are independently chosen IVomH, acyi, Cj-Ce-alkyl, 2- io 6~membered heteroalkyj, aryl, 5- or 6-membered hctemaryl, C3-C3 cycioalkyl and 3- io 8-membered heterocydoalkyi, wherein R17 and Ri8» together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-membered heterocyclic ring, Ri9 is independently chosen from acyl. Ci-Q-alkyl, 2- to 6~msrabered heteroalkyl, aryl (e.g., phenyl), 5- or 6-niembered heteroaryl, Cs-Cs cycloalkyf and 3- to 8-membered heterocyeloalkyl. In one example, each R4 is mdepen.den.tly chosen from H, alkyl (e.g,, Cj-Ci-aikyi), alkenyl (e.g., Ci-Ce-alkenyl), alkynyl (e.g,, CrQ-alkynyl), haloalkyi (e.g,, Ci-Ce-haloalkyl), heteiocycloalkyl (e.g,, 3- to 8-membered heterocydoalkyi), eycloalfcyi (e.g., CrCf.-cydoal.kyl), aryl (e.g., phenyl) and heteroaiyf. In anotiier example, each R' is independently chosen from H, alkyl (e.g., CpCs-alkyl), alkenyl (e.g., Cx-C«~alkenyl), alkynyl (e.g., Ci-Cg-aikynyl), haloalkyi (e.g., C?-Cs-haloaJkyI), heterocydoalkyi (e.g,, 3-to 8-membered heterocyeloalkyl), cycloalkyl (e.g., Ck-Cg-oydoalkyl), aryl (e.g., phenyl), heteroaryl, CN, halogen. OR1SR17 and NR1?RiS, wherein R17 and. R18 are defined as above.

[11088] Alternatively, any of die R ' substituents and/or R4 substituents, together with the atoms to which they are attached, form a 5- io 7-membered ring. For example, if two of Υκ, YJ, and Y4 are NRJ, then the two R3 groups may form a 5- to 7-membered ring. In another embodiment, if two ofY2, YJ, and Y4 are CR4, them the two R*' groups may form a 5- to 7-membered ring. In yet another embodiment, if one of Yy Yy and Y4 is NR3 and a second of Yy Y‘\ and Y4 is CR4, then the R’ and R4 groups may form a 5~ to 7-membered ring.

[0089 j In another example, in. Formual (11), Y5 is M In a further example, Y1 is N and Yy Y3 and Y4 form a iriaz.ole, thiazole, oxazole, oxadiazole, imidazole, pyrazoSe or teirazole ring. In yet another example. Y1 is N and Yy Y'3 and Υ~* form a. triazoie ring.

[0990} In one example, in Forrnuia 00. whoa Y7 sad Y4 are both OR'3 and Y1 is N, the·; Y" -s other than S. In another example, when Y' and Y' arc both CR'1 and Y* is N, then Y: is other than S. In a further example, when A is thiophene, then the moiety:

is not thiazole. In a further example, when. A is thiophene, then the above moiety is not bcazottuazole. In a further example, when A. is thiophene, then the above moiety is not benzimidazole, in a further example, when Λ is ihiazole, then the moiety is other than benzimidazole. In a further example, when A is thiophene or ihiazole, then the above moiety is not thiazole-2-yl, bcuso[i5Qthi'a2öl-2-}d or 1 /Abenzo[d]insidazole-2»yL 1009.1} in another example, in Formula (II), when Y‘ is NR5, then R5 is H, In another example, in Formula (II), when Y2 is CR4, then R? is H.

[0992) In another example, in Formula (II), W is substituted or unsubstituted methylene. In a further example, W is -CHr. In another example, each R3 is H. In yet another example, each BC is chosen from H and methyl. In a. further example, in Formula ill), R' is H. in another example, (o Formula (11), W is methylene and R7 is II.

Ring A

[9993J In one example, in Formula II) t«J.d Formula (.11), ring A is a 5· membered heteroaromatic ring.. In another example, in Formula (I) and Formula (II), ring A is a 6- membered aroma lie or heteroaromatic ring. Exemplary rings for A include phenyl, pyridine, thiophene, thiazole and oxaxoie. In a one example, in Formula (I) or (II), ring A. is chosen from thiophene and ihiazole. In another example, in Formula (I) or (II), ring A. is chosen from thiophene and thiazole, wherein the thiophene is optionally substituted with I or 2 substituents and the thiazoie is optionally substituted with 1 substituent wherein each substituent is independently chosen from Cj-C* alkyl (e,g., methyl, ethyl, fro-propyl, nmAbufyl), CVC* cydoailryl (e.g,, cyebpropyl), Cj-C4 haloalkyi (e.g., CF\, CHF2, CfRF, CH;-CF;), halogen (e.g., F, CL Br) and CN. In another example, ring A is thiophene or thiazoie, Yl is N and Y2, Y5 and Y4 form a triazole ring.

[0094] In yet another example, ring A is a 5-menxbered heteroaromatic ring and tine compounds of Formula (II) have a structure according to Formula (Ilia) or Formula (i lib)'

or a salt or solvate thereof, wherein Z, Rs, W, Cy, Y1, Y2, Y3 and Y4 are defined as for Formula (I) and Formula (IT), above. (Ilia) (111b) [0(105; I:r Formula (lila) and (Hlb), X1, X2 and X3 are independently chosen from S, O, N, NR! arid €R2, with She proviso that at least one of X5, X2 and X'1 is other than CR2. R* is chosen from 1L substituted or unsubstituted alky] (e.g., CrCg-alkyl), substituted or unsubsiituted alkenyl (e.g., Ci-Cg-alkenyl), substituted or unsubsfituted aikynyl (e.g., Cj-Ce-aUcynyl), haloalkyl (e.g., Ci-Cg-haloalkyl), substituted or unsubsiituted cycloalkyl (e.g,, Cd-Cg-cydoalkyl), substituted or xmsubstituted heteroeycloalkyl (e.g., 3- to 8-membered heieroeycloalkyl), substituted or unsubstituted aryl (e.g,, phenyl), substituted or unsubstituted heteroaryl (e.g., pyridyl). In one example, R1 is chosen from H, substituted or unsubstituted Cj-Ce alkyl (e.g., methyl or ethyl) and [6096] Ia Formula (Ilia) and (mb), each R2 is independently chosen From aryl group subsHmenls as defined herein. In one example, each R ’ is independently chosen front H, substituted or unsubstituted alkyl (e.g., Ct-Cg-aikyl), substituted or unsubstituted alkenyl (e.g., Ci-C^-alkenyl), substituted or unsubstituted alkynyl (e.g., CcQ-alkynyi), haloalkyl (e.g,, Ci-Cs-baloalkyl), substituted or unsubstituted beteroalkyl (e.g., 2- to 6-membered beteroalkyl), substituted or unsubstituted cydoalkyl (e.g., Cj-Cs-cycloalkyl), substituted or unsubstituted heterocyeloalkyl (e.g,, 3- to S-mernbered heterocycloalkyl), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted lieleroaryi (e.g.., 5- or 6-membered heteroaryl), CN, halogen, OR*2, SR22, MR22Rm, C(0)R“4, C(0)NR22R2l OCiOjNR^R23, €{0)OR22, NR2SC(0)R24, lSTtMC(0)0R22, NR2SC(0)NR22R23, NR2sC(S)NR22R2-', NR2sS(0)2R24, S(ö)2MR22R2-\ S(0)R24 and SCO.feR24, wherein R22, R2j and are independently chosen, from H, acyl, Cj-Cg-alkvl, 2- to 6-membered heteroaikyL aryl, 5- or 6-membered heteroaryl, C3~Cg cycloalkyl and 3~ to 8~membered heterocydoalkyl, wherein Ri2 and Ry\ together with «be nitrogen atom to which they are bound are optionally joined to form a 5- to 7~membcred heterocyclic ring, R.34 is independently chosen from acyl, Ci-Q-alkyl, 2- to 6-membered beteroalkyl, aryl, 5- or 6-mcmbered heteroaryl, CVO, cydoalkyl and 3- to 8-membered heterocycioaikyl. In one example, each R2 is independently chosen from H, Q -C4 alkyl (e.g,, methyl, ethyl, iso-propyl, te/ï-feutyl), C3~C6 cydoalkyl (e,g.s cyclopropyl), Q-C4 haloalkyl (e.g., CFj, CHF2, CH?F, Cl IjCFj), .halogen (e.g.. F, Cl, Br) and CM.

[Θ097] 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); CV);

(VH: (VII) or a salt or solvate thereof, wherein C'y, W, Rs, Y1, Y2 Y2 and Y4 are defined as hereinabove in Formulae (1), (I!) and (ill), respectively, [ÖÖ9S] In Formulae (IV) to (VII), IV and R2a are each defined as R2 in Formula (Ilia) and (Mb), In. one example, .R.2 and R2a are independently chosen from H, C1-C4 alkyl (e.g., methyl, ethyl, /jo-propyl, terf-butyl), Cs-C* eycloalkyl (e.g., cyciopropyi), Q-C4 haloalkyi (e.g,, CF3, CHF2, CH2F, CH2CF3), halogen (e.g,, F, Cl. Br) and ÜW. In. another example, R2 and R2* are both H. In yet another example, at least one of R' and R2* is halogen (e.g., F, Cl, Br). In a further example, at least one ofR2 and R4* is CN, In another example, at least one of R' and R"'s is methyl.

[80991 In one embodiment, ring Z is chosen from 5-merobered and 6-membered heteroaromatic rings. Exemplary 6-membered heteroaromatic 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 a tom of ring Z. Hence, in one example, ring Z is connected to the remainder of the molecule via a carbon atom. )99108 i 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 Yl is NR2, then R’ is H. In another example, when Y ' is €R4, then R.4 is H. {¢01011 Exemplary 3-membcred hercroaroxnatio rings for Z in Formula (1 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, tctrazolcs, oxadiazolcs (e.g., 1,2,4-oxadiazoles or 1,3,4-oxadiazoles), thiadiazoles (e.g., 1,2,4-thiadiazoIes or 1,3,4-thiadiazoles), pymzoles, imidazoles and tetrazoles. In another example, ring Z has a structure, which is chosen from:

wherein Y5 is chosen Jhsm O, S and NR·’, wherein R’ is defined as for Formula (II), above. In one example, each R* is independently chosen from H, alkyl (e.g., Ci-Q-alkyl), alkenyl (e.g., Cf-Ce-alkenyl), alkynyl (e.g,, Ci-Ce-alkynyl), haloalkyl (e.g., Ci-Qs-haloaikyl), heterocydoalkyl (e.g., 3- to S-membered heterocycloalkyl), cycloaikyf (e.g., Cj-Q-cycloalkyl), aryl (e.g., phenyl) and heteroaryl. In another example, R* in the above structures is chosen, from H, CrC< alkyl (e.g,, methyl) and Q-C? haloalkyl. (00102] In the above structures, R4 and R% are independently chosen and are e?sch defined as R4 in Formula (II), above. In one example, R4 and R4® are independently chosen from H, alkvl (e.g,, Ci-Ce-alkyl), alkenyl (e.g., CrOs-alkenyl), alkynyl (e.g., Cr Ce-alkynyl), haloalkyl (e.g,, Ci-Ce-haloalkyl), heterocydoalkyi (e.g., 3-to 8-membered heterocycloalkyl), eycloalkyl (e.g., Cs-Cs-cycloalkyl), aryl (e.g., phenyl), heteroaryl, CN, halogen, OR5 \ SR1' and NR17R18, wherein R17 and R:S are defined as above. Is another example, R4 and R’a in the above structures are independently chosen from H, substituted or un,substituted CrCd alkyl (e,g„ methyl), Cs-C* cycloalkyl (e.g., cyclopropyl) and NR,17R^. In another example, R‘,!i In the above structures is H. In yet another example in die above structures, R* is H. la yet another example R* in the above structures is 11, In a further example in. the above structures, R“, R4 and R4® are each H.

[001Ö3J Alternatively, any of the R:’ substituents and/or R4 substituents, together with the atoms to which they are attached, form a 5- to 7-membered ring. For example, if two of Y'\ Y*, and Y4 are NR\ then the rwo R’ groups may form a S~ to 7- ineaibercd ring. Ia another cmboduneiii, if 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>inejubered ring, {00104] In one examples, ring Z in Formula (!) or (HIM or ihe moiety:

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

[ÖS105] or a tautomer or mixture of tautomers thereof, wherein. R4, R4d and R,s are defined as hereinabove. In one example, R4,and R" are independently chosen from H, substituted or unsubstituted alkyl, substituted or uasubsuluted heteroalltyl, substituted or unsubstituted cycloaikyl, substituted or unsubstituted heterocydoaLkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR1? and NR1 'RiS, wherein R5' and R:* are independently chosen from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloaikyl, substituted or unsubstituted heteroeydoalkyl, and wherein R1' and R;S, together with the nitrogen atom to which they are attached, are optionally joined to form a 5- to 7-merabered 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-membercd ring. For example, one of Ry R4 and R4a and one of R1' and RIS, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring. In another example, R3 and R4 or R4 and R4b, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-m.embered ring.. In one embodiment, in any of the above structures, R3 is H.

[00106] In one embodiment, in the above structures, R4a is H. In another embodiment, in the above siruciures, R‘1 is H, methyl, cyciopropyl or amino.. In yet another embodiment, in the above structures, R4a (when present) is H and R4 is H. In yet another embodiment, in the above structures, R4* (when present) is H and R4 is methyl.

In a further embodiment, in the above structures, R4a (when present) is H and R“ is cyciopropyl [00107] In one example, Z in Formula {ΊΠ or(HTb) or hie moiety:

in 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 R'' 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,

[OÖ1091 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 (VHIb) or Formula (VIIIc): (Villa) (vuib)

(VÏIIc) or a tautomer, mixture of tautomers, salt or solvate thereof.

[00110] In Formulae (Villa), (VUIb) and (VUIe), ring A, Ca, Cb, R.\ R4, R5, W and Cy are defined as hereinabove. In one example, R4 is H. In another example, R4 is methyl, In Formula (Vllib), R3 and R“, hu oth„r with the atoms to which they are attached, are optionally joined to form a 5- to 7-memhered ring.

[Θ01111 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):

(IVa); (Va);

(Vla); (Vila) or ti taulornci, mixture of tautomers, salt or solvate thereof, wherein Gy, W, R4 and R"' are defined as for Formula (1). above. R“ and R":l are defined as in Formulae 0 V) to (VÏÏ) hereinabove, hr one example. R“ is H or methyl [081121 Exemplary 6-membered heteroaromatic rings for Z, e.g., in Formula (I) and Formula (IHb), include pyridh-ea, pyrarines, pyrimidines, pyridagtnes and iriazincs (e.g., 1,2,3-triazines; 1,2,4-iriazisnes or 1,3,5-idazines). In one example, Z in Formula (I) or (llib) has a structure, which is chosen from;

wherein n is an integer chosen from 0 to 4, m is an integer chosen from 0 to 3 and o is an integer chosen from 0 to 2, Each R:ii is independently chosen from Hs substituted or ««substituted alkyl (e.g., Ci-Ce-alkyl), substituted or unsubstituted alkenyl (e.g„, CrC«-rfkenyl), substituted or unsufcstituted aikynyl (e.g., Cs-Ce-alkynyl), haloalkyl (e.g., €-€(,-haloalkylj, substituted or unsubsiituted heteroalkyl (e.g., 2- to 6-membered heteroalkyl), substituted or unsubstituted cydoalkyl (e.g,, C.rCV-eydoalkyl), substituted or n «.substituted bererecycloaifcyl (e.g., 3~ ίο 8-mcmbcrcd heterocycicaiky I), substituted or unsuhstituted atyl (e.g., phenyl), substituted or unsubstituted heteroatyl (e.g., 5- or 6-membered heteroaryl), CN, halogen, OR3", SR32, NR32R33, C(0)R?4, €(0)14¾3¾33. 0C(0)NR32R33, C(0)0R32, NR3SC(0}R34, NR33C(0)0R32, NRJ5ciO)NR32R33, NR3SC(S)MR32R33, NR3SSCO)2Rm5 S(0)2NR32R33, S(0)R34 and S(0)?R34, wherein R32, R '3 and R33 are independently chosen from R, acyl, Cj-Ce-aikyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6~membered heteroaryl, C.rCg cycloalkyl and 3- to 8-membered heterocycloalkyl, wherein R3'· and R'i3, together with the nitrogen. atom to which they are bound are optionally joined to form a 5- to 7-menibered heterocyclic ring, R34 is independently chosen from acyl, Ci-Cc-alkyl, 2- to 6-membered heteroalkyl aryl, 5- or 6-membered heteroaryl, Cs-Cr cycioaikyl and 3- to 8-membered heterocycloalkyl Adjacent R!iI, together with the carbon atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring.

[00113] in another example, 2 is a fused ring system, which includes a- least one of the above 5- or 6-mcnibcrcd rings. In one example, Z is chosen from benzo- or pyrido-imidazole, benzo- or pyrido-oxazoie, benzo·· or pyrido-tMazole, benzo- or pyrido-isox azole arid benzo» or pyrido-isotldazoie.

[00 ί 14] In one example, when ring A is thiophene, then Z is other than oxadtazole. In another example, when ring A Is thiophene, then Z is other than substituted (e.g.. phenyl-substituted) oxadiazolc. in yet another example, when ring A is thiophene, then Z is other than oxadiazole substituted with phenyl or substituted phenyl. In yet another example, when ring A is thiophene, then Z is other than oxadiazole, wherein the oxadiazole is substituted with a phenyl, 4-methyl-phenyl, or a4-ethyl-phenyl group. In another example, when ring A is methyl- or ethyl-substituted thiophene, then Z is other than oxadiazole.

[00115] In another example, when ring A is thiophene, then Z is other than pyrirnidmone. In another example, when ring A is thiophene, then Z Is other than substituted pyrimidinone (e.g„ pyriimdinone substituted with at least one of hydroxy, carboxy or hydroxy-methylene)

W

[OMlfi] In another example according to any of the above embodiments of Formulae (I) to (IX), W is straight chain alkylene represented by -{CRi0R1,)i1- wherein n is chosen from 1 to 10 and Ri0 and Rn are defined as herdnbdow for Formulae (X) and (XI). In another example, W is straight chain alkylene represented by -(CHh)*-, 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 embodiments of Formula (T) to (IX), W is uasubstituted methylene [ÖÖ117] The present disclosure further provides a compound, having a structure according to Formula (X) or Formula (XI): (X)

(XI) or a salt or solvate thereof, wherein Z, RJ and Cy are defined as for Formula (I) above, (0911.8'j In Formula (X) and Formula (XI), X1 and XJ are independendy chosen from N and CRA. R' and are each independently defined as R' in Formula (Ilia) and Formula (mb). In one example,, R2 and R.^ are independently chosen from H, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubst-tnied 3- to 10-mernbcred heteroalky], substituted or unsubstituted Cj-Cs cycloaikyl, substituted or unsubstituted 3- to 8-mernbersd heterocycioaikyl, substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroa-yl (e.g., pyridyi), CM and halogen. In another example., R' and R2® arc iudepeotienily chosen from H, C1-C4 alkyl (e.g.. methyl, ethyl, iso-propyi, tcrt-butyl), C3-C6 cycloalkyl (e.g., cycioprppyl), Ct-G, haloalkyl (e.g., CF*, CHF2, €H2F, CH2CF3), halogen (e.g., F. €1 or Br) and CN. In one example. R2 and Rza are independently chosen from li, methyl, halogen and €N, I DO 119 j In Formula (X) and Formula (XI), Rlü and R11 are independently chosen from H, substituted or unsubstituted alkyl (e.g., Cj-Cg-alkyl), substituted or unsubstituted alkenyl (e.g,, Ci-Cs-alkenyl), substituted or unsubstituted alkynyl (e.g., CN~ Cs-alkynyl), haloalkyl (e.g,, Cj-Q-haloalkyl), substituted or unsubstituted heteroalkyl (e.g., 2- to 6-niembered heteroalkyl), substituted or unsubstituted cycloaikyl (e.g,, Cj-Q-cycloalkyl), substituted, or unsubstituted heterocycloalkyi (e.g., 3- to 8-membered heterocycloalkyi), substituted or 'unsubstituted aryl (e.g,, phenyl), substituted or unsubstituted heteroaryl (e.g.s 5- or 6-membered heteroatyl), CN, halogen, OR42, SR42, Ml42R.43, CiOyR44. C(0)NR42R43, 0C(C»NR42R4\ C(0)0R42, NR45C(0)R44, NR4SC(0)0R42, NR45C(0)NR42R43, NR45C(S)m42R43, NR45S(0)2R4i\ S(0)2NR42R43, 8(0)¾44 and S(0)?R44. wherein R^2, R1"3 and R4'1 are independently chosen from H, acyl, Cj-Q-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, Cs-Cg cycloalkyl and 3- to S-membered heterocycloalkyi, wherein R42 and R43, together with the nitrogen atom to which they are bound are optionally joined to form u 5- to 7-membered heterocyclic ring. R"’4 is independently chosen from acyl, Ci-Ce-aikvi. 2- to 6-membered hetsroalkyl, aryl, 5- or 6-tnembered heteroaryl, Cj-Cg cycloalkyl and 3- to 8-membered heterocycloalkyi. In one example, Rtli and R:1 are both H.

[0(1120| In Formula (X) and Formula (XT), Z is chosen from those Z-groups described herein, above. In one example, Z in Formula (X) or Formula (XI»is chosen from.;

wherein n, m. o, Y", R”, K*, and Rju are defined as hereinabove, in another example, Z ία Formula is a m’azole.

Substituent {IHII2Ij in any of the embodiments ei Formula (I) to (XI), R5 is defined as tor Formula (i). In one example, according to any of the above embodiments of Formulae (I) to (XI), RJ is H or Ci-C.·? alkyl. In another example, according to any of the above embodiments of Formulae (1 ϊ to (XI), R: is H. In another example according to any of the above embodiments of Formula (I) to (XI), R5 is H and W is methylene (--CiL·--). |00122J In one example, the compounds of the present disclosure have a structure according to Formula (XII), Formula (XIII), Formula (XIV) or Formula (XV):

(Ml)

(XIV) [00123] of a 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 CHFj), In another example, R4 is H or methyl. In yet another example, R' and R2* (when present) are independently H, halogen (e.g., F, Cl, Br) or halogen-substituted methyl, and R4 is H or methyl. tytlg. vet (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 Cs-Cts cycloalkyl (e.g,, substituted or unsubstituted cyclopentauc, cyclohexane, siorbomane or adamantarte), substituted or unsubstituted 3- to 12-membered heteroeycioalkyl (e.g., substituted or unsubstituted morpholine), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl), substituted or unsubstituted heieroary! (e.g., substituted or unsubstituted pyridyl, substituted or unsubstituted quinoline, substituted or unsubstituted isoquinohne, substituted or on substituted quinoxalme, substituted or unsubstituted quinazob’ne) and other fused ring systems (e.g., substituted or unsubstituted 3,4~dibydmqmnonn-2-one, and substituted or unsubstitu ted 3,4-di hydro-1,6-naphthyridin"2”One). In one example, each of the above cycloalkyl, heteroeycioalkyl, aryl, or heteroaryl groups is optionally substituted with from 1 to 8 R20 groups, wherein each R26 is independently chosen from substituted or unsubstituted alkyl (e.g., Cj-CVaikyl), substituted or unsubstituted alkenyl (e.g.. Ci-Cs-alkenyl), substituted or unsubstituted alkynyl (e.g., Cj-Cg-alkyny!), batoalkyi (e.g., Cj-C*-haloaikyl), substituted or unsubstituted hetcroalkyl (e.g., 2- to 6-rnernbered beteroalkyl), substituted or unsubstituted cycloalkyl (e.g., Cj-Cg-eydoalkyl), substituted or unsubstituted heteroeycioalkyl (e.g,, 3- to 8-membered heteroeycioalkyl), substituted or unsubstituted aryl (e.g., phenyl), substituted or unsubstituted heteroaryl (e.g., 5- or 6-membered heteroaryl), CN, halogen, ORizs SR52, NR^R5”, C(0)Ry\, C{G)MRi2R;,'\ 0C(0)NRS2RS3, C(0)ÖR52, NR33C(0)R34, NR55C(0)0R52, NR33C(0)NR32R3\ NR55C(S)NR52R53, NR55S(0)2R54, S(0)2NR52R53» S(0)R.S4 and S(G)2RÏ4, wherein R52, R::J and R55 are independently chosen from H, acyl, Ci-Q-alkyl, 2~ to 6~membered heteroalkyl, aryl, 5- or 6-membered heteroatyl, CrCa cycloalkyl and 3- to 8-membered heteroeycioalkyl, wherein R ~ and R.5'\ together with the nitrogen atom to which they are bound are optionally joined to form a 5- to 7-meoibered heterocyclic ring. R54 is independently chosen from acyl, CrQ>-aikyl, 2- to 6>membered hetemaikyl, aryl, 5- or 6-membered heteroaiyl, Cj-Os cycloalkyl and 3- to 8-membered heterocycloalkyi.

[001251 in one example, Cy in any of the above embodiments of Formula (1} to (XV) has a structure chosen from:

1001261 wherein q is an integer chosen from 0 to 5, r is an integer chosen from 0 to 4. s is an integer chosen from 0 to 6, t is an integer chosen from 0 to 8 and each is independently defined as above. At least two R2'J, together with the atoms to which they are attached, are optionally joined to form a 5- to 7-membered ring. In one example, two R70, 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., pyridyl, pyrimidyl, pyrazyl, thienyl or pyranole) ring. 100127] in a further example, Cy in any of the above embodiments of Formula (I) to (XV) is 4-subslitoted or 3-substituted phenyl or pyridyl. For example, Cy has a struct are chosen from:

wherein u is an integer chosen from 0 to 4 and v is an integer chosen, from Ö to 3. R/0 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 R~0a in the above structures is independently chosen from R20 groups as defined herein above. In one example, the integer is or the integer v are 0 and R20* in the above structures is absent.

[00128] in a further example. Cy in arty of the above embodiments of .Formula {;) « (XV) is ehosctj from.:

wherein R20 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, I §§1291 In yet another example, Cy in any of the above embodiments of Formol» (I) to (XV) is chosen from:

[001301 wherein v is an integer chosen from 0 to 3, w is an integer chosen from 0 to 2, x is an integer chosen from 0 to 4S and y is an integer chosen from Θ to 2. Each R20* 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, Ys and Yv are independently chosen from N and €R20b, wherein each Riüb is independently chosen from H and R20 as defined herein above. In one example, Y6, Y7, Y8 and Y9 are chosen from N and CH, Y10 is a chosen from O and S. In another example, Y30 is S. $01311 In a further example, Cy in any of the above embodiments of Formula (I) fo (XV i is chosen from;

wherein v\ x. R^”"' and R"'*' arc debited 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 simei ores, each U2u* is absent and each R20b is H. in Vitro Activities 100132] Certain compounds of ike 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-temiinal kinases (JNKs). In vitro assays for the determination of INK activities are known in the art and exemplary assay formats are described herein (see e.g., Example 14). Many compounds of the present: disclosure arc especially active against JNK3 (e.g,, aJNK3 or cJNK3) but may also inhibit JNK.1 and JNK2. f001331 In one example, the compounds of the present disclosure may be inhibitors of aJNK3 with an IC50 of less than about 50 μΜ, less than about 40 μΜ, less than about 30 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 aJNK3 with an IC50 of less than about 9 μΜ, less than about 8 μΜ, less than about 7 μΜ, less than, about 6 μΜ, less than about 5 μΜ, less than about 4 μΜ, less than about 3 uM, less than about 2 μΜ, or less than about 1 μΜ. In yet another example, the compounds of the present disclosure may exhibit inhibitory activity against alNK3 with an IC» of less than about 0.9 μΜ, less than about 0.8 μΜ, less than 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 compounds of the present disclosure may exhibit inhibitory activity against aJNKB with an IC$o of less than about 0,1 μΜ (1ÖÖ τιΜ). In another example, the compounds of the present disclosure may exhibit inhibitory activity against a JNK3 with au 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 au IC5.3 of less than about 10 nM.

[00134] Certain compounds of the present disclosure do not only exhibit inhibitory activity 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 no inhibitory activity against p38 and/or MAPK. For the purpose of this uppl ieation 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 c.g.. Example 14).

[00135! Certain compounds of the present disclosure are characterized by the following inhibitory activities involving aJNK3 and p38. In one example, the ratio of ÏC50 (aJNK3y IC50 (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 ofICso (aJNK3y i€ji> (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 ofICso (aJN£3)/ ICso (p38) 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 than about 0.003, less than about 0.002 or less than about 0.001. In yet another example, the ratio ofICso (aJMK3)/ IC'c<; ί ρ38) is less than about 0.0009, less than about 0.0008, less than about Ö.0ÖÖ7, 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.

[§01361 Certain compounds of the present disclosure are characterized by the following inhibitory activities involving aiNK3 and MAPK. in one example, the ratio of ICso (aJKK3)/ IC50 (MAPK) 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 ICso (aJNK3)/ ÏC50 (MAPK) 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 IC50 (a3NK3)/ ICso (MAPK) is less than about 0.009, less than about 0,008, less than about 0.007, less than about Q.ÖÖ6. loss than about Ö.ÖÖ5, less than about 0.004, less than about 0.003, less than about Ö.002 or less than about 0.001. In yet another example, the ratio ofICso (aJNK3)/ ICso (MAPK) is 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. 100137 j Certain compounds of the present disclosure are characterized by the following inhibitory acti vities involving aJNK3, p38 and MAPK. In one example, the ratio ofICso (aJNK3)/ IC50 (MAPK) and the ratio ofICso (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 ofICso (aJNK3)/ ICso (MAPK) and the ratio of ICso (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 Ö.G2 or less titan about 0.01. In a further example, the ratio ofICso (aJNK3)/ ICso (MAPK) and the ratio ofICso (aJNK3)/ IC50 (p38) is each less than about 0.009, less than about 0.008, less than about 0.007, less than about Ö.Ö06, 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 ofICso (aJNK3)/ IC50 (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 0.0GÖ2 or less than about 0.0001.

[00138] Exemplary compounds of the present disclosure and their in vitro biological activities are listed in Table 1, below. ICso values in Table 1 were determined using the procedures o?Example 14.

Jhltkl

In Vitro Biological Activities

(ΉΗ-) Kb,ο <0.1 μΜ (Ή ) ICso 0,1 μ Μ - 10 μΜ (+) IC.so > 10 μΜ (-) Activity below level of detection in assay used (IC50 >50 μΜ) fe Vivo Activities |®D139] Certain compounds of ike present disclosure exhibit in 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 cm be induced experimentally by the administration of kainic acid. Peripheral injection of kaink acid results in the degeneration of neurons in the hippocampus. Mice lacking the Jnk3 gene are resistant to kainic acid-induced upregulation of phosphorylated c-jun fp-ejim) and hippocampal neuronal apotosis (.see e.g., Yang D.D. et ai., Nature 1997, 389: 865-870). Phosphorylated c-jun in wildtype mice is upreguiated after kainic acid administration and demonstrate that this upregulation is inhibited by certain compounds of the present disclosure. 100140] €'erb.;n compound* of the present disclosure are characterised by the following in vivo biological activities involving the concentration of p-cjim 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., kainic acid). In one example, adaiinislration of a compound of the present disclosure to a test animal (e.g., at a dose of at least about 100. 200 or 3G0i.n.g/kg), results ia a reduction of kainic acid-induced p-ejun concentration in. the brain tissue of-he 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, untreated (vehicle treated) test animal In 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 300mg/kg), results in a reduction of kainic acid-induced p-ejun 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 15%, 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-ejua 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 100,200 or 300mg/kg), results in a reduction of kaiuic 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, 2ÖÖ or 300nag/kg), results in a reduction of kainic acid-induced p-ejun concentration in the brain tissue of the test animal by at least about 31%, at least 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 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 100, 200 or 300 mg/kg), results in a reduction of kainic acid-induced p-ejun concentration in the brain tissue of the test animal by at least about 4130, at least about 4236, at least about 43%, at least about 44%, at least ahorn 43%, at least aoout 4bv<>, at least at'-om 4/%. at least about 48%, at least about 991¾ or at least about 50% relative to the p-cjxra 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 ofkainic 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% relati ve to the p-ejun concentration found in brain tissue of a comparable, untreated (vehicle treated) test animal.

Synthesis of Compounds [00141) 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). ihe .starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds, and/or prepared using known synt hetic methods. For example, the compounds of the present disclosure, as well as all intermediates, can be synthesized by known processes using either solution or solid phase techniques. Exemplary procedures for preparing compounds of the present disclosure are outlined in the following schemes. )60142} 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 reactions. Su itable protecting groups for various functional groups as well as suitable conditions for protecting and deproteciing particular functional groups are welt known in the art. For example, numerous protecting groups are described in T. W. Greene and P.G. M. Wats, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, '1999, and references cited therein.

[§61431 In one example, the compounds of the present disclosure arc prepared using a procedure outlined in Scheme la, below:

Scheme la

[dÖ144{ in Scheme ia, Cy and W ace denned as herein above. Xs find 'X' are independently chosen trom CR2, S and N with the proviso that at least one of X3 and X* is S. R·4 is deFmed as herein above. R* is chosen from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted, or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, In one example, R* in Scheme la is Ci-G, alkyl (e.g., methyl or ethyl). The moiety ~C(0)E of compound II represents a carboxylic acid group fin which E is OH), an. acid chloride (in wiueh E is Cl) or an activated ester, such as a N-hydroxysucclnimide ester (NMS-ester), t carbodhmide, a triazolol and the like, The activated ester is optionally formed in situ from tire corresponding acid, in which E is OB. In one example, compound 111 is formed by contacting compound I and compound II (wherein E is OH) in the presence of a coupling reagent and optionally an organic base, such as au anune (e.g., düsopropylethyi amine, DIPEA). Coupling reagents suitable for amide bond, formation ate known to those of skill in the art and include dicydobaxylorixiddroide i'iX'Ci). diisopropylcarbodiimide (DiC), 1 -hydroxybmzo-triazole (HOBT), 1 diydroxy-A-aza··· beszoiriaxole (HOAt), 6-ddaro-I-hydroxybvitzoinazole (Ü1-BOBT), l-ef.hyl-3-(3!-dimethylaminopropylicarbodiimide (EDC),Ν-[(ΊΗ· 'benzotriazol-1-ylXdimd.hyiammo)meth.ylenej-bl»mdhyltnethaiiamii3inm hexafluorophospbate M-oxide (MB.IU), N-[fdtmethylamuto)-! I-M ,2,3*tnas5olo(4,5-bjpyridine-.l -vimethlemfj-N-methyimethanasnnium hexatlco.ropbaspftate (JiATU), benzotriazol-l-yi-N-oxy·-uis(pyrrolidino)phosphotuu.ni hexailuorophosphate (PyBOP) and combinations thereof. Aitemanvely, PQCij and a base (e.g., pyridine) can he used to Form an amide bond. reewsj After coupling, the ester group of compound HI can be converted to a hetero-aromatic group Z. Exemplary groups Z are described herein above. Schemes 2 to 8 outline the formation of various Z groups. A person of skill in die an: will appreciate that the conversions shown in Schemes 2 to 8 are exemplary and that compounds, which include other Z groups can be synthesized using known methodologies and methods modified from those presented. f00146] In one example, Z can be covalently linked to the core moiety via an aryl-aryl cross eouplmg reaction, such as a Suzuki or Stille-type reaction. An exemplary reaction is outlined in Scheme lb, below.

Scheme lb

[00147] In Scheme lb, 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 example, Y is a leaving group suitable for a Stillc-type cross-coupling reaction, e.g,, a trialkylstarmyl (e.g,, tributyistanayi). In another example, Y is a leaving group suitable for a Suzuki-type cross-coupling reaction, e.g., a boronie add group, it is well within the capabilities of a skilled person to select a suitable catalyst. 1 ypicaJty, the cross-coupling reaction will be palladium-catalyzed. However, other transition metal catalysts can also be used. In one example, the catalyst is a palladium phosphine, such as triphenyl phosphine, Pd(PPh3)4. lit another example, the catalyst ss a copper-based catalyst. The reducing agent can be any reagent suitable for the reduction of a nitro group to an amino group. Exemplary reagents include hydrosen in combination with a metal catalyst, such as palladium on carbon (Pd/C); and tin (If) reagents, such as StiCfi.

[ΘΘ148] In Scheme lb, the nitro analog is first coupled to Z. followed by 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 its Scheme la,

In another example, the coupling reaction is performed after the amide has been formed as outlined in Scheme 1c, below,

Scheme! e

[00149] In Scheme Ic, Z, Y, X1, X', Rf, X and the catalyst are defined as herein above (see, e.g;, Scheme lb).

[Obi SO] In another example, the compounds of the present disclosure are prepared according to a procedure outlined in Scheme Id, below:

Scheme Id

[ObiSI 1 .in Scheme kl, R\ Xs and Xs are defined as herein above and X is a. leaving group, such as halogen (e.g,. Cl, Br, .1),. tosyfate, mesylate and the like. Ring B represents any heterocyclic or hetmsaromatic ring, (e.g., imidazole. pyrazole). Ring B can optionally be part of a larger ring system (e.g., indoiyi). In Scheme 1 d, compound Illb Is reacted with compound iVb, e.g., by heating (he components in a suitable solvent, such as acetonitrile, to ahorn compound Vb, The nitre group of Compound Vb can then be reduced to an amino group, e.g., using a metal reducing agent, such as iron (Fe) or zinc to aiiord compound Ylb. 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 the reaction outlined in Scheme 1 a. ixymnes [00152 j In another example, the compounds of the present disclosure include a rriazoie moiety as the ring 7. ana arc prepared using a procedure outlined in Schemes 2a or 2b, below.

Scheme 2a

jööi53] in Scheme 2a, die osier ill b nod converted to the hvdrazide V (c,p., using a hydrazine), which is further reacted with an iroidamide (e.g., acedmidamide or propiouimidamids) in the presence of a base in order to give the triazole VII. In Scheme 2a, X1, X3, Rk R1, Cy and W are defined as herein above, In one esample, R4 is chosen from substituted or unsubstituted alkyl substituted or unsubstitated aryl, substituted or unsubstituted heteroaryl and amino (e.g., alkyl-amino). WhetiR4 is amino, the imidanuae reagent VI of Scheme 2a can be a guanidine. In. Scheme 2a, X3 andX3 are ifificpcaoentiy chosen from CR", S and N, with the proviso that at least one of X1 and X" is S. Rz is defined as herein above.

[110.154] Alternatively, the carboxylic acid Ilia can be converted to a primary amide, which is then, reacted with hydrazine to form a triazolc, e.g., as outlined in Scheme 2b, below:

Scheme 2 b

lii Scheme 2 he X , X , X . cy c e d W ato d.eimed e.s herein e. bovc. Üxadlazolc [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 m Schemes 3a to 3e, below,

Scheme 3a

[091561 la Scheme 3a, X1, X3, Mb, Cy and W are defined as herein above. In Scheme 3a, the hydraadde V is reacted with triaUroxy-rnethane (e,g., triethoxvmetliane) to

form the 1,3,4-oxadiazole analog VIIL

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

Scheme 3b

[d@158| to Scheme 3b, X’\, X3, 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 isocyanoitnino-triphenyi-phosphorane.

Scheme 3c

[88159] In Scheme 3c, X1, X’, Rfi Rfi Cy and VV are defined as herein above.

In Scheme 3c, the ester III is reacted with a hydroxyimidami.de IX [e.g,, (£)~/V-hydroxyaceiimidamtde] to form the l,2,4~oxadiazoie analog X.

Scheme 3d

[O0i@O| In Scheme 3d, X1, XJ, R2, Cy and W are defined as herein above. In Scheme 3d, the carboxylic acid Ilia, which can optionally be prepared through saponification of ester III, is first converted to the primary amide XI (e.g.,, using ammonium hydroxide and a catalytic amount of ammonium chloride) and then further converted to the I ^,4-oxadiazols analog XII, e.g., by means of iV,V-dimcthylforrrtamide dimethyl acetal (DMF-DMA) followed by hydxoxylamme.

Scheme 3e v\\\\\\\\\\\\\\\\uuu\\\

190161] in Scheme 3e, the nitrile IIIc, is first converted to the corresponding imidamide (e.g., using hydroxylamine), which is further reacted with an acid chloride (e.g., acetyl chloride) to give an oxadiazole. In Scheme 3e. X3, X3, R2. R3,. Cy and W are defined as herein above. In one example, R4 is C1-C4 alkyl (e.g., methyl).

Oxaaoie/TMazols 100162] In vet another example, the compounds of the present disclosure induce an ox azole or a thiaxolc moiety as the nng /· and are prepared us-ng a procedure outlined in Scheme 4, below

100163] In Scheme 4, X1, X3, R2, R4, R4*, Cy, W and E are defined as herein above, e.g , for Scheme la. X is halogen (e.g., CL Br or 1). In one example, X is Cl or Br, Y2 is chosen from O and S. The catalyst can be any transition metal catalyst suitable for a Siiilc-lype reaction. In one example, the catalyst in Scheme 4 is a palladium catalyst, such a? a palladium phosphite, e.g. palIadham(0)tstrakistnphenyiphosphiae,

Pd(PPhi).:, [00164] In Scheme 4, the nitro analog XIII is first covalently linked to the oxazoic or thiazide XIV, I he aitit) group ot toe resulting cross-coupled product XV is reduced to an amino group using an appropriate reducing agent, such as hydrogen in combination with κ metal catalyst, such as Pd/C. The reduced analog XVI can then be coupled to an appropriate carboxylic acid analog, e.g,, compound 11, c.g,5 as outlined in Scheme la, to produce the desired oxazole or thiazole, [00165] A person of ordinary skill in the art will appreciate that compound XIV in Scheme 4 can be replaced with another oxazole, thiazole, isoxazole or ssothiazoie derivative to produce the corresponding products. Exemplary reagents are:

wherein R4 is defined as hereinabove and Y2 is O or S.

Imidazole [001.66] In a. further example, the compo unds of the present disclosure include an imidazole moiety' as the ring Z and are prepared using a related procedure outlined in. Scheme 5, below.

[00 \ 671 In Scheme 5, X1, X'5, R';, RJ, R4, K-"1, Cy, W and E are defined as herein abo^e (see, e.g., Scheme la). X is halogen (e.g., Cl, Br or 1). In one example, X is Cl or Br. The catalyst can be any transition metal catalyst suitable fox- a Stille-type reaction. In one example, the catalyst in Scheme 5 is a palladium catalyst, such as a palladium phosphine, e.g. Pd(FFh3«, [06168) A person of ordinary skill in the art will appreciate that compound XVII ra scheme 5 can be replaced with another imidazole derivative to produce the corresponding product. An exemplary reagent is:

wherein R", R." and R”* are defined ax hereinabove [Ö0169J Alternatively, In Schemes 4 and 5, the coupling reaction with the imidazole, ihiazole, oxazole and the like is performed, subsequent to the amide formation, starting with, compound XX. An exemplary coupling reaction is outlined below.

Tslrazolc [00170| Jn another example, the compounds of the present disclosure include « tetrazole moiety as the ring Z. The tebwrole moiety cor- be prepared from the corresponding nitrile through mac-ion with an mdo-frialkylstaimsae. An exemplary procedure is outlined is Scheme 6, below. For example, the nitrile XXI is reacted with azidotrifeutyistannane (Bu3SnN3) to form the tetrazole XXII. The tetrazole hydrogen can be replaced with another substituent (e.g., an alkyl group) by contacting the tetrazole with an electrophile and, optionally, an organic or inorganic base (e.g., carbonate or trieihyiamine). Exemplary electrophiles include X-R4, wherein R4 is defined as herein above and X is a leaving group, such as halogen (e.g., Ci, Br, I). In one example, X-R4 is a halogen-substituted alkyl or heteroalkyl reagents (e.g,, Mel).

Ssfessti

[00171J In Scheme 6, X1, X ; R', R4, Cy and W are defined as herein above (see, e.g.. Scheme lay K is alkyl (e.g., Ci-C-io alkyl). A person of skill in the art will appreciate that the tetrazole moiety can alternatively be formed prior to amide formation (e.g., starting with an appropriate e-yaao nitro analog). pvr^ok* [0(11.7:2] in another example, the compounds of the present disclosure include a pyrazoie moiety as the nng 7., and can bo prepared using a procedures outlined in Scheme 7, below.

Scheme 7

[00173] In Scheme 7, Xs, X3, R2, R\ r* Cy and W are defined as herein above iscc, e.b>„ Scheme la). In one example, R4 is 0 or methyl. In Scheme 7, the acetyl analog XXIV is first converted to the dmiethyianrino aeryloyl analog XXV, which is then converted to the pyrazoie XXVI by reaction with a hydrazide. A person of skill, in the art will appreciate that the pyrazoie moiety can alternatively be formed prior to amide formation..

[00174] In another example, the pyrazoie moiety cart be coupled to the remainder of I he molecule via a nitrogen atom, e.g„ as outlined in Scheme 7b,

Scheme 7b

i001 /»! in. Scheme lb, X5, X', Rf R and R4" are defined as herein above (see, e.g., Scheme la).

Evridine/Pyrazlnc [00176] In another example, the compounds of the present disclosure include 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.

Scffi 85¾

100177] In Scheme 8a, Ys is N or CE4, X1, X3, R2, R4, R4\ Cy, W and the catalyst are defined as herein above (see, e.g., Scheme la and Scheme lb). In one example, the catalyst is a palladium phosphine, e.g., FdtPFh;;)^, IÖÖ178J Alternatively, the pyridine or pyrazine moiety can be coupled prior to amide formation starting from the nitro analog XIII as outlined in Scheme 8b, below.

Scheme 8b

[001791 Schcrac 8b, V5 is N ox CR*. X\ X", R.\ R\ R4*, Cy, W and the catalyst are defined as herein above (see, e.g., Scheme la and Scheme lb). In one example, the catalyst is a palladium, phosphine, e.g., FdfFFha)^, [001 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 R2a is other than H, Halogen-substituted analogs may be prepared using the procedure outlined in Scheme 9.

Scheme g

|00 181 j in Scheme 9, Rb is a ring and X is a halogen (e.g.s Br or Cl). In ons example. X in Scheme 9 is Br. in another example. Rb is chosen from substituted or iJtjNubsiituied. cycloalkyl, substituted or unsubstituted heterocyeloalkyl,, substituted or unaubstihited aryl and substituted ox unsubslituted heieroaryl. For example, Rb is 9H~ fluorene. In Scheme 9, the isothiocyanate XXVII is eydized with the chioro beta-ketocster XXVJII in the presence of a base to give the carbamate XXIX, Deprotection of me amino group (e.g., using motpholine ίο remove iluorene protecting group) affords the halogenated. thiophene ester XXXSL Compound XXXI can be further converted to an amide by coupling to an appropriate carboxylic add, similarly to the reaction outlined in Scheme 1.

[08I82j Alternatively the halogen can be replaced with another moiety’· (e.g., either before deproteclion of the ammo 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 (-CF3) group, e.g., using CF3-CO2-Cul or methyl z,2«difluoro-2-(fluorostiIfbn.yl)acetat©?CuL In another example, halogen X is replaced with halogen .X* or CN, e.g., utilizing Sandmeyer or Sandmeyer-type reactions. For example, Br can be replaced with CL using a reagent including CnCl (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 fee 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., 108183.1 Analogs including an alkyl group as R.2 can be prepared using appropriate starting materials such as roethyl-2-aminO”4”methyl-3“thiophens carboxylate, which is commercially available (e.g., Oakwood, Floorochem):

{ÖÖIS4j ïhe disclosure further provides pharmaceutical compositions including a compound of the present disclosure, e.g., those of Fonnuiae fi) to fXV) (or ar,y embodiment thereof), and at least one pharmaceutically acceptable earner. The term ‘pharmaceutically acceptable carrier” means ail pharmaceutically acceptable ingredients known to those of skill in the art, which are typically considered non-active ingredients, Fhe 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,, anti-oxidants I, flavoring agents, sweetening agents, thickening agents, buffering agents, coloring agents and the like, as tvell as any mixtures thereof. Exemplary carriers (ie„ excipients) are described In, e,g„ Handbook oj Pharmaceutical Manufacturing Formulations* Volumes 1-6, Mazi, Sarfaraz Kb, Taylor Sc, Fiam.is Clroup — 0Ü5. wdrich is iucorporateu Herein bv reference in its entirety. A pharmaceutical composition of the present disclosure may include one or more compounds of the present disclosure in association with, one or more pharmaceutically acceptable carrier and optionally other active Ingredients, jOtiIS$| The compounds of the present disclosure may be administered orally, topically, psrsnterally, by inhalation or spray or reciallv in dosage unit formulations containing ai least one pharmaceutically acceptable carrier. The term, “parenteral” as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. The pharmaceutical compositions containing compounds of tlic 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.

[0(11 Sé] Compositions mienoed tor oral use may be prepared according to any method known to the art for die 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 with non-toxic pharmaceutically acceptable excinicnis that are suitable for the maraifacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or aigmie add; binding agents, for example starch, gelatin or acacia, and lubricating agents, tor example magnesium stearate, slcanc acid or tale. The tablets may be uneoated or tLcy may be coated by known techniques. In some cases such coatings may be prepared by known iecnni.que.s to delay oisintegration and absorption m the gastrointestinal tract and thereby piovme a sustained action over a longer period. For example, a time delay material such as glyceryl monosierate or glyceryl oistcarale may be employed. |§§187J Formulations lor 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 soil gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liqu id paraffin or olive oil. Formulations ibr oral use may also be presented as lozenges. fOOlSSj Aqueous suspensions contain the active materials in admixture with excipients .suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellnlose, melhykelluiose, hydro propyl -methyl cell those, sodium alginate, polyvinyipvrrotidone, gum travaesnth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fattv acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadeeaethyleneoxyeetanol, or condensation products oi ethylene oxide with partial esters derived from fatty acids and a hexiioi such as polyoxyethylene sorbitol monooleate,, or condensation products of ethylene oxide with pditiaf esters derived from fatty acids and hexitol anhydrides, for examole polyethylene sorbitan. monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl ρ-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin, [00189] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example araeliis 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 ora! preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[ÖÖ190] Dispersible powders and granules suitable 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, tor example sweetening, flavoring and coloring agents, may also he present, [Θ0Ϊ911 Pharmaceutical 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 naforaUy-occurring gums, for example gum acacia or gum iragacanth. naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty adds and hexiiol, 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. I8Ö192] 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 aett 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 the known art usiog those suitable dispersing or wetting agents and suspending agents that have been mentioned above. 1¼ sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in J ,3-buiajnediol. Among the acceptable vehicles and solvents that rnay be employed are water. Ringer’s solution and isotonic sodhirn chloride solution. In aoduion, stente, fixed oils ate conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic xnono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 100193 J The compounds of the present disclosure may a lso be administered in tnc form of suppositories, e.g,, for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable rsoo-irntaring escipieni that is solid at ordinary' temperatures but liquid a: ibe rectal temperature and will therefore melt in the eectum to release the orog, Such materiaLs melude cocoa feutter and polyethylene glycols.

[00194] Compounds of fhe present disclosure may be administered parenterally in a sterile medium, j uc compound, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle, In one embodiment, aditivants such as local imesthcd.cs, preservatives and buffering agents can be dissolved in the vehicle.

[Ö0I951 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 i>0/"o 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, |Θ0196] Alternatively, the active ingredients may be formulated in a cream with an oil-ia-water cream base, If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-l}c-dioS, mannitol, sorbitol, 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 such dermal penetration enhancers include dimethylsuifoxide and related analogs. The compounds of this present disclosure can also fee administered by a tramderaml device.

In one embodiment, topical administration will be accomplished using a patch e-ther of the reservoir and porous membrane lype or of a solid matrix variety, in cither ease, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesi ve, which is in contact with the skin or mucosa of the recipient. If the active agent ;s absorbed, through the skin, a controlled and predetermined Now ot the active agent is administered to the recipient. In the case of mieroe&amp;psules, the encapsulating agent may also function as the membrane. The tomsdermal. 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 from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat. or oil or wsih both a tat and an oil. In one embodiment, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which, acts as a stabilizer. The phase may, for example,include both an oil and a fat. Together, the smulslfierfs) 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, myrisiy! alcohol, glyceryl monostearate, and sodium laury! 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, tor 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 alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oieate, isopropyl paknitaie, butyl stearate, 2~eth.yih.exyl 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. 11101971 Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent tor the active mgredieots. The aatirinflammotory active ingredients may, tor example, be present in such formulations in a concentration o? 0.5 to such a> ü.5 to > u%. for example about 1 „>% wAv. For therapeutic purposes, the active compounds of the present disclosure arc ordinarily com bined 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, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tabieted or encapsulated for convenient administration. Such capsules or tablets may contain a control led-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration maybe in the form of aqueous or noo-aqueous isotonic sterile injection solutions or sirsoensions These solutions and suspensions may be prepared trom sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. Ice compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known m the pharmaceutical art. j0O198j Dosage levels of the order of from about 0.005 me to about 80 mg per kilogram of body weight per day are useful m the treatment of the diseases and conditions described herein (e.g., about 0.35 mg to about 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 four times a day. 100199] Formulations suitable for inhalation or nisufitotiun include solutions and suspensions in. pharmaceutically acceptable aqueous or organic solvents, or mixtures tlierof, and powders. The liquid or solid compositions may contain suitable pharraaeeotically acceptable excipients as describe above. The compositions maybe abmunstcred by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases or vaporized, and breathed directly from the nebuimng/vaporiziug device or die nebulising device may be attached to a facemask tent or intermittent positive pressure-breathing machine.

[03200] 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 undergoing therapy.

[00201] for administration to non-human animals, tne composition may also be added to the nuima.1 feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically aPPi0priate quantify oi the composition along with its dief. It may also be convenient to present the composition as a premix for addition to the feed or drinking wafer.

Methods [392112] Over-act; vation of JNK. is believed 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, INKx 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. Hcn.cc, the current disclosure provides a method (i.c,, an in vitro assay) that includes; (i) cootacting a compound of the present disclosure with a kinase (e.g.s JNK, p38, MAPK and die 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 of phosphoryiated kinase substrate. The method can further include (iii) measuring the amount of phosphoryiated kinase substrate. The amount of phosphoryiated substrate may be accomplished using a detection reagent. Suitable detection reagents can include a metal reagent, such as a laathanoid (e.g., Eu-63), a radioactive probe, a labeled (e.g., fiuomseeiitly labelled) antibody and combinations thereof In one example, the assay is a fluorescence resonance energy transter (FRET) assay (e.g,, TR-h'RTT). Examples of such assays are riesenoed in Ex.ai.nple i4. In another embodiment, compounds of the present disclosure is used as a reference standard to determine the in vitro activity of other compounds in a kinase assay as described above, hi another example, the compounds of the present disclosure is used m an in vitro assay for identifying candidate compounds that are capable of inhibiting INK..

[011203] Over-activation of JNK is believed to be an important mechanism in autoimmune, inflammatory, metabolic, neurological diseases as well as cancer and pain. Hence, compounds and compositions ot the present disclosure may be useful in the treatment and/or prevention of c-Jun N-temiinai kinase mediated disorders, such as autoimmune disorders, inflammatory disorders, metabolic disorders, neurological diseases, pain and cancer.

[00204) One member of the INK family, Jnk3. 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 neurodegeaeradve 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. 100205) Exeitotoxic cell death can be induced experimentally by the administration of kainic acid, 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. EL et ah. 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). Phosphoiylated c-jun in wildtype mice is upiegulated 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 phosphorylaled c-jun (e.g,, which is induced by an excitatory amino acid or an analog thereof!, in the brain 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 acid. The method can further include measuring the amount of phosphorylated c-jun in the brain, (e.g., hippocampus) of the test animal.

[ΘΘ2Θ7] 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.

[0020§j In one example, the disease is a neurodegeuerative disease. lu 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, [O8209J Neurodegeneralive 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 (ATS), traumatic brain injuries, 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), neurodegenemtioo induced by viral infection {e.g. AIDS, encephalopathies) and other degenerative dementias, including dementias of mixed vascular and degenerative origin, cemer-tia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, Neurodegenerative diseases also includes epilepsy, seizures, neurodegenerative disease caused by traumatic injury, isehemia/reperfusion in stroke, cerebral ischemias, acute hypoxia, and -senerma or glutamate neurotoxicity, in a one example, the neuronegenerniive disease is Alzheimer's disease or diffuse Fewv hodv type of Alzheimer’s disease. In. one example, the neurodegenerative disease which can be treated using the compounds of this disclosure is Alzheimer’s disease. The treatment of Akheimers disease (AD) can Include methods of treating a patient who has AD, methods of preventing a patient nors gearing AID, methods of preventing or delaying the onset of AD; e.g., delaying or preventing the progression hom MO to AD. In another example, the n eurodogen erative disease is diffuse Lewy body type of Alzheimer’s disease. In yet another example, the disease is mild cognitive impairment (MCI), [00210] 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 nenrodegcneratlon 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 ai 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, AS.per's disease, ataxia telangiectasia. Batten disease (also known as Spielmeyer-Vogt-Sjogrsu-Batten disease), prion diseases, bovine spongiform encephalopathy (BSE), Canavan disease, cerebral palsy, Cockayne syndrome, corricofcasai degeneration, Creutzfeldt-iakob disease, frontotemporal lobar degeneration, Huntington’s disease, HIV-associated dementia, Kennedy's disease, Krabbe’s disease, Levvy body dementia, neuroborreliosis, Machado-Joseph disease fe.g., spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann Pick disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, progressive supranuclear palsy, Refsum's disease, Sandhotfs disease» Schildert disease, subacute combined degeneration of spinal cord secondary to pernicious anaemia, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease and tabes dorsalis.

[00211) 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, chrome thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autosm-mme neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis and graft versus host disease (GVHDh The compounds and compositions oi toe present disclosure may also be useful to treat pathologic immune response* such as that caused by T cell activation and thrombin-induced ol&amp;toiet aggregation.

[110212) Additional specific conditions or cusenses that may be treated writ; the compounds or compositions of the present disclosure include, without limitation, myocardial ischemia, isehenua/reperfusion in heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, hepatic ischemia, liver 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 with the compounds or compositions of the present disclosure include, without limitation, angiogenic disorders, including solid tumors, liquid tumors, tumor metastasis, ocular neovaswilijsation, infantile haemangiomas. Proliferative diseases which may be treated or prevented by the compounds oi this disclosure include, but are not limited to, ae-ite myelogenous leukemia, chronic myelogenous leukemia, jnctatfatic melanoma, Kaposi’s sarcoma, multiple myeloma and HTLV-i mediated tiimorigenesis. ?002i4] Other speejise conditions or diseases that may be treated with the compounds or compositions of the present disclosure include, without: limitation, acute pancreatitis, chrome pancreatitis, asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, 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 characterized by massive neutrophil infiltration, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease, allograft rejections, fever and myalgias due to irneerion, cachexia secondary iy infection, mcioiti formation, sear tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.

[01)215] In addition, .INK inhibitors of the instant disclosure may he capable of inhibiting the expression of inducible pro-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 pais, migrains, cancer pain, dental pain and arthritis pain. 1§0216J lit addi tion to the compounds of this disclosure, pharmaceutically acceptable derivatives or pnvirugs of the compounds of this disclosure may also be employed in compositions to treat or prevent the above-identified disorders.

[Θ0217| The disclosures in this document of all articles and. references, including patents, are incorporated herein by reference in their entirety.

[00218] Tbs instant disclosure is illustrated further 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 alternative synthetic mu tes within the. scope of the present disclosure will be apparent to those skilled in the art,

EXAMPLES

General: [002191 Reagents and solvents obtained from commercial suppliers were used without furtaer 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 chromatography 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 Yariati Prepsiar high performance liquid chromatograph. !H and i3C NMR spectra were recorded at 300 MHz and 75 MHz, respectively, on a Varian Gemini or Bmker Avance spectrometer. Chemical shifts are reported in parts per million (ppm) downrield relative to tetramethylsilane (TMS) or to proton resonances resulting from incomplete deuleration of the NMR solvent (S scale). Mass spectra were recorded on an Agilent series 1100 mass spectrometer connected to an Agilent series 1100 HPLC.

[Ö022O1 Compound, purity was typically determined by HPLC/MS analysis using a variety of analytical -methods. Exemplary methods are described below.

[I] ~ 20% [B]; 80% [A] to 70% [Bj: 30% [A] gradient in 1.75 min, then hold, at 2 rnL/min, where |A]=0.1 % trifluoroaeetic acid in water; [B]=0.1 % irifluoroacetic acid in acetonitrile on a Phenomenex Luna Cl 8 (2) 4.6 mm X 30 cm column, 3 micron packing, .210 run detection, at 35 °C.

[2] = 50% [Bj: 50% [A] to 95% [B]: 5% [A] gradient in 2.5 min, then hold, at 2 mL/min, where [A]~0.1% trifluoroaeetic acid in water; jB]=0.1% irifluoroacetic acid in acetonitrile on a Ptsenomencx Luna CIS (2 ) 4.6 mm X 30 cm column, 3 micron packing, 2.10 ms detection, at 35 °C.

[3] ~ 5% [B]: 95% [A] to 20% [B]: 80% [A] gradient in 2.5 min, then hold, at 2 mL/min, where [A]=0,1% trifluoroaeetic acid in water; [B]“-G, 1%> trifluoroacelic acid in acetonitrile on a Phenomenex Luna C18 (2) 4.6 mm X 30 cm column, 3 micron packing, 210 nm detection, at 35 °C.

[4] - 20% [Bj: 80% [A] to 70% }B]: 30% [A] gradient in 2.33 minr then hold, at 1.5 snLmin, wnere ; α]·--·0.α '/t> trifl uoroaccüc acid ui water; [Bj-::0,1% trifluoroaccüc acid in acetonitrile on a Phenomencx Luna C 18 (2) 4.6 mm X 30 cm column, 3 micron packing, 2IÖ nm detection, at 35 °C.

[5] =-- 50% [Bj; 50% [A] to 95% j B): 51¾ [A] gradient in 3,33 min, then Hold, at 1,5 mL/min, where [A]—0.1% trifluoroaeetic acid in water; [B]~0. .1 % triflsjoroaeetic acid in acciormri-e on a Phenomcnex Lima C18 (2) 4.6 mm X 30 errs column, 3 mses’en packing, 210 rsrn detection, at 35 SC.

[6] = 5%-« |B]: 95% [A] So 20% [B] : 80% [A] gradient in 3.33 mirs, then hold, at 1.5 mL/min, where [Aj~i).l% trifluoroaeetic acid in water; [B]~0.1% trifluoroaeetic acid in acetonitrile on a Phenomencx Luna Cl 8 (2) 4.6 nun X 30 cm column, 3 micron packing, 210 nm detection, at 35 ft€. i?j “ 20% jBj: 80% (Aj to 705¾ {BJ: 30% [A] gradient in 10.0 mist, then hold, at 1.5 mL/min, where [A]=0.1% trifluoroaeetic acid in water; [B]=Q.1% trifluoroaeetic acid in acetonitrile on a Phenomencx Luna CIS (2) 4.6 mm X 3 cm column, 3 micron packing, 210 nm detection, at 35 °C.

[8] ::: lG% [Bj: 90% [A] to 4ö“i [B|: 60% [AJ gradientin 10.0 min, then hold, at 1.5 mL/min, where [A]::::0.1% trifluoroacetsc acid in water; [B]=0,1% trifluoroaeetic acid in acetonitrile on a Phenomenex Luna Cl 8 (2) 4.6 turn X 3 cm co'urtn, 3 micron packing, 210 sim detection, at 35 °C.

[9] = 23% [B]: 77% [A] to 30% [Bj: 70% [A] gradient in i 5.0 min. then hold, at 1.0 mL/min, where [Aj-0.1% triihsoroacetic acid in water; fB] 0.1% trifluoroaeetic acid in acetonitrile on aZotbex SB-phenyl C18 2.1 mmX 5 an column, 5 micron packing, 210 nm detection, at 30 °C.

[]0j50¾ [Bj; 50% [A] to 95% [BJ: 5% (A) gradient in 10.0 m;r·, then hold, at 1.5 mL/mio, where [Aj^0.1% trifluoroaeeiic acid in water; [B]=0.1% trifluoroacetic acid in acetonitrile a Phenomena Lima CIS (2) 4.6 mm X 3 cm column, 3 micron packing, 210 mil detection, at 35 °C.

[11] ::: 5% [B]: 95% [A] to 20% [B]: 80% [A] gradient in 10.0 min, then hold, at 1,5 mL/rnin, where [A]=Q.1% trill uoroaeefic acid in water; [83==0.1% triflnoroacetic acid in acetonitrile a Phenomenex Luna CIS (2) 4.6 mm X 3 cm column, 3 micron packing, 210 am detection, at 35 °C, [12] = 30% [B]:7G% [A] to 60%[B]:40%[A] gradient in 30 min,then hold, at 16 ml Art In. where [A]=0.1% triiluoroacetic acid in water; 0.1% trifluoroaeeiic acid in acetonitrile on a Pheaomenex synergi Hydro-RP 2 X 25 cm column, 4.0 micron pacing,

210 nm detection, at 35'C

[13] = 10% [B j: 90% [A] to 40% [B]; 60% [A] gradient in. 10.0 min, then hold, at 1.5 mL/min, where [A]-Q.l% triflnoroacetic acid ίο water; [B]=0.1% trifluoroaeeiic add in acetonitrile a Phenomenex Synergi F©!ar-RP 4.6 mm X 5 cm column, 2.5 micron packing, 210 ma detection, at 35 °C.

General Procedures:;

Protocol A

[011221] To a sotution of the caiboxylic acid (e.g,, 1.00 mmol) and the amine (e.g., LÖ0 mmol) in pyridine (e.g., 0,5 M) at about 0 °C was added phosphorus oxychloride (POOL, e.g., 1.1 mmol) and the resulting solution was stirred at about 0 °C for about 30 minutes. Water was added to the reaction mixture and the resulting solution was diluted (e.g., with methylene chloride). Hie mixture was washed with saturated aqueous Nal-lCO? and the aqueous phase was separated and extracted with methylene chloride. The combined organic phases were dried (e.g., NajSO.»), filtered, concentrated under vacuum and the residue was optionally purified (e.g,, sil ica gel column chromatography and/or preparative HPLC),

ProtocolB

[00222] [OöölJ To a .solution of the carboxylic acid (e.g., 1.00 mmol) and the amine (e.g., 1.00 mmol) in methylene chloride (0.3 M) was added 1-(3-dÏxnethyiaminopropyl)-3-ethy[carbodüiiiide hydrochloride (EDCIS 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 HQ and saturated NaRCiri, Hie organic phase was separated, dried (Na^SCfi), filtered, concentrated under vacuum and. the residue was optionally purified te.g,, silica gel colurnn chrornatography}.

Protocol C 100223] The carboxamide (e.g., 1.00 mmol) was dissolved in dintcthylfbrnwmide dirocthykcetaf (DMF-DMA, e.g., 10.0 mmol) and the resulting 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. IÖ mmol) was added to the solution and the mixture was heated to about 90 °C for about 30 minutes. The reaction mixture was concentrated under vacuum and the residue was optionally purified (e.g,, by preparative HPLC).

Protocol 1> (002241 4 he carboxamide (1.00 mmol) was dissolved in dimcthylaectamide 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

[002251 The chlorothiophsne (e.g., i .00 mmol), stann&amp;nc (e.g., 1.00 mmol), and PdfPPhj)^ (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 IS h and the resulting solution was cooled to room temperature and diluted vyuh Ιϊί20. The solution was washed with brine and ihe organic phase was separatect, dried. (N&amp;2SO4), filtered, concentrated under vacuum and optionally purified (e.g., silica gef column chromatography).

Protocol F

[00226] The mi.ro thiophene and 10% palladium on. carbon in ethyl acetate (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 diatomaccous earth and the filtrate was concentrated under vacuum.

ProtocolG

[00227] CuCl (e.g., S mmol) was added lo a solution of the bromothiophene (e.g., 1 mmol) in DMF (e.g., 0,3 M) and. the resulting suspension 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 £t2Q and washed with brine, The organic phase was separated, dried (Ka^SChj), filtered, concentrated under vacuum attd optionally purified (e.g., silica gel column chromatography).

Protocol If [00228] Ammonium cniondc (e.g., 0.05 mmoli was added to a solution of tbs 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 (Na2SC>4), filtered, concentrated under vacuum and optionally purified (e.g., silica gel column chromatography).

Protocol I

[00220] DMF-DMA (e.g., 1.00 mmol) was added to a solution of the carboxamide (e.g., t.OO mrnoi) methylene chloride (c,g., 0.2 M) and the resulting solution was stirred at room temperature for about 30 minutes. Tire solution was concentrated under vacuum and the residue was dissolved in acetic acid (e.g., 0.5 M).

Hydrazine monohydrate (e.g., 1 JO mmol) was added to the solution arid the mixture was stirred at room temperature for about 5 minutes. The reaction mixture was concentrated under vacuum and the residue was optionally purified (e.g., preparative HPLC),

ProtocolJ

[ÖÖ23Ö] DMP-DMA (e.g., 2,00 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 add (e.g., 0.5 M). Metltylhydrazine (e.g., 2.0 mmol) was added to the solution and the mixture was stirred at room temperature for about 5 minutes. The reaction mixture was concentrated under vacuum and the residue was optionally purified (e.g., preparative HPLC).

Protocol ff [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-bromoacetaie (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 Et20). The solution was washed with brine and the organic phase was separated, dried (e.g., Na2SCL), filtered, concentrated under vacuum and purified (e.g., silica gel column).

ProtocolL

[00232] To a solution of tire carboxylic acid (e.g., 1.00 mmol) and the amine (e.g., LOO mmol) in DMF (e.g., 0.3 M) was added EDCI (e.g., 3.5 tmnol), DMAP (e.g., 0.5 mmol) and HOBt (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., Na2SC>4), filtered, concentrated under vacuum and the residue was purified (e.g., silica gel column and/or preparative HPLC).

Protocol M

[00233] The aryl halide (c.g., I .00 nanoi), trieihylamine (e.g., 2.00 mmol) and P(o-iol)3 (e.g., 0,30 mmol) were dissolved in acetonitrile (e.g., 0.5 M) in a glass pressure lube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 minutes. Ethvi 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).

ProtocolN

[00234] [0002] Sodium etboxide (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 aborn 60CC for about 2 h. The reaction mixture was diluted (e.g,, with ethyl acetate) and washed with brine. The organic phase was separated, dneo (e.g., Νη?8ϋ-·). filtered, concentrated under 'vacuum and the residue was purified (c.g., silica gel column).

Synthesis of Visions Intermediate: 2-(6-FluoroqainollH'-S-yl)acetle add and 2-(6-0uoroqninölin-?-yI)ueeiie acid Protocol O: [00235] To a solution of o-fluoro benzoic acid (30,0 g. 0.19mol) in cone, sulfuric add (50 mL) and water (10 mL) was added dropwise a solution of filming nitric acid (10 mL) in water (10 mL) at Ö IjC. 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-fluoro-5-tiitrophenyl)aeetic acid as a white solid (35.2 g, 91%).

[00236] To a suspension of 2-(2-.fluoro-5-nitrophenyl)acetic acid (15.0 g, 75.3mmol) in ethanol (BQOmL), THF (40GmL), and water (200mL) was added ammonium chloride (4.46 g, 83,4mmol) 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 oil while it was hot. The filtrate was evaporated under vacuum and the crude residue was diluted with ethyl acetate (200mL) and washed with water (3 x lOOmL). The combined organic layer was washed with brine, dried over Na2S04 and evaporated under vacuum m afford 2-(5“ann;xv2~rii!oropiieny3)acetic acid as a grey solid which was used foi tiiO next siep ws shout iuzlnor ρur· bear=on (6, 13 g, 48%:K

[ÖÖ237J To a solution of 2~(5~ammo-2-tluoropkenyi)aeetic acid (6.13 g„ 36,2mmoi) in ethanol (15mL) was added cone, sulfuric acid (2mL) dropwise. The reaction mixture was stirred under N2 at 80 °C for Ihr. After the reaction mixture was cooled to RT and neutralized with aqueous N&amp;jCOj to pH 7-8, the aqueous solution was extracted with ethyl acetate (3 x lOGmL). The combined organic layer was washed with brine, dried over Na2SC)4 and evaporated under vacuum to afford ethyl 2-(S-amino-2-fiuorophenyl)aeetate as a yellow oil which was used for the next step without further purification (6.13 g, 95%). f00238] To a mixture of ethyl 2-(5-ammo-2~fluorophenyl.)acetate (3.7 g, i 8.8mmol), glycerol (6.92 g, 75.2mtn.ol), nitrobenzene (4.63 g, 37.6mmol) and ferrous sulfate (1.06 g. 3.76mmof) 'was added cone, sulfuric acid (4.5mL) dropurise, 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-fiuoroquinoSin-5~yl)iicetic acid and 2-(6-fluoroqutnoji»-7-yi)aceHc acid (1.7 g, 44%). LC~ MS (0.05%TFA): [M+l Y 20(>. 1. 1 i l-.MMR iDMSO-dó, 40(3MHz): 512.66 (brs, 1H), 8.90 (rn, 1.H), 8.35 (m, 1H)S 8.04(mJH), 7,76 (m, iB), 7.56 (m, 1H), 3.88(ss 2H), 2~(8-Flnoroqninolln”S"yI)ac8tk acid [Θ0239] The title compound (1,2g) was prepared from p-fluorobeuzoic acid (10.1 g, 65.5mmol) according to Protocol O, above. LCMS (0.05%TFA): [MH )^206.0. ‘H-NMR (CDsOD, 400 MHz): S 8.91 (d, IH, 1===2,8 Hz), 8.58 (d, IH, J=6.8Hz), 7.68 (m. 1H), 7,53 (m, 1H), 7.50 (rn, HI), 4.12 (s, 2H). 2*(8"(TrÏfl^öroïBêt!iyi)qiïiisoIta-S”-yl)a££iic add (00246] To a solution of 1, 4-dt hromo-2-mirobenzene (5 g, 17.8mmol) in N- reethylpyrrolidinone (40mL) were added methyl dtfluofo(fluOTosalft>nyl)acet*te (4.5ml... 35.6mmol) and copper(l) iodide. The mixture was heated at 80 °C 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 flash chromatography (0-3 OOpercent ethyl acetate in petroleum) to give 4-bromo-2-nitro-l-(trifiuoromethyl)benzme (4.1 g, 85%) as a yellow oil. 106241] To a suspension of 4-bromo-2-nitro-l-(trifluoromerhyl)benzene (4.0 g, 34.9nunol) in ethanol (230mL), THF (8SmL), and water (40mL) was added ammonium chloride (1.0 g, 18.8mmol) and ferrous powder (5.06 g, 90mmol). 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 storing 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 (lOGmL) and washed with water (3 x SOmL). The combined organic layer was washed with brine, dried over Na^SG* and evaporated under vacuum to afford 5-brom.o-2-(trifluoromethyl)amline as a solid (3,2g, 90%).

[00242] To a mixture of 5 foromo-2-(irifiuorometh:yI)amline (3.0g, 12.6mm.oi), glycerol (4.64g, SO.Ommol), and ferrous sulfate (0.56 g, 2,0mmol) was added cone, sulfuric acid (2.2ml.) dropwxse. 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. NaOB was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over NajSO^ and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo-8-(trifluoromethyl)quinoliiie (l,2g, 48%).

[6024.1] 5-Bromo-8-(trifluoromethyl)quinolme (1,0g, 3.6mmoI) was subjected to protocol P to give tcrt-butyl 2-(8-(irifiuoromethyl)qumolin"5"yl)acetate (450mg, 40%).

[ÖÖ244J To a solution of tert-butyi 2-(8“(trifiuommethy1)qumo1in-5-yl)acctatc (4G0mg, ί .28mmol) in DCM (5mL) was added TFA (1 QmL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was comp lore, the solvent was removed and the residue was purified (silica gel cinematography) to give the final product 2-(8-(tri.fluoromethyl)quinoHn-5-yi)acetic acid (180tng, 54%). LC-MS (0.05%TFA): [M+lf 256.1. ’H-NMR (DMSO-46, 400MHz): δ 12.70 (s, 1H), 9.07(ms IH), 8.56 (m, III), 8.15 (d, 1H), 7.74(m,lH), 7,68(ra,lK), 4,23(s, 2H). !3C-NMR (DMSO-d6,100MHz): 6171.9, .151.0, 144.0, 138.3, 133.5,127.87, 127.83, 127.78, 125.3,123,1, 122,2, 37.7, 2-f Isoquin oMn-4-yl)ftee;tk add 1002451 5.2g of Zn powder was put into a 250mL of three-neck flask under Ma protection, and then O.SniL of TMSC1 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 6niL of tert-buiyl 2-bromoacetatc 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~Broraoisoquii'ioIisie (2„0g, 9.7mmol) was subjected to protoad P to give a residue which was purified with silica gel chromatography to give tert-butyi 2-(isoquinolin~4~yi [acetate (1.9g, 81 %).

[0Ö247] To a solution of tert-butyl 2-(isoquinolin~4~yl)acetate (1,8g, 7,4ramol) in DCM (1 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 (1.3g, 93%) LC-MS(0.05%TFA): [Μ+1Γ 188,1. lH~NMR (DMSO-d6, 400MHz); 69.39 (s, !H), 8.48 (s. 1H), 8.24 id, IH, J-6.4Hz), 7.93 (t, 1H), 7,79 (m, IH), 4.11 (s, 2H). 2-(.lsö9nhKdsn-8-yl)acetk add [902481 2-bromohen;;aldehyde (18.4g, 0. knoll and 2,2-dimc4hoxyethanaminc (i 1 -55g, 0.1 i mol) in 200mL of toluene was heated to reflux for 4hr. The reaction mixture was evaporated under vacuum to give an oil of 2-bromo-N-i2,2-dimcthyos.yetaylidene)amline which was used for the next step without purification. The oil was dropped into 50mL of concentrated if.SO.j and the mixture was heated to 130-140 °C for 30muis, then the reaction mixture was poured into 500mL if ice-water and adjust to pH-8 with 5N sodium hydroxide solution. The aqueous solution was extracted with DCM (250mLX5) and washed witSi water (3 x SOixiL·). 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 E-bromoisoquinoline (2.2g, two steps 10,6%).

Protocol P

[00249] To a suspension of 8-bromoisoquinoline (2„0g, 9,7mmoi), Q-phos (68mgs Q.096mmol) and Pd(dba)2 (132mg, Ö J4mmol) in dry THF (30mL) was added 40mL of {2-tert-butoxy-2-Qxoetiiyl)2mc(II) bromide solution under N2 protection. The resulting mixture was heated at 80 °€ 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 NazSO.* and the solvent was evaporated under vacuum to give a residue which was purified with silica gel chromatography to give tert-birty! 2-(isoquinolin-8-yl)acetate (1.85g, 78%). 100250] To a solution of tert-butyl 2-(isoquinolm-8-yl)acetate (1.8g) in DCM (lOmL) was added TFA (lOmL) dropwise. The reaction was stirred at room temperature overnight. After the reaction was complete, the solvent was 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 gel coulunm chromatography) to afford 2-(isoquiiioiin-8-yl)aceiic acid as a solid (1.2g, 87%). LC-MS (0.05%TFA): [M+lf 188.1,3H-NMR (DMSO-d6, 400MHz): 513,0 (bra* IE), 9.65(s,lH), 8.61(d, 1H, *=4.813/.), 8.16 (d, IE, J=4.SH/.), 8.05 (d, 1T-I, J-6.8Hz),7.92 (t, IB), 7.72 (d. lH,J~6.8Hz). 4.29 (s, 2H). 2-(QalHollïï-8“yl)aefi!tlc add {0(1251 ] The title compound (278mg) was prepared frons 8-bromoquinoline (3.0g, ]4.5ramoi) according to protocol P above. LCMS (0.05%TFA); [M+lf 188.1. Ή-NMR. (CD3OD, 400 ΜΗ?.): δ 9.01((1,1 Η. 3===3.6Hz), 8.72(0, IΠ, J=ró.4Hz), 8,06 <d, ΙΕ, J-6.8Hζ), 7.87 (d, 1Η, J=5.6Hz),7.77 <m, 2H), 4.31 (s, 20).

Preparation of 2~(beszo[d]thlazo!"7-yI)aceilc add [08252) To a solution of ó-mtrobenzothiazale (3.8 g, 0,02moi) in 40 ml 2N HC1 was added SnCi; (15.9 g, 0.06mol), 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 benzo [d]thiazo3~6~amme (3g, 72%).

[08253) To a so-cuion of benzofdjih=asoi-6-amine (100 mg, 0.67mmoi) in 6 ml CHCtj was added Br?. (42 mg, 0.27mmol) m {..ΉΟί.3 (10ml) dropwiss about 15 min. The mixture was concentrated under reduced pressure, and the residue was crystallized horn DCMdVIeOB (5:1) to give 7-hxoinoberr?o[d]thia2ol-6"amine (80mg, 80%). )082s4) To a solution of bi'omohenzo[d]thiazol”6-amme (30 mg, 0.13mmol) was added 50% H2SO4 (38 mg, 0.39mmol), and then MaNi>2 (18 mg, 0.26mmol) was attded to the mixture at 0-5 °C. The reaction mixture was stirred about 15 min at f)~5 °C, o0% iri.iPO-.· {; 7 mg, 0.26mmol) was added. The mixture was stirred at room temperature overnight, quenched with aq.NaHCCh solution, extracted with ethyl acetate. The combined organic layer was concentrated under vacuum to give a residue which was purified with chromatography (ethyl acetate/petroleum ether=*0.06) to give 7~ bromobcnzoidlthiazolc (10 mg, 30%). )002551 The title compound (20 mg) was prepared from 7-bromobenzo[d]thiazoic according to protocol P, LCMS (0.05%TPA): [M-Hf 194.1. :H-NMR (CDCli, 400MHz); 59.03 (s, 1.H), 8.10(d, HI, J:::;6.8.Hz), 7.53 (m, lf-1), 7,39 (d, i'(J. J=6.8Hz), 3.96(s, 2H).

[88256) ^-Aminodiiophenc-J-carOonitrise (c.75 g, 22.? mmoli tn formic acid (15 ml) and concentrated sulfuric acid (1 ml) wag heated in a microwave for 15 min at 100 ¢.-, The solution was diluted with water, filtered, and the filtrated was concentrated imdcr reduced pressure to yield thjeno[23-«'/jpyrirrsidiö-4(3//)-one as a purple film. Method [d] retention time 2.09 min by HPLC (ΛΉ 153), [00257] Thieno[2,3~iflpyrümdin~4{3iï)-one5 sodium acetate (20.92 g, 255 mmol), and bromine (3.0 ml, 58.2 mmol) in glacial acetic acid (100 ml) was stirred for 24 h, A second portion of bromine (10 ml, 194 mmol) was added and the heterogeneous mixture hssied 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 ;ö. 1, 49:1:0,.1, 24:1:0.1, and 23:2:0.2 methylene cUoride:methanol:conceotrated ammonium hydroxide as the eluant to afford 1.96 g (29% yield over two steps) of 5,6-dibromothieiio[2,3~ tfjpyninidb>4{3H)-ose as &amp; yellow solid. Method [8] retention time 6,19 min by HPLC (M+309, 311, and 33 3). 100258] Zinc dust (210 mg, 3,21 mmol) was added to a solution of 5,6-dibromodne;.:o[23-i/jpyrimidin--4(3f/)--one (910 mg, 2.94 mmol) in glacial acetic acid (8 ml; and water (2 ml). Aller sturing for 4 h, a second portion of zinc dust (2 j 4 mg, 3,2? mmol ) was added and the heterogeneous mixture was placed into a preheated oil bath at 60°C. The heterogeneous mixture became a clear solution in 30 min. The solution was diluted with water and ext?acted with ethyl acetate. The oomoined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 5-bremothièno[2,3-d]pyrimidin.-4(3i?)-on.e as a white solid. Method [8] retention time 2.68 min by HPLC (M+ 231 and 233), [08259] 5-Brornoih i eno[2,3 ~d\ pyri rrid ηι~4(3 //Tone in 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/}pyrimidine. Method [8] retention time 8.72 min by HPLC (Mt 249, 251, and 253) major peak intensities.

[08260] 5-Brotno-4- chlorothieno[2,3-</]pyrirmdine and hydrazine monohydrate (2 ml, 41.2 mmol) in absolute ethanol (10 ml) was heated to 75°C. After stirring for 1 h, the solution was concentrated to yield 5-brorao~4"hydraziöylthionoi2,3-<-/]pyrimidinc.

Method [8] retention time 0.80 min by HPLC (M-f- 245 and 247).

[002611 5 ~bromo"4-bydrazinyithieoo| 2 , 3 v7{ pyrimidine and triethylortho formate (40 ml) m ethanol (10 ml) was placed into a preheated oil bath at lOCfC for 24 h. The soiniicm was concentrated and the residue was flash ehromtographed with 9:1,4:1, and /.„> medtylene chloride:ethyl acetate as the eluant to afford 578 nig (38% yield over 4 stops ? or %bromotr::eTKd3,2-i,']ri,2,4]rriaeob[4,3<:]pyriir;idinc as a yellow'solid. Method 18] retention time 4.17 min by HPLC (M+ 255 and 257), [00262] 9-BiOmothieno[3,2-e][l,2,4]triazolo[453-c]pyrirnidine (551 mg, 2,16 mmol) and /v'-roethylethane-1 /’-diamine (I ml, 1! .3 mmol) in methanol (20 ml) was placed into a preheated oil bath at o0 (., Alter stirring tor 15 ram, tire 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 525 mg (99% yield) of 4-bromo-3-(4/7-1,2,4-triazol-3-yI)thiophen-2-arnine as a brown solid. Method [8] retention time 2.25 min by HPLC (M-r 245 arid 247).

Example i

Synthesis of Thiophene Tri&amp;iofes 1.1, Synthesis i^N-i2^JJ-M^2A-irkmA-5-yl}thmphm~3~yïh2~(jmpMh&amp;ïm-~i~· yijaeetamide (1)

1.1.1, 3~(2~{A'flipktk8jleft-l~ji)&amp;cei(4ffiid&amp;}tki&amp;pkeMe~2~carh&amp;xyUc ucid [00263) Methyl 3-(2-(oaphtlial«i-l-yl)acet8.mido)fhiopheni.*-2-carboxylaie (210 Qig, 0,645 mmol) was dissolved in THF/II^O (2.5 m.L, 4/1, v/vSodium hydroxide (129 mg, 3.22 mmol) was added and the reaction mixture was stirred at 50 “C for 20 h. The resulting solution was ackniied with 10% aqueous HCI and extracted with ethyl acetate.

TjiL organic phase was separated, dried (1SUJSO4), lihei’eo and concentrated under vacuum to give 3-(2~(naphihalen-l-yl)acetamidG}ihiophene-2~carboxyiie acid. Retention 1.962 min, method [1], MS(ESI) 312J (M+H). LL2. 3-(2~(Napkthaleit~I~yi}&amp;eeiamMe)thi&amp;phme~2-c(!r&amp;0xemidie {00264) 3 -(2 -(Naphthalen-1 -yl)aceiamido)thiophene-2~earboxylie acid (151 mgs 0.485 muiol) was dissolved in tMonyl chloride (2 mL) and the resulting solution was stirred at 60 CC for 30 minutes. Fire 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 (Na2S04), filtered, concentrated under vacuum and the residue was purified on a silica gsl column (eluant hexane/etnyl acetate, 8/2 to 1/1) to give 3«(2-(naphthaledti-l-yl)acetaniido)thiophene-2~ carboxamide (81 mg, 0.26 mmol, 54%). Retention time (min) = 4.917, method [7], MS (ESI) 311.] (M+H). 2.1.5. t2>4"Triuz(ti-5~yl)tkh}pk<i%-3~yi)~2~{ft%phihi!.len'-l~yi}a(!eMffli(ie [0826SJ The title compound was prepared from 3-{2-<napbthalen-1 ~ yl)aceiamido)lhiophene~2~carboxamide (104 mg, 0.335 mmol) according to protocol C. Method [7] retention time (min) = 5,105, MS(ESI) 335.1 (M+H); !H NMR (30() MHz, CDClj) δ 10.43 (s, !H), 8.15 (d, J= 5.4 Hz, 1H), 8,05-8.08 (m, 1H), 7.90-7.94 (m, 1H), 7.80 (s, HI), 7,29-7.60 (m, 4H), 7.27 (s, 1H), 4,32 (s, 2H). 1.2. Synthesis of A-(2-(3“ïricthyT17/"l,2.4-triaxo!-S-yl)tlrlöpheu“3-yi)-2· (na phths ten-1 -yfiace tarn id e (2) 1102661 The title compound was prepared from 3-(2-(naphthalen~l-yl)acetamido)thiopbene-2-earboxamide (72 mg, 0.23 mmol) according to protocol D. Retention time (min) = 4.919, method [7], MS(ESI) 349.0 (M+H); !Η NMR (300 MHz, CDCfi) δ 10,32 (s, 1H), 8.16 (d,/=5.5 Hz, 1H), 8.08-8.11 (m, 1H), 7.87-7.92 (ηι,2Η), 7.52-7.61 (m, 4H), 7.24 (d, ./= 5.5 Hz, IB), 4.28 (s, 2H), 2.32 (s, 3H). IJ, Synthesis si N~(2 {J J-diraefhyl·- ί //-1,2,4“iriazoM”yi}ihioj>hen-3-yI)-2~ (napMhalen-I~yl)aeeinmïde (3) (G0267| The title compound was prepared from 3-(2-(naphtiiden-1 -yl)acetamido)thiophene-2-earboxamide (71 mg, 0.22 mmol) using protocol D except that methyl hydrazine was used instead of hydrazine. The crude product was purified by preparative HFLC to give AH2~(3~meihyMHH Js4~triazoI~5~yI)thiopheii~3~yl)~2~ (naphihalen-l -yi)acetamide. Retention time (min) = 6.636, method [?], MSfESI} 363.1 (MtH); lH NMR (300 MHz, CDCh) 5 11.20 (a, 1H), 8,30 (d,,/- 5.5 Hz, 1H), 8. 32 (d, J = 8.2 Hz, Hi), 7,85-7,91 (m, 2H), 7,48-7.62 (re, 4H), 7.40 (df /= 5.5 Hz, Hi), 4.27 (s, 2H), 3.96 (s, 3IT), 2.19 (s. 3.H). 1,4. Synthesis of Λ'-(2··( 1 - snethyL 1//-1JJ-triazGl-o-yilf h sopheo-3 yi)-2·· (naphthalan-j -yl)aeetamide (4) 108268] The title compound was prepared from 3~(2~(na.phthalen-1 -yl)acetainido)ihiophene-2”Cartx)xamide (104 mg, 0.335 mmol) according to protocol C except that methyl hydrazine was used instead of hydrazine. The reaction mixture was purified by preparative HFLC to give A~(2-(l-methyl~l//-l,2s44riazol-5-yi)thiophen-3-yl)-2-(nap.htha1en-1 -yl)aceiamide. Retention time (min) = 6.494, method [7], MSfESI) 349.1 (M+H); 1H NMR (300 MHz, CDClj) 6 11.26(¾ IH), 8.30 (d,,/- 5,5 Hz, 1H), 7.88-8.06 (m, 3H), 7.42-7.59 (m, 5H), 7.41 (d, J = .5.5 Hz, 1H), 4.30 (s, 2H), 3.98 (s, 3H).

Synthesis of2-(4-Methoiyplsenyl)”7V-(2”(3-meilsyl-lj¥~ls2i4-trta^ol~S"yI)tliInphea-'3“ y1}acetamlde (5)

/.5./, Methyl S~(2~(4~methox}!pkënyi)izceiümi4e}ihmphene~2~cürb&amp;x\4ste (90269] The title compound was prepared from 2-{4-mefhoxyphenyi)aceiie acid (3,18 g, 19.2 mmol) and methyl 3-aminothiophene-2-carboxylate ¢3.02 g, 19,2 mmol) according to protocol B, Retention time (min) - 2,143 , method [1], M.S(ESI) 306.1 (M+H).

1„5,2. 3-(2-(4~snef.h(}xyphen}'i}aeetiimido)thk^pkens~2-c&amp;rbi}x^Uc ucM

[00270] Methyl 3~(2~(4-methoxyphenyl)aeetaimd.o)thiophenc-2-earhoxyIate (5.7g, 18,7 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 HC1 and extracted with ethyl acetate. The organic phase was separated, dried (NajSi^), filtered and concentrated under vacuum, to give 3-(2"(4-meiiioxypheiiyl)acetaniido)tliiophene-2«carboxylic acid. Retention time (min) - 1.678, method [ 1], MS(ESI) 292.1 (M+H). 1,53. 3-(2-(4-Metk&amp;jQ,phe^yl}si€etemide)thii}phe^e~2-ca/‘boxiimMe [00271] The title compound was prepared from 3-(2-(4-methoxyphcnyl)aeelamido)-thiophene-2-earboxyiic add (1.51 g, 4.95 mmol) according to protocol B (504 mg, 1.73 mmol, 35%). Retention time (min) === 1.446, method [1], MS(KSi) 329.1 (M+H). /.5.4, 2-(4-Af0thexyphmyO-N~(2-(3~meihyl~nf~l!2>4~irmz0i~5~yi}thhpheift-3-yi}acetamide (00272] The title compound was prepared irons 3-(2-(4-tnet!xoxypheny1)acctainidoHbiophcnc-2-carboxamidu (204 mg, 0.703 mmol) according to protocol D Retention time (min) = 3.893, method j?j; MS(1-SJ) 329,1 (M+H); lH NMR(300 MHz, CDC13) 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, 31:1). 1.6. Synthesis of/V-(2-(3-melliyMjr-l^-triazol-5-y]>thiopheii-3-yi)-2- (quluol!n~5-y!)a€etasfiidc (6) (00273] The title compound can be made from 3~(2-(qumoiin-5-yl)acctantido)thioph.cnc~2-carboxatnide (see Example 1.27.1, below) using protocol D. 1.7. Synthesis of /¥~(2-(lff-l,2?4-trsaa;ol~5~yl)thiophen-3~yl)-2~C4~ methosyptsenyl)acetamiile (7) [002741 The title compound was prepared from 3-(2-(4-mc{hoxypberjyi)acetaiTiisdo>-t.hiophetje-2-carboxatnide (Example 1.5.3., 2?! mg, 0.933 mmol) according to protocol C. Retention time (min)3.754, method [7], MS(ESI) 315.1 (M+H); iH NMR (300 MHz, CDCb) S 10.48 (s, 1H), 8.12-8.16 (m, 2H), 7.28-7.33 (m, 3H), 6.97 (d, J= 8.3 Hz, 2H). 3.87 <s, 3H), 3.79 (s, 2H). 1.8, Syntheses of 2,4~TrIazol~l-yI)ihIöpheii~3~yI)-2-(4- snethoxyphenyl)aceiamide (8)

./,8,./, l~0~Niéretfiiiiphen-2-yl)~XR-l}2,4~t?iazii}ie [00275] l H~ 1,2,4-triazole (582 mg, 8.43 mmol), 2-ehloro-3-mtothiophene (1.15 g, 7.03 mmol) and potassium t-butoxide (944 mg, 8.43 mmol) were dissolved in. DM.F (30 mL). The resulting solution was stirred at 90 °C for 2 h, after which the reaction mixture was cooled to room temperature and diluted with ,Et20. The solution was washed with brine and the organic phase was separated, dried (Na2S04), filtered, concentrated under vacuum to give l-(3-mtothiophen-2-yl)-li/-J ,2,4-triazole. Retention time (min) = 1,073, method [1], MS(ESI) 197.0 (M+H). 1,8,2, 2~{lH~ls2r4~Trieszol~l~yl}thiepheii~3~amiise [00276] A mixture of 1 -(3-nitrothioph<ai-2-yl> 1 J¥-l ^,4-triazole (462 mg, 2,35 mmol), iron (1.31 g, 23.5 tnmoi) and ammonium chloride (163 mg, 3.06 mmol) in water (5 mL) was stirred at 1G0 *€ for 18 b. The restilting suspension was filtered through a pad of diatomaceons 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.2SCL>. filtered and concentrated under vacuum to give 2-(11/-1 ^,4-triazol-l -yi)thiophen-3-armne (314 mg, 1.89 mmol, 80%). Retention time (mis) · 0,454, method [I], MS(ESI) 167.0 (M+H), L8.3, ft!~(2~{lH~l}2t4-TrMz&amp;$~2~},$)tki&amp;phgft~3-yi)-2-(4-me£hex}pkeïi},l)&amp;cet&amp;f!ïide [00277] The title compound was prepared from 2-(4-methoxyphenyl)scetic acid (233 mg, 1.41 mmol) and 2-(17/- l,2,4-triazo]-l-yi)thiophen-3-amine (234 mg, 1.41 mmol) according to protocol B. Retention time (min) - 2.847, method [7], MS(ESl) 315,2 (M+H); Ή NMR (300 MHz, CDCI3) 5 9.27 (&amp;, 1H), 8.31 (s, 1H), 7.99 (d5 J = 5.3 Hz, 1H), 7.83 (s, 1H), 7.22 (d, J= 8.1 Hz, 2H), 7,09 (d, J= 5.3 Hz, 1H), 6.94 (d, J= 8.1 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 2H). 1,9. Synthesis of 2»(4~mettiosypheny!)"A~(4-metl!yKl“(3-nietMyl-l/T-i,2,4- tria2oI-5-yl)thtoplsen~2-yl)a£etamide (9)

1.0,/, 2~{2~(4~Metki}xjphenj?i)seeMmi{b)~4~meth¥ifMi>pkene~3~cm'hoxumide [ÖÖ278] The title compound was prepared from 2~{4~mc&amp;oxyphenyl)aeetic add (1.21 g, 7,22 mmol) and 2-^imno-4-methylthiopheae-3-earboxamide (1,1.2 g, 7.22 mmol) according to protocol B. Retention time (min) ~ 1,903, method [1], MS(ESX) 305.0 (M+H). 19.2, 2~{4~Metkt\x}pheMyi)-N-(4-methyl~3~{3-mefkyi-lH-l,2f4~iriami-5- yl}thi&amp;phm~2~yi)neet.amMe [002-79] The title compound was prepared from 2-(2-(4-methoxyphenyl)acetamido)”4-methylthioplieiie-3-ca?box.amide (604 mg. 1.98 mmol) according to protocol D Retention time (min) - 4.530, method [7], MS(ESI) 343.1 (M+H); *H NMR (300 MHz, CDClj) δ 11.95 (s, IB), 7.33 (d,J= 9.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H), 6.52 (s, IB), 3,83 (s, 3H), 3.82 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H). L10. Synthesis of ^2-(2//-I,2^-.tri«a»l-2«yl)thlophea-3-yl>-2-(4- methox vpheuyli&amp;cetamsde (10)

1,10,1. 2-(3~Niiroihi&amp;pheM~2~yi)~2H~l,2f3-4riaz&amp;ie |SÖ280| A solution of 1,2,3-triazole (430 rog, 6.23 mmol), 2-di!oro-3-nitiothiophene (1.02 g, 6.23 mmol) and potassium t-butoxide (838 mg, 7,48mmol) in. DMF (20 mL) was stirred at 90 °C for 4 h, after which the reaction mixture was cooled to room temperature and diluted with Et2(). The solution was washed with brine and the organic phase was separated, dried (N%$04), filtered, concentrated under vacuum and purified by silica gel column chromatography (eluant hexane/ethyl acetate, 8/2 to 1/1) to give a 1:1 mixture of 2-(3"nitrothiophcD~2~yl)"2.ff" 1,2,3triazole and I~(3~nitrothiophcii-2-yl)-i/7-1 ,.z,.j-triazcuc /1,08 c. 5.66 mot, 8977}, Retention trow frnrrO 1 2X(> ::i method [1], MS(ESI) 197.0 (M+H). L1 &amp;, 2, 2~{2 H-1,2,3- Triazi!$~2~yi)fhi&amp;phe}i~3~izmmg [00281] The title compound was prepared from 2-(3-mtrotMopheH-2~yI)-2i7-1,2,3-triazole and l-(3-nitrothiophen-2-yl)-li/-l,2f3--triazole (514 mg, 2.61 mmol) according to protocol F to give a 1/.1 mixture of 2-(2//-1,2,3-(riazoi-2-yl)tHophen-3-amine and 1.-(1//-1,2,34riazol-2-yd)thiop3ren-3-arnine (431 mg, 2.63 mmol, quantitative). Retention time (min) - 0.581 and 1.035, method [1], MS(EST) 167,0 (M+H). 1.10,3, N~{2~(2Il-lf2:f3“Tï‘iez8$~2~yi)tki&amp;pkefi-3-yï)-2-(4-fti£!tk&amp;xyphëïtyi}-&amp;ce&amp;ïffii(i&amp; [00282] The title compound was prepared from (2-(4-methoxypheny3)acetic acid (1,2! g, 7.2.: mmol) and a S: i mixture of 2-(2//-],23-tria2»3“2-yJ)thiophen-3-8'fnine and ! -{1/M A3-triazol-2-yl)thioph.öö-3-«mme (431 mg, 2,61 mmol) according to protocol B to give N-(2~(2H~ 1,2,3“tria7xd-2~yl)thioplien-3-yl)~2-(4-metfeoxyphenyOaectamide. Retention time (min) - 5.712, method [7], MS(FSl) 315.0 (?vHT!}; lH NME (300 MHz, CDC13) δ 9.99 (s, 1H), 8.06 (d, J= 6.4 Hz, 1H), 7.67 (s, 2H), 7.28-7.31 (m, 2H), 7.02 (d, J = 5.7 Hz, 1H), 6.98 (d, ,/-9.1 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 2H).

Lll, Synthesis of A~{2~(3--Cyc!opriïpyl·!ίί-Ϊ2·.·4-tria2:oï"5"yi)tlsïopheïï-^-yJ)-2-(4- m£thmyphmyi)&amp;€£t%mM£ (ίί)

ÏJI.L N-(2-(Mydrmmeeari>&amp;nyi}tkiophen~3-fi}-2-{4-meihiixyphmyi)~ acetamide [002S3J Hydrazine monohydrate (0.825 mL, 17,1 mmol) was added to a solution of methyl 3~(2~(4-methoxypheüyI)acelamido)thiopiieiie-2-carhoxylate (3.48 g, 11.4 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 (Na^SCL), filtered, concentrated under vacuum and purified on a silica gel column (eluant, hexane/ethyl acetate, 1/1 to 1/9) to give #-(2-(hydraztne-earbouyl)thioplien-3-y 1)-2~(4-metboxyphenyl)aceiamide (1.71 g, 5.60 mmol 49%). Retention time (min) == 1.300, method [1], MS(ESI) 306.0 (M+H), J.II.2 N~{2~(3~Cychpr&amp;pyl~TH~J.}2>4~trmz&amp;i~S~yi)thii)pheti~3”^}-2-(4~ m eth&amp;xpphmyï)&amp;cet®mMe [002841 A mixture of jV"(2-(hydra2inecarbonyi)thtoplieu~3~yl)-2~(4-mcihoxyphenyl)acctamide (101 mg, 0.30 mmol), eyclopropyicarbamidine hydrochloride (47 mg, 0.39 mmol) and sodium, methoxide (39 mg, 0.72 mmol) in ethanol (3 mL) was stirred at 120 °€ for 17 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2S04), filtered, concentrated under vacuum and purified by preparative HPLC to give Ar-{2-(3-cyclopiOpyl~l.iF/-l,2.4-triazol~ 5"yi)thi0pbon-3~yi)~2~(4-methoxyphenyl)acetam!de. Retention time (rnih) ···· 5.578, method [7], MS(E5I) 354.43 (M+H); SHNMR (300 MHz, CDCij) δ 10.48 (s, 1H)S 8.11 (cl J 5.6 Hz, lid), 7.25-7.32 (m, 3H), 6.94 (d, J = 8.8 lh\ 2H), 3.83 (s, 313), 3.74 (s, 2H), 1,98-2.03 (m, 1H), 1.07-1.17 (m, 4H).

[002851 The following compounds were symbolized from N-{2~ (hyara2inecar!.»orsyO~{h-!opheïi-3-yi)“2««ii4-mctbox%'phci5yi)acetatr!ide (Example 1.11J) and the appropriate and dine using die procedure described above in Example 1.11.2; 1.12. A”(2""{3"Etliyl~lif~l?2,4-'iriaKOl~5~yl)l:Mopl3esi-3-yl)-2-'(4“ meth«xypSnmyll}ae£tamkie (12) [90286} .Oriïpionimidarnldc hydrochloride was used. Retention time (min)~ 4.404, method [7], MS(RSI) 343,1 (M+H); ;H NMR 1300 MHz, CDC13) δ 10,54 (s, 1H), 8.14 (d, J------ 5,4 Hz, 1H), 7.24-.7.34 (m, 3H), 6.92 (d, /--- 8.3 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 2B), 2,79 (q,/- 7.8 Hz, 2H), 1.36 (t, J- 7.8 Hz, 3H>. 1.13. A-(2-(3~ieri;~Entyl”li7~l,2,4~trlazol-5-yI)tlst0|>hen~3--yI)-2-(4-i!iethoxypheuyS)acetamlde (13) [00207 i Pivafimidamide hydrochloride was used. Retention time (min) ::: 6,103, method [7J, MS(ESI) 37.1.1 (M+H); !H NMR (300 MHz, CBCb) 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). L14. 2~(4-Methox5phe!iy!)-J'V-(2-(3“(tstrahydrofura!i-2-yi)-l//-152,4-tnazöl-5-yl)tiilopii en-3 -yi)aeetansf d e (14) [00208j Teirahydmfurau-2-carboximjdamide acetate was used. Retention time (min) - 4.585, method [7], MS(ESI) 385.1 (M+H); *H NMR (300 MHz, CDQ3) 8 10.37 (s, 1H), 8.14 (d, J- 5.4 Hz, 1.H), 7.25-7.32 (m, 3H), 6.94 (d, /= 8.8 Hz, 2H), 5,08 (dd, J = 7.6. 5.8 Hz, 1H), 3.96-4,09 (π, 2H), 3.84 (s, 3H), 3.80 (s, 2H), 2,41-2.45 (m, 1H), 1.95-2JO (m, 3H). L15L 2-'(4-Metlu.izypiMinyihA'-i2''0-(trslluoromethylRl//-L2,44.8inzol-5·· yl)thiophen-3-yl)aeetamide (15) [09289} 2,2,2-Trifluoroacetiruidamide was used. Retention time (min) = 6,744, method [7], MS(ESI) 383,1 (M+H); !H NMR (300 MHz, CDCH) δ 10.38 (s, 1H), 8.11 (d, /= 5.4 Hz, 1H), 7.28-7.34 (m, 3? f), 6.90 (d,/= 8,8 Hz, 2H) 3.81 {s, 3H), 3.79 (s, 2I-I), L16, Synthesis ofA'-i4-siiêfliy!-3-.(i/]f-l,2,4-trk^ol-5-yI)!lifephesï-2-yl)-2-(2~öi:0" 3,4-dilïydroqsJtaiïIin~l(2fl)~yl)acetaïï3lde (16)

1J6J 4-Methyl-2-(2-(2~ox&amp;-3}4~&amp;kydr(squwoün~l{21I)~yl}aeeiainiéö)~ thmph^m-S-mrb&amp;x&amp;mide [0Ö29ÖJ 4-Methyi-2-(2~(2-oxo-3,4-dihydroquinolin-l{2/7)-yl)acetamido)thiophene-3-carix>xamide was prepared from 2-(2-οχο-3,4-dihydroquinolm-1(2/i)~yi)aeetic acid (0.49 g, 2,38 mmoi) and 2-amino-4~ methylthiophene-3-caiboxainide (0.37 g, 2.38 mmof) according to protocol B Retention time (min) 3,405, method [1], MS(ESi) 344.0 (M+H), 1.16.2. N~{4~Metkyi~3~(LH-L2,4^n(md~S~yï}ikivpk&amp;ti~2~yiy2~{2~exe~3,4-dshydmqmmiiin~l(2H)~yi)aceiamide [¢€12911 ?v-(4-Methy 3 -3 -(177-] ,2,4~iriazol-5 -y l)thiophen-2»y!)-2-(2-oxo~3,4~ dïliydroquinolïri-I(2iï)~yi)aeetamïde was prepared from 4-meihyl-2-(2-<2-oxo-3}4-dihydi»qijinolra-i(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, 2H), 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. Synthesis of A-(4-Methyl~3~(3-msthyl-lfl»l,2,44rkKöfr5~yl)t1iioplms-2-yI)-2~(2~o;o>3,4-dih vdroqu imdht-1 (2//)»y!)aeetamlde (17)

1*1 7Λ Methyl 4~methyl~2~(2-(2~oxi»~3,,4~dihydr9qMm(}im~l(2H)~ y!)s€et(iMiéo)tki&amp;phene-3-c&amp;rèox}ietë [1HI292] The title compound was prepared from 2-(2-oxo-3,4-dihydroqumolin~ l(2ii)-yl)aceiic acid (0,43 g; 2.09 mmol) and methyl. 2-ammo~4-methylihiophene-3~ carboxylate (0,358 g„ 2,09 mmol) according to protocol B. Retention time (min) = 6,895, method [7], MS(ESI) 359,1 (M+H). I.IZ2 N^3-{Hydrudnemrii>onylW-Biethyithiopkim-2-yfy-2~(2-0xo-3,4- dikydreqmmdm3f2H}yd)iuMamïde [09293] Hydrazine monohydrate (0,059 ml., 1.23 mmol) was added to a solution of methyl 4-mcthyl-2~(2-{2-o.\ö”3.4-dIh.ydro(|uinoIïa-1 (2//)-yi)acetainido)thiophene-3-cariK>xylate (221 mg, 0.616mmol) in ethanol (2 ml,) and the resulting solution was stirred at 50 °C for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (MfcSO,,), filtered, concentrated under vacuum to give AL(3-(hydrazinscarbonyt)-4-methyltMopheU"2-yl)-2” (2-GX0-3,4-dihydroquinolin-1 (2f/)~yi)acetamide (174 mg, 0.485 mmol, 79%). Retention time (min) - 1.435, method [1], MS(ESJ) 359.1 (M+H). 7:173. N~(4~Methyt3-{3~methyMH~l}2i4-irmz8l~5~yl)thï&amp;phen-2-yï)~2--(2--i}X{}-3>4-dihydmquimim~l{2M)~yl)acgtamide [09294 ( The title compound was prepared from acetimidamide hydrochloride (55 mg, 0.590 mmol) aiidA,-(3-(hydrazineearhoayl)~4-methylthiophen-2~yl)-2~(2~oxo-3,4”dihydroquinoIin-l(2if)-yl)acetamide (141 mg, 0.393 mmol) according to the procedure of Example 1.11.2, above. Retention time (min) = 4.106, method [7], MS(ESI) 382.1 (M+H); lH NMR (300 MHz, CDCh) δ 12.07 (s, 1H), 7.23-7.31 (m, 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-(4~metli©xypiseny!)-A-(2-(3~(pyriilin-4-yI)~li2-l ,2,4-triaxöl-S-yl)t h soph jaeei&amp;m id e (1 i) [00295] The title compound was prepared from pyxidme-d-carboximidamide hydrochloride( 157 mg, 1,00 mmol) andiV-(2-(hydrazinecarbonyl)thiophen-3-yl)-2-(4-metboxyplieayl)acetanoidc (Example 111.1,, 204 mg, 0.668 mmol) according to the procedure described in Example 1.11.2., above. Retention time (min) - 2.511, method [7], MS(ESi) 392.1 (iVKW); 'H NMR(300MHz, BMSO-ö6) S 10.52 <«, IHj, 8.87 (d,J = 4.5 Hz, 2H), 8,08-8.16 (m, 2H), 7,94 fd J= 5.0 Hz, 1H), 7.67-7.70 (m, 1H), 7.3.1 (d,J= 5.6 Hz, 2H), 7,88 (d, J = 8.6 Hz, 2H), 3.88 (s, 2H), 3.67 (s, 3H). 1.19, Synthesis of Af-(2<3-amino-l£r-l,2,4-triazol-5~yl)thlopheit-3-yl>-2-(4- methoxyphessyS)aeetamide (19) [00296] The title compound was prepared from N-(2-(liydrazmecarbony1)tliiophen-3-yJ)-2~(4--niethoxyphenyI)aeetainide (Example 1.11.1., 152 mg, 0,497 mmol) and S-methylisothiooroninm 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 methoxide). Retention time (min) = 2.324, method [7], MS(ESI) 330,0 (M+H); !H NMR (300 MHz, CDCI3) 5 9,95 (s, 1H)S 8.07 (d, J = 5.7 Hz, 1H), 7,267,29 (m, 3H), 6.94 (d, J= 7.9 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 2H). L2Ö, Synthesis of JV-(4-cliIoro-3-(m-l,2v4-tr!azol-S-yl>thioplieii-2-yl>-2-(2-oxo- 3,4-diliydroqjjlnolin-I(277)-yl)aeeiamlde (2(1)

E 2 (A /, .Meihy H 4"hwmsj~2A2~{2~i)xi}»$,4»dikydmqMini}im-A (2H)~ .vOeceiaimidojthifipheneS^athfm’Suie [00297] The title compound was prepared from 2-(2-oxo~3s4~dxhydroqiikoiin-l(2H)-yl)acetie add (447 mg, 2.18 mmol) and methyl 2-&amp;mino~4-bramofhk)phene~3~ carboxylate (516 mg, 2.18 mmol) according to protocol A. Retention time (min; === 2.528, method [1], MS(ESI) 423.0 (M+H). L2Ch2, Methyl 4~chï&amp;r&amp;~2~{2~(2-exü~B}4~dihydroquiitoUn~l (2H}~ yfys&amp;ef&amp;midoJthiopkme-S-carboxpiaie [ÖÖ29HJ The title compound was prepared frons methyl 4 - bro m o - 2 -{2 -f 2 ~oxq 3s4~dihydroquino1in'l{2ii)~yl}acetamido}thiophei]e“3-earboxyia-te (148 mgs 0.35 mmol) according to protocol C. Retention time (min) === 2.540., method [i j, MS(ESl) 379.0 (Μ-4-1), L2§3* ^~Oiii}ro~2~(2~(2~ax&amp;-33~^ihyérüqmf$&amp;im~l(2H)~yi)m:eiamié{?}~ thiophetse~3-carhoxamide [002991 The title compound was prepared from methyl 4-chlo3t>-2-(2-(2-oxo-354”dihydro<juit50iiti~ 1 \3ffy·y s )acetamido)thiopliene-3-'Cafboxylate (254 mg, 0.67 mmol) according to protocol H. Retention time (min) = 2.034, method [1], MS(ESI) 364.0 (M+H). L2&amp;.4, N4é-Chfaw3~{lH-l>2,4~triiiz(fl-5-yi)thi0phe&amp;-2-’yi}-2-{2-0Xii~3>4-dihyér&amp;qum&amp;im-lfêffj-yij&amp;eefumide [00300) The title compound was prepared from 4~chloro-2-(2-(2-oxo~3s4-dihydroqidnolin-l(2/i)-'yl)acetamido)thlophene-3-carboxamide (238 mg, 0,601 mmol) according to protocol C. Retention time (min) === 4.171, method [7], MS(.ESI) 388.0 (M+H); !I-I NMR (300 MHz, CDCls) δ 7.85 (s, 1H), 7.21-7.30 (m, 2H), 7.07 (dd, J= 7,4, 7.3 Hz, 1H), 6.94 (d, J= 8.3 Hz, 1H), 6.83 fs, IH), 4.93 (s, 2H), 3.09-3.14 (m, 2H), 2.892.94 (m, 2H). 1*21. Synthesis of Ai~(3~(t H- l(2,4-irIazol-S~yl)tlsiopls ess -2-^1)-2-(2-050-3^4-dibydroqtiinelin-l (2I#)~yl)aeetaimide (2!)

[003011 Λ-(3-(17/~ 1,2.,4-Triazo!-5-yl)thiophen-2-yl)-2~(2-oxo-3,4-dihydroquinoim-l(2fl)-yi)acetamide was isolated during the purification of Af-(4~eh].oro-3~( 1//-1,2,4-triazoi-S~yf)thiopkm-2-yi}~2~(2-oxo-3,4»dihydroqumolin-l(2?i)- yl)aeetamide (i ,20.4., The dcs-cb loro thiophene was likely formed during the conversion of<i-bromo-2-(2-(2-oxo-3>4*dihydiOquix3olin"i(22:/)-yI)aceiamido)rhiophene-3-caröoxylaie to methyl 4toh'oro-2-(2'(2toxo-3,4-dthydroqumo1in"l(2j8}··· yl)acetam}cto)th{oph8ne-3"tiirb«xyiató. Retention lime (min) = 3.296, method [7], MS(ESI) 354.0 (M+H); iH NMR (300 MHz, CDC13) δ 7.99 (s, 1H), 7.23-7.29 (m, 3H), 7.06-7.10 (tn, 2H), 6.88 (d,J = 6.3 Ηζ„ 1H), 4.92 (s, 2H), 3.07-320 (m, 2H), 2.92-2.95 (m, 2H). 1.22. Synthesis of iV"(4“Clïls>ro-3-(lüi~i,2i4-triazol-5“y1)il5iopi5en-2-yi)-2" (isoqnlnoIin-5-y1)ae$iam!d$ (22)

1-223 Methyl 4~èroma~2~(2~(isoqum0im~S~yl)(icetiimMo}thmpheit&amp;-3~aitifüxyi((ie [09302} The tide compound was prepared from 2-(ij»quinolin-5-yl)acetic add (427 mg, 2.18 mmol) and methyl 2~ammo-4-bromothiophene-3-carhoxylate (514 me, 2.3 8 mmol) according to protocol A. Retention time (min) - 1.634, method [ 11 MSfESI) 405.0 (M+H). 1,22,2 Methyl 4~ckïüm~2~(2-(ïs&amp;qum&amp;im~5~}4}&amp;ceiümMo)thmphene~3~eurè&amp;xylüte [003Θ3| The title compound was prepared from methyl 4-bromo-2-(2-(iroquinolm~5~yl)aectamido)ihiQplicne-3-carboxyl ate (124 mg, 0.306 mmol) according to protocol G. Retention time (min) ~ 1.609, method [1], MS(ESI) 361.0 (M+H). 1.223, 4~Chl{?ro-2-f2~{is®qMm&amp;lin3~yl)meiMmde)tkki'phem-3~c&amp;rhox®mide [99394] The title compound was prepared from methyl 4-chloro-2-(2> (isoqüJTSoim-5-yi>acetamido)ihiophcn©-3-carboxylatc (110 mg, 0.306 mmol) according to piOiOCOi hu Retention time (mm) ::: 1.139, method [.1 j, MS{ES1) 346.0 {M+Hh 122,4 N~(4-Chhtr&amp;~3~(lff~l^f4^?Mgai-5~yl)thte>phm~2~yl)~2-(iS0qfimeli!t~5- yijacetamide [00305] The tills compound was prepared from 4-cMorG-2-(2-(isoqumolin-5-yi)acelamkio)tMop?iene~3-carboxamide (104 rag, 0.306 mmol) according to protocol C, Retention time (min) = 1.570, method [7], MS(ESI) 370.1 (M+H); SH NMR (300 MHz, CD3OD) 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). L23. Synthesis ofAr-(4-£Moro-3-{lH“!,2,4-£r!&amp;zo1~5-yi)thtophen-2“¥!)-2“(i|niin»lin-5-yl)aeefesmk1e (23)

1,23.L Methyl 4~hrmw~2~{2~{qmn^liM~5~yi}iicetamMe)ihi&amp;phe^e~3-ce}rh&amp;xyl(tte 100306] Methyl 4-bronio-2-(2-(quirtolin-5-yl)acetaiaido)tliiophene-3~ carboxylate was prepared from 2-(qumo!in-5-yl)acetic acid (427 mg, 2.18 mmol) and methyl 2-aminO"4-bromothiopheiie--3“Carboxylate (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-chUm>-2-(2-(q&amp;moUn~5~yl}aceiaMid0)tMephene~3~earbox\>late [ÖÖ3Ö7] Methyl 4~ehloro-2“(2”(quiriolm-5-yi)aceiamido)diiophsne~3" carboxyiate was prepared from methyl 4-bromo~2~(2-(qninolin-5” yl)aceta.niido)thiophen©-3-carboxyiate (350 mg, 0.86 mmol) according to protocol G. Retention time (min) = 1.629, method [1], MS(ESI) 361.0 (M+H). T 23,3, 4~€kim^~2"(2--iquimHtt-5~yi}iieciatxidmikbphsne~3~Ga¥btixamide (00308] 4-Chloro-2~(2-(quinolin-5-yl)acetamido)thiophcnc-3-carboxamidewas prepared from methyl 4-ehloro~2~(2-(quinoim-5-yl)aeei&amp;mido)thiophene-S~carboxylate (151 mg, 0,418 mmol) according to protocol H, Retention time (min) ::: 1.151, method [1 j, MS(ESJi) 346.0 (M+H), LJ3,4. N~(4- CMom~3~i4H~lJf 4~irmzoi‘S~yi)thi&amp;pken~2‘ji}~2~{qmmUn~S~ yl}aeemmMe [00309] Af~(4-€hloro~3-( 1 Η -1,2,4-triazoI“5-y!)thiophen-2-y!)-2-(quiRoHn-5- yl)aeetamide was prepared from 4-chloro-2-(2-(qumoIm-5-yl)aceismido)tliiopiiene~3-carboxamide (78 mg, 0.225 mmol) according ίο protocol I Retention time (min) = 1.429, method [7], MS(ESI) 370.0 (M+H); lH NMR (300 MHz, CD3OD) 8 9.15-9.19 fm, 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, 2H). 1.24. Synthesis of 2,4-trlazol-5-yl)tbiophen~3-yl>-2-(2,3- dshydrofoenao jb] ll?41dioxln~6~yi)aeeiamide (24)

L24J. 3-(2-(2J~Mk}^oh£m^JilJldioxi?i-fjh.yl}ueetmsidt})thit}pkeiig-2- carboxamide |00310| The title compound was prepared from 2-(2,3-dihydrobenzo[b][l,4jdioxni-6-yI)acetic acid (450 mg) and 2~am.inotMophen.e~3-carboxamide (345 mg) according to protocol B, The crude product mixture was taken directly to the next reaction without further purification. Method]!], MSfBSI) 319.2 [M+H], Retention time · 1,496 min, 1-24J, N-{2~(lH~l,2f4~Trmol-5-yi)tkiepkeit-3-yi)-2-(2,3-<lik2>dr0betizofb][lt4jdi0xisi- (00311| The title compound was prepared from 3-(2-(2,3-dihydro!>cnzo[/(|[l,4]dioxin-6-yl)iuxrtaniido)tbiophene-2-carboxamide according to protocol C. The crude product was purified via preparative HPÏ..C to give N-(1-(! H- 1,2,4-trra;-m[-5-y:)dtiophen-3-y 1)-2-(2,3~i1iiiydrobcnzo] hj[ \ ,4jdioxm~6-yl}«cet<Tmide; Method[7], MSfESI) 343.0 [M-t H], Retention time - 3.39 min; (300 MHz, COO;) δ 10.51 (s, 1H), 8.21 (s, IB), 8.11 (d, J= 5.5 Hz, 1H), 7.28 -7,26 (m, IB), 7.31 (d, 5.5 Hz, 3H), 6.93 - 6.83 (m, 2H), 4,27 (S) 4H), 3.73 (s, 2B). 1.25. Synthesis fquir5oïta~5-y!)acetamicie (25)

L25J. 4~Meihyl~2~(2-fquitit}UïiS~yl]iiicgiffliiide)thiophgttei~3~curhex(ffiiïde (0331.21 The title compound was prepared from 2-(quinolin-5-yS)acetic acid and 3-ammo-4-meihyithsophcnc-2“earboxa?mdc using protocol B. Method Π 1, MS(ES!) 326.0 Retention time - 0.767 mm. 1,25,2. N~(4~Methji~3~{lS~lt2>4~iriaz(^~5~}fi)thii}phen~2~yi.)~2~{qumalm-5~ yl)ecet&amp;mMe (00313( The title compound was prepared from 4-methyl"2-(2~(quinoliu-5-yl)acetamido)thiGphene-3-earboxamide using protocol C. The crude product was purified via preparative HPLC to giveN-(4-mcthyl~3-(lH-l,2,4-triazol-5-yl)tMGp!ien-2-yl)-2-(quhtolm-5-y 1 )acetamide. Method]?], MS(ESI) 350.1 (M+H], Retention time 1.43 min; T-I-NMR ¢300 MHz, CDCL) S .11.16 (s, 1H), 9.02 (d, J= 4.94 Hz, 1H), 8.96 (d, J= 8.2 Hz, ΓΗ), 8.6 (d, J - 8.2 Hz, IB), 8.13 - 8.08 (m, IB), 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 [6] (1 s4| diox tsi-6-y!)riV~(2~{3-metiiyl~ 1 H-t ,2,4-M&amp;zoT5-yl)tMophen-3~y1)steetamide (26) 100314] The title compound was prepared from 2-(2-(2,3-

dihydrobenzo[i>][.1,43dioxin-6-yi)acetamido)thiophenie-3-carboxatnide using protocol D except that the DMF was also used in the DMA-DMA step with heating to 95°C (rather than 110°€) and the hydrazine step was heated at 95°C (rather -hars 90°C). The product was purified via preparative HPLC to give 2-(2,3-djhydrobenzo[bJ[ i ,4]dioxia-6-yl)-M-(2- (3-meihyhIH-1.2,4-triazol-5~ylhhiophim-.?-yl)aceiamidc; Method]?]. MS(ESI) 357.1 [M-H-i], Retention time - 3.56 min; *H-NMR (300 MHz, CDCh) δ 10.33 (s, 1H), 8.06 (d, ./- 5.5 Hz, 1H), 7,29 (d, J= 5.5 Hz, 1H), 7.27 - 7.26 (m, 1H), 6.88 - 6.86 (m, IB), 6.84 - 6.82 (m, 1H), 4.22 (s, 4H), 3.70 (s, 2H)S 2.S1 (s, 3H). *•27. SjnBtii^of.iV^2~(l//-I^triaMï^y!)IIUophen^yl)-2-{qMin©fïn-5- ylj&amp;cet&amp;mïde (27)

1,27.1. 3~(2~(Q&amp;inóU»-5-yl}ee&amp;umii!ti}ihkiph.ene~2-carb0xamide [00315] Ihe title compound was prepared from 2-{qiiinalin~5~yi)aeetic acid and 3-atnii»othiophene-2-carboxait3ide using protocol B. Method] 1], MS(ESI) 312,1 [M+H], Retention time ~ 0,35.1 min. 1.27, a. N-(2~fm-ls2,4~Trmzol~§~yi)ihiepheit~3-yt}~2-{qmnoUn~5-yi)(icetamide [00316] This compound was made from 2-(2-<Quino!in-5- yl)acetamido)4-hiophen.e~3~carboxainide using protocol C and was purified via preparative HPLCL Mcthod[9], MS(ESI) 336.0 [M+H], rt = 6.526 min; ^-NMR (300 MHz, COCl3) 5 9.30 (s, ΪΗ), 9.05 (d, J= 8,24 Hz, 1H), 8.98 (d,/= 4.95 Hz, 1H), 8.63 <d, J- 8.8 Hz, ΓΗ), 8.20 - 8.15 (m, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.99 - 7,91 (m, 3H), 4,47 (s, 2H), 1.28, Synthesis of i¥~(4--methyl~3~(3~methyl.li9-l,254~trIaznH5-yl)thiophea~2-yl)~ 2-{<|uinoISiï-S~yI)aeetamide (28) [00317] This compound was made from 4-metliyl-2-(2-(Qumolin-5-yl)aeetamido)4Mophene-3-carboaamide using protocol D, The product was purified via preparative HPLC to give A'-(4 -methyl-,2,4-triazol-5-yl)ihiophen~2~yi)-2-(qoino{itt-5-> t taeetamide. Method [9], MS(ESI) 364.1 [M+H], Retention time - 8,72 min; Ή-NMR (300 MHz, CDCld) 6 10.76 (s, 1H), 9,04 (ss IB), 9,0 (d, J·-- 3,85 Hz, 1H), 8,61 (d, J - 8.8Hz, IH), 8.14 (dd,./-8.8,7.7 Hz, !H), 7.94 ~ 7.89 (rn, 2H), 6.49 (s, 1H), 4,46 (s, 2H). 2,41 (s, 3H), 2.40 (s, 3H), 1.29, Synthesis ofA-(4-methyl"3-(liir-l:^i4-trlazoI-S-3'1)thlophea-2~yl)-2-(qtiroexa!m-S~yl)aeetaitfide (29)

L29.L Tëiï-fruiyi 2~(qmn&amp;xg£iis-5-$}aeeistte [00318| The title compound was prepared 5-bromoquinoxaline (5ÖÖ mg, 1,0 eq) according to protocol P to give tcrt-bulyl 2-fquinosalio-5-yi)scciate. Method [1 ], MSs ESI) 245,1 jM-4-ï], Retention time -= 2.30? mm 2-29.X 4~Meihyi~2-(2~(q}im&amp;xaim-S~y>ï)met^mM&amp;)ihiophem~3~cerboxamMe [00319] To a stirring mixture of tert-buiyi 2-(quiaoxalin-5-yi)acetate (200 mg) irs HOAc (5 mL) was added 6hi HCf (5 raL). The reach on mixture was warmed to 80 °C for 2h, The crude proauct mixture was concentrated under reduced pressure to give 2-(qymoxalin«5-yl)aceiic acid, which was used in the next reaction without further purification. Method! 3], MS(ESl) 189.0 [M+Hj, Retention time = 0.722 mm.

[0Ö32ÖJ The title compound was prepared from 2~(quinoxalis-5-yl)acetic acid and 2“arnmo-4-metiiyitj-iiophene-3“Carboxamide using protocol B. Method[ f], MS(ESi) 327,0 [M+H], Retention time = 1.644 min. 2<293, N~(4~Me$iyk3-{lH~lf2,4-trmwl-5~yt)tki&amp;phen~2~$l)-2-{qMimx&amp;tm-5-yl}acetmnde 100321 j This analog was prepared from 4-meUiyi-2-(2-(quinoxalm-5- yi)aeetamido)thiophene-3'Carboxamide using protocol C. Method[7], MS(ESI) 351.1 [M+H], Retention time = 3.36 min. ^I-NMR (300 MHz, CDC13) δ 11.84 (s, 1H), 8.90 -8.87 (m, 211), 8.21 - 8.18 (m, 1H), 7.93 - 7J5(m, 2H), 7.73 (s, 1H), 6.52 (s, 111), 4.56 (s, 2H), 2.45 (s, 3H). 130, Synthesis of A-(4-escthyl-3-(3-metliyl-lT/-l,2,44riagoI-5-yI)thi0ptmM-2-yl)~ 2-(quiïioxallii-S"yï)acêt8aiide (30) [00322] This analog was made from 4-meihyl-2-(2-(quinoxalm-5-y!)acetamido)tMophene-3-earboxarmde using protocol D except that the DMT was also used in the DMA-DMA step with heating to 95°C (rather than 110nC) and the hydrazine step was heated at 95°C (rather tfaaa 90°C). Method[7], MS(ESI) 365.1 {M+Hj,

Retention time - 3.58 min; iH-NMR (300 MHz, CDClj) 611.9 (s, 1H), 8.87 (s, 2H), 8.17 - 8.14 (tn, 1H), 7.92 - 7.83 (m, 2H), 6.50 (s, 1H), 4.53 (s, 2H), 2.45 (s, 3H), 2.30 (s, 3H). 1.31. Synthesis of .(¥-(4-meihy!-3-(l//-i ,2,4 Aii£mfi~5“y!)tMophen~2~yl)»2-(4-(3- (piper!dln~l~yl}propoxy)pImtyl)aeeMmide (31)

1.5 LL Methyl 2-(4-(5-(piperidm~l-$i)propoxy)phenyi)ttcetate IOÖ323J 1) To a stirring mixture of methyl 2-(4-hydroxyphenyi)aeetate (Ig) in acetonitrile (12 mLs 0.5M) was added bromo-S-cMoropropane (911 mg), K2CO3 (2.4 g), 1 he reaction mixture was heated to 100 °C for 2h, then quenched with water and extracted with EtOAc. The organic layers were dried over MgS04, filtered, and concentrated. The crude product was used without further purification in the next reaction step. Methodjl], MS(ESI) 243.0 [M+H], Retention time:::: 2.50 min.

[0(1324| 2) To a stirring mixture of crude methyl 2-(4-(3- chioropropoxy)pheny!)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 over MgSCLf, filtered, and concentrated. The crude product was taken directly to (he next reaction. Method[lj, MS(ESI) 292.1 {MM Ï], Retention time = 1.330 min. 1,31.2. 2~i4~{S-(Plpendiu-l~yi)prep&amp;xy)phenyi)gsmHc acid [0Ö325] To a stirring mixture of methyl 2-(4-(3-(piperidin-1 -yllpropoxy)pftenyf}aeet&amp;te (.570 mg) in HO.Ac (5 ml.) was added 6N fiCI (10 mL). The reaction mixture was warmed to 80 °C for 2h, 'The crude product mixture was concentrated under reduced pressure and directly taken to the nest reaction without further purification. Methodfl], MS(ESI) 278.1 [M+H], Retention time = 0.666 min. 2,31,3. 4~Μί^}2-’2~(2~(4-(3~{ριρ@η$ίη-2-β)ρ}νρ&amp;χ);)ρΗ£ηβί)-8^ϊίΐΐΜΗί8)ίΜ&amp;ρΗ£ηβ~3~ carboxamide

ProtoepfXl 10Ö326J To a stirring mixture of 2-(4-{3~(piperidin~I-yi)piX)poxy)pheoyi}acetic acid (800 mg) in DMF/DCM (6 ml·, 1:1) was added triethylammc (1,2 mL), DMA? (180 rag), 2-amino-4-methylthiophene-3“earboxatrside (440 rng)s and EDO (1.1 g). The reaction mixture was stirred at it overnight, quenched with saturated NaHCOs solution and extracted with EiOAc. The organic layers were dried over MgSO^s, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC to give 4-methyl-2-(2-(4“(3-(piperidin-1 -yl)propoxy)phenyl)acetamido)thiopliene-3-carboxamide. Method[7], MS(ESI) 416,2 [M+H], Retention time - 2,254 min. L3L4, N-{4~Meihyt-3~iM~l>2,4~triuz{i$.~§~yi}tkwpk?M~2-yi)~2~{4~{3-{pipedditt~l~ yi}propa}xy)phenyi)ac@tmmde 100327] This compound was prepared from ~methyl--2-(2-(4~(3-(pipmdin-l -yi)propoxy)phenyi)-acetamido)fhiopheue"3-earboxamide using Protocol C. The crude product was purified via preparative HPLC to give N^4-methy1-3-(iH-ϊ,2,4·ΊΠ32»1-5-yl)thiophen-2-yl)"2-fT(3-(pipcr!din-]-yl)propOA_v)phenyl)acetaïnidc, Method[7], MSBiSl )440.2 ίΜ+Hj, Retention time - 2.86.5 min; {H-NMR {TOO MHz, CDCh) δ .11.64 (s, 1H), 7.96 (s, IB), 7.31 (s, 1H)S 7.29 - 7.20 <m, 1H)S 6.91 (d, J- 8.2 Hz, 2H), 6.50 (s, 1H), 4.16 -4.12 (m, 2H), 3.81 (s, 2H), 3.69 -3.65 (ms2H), 3.42-3.11 (m, 3H), 2.78 - 2.60 (m, 2H), 2.43 (s, 3H), 2.33 - 2.19 (m, 2H), 2,09 - 1,91 (m, 4H), 1.50 - 1.42 (m, 1H). 1.32. Synthesis of A·~ (4 ~ m e fhy 1-3 - (3 m ε t hy M /7-1,2,4~i:r1a?;ol"S"yl>fhii>phi'0“2~y|)-2"(4~(3~(pipericiis?-l-yI)propösy)pheïsyl)seetaiï5Me (32) [00328] This compound was prepared from 4-methyl-2-(2-(4-(3-(pipeHdi:n~I-yl)propoxy)phenyi}acetamido)thiophene-3--earhoxarnide (Example 1.31.3) using Protocol D. Method[?j, MS(ESI) 454,2 [M+H], Retention time ~ 2,857 min; Ή-NMR (300 MHz, CDCi;,) δ 11.35 (s, Hi), 7.28 - 6.92 (in, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 4.11 - 4,08 (m, 2H), 3.78 (s, 2H), 3.72 - 3.68 (τη, 2H), 3.35 - 3.20 (τη, 2H), 2,75 - 2.61 (m, 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--(17/-1 mki&amp;ml-1 -yftefhoxy}phen νΙ)-Λ-{4~methyl-3·(ί H-054Ariazol~5~yI)fhiophes-2-yI)aceians]de (33)

1.33.2. Methyi 2-(4-(2-(2 H~imi(iawi~2~yi}efhexy}pheityi)<sreeteie [00329] To a stirring mixture of the methyl 2-(4-hydroxypheny)>cetate (1.4 g, 1 EQ) and 2-(1 H-imidazol-l-yl)etiiaiiol (1.0 g) in THE (0.5 ml,, 0,5 M) at 0 °C wes added PPh? (2.9 g). To this mixture was added dropwis© D1AD (2,2 mL) oyer 10 min.

The reaction mixture was wanned to ambient temperature overnight, A normal aqueous workup with water and EtOAc was followed. The organic layers were dried over MgS04, filtered, and concentrated under reduced pressure, The erode product was purified via silica gel chromatography to give methyl 2-(4-(2-(1 H-imidazol-1-yl)ethoxy)phenyi)acetate. Method[i], MS(EST) 261.1, Retention time = 0,782 min, /.53,2. 2-(4-(2-(/ H~lmhfaz&amp;l~2~y$)gihexy)pkettyi)igce,iic acid [00330] To a stirring mixture of 2-(4-(2-( IH-imidazoi-l-yl)ethoxy)phenyl)acetate (240 mg) in THF/water (3.3 mL, 10:1) was added fine powder (COH (77 mg), The reaction mixture was stirred at rt overnight. The crude product mixture was acidified with 1,0 N HQ. and diluted with EtOAc. A normal aqueous workup wilei EtOAc was followed. The organic layers were dried over MgSO.-j, filtered, and concentrated under reduce pressure. The crude acid was taken directly to the next reaction without further purification. Methodfl ], MS(ESI) 247.1, Retexttion time - 0.323 2333, 2^2-(4^2~{lïï-ImMazö$~l-yi)eth&amp;xj>)pkmyl)eceUmié&amp;}-4-methï'ithi&amp;pkme~3-carboxamide 1003311 This compound was prepared from 2-(4-(2-(lH~imidazol-1- yl)et!ioxy)phenyl}aeeijc acid and 2-ammo~4~meihy!thiophene-3-earboxamide using protocol B except that triethylamine was also added. The crude product was purified via silica gd column chromatography. Mcthodjri], MS(ESI) 385.1, Retention time = 1.254 min. 1333, 2-(4-(2-(lH-ImMazei~l~$)ethwcy)pkmyi)-N-{4~methyl-3~(lH~li2i4-trMZ0l~5-}3)tkhipken-2~yi)®eetamMe [003321 The title compound was prepared from 2-(2-(4-(2-(IH-imidarol-l-yl)ethoxy)plienyl)aceiamido)-4-rncthyhh.:ioph.cne-3-carboxamide using protocol C. Melhod[7], MS(EI) 409.1 [M+H], Retention time - 2352 min; ’H-NMR (300 MHz, CD>OD) δ 9.08 (s, lli h 8.24 φ s, IH), 7.79 (t, J = 1.65 Hz, IH), 7.62 (t, /= 1.65 Hz, IH), 7.36 - 7.33 (m, 2H), 7.02 - 7.0 (m, 2H), 6,62 (s, IH), 4.72 (t, J - 4.94 Hz, 2H), 4.45 - 4.42 in), 2H), 3.80 (s, 2H), 2,48 (s, 3H). 1.34 Synthesis of ,¥~(4~Bromo~3~(lJM,2yi-trkKol~5~yI)thtapihen-2-yl)~2~ (1 sopninofin-5-y!)aeetam\rie (34)

234.6 Methyl 2~&amp;mmo~4-hrstmothiopheite-3~carb&amp;xyiute 100333 j Methyl 2-(((9H-fluoren-9-y!)rneihoxy)earbonylamino)-4-hromothiophcne-3-carboxykte (1 g) was stirred in f)CM/'morpholine (12 ml., 3:1) at rt unfd all the ester was consumed, The crude mixture 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/pentaae (20 xnL) was addecï. An additions] white .sol;d was removed. The organic layer was concentrated under reduced pressure and the crude mixture was placed under high vacuum to remove the excess of moiphoiinc. The crude amine was taken directly to the next reaction step without further purification. Methodjd], MS(ESl) 235.9 [M+H], Retention time = 1.919 min. 2.34.2, Methyl 4~bmm&amp;-2-(2~(isoqmmim~S-yi)iscetamMe)thiophen&amp;-3~€arboxyiate [0(034] This compound was prepared from methyl 2-amino~4~bromothiophese- 3-carboxyfatc and 2~(isoquinolia“5-yl)acctic acid using protocol A. Mcthod[l], MS(ESI) 4Ö4.9 [M+H], Retention time = 1,678 min. 1.34.3, 4~Emm^-2-{2~{isoqmmMin~S~yi)^ee2umMo)thmphe^e-3-mrbi>xumMe [00335] The title compound was prepared from methyl 4-bromo-2-(2~ (isoqumoliri-5-yl)acsiamido)thiophsne~3-carboxyiate using protocol H. The etude product was purified by preparative Η PI X., Method] 1}, MS(ESI) 389.9, Retention time ::: 1.166 min. 1.34.4, N~(4-Bwm0~3~{llI~lf2<,4~triuzo$-5~yi]tM&amp;pkeft»2~yi)-2~{imqMiswiiM~5~ yi/acetamide [00330] The title compound was prepared from 4-bromo~2~(2-(isoquiaoHn-5-yi)acetamido)thiophene-3-carboxarmde (28 mg) using protocol C and was purified by preparative HPLC, Method]?], MS(E5I) 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 fd, J= 6.6 Hz, 2H), 8.09 - 8.04 (τη, 1H), 7.11 (s, 1H), 4.55 (s, 2H). US. Synthesis of A+(4~Bromn~3~(lff4,2s4-trla2oJ-5-yl)tls!ophen-2-yl)-2- {quinoIin-'S-yilacetamide (35)

/.55.1. .Methyl 4~bf’&amp;fflG-2-(2~(guifi&amp;liii-$-yi)&amp;c€t(iiiiid&amp;}ihiS'phgi$e"3"CiiFib@xyl8tg [00337] This compound was prepared from methyl 2~amino~4~bromothiGphene- 3-carboxylafe and 2-(quiao1in-5-y1)acetic acid using protocol A. Method[l], MS(ESI) 405,0 [M+H], Retention time ^ 1.650 min. 1,35.2* ^‘'15Fefti&amp;~2~{2-(qMifti)HH“5~}3}üCiïhïisiido)tkiopheïte~3~c(i}'b(ïx&amp;?ïiid&amp; [00338] This compound was synthesized from methyl 4-hromo-2~(2*(quinoiin-5-yl)acctamido)tliiophene-3-carboxylate using protocol H. Method[l], MS(ESl) 390.0 [M+H], Retention time = 1.174 min. /. 35.5. M~ll2,4~ti‘iszol~5~yl)ihi&amp;pheft~2~yi)~2-(^tilHoU.fi-§- yijaceiamide [00339] This analog was made from 4-bromo-2-(2-<qdnoiin-5-yi)aeetam!do)thiophene-3-carboxamide using protocol C. The crude product was purified via prep. HPLC to give N<4-im>mo-3KlHn52^triaz»1.5-yl)thiophen-2-yi)-2-(quinolin-5-yl)acetamide. Method[9]s MS{ESI}413.9 [M+H], Retention time - 9.42 min; ^-NMR (300 MHz, CD3OD) δ 9.15 -- 9,14 (m, 1H), 9.12 is, 1H), 8.25 - 8.21 (m, 2H), 8,16 - 8,10 (m, 1H), 8.0 - 7.97 (m, 1H), 7.96 - 7.94 (m, 1H), 7.10 (s, 1H), 4.56 (s, 2H). 1,36. Synthesis of A-(4"”BronjO'3-(1..ff'i,2s4-trlazol-S“yi}thiopheji-2“Vl)“2-(2-oxo- 3,4-di0ydroquiuolin-l(2H)-yl)a€etamide (36)

/.34/. 4~3romo~2~(2-{2-ox&amp;~3, d-dihydtoqttmoiffi-l {2M)~ yl}ucelamMü}ihiitph&amp;te~3-cstb()xamide [00340] This compound was prepared from methyl 4-feromo-2-(2-(2-oxo-3,4- dihydroqumolin-1 (2H}-yl)aceiamido)thiopiiefie-3-carboxylate using protocol H,

Mefhodp ], MS(ESi) 407.9 [M+H], Retention lime = 2,043 min. 136.2, N-{4-Brmso~3~(m~lX44H(iwi~5~yl)ikmiihm~2-yi)~2~{2~oxs~3i4~ dihydrt}qmmMn~l{2R}~yl)meiamid£ [00341] This analog was synthesized from 445^^.0-2-(2-(2-0^0-3,4-dihydn>qi!inolin-l(2H)~yl)acetamido)thiophene-3"Carboxamide using protocol C. Method[7], MS(ESI) 432,0 jM+H], Retention time == 4,311 min; 'H-NMR (300 MHz, CD3CI) 3 7,89 (b s, 1H), 7.30 -7.20 (m, 3H), 7.09 - 7.04 (m, 1H). 6.95 - 6.93 (m. 2H), 4,92 (s, 2H), 3.11 - 3.07 (m, 2H): 2 93 - 2.88 (m, 2H). 1J7. Synthesis of iV-(4-Cyano-3"(lfl-l,2^4-triaz©l~S-yI)tfeiophen~2-yi)-2~ (isoquln elïsi~S-yl)aeetaniicle (37)

7.3/./. Methyl 4~eytifto~2~(2~{iSï!quimïim~S~yï}&amp;ceMmid&amp;}thmphene~3-

Cisrhoxykiie

PretoCQl ¥; [00342] To a stirring mixture of methyl 4-bromo-2-(2-(isoquinolin-5-yI.)a&amp;ötamido)tmophene-3-carboxylate (100 mg) in DMF (0.5 naL) was added CuCN (150 mg)„ the i «suiting mixture was nested to 100 C overnight. The reaction mixture was cooled to room temperature. To this mixture was added a 10% NÏ 1.,011 solution and ethyl ether. The crude mixture was stirred at rt for 1 h. A normal aqueous workup with ethyl ethei was followed, ihe organic layers were dried over MgS04, filtered and concentrated under 1 educe pressure. Ihe crude product mixture was purified by silica gel column chromatography to give methyl 4~cyanO“2-i 2“(isf>t|uinoliri~5~yi)aeetaiiiido)tliiophene-3“ carboxyiate, Methodfl], MS(ESI) 352,0 jM-H-I], Retention time ::: 1.343 min. L 3 7,2, 4~Cyam~2~(2-(tmqumeim~S-yi)meiumM&amp;)thwphme~3~carh&amp;xamide [@0343] This compound was prepared from methyl 4-eyano-2-(2-(isoquinolm~ 5-y1)acetamido>tMophene-3-caxboxyiate using protocol H, Method[l], MS(ESI) 337.0 [M+H], Retention time = 0.673 min. 1373, N^4-C^o~3^m-lJ,4^iawl-5-ji)thiopheit-2-yl)-2-(isoqmiioBn-5- yfymetamide I00344J The title compound was prepared from 4-cyano~2-(2~(isoqiunolin-5-yl)aeetamido)thiophene"3-carbox:amide (J5 mg) according to protocol € 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"Cyano-3~(IH-L2,4~triazol~5-yi)thiophen-2-yi)-2»(isoqiJmo!m~5~yl)acetamide, Mcthod[7], MS(ESI) 361.1 [M+Hj, rt - 1.273 min; lH-NMR(300 MHz, CD3OD) δ 9.62 (b s , IH), 8.60 - 8,57 (m, IH), 8.44 - 8.37 (m, 2H), 8.34 (s, 1H), 8.29 - 8,20 (m, IH), 8.04 - 8,0 (m, IK), 7.86 (s, IH), 4,56 (s, 2H). 1.38. Synthesis of JV-(4“Cyano-3-(Iff-l;,2,4-triazol-S“yl)thlopheïi"2”}1)“2“(2-oxo- 3,4~dShydroquiiioiln-l(2J]l)~yl)acetamld® (38)

138,1. Methyl 4-cyaiw~2-i2~{2~ox0~3,4-dihydrt}qmmUn-l{2H)- yl)acetamid8)thuiphem~3~ciirtsoxytate (003451 This compound was prepared from methyl 4~bromo-2-(2-(2-oxo-3,4-dihydroquinoiin-l (2H)-yi)acetamido)ihiophcnc-3-carboxyiate using protocol Y. MethodjT], MS(ESï) 370.0 [M+H], Retention time ~ 2.237 min. L 38.2, 4-Cyan&amp;~2~(2- (2~&amp;x&amp;-3A-dihydr®qum&amp;lm~l {2H)~yl}aceitmid&amp;}thi&amp;phene~5~ c&amp;rbmamide 1003461 Tins compound was prepared from methyl 4-cyanO"2-(2-(2-oxo~3,4-dihydroquinolin-l(2H)*yl)acetaxm"do)thiqpheae-3-carboxylate using protocol H, Method[l], MS(ESI) 355.0 [M+H], Retention time ~ 3.392 min. L3SJ, N~{4-Cym&amp;~3~(lH‘l,2f4~iriaz^~S~}4)thi0phm~2-Yi/~2~{2~^.m~3f4~ dihydriiqmmim-l{2H}-yl)@cekmide [00347] This analog was synthesized from 4-cyano-2-(2-(2-oxo-3,4-dihydK'squmolm-'l(2H)-yi)acetamido)tMopSiene“3"Carboxamide using protocol C, The crude product was purified via preparative HPLC to give N-(4-cyaao-3-(lH-l /2,4-triazoh 5-y I Mu ophe π 2 -yl)-2-(2-oxo-3,4-di hydroqianolin-1 (2H)-yl)acetaaude- Method[7] , MS(ESf) 379.1 [M-tffl, Retention time - 3.9] min; 'TT-NMR (300 MHz, CDC13) S 12.34 (s, 1H), 8.13 (s, IE), 7.62 (s, 1H), 7.28 - 7.10 (m, 2E), 7.06 - 7.0.1 (m, IB), 6.94 (d,/-7.7 Hz, IB), 4.92 (s, 2H), 3.12 - 3.06 (m, 2H), 2.91 - 2,86 (m, 2H). U9, Synthesis of JV~{2~(3“metfoyI-l/f-l,2544ria2eI“5“y1)thiophen^-yI)-2-i4-{2-oxopy rrulldia-1 -yl)phenyl)aee£asmde (39)

/,3.¾ f, 3‘{2~{4~k>d(fphmyl}aceiamid0}thmpkem~2~carb&amp;xemide [00348] This compound was prepared from 2-(4~iodophenyf}acctic acid and 3-ammoitiiophene-2~earbox&amp;ntide using protocol B. Mcthod[l], MS(ESI) 387.0, Retention lime - 1.777 min. 1,39*2* 3~ (2~(4-(2-Oxupyrr&amp;Udm~l ~yi)pkenyi)uceiumido0mphme~2~carboxMmide [ÖÖ349] To a stirring mixture of 3-(2-(4-iodophen.yl)acetainido)tMophene-2“ carboxamide (300 mg) in dioxane (2 mL) at rt was added CuI (103 mg), K2COs (325 tug), pyrro]idm~2~one (80 mg), and racMimethyl cyclohexane/,2-diamme (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 MgS04, filtered, and concentrated under reduced pressure. The product was purified via silica gel chromatography to give 2~(2-(4-(2-oxopyrrolidin-1 -yI)phenyl)acetamido)thiophene-3-carboxamide. Method[l], MS(ESI) 344.1, Retention time = 1.476 min. 1.39,3, ft-i'2-(3-methyi-lH~l,2,4~tii'ia%0i-$-yl)tki0phen~3~yi)~2-(4-(2-&amp;X0pyrr0lidin~l~ yi}phe}i}'ï}acelsmide [00350J This analog was prepared from 3-(2-(4-(2-oxopym>Sidin-1 ~y3)phenyl}-acetemido)thiophene-2-carboxan5tde using protocol ¢2 MethodJT], MS( ESI) 382.1 fM+H], Retention time === 3.46 min; *Η-ΝΜΚ (300 MHz, COCij) Ö 10.02 is, 1H), 8.13 (d i- 5.5 Hz, 1H), 7.46 - 7.38 (m, 4H), 7.30 (d,/=== 5.5 Hz, 1H), 3.97 ~ 3.93 (m, 2H), 3.87 (s, 2H), 2.78 ~ 2.72 (m, 2H), 2.52 (s, 3H), 2.40- 2.25 (m, 2H). 1.40. Synthesis of A-(4-methyl~3-(5-meiliyl-4//-ls2,4-trteznl-3-yI)thioplieii-2-yl)~2~(4-(pyddta-4-yI)piienyl)acetamMe(40)

1.40, L 2-(2-( 4-lodop!H‘}tyi({icemmi4&amp;)-4~msikyiihig)phe.mi~3~mrbexmnide [00351.] To a solution of 2-ammo-4-metl5ylthiophenc-3-carboxamide (.1 g, 6.4mmoi) and 2-(4riodopheny[)acetie acid fl.83g, 7.0mmol) in methylene chloride (lOmL) was added Hunig’s base (i.e., N,N-diisopropylgtJtyJarniir:c) (3. imL, 18mmol) and HATU (2.66g, 7.0mmol). The heterogeneous mixture was stirred for 18 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the diphasic 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, 1,40,2, 2~{4-l8düphenyi)-N-(4-Mëth)4~3"{5-iHethyi-4H-ït2,4~triüz®l"3-yl)tkuiph ezi-2-y()aeetmside IÖ03521 The title compound was prepared from 2-(2-(4-iodophenyi)aeeiaraido)-4-methylthiophetie»3-carboxamide (277mg, 0.69mmol) using protocol D and was purified by column chromatography using 3%MeOH/methylene chloride (140mg, 46% yield). Method [1]: rt == 2,11 min; MH+ 438,9, 1,4&amp; 3, P»/~(4~Meikyi-3~{5~meih$~4H'-l,2>4-$naz&amp;$-3-yl)ih$&amp;phm-2~}t$)~2~{4~{p}Tidift-4-yï)phenyi)aeeMmide [0Ö3S3J [CIÖÖ3 I A 30nxL reaction vial was charged with 2-(4~ii>doplienyl)-N~(4-metbyI“3-(5~methy1-4H«l,2,4-tria:2oI-3-yl)thiopheri-2-yi)acetamide (140mg, 0.32mmol), pyridm-4-ylborontc add (60mg, 0.48mmol), sodium bicarbonate (IQOmg, .1.2mmol), DME (2mL), and water (2mL). The heterogeneous mixture was stirred vigorously under a stream of nitrogen tor 5 minutes before PdCPPhj)^ 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 wax 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/methylene chloride) Yield: SO.Omg (8%). Method [1]: rt = LI36 min; MH-f 390.2. ‘B-NMR (300MHz, CD3OD) 5 8.71 (d,/=6.3 Hz, 1H), 8,60 (del, /== 4.6,1.6 Hz, 2H), 7,84 (d, /=8,0 Hz, 2H), 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 A'~(4~eyanö-3-{4/f~i,2,4“tFi&amp;z8!~3~y!)tMöphen-2-y!)~2--{c[sri$ïö!in-S-yl)aeetaoilde (41)

L4LL Methyl 4~hr&amp;mo~2~{2"k0ihiöIin~5~}4)tti'ei&amp;Midöïfhwph£ne~3~c{Ï} hoxvïuk' [Θ0354] The title compound was prepared from methyl 2-amino-4-broraothmpheöe-3-carboxylalc (660mg, 2.8m3nolj and 2-<qukolin~5-yl)acetic acid using protocol A. 560mg (49% yield). Method [1]: rt = 1,666 min; MH+ 405/407. L4L2'» Methyl 4~cymü~2~(2-{qmmdm~S~yi)üceMmiik>}ÏhwpheneM~carb&amp;xyïüte {00355J A 20mL microwave vessel, was charged with methyl 4-bromo-2-(2-(quinolin-5-yl)acctamido)thiophene-3-carboxylate (560mg, 1.38mmoi)f CuCN (540mg, 6ramol), DMF (8mL), and {IRjlRj-N^N^-dimethylcyclohexane-l,2-diamine (300uL).

The reaction mixture was flushed with nitrogen and sealed under a teflon cap before being heated to 150 °C using microwave radiation for O.Sh. The reaction mixture was concentrated under reduced pressure to give an oil that was partitioned between an organic layer of 10% iPrOB'chlorofomi 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 by column chromatography with 60-70% ethyl acetate / hexanes. Yield: 40mg (8%). Method [1]: rt - 1,401 min; MH+ 352.0. 1,4L 5» 4MyimeM-{2-iqi4iwMit~Sy4}(iceiamido)thl()phme-3<'iith»xamkfe [0Ö356J The title compound was prepared from methyl 4-cyano~2-(2-(quinolin~ 5-yl)acetamido)thiophene-3-carboxylate using protocol H (8mg, 80% yield), Method [1] : rt = 0.665 min; MH+ 337,0. L4Ï,4. (^)~4~€yunü~IS'--l(dmteikylsmïnü)meihylene)~2~(2-{quitwim~S~fI)ücetümMG}~ thwphme-3-curboxmmMe [003571 The title compound was prepared from 4-eyano-2-(2~(qumolin-5~ yl)aeetamido)ihiopheiie-3-earboxamide (37mg, 0.1 Immol) according to protocol C and was used without further purification. Method [1]: ::: 1.291 min; MH+ 392,1, L41.S. &amp;~(4~tym0~3-(4H~]f2,4jruiwi~3~yi}rhiephi!t!~2~yl)‘2~(qMit(tijn"S- [O0358J To a mixture of 4<yaao-N-((dime0iyIamiijo>i3eihylene)~2-{2-(quinolra~5-yi)acetamido)thiop.hene-3~carboxainide (0,1 linmo!) 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/chloroform solution and washed with a saturated, aqueous solution of sodrarn bicarbonate. The organic solution was dried over sodium sulfate and concentrated to give a solid, which was purified by column chromatography (using 5 to 10%· methanol / methylene chloride) and prep-HPLC (5-40% MeCN gradient). Snags (13% for the final 2 steps). Method £8] :rt = 8.1 min; MH+ 361.1. 3H-N.MR (300MHz, CDC1?) S 8.86 (s, IH), 8.48 (d, ,fo8,6H.z, 11-1), 8.14 (d,,/*8.5Hz, 1H), 7.83 (m, 2H), 7,69 (d, J~6.6Hz, IH), 7.54 (m. 2H1, 4.34 (s, 21Π, 3.30 (s. 3Hj. ,jC-NMR (75MHz, DMSO-4«)δ 168.7, 158.9, 158.4, 149.5, 139.5, 132.3, 131,3, 131.2, 130,.5, 127.9, 127,2. 122.3, 118.3, 115.7, 112.5, 105.7, 105.6, [Θβ359| Compounds of Examples 1.42 through 1.48, below, were synthesized by activation or the corresponding carboxylic acids and condensation with 4-bromo-3~ (4H--lJ2,4-triaaol-a-yl)thk}ph.en-2-amine. which was prepared according to the scheme, below,

1,42. AH4«Rrfimo-3-{ljT-l52i4-tri&amp;2fjI~5~y!)iMophen~2-y!)-2-(2~OM·-?- (trjfluorcn'nc4hyl)qninoIin--i(2f/pyI)acetamikle

[00360] Retention time {min) - 5.456, method {?], MS(ES0 497.9 (M+H); ‘H 'NMR (300 MHz, CD»OD) -3 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-(τΜ20ΐ~5->Ί){1ϊΙηρ1ϊ£!η~2^·Ι)-2-(6-ί1«©Γθ-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, 1E1), 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-li2,4~triaxo!-5-yS)thtop!sen~2~jI)-2-(7-ilporo-'2-öxöqMsnoMn~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~irtezoI-5-yJ)ffyophen~;Hyl)-2-(7-ehJ«r©-2“C>so-3,4-

[00363] Mc«hod[7], MS(FSJ) 466.0 [M4H], Retention time =· 5,594 min; ;H-N'MR (300 MHz. CDCI>) 6 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-

1003641 Method[71, MS(ESS) 465.9 [jVBH], Rdeaiion 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©ïS5o~3~(.liM52,4-irkjï(ikS~yI)thiop.hess-2-yi)~2~(2-oso-6-(trlflïsörosïjetlïyl)i|omolm~l(2i9)-yl)ac£tamlde

[0036?! Method[73, MS(ESI) 497.9 [M+H], Retention time ::: 5,696 min; Ή-NMR (300 MHz, CDC'b) δ 12.87 (b s, IH), 7.92 (d, J = 6.6 Hz, i H), 7.73 (s, 1H), 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-Brömo-3-(17r-l,254-triazol~S-yl)tliiophe8ï-2-Yl)-2-(6'~il8ioro-2- oxoq(*lnoliK"1(2//)“yl)aeetaniide

[Ö0366] Melhod[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). 1,4ft, Synthesis of N-{4-bromO"3”mi-l,2y4~triazoI~5"yi)thiopfeen-2~y1)-2“(2-oxO“),6- smpWSsyridki~1.(2M)~yl)iicè£ssïiid« ’

L 49, /, Methyl 2-{2~axo~I>6~mnpkfhyn4m~l(2II)~)>i)acetaie [00367] The title compound was prepared from l56~napkthyridin-2(l//)~one according to protocol IL Retention time (min) - 0.949, method [3], MS(ESI) 219.1 (M+H), 149.2. 2-{2-€hco~ 1,é-mphtkyridin-2 (2B)-yi)ecetie mid [00368} To a solution of methyl 2-(2-oxo-l }6-naphthyridin-i(2ff)-yl)acetate (L51 g, 6.92 mmol) in THF (10 mL) was added sodium hydroxide (4 mL of a 3 N aqueous solution, 13.8mmo0 and the reaction mixture was stirred at room temperature for IB h„ The resulting solution was diluted with ethyl acetate and washed with water, ike aqueous phase was separated, adjusted to pH 2 with a a neons HC1 and extracted wish ethyl acende. The organic phase was separated, dried (Na^SO*), filtered and concentrated under vacuum to give 2-(2-0,^0-1 d')-i;aphthynhlin-l(2/i!)-yl)3ceiie acid. Retention time (min) - 0.368, method [3], MS(ESI) 205.0 (M+H), 7.49.3, N-(4-Bnmm3~{lH~l,2,4~iriezoï~5~}i)fhi^kim~2~-yi)-2~{2~i?xi}~2,6- mphfh)>ridm~J{2.H)-}4}aeet(imMe [ÖÖ369] The title compound was prepared from 2-(2-oxo-1,6-naphthyridin-1 (2iT)-yI)acetic acid (62 mg, 0.306 mmol) and 4-bromo-3-(li/-l,2,4-triazoI-5-yl)thiophen-2-amine (25 mg, 0.101 mmol) according to Protocol L. Retention time (min) - 1.258, method [7], MS(ESi) 43 i .0 (M+H); lH NMR (300 MHz, CD3OD) δ 9.10 (s, 1H), 8.65 (d, J= 6.5 Hz, 1H), 8.33 (s, 1H), 8.23 (d, J ~ 9.7 Hz, 1H), 7.75 (d, J::: 6.5 Hz, IB), 7.15 (8, 1H), 7.01 (d, ,/=== 9.7 Hz, 1H), 5.39 (s, 2H). 1-S0. Synthesis of j¥-(4-bromo-3~(IH.L2,4-trtezol-S-yI)fhlophen-2-yl)-2-(2-oxo- 1,5~n apkthyrMm-1 (2H)~y!)acetamid.e

1, SÖJ, Meihyi 2-Q-&amp;xo-ï,5-n@phtky?iém-l(2H)~yi)acei&amp;te.

[0Ö370J 1,S-napfathyridïn-2(1 i/J-one (2.05 g, 14.0 mmol) was treated with lithium hexamethyidisilazide instead of sodium hydride according to protocol K to give methyl 2”(2-oxo-li5-naphth>'ridin-lf2/f>yl)acetate (224 mg). Retention time (min) -2.084, method [3], MS(ESI) 219.0 (M+H), L5&amp;.2, 2~{2~Ox&amp;~l}5-naphtkyridifs-I(2M)~yi)acetic acid [6Ö37IJ To a solution of methyl 2-(2~oxo”l,5-naphthyridiii-l(2i^-yl)acetate (Ö.205 g. Ö.939 mmol) in THE (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 °C for Ö.S h. The resulting .solution was concentrated under vacuum and co-evaporated from toluene to give 2-(2-oxo-l,5-naphthyridin.-l(2i0-y{)acetic acid. Retention time (min) = 1.033, method [3], MS(ESI) 205.1 (M+H). LS&amp;J. N~(4-Mr&amp;mo-3-(!M~2:,2,4-irmzai-S-yi)thiaphen~2~yi)~2~(2~&amp;xo-l!5~ iiaphthyridin~l {2H)-}4)aeetmii.d&amp; [00372] The title compound was prepared from 2-(2-oxo-l ,5-naphthyridin·-i(2/i)~yl)acetic acid (42 mg, 0.204 mmol) and 4-bromo-3-(lH-l ,2,4-triazol-5-yl)thiophen-2-amm.e (25 mg, 0.101 mmol) according to protocol A. Retention time (min) ::: 2.295, method [7], MS(ESI) 431.Ö (M+H); 3I-INMR (3ÖÖ MHz, CffrOD) b 8.57 (dd, J - 4,6. 1.7 Hz, 1H), 8.16 (d, J === 9.9 Hz, 1H), 8.11 (s, 11IX 7.98 (d, J = 9.1 Hz, 1H), 7.62 (do, J- 8.8, 5.1 Hz, 1H), 7.01 (d, J= 4.3 Hz, IH). 7.05 (s, j H), 5.33 (&amp;, 2H). l. 5L Synthesis of .'V-(4-l5roisso-3-ilH-I,2,4-trsaKoI~«:-yl)fhiOpiie«-2-yl)-2~{2-o\<i~3,4-dihy<iro~lsè~iiaphiii>Tidm-i{2II)"\I)aceiaïïïiiic

LSL L 2-{2-Oxe-3,4-dikyérfi··l9è~naphthyném~^(2ff)~yl)mï<stk add [003731 A suspension of 2-(2-oxo-l ,6-naphthyridin-l (2//)~yl)ax:eÉic acid (150 m. g, 0,734 mmol) and Pd/C (20 mg) in methanol was shaken under a 40 psi atmosphere of 1¾ rbf 18 h. The suspension was filtered through Celtic and the filtrate was concentrated under vacuum to give 2-(2^>xo-3,4-dihydro-1,6-naph'ihyridiii-l(2/i)-y!)acetic aad. Retention time (min) - 0.343, method |3j, MS(ESI) 2074 (M+H). L5L2. N~{4-Bmme-3~f]MdJJdnazoi-5-yl)tkwpheM-2-yl)-2~(2-m®~3,4~dikydre-!,6-mphthyddm-l{2B)~yl}acetamide [003741 The tide compound was prepared from 2~(2-oxo-3,4~dihydro~ 1,6-naphthyridin-1 (2f/)-yl)acetic acid (40 mg, 0.195 mmol) and 4-bromo-3-(l/(4,2,4-1ria2»]-5-yl)tMophen-2-aniise (24 mg, 0.0979 mniol) according to protocol A. Retention time (min) - 8.108, method [6], MS(EST) 433.0 (M+H); lR NMR (300 MHz, CD/JD) δ 8.618.48 (m, 3H), 7.51 (d, J= 6.8 Hz, 1H), 7.16 (s, 1H), 5.08 (s, 2H) 3.29-3.25 (m, 2H), 2.982.93 (m, 2H). 1,S2, Synthesis of Ar~(4-hrojnO"3-(J II~!,2,4"irliszol-S-yI)tMophen-2-yl)-2-(2-ox©~ 3,4~d.lhydro-l,S~ïiaphihyridiïï-l(2H)-yI)aeetanïlde

2*52. L· 2-^^xth3,4-^hydr&amp;-l,5~n^hthyHdm~l(2H)-*yl)acetkaad [00375] 2-(2-oxo-l,5-naphthyridra· i(2//)-y!)acel:ie acid (90 mg, 0,441 mmol) was treated according to Example 1.51,.1 to give 2··ί2-oxo-3,4-difaydro-l^-aaphthyri.dtn-lCliO-y^acetic add, Retention time (min) = 0.262, method [3], MS(ESI) 207.ö (M+H). 1>$2.2. A-(4"Broiiio~3”(li9-l,2,4-irIa^ol~5-yI)t!!lopbea~2~yI)~2-(2~03:o-3^4-dIliyclro- 1 ,5-saphihyfi<lin~ 1 (2/7)-y!)3.cetamide [00376] Λ'~(4 -Bromo-3-( 1/7-1,2,4 -triazol-5 -y i )thiop3icn-2-yl)-2-(2 -oxo~3,4 ~ dihydro~l,5-iiapht]iyridin-l(2i7)-yl)acetamide was prepared from 2-(2-oxo-3,4-dihydro- l,5-iiaphthyridi.n-l(2//)-yl)aceiic acid (42 mg, Ö.203 mmol) and 4-brorno-3-(lJ7”l,2,4-triazol-5-yi)thiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (min) - 1.274, method [7], MS(ESI) 433.0 (M+H); 'H 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, 1H)S 7.12 (s, 1H), 4.91 (s, 2H.j 3.34-3.33 (m, 2H), 2.98-2.93 (m, 2H). L53, Synthds ofAf~(4-brsmo-3“(l.ff~l,2,4-irtez©1-5-yl)thioplsea-2-yI)-2-(2~o»~7- (irifluoromei h ©xy)qs*I»©Iln- l(21#)-yl)aeetaralde

L5$. L Ethyl 3~(2~wmm?~4~{t^mmmetkoxy}pkmyl)8cryime [00377] The title compound was prepared from 2-bromo~5~ (trifl«oromethoxy)aniline according to protocol M. Retention time (min) - 2.693, method [1], MS(ES]) 276.1 (M+H). 1*53.1 7-{T^mmmeihüxy)quimlm~2(lH)~me [00378] 7"(Trifluoromethoxy)mnno!m-2(l./f)-one was prepared from ethyl 3-(2-amino-4-(trifluoromeÜ30xy)phony})aefy]ate according to protocol N. Retention time (min) - 1.803, method [1], M Si ESI; 230. ï (M---H). L 5.11. Methyl 2~(2~am~ 7~{triflu&amp;mmetk&amp;xy}qmmi>tm~l (2H)~yl)scetute [00379J The iitie compound was prepared from 7-(trifluoromtfhoxy)qumoHn.~ 2( I Hr-om according to protocol K. Retention lime (mm) - .>,226, meihod [1), MS(ES0 302.0 (M+H). 1.53,4, 2~(2~Ox0"7-(t^mmmeth@x})qmm!iin-l(2H)-y!)aceti€®dd [ÖCI3S0I Methyl 2~(2--oxo-7-{triflmnOmethoxy4qumoI.m4i2f7)-y1)a;cet8te (0.49 g, 1.62 mmol) was dissolved in THF (4 inL). Sodium hydroxide (1.0B ml. of a 3 N aqueous solution, 3,23 mmol} was added and the reaction mixture was stirred 60 °C for 2 b. The resulting solution was diluted with ethyl acetate and washed with water, The aqueous phase was separated, adjusted to pH 2 with aqueous HCi and extracted with ethyl acetate. The organic phase vras separated, dried (NaaSCL), filtered and concentrated under vacuum to give 2-(2-oxo-7-(1rifluorometlmy)quinolin-I(2fl)-yl)acetjc acid. Retention time (min) - L75, method [1], MS(ESI) 288,1 (M+H). I* S3o 5, N~{H~!f2f4~frm&amp;}i~S~yi}thmpkm-2~vi)~2~(2~sKW~ 7~ {tFif$Mimmethoxy}qMimün~ï{2ïl}~yl)®£gtmmée [00.181 j The title compound was prepared .from 2-{2-oxo-7-(trifliK>iX)mcthoxy)qüino!3n” i ('2A?)-yi)accSic acid (79 mg, 0.275 mmol) and 4-bromo-3-(17/"!,2,4~inaxol-0"yi)thiopneu-2*amine (30 mg, 0.137 mmol) according to protocol A. Retention lime (min) ------ 6,037, method [ 7], MS(ESI) 514,0 (Μ- Η K SH NMR (300 MHz, CD3OD) 5 8,15 (s, 1H), 8.11 (d, J ------ 9.9 Hz, 1H), 7.88 (d,J=9.1 Hz, 1H), 7.41 (s, 1H), 7.26 (m, 1H), 7.10 (s, 1H), 6.81 (d, J = 9.9 Hz, 1H), 531 (s, 2H), 1.54 Syutfads of /V-{4-bromo-3-{ii£-! ,2?43rlaMl-5-yI)th!opheu~2-yI)-2-(7--cyau©- 2~ox«qidno!in-l{2//}-yI)a£i+&amp;mide

1,54.L Methyl 2~{7-brüM&amp;M~oxoqmm?Un~ji{2H}“Vi)üi'etate (90382] The title compound was prepared from 7-bromoqiiinoi in-2{IBhons according to protocol K. Retention time (min) = 1.89, method [1], MS(ESi) 296.0 (M+fJ). I, 54< λ Methyl 2-(?-cy®m)-2~m&amp;qmmim-l (2H)~yf)ncetate [00383] CuCN (0.211 g, 2.36 mmol) and Pdt'PPh?^ (0.136 g, 0.118 mmol) were added to a solution of methyl 2-(7-bromo~2-osoqx3 inoiin-1 (2 W)-y5)acctatc (0.35 g, 1.18 mmol) in DMF (1 mL) in a screw cap vial. The vial was sealed and placed into a oil bath at 120 °C; and the reaction mixture was stirred for 18 h. The resulting mixture was diluted 'witn Efeö and washed with brine. The organic phase was separated, dried (NaaSO-s), filtered, concentrated under vacuum and the residue was purified on a silica gel column to give methyl 2<7Hjyano-2-oxoquinoliii»l(2//)-yi)acetate (0 204 g, 71%). Retention time (min) = 1 /164, method (I j, MS(ESI) 243,1 (M Mi). 1.54.3, 2~(7~45yu«o~2^xoquiit&amp;lin~l(2H)-yl)aceticecid {09384] Irimethyl tin hydroxide ¢0,388 g, 2.14 mmol) was added to a solution of methyl 2-(7~eyano-2-oxoquinoHn-l(27/)~yj)aceiate (0.104 g, 0.429 mmol) in 1,2-dichloroetnane (5 roL) and the resulting suspension was stirred at reflux for 4 h. The reaction mixture was diluted with diehloromethane and washed with IN aqueous HCL Filtration of the organic phase provided 87 mg (89%) of2-(7-cyano-2-oxoquinoHn-;<2/-/Vyi)acetic acid., Retention time (min) = 0.987. method [1], MS(ESI) 229.1 (Ml-H). /. 54,4. N~(4~Br(mw~3~{ IH~I,2,4-4tiiiZiil~5-yl}thbphett~2~yl)~2~{?~cy(m&amp;-2~ ox&amp;qmmim~l(2H)~yl)aceiamide [00385] A^4-BïtmïO-3-(l#-l,2,4~toazol-5-yi)tMophm-2~yl)-2-(7-cyano-2- oxoquinolin-1 (2i¥)-yl)acetamide was prepared item 2-(7-cyar:0~2-oxoqumoiin-1(2/7)-y1)acetic acid (65 mg, 0.286 mmol) and 4-bromo-3-(li?-l^54-triszol-5-yl)lhiophe3i-2- amine (21 mg, 0 143 mmol) according to protocol A. Retention time (min) =1 4.143, method [7], MS(ESl) 454.9 fM-HH); JH NMR (300 MHz, DMSO-ds) δ 12.18 (s, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 8.16 (d,/- 9.0 Hz, IB), 8.01 id, J- 8.0 Hz, 1H), 7.70 td,./ 8.01 Hz, 1H), 7.28 (s, 1H), 6.90 (d /- 9.0 Hz, 111). 5,31 (s, 2H). £•55« Synthesis of j¥-{4-bromo-3-(li:/-li2,4-triaEol-S-¥!)thlopheo-2-yI>2-(Isoqinn oIm-8-y m s be [00386} /V-(4-BromO”3-( 1 Η-1 ^^-triazoi-S-yl^iophen-S-yl^-iisoquinoIin-S-yl)acetamide was prepared from 2~(isoqmnQlin~8-yl)acetie acid (53 mg, 0,286 mmol) and 4-brorno~3-(lH-! ,2,4-triazol“5-yi)thiophes~2~am.me (35 mg, 0.143 mmol) according to protocol A. Retention time (min) = 1,769, method [7], MS(ESI) 414.0 (M+H); ’H NMR (300 MHz, CD3OD) δ 9.84 (bs, 1H), 8.55 (bs, 1H), 8.41 (d,/= 6.0 Hz, 1H), 8.26-8.23 (nr, 2H), 8,18 (dd,J= 8.1, 7.2 Hz, 1H), 7,99 (d,/= 4.0 Hz, 1H), 7.09 (s, 1H), 4.61 (s, 2H), 1.56, Synthesis of A?~(4~fer©3ao-3-(li?”l^,4-irkzo!-S~yI)ilitopiies-2-yl)-2-(6-flsinreqMeoMn-S-yOaeotamde [00387] Λ'-(4 hromo-3-(l //-1 f2,4-triazol~5~yi)thiopben”2-yi)-2-(6-ilLforoqoino!ta-5-yl)acetaniide was prepared from 2~(6-fluoroqninoiin-5 -yl)aeetic acid (42 mg, 0.203 mmol) and 4-bromo-3-(ljy-l,2,4-triaml-5-yl>hjophen-2-aimne (25 mg, 0.102 mmol Ï according to protocol A. Retention time (min) = 2,499., method [?], MS(ESI) 432.0 (M-iK); Ή NMR (300 MHz, CD3OD) δ 8.99 (dd, J = 4,2, 1.1 Hz, 1H), 8.86 id, J = 7.9 Hz, 1H), 8.23 (dd, J ~ 8.9, 4.5 Hz, 1H), 8.08 (s, .1H), 7.85 (dd, J- 9.4, 9.2 Hz, i H), 7.81 (dd, ./ = 9.2, 4.5 Hz, 1B), 7.07 (s, 1H), 4.48 (s, 211). 1.57 Synthesis of AH4-bromo~S<ii4~l,2s4~tri8zoI»5"yI)tMophen-2~yl>-2-(6- flnor0qolaolin-7-yl)aeetnmlde [00388] ¥“(4-Bromo-3~(l/7~ls2,4-triazoi-5-yl)ihi.osheri-2-yl)-2-(6~ flroroquinolixi-7-yljaeetamide was prepared from 2-(6-fsaoiX)quinoIiö-7-y})aceti.c add (42 mg. 0,203 mmol) and4-bromo-3~(l//~ls2s4-tÏiazofr5-yi)thiopheti-2~amme(25 mg, 0,102 mmol) according to protocol A. Retention time (min) =- 2.338, method [7], MS(ESl) 432.0 (M+H); ;H NMR (300 MHz, CD.,OD) 6 9.02 (d, J 4,2 Hz, 1H), 8.73 (d, J = 8.0

Hz, 1H), 8,24 (d, J= 7,2 Hz, 1H), 7.93 (s, 1H), 7.88 (d, 10.0 Hz, 1H), 7.82 (dd,«ƒ = 9.0,4.2 Hz. 1H). 7.09 (s, 1H), 4.42 (s, 2H). 1.58. Synthesis nfi¥~(4~Eromö-3-(l//»l,2,4~triaz0l-5-yl)tbiophen-2-yl)-2-(2-oxo-7“ (tr ill u oronsethyl)-1,6-napbtl!yrsdhrl(2/f)-y1)acetainid e

L 58.1. 5-fohn- 2~{t?ifiuvr(}meih}l}pwidm~4~i)l ί003891 Iodine (8.16 g, 32.1 minol) was added in five perilous to a solution of 2-(frif!uoromethyl)pyridm-4-ol (5 g, 30,65 mmol) and K2COs (4.66 g, 33.7 mmol) in methanol (34 ml.) at 0 °C and the resulting mixture was stirred at room temperature for 20 re The solution was vvasnefl with saturated aqueous sodium sulfite then acetic acid (IÖ ivif...) was added arid the solution was extracted with ethyl acetate, dried (NaiSGi), filtered, concentrated unde·· vacuum and the residue was purified on a silica gel column to give 5-i.odo-2-(irifiuoK>mediyl)pyridin-4-ol (5,1 g, 57%). Retention time (min) = 1,761, method [1], MS(ESI) 290.9 (M+H). 158.2. 4~Chi&amp;r&amp;-5~ii»do~2~(iriflki(fr0ffleikyi)pyndine (06390] A solution of 5--iodO"2--(tiifluorornethyi}pyridin-4-Gl (4.8 g, 16,6 mmol) in RÖCI* (30 mL) was heated to 100°C for 30 minutes. The resulting solution was concentrated under vacuum and the residue was neutralized by the addition of ice and aqueous potassium carbonate. The solution was extracted with ethyl acetate, dried (NajSOi), filtered and concentrated under vacuum to gi ve 4~chtom-5-iodo-2-(triiluoromeihyl)pyridme, Retention time (min) = 2.594, method [1 ], MS(FSS) 307.9 (M+H), LS8.3. 5-If)de~2-(tr$mmmetkyl)pymHtt-4-emwe 101)3911 Concentrated aqueous ammonium hydroxide (.10 ml.) was added to a solution of 4-ch]oro-5-iodo-2-(tri.fluoromethyl)pyridme (4.11 g, 13.3 mmol) in DMSÖ m a glass pressure tube. The lube was sealed and placed in an oil bath pre-heated to 110 °C for 48 h. The resulting solution was chimed with brine, extracted with ethyl acetate, dried (NasSGij), filtered and concentrated under vacuum to give 5-iodo-2~ (irrf1uorciriOihyI)pyrKii-V'4-afflirte. Retention time (mis) :.584, method []], MS(ESI) 289.0 (M+H). L SS, 4. Eikyi 3-(4~amm0~8~(t^mimmetkyl)pymim~S-)4)actyiate [00392) Ethyl 3~(4-arnmo-6~(trif3uoromcthyl)p3S'idin-3-yl)acrylate was prepared from 5-iodo-2-(tritluoromethy!)pyridi»-4“ainme according to protocol M. Retention time (min) = 1.064, method [1], MS(ESI) 215.1 (M+H). i 58.5. 7~{Triflmrmmth}4)~l&amp;n&amp;phihyrMin~2(lH)-&amp;ne [Θ0393) 7-ΓΤrifSuoromethyj)-1js-ttaphihyridin-2(.1 /7)oae was prepared from ethyi 3-(4-amino-6-(ir5flnororfiethy()pyridine-3-yl)aciylate according to protocol N. Retention time (min) - 1.064, method [1], MSfESI) 215 J (M+H). 2.58.4 Methyl. 2-{2-oxo~ 7 (ts i]luorometkyl)-lfaapMyridm-l(2H)-yl)a&amp;totie )00394) Methyl 2-(2-oxo~7-(trifluoromethyi)-L6-na.phtli>Tidin-l(2ii>-jd)acetate was prepared from 7-(trifluoromethyl)-l,6-naphthyridin-2(li0-one according to Protocol K. Retention time (min) - 1,621, method [1], MS(ESI) 287.1 (M+H). 2.58.7. 2-(2~Oxo~7-(iriflmremethyl}M! 6~mphthyridin-l f'2M)~yi)acetic add )00395] Methyl 2-(2-oxo-7-(trifluoiomethyl)-l ,6-naphthyridm-J (2fl)-yl)acetate (0.069 g, 0.10 mmol) was treated according to Example 1.53.4 to give 2-(2-oxo-7-(triflnoromethyl)-1,6-naphtliyridin-1 (2H)-yi)aceiic acid. Retention time (min) - 1.081, method [1], MS(ESI) 273.1 (M+H). 1.58.8. N~(4~Bmme-3~(lH~2i2,4~inazei~5~yl}tki(ipheti~2~y2)~2~(2~ox(h· 7-(irifluGnmmhyl}-l,8~mphihyHdin~l{2R)~yl)mmmüüe )04396) The title compound was prepared from 2-(2-oxo-7-dritluoroiT5ethyl)- 1,6-naphthyridin-1(2H)·yl)acetic acid (55 mg, 0.203 mmol) and 4-bromo-3-( 1//-1,2.4-triazol-5-yi}thiophen-2-a.mine (25 mg, Ö.J02 mmol) according to protocol A. Retention time (min) === 4.505, method [7], MS(ESI) 499.0 (M+H); *H NMR (300 MHz, CD3OD) δ 9.06 (s, 1H), 832 (s, III), 8.24 (d, /== 9.4 Hz, 1H), 7.94 (s, 2H), 7.14 (s, 1H), 6.99 (6,/= 9.4 Hz, i.H>, 5.39 (s, 2H) .1 .59, Synthesis o1 l/f-l,2,4-iiia?.ol~S--yi)th!opiien-2-yi)-2-(5- ÖSO py r aaolo 11 J-a ] pyrs mid in-4 {SH)-y i)»cetam Ida

1.59.1. Pyrszoiailf 5~a]pyrimidinS(4Hhone |0039?| 1 ,3-Oimcihyl uracil (3.15 g, 22.5 mmol) and sodium ethoxide (23 ml, of a 21 % solution in ethanol) were added to a solution of l#-pyrazol~5-amme (1.7 g, 20,4 mmol) in eiüanol (50 niL). The resuiting mixture was heated to 60 °C for 2 h and was then cooled to room temperature. The pale brown solid was isolated by filtration to give pyrazolofl ,5-a]pyrin3idia-5(4fl)~one (1.6 g, 58%). Retention time (min) ^ 0.820, method [3], MS(ESI) 136.1 (Mi ll). 1.59.2. Methyl· 2-(5-oxop}TmMnil?5~ajpyrimidm~4{5H)~}4}aeeme [00398] Methyl 2-(5-oxopyrazolo[ 1,5»a]pytimidln-4(5??)-yi)aceta.ie was prepared ftom pyrazoio[l,5-ajpyrimidin-5(4//}-one according to Protocol K, Retention time (min) = 1.951, method [3]s MS(ESI) 208.1 (M+H). L593, 2353}xüp}naz{dnrh5~o]pynmïdin,4{5H}y4meetk acid [90399] .Methyl 2-(5-oxopyrazo lo[ 1,5-ajpy njnidtn-4(5i7)-yl jucetate (0.26 g, 1.25 mmoi) was treated aocoramg to Example 1,54,3 to give 2~(5-ox©pyrazolo[l .5- a]pyrimidin-4(5.ff)-yi)aceiic acid. Retention time (min) - j ,00, method [3], MS(ESI) 194.1 (M-i-H), L 59,4. H~{4~Emm&amp;~3~{lM~l,2t4~iria&amp;i~5~yl)thi&amp;phen~2-yi)~2~(5~f)X9pymzoi&amp;i2,5-njpyrmMm~4{5E)~yi)acemmide

[00400] The title compound was prepared from 2-(5-oxopyrazolo[ 1. ,5~ a]pyrimidm-4(57/)-yl)acetie acid (39 mg, 0.203 mmol) and 4-l5romo-3-(lff-L2,4-triazoT 5-yljthiophen-2-amine (25 mg, 0.102 mmol) according to protocol A. Retention time (mis) - 2.45.1, method [7], MS(ESJ) 420.0 (M+H); !HNMR (300 MHz, CDClj) 0 8.28 (d,/= 8.5 Hz, .10), 7.83 (s, 1H), 7.77 (d,/ = 2.6 Hz, !H), 6.97 (s, 1H), 6.25 (d,/= 7.9 Hz, IH), 5.94 (d, / = 2.6 Hz, IK), 4.98 (s, 2Ή l 1.60. Synthesis! of 2-(2-öTO~l,6~rapMhyridlswl(2ff}~y!)-A^2-(thiaz©I-4~ yl)thlophen~3~yl)£cetamide [00401] The title compound was prepared from 2-(2-oxo-1 ,6-naphthyridin~ 1 (2ffVyl)acetic acid (83 mg, 0.307 mmol) and 3-(1 H~ 1,2,4-triazol-5-y1)thiophen-2-ainiae (28 mg, 0.154 mmol) according to protocol A. Retention time (min) = 1,460, method [7], MSfESI) 369.! (M+H); Ή NMR (300 MHz, CD3OD) δ 9.09 (s, IH), 8.89 (d,/= 2.3 Hz, !H), 8.62 (d, /- 6,6 Hz, IH), 8.23 (d, /-9.7 Hz, IH), 7.81-7.76 (m, 2H), 7.65 (d, /= 2.3 Hz, IH), 7.35 (d, / = 5.5 Hz, IH), 7.01 (d, /- 9.0 Hz, IH), 5.30 (§, 2H). 1.61. Synthesis of A- i44>ron'iö-3-(I//-H254-tnaztd-5-yl)thh.^hes-2-yi>-2-(2-ox»-6· (triflusronii7liy!)-l55-ijapisthyridio-l(2/7)-yl)a£etamkte

1.62 J, 2~I&amp;de-é~{tnf!it0r#miith}>}}pyndii!~3-eMme [004021 Iodine :,7.83 g. 30,8-1 mmo!) and silver sulfate (9.6 g, 30,84 mmol) were adacd to a solution of 6«(tnfluoromeihyl)pyridin~3-amine (5 g, 30.84 mmol) in ethanol (200 ml) and the resulting suspension was stirred at room temperature for 18 h. tnc solution was filtered and the riiiratc was concentrated under vacuum. T he residue was re-dissolved in methylene chloride and washed with aqueous NaOH (1 Nl, dried (NavSOj), filtered and concentrated under vacuum to give 2-iodo-6~ (trifi\3otomcthyl)pyridm~3-arriiiie. Retention time (min) === 2.136, method [1], MS(ESi) 289.01 (Μ+Ή). L 61.2. Ethyl 3-(3-amme-6~{ir^i-imt&amp;methyi)pyriilm~2~yi)msy2sie [Θ0403] Ethyl 3-{3-aniiiio-ó-(trifi,uorQmeihyi)pyridin~2~yi)aerylaie was prepared from 2.-:odo-6-(iriiluoromcthyl)pyridin-3-amine according to protocol M. Retention time (min) = 2.350, method [1 ], MS(ESI) 261,1 (M+H). ÏMJ. 6^?iftuiir&amp;ffiethyVt-l,S~n&amp;phthvriitm~2(lH}~om [004041 6-(Triiluororae-hyl}-1,5maphthyridln--2( ÏH}~one was prepared trom erhy! 3~(3^rnlrio-6-{iTin«oromethyl^)yridm'2~yJ)acfylate according to protocol N. Retention time (min) = J „40 L method [1], MS(ESI) 215.0 (M+H), L61A Methy!2A2^xa~é-/triflmmmmkyi}-lJ~nepk-tkyridm-l(2H)-yi)acé!iete [00405] Methyl 2-(2-oxo*6-(trifluoromethyl)-1,5-rmphthyridin-l (2/i)-yl)seetate was prepared from 6-(trifluoromethyl)-1,5-naphihyridiQ-2(l/f>-one according to Protocol K, Retention time (min) = 1.822, method [I], MS(ESI) 287.1 (M+H). 1.61S, 2~{2~Oxa-6-(^uar(fimtkyi}~lJ-mphtkyridm-J(2H}~yi}aceiic acid [(10406] Methyl 2~(2-öxo-6~(trifiuoromeihyl)-1 ,5-naphtbyridin- Ï (2/f)-yl)acetate (0.15 g, 0.524 mmol) was treated according to Ex. 1.53,4 to give 2-(2-oxo-6-(irifnsoromeihyl)-l ,5-naphthyrfdin-l (2//Vyl)acct3C add. Retention time (min) - 1.535, medmd [1), MS(ESI) 273.0 (M+H), 1.6SA N^4~Bromo-3Al&amp;~lJ^-JmiZid-5-y!}thmphefi-2-yi)-2-(2-oxo~6~ (tr^uorimetkyi)A>S~mpkihyridinA(2H}~yi}aceMmide [00407] The title compound was prepared from 2-(2-oxo~6-(trifluoromethyI)-1,5-naphftyridin*l(2H)-yl)acetic acid (66 mg, 0.,245 mmol) and 4-bromo-3-( 127-1,2,4-triazol-5»yl)thioplicn~2~amine (30 mg, 0.122 mmol) according to protocol A. Retention time (min) = 5.195, method [7], MS(ESI) 499.0 (M+H); 4-1NMR (300 MHz, CD/iD) 5 8,26-8,21 (m, 3H), 7,96 (d,J = 8.9 Hz, IH), 7.17-7.13 (m, 20), 5.37 (s, 2H). 1.62. Synthesis of Ar-(4~hr©m0-3-(ii7-l,2}4-triaz©l-5-yi)tIiiophen-2-yl>2~(5-oxi>-2-(triflMorom£thyi)pyra£o!0[!55~a]pyrimidln-4(5l7)~yI)&amp;eet5MBMle

L éZ 2. 2~(Trifl»0r0mefkyi)pymz0l&amp;iI,5^]pyrimidm-5{4ii)-etie [e<MOS| 3-('l'nilj«>tx)mcthy[)-]/i-pyrazoi»5~amiiie (4.8 g» 31.? mraol) was subjected to the protocol in Example 1.59.1 to give 2-(trifluotomethyl)pyrazoto[ l,5-ajpyrimi din-5(4i/)~one. Retention lime (min) - 1.220, method [1], MS(E3!) 204.0 (M+H). 2.62.2. Methyi 2”(S-oxo~2-(iriflmmimethyi)p},rsziii0l2,S~aJp)ftimiiiin-4{SH)-yi}aceteite (00409] Methyl 2"(5-oxo-2-(irifluoromc%l)pyrazolo[l ,.Ea]pyrmiidirs--4(5/:ir}~ yDaeetate was prepared from 2--(trifluoroniethyl)pyTazo!o[L5-a]pyrimidin*5(4if)-one according to protocol K. Retention time (min) = 1.846, method [1], MS(ESI) 276.0 (M+H). 2*62J. 2-(S-42x&amp;-2-{iri^erometktf)p)&amp;azoieflf5-^y?iMMm-4($H)-yl}ace$i£aeid (00410] Methyl 2-(5-oxo-2-{trifluorometiiyl)pyrazolo[l,5-a]pyrimidin-4(5i7)-yl)acetaie (0.129 g, 0.469 mmol) was subjected to the conditions in Example 1.54.3 to give 2-(5-oxo~2-(trifeoromethy;}pyrazo!o[l,5-ajpyrimldim4(5//)-y!)aochc acid.

Retention time (min) = 1.448, method [1], MS(ESf) 262.2 (M+H). 2.614. N^4-Bmmfr2^2H-l,2,4<töaz0i~5-yl)ihmpkm~2-yl)-2-(5-@xth2- (trifi^oromefh^)pyremb[2,S^Jp}vrmMm‘4m2)~yt)iirntsmide (00411] The title compound was prepared from 2-{5~oxo-2-(iriflüOroTnethyi)pyr«2olo[U-ajpyrimidiï3"4(5//)“yi)acctic acid (63 mg, 0.244 mmol) and 4-broroo~3-(l£T-l,2,4-toazol-5-y!_Hbinphen”2'aniine (30 mg, 0.122 mmol) according to protocol A. Retention time (min) = 4,975, method [7], MS(ESI) 488,0 (M+H); lB NMR (300 MHz, DMSO~i4) δ 8.79 (d, J= 7.4 .Hz, 1H), 8.6.1 (bs, 1H), 732 (s, 111), 6.96 (s, 1H), 6.45 (d,J - 7.4 Hz, 1H), 5.01 (s, 2H). 1.63. Sy nthesls of Λ-(4- bromo-3-i 1 -mefh \ I-1 ƒ/-1,2,4-trin2ol-3~yI)ihiophen-2-yI)-2~ (2”Oso-3,4“dihydrO”L5-naplttliyrMln-i(2^)-yl)neetamide (00412] Sodium hydride (4.2 mg of a 60% dispersion in mineral oil, 0.107 mmol) was added to a solution ofJV-(4-bromti-3-(l/i-l,2,4-iriazoi-3-y!)shiophen.-2-yl)~2-

(2-OXO-3,4-dihydro-l,5-naphthyTidm-.l(2/f)-yl)aeeiamide (31 mg, 0.07'! 5 mmol) in DMF (0.1 mL) si ö °C. The suspension was stirred for 5 minutes after which iodotsethane (i 2 mg, 0.058 mïïioi) was added. I he reaction mixture was stirred at room temperature for 20 minutes then, diluted with water, extracted with ethyl acetate, dried (Na2SO^), filtered, concentrated ander vacuum, and purified by preparative HPLC to give ;V~(4-bromo~3~(l~ methyl-l//-l,2,4-tria2oi-3-yl)üiiophen«2~yl)-2-(2-oxo-3,4>dihydïo-i,5-naphth.yridin- 1 (2//)-yl)aectam.idc. Retention time (min) = 1.740, method [7], MS(ESI) 447.0 (M+H); JH NMR (300 MHz, CD3OD) δ 8.47 (s, IH), 8.33 (d, ./= 5.2 Hz, 1H), 7.85 (bs, 1H), 7.61 (bs, !H), 7.11 (s, 1H), 4.94 (s, 2H), 4,02 (s, 3H), 3.41-3.36 (m, 2H), 3.01-2,4 / im, 2H). 1.64. Synthesis of ,¥»(4-€hIoro-3-(i//-1 Js4~irk2©RS-yl)thiopiien-2-yi)~.2-(5- oxnpyra2;olo|l,5-a]pyrimldIn"4(S/f)-yl)aeetasikle [0041.31 The title compound was prepared from 2-(5-oxopvras5olo[ 3 „5-ajp\>ri.rnidin-4(5//hy[)acetic acid (94 mg, 0.488 mmol) and 4-chloro-3-(lff-l,2,4-tria2ol- 5-y 1 jthiophen-2-amme (49 mg, Ö.244 mmoL according to protocol A, Retention time (min) = 2.161, method [7], MSfESI) 376.0 (M+H); !H NMR (300 MHz, CDCI3) δ 8.31 (d,7- 8.1 Hz, IH), 7.83 (s, 1H), 7.76(s, Hi), 6.85 (s, HI), 6.27 (d,J = 8.1 Hz, IH), 5.94 (s, IH), 4.98 (s, 2H). L65, Synthesis of Λ'··{4 € hIoro-3-( 1 -methyl- iif-1,2,4-tria»I-3~y))tWophen~2~y!)- 2-(5mxopyrazttio[l,5-a)|wrintiifin-4t5/f>-yl)ncemmsde [00414] Todomethane- (36 mg, 0.255 mmol) and K2C03 (44 mg, 0.319 mmol) were added to a solution of ,¥~(4“ChIoro-3-(l/f-l,2,4-tnazol-3-yl)thiophen-2“yl)-2-(5-oxopyrazoio[l ,5-a]pyrimldm-4(5//)-yl)acetainide (80 mg, 0.212 mmol) in DMF (1 niL), I he 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 (NasSCfi), filtered, concentrated under vacuum and purified by preparative HPLC to give A'-(4~ehlorO“3-f I -methyl-1 H-l s2i4-triazol~3-yl)thiopheii~2-yi)-2-(5-oxopyraz:o1o[] ,5-a]pyrimidin~4(5H)-yi)acetamide. Retention time (min) ** 3.00, method [7], MS(ESI) 390.1 (M+H); Ή NMR (300 MHz, CD3C1) δ 8.25 (d, J- 8.2 Hz, IH), 7.90 (s, IH), 7.76 (0,7 = 2.1 Hz, IH), 6.79(s, IH), 6,22 (d, J=8.2 Hz, IH), 5.97 (d, 2.1 Hz, IH), 5.36 (s, 2H), 3.99 (s, 3H),

1.66, SyetlK^dsofA:'.{44:,66K'0-3^(i--ïSK>f6y^m-J?2,44riazol-3-yI)tlïIopbeï^2~vlV 2-(2-oxo-6-{lrsfiMoroniethyI)-l,5"iiaphihyriiiisi-K2if)-yI)acetsmMe [60415J The title compound was prepared from A7~(4~cMoro~3-(! Η-1 .,2,4- triazol-3-y!)ihiophen-2-yl)-2-(2-oxo-6"(triiluoFomethyl)-l,5“tiaphihyr!dm-l(2//)- yl)acetamide (51 mg, 0.112 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, DMSO-<a?6) δ 8.5.1 (s, 1H), 8.31 (d, /= 8.9 Hz, 1H), 8.20 (d, J“ 9.8 Hz, 1H), 8.10 (d, / = 8.9 Hz, 1.H), 7.18 (s, 1H), 7,13 (d, /= 9.8 Hz, IB), 5.35 (s. 2H), 3,92 (s, 3H). 1.67, Synthesis of AK4-chloro-3-(l/r-l,2,4-triazol-3-yl)thlopheH-2-yl)-2-(2-oio-6-(trifiaorometbyf)-l,SHnaphthyiidiD-l(2£r)-yl)acetaniide [004161 The title compound was prepared fro in 2-(2-oxo-6"(trifluoromethyi)-l,5-naphthyridm-l(2ii/)-yl)acetic acid (160 mg, 0.588 mmol) and 4-chIoro-3-(l//-l ,2,4-triazol-3-yI)thiophen-2-amme (59 mg, 0.294) mmol) according to protocol A. Retention time (min) = 5.046, method [7], MS(ESI) 455.1 (M+H); *Η NMR (300 MHz, DMSO-/6) 5 8,62 (s, JH), 8,30 (d, /= 8,9 Hz, 1H), 8.21 (d, /= 9.8 Hz, 1H), 8.09 (d,/= 8.9 Hz, IH), 7.20 (s, 1H), 7.13 (d, / = 9.8 Hz, 1H), 5.36 (s, 2H). 1.68, Synthesis of N-(4“bi,®riso~3"(lH-l^,4“irlazoI"3-yl)tMopheffi“2-y1)"2"(3-fluoriM|uisolm-8-y!)aeetaisdde

L 68. L |00417f * en-buxyluitrile (4.6 ml, 38, > mmot) was added dropwise over 15 min to a solution oi qiriffi}Iin~3-aminc (4.61 g. 32.0 mmol) and borontrifluoride-ethesrate (6 ml, 47.3 mmol) in dichiorofcsnzene(]00 ml). The solution was heated ίο 100T. After stirring for for 1 h, the sofutson was cooled to ambient temperature and the dicbΙοrobenzette was deca niet: teaving oriluorouutnohne as <: black residue. Me tb o d [8 j retention time 3.28 min by HFLC (M+ 148). 1.68,2. 3-Fimre-8-nitmquimUne attd 3~fiuow-5-niiroquinoUne [004181 A solution of 3:1 concentrated sulfuric aeid/concentrated nitric add (32 ndj was added dropwise to B-iluoroquinobac (13,04 g, 88.6 mmol) in concentrated sulfuric acid (100 ml) at 0V'C. After stirring for 2 h, the solution was made alkaline with ION aq. NaOH and extracted with diethyl etoer. The combinedorganic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 3-fluoro-8--miroqiimoline and 3~fluoro~5-nitmi|iiisioline as a yellow solid. Method [7] retention time 3.50 and 3.92 min by HPLC (M+ 193) and (Mi- 193). 1.683. 3~Fïu&amp;mqmmdm-4~mdm and B-fimmiqmmsMn-S-amine 1§0419) 3-Fiuoro~8mitroquinoline, 3~fluorO“5miiroquiuoline, and tm(II)cMoride~dihydrate (68.23 g, 302 mmol) in ethyl acetate (2ÖÖ 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 bexane:ethyi acetate as the eluant to afford 2.14 g (11 % yield over two steps) 3-fliioroquinolin~8~am.me and 7,02 g (37% yield over two steps) of 3-fluoroquinoliii-5~amme. Method [6] retention time 1.57 and 4.02 min by HPLC (M+ 163) and (M+ 163). L 68.4, 8- E ra m &amp;··3 -fiamuq a im? Un e [00420] S-Fiuoroquinohn-S-amine (900 mg, 5,55 mmol) was added to tert~ butyhiitrite (1.3 ml. 10.9 mmol) and cupric bromide (1.37 g, 6.13 mmol) in acetonitrile (10 ml). The heterogenous mixture was heated to 70f,C. After stirring for 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 purified by flash chromatography (hexane:ethyl acetate] to afford 568 mg (45% yield) of 8-bromo-3-fluoroquinoline. Method [7] retention time 4.76 min by HPLC (M+ 226 and 228). 1.68,3. 2~{3-Fimmqmns}im~8~yi)aceiic mid [904211 The title compound was prepared from 8-bromo-3*fluoroquraoline (568 mg} 2.51 mmol) and 0.5 M (2-?efrf-butoxy-2-oxoethyl)ziittc(II) chloride according to Protocol F, accept that the ester was converted to the add using NaOH and MeOH in dioxane. Method [7] retention time 2.39 mm by HPLC (M+=206). 1,68.6, N~{4~Bf@mo-3-(] 1,2 A~iri&amp;z®l~i™yl)iki&amp;ph&amp;n~2~yl)~2~(3~flmroqumolin~8~ yl)metamide 100422] 4«Bromo-3-(4fi,-l»2>4-triazol.'>3»yl)thiophcn-2-aiTane (.17 nig, 69.4 umol), 2~(3-fl\3oroquinolm-8>yl)aoetic acid hydrogen chloride (22 mg, 91.0 nmol), 2-chloro-1 -methyjpyridinsurn iodide (301 mg, 395 umol) and triethylamine (0.2 ml) in methylene chloride (1 ml) was heated to reflux. After stirring for 1 h, the solution was concentrated and the residue was purified by HPLC to yield Ar~(4-;iromo~3-(l//-l52,4-triazo!~3-y! )thiop.bc:v2--yl)~7-(3-flnoroqumolm-8-yl)acetamide. Method [7] retention rime 5.67 min by HPLC (M t 432 and 434) and (M+Na 454 and 456). !H NMR (300 MHz, CDCli) δ 12.25 (s, 1H), 8,83 td, 1=3.3 Hz, 1H), 7.87 (τη, 2 HE 7.80 -d, J=6.0 Hz, 1H), 7.73 (s, 1H), 7,66 (t, J=7.8 Hz, 1H)S 6.90 (s, 1H), 6.70 (broad s, 2H), 4.56 (s, 2H). 1,69. Synthesis of A"(4~brosiïö~3“(lW-ii2i4-triazol“3-yI)ihiopheiï“2“yl)^2-(3-flïsöroqotaolio-5-yl)aeetaoïide

[011423 ] The title compound was prepared by converting 3 - Huoroq tuneI in-5-ttmiiie (850 mg, 5.24 mmol) into 2-(3-fluoroquinolin-5»yl)aeetic acid hydrogen chloride (76 mg, .)15 umol) and reaction with 4~bromo-3-(4H-l,2,44riazol-3-yl)thk)phen~2-amine (34 mg, 139 umol) as outlined in Example 1.68., above. Method [8] retention time 2.46 mm by HPLC (Ml 206). *H NMR (300 MHz„ CDC15) δ 12.35 (s. 1H), 8.89 (d, 3==2.7 Hz, 1H), 8 36 (ü. 3=8.7 Hz, 1H), 8.07 (dd, 3=9.3 and2.7Hz, 1H), 7.83 fm. 1H), 7.74 (d, 3==6.9 Hz, 1H), 7.59 (s, .1H), 6.93 (s, 1H), 4.33 (s, 2H). 1.70, Synthesis of i¥-(4~broiïio-3-(IHl-l>2,4-t'ria2ol“3-5'l)ihlophen“2“y!)“2-(3~ (irlfi«ora£Keiiiyl)qulBollM~5»yi)a.ce4amSde

L 70.1. 3-Iod&amp;qiiimiine [00424] 3-Bromoqumoline (64.00 g, 308 mol). NjSF-diinctiiyicthylcacdiaminc (13.5 ml, 127 mmol), cuprous iodide (12.00 g, 63.0 rmno!) 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 witn methylene eliloride. 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-iodoqumoIme as a yellow solid. Method [8] retention time 6.47 min by HPLC (M+=256). 1,71KZ 3~{Triflu9mmsthyi}qmmUne [00425] 3-Iodoqrriaoiiue ¢13.65 g, 53,5 mmol), cuprous iodide (21.12, 111 mnioi), potassium fluoride (7.11 g, 122 mmol), and methyl 2-cMoro~2,2~difiuoroacetsfce (23 ml, 216 mmol) m asroemy tforamide (20U mi) was placed into a preheated oil bath at. 12Ö C. After stirring for 6 h, the solution was diluted water and extracted with diethyl ether. The combined organic extracts were dned over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was Hash c hrom ar o gra o bed with 99:1, 49:1, 24:1,23:2, 9:1, and 4:1 hexarse:ethyl acetate as the eluant to afford 3,89 g (37% yield) of 3~(tnfluoiomcthy1)qumolinc. Method [7] retention time 4,67 min by HPLC (Mi- 198). L 703, 8~Erom&amp;3~{iriflmr&amp;methyi}qmm}Um and S-brmm-S-(tnfimt&amp;methyi}qumoïim [00426] 3-iTrifluoriwnethyDquinoHne (7.00 g, 35.5 mmol) and N-bromosuceiniroide (9.00 g, 50.6 mmol) in concentrated sulfuric acid (50 ml) was heated io 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 ag. 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-bixmio~3~(trifiuoromethyi)qumoline and 3.89 g (37% yield) of 5*bromo~3-(trifluoromethyi)quinohiie. Method [8] Retention time 6.75 and 7.47 min by HPLC (M+=276 and 278) and (M+=276 and 278). L 7Θ, 4. 2~(3-(Ttiffίίύη>meihylfqurnoiin -S-yl)acetic acid [004271 1 he title compound was prepared from 5-bromo-3- (triiiuoron;ethy!)quin.o!ine (3.59 g, 13,0 mmol) according to the procedures outlined in Protocol P. Method (7] retention time 2.80 min by HPLC (M+=256). L7Ö3, J$-(4~hremo -3-(1H-/,2,4-triaz#l-3-yi}thi»phen-2-yi)~2~(S- imJlmm>meikyi)qulnoim-S-yi)ecei&amp;mide [00428] The title compound was prepared from 44romo~3-(4//-1,2,4-friazol-3~ yl)thioph«a-2-amme (56 mg, 228 nmol) and 2-(3-trifluoromethylquinolin-5-yl)aeetic acid hydrogen chloride (2ÖÖ mg, 784 nmol) according to the procedures outlined in Example 1.68.6,, above. Method [7] retention time 5.93 min by HPLC (M+ 482 and 484) and (M+Na 504 and 506). ]H NM'E (300 MHz., COCI3) δ 12.45 (s, IM), 9.23 (s, IB), 8.84 (s, 1H)S 8.37 (d, 3=“8.4 H:r, 1H), 8.03 (m, 1H), 7.85 (d, ,M6.9 Hz, 1H), 7.74 (s, 1H), 6.95 (s, 1H), 4.38 (s,2H).

Synthesis ofA%4-bromo~3-(iff~i,2,44riazol~3”y!)thiophe®-2-y!)-2~(3-(tïiflnoromeÏhyl)qiÏl!iolin-i-yi)acetantlde

L 7LL 2~{i~{Trijhi<ir(>mgihv!jquim}ïm~ê~yl)aceüe acid [0(1429] The title compound was synthesized from 2-ft?nMxdoxy~2~ oxoethyi)zkc(H) chloride and 8-bromo-3-(trifiisoromothyi)qyinolke (4,55 g) according to protocol P. Method [7] retention time 3,78 min by HP'LC (M+ 256). /.7/.2, N-{4~braMa-3~{lH~i;,2s4~t}'mz®l~3-yt)i.hmphen~2~}4}~2-(3~ (tniflmwmeihyï)quimUn"8-}i}acemmiée [00430] The title compound was synthesized from 4~bron«>3-(4i7-l ,2,4-triazol-3~yI)thioplien“2-amine (40 mg, 163 nmol) and 2-{3-fïuoit>quinolin-8'-yI)acetic acid hydiogen chloride (284 mg, 1.1.1 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). AH NMR (300 MHz, DMSO-*&amp;) 5 11.80 (s, 1H), 9.20 (d, J=2.7 Hz, 1H), 9.01 (s, 1H), 8.39 (broad s, 1H), 8,25 (d, 1=8.1 Hz, 1H), 8.08 (d, 1=6,6 Hz, 1H), 7.79 (t, 1=7.2 Hz, HI), 7.21 (,s, 1H), 4.38 (s, 2H). 1,72. Synthesis of .¥"(4~cIiteri)-3-(3~isopropyl-IEf-1,2,4-tnnzoI-S-yS)fbsopheri~2-yI)“2-(2~exci"3,,4-ciihydro~is5~oaphthyTiiIin-l(2H)»y!)acetnmide

L 72. Λ 5-LMem- 4-kydr ariseyUh dm oƒ2,.?-djpyi imidiac 1664311 5-C.hioroM.chlorothieno[253-rfJpyrimidme (1.38 g, 6.73 mmol) and hydrazim, monohydrate (5.Ö ml,10o mmol) in absolute ethanol (20 mi) worn heated at 75 C, After stirring for 24 h, the solution was concentrated to yield 5~chloro~4-hydrazisylthieno[2J-d]pyrimidi:;o, Method [6] Retention time 035 min by H.PLC {M*~201 and. 203). 1,72,2, 9-CM8ro-3~impropyithim&amp;[3,2-ej$l!2i4]iri8zol&amp;[4£~c}i>yrifflidim [004321 5-CbIoro-4~hydrazmyhhieno[2,3-<%yrimidine and 1.,1,.l-iricthoxy-2-metbylpropane (10 mi) in ethanol (10 mi) were heated at 100°C for 2 h. The solution was concentrated and the residue was flash chromtogiaphed with 9:1,4:1, 7:3, and 3:2 hexane:eihyl acetate as the eluant to afford 300 mg (24% yield over 2 steps) of 9-chloro- 3-isopropylthieno[3,2-e][l52,4]tTiazoIo[43-e]pyTimidm.e as a brown solid. Method [8] Retention time 4.62 min by HPLC (M+-253 and 255), L723, 4~Cltl&amp;r&amp;~3~(34s&amp;pr&amp;pyi~2H-lf2!,4-4riiiziii~5~}i)thiopheii~2~imme [004331 9-chlon>~3-isopropylthieno[3,2-e][l,2?4]triar:oIo[43-c]pyrimidme (300 mg, 1.19 mmol) and Mmethyiethane- 1,2-diamine (0,50 ml, 5.67 mmol) in methanol (10 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 yield 4~chloro-3-(3-isoprepykI./Al ,2,4~triazo1~5-yJ)thiophen-2-amine. Method [7] Retention time 1.39 min by HPLC (M+=243 and 245), 1,72,4, N-(4~ck!0m~3~{3~i$apropy$~lff-li2i4-triezet-5~yl)thi8phm-2-yi)-2-(2-&amp;x&amp;-3lt4-dihydm-L 5-napktkyridm~l {2M}~yi)aceiamidis [ΘΘ434) The title compound was prepared from 4-chloro~3-(3 -isopropyl-1 H~ 1,2,4~triazol-5-yl)tMophen-2-anmie (117 mg, 482 nmol) and 2-(2-oxo-3,4-dihydno-.l ,5-naphthyridin-1 (2fl)-yl)acetic acid (155 mg, 752 umoi) using protocol A and was purified by HPLC to yield. AL(4-chloro-3-(3-isopropyl-l/7-l,2,4-triazol-5-yl)ihtopheri-2~yt)-2-(2~ oxo-3,4-difaydn.>-l,5-naphthyridin-l(2i?)-yi)acetamide. Method [7] Retention time 0.35 min by HPLC (M-H=431 and 433) and (M+Na=453 and 455). ’H NMR (300 MHz, DMSO-dft) δ 12.28 (s, 1H), 8.30 (d, 3=5,1 Hz, IH), 7.76 (d, JM8.7 Hz, 1H), 7,51 (m, 1H), 7.16 (d, 3=1.8 Hz, I H), 4.89 (s, 2H) 3.17 (m, 2H), 2,98 (m, IB), 2.81 (m, 2H), 1.28 (d, 3=7.2 Hz, ÓH). L7A Synthesis of/V-(4-cfeiorO"3"{3"«thyl-i//-1^4-irlazoI“5-yi)ihlopheü"2”yI)" 2-(2-o.ï«~3il4-dlhydro-li5“eiaphilïyrIdiïï«i<2//)-yi)aceÏaïïïi{ie

1,711. 9^Η^Γ0~$^Η$ϊίΗϊ€ίϊθ13,2-βϊβ&amp;4ί&amp;ίαχ&amp;1{}[4β^ρνηηίί(Ιιΐϊ&amp; [00435] 5-Ch1orp-d-,,ydrazmyithieno|2>3*rf]pynrrsjdine and 1,1,1-tricthoxyprapane ¢5 ml) in etrv.no! (5 mi) was placed into a preheated oil bath at 1004,C for 2 h. The solution was concentrated and the residue was flash chromtogr&amp;phed with 9:1,4: ί, 7:3, and 3:2 hexanerethyi acetate as the eluant to afford 20 mg of 9-ch!oro-3-ethylthi€no[352-e][lJ2,4]triazolo[43"C]pyrfoiidine, Method [8] Retention time 6,31 min by HPLC (M+:::239 and 241). 1.73,2, 4-Chbr&amp;-3-0^ethyl-iH~lf2,4-4ria&amp;fi-S^}tkbphm~2-amine )00436) 9-ChIoro-3-ethyltliieuo[3,2-cj [ 1 }2s4]triazoioi4,3<]pyrimidine (20 mg, 83,8 umoi) and A-rnethylcthanc-^-diammc (0,05 ml, 5.67 nmol) in methanol (2 ml) was placed into a preheated oil hath at 60l'C'. After stirring tor 15 tuin, the solution was diluted with saturated animonhon 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 (94% yield) of 4-ehlom--3--( 3-ethyl-1//-.1,2,4-triaaol-o-y^iiuopheii^amise as a brown solid, Method [8] Retention time 2,63 min by HPLC (M+ 229 and 231). L73J, N~(4~c.h!or0~3~(3~ethyl~m~lt2f4^rim>l~S~yi)thmphea~2~yi)~2~(2~exe~3,4~ dihydMi~l,5-mpktkyridin~${2H)~y!)a£et&amp;mide [00437) The title compound was prepared from 4-cHoro-3-(3-ethy1-li/-1,2,4-tria2ol-5-yl)thiophen-2-amine (18 mg, 78,7 umoi) and 2-(2-oxo-3s4-dihydro~ls5~ naphthyridin-l(2//)-yi)acetic acid (20 mg, 97,0 umoi) using protocol A, The residue was purified by HPLC to yield iV-(4-chloro-3-(3-ethyl-liif-l>2,4-triazol-5-yl)thiopheii~2-yl)-2-(2-OXO-3,4~dihydro-1,5-aaphihyridin-1 (2//)-yl)acetamide. Method [8] Retention time 4,47 min by HPLC (Mr =417 and 419) and (M+Na=439 and 441). 1H NMR (300 MHz, CDUj) δ 8.>9 (dd, J-d.4 and 1.2 Hz, IH), 7.67 (dd, .0--8.1 and 1.2 Hz, IH), 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, 1=7.8 Hz, 3.B). 1.74. Synthesis of Afo4w4ihnaMLf3~ methyl- 1//-1,2,4-ioazob5-)1)tbÏnp.be?!“2--yi>-2-(2-oxo~3?4™dihydrO“i,>>iïaphfhyridiiï"l(2iï)"yi)acetaïïilil® 1.74, L 9~Cki0W-3-metkyfaMm&amp;f3f2-eJfi,2f4jtrkiwlt>f4J~£jpyriMMim [0Ö438j 5 -Chloro-4-hydrazixiyithieti o[2,3 -rijpyritnidine and 1,1,1-trielhoxyethane (10 ml) in ethanol (10 ml) was placed into a preheated oil bath at 100°C for 2 h. The solution was concentrated and the residue was flash chmmtographed witli 9:1, 4:1, 7:3, and 3:2 hexaixe:ethyl acetate as the eluant to afford 92 mg of 9-chioro-3~ mcf h.yhhierso[3,2-c][! ,2,4]tnazoioj4,3-c]pyrinsidine white-pink solid. Method [7] Retention time 3.77 mm by HPLC (M+=225 and 227). L 74,2, 4~CM&amp;ri>~3~i3~sitethyl~lH-l}2f4-iÏ‘ktz&amp;ï~S-yï)Ïkiophen-2-amms [00439] 9-Chloro-3-methylthieno[3,2-e][ 1,2,4]triazolo[4,3-c]pyrimidine (82 mg, 365 imiol) and /V-methylethane-l,2-diamine (0.30 ml, 3.40 mmol) in methanol (2 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, tillered, and concentrated under reduced pressure to afford 69 mg (88% Held) of 4-chloro-3-(3-methyI~'l //-1,2,4-triazoI-5~yl)thiophen-2-amine as a yellow solid.Method [.1] Retention time 0.61 min by HPLC (M-M215 and 217). 1.743, 7k>!~{4"€hbro-3"{3~meikyi~llI~l,2,4~trmz&amp;i~S~yi)thi0pken~2-yi}-2-(2-oxo~3s4- dihydm33-Mpkthm'dm~!{2H)-)i}mrMmide 100440] I he title compound was prepared from 4-chlorO"3-(3-m«Üiyl-1 //-1,2,4- triazoi-5-yl)ütiophen-2-amine (69 mg, 321 nmol) and 2-(2 -oxo-3,4-dihydro--ls5- naphthyridin-1 (2iJ)-yl)aeefic acid (82 mg, 397 umol) using protocol A, The residue was purifled by HPLC. Method [8] Retention time 3.40 min by HPLC (Mf-403 and 405) and (M.+Na=425 and 427). ’H NMR (300 MHz, CDClj) δ 8.39 (d, J»5.4 Hz, IH), 7.67 id, 1=8.4 Hz, IK), 7.49 (dd, J-8.4 and 5.4 Hz, JH>, 6.86 (a, 1H), 5.46 (broad s, 2H), 4.95 (s, 2H), 3.,49 (m, 2H), 3.01 (ms 2H), 2,50 (s, 3H). 1.75. Synthesis of JV-(4-chloro-3~(l /M,2v4-triaa»l*3-yI)thiophen-2~yl)-2-(2-oxiMi- (irlflworoni8thyl)qBinoIiii-l(2//)-yl)aeeiamlde [09441] The title compound was prepared from 4-chloro~3~(1 /7-'I s2.4-triazol-3-yl)thk>phen-2-amme (502 mg, 2.50 mmol) and 2-(2«oxo-6-(trifluoromethyl)qiii«oim- 1 (2i/)~yl)acetic acid (675 mg, 2.49 mmol) using protocol A (626 mg, 55% yield). Method [7] Retention time 5.59 min by HPLC (M+=454 and 456) and (M+Na-476 and 478). lH NMR (300 MHz, DMSO-4) β 12.23 (a, ill), 8.38 (broad s, 1H), 8.27 (s, JH), 8.22 (d, J=9.3 Hz, 1H), 7.89 (d, 1=9.3 Hz, 1H), 7.70 (d, 3=9.3, IE), 7.17 (s, 10), 6.87 (d, 1=9.9 Hz, .10),5.31 (s, 2H). 1.76. SyetlieslsofA%4-dstoro-3-(l--(3-(dtoietliylammo)prepyiH2^1>2J4-titazol-3-yl)4hfophea<2-]d)-2-(2-ozo-6-(tiiflBoroinethyQquineilik-f(2//)-yl>ieetamlde [00442J Diisopropyl azodicarboxyiate (0.30 ml, 1.52 mmol) was added dropwise to a heterogeneous mixture ofJV~(4-chloro-3-(liir»l,2,4-triazo!-3"yi)thiophsn-2-ylj“2-i2~oxo-o-itnfluoromctnyl;quinolin~i(2i7)*yl)acefamide (I II mg, 245 nmol), polymer supported triphenyl phosphine (500 mg, 1.50 mmol), and 3-(dimethylamino)pix>pan-l~ol (300 mg, 2,91 mmol) in tetrahydrofuran (5 ml) at 0°C.

After stirring for 2 h, the heterogeneous mixture was filtered through a pad of oelite and concentrated under reduced pressure. The residue was -punned by HPLC to yield 7/-(4-ch!oro~3~( I -(3-(dimethyl.antino)propy!)-1 //-1,2,4-iriazol-3-yl)ih}Ophen-2-yl)-2-(2-oxo-6-( irifinoromcthyljquinolia-i(2A')-yI)acetan'sidc. Method [7] Retention time 4.33 min by HPLC (M+=539 and 54.1). Ή MMR (300 MHz, DMSO-4) δ 12.10 (s, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 8.22 (d, J=9.6 Hz, 1H), 7.92 (d, 1=8.7 Hz, 1H), 7.72 (d, J=8.7,1H), 7.18 (s, 1H)S 6.87 (d, .1=9,6 Hz, 1H), 5.32 (s, 2H), 4.31 (t 1=6.6 Hz, 2H), 3.09 (t, 1=6.6 Hz, 2H), 2.75 (s, 6H), 2.17 (m, 2H>. 1.77. Synthesis of/V-(4-chlori)~3~(l.-(2-(dimethylamiïïo)ethyi)-lJÏ~l^,4-trlazol-3-yl)tlsiöplïeii-2~yi)-2-(2-oxo-6”ttrillnoromet!iyï)qtiliïoli!i-li2fl)-yl)aeêtnmMê [00443J The title compound was prepared from i¥-(4~diioro-3-(l//-l,2f4-iriazol-3-yl)thiophen~2~yI)-2~(2-oxo-6"(tófluoromethyl)quinolm--l(2fif)-yl)aeetamide (125 mg, 275 umol) and 2~(dimethylamino)ethanol (331 mg, 3.49 mmol) «sing the procedures described in Example 1.76 except that the reaction was run at 60°C (rather than IfC). The residue was purified by HPLC to yield jY-(4-ehloro~3~i1 -(2-(dimethy I amitio)eihyl)-177-1,2,4~iriazol ~3 ~y I)thiopheu-2-yi)~2-(2-oxO“6~ (trifluoromethyl)quiiioim-i(2//)~yl)acetamide, Method [7] Retention time 4.40 min by HPLC (M+=525 and 527) and (M+Na=547 and 549). lH NMR (300 MHz, DMSO-rig) δ 8.41 (s, 1H), 8.28 (s, 1.H), 8.22 (d, 1=9.3 Hz, 1H), 7.90 (d, 1=8.7 Hz, ΪΗ), 7.72 (d, J--8.7, IE), 7.16 (s, 1H), 6.87 (d, 1=9,3 Hz, lHi, 532 <s, 2H\ 4.28 ((, 1=6,0 Hz, 2H), 2,64 (t, 1=6.0 Hz, 2H), 2.15 (s, 6H). L78, Synthesis of JV~(4-cfeloro-3“(1~(3-(4~meihylplperaziK-l-yl)propyI)-ii?- L2,4-'triazol''3"yl)riiIoph€H--2'-yl)-2~(2-'Os;o~'6~(trifluoromeihyl)<|ulnotio-l(227)- yl)acet&amp;mïde [00444] The title compound was prepared from A-(4-eMoro-3~( I17-I ,2,4- lTiazo1-'3“yl)thiophea-2-yl)-2-(2-oxo-6-((rifluoromethyi)quiaoiin-l(2iO-yl)acetamide (108 mg, 248 umol) and 3-(4-meihyipiperazin-l~yl)propa.n-I-ol (350 mg, 2.21 mmol) using the procedures described in Example 1.76. HPLC purification gave jV-(4-chlorx>~3-(l-(3-(4-methyipiperazin-l-yl)propyl)-l.H-ls2s4-triazol-3”yi)thlophen-2-yl)-2-(2-oxo-6-(trifiuorometliyl)£juinoiin-l(27/)~yI)aeetamide. Method [7] retention time 4.27 min by HPLC (M+=594 and 596), ‘i-i NMR (300 MHz, DMSO-ifc) δ 12.13 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.22 (d, 1=9.9 Hz, 1H), 7.92 (d, 1=7,2 Hz, 1H), 7.72 (d, 1=8.7 Hz, 1H), 7.17 (s, 1H), 6.87 (d, 1=9.3 Hz, 1H), 5,32 (s, 2H), 4.25 (t, 1=6,6 Hz, 2H), 2.95 (broad m, 1QH), 2.73 (s,3H), 1.97 (m, 2H). 1.79. Synthesis o.f.IV-(4-chloro~3-(l-(3~morpholsnopropyl)-li:/"ls2,4-trMz©l-3- y])thinph®n~2~yl)-2-(2-öxo-é-(trlfliioromeihy1)qnitïoMn”i(2/]l)”yl)nce;lanslite [00445] The title compound was prepared from jY-(4~chIoro»3-(117-1,2,4-triazol“3-yl)ihiophen-2-yl)-2-(2-oxo-6-(trifluoromeihyi)quinolin-l(21c/)-yi)acetamide (110 mg, 242 umol) and S-morpholinopropan-l-ol (350 mg, 2.41 mmol) using the procedure described in Example 1.76. HPLC purification gave jV-(4-chloro-3-(l~(3~ moiphoJinopropyl)-lJï-ï,2,4-triazol-3-yl)thiophen-2--yl)-2-(2-oxo-6- (irifSuorometh.yl)qumo1ïn-l(2i/)-yI)acetamide. Method [7] Retendon time 4.58 min by HPLC (M+=581 and 583) and (M+Na-603 and 605). *HNMR (300 MHz, BMSO~ds} δ 12JO (s, 30), 8.47 (s, 1H), 8.26 (s, 1H), 8.20 (d, 3=9.3 Hz, 1H), 7.91 (d, 1=7.2 Hz, IH), 7.70 (d, 3=9.3 Hz, IH), 7,.16 (s, IH), 6.86 (d, J=9.3 Hz, 1H), 5.30 (s, 2H), 4,30 (t, 3=7.2 Hz, 2H), 3.20 (broad m, 10H), 1.20 (m, 2H). 3.80. Synthesis of A“(4-'Chiörö-3-(l~(3.(pyrrölidisï-i-yI)pröpyi>!&amp;l,2,4~ triazo]-3-yl)thl«jphen-2-yI)~2-(2-öso-6-(trfflïror®inetlïyl)f|Min«>lin-i(2//)-yI)a€eteinide [00446J The title compound was prepared from jy~(4-eMoro·-3-( .1//-1,2,4- üdazol-3~yS)thiophen-2-yi)-2-(2-oxo--6-(iri..fluo«OmeÜiyl)qumolin-l(2//)-yl)acetamide (110 mg, 242 nmol) and 3-(pym>lidiö-.l-y!.)propan-l-ol (3.25 mg, 2.52 mmol) using the procedures described in Example 1.76. HPLC purification gaveiV-<4->chloiro-3-(l-(3-(pym»lidin*l-yl)p»opyl)-.lJÏ-1>2,4-fttazol-3"yI)titiophen-2-yl)“2“(2-oxo-6-(trifl«oromethyl)q«inolm~l(2/ï>yl)acetamidc. Method [71 Retention time 4.65 miss by HPLC (M+=565 and 567). lH NMR (300 MHz, DMSO-ri6) δ 12.10 (s, IH), 8.50 (s, 1.H), 8.28 (s, IH), 8.21 (d, 3=9.3 Hz, IH), 7.91 (d, J=9.3 Hz, IH), 7.70 (d, 3=9.3 Hz, IH), 7.17 (s, IH), 6.86 (d, 1=9.3 Hz, IH), 5.31 (s, 2H), 4.33 (t, 3=6.6 Hz, 2H), 3.20 (broad m, 6H), • 18 (m, 211), 1.99 rim 2H), 1.83 (m, 2H). L8L Synthesis of 2“(6-bront0-2-oxoi|uii3oIin-!(2i7)~yl)-N-(4-bromi>3~(l tHazoKLyI)thtophen-2-yl)aeetamide

L8L2. 2~{i>~Bwm(}~2~oxoqmn(dm~H2H}~yï}m.etie acid [00447] 6-Bromoquinolin-2(1 H)-one (5.03 g, 22.5 mmol) was subjected to protocol R. with, ethyl bromoacctaie instead of methyl bromoacetatc to afford 6.96 g (100% yield) of ethyl 2-(6-bromo-2-oxoqumotin-1 (2//)-yl>scet.atc as a white solid.

Method [7] Retention time 4.79 min by HPLC (M+=310 and 312) and (M+Na=»332 and 3^‘ί), The acetate ί318 mg. 1,03 miaoi) was subjected to trie protocol in Example 1.53.4 to afford 228 mg (83% yield) of2-(6-bromo-2-oxoquinoiin-l(2//)-yl)acetic acid as a white solid. Method [B] Retention time 4.79 min by HPLC (M+=2&amp;2 and 282) and (M+Na=304 and 306). I.S1.2 2~(&amp;Brem&amp;-2~0xequM0im-ï(2I%-yi)-N-(4^mmi}-3-(lH-lf2,4-triaz0i~3~ fi}thmpkea~2~yi)m:et&amp;mide [M448J The title compound was prepared from 4"bromo-3-(lfl-l,2,4-triazoi-3-yl)thiophen-2-amme (55 mg, 224 umol) and 2-(6-bromo-2-oxoquinolin-!(2//>yI)acdic acid (85 mg, 301 umol) according to protocol A. HPLC purification gave 2-(6-bromo-2« oxoquiaolm-l(2fl)-yl)~iV-(4-bron3o-3-(l/f~l,2s4-triazol-3-yl)thiophen-2-yI)acetajnide.

Method [7] retention time 5,41 min by HPLC (M+=508, 510, and 512). Ή MMR (300 MHz, CDCis) δ 7.80 (m, 2H), 7.70 (s, 1H), 7.63 (dd, J=9.Q arid 2.4 Hz, 1H), 7,19 (d, .1=9.0 Hz., 1H), 6.94 (m, 2H), 531 (s, 2H). 1.82. Synthesis of 2-(6"bromo-2»oxoqnmolm-l.(2ff)-yl)-A’~(4-eMoTO.3.(lif- l,2,4”fel&amp;gGl~3~yI)tMophm~2-yi)&amp;£etamid£ [9Ö449J The title compound was prepared from 4~chtero-3-(177-1 ,2s4~iriazol-3- yl}titiophen-2~amine (115 mg, 573 umol) and 2-(6-bromo-2-oxoquinolin-l(2//)-yl)acetic acid (135 mg, 479 umol) according to protocol A. HPLC purification gave 2-(6-bromo- 2-oxoquiiiolm-l(2H)-yl)“iV'-(4-chlorO”3-(lir-l>2,4-triazo1-3-yi}thiophen-2-yi)acetamide.

Method [7] Retention time 5.30 min by HPLC (M-H=464,466, and 468) are the major peak intensities. Ή NMR (300 MHz, CDCl3) δ 7.80 (m, 2H), 7.70 (s, 1H), 7.64 (dd, J=9,0 and 2.4 Hz, 1H), 7,19 (d, J=9.0 Hz, HI), 6,94 (d, J=9.3 Hz, 1H), 6.82 (s, IB), 5.30 (s, 2H).

Synthesis otiV-(4~bromO“3”(l ff-l;,2>4-trlazoI~3~yl)thIopIsen-2-yl)-2-(6-eyMO“2-oxoquinolIö-l(2iï)~yl)aeetamSde

L83.L Ethyl 2-f$~cyam 2~öxequin&amp;lm~ / (2H}-yi}uceiate [00458} Ethyl 2-(ó-bronKj~2-ox0qumoiin-1(2H)~yj>eetate (2,37 g, 7.64 n»nol)cuprous cyanide (8,87 g, 99,0 mrool), and leirakis(tEiphenylpliosphi[ie)paUadium(O) (3,50 g, 3,03 mmol) in dimethyiforamide (100 m!) was placed into a preheated oil bath at 140°C. After stirring for 24 h, the solution was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried aver magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, and 3:2 methylene chlorideretbyl acetate as the eluant to afford 0.74 g (38% yield) of ethyl 2-{6-cyano-2-oxoquinolm-1 (2//)-y!)acelate. Method [7] retention time 2.87 min by HPLC (M+ 257). L 83.2, 2-(§~€vam}~2~m:omin&amp;lm-l (2M)-yi)aeedc ucul [004511 Ethyl 2-(6-eyano-2-oxoquinolin~l(2//)-yl)acetate was subjected to the protocol in Example 1.53.4 to affm d 550 mg (83% yield) of 2-(6-cyaao-2-oxoquinoh'n-l(2i7)~yi)aeetic acid as a yellow solid. Method [7] retention time 2,44 min by HPLC (Mi 229). 1.833. N-(4~èrom@~3~{l Pi-I?2s4-£rmzff$-3-y$)thwpheft~2-yi}-2-{é-cy(mo-2-oxeqmmii!t-l(2H)~yl)acemmiiie [00452] The title compound was prepared from 4-bromo-3~(l//-1,2,44riazol-3-yl)f hiopben-z-amine (253 mg, 1,03 mmol) and 2-(6-cyano-2-oxoquinoiin-1 (2^)-yl)acetic acid (325 mg, 1,42 mmol) according to protocol A. HPLC purification gave JV-("4-bromo~ 3-(.1.//-1,2,4-tn.szol~3 -y i)thiophen-2-yl)-2-(6-cyano-2 -oxoquinolin- .1 (2.//)-y l)acetamide. Method [7] Retention time 4.00 min by HPLC (M-H*455 and 457). NMR (300 MHz, DMSO-4) δ 8.42 (broad s, 1H), 8.3? (s, 1H), 8.13 (d, 3=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, 3=9.3 Hz, 1H), 5.30 (s, 2H). 1.84. Svss thesis of /V~{4~eh ioro-3-{l.ff- 1,2,4-trfazoI-3-yI)lhiophen-2-yï)-2-<6-eyano»2-oxoi|5iinolir8-l(2H)-yi)ncetaiiiMe [00453] The title compound was prepared from 4-ehloro~3~(1 Η-1 ,2,4-triazoi~3-yi)tfaiophen-2-amïne (215 mg, 1,07 mmol) and 2-(6~cyam>2-oxoquiiioHn-l(2/7)-yl)aectic acid. (325 mg, 1,42 mmol) using protocol A. HPLC purification gave JV-(4-chloro-3-(li/-1 „2J4-üiazoi'-3-yl)thiop.hen-2-yi)-2-(6-cyaEio-2-oxoquii!.olin-1 (2//)-yl)acetamide, Method [7] Retention time 3.83 min by HPLC (M+=411 and 413). 3HNMR (300 MHz, DMSO-d6) δ 8.37 (s, 2H), 8.13 (d, J=9.9 Hz, IH), 7.98 (d, J=S,7 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.17 (s, 1H), 6.86 (d, 1=-9.9 Hzs 1H), 5.3,1 (s, 2H). 1.85. Synthesis of N-(4-hromo-344^-l52,4-triiissoI-3"yI)thtophen~2-yi>.2-(isoq ïs!no!M»4»yl)aeetaBïÏde [00454] To a solution of 4-bromo-3~(4H-l,2,4-trta2»>i-3-yl)thioph.®i-2-aniine (50ntg, G.zmmoi) and 2~(Iso£|uinoliii-4-yl)EcetIc acid (5óxng, G.Bixnnol} in methviene chloride (2mL) were added Hunig s base (i.e., Ν,Ν-düsopropylethylainme) (71uL„ 0.4.mmo1) and HBTU \133mg, O.35mmo3.), The heterogeneous reaction mixture was homogenous after 3h. Ih© 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, i he resulting solution was concentrated to provide a pals red solid, which was purified by column chromatography using 3.5% MeOH/€H2€l2. LCMS: retention time 1.955 min using analytical method [7] with an M-i-Na of 414.0. 19.0 mg (15% yield): white solid. 'H-NMR (300MHz, CDC13) δ 9.34 (s, IH), 8.66 (s,IH), 8.07 (d, JNS.OHz, IH), 8.01 (d, J-8.0Hz; IH), 7.75 (m, IH), 7.65 (m. 2H), 6,88 (d, J=G.5Hz, IH), 4.30 (s, 2H). ?3C-NMR (75MHz, CDC13) 8 168.3, 153.2,144,8,142.8, 135.0, 131.5, 128.7, 128.4,127.8, 123.5, 122.9,116.2, 104.7, 38.7. L86. Synthesis of A^4-brömo-3-(42/-1,2,4~triazol-3-y!)thiophen»2-yl)-2--(3,3-difl uoro-2*i>jsnhi ύ nlm~1 -yliaceiismld e

LB6.L 3f3~BiJhmmmd&amp;iin~2~em [08455] A 1 OOmL reaction flask was charged with indoime~2,3~dione (0.88g, 6.0rmnof). DCM (40niL) was added, followed by OAST (2.4g, 15.0ntmol). The reaction was stirred for ! 6h before being quenched by the addition of 2nVL MeOI-1. The oreanic reaction mixture was rinsed with water end 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 mbs of 170,0 at a method [1] retention, time of 1.673min in, L86J, tiwi-Buiyi 2-(3>3-diftuom~2~&amp;xemd&amp;im-l~yl)acemte [09456) The title compound was prepared from 333~difiuoKnndolin~2~Gne using protocol K except using tert-butyi 2-bromoacelate to give crude test-butyl 2-(3.3-difIuoro-2-oxomdolin-1 -yl)acetate as a yellow oil LCMS method [1] showed an M+ Na peak of 306,1 with a retention time of 2.502min. L 86,3. 2~{3}3~Difliiore-2-i}X8mikiUn~l~yi)s£@tic acid [004571 A 30ml, reaction vial was charged with tert-butyl 2-(3,3-difluoro-2~ oxoindolin-1 -yi)aeefate (275mg, Iramo!) 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-dif].uoro~2-oxoindoliö-1 -yl)acetic acid as a yellow solid. Ihe desired M+H (228) was observed in the LCMS using the method [1] with a retention time of 3,652mm. ommdaim~l~yl)acet&amp;mide [Ö0458J The title compound was prepared from 2-(3,3-difluoro-2-oxoindo1m-l-yl)acetic acid (50mg„ 0.22mmol)s 4-bmmo-3-(4H-l,2,4-tria»>l-3-yi)thiophm-2-amme (45mg, OJSrnmol) using protocol A, HPLC purification gave N-id-broruo-3-(4H-l,2,4~ triaKol-3-yi)thiophen~2~yS)-2-(3}3-difluoro~2~oxoindolin-i-yI)aceiamide (I2mg) as a white solid (m/z454.0, retention of 5.696min m [7]), ‘H-NMR (300MHz, CDC13) S 13.1 (s, 1H), 7,82 (s,lH), 7,70 (dd, J:::7.5, 3 5 Hz, Hi?, 7.50 (1.0.,7=7.9, 1.2Hz, Hi), 6.99 (s, 1H), 6.92 (d, ./=7.902, IK), 4.71 (s, 2H). L87, Synthesis of Ai-(4-feromo-3~(4/f-l52>4-trIazol-3-yl)tfeiophesj~2~yl)-2-(7- (trifluoromethyOqidnoiiu-S-ySJaeetamMe and N~(4-hmmo-3-(4H-1,2,4-$riazoI-3-yI)thloph en~2-yS)-2»(5-(trilltioroin ethyl)q olnoli n-7~yl)acetami de

L 8/. ï, 7Br<mo-S~(irifimmmethyi)quimdine md 5~hromo-7- (iriflmmmeihylhpdnidine [00459] 3-bn>mo~54 trII1uororftethyl)amime (1 17 g, 48,5 mmo?) ws&amp; (aken up in glycerol (7.,? mL) and conc. FT-;SÖ^ (.13 mL), Nitrobenzene (5.0 mL) and FeSÖ-pTHjO (800 mg, 2.88 mmol) were added, and. tne mixture was slowly wanned to 130 °C for 4 h. Isolation lea to a 3:2 mixture oi regioisomers, which was used without further purification sn the subsequent .reaction. HPLC method [4], retention time 2.53 and 2,59 min; MS(fcSi) 278,0 (MH+ sSiBr). L 87,2, tert-Butyl 2-{S~(tri/lmmmeihyi}quhwUn- 7~yi)acetate md tett~hutyl 2-(7-{t^mmmethyijquimdm-S-yijacgtuii: [ÜS46ÖJ The title compounds were prepared from 7-bromo-5-(triilooromethyl)quinoime and 5-brom.o-7-(trifiimromethyl)quinoline (550 mg, 2,0 mmol) using protocol P, Flash chromatography (10-30% ElOAc/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+). LS7J, 2~{S-(Trifluemmeth}i)quimii?i-7-y$}iseeiic acid md 2-(7-(t^is&amp;remetkyi}qum&amp;lm~S-},i)eeeiiceeid [0046!] A mixture of tert-buty! 2-(5~(tn'lluoromethy])quinolin-7-y1)aceiate and tert-butyl 2-(7-(trifiuoromethyl)quinoliti“5-yl)aceiate (400 mg, ] .3 mmol) was dissolved in glacial AcOH (8 mL) and 6 N HC1 (8 mL), The mixture was heated to 70 °C for 1 h, then 80 C tor 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 L29 min; MS(ESI) 256.0 (MHt), A 8 7,4. Ν-(4~Βτομ&amp;~3-(4Η-1^} 4~iriaz(d-3-yi}ihiophen-2~yi}-2-(7-(trijïmwmeihyi)qaimdm-S~yi)iicetamide snd IV~(4-hmmo-3-(47i-lf2,4-Muzoi-3-}d)tM(^phen-2-yi)-2~(5~(iri/ÏM0ti>methyi)qmmim-7~yi}iimiamide [ÖÖ462] 2-(5^tiif:uoir>rx3cJhyl}quir«o!in-7-y|)acetic acid and the mixture of 2-(7-(triflu.OR>ïnethyi>qu3ooiin-5-yï>acetic acid (28 3 mg, 0.11 mmol) and 4-hromo-3-(4H-L2s4-iriazol-3-yl)thiophcÏi-2-amine (23 mg, 0.094 mmol) were treated according to protocol. A. The crude product mixture was purified by HPLC to afford A;~(4-bromo~3- (4//-.1,2f4-triazoi-3-yl)ihiophen“2-ylj-2-t5-(trifIuoromethyi)qumolisi~7-y1}aeetaïmde and A-(4~bromo-j-(4//-.l,2,4-triazoi-3-yi)thioplien-2-yI}-2-(7-(triiluoromethyl)i]uinolin»5- yl)acetamide, LCMS method [13], retention time (mm)lö.löö and 10.386; MS(ES1) 482.0 (Milt, '9Br); lB NMR (300 MHz, CD3OD) δ 9.01 (dd, J- 4.3, 1.6 Hz, 1H), 8.62 (d, /= 8.4 Hz, 1H). 8.41 (s, 1H), 7.98 (s, 1H), 7,70 (dd../- 8.7, 4,3 Hz, 1H), 4.50 (s, 2H). 1.88. Synthesis of /¥-(4-bromo-3-(4£f~l,2^-4riazo!-3-y!)ihlopheM-2-yl>-2-(2·- (triflnoromethyl)qiitaolIn-7~yl)acetamide

L 88, L ten-B&amp;tyi 2~(2~{ïriflmmmeihyi}qmmim~ 7~yi)aceiate [00463] Ϊ he title compound was prepared from 7-bromo-2-(trifluoromethyl)qoinoline (Keller, H. and Schiosser, M. Tetrahedron 1996, 52; 46374644) (45 mg, Ö. 163 mmol) using protocol P and was puri fied by hash chromatography (10-30% EtOAc/hexaaes elution) ίο afforded a brown oil HPLC method [5], retention time 1.875 min; MS(ESI) 312.0 (MH-f). /. 88.2. 242~{Jnfiiwr(mMkyi}qmmim~ 7~yi)aeesic acid [ÖÖ484] tert-Butyl 2~(2-(triflnoromethyl)quinoiin-7-yI)aceiate was dissolved in glacial AcOH (0.8 mL) and 6 N HCI (0.8 mL) and heated to 80 °C for 2 hr. The reaction mixtmc was concentrated in vacuo to afford the crude product, which was used without further purification. HPLC’ method [4], retention time - 1.874 min; MSiESF) 256.1 (MH+). L883, {trifla&amp;romethyl}quinolm~7~yi)(icetsmide [0Ö46S1 The title compound was synthesized via protocol B from 2-(2-(irifluoromethyl)qninolin-7"yl)acetic acid and 4-bronto-3-(4H-1,2,4-tria2ol-3- yi)fhiophen~2~amine, using HOAr instead of HOBt HPLC purification afforded the product as &amp; white solid, HPLC method [7], retention time 8.68 min; MS(ESI) 484.2 (ΙνίΗ+5 81Br);*H NMR (300 MHz, CDjOD) δ 8.76 (d, J------ 9.5 Hz, 1.H), 8.25 (d, J- 9.0 ïfe51H), 7.96 (dd,/= 8.7, 7.3 Hz, 1H), 7.92-7.8,1 (m, 10), 7.11-6.97 (ms 1H), 4,4.5 (s, 2H). 1.89. Synthesis of A-(4-cyano-3-(i7Ll ,254-triazol-3~yI)thlophen~2~yl)-2~(2~i)Xi>- S^-dlhyflro-ijS-naplithysidin-lCl/iJ-yllseetamWe

L89J. TMsmi[3,2-ejf? ,2,S-c]pytimMme- 9<mh<mtink [004661 9"Bromothieno[3,2»e][l?2,4]triazolo[ls5-c]pyrimidine (1.16 g, 4.55 mmol) was dissolved in DMF (23 znL)„ and eopper(I) cyanide (817 mg, 9.1 mmol) was added. This mixture was heated to ISO °C for 23 h, whereupon the reaction mixture was concentrated under 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, CDC!3) S 9.36 (s, 1H), 8.57 (s, 1H), 8.32 (s, IH).

Lb 9,2, 5~Aminii-4^{2ÏI~h2f4~trÏaz(9.~3~vI}fhisipkefie‘-3~cürh/}nitriie 1004671 l‘hieno[3J2-e][i!,2!4]triazolo[I,5-c]pyriimdine-9-carhomirile (251 mg, 1.25 mmol) was dissolved in MeOH (6.2 mL), andAft-melhylethane-l,2-diamine (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 NH-Cl (30 mL) was added, then the aqueous mixture was extracted with 10% iPrGH/CHCU (3x). The organic layers were combined, dried (MgSCL), filtered and concentrated under reduced pressure to give the titled compound as a single peak on LO'MS: method [41, retention time - 0.658 min; MS(ESB 192.0 (MH t). 189J. N~(4-Cyane-B^lH~l£,4-4riaz0l-$~yiXhfopkm-2-yl)-2-(2-tKX0-3,4-dihy>tir0-i,5- nupkthyridm~2{2E}-yi}ueef&amp;mide [0Ö468] ï he title compound wa» svnthesized according to protocol A from 5-ambio-4-(4H-l52s4-triazoi“3-yi)th!ophene~3~oatbonitrile (69 mg, 0,364 mmol) and 2-(2-oxo-3,4-dihydro-l s5-naphthyridin-l(2H)-yl)acetic acid hydrochloride (89 mg, 0.367 mmol). HPLC purification afforded desired product as a white .solid. LCMS method [11], retention time - 6.22 min; MS(ESI) 380.3 (MHr); Ή NMR (300 MHz, C:>;C)D) 6 8.52 (s, 1H), 8.28 (d, J- 5.2 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J= 8.4 Hz, IB), 7.55 (dd, /-8.4, 5.3 Hz, JH), 5.01 (s, 2H), 3.37 (t, J- 7.6 Hz, 2H), 2.99(1,/ = 7.6 Hz, 2H). 1.90, Synthesis of A44-cy*ne-3-(l-niethyl-liSr-lA4-friiisio!-3-ylHhiopheii-2-yl)- 2-(2-0xo-3,4-dIIiydro-l ,5-naphthyridln~ 1 (2^)-yl)aeef amide [804691 N-(4-cyano-3--(lB-ls2,4"triazoi-3-yi)tliiopheii-2-yi)-2-(2~oxo-3,4-dihy dro-1,5-naphthylidm- 1 (2H)~yl jacetamide (180 mg, 0,475 mmol) was dissolved in MeOH/CH2Cl2 (1:1, 4mL total), andTMSCHN2 (Aldrich, 2.0 M in diethyl ether, 8 ml... 16 mmol) was added at rt. 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 trifluoroacetic add salt: method [13], retention time - 7.56 min; MSfESI) 394,2 (MH-t); NMR (300 MHz, CTHOB) 8.41 (s, 1H), 8.25 (d, /- 5.0 Hz, 1H)S 7.87 (s, 1H), 7.72 (d, /= 8.7 Hz, 1H), 7.52-7.42 (m, 1H), 4.98 (&amp;, 2H), 3.97 (s, 3H), 3.403,20 (m, 2H), 2.96 (t, J - 8.3 Hz, 2H), 1.91, Synthesis ofiV-(4-chloro-3-<l-BBethyl-lflr-lA4-trlazoJ-3-yl)thlophen-2- .y!)-2-(2“Oso-3j4~dl!iydr©”l,5-Baphthyridlit-l(2i^-yl}aceiaïn!de

L 91.1. 4~t hiaro-3-lHl- /,2..4-iHsmi~3~yi)tki&amp;pken-2~mmm.

[004701 This compound was made via a sequence analogous to the synthesis of 4-bromo-3-<4H“l,2,4-triazol-3-yl)thioph«5.-2-amme: method [11], retention time - 3.73 mm; MS(ESI) 201,0 {MH+, JS€1); ]1I NMR (300 MHz, DMSO-ife) δ .13.68 (br s, 1H), 8.35 (br s, 1H), 7,14 (br s, 2H), 6.48 (s, 1H). L9L2' N~(4~Oti&amp;m~3~{ÏH~l.i2?4~tri®z!>l-3-yï}thie>pken~2~yi)-2-f2~&amp;x()~3>4-dikydm~ï>5~ b «phthyridin·/ {IHj-vijiiceMimiëe [004711 The titled compound was synthesized from 4-cbloro-3-(4H-1.2,4- triazol-3~yl}t.hiophen~2~armnea.nd2ri2-oxo-3!4-dihydro~I,5-iiaphihyridin-li2H)-yl)acefie acid via protocol A. LCMS method [4], retention time :== 1.035; MS(ESI) 389,1 (MH+, :·5α). dihydm~ls5-?i@phihyHdm-l{2H)~yl)ücetMMid£ [00472] The titled compound was synthesized from N-(4-chloro-3-(TH-l,2,4~ t.riazoi-3~yf)tliiophen-2-yi)~2-(2-oso~3>4-diliydro-l,5~naphlhyridin-1(2H)-yl)aeetamide and TMSCHNj. HPLC purification afforded a white solid. LCMS method [.1.1], retention time = 7.322 min; MS(ESl) 403.2 (MH+, 35C1); NMR (300 MHz, CD3OD) δ 8.43 (s, 1H)S 8.29 (d, ./- 5.3 HzJH), 7.85 (d, /= 8.0 Hz, 1.H), 7.59 (t, /= 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 JV-(4-bromo-3-(U7-l ,2,4AriazohS-yi)thkiphen~2~¥l>2-(quinolin-g-l)aeetamide [004 /3] ί o a mixture of 2-(qume4m-8-yl)aeelk acid (35.6 rag, 0.19 mmol) and 4-bromo- 3-(1//-1,2,4--triazoi-5-yi)thiophcn-2-ainine (27.6 mg, 0,11 mmol) in methylene chloride (1.0 ml.) and tricthylaniine (0.1 rtsL) was added S-chloro-l-methvlpyridinium iodide (46.5 mg, 0.18 mmol) at rt After stirring for 15 min, the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave lV-(5-bromo-3-( 1//-1,2,4-»iazol-5-yl)ihio|»hen~2-yl)-2-(qniiiolin~8-l)acetamide (12 rags, 26%). The desired product was submitted to prep HPLC for Anther purification. Retention time (min) - 3.486, method [7], MS(ESI) 415.9 (M+H), !HNMR (CDCS?) S 12.42 (s, Γ1Ί), 9.09(d,/ = 1.7 Hz, 1H), 8.40 (d, J- 8.5 Hz, 1H), 7.96 (d, J= 8.6 Hz, 1H), 7.89 (d, J — 8,6 Hz, IH), 7.73 (s, IH), 7.71 (d, J~ 8.01-1¾ 1H), 7,66 (d,/= 8.0 Hz, 1H), 7.58 (d, /= 4.5 Hz, 1H), 6.86 (s, 1H), 4.62 (s, 2H). 1.93, Synthesis ©i2-(beBzof<i|thiaaM)i-7-yï>-A,-(4-breiBO-3«(lif'it2,4-tri«2:6i-S- yI}iM©p]tsesï-2-yI)aem!oidde [00474( The title compound was prepared from 2-(benzo[<3f|thia?ol-7-yl)acetic· acid (25,5 mg, 0,13 mmol) and 44momo-3--(l//'I,2!4-tria2:oT5-y])tliiopheiï-2-amiae (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). ]H NMR (CDC!3) δ 12.39 (s, 1H), 9.02 (s, 1H), 8.22, (d, 6.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.54 (s, 1H), 7.55-7.49 (m, 1H), 6,90 (s, 1H), 4,19 (&amp;, 2H). 1.94, Synthesis of A~(4~br«ïmo-3-(l/!T~l?2,4-triMol-5-yl)tliiopheii-2-yl>-2-(7. llsioroqjiinollri“5-yI)acetamsde 194, L ^>r~0~^^&amp;~S~0msr&amp;pkenyi}&amp;.ceiamMe I0047S] To a mixture of tris(dibenzvMdenc^ctone)dipalladi«m (0.20 g, 0.22 mmol), 9,9-dimethyl-4,5-bjs(ntphenylpijosphi:i3e)xantbene (0.13,0.22 mmol) and cesium carbonate (5.0 e, 15.4; mmol) under X?. gas was added acetamide (0.90,14.73 mmol), 1,3-dibromo-5-fluorobenzene (x,8 g, 10.83 mmol) and öioxane (22 mL). The reaction mixture was heated at 80°€ overnight and concentrated under reduced pressure. Purification by flash chromatography (silica, 50:50 ethyl acetatedhexane) gave 7/-(3-bromo~5-fluorophenyl)acctgmide (3.5i g, quantitative). Retention time (min) -·· 1,945, method [4], MS(ES1) 232,0 (M-M-I), 1.94,2. S-Bt&amp;mo-S-fluorosiiUim kydr&amp;eHorMe [004761 To a solution of Af-O-brerao-5-fluoB3phenyl)acetainide (3.5 g, 15.13 mmole) in absolute ethanol (40 ml.,) was added BC1 (50 mL of a 11% aqueous solution), The reaction mixture was stored while refluxing in an oil bath set at 110 C overnight.

Cone hydfoemone acid (o mL) was added and stirred for an additional 5h prior to concentrating under reduce pressure. The resulting 3-bromo-5-fiuoroanilme hydrochloride (2.9 g, 85 % yield) was used in the next reaction without further purification. Retention time (min) = 2.Ö77, method [4], MS(E$I) 192.0 (M+H), h 943. S~Bmmü~ 7-fluorequmeïme md 7-hremo-S-fimreqmmiine 100477} ï o 3-broTno-5'f|yoK)aniline hydrochloride (2,9 g, ] 2.89 mmol) was added glycerol (1.9 mL, 25.99 sranol), nitrobenzene (1.3 ml.), sulforic acid (3.5 mL) and iron (U; swiktc heptahydrate ï 0.23 g, 0.82 nnnoi). Fee reaction mixture w as placed lo an oil bath set at 80 L'C and stirred overnight followed by hasific&amp;tion with 12N NaOH and extraction with dich torosnaihano. Tee organic phase was cuiicctcd, dried (sodium suifate), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 50:50 ethyl acetate/hexane) gave 5>-bioiiJO-?-fiuoioquiiiohne and 7»bromo~5"fl«oroquinolme (1.03 g, 30%) Retention time (min) ~ 1.877 and 1,967, method [4], MS(ESI) 227,9 (M+H), L 94,4. iert~Emyi 2~(7-fiu&amp;mqmmim-5~yï)ace&amp;ite ami tert-Eutyi 2~{$~fïmm)q$dmlm- (§0478] The title compounds were prepared from S-bromo-7-fluoroquinoime and 7-bromo-5-fluoroquiTioiine (1.0 g, 4.356 mmol) using protocol P. Purification by fla«h chromafograpuy (silica, 30: H) ctnyj acetate/hex&amp;ne) gave a mixture of teri-butyl 2-(7-fliioioqumoUao-yi)acct&amp;tc and iert-butyl 2-(5”fluoroquinoim-7-yl)acetatie (0.500 g, 42%) Retention time (min) = 1.559 and 1.725, method [4], MS(ESi) 262.1 (M4H ), /. 94,5. 2~(7~Fiuifmqmm4m~3~}!i)acetie acid (094791 To a solution of ieri-butyl 2~(7~fluGxoquino]in-5-yl}aeeiate and tert-biityi ^-(5-41 uoroquinolm-/-yl)&amp;i;efatc (0,50 g, t.91 mmol s m acetic acid (5 mL) wss added 4M hydrochloric ac:a m I pfrdiaxane (10 mL). The reaction mixture was heated in an oil. bath set at 6(ht under condenser with N? (g) inlet overnight. The mixture was concentrated undei reduced pressure and purified by flash chromatography (silica, 60:40 ethyl acetate,'hexane followed by 20:80 methanobdicbloromethane). Further purification and separation by prep HPLC yielded the single regio-isotner 2-(7-11 non> q u inoiin··5» yl)aeetic acid (0,025g, 6%). Retention time (min) - 0,337, method [4], MS(ESI) 206.1 (M+H). 4,94,6, ^~]f2EErmzai~S~}!i)ihii>phenE-yiE2E?~fktomqiime!m~5^ }4)acetamMe [06480] The title compound was prepared .trom 2-(7~i'htoroqumGliri~5-yl)acetie acid (0.025 g, 0.122 mmol) and 4-br0mo~3~(ii7--I,2,4--mazoi~5~yl)thiophen~2~yl~amine (0,20 g, 0,083 mmol) according ίο protocol A, The desired product was submitted to prep HPLC for further purification. Retention time (min) = 2,33, method [7], MS(ESl) 434.0 (M+H). NMR (CDCI3) S 11.79 (s, IB), 8.94 (d,J-4.0 Hzs !H), 8.54(d, J-8.1 Hz, Hi) 8,38 (s, 1H broad), 7,80 (d10.1 Hz, IH), 7.70 (d, J= 10.1 Hz, 1H>, 7.59-7.55 (m IH), 7.:22 (s, 111), 4.47 (s, 2H), j.9». Synthesis of rill nor omet hy E)qnisoiin~ 1 (2/2)-yl)aceta sn ids

i, 95,1, S-IMtm~4~{2Ii~lf2f3~irmz{}i~J~y!)thwpheHe~3~Ciirb&amp;HkrUe &amp;nd S-fsitw~4~ (2H~lf2)3~ttsuz^i~2~yi)ihwphë?së~3~cii}büitits°iis [00481] A mixture of 4-bromo-5~nitrothiopheiie-3-cafbonitrile (0.53 g, 2.26 mmol), 177-1,2,3-triazole (20 pL, 0,35 mmol) and sodium bicarbonate (O.GSOg, 0.60 mmol) in DMF (0.6 mL) were stirred in an oil bath set at 110JC 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, 30'7Q ethyl acetate/hexane) gave the regio-isomer of each nitro intermediate (0, .138 g and 0.116g, 67% of .1:1 mixture). Retention time (min) = 1,260 and 1,692, method [4], MS(FSJ) 222.0 (M+H). /.95.2. / H-l~yl)thiopheae-3~cufboiitïttUe [00482] 5-ammo-4-if 77-1,2,3driazol-!-yt)thiqphen&amp;-3-carbonitriJe was prepared from imrlro-4-(i.7.7-I,2,3-triazol“l“yl)i.hiopheHe-3~carbo:iitri]e (0.12 a.. 0.52 mmoi) aecordsng to protocol P. Retention time (min; 2,114. method ]«], MSfESB 192.0 (M+H). L953. N-{4~Cym&amp;~3^1H-J>2J-4rmzoi‘i~yi)tkbphe!t~2~yi}-2‘-(2~(ix&amp;~6~ (frifimroMetkyi)quin&amp;iiïi-1 (2Hi~yl}aet>ismide [00483] The tide compound was prepared from 2-(2-oxo-6-(trifluo'romethyf)qumolin~ 1 (2i7)--yl)aeetic acid (0.072 g, 0.27 mmol) and 5-amino-4-(177- 1,2,3 tria^ol- .s -/l)thiophene-j~carbonitriIe (0.025 g, 0.13 mmoi) according to protocol A. ïhc crude product was purified by prep HPLC. LCMS retention time (min) = 5.505, method [7], MS(ESI) 445.1 (M+H). ®H NMR (CDCfi) δ 11,17 (s, IH)} 8.41 (s, 1H), 7.91-7.87 (m, 3H), 7.79 (d,J= 9.0 Hz. IK), 7.67 (s, 1H), 7.48 (d, /= 9.0 Hz, 1H), 5,26 (s, 2H). 1.96. Synthesis ofA'-(4~cyano-3-(2/7-l,2,3-trlazori2-yl)üfinpheH-2-yrri2-(:2~«xii- 6-(tdfIiiorometliyI)q«lBo!Sn-l(2-H)-yl)aceiamid«

2.96.1. 5~AmhH)~4~(2E~lJJ~i?Mz&amp;i~2~pi}$kwpkem~3~earèmifrik (00484] 5 -amino --4- (2 h’~i ,2,3 -triazol-2-y i}ihioph.ene- 3 -c arbomf.r: le was prepared from 5-mtro-4-(^/j'-],2>34riazoj-2~yl){hiophcnc-3-carbt)nitrijc (0.11 g, 0,62 mmole) according to protocol F. Retention time (tnin)::: 1.304, method [41, MS(ESI) 192.1 (M+H). 1.96.2, A - (4- Cyan o~3--/2/I~Ji 2,3-iriazo!~2~yi)thi4>phe^~2~yi)~2~(2~&amp;xo-6~ {ïi'iJIuiyi'ijifi ethyl)quin &amp;Ua~ / (2M) - yi)sc€füfiuds [09485] iV-(4-cyanO“3-(2i/-l,2,3-triazol-2-yl)thiophm-2-yl)-2-(2-oxo-6- (lrifluoromeihyl)quiiiolin-I(2i7)-yl)acetaxnide was prepared from 2-(2-oxo-6-(triflu.oromethyl)qu!i!olin-l(2i/)-yi)acetic acid (0.15 g, 0.56 mmol) and 5-arainö-4-(2/f-1,253-öiazol-2-yl)thiopnene-3-earbonitrüc (0,070 g, 0.37 mmol) according to protocol A. The crude product was purified by prep HFLC. Retention time (min) = 6.5, method [7], MS(ESl) 467.1 (M+Na). JH NMR (CDC13) δ 11,50 fs„ 1 H)v 7.93-7.85 (m, 4H), 7.8'(s 11 *>> 7·64 Oh 1H), 7.60 (d, J = 8.5 Hz, IH), 6.95 (d, .7- 9.7 Hz, 1H), 5.29(s. 2H). 1.97. SynihesïsofiV^-bromo-a-i^-i^^-iïla^l-i-yl^luopfcea-i-yO-a-iJ-oxo-6"{trlf! αο r om€thyl)<| ui nolte-l (2 Ji)-y ï)&amp;eeta mld e

ί06486| A mixture ot 3,4--dibiOmo-2~nitrothiophene (1.5 gs 5.23 mmol), iff-1,2,3-iriazole (0.30 m.L, 5.18 mmol) and potassium bicarbonate (0.54 g, 5,36 mmol) m DA1F (13 ml,) were stirred in an oil bath, set at 1 i(f€ under condenser with. Nj (g) inlet for Ih. file teaedon mixture was quenched with HjO and extracted with ethyl acetate.

The organic phase was collected, dried (sodium sulfate), filtered and concent rated under reduced pressure. Purification by flash chromatography (silica, 30:70 ethyl acetatc/hexane) gave the regio-rscmor nitro mteimediate of interest (0.5 IBg, 3651,).

Renin; ion time (min) =1,950, method [4], MS(ESl) 276.9 (M+H). 1,97.2, ^~8wmf}~3~{2M~lr2,3~irmz^i-2~}ti)ihmpkem~2~amme 1004871 A mixture of 2»(4"broroo-2-nitroibiophen~3-yl)-2/f-l523-tria2K)je (0.59 g, 2.15 mmoi), «ron powder (0,75 g, 13.38 mmol), glacial acetic add (8,4 mL) and HjO (1.,2 niL) was heated ;n an oil bath set at 70°C under condenser wit 6½ (g) inlet for Ih. Purification by (lash chromatography (silica, 40:60 ethyl acetate/hexane) gave 4-bromo- 3-(277-1,2,3-triazol-2-yl)thiQphene-2-amiiie (0.35 g, 66%).Retenticm rime (min) =1.540, method [4], MS(ESI) 246.9 (M+H). L973. W^4-Bn>m0-3^H-lJJ-triaz0t-2-yOtktophen-2-yt)-2-(2-mc0~6-(tnftuoromethyl)quinaiu-l(2H)-yl)eeeUimide (1)0488] The title compound was prepared from 2-(2~oxo-6-(trifluoromethyl)quinolm-l(2fl>yl)acctic add (0.31 g, 1.14 mmol) and 4-bromo-3-(2/7~ ls^i3-iria£ol-2-yl)tlfiopheiie-2-amine (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 [7], MS(ESI) 498.0 (M+H). Ή NMR (CDCh) 5 10.56 (s, IH), 7.90-7.89 (m, 2H), 7.86 (a, IR), 7.83 (d,,/ - 8.9 Hz. 1H), 7.66 id,./ - 8.9 Hz, 1H), 6.97 (&amp;, 1H), 6.92 (d, ./--- 8,9 Hz, 2H), 5.16 (s, 2H), L98. Synthesis of ,2,4-irlagcïl 1>4Sïii>pts®5s~2~ yl)"2~(2-oso~ 1, 3~ n a p Ii thy ri dim1 (2iT)~yI)aeetaiïjMe

n&amp;phthyruim~i {2} f}~yl} a ceu?m ide r#0489j The title compound wa$ prepared from 2-(2-oxo~.1,5-aaphthyridin.-i(2A>yi)acetic acid (0.13 g, 0.62 mmol) and 4..chioio~3-(li?-U,4-ftdazöi-3-yl}diiopfeen-2-amme (0.22 g, 1.12 mmol) according to protocol A. and purified by prep HPLC, Retention time (min) - 1.010, method [4}, MS(ESI) 389.0 (M+Hj. ÏM.2, ^4-CMn^3^1~methyf‘m-l^,4~ti^noi-3-yiMkkphen^2^l)-2‘i2^xo-2fS- ft8phfkyri<Utt-~i{2E}~}i)aceiamide [Ö0490J To a solution ofAr-(4-chloro-3-(liy4,2,4-triazol-3-yl)thiophen-2-yl>-2- (2-oxo-l ,5-naphthyridin-l(2iï)-yl)aceiamide (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). Afiei 2 h the reaction mixture was partitioned between H2O and ethyl acetate. The organic phas»,. was collected, dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product was submitted to prep HPLC for further purification. Retention time (rnin) = 4.407, method [8], MS(ESi) 403,1 (M-HR). lU NMR (CDCI3) 5 12.40 (s, 1H), 8,32 (d, J= 5.1 Hz, 1H), 8.07 (s, 1H), 7,56 (ά, J*= 8 1 Hz lH"s 7,4.] (d, J- 5.1 Hz, 1H), 7.39 (d, J - 5.1 Hz, 1H) 6.81 (s, 1H}; 4,89 fs, 2H), 4.02 (s, 3H), 3.47-3.42 (m, 2H)S 3.03-2.98 (m, 2H).

Synthesis ofJV-(4~broi!to-3~(l.ff~li)2,4"irIazoi-5-yl)thiopheii“2"yI)-2-(8~ fluoroisoqHinolln-5-yl)acetamlti8

/ 99 L S-Bromo-S-miroiso^umoHm 100491] KNOj (S.lg, 5ifcnrnoi) was suspended in sulfuric acid (40mL) and chilled to 0 C. S-bromoisoquinoline (4g. 19.2rnrnol) was added slowly over the course ot aQ minutes. Tlis yellow, heterogeneous solution was brought to pH 8 by slow addition of ammonium hydroxide. Tellow solid'was filtered off and recryst&amp;IHzed from methanol to give 7.5g of 5~bromo-8-nitroisoquinoiine, LCMS showed an tn/z of 253.0/255.0 with a retention time of 1,797mm, method [1], 1.99.2, S~Er&amp;moisoqmn€>lm~8~^mme [00492] A 3-neck flask was charged with 5-bromo-8-miroisoqumoline (4g, 15,8rnmol) and dissolved in MeOH (5GmL). A condenser was affixed and the mixture was heated to 100 °C. Aqueous (20mL) solution of ammonium eliloride (4,12g, 79mmo!) wras added slowly, followed by iron powder (3g, 53.7mmol). The heterogeneous mixture was stirred at 100 CC 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 of 225,0/223.0 with a retention time of 0.767mm, method ]'!]. 1.99.3, S-Bmmo-S-JluormmqmmUm? [ÖÖ493] To a solution of S-antmo-S-bromoisoquinoline in 48% HBF4 (30mL) at Ö VC was slowly added an aqueous (IGmL) solution of NaNO; {172mg, 2.5mmol). The reaction imxtmx- ’was sth icd at Ö t. for !h and was then concentrated under reduced pressure to give a dark residue. The dark residue was heated ίο I SO °C for 16h. The resuiting dark oil was cooled to 23 quenched with ammonium hydroxide and vxtracted with DCM, The organic solution was concentrated and the resulting dark solid was recrysfaihzed from EtOAc/Tlexanes, The desired product (lOOmg) was in the mother hquor while the by-product was filtered away as a solid, LCMS showed an mfz of 228.0/226.0 with a retention tirneof L3i8min. method [1 j. 1 c 99,4, 2~(H-Flaoroisoqu$n(>Uii~S~yï}acsSfe acid [09494] A 30mL reaction vial was flame dried and charged with ««©propylamine (G,67mL. A .8mmol) in toluene (3mL). The solution was chilled to 0 °C before a 1.5M solution of nBuLi (4,8mrnol 3.2mL) was added, Pd/dbati catalyst (184mg, 0.2«mjol) was added, followed by ligand 2,-(d(cyclohcxyipbosphino)-M,N-dimeihyit»phcnyl-2-atntnc (ioOmg, 0.4mmol)s and t~butylaccialc (464mg, 4mmol). After 1 6min, a toluene (3mL) solution of 5-bromo-8-fluoroisoqumoline (200mg, 0,9rnmo!) was added. The inaction was stirred for 16h while warming to 23 °C, 1’hc crude mixture was purified by column chromatography (3% MeOH/DCM) to give teil-butyl 2-(8-öuoroisoqumolin-5~y 1 laeetate (140rng). I.CMS Showed an ns/z of 262.1 with a retention time of 1.469mm, method [1], [09495] To a solution of the above ester <200mg) in TX’M (2rnL) was added formic acid (3mL). The reaction was scaled with a Teflon cap and heater to 50 °C for 16h. Tho solvent was removed and the crude product was used without further purifeation. LCMS showed an m/z of 206.1 with a retention time of 0.437mm, method m. 1,99,5, ^'(4~Mr&amp;m&amp;-3-(2H~l,2i4~lriaz&amp;i-5~yl)ikk}pken~2~}fi)~2~f8~JImr&amp;is&amp;qum{}im~5~ yi}aee$mnide [99496] The title compound was prepared from 2-(8-fluoroisoquino!m-5-yl)acetie acid and 4-910315.0-3-(12/-1,2!4-iriazo1-5"yl)thiophsn-'2"aini0e using protocol B. Retention time (min) = 1,987, method [7], MS(ESI) 432.0 (M+H); NMR (300 MHz, CD3OD) 0 9.74 (s, 1H), 8.66 (d, /= 6.6 Hz. 1H), 8.30 (d, J = 6.1 Hz, 1H), 8,20 (b s, 1H), 8.1 (dd, J ----- 8.24, 5,5 Hz, 1H), 7.67 (dd, /- 9.9, 7,7 Hz, 1H), 7.1 (s, 1H), 4,46 (a, 2H).

Synthesis ofA-i4~hromo-3-(l//-I,2,4-trfeziïi-5-yl)tl3lophen-2“yl)"2-(2-050-6“ (irM1uoromeihoxy)quluolls-l(2Tr)-yI}ncei^mMe

/, 1&amp;&amp;.1 (E)~Ethyï 3-{2~&amp;i}iift&amp;~5~ (tvifUiowMethoxy^pheny^acfylsste [00497] 1 o a mixture of 2-bromo-4-{irifluoromeihoxy)ai5iline (1.00 mmoi), triethylamine (1.5 mmol) and P(s>ioi)3 (0.40 mmol) in DMF (0,5 M) in a glass pressure tube under nitrogen, gas were added ethyl acrylate (1.0 mmol) and palladium acetate (0,20 mmol). The tube was sealed and heated to 120 °C for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time (min) = 2.467, method [1], MS(ESl) 276.1 (M+H). /. i ftik 2, 6~{Tnfim}r&amp;MêiJmxy)qmmdm~2{ïlÏ)~ime [00498] To a stirring mixture of (E)-eihyl 3~(2~ammo-5-(trifluoromethoxy)phenyl)acrylate (2,2 mmol) in 4N HO in dioxane (25 mL) was added concent!ated IIC1 (2 mi.). The resulting mixture was warmed to 100 °C overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCUs solution until pH > ;. 1 he product was extracted with EtOAe and used without further purification. Retention time (min).! .804, method [1 ], MS(ESI) 230.1 (M+H), 1.1&amp;0.3. Methyl 2~{2~&amp;x^6~(tri/hwmmeih(ixy)qmn&amp;im~l{2ff)-yi)^cetaie [00499] Methyl 2-(2~oxo-6-(trifluoromethoxy)quinolirol(2H)-yl)acelaie was prepared from 6~(trifluoromethoxy)qumolin-2(lH)-one according to Protocol K.

Retention time (min) - 2.083, method [1], MS(ESI) 302J (M+H). LIM, 4, 2-{2-Ox&amp;-6~{(2H)~}>ï)acetic add [00508] To a stirring solution of methyl 2~(2"Oxo-6-(tiifi,uoromethoxy)quinoHn-l(2H)-y!)acetate (1.2 mmol) m 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 (MgS04), filtered and concentrated under vacuum to give 2~(2-oxo-6-(trifIuommetboxy)qiiinoim-l(2ï5)-yi)acctic· acid. Retention lime (min) » 1.783, method [1], MS(ESI) 288.1 (M+H). 1.106,5. Ai-(4-Br0mQ-3-{lff~l!2>4-ttmz&amp;i-5-yi)thi0pkefi~2~yl}~2~(2-@xo~6·" (triJïii&amp;r&amp;ffieih&amp;xy)qMti&amp;iffl~l(2Iï)~yi)ecet0imide [00501 1 The title compound was prepared from 2-(2~oxo-6-(trifluorDinethosy)quii5oIix3~{(2H)~yi)aeetic acid (40 mg, 0.14 mmol) and 4-bromo~3~(l //-L2;4ririazoI-5-yl)thiöphen~2~amine (28 mg, 0.11 mmol) according to protocol A. Retention time (min) = 6.06, method [7], MS(ESI) 514.0 (M+H); *H NMR (300 MHz, CDsCl) 3 7.85 (d, ./-9.35 Hz, 1.H), 7,73 (s, 1H), 7.50 (s, 1H), 7.44 - 7.41 (in, 1H), 7.35 - 7.33 (m, 1B), 6.97 (d, J= 9.9 Hz, 1H), 6.95 (s, 1H), 5,31 (s, 2H). 1*101· Synthesis of A-iS-ehioro-d-i 1//-1,254~trsazal"5"yi)ii5io|>Isen-2“y 1)-2-(2-0^0-6- (trIfluoromcthyl)i|tilsoIm-l(2/l)-yl)ai;etamWe

/. /#/, L S~ChJors}thiim(?f5,.2-ej[lf2f4]irmzoki[4f3~<';jpj?rimkiine [00502] 7b a stirring mixture of thieno[3,2-e][l,2,4]iriazoSo[4,3~e]pyrimidme (123 mg, 0.7 mmol) in HOAc (1 mL) was added NCS (200 mg, 1.5 mmol), Fd(OA.ci2 (48 mg, 0.21 mmol). I he reaction uuxmre was stirred at 120 JC overnight. The reaction was neutralized with a saturated NaHCUj solution and extracted with. DCM. This product was purified via an isco column to give 8~ehlorothieoo[352-e][l,2,4]triazolo[4,3»e]pyrimidine as the major product. Retention time (min) - 1.663, method [1], MS(ESI) 211.0 (M+H). 1,161.2, 5-Chieffi~3-(4iI-lf2f4-trmze$-3-y$)thi&amp;phest~2~@tfiffle [005031 To a stirring mixture of 8-e.hlorothieno[3,2-e][l,2,4]triazolo[453-cjpyrimidine (60 mg, 0.285 mmol) in MeOH (10 mL) was added N-methyiethyi 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 washed several rimes with a saturated NFLiCI solution. The organic layer was dried over MgSCh, filtered, and concentrated under reduced pressure to give 5~chloro-3-(4H-!,2s4-triazol.-i-yl)thiophea-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). L S&amp;Ï.3, J%'~{5~cki&amp;re-3-{lïi-l,2,4~tri8g0i-5~yl)iki0pheM~2-yi}~2-(2~8xo~é-(triJJ.mmme(.hyi)qiiimim~l{2H)~yi)aceiamde [tM)504| The title compound was synthesized from 2-{2-oxo-6-ftiifSuore methyl)quinolin-1 (2H)-yl)acetie acid and 5-chloro~3-(4H-1,2,4-triazo 1-3 -yl)thiophen-2-amine according to protocol A, Retention time (min) =16.178, method [7]s MS(ESI) 454.1 }; JH NMR (300 MHz, CD3C1) δ 11.93 (b s, 1H), 8.0 (s, IB), 7.92 - 7.86 (m, 2H), 7.84 - 7.81 (m, 1H), 7.58 (d, J= 8.8 Hz, 1H), 7.17 is, 1H), 6.97 (d, J ------ 9.34 Hz, ΪΗ), 5.30 (s, 2H). 1.102, Synthesis of A'-{4-hroso0-3-(1 H-1,2,4-triarol-S-yl}tlssophen~2-yl>2”{2-oxo-5- (tntluorosB4-th}1)quïsiiolïn“l{2i!f)-yl)acetamsde

1. W2> 1, (ELEtkvï 3~{2~amimï~é~{irifium-ometh}^phemi)iierykiie [00505] The aryl halide (2.1 mmol) and P(PPh),j (0.82 mmol) were dissolved in triethyiamine (3.15 mmol) in a glass pressure tube and nitrogen gas was bubbled through the solution, via a gas dispersion tube for 10 minutes. Ethyl acrylate (2.3 mmol) and palladium acetate (0.41 mmol) were added to the reaction mixture and. the tube was sealed and placed into an oil bath pre-heated to 120 °C for 18 h. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min) = 2.416, method [1], MS(ESI) 260.1 (M+H). LI&amp;2J. 5~jlrifimmmietkyi}qum)iiM-2(lH}~me [00506] To it stirring mixture of (E)-eihyl 3-(2-an\mo"6- (trifluoromethyl)phenyl)acrylate in 4N HC1 in dioxnne (25 mL) was added concentrated H€1 (2 mL), The resulting mixture was wanned to 100 °C overnight. The reaction mixture was cooled to rt and tlien slowly quenched with a cold saturated NaHCC>3 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) = L892, method [1], MS(ESi) 214.0 (M+H). L1Ü2,3, Methyl· 2~(2-@x&amp;~$~firifiM&amp;r(Wielky.!)%mmHm~J(2H}~yl)meMie f00507] Methyl 2-(2-oxo-5-(trifluorOmethyl)quinol3n-l(2H)“yl)acetate was prepared from 5-(trifluoromethoxy)quiiiolii>2(1H)~one (T, Sakamoto, Y. Kendo, H, \ amartaka, Chem. Phar,. Bull., 33,1985,4764) according to protocol K. Retea.ti.on time (min) = 2.02, method [1], MS(ESI) 286.1 (M+H). To a stirring solution of the acetate (0.33 mmol) in THF/watsr (10:1) was added LiOH-H20 (2.33 mmol). The resulting mixture was stirred overnight. The erode product, mixture was slowly acidified with IN HO .solution and then extracted with EtOAc. The organic phase was separated, dried (MgSO-fs, filtered, and concentrated under vacuum to give 2-(2-oxo-5-(trifluorometh.oxy)qnmolin-1 (2H )-y l)aeette acid. Retention time (min) = 1.710, method [1], MS(ESI) 272.1 (M+H). 1,102,4, N-(4-hrom(^3^2H-l&amp;4-4riezitti~'5-yi)iki0pken-2-yl)~2-(2-0xe-$·· {mfUto?WKe?h}ijquiwühi~l(2H}yl}ai'eiamide [00508] The title compound was synthesized from 2~(2-oxo-5-(trifluoromethoxy)qnmi>liö-l(2H)-yl)acetie acid and 4-bromo-3Tli7· 1,2,4-triazol-5~ yi)thiophen~2~amine according to protocol A. Retention time (min) = 5.810, method [7], MSt'ESi) 498.0 (M-Hfi). lH NMR (300 MHz, CD3C1) δ 8.30 - 8.23 (m, 1H), 7.67 (s, 1H), 7.65 - 7.62 (m, i H)„ 7.63 (s, 1H), 7.57 - 7.53 (m, 1H), 7.05 (d, J= 9.9 Hz, 3 H), 6.95 (s, lH),5.37(s,2H). L!03. Synthesis of Ar-(4~bromo~3~(lfl-i?2;4~triaï::öI~5~yi)tliiophen-2-yl>-2~(2-oxo-6-(trlflooronietl5yl)-3,4“dlhydr0qsilnolin-l(2/2)-yI)aeetnTOlde

h 103. L 2~(2~(}χϋ~6~ftriflu&amp;r&amp;methyï)~3,4~iMhydmquimdm~l(2H)~yi)aeetie acid [805091 To a stirring mixture of 2-(2K?xo~6-(trifluoromethyl)qiiinoiin-1 (214)-yl)acetic 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, ping of celite. The plug was washed several titties 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(ESI) 274.1 (M+H). LI 03.2, N-(4-hr{mm~3~($if~l}2}4~trMmI‘5-yi)tkêf!pken~2~yl)~2~{2~$Xi>~6~ {MJiii&amp;rmmth}i)--3,4~dihyiir(iqum&amp;im~2{2fI)~yi)acetamide [00510] The title compound was synthesized from 2-(2~oxo~6~(trifiuoromethyl)“ 3f4-dihydroqiiinolin-l(2ïï)-y1)acctie add and 4-brorao-3-( Iff-1 s2}4-triazol~5-yl)thiophcn-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 (s, 1H), 7.48 (d, /-6.6 Hz, 1H), 7.03 (d, /-9.34, 1H), 6.90 (s, 1H), 4.92 (s, 214), 3.20 - 3.14 (m, 2H), 2.93 -2,90 (m, 2H). 1,104. Synthesis of 4-tria*ol~S~yi)thiophes--2-yl)-2-(6- etbyny!-2~oxoqumo!ln~!(2h!)~yl)aeet&amp;mMe

i. 104.1 Methyi 2~$^xe^({iriMetk$$Uyi)gthynyi)qmmiw-l(2H}~yi)acetaie [0051 Ij Methyl 2-(6-bromo-2-oxoquinolm~l(2H)-yl)acetate (0,67 mmol), Cul (0.67 mmol) and PdöhiPPha^ (Ö.4Ö mmol) were dissolved in trieihylatmne (3 mL) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 5 minutes. Ethynyitrimethylsilane (3.5 mmol) was added to the reaction mixture and the tube was seated and placed into an oil hath pre-heated to 80 °C 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+IT). I.ΙΘ4.2. 2~(6~Ethyiiyi~2~&amp;xg}qmm)im~l(2M)--yi)acetk acid (00512] Methyl 2-(2-oxo-6-((trimeth.ylsilyl)ethynyl)qumolin-1 {2H)-y1)acetaie (0.128 mmol) was subjected to the protocol in Example 1.53.4. except with LiGHTI20 instead ofNaOH. Retention time (mm) =- 1.435, method [1], MS(ESI) 228.1 (MfR). 1JS43. Nd4-Mram(!~3~(ni~J,2!4-mazi>i~S~yi}fhhpheM~2~yi)~2~{6~eiky^}4~2~ ox&amp;qum&amp;Un^l{2H}~yl}aceimmde 1005131 The title compound was synthesized from 2-(&amp;-ethynyl-2-x>xoqumolm-l(2H)-yl)acctic add and and 4-btomo-3-<lii-l,2,4-triazoi-5-yl)thlophen-2-amine according to protocol A. Retention time (min)- 6.563, method [71, MSi bSi) 454.0 (Mi-1-1); ‘H NMR (300 MHz, DMSO-d0)S 8.51 (s, 1H>, 8.07 (d, J-9.3S Hz, 1H), 8.017.97 (m, 1H), 7.68- 7.63 (m, 1H), 7.50 (d, J-8.80 Hz, IB), 7.30 is, iH). 6.80 (d,/-9.9 Hz, 1H), 5.27 (s, 2H), 4.23 (s, 1H). 1.105. Synthesis of A“(4“bs't>mt>"-3~(lE?~l;i2,4-triazol»S-yl)ttik>phen~2-yI)-2~(6~ methyMmldazoi2}1“h]tMazo.l-3"yl)ncetamide [00514] T lie title compound was synthesized from 2-(6-meÜiyliimdazo[2,1 -b]thiazoi-3-yl)aceiie acid and 4~bromo-3-(lH-l52,4-1riazol-5-y])thiophcn~2~amine according to protocol A. Retention time (mm) = 8.520, method [6], MS(ESI) 423.0 (M+H); NMR (300 MHz, CD3C1) δ 8.12 (s, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 7.0 (s, IH), 4.15 (s, 2B), 2.50 (s,3H). L106. Synthesis of N“(4-bromn~3~(Iff~l^,4”triaziiI"5-yl)thlophen~2~yl)-2~ (imldazo ] 1,2-a] pyddin-S-ybaeetamide

λϊθύ.1 teri-Batyl 2~{itnkiüzvi2 J~alpy?ïdm~5~yï)m:emi.e f005151 The title compound was prepared from 5-bromoimidazo[ 152~a]pyrldine (1.0 g) according to protocol P. The erode product mixture was purified via normal phase chromatography to give teit-butyl 2~(imidazo[ld^-8]pyridin~5-yI}aceiate. Mefhsd[lj. MS(ESl) 233.1 Retention time = 0,951 min, LI&amp;6,2, 2~{Imida zo(1,2^jpy^idm~5~yi}aceUc acid [00516] To a stirring mixture of teri-butyi 2-(imidazo[ 1,2-a]pyridm-5-yl)acetaie (200 mg) hi HO Ac (5 mL) was added 6N HO (5 niL), The reaction mixture was warmed to 80 C for 2 h, 1 he 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+H], Retention .time::: 0.303 min, LW63, N^4-Bromo-3-(lff-l,2t4~tn(iwl-S-$)tkwpkeii~2-yi)-2-(iMidez0fl,2~iijpyritlm-S~yi)metmmde [00517] N-(4-bromo-3 -(1 H-1,2,4 -triazol-5 -yl)thiopfien ~2 -yl)-2--(imidazo [ 1,2-a]pyridin-5-yi)aeetumide was synthesized from 2^iroidaz»[i ,2-a]pyridia-5-yl)acetic acid and 4~brorno~3~(liAlJ2s44riazoi“5~yl)thioplien-2“aoiine according to protocol A. Retention time (min) - 7.958, method [6], MS(ESi) 403.0 (M+H); 3H NMR (300 MHz, CD:?OD) δ 8.46 (b s. Iff), 8.35 (d, J-2,2 Hz, 1H), 8.12 (d, J = 2,2 Hz, 1H), 8.08 - 7.96 (m, 2H), 7.58 <d, J = 7.2 Hz, IB), 7.16 <S> 1H), 4.64 (s, 2H). 1.107. Synthesis of jY-(4-!>romo-3-(IH-l,2,4-triazol~S~yl)tIiiophen-2-yl>2-(7~fluore-· 2-oxi>-6-{trM1uoronrethyl)qninolin~l(2if).yl)a£datnid£

1,1 &amp;7,L 2~Brmw~5~ftmroA~{trifiuQr&amp;M&amp;tkyl)&amp;mime [0051$] To a s< faring inixture of 3-fluoro-4-{iriili5oromeihyl>arii?me (1.5 g) in DCM (\ 2 ml) at room, temperature was added dropwise a solution of MBS (1.5 g) in DC'M (24 mL) over 15 min. The reaction mixture was stirred at, rt for 1.5 fa. The product mixture was concentrated under reduced pressure to one half of its original volumn. The white solid was filtered off and the crude product mixture was further purified via. column chromatography. Retention time (min) - 2.49Ö, method [1], MS(ESI) 257.9 (M+H). 1.137,2, (E)~Ethy( 3~(2~amim~4-fiu(im~5~(tnflu&amp;mmetkv!)pkest}l)acr}>iaie [00519] 2~Bromo-5~fluoro-4-(trifluoromethyl)anilme (0.97 mmol) and F(o~toi)i (0.40 mmol) were dissolved in trieiliylamme (2.0 ml.) in a glass pressure tube and nitrogen gas was bubbled through the solution via a gas dispersion tube for 10 minutes. Ethyl acrylate (.1.0 mmol) and palladium acetate (0.20 mmol) were added to the reaction mixture and the tube was sealed and placed into an oil bath pre-heated to 85 °C for 18 fa. The resulting solution was concentrated under vacuum and purified via an isco column. Retention time (min) ::: 2.504, method [1]s MS(ESI) 278.0 (M+H), iJ07.il 7~Fiu&amp;m~ê~{iriftmwmeihyi)qmmfUn~2(iB)~one [005201 To a stirring mixture of (E)-ethyl 3-(2-amino~4-f!-uoro-5·-(trifluoT»mcthyl)pfaenyl)acrylate in. 4N HC1 in dioxane (.lOmL) was added concentrated HC1 (2 mL). The resulting mixture was warmed to 100 °C overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCCh solution until pH > 7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time (min) = 1.887, method [1], MS(ESl) 232.0 (M+H). L1&amp;7A. Methyl 2-{?-fiuom-2~ox&amp;~6JMfttmrimiiihyl}qiHmim~l{2H}hy$)&amp;cM®te [00521] The title compound was prepared from 7-fluoro-6-(iniluoromethyl)quinolin~2( IH)-one (T. Sakamoto, Y. Kondo, H» Yamanaka, Chem.

Phar, Bull., Ah j 985, 4764) according to protocol K. Retention time- (min) = 2.,224, method [1], MS(ES.T) 304.0 (M+H). 1.137,5 2~(7~Fimm)~2~oxo~6~{irifimwmmthyi)qmmim~l(2H}~vi)&amp;cetk acid [00522] To a stirrmg solution of mediy: n'cthyi 2--(- i\\i o ro ~ 2 ~oxo- π -. (trif!uoromethyl)quinolin-1(2H)-y!)acetate (0.59 mmol) in IHF/waier (5:1) was added LiOH.HjO ¢ 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 (MgSCri). filtered, and concentrated under vacuum to give 2»(7-fluoro-2~oxo-6-(trifluoromethyI)quinolin-l(2H)~yi)acetic add. Retention time (min) - 1.90, method [1], MS(EST> 290.1 (M+H). 1,107.6 N^4-BmM0~3~(lH~lf2t4~tri(^i-5-yf)thwpheit-2-yi)-2-(7^mre~2~exo-6-· f005231 N-(4-broniO“0-(lH- U2s4-tria2i>l--5--y3)thiophen“2“yr)-2”i7~i'luoro~2-oxo·- 6-(trifluoromethyI)quinoIin-l(2Ii)-yl)acetamide was synthesized fiom 2-{7-fluoT©~2-oxo- 6-(trifluommet3tyl)qinnolin-l (2H)~yl)acctic add and 4~bromo-3-(17/-l,2,4“iriazo!-5-yl)thk>phen-2-amine according to protocol A. Retention time (min) == 6,276, method [7], MS (ESI) 516.0 (M+H); NMR (300 MHz, DMSCMs) δ 8.54 (b 8, 1H), 8.37 (d, J = B.24 Hz, 1H), 8.20 (d,/ = 9,34 Hz, 1H), 7.89 (d, J = 13.72 Hz, ί H), 7.31 (s, 1H), 6,81 (d, ,/-9.34 Hz, 1H), 5.28 (s, 2H). 1,108. Synthesis of A~(4~bromo-3»(liT-l?2,4~tsiazol~5"yI)thtophen”2~yl)-2.(6" fln§roisöiiolnoiin-5-yl)acêtamicle

1.108,1 1005241 To a stirring mixture of 6-fluoroisoqmnoime »a H2Sf).3 (5 mL) at 0 °C was added solid NBS (1.5 £,Q) slowly over 5 mm. The reaction mixture was reacted at 0 °C for 1 h. To this reaction mixture was added NBS (0.5 EQ). The cold hath was then removed, The reaction mixture was reacted until all the starting material was consumed.

To this reaction mixture was neutralized with a cold solution ofNaOH i5N) until the pH of this mixture >10. The white solid was filtered off and dissolved in DCM and washed with a solution ofNaOH (IN). The organic layer was dried over MgSO.t, filtered, and conconnuuïd us ids.' rcütsccü pressure, Ï no cf lulu product was purified vis s column to give 5-brornO"6"fluoroi.soqumo]ine. Retention time (min) = 2.BIO. method |3i. 'MS; ESI) 226.0 (M+H). L1 §8.2. te.ri-Butyï 2-(6~flwaroisoqumoim~S~yi)iicetate [00525J The title compound was prepared from S-bromo-ó-fluoroisoquinoline (290 mg) using protocol F. I he crude product was purified via normal phase chromatography to gi ve tort-butyl 2-(6-fluoroisoqumolin-5-yl)acetate, Met!iod[l ]s MS(ESI) 262.1 [ΜΊ-Η], Retention time:::: 1,503 min. L1@8.3 2-((i-FlmwmmqmmMn-S-yl^aceüc, acid [005261 To a stirring mixture tert-butyl 2-<6-fluoix)isoquinoh'n~5>y1)acetate (150 mg) in HOAc (5 ml.) was added 6.N HC1 (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)'1 ]s MS(ESI) 206.1 [M+H], Retention time ~ 0,2-13 min. LI88,4, 2¥-(d~Er&amp;M8-3-(lH-2,2,4drmz8$-5-yi)fki&amp;pkë}i~2-yi!)-2-{6-:fïïw?aimqum&amp;lm-5~ yijecetamide {Ö0527J N-(4-bromo-3“(lH~l,2,4-triazol-5-y!)thiophen-2-yl)~2-(6-fluoroisoquinoiin-5~yl)acetamide was prepared from 2-(6-fluon>isoquinolin-5-yl)acetic acid and 4-bramo~3-( 1 ! ,2,4-tria2JoI-5-yl)thiophen-2-amine according to protocol A.

Retention time (min) - 1.901, method [7], MS(ES1) 432,0 (M+H); !H NMR (300 MHz, DMSO-de) , 11.96 (b s, 1H), 9.58 (s, 1H), 8.64 (d, /- 6.05 Hz, 1H), 8.46 - 8,4.1 (m, 1H), 8.24 (d, /- 6.05 Hz, 1H), 7.84 (i, /- 9.34 Hz, 1H), 7.27 (s, 1H), 4.46 (s, 2H).

Example 2

Thiophene Thiazide Analogs 2.1« Synthesis oi 2-(1 soq n1nQiin-5-yi>-<V«(2''{4~m£!l.Uy1tya2x>1-«2«>yi)1hi<)phciHi'-3- yilaeefamRic (42)

2,.L L 4~Methyi-2~(3~mir&amp;thi&amp;pheH~2-yi)thmz&amp;le [Ö0S28] 4-Methyl~2~(3-iiiirothiopheH"2-yl)thiazole was prepared from 2-ch3oro-3-mfrothiophene (219 mg, 1,34 mmol) aHd4-methyl-2-(tributyLslamiyi)thiazole (520 mg, 1.34 mmol) according to protocol E. Retention time (min) = 2.462, method [1], MS(EST) 227,0 (M+H), 2. L 2, 2-(4-M.ethylihiaz0i~2-yl)ikhpke.n~2~mmne [065291 2-(4-Methylthiazol-2~yi)thiopheii-3-amine was prepared from 4-methyl"2-(3-nitrothiopheïi~2-yï)thiazoie (69 mg, 0.3Ö5 mmol) according to protocol F. Retention time (min) = 1.828, method [1], MS(ESI) 197.0 (M+H). 2.2.3, 2-(2söquimlm-S-yi)-N-(2-(4-meth^ihimsl-2-yl)thiepkeii~3~yï)(icetamide :00539] 2~(isoquinolin-5"yI)~A'"(2-(4~methyithiazol"2“yi)thiophen-3-yi)acetamide was prepared from 2-(isoquinolin-5-yl)acetic acid (63 mg, 0.341 mmol) and 2“(4-methyIthiazol~2-y1)thiophen-3-am:me (67 mg, 0.34! mmol) according to protocol A. Retention time (min) - 3.130, method [7], MS(ESI) 366.0 (M+H); !H NMR (300 MHz, CDCla) δ i 1.55 (s, IH), 9.64 (s, 1H), 8.60 (d,J=6.8 Hz, 1H), 8.39 (d, ./-6.6 Hz, Hi), 8.20 (d, J- 8.4 Hz, IH), 8.05-8.08 (m, 2H), 7.88-7.91 (m, IH), 7.24 (d, ./-5,5 Hz, IH), 6.74 (s, IH), 4.3! (s, 2H), 2,45 (s, 3H), 2,2. Sy ο I hesis of 2-(isoq u in oiIn-5-yl)~A;~{2-(f hiassi>l~4~y3)l.hiophen-3"yl)acetan}ld e (43)

2,2,1, 4-(3-Niir&amp;thi&amp;phen~2~yl)ihi&amp;zitk! [ÖÜ531J 4~(3-NitTOtMophen~2~yl)tMazo]e was prepared, from 4-(tributyistanayi)thia2»Ie (0.5] g, 1.31 mmol.) and 2-chloro-3-nitro1hiophmc (0.21 g, ] .31 mmol) according ίο protocol E. Retention time (min) = 2,013, method [1 js MS(£SI) 212.9 (M+H). 2.2 2. 2~{Thm^i~4~yi}thk^phm~3~amim 1005321 2-( Thi aaol-4“yl)Üiiophen-3-armne was prepared from 4--(3-- niirothiophen -2--yl)thia2X>lc (151 mg, 0,838 mmol)) according ίο protocol F RueaLon time (min) ;;; Ö.544, method [1], MS(ESij 183.0 (M+H), 2.2.3, 2~(lmq&amp;in&amp;!i%~5~yl}"N-*(2"(thi8z&amp;l-4-yl}ihi&amp;phen~3~}il}acetamMe [0S533] 2^Isoquiiioliii-5-yi)-iV-{2~(thia2»l-4-yl)thiophen-3-yl)acetamide was prepared from 2-(isoqumolin.-5>yl)acetic add (120 mg, 0.64] mmol) and 2-(thiazol-4-yl)thiophen-3-amins (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, CDC13) 8 10.99 (s, Hi), 9,63 (s, 1H), 8.59 (d, J- 5.9 Hz, 1H), 8.43 (d,.Z === 1.6 Hz, IE), 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 (a, 2H). 2.3, Synthesis of 2-f2-Oxo--3,4--dihydro~l,6~naplrths;ddm'-](2//)~yi)"A'--(3~' (tMnzölM~yl)tMöphen-3-yJ)&amp;eetamMe (44)

Èiëthyl 2~(2~üx&amp;~3f4~dihydt(>-l}é~fUiphthy!'i-di'ii-i{2M)~yi)ücs!'f£it/i [00534] The title compound was prepared from 3,4-dihydro-1 .6-naphihyridia- 2{ïff)-one (0.84 g, 5,67 mmol) using protocol K to give methyl 2-(2~oxo-3,4-dihydro-l,6-naphthyridiï3-l(2i0-yl)acetate. Retention time (min) ==· 0341, method [1], MS(ESI) 22 LQ (M+H), 23,2, 2-(2~Ox0-3i4-éikyifao~l)(i~H<q>hthyridin~2Qllhyi)iiCütk utié f00535] Aqueous tN HCi f2 mL) was added to a solution of methyl 2"{2-oxo-3,4-dihydiX)-I„O-napfithyridin-l(2//j-y[)acelatc (1.24 g, 5.67 mmol) in acetic acid (5 tnL) and the resulting mixture was heated to 60 CC for 4 h. The solution was concentrated under vacuum to give 2-{2-Oxo-3,4-dihydiO-l ,6-naphthyridin·· 1 (2//)-yl)acetic acid Retenn'ofl lime (min) === 0.275, method [1], MS(ESl) 207.0 (M+H), 2,3.3- 2~{2~(}xo~3,4~dihj,dt&amp;~2fé~iiiiphthytiéifi~l{2M}~yl}~N~{2~{iki(sz&amp;i~4~ji)ihiaphfffi~ 3-yi)acetamiée [00536] The title compound was prepared from 2~{2-oxo-3,4-dihydro-1,6-naphthyridin-1 (2if)-yl)acetic acid (65 mg, 0.32 mmol) and 2-(lhiazol-4~yI)tbiophen-3-amine (57 mg, 0.32 mmol) according to protocol A. Retention time (min) = 1.471, method [7], MS(ESI) 371.1 (M+H); lH NMR (300 MHz, CDC13) 8 11.48 (s, fH), 8.87 (d, /- 1.8 Hz, 1H), 8.48-8.76 (m, 1H), 7.99 (d, J= 5.4 Hz, 1H), 7.37 (d,J= 1.8 Hz, 1H), 7.27-2.28 (m, 2B), 7.23 (d,J- 5,4 Hz, 1H), 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~dihydi"oqumoIlu~l(2S>yl)-Ar-(2-(thiaz@I-4” ylllhiop hen-3-v l)a eetam sde (45) [005371 The title compound was prepared from 2-(2-oxo-3s4-dihvdroquinoiin-l(2H}-yl)acetic acid (88 mg, 0.43 mmol) and 2-(1hiazol-4-yi)thiophen-3-arain.c 179 mg, 0.43 mmol) according to protocol A. Retention time (mm) = 5.703, method 17], MS(EST) 370.0 (M+H); lH NMR (300 MHz, COO:!) 8 f 1.2 (s, 1H), 8.49 9d, ./= 2.7 Hz, 1H), 8.13 (d,/= 5.4 Hz, m, 7.19-7.25 (in, 4H), 7.02-7.08 (to, 2H), 4.81 (s, 2H), 3.05-3.09 (m, 2H), 3,2.85-2.89 (m, 2H). 2,5, Synthesis fti 2“(iSoqi3inolirï-5--y!)-Af-(2-{2’'meUïOiLnl.ïiSïöl-4-tvi)itïiOs>hen~3- yï)tseetamMe (46)

2,5Λ. 2-Meth&amp;xy~4-{3~mirothmphm~2~yi)iM(tz&amp;ie [09538j 2"Methoxy-4"(3-ixiüt>ihiophen-2-yl)thi^ole was prepared from 2-meihoxy-4-(tnbutyistaimyl)lHazole (1,0 g, 2,47 mmol) and 2~ch!oro~3"iirl'rothiopiiene (0.404 g, 2.47 mmol) according to protocol E, Retention time (min) = 2.516, method [1], MS(ESI) 242,9 (M+H), 2, .12. 2-{2~MeShexythmz0i-4-yl}thi&amp;phen~S~smme [ÖÖ539J 2-(2"Methxsxythiazöl~4-yI)thiophen-3-at!iiiie was prepared from 2-methoxy-4-(3mitrotinopheii~2~yl)lhiazole (209 mg, 0.862 mmol) according to protocol F. Retention time (min) = 1,17, method [1 ], MS(ESi) 213.0 (M+H). 2.5. A %-{$$oquffi8Un~5~yi$~N~{2~{2-meihoxytki&amp;z0i-4-yi)thiophen-$-yi)e€et&amp;mide [00540] The title compound was prepared from 2-(isoqumolm~5~yl)acetic acid (72 mg, 0.36 mmoi) and 2-(2-mcthoxythiaz:öl-4~yl)ihiophcii-3-amme (78 mg, 0.36 mmol) according to protocol A, Retention time (min) = 3.237, method [7], MS(ESI) 382,0 (M+H); NMR (300 MHz, CDC13) 8 10.99 (s, 1H), 9.69 (s, HI), 8.60 (d, /= 6.5 Hz, 1H), 8,39 (d, /= 6.5 Hz, IB), 8.23 (d, J= 8,4 Hz, IB), 8.06 (d, /= 7,3 Hz, 1H), 7.96 (d, / = 5.5 Hz, 1H), 7.89 (dd,/ = 8.4, 7.3,1H), 7.15 (d,J = 5.5, 1H), 6.70 (s, 1H), 4.26(¾ 2H), 4.17 (s, 3H). 2.6. Synthesis of A;~(2~(2»chtorotliiiizoR4-yi)thiophen-3-yI)-2-(isöqnlnolm-5" yl)acetamide (47)

2.6.1, 2~€hUm>~4-0~mtmiki0phen~2~yï)thMz&amp;ie 100S41J A solution of 2-methoxy-4-{3-mtotMophen-2-yi)ihiazole (403 mg, 1.66 mmol) in POCi3 (2 niL) was heated at 60 °C for 1 h then to 100 °C for a farther 2 h. The resulting solution was cooled to room temperature and diluted with cold 020 then saturated aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and the combined organic phases were dried (jMa?SO.:}, filtered and concentrated under vacuum to give 2-eMorG-4-(3-mtrothiopkcn~2~yi)tinazolc. Retention virnc (min) = 2.550, method [1], MS(ESI) 246.9 (M+H). 2.6.2, 2-(2~CM&amp;F&amp;thmz&amp;i-4-yl)ihi&amp;phen~3~amme f085421 2*(2~Ch!orothiazol-4-yl)thiophen-3-amine was prepared from 2-chloro-4~(3-iiitrothiophen~2~yl)thiazole (307 mg, 1.24 mmol) according to protocol F, Retention time (min) - i 579. method [1], MS(ESI) 216.9 (M+H). 2.6.3, N~(2-(2-eki&amp;rothmzol~4-yl)fki0pkm~3-yl)-2-(i$GqMMlin~5~yl)ucetamide [00543] The title compound was prepared from 2~(isoqumolm-5-yl)acetic acid (218 mg, 1.11 mmol) and 2~(2-chiorothiazoi-4-yl)thiophen-3~axniiie (241 mg, 1.11 mmol) according to protocol A. Retention time (min) = 3.049, method [7], MS(ESI) 385.89 (M+H); 3H NMR (300 MHz, CD,OD) δ 9.54 <s, 1H), 8.56 (d, J - 6.4 Hz, 1H), 8.39 (d, J = 6.4 Hz, IB), 8.31 id, ./-8.1 Hz, Hi), 8.16 (d,J= 6.8 Hz, IB)., 7.94 idd, 8.1, 7.2 Hz. 1H), 7,73 (d,/- 3.5 Hz, IB), 7.45 (s, 1H), 7.37 (d, J2* 5.5 .1¾ 1H), 4.39 (s, 2H). 2.7. Synthesis of 2~(lsoqulsroIIn-5-yI)~N~(2--(ihiazoF2.yf)th!ophen-3~Y!)acetaotlile (48)

2.7.1, 2~{Tkïawl~2~yl)tkmphen-$~®mine [00544] 2-{3-NitroÖjiophen~2-y])thiazo!e was synthesized from 2-ch!oro-3-nitrothiophene according to protocol E except that 2-(tributyistanny])i1iiazole was used. Method] 1], MS(ESI) 212.9 [M+H]f Retendon time === 2,163 mirs. 2-{Thia2ol-2-yl)ihiophen-3~amifie was synthesized from 2'(3-nitrothiop].ict5~2~yi)thiazok' according to protocol F. Method] 1 j, MS(ESl) 183 [M+Hj, Retention time = 1.718 min. 2.7.2, 2~{imquimMn~S~}4)~N~(2~(iMazoi~2~yl)ihk)phen~i~yï)acetamiAe [09545] [0004] The title compound was prepared from 2-(thiazol-2- yl)thiophen~3-amine and 2-(isoquinolin-5-yl)acetic acid according to protocol A. Preparative HPLC gave 2-(isoquinolin~5 -y 1} -N-(2- (thi azol-2 -yl)thiophen-3-y l)aeetami de. Mcthod[7], MS(ESl) 352,1 [M+H], Retention time = 2.59 min; *H-NMR (300 MHz, CDCIa) δ .11.32 (s, 1H), 8.26 (d, / = 8.2 Hz, 1H), 8.10 - 8,09 (m, 1H), 8.07 (s, !H), 7.94 (t, /= 7.7 Hz. ί H), 7.35 (d, /- 3.3 Hz, 1H), 7.31 - 7,24 (m, 4H), 7.10 (d,/= 3.3 Hz, 1H), 4,33 (s. 2Hi. 2-8. Synthesis of 2--(isoqnincIin-5-y!)~A;/2~(5--nmtliyRht32iil-2-y!}thlophen-3-yl)a«tiamide (49)

2.8, /. 2~(5~Metky&amp;M&amp;%&amp;&amp;-2-yi)thiephets-3-iimim [110546] This amine was prepared from 2-chioro-3~ititroihiophene using protocols E and F. Method];], MS(ESI) 227.Ö IM Hi], Retention time = 2.538 min, 2.8.2, 2~iheqtimeUn~5»yi}"N~{2"(5-methvi{kv2Zi8~2~yi}fkhmhett~3~)ikieetmnide Ï0ÖS47} The title compound was prepared from 2~fiNoquinolin-5-yl)acetJC add and 2-(5-methyithsa2Ol-2-y!)th3opben-3-anune using Protocol A. Method}?}. MSfESX) 366.0 [M+HJ, Retention time =·· 3.157 min; 'H-NMR (3ÖÖ MHz, CDC13) S 11.24 (s, 1H), 9.67 (s, IH), 8.57 (d, J- 6.6 Hz, IH), 8,30 id, J-6.6 Bz, 1Π), 8.26 (d, J= 8.24 Hr, Ills, 8.08 - 8.04 (m, 2H), 7.96 - 7.91 (m, 1H), 7,20 (d,J- 5,5 Hz, !H). 6,97 (d,./= 1.1 Hz, IH), 4.31 (s. 2H), 2.43 (d, J - 1.1 Hz, 3H). 2.9, Synthesis of 2-(4-<3-(piperidfn-l-yi)proposy)phenyl)~JV-<2-(tlilfizeM- yl}thiopheK-3-yl)acet.asï1deC50)

2.9.1. 2~{Thmgifi-4~yi)thwphe^~3-a'mme [00548} This amine was prepared from 2-chl oro~3~nitrotlriopheoe using Protocols E and F except that 4-(tributylstarmyd)tMazole was used. Meibod[.1 ], MS(ESI) 183.0 [M+Hj, Retention time = 0.518 min. 2.9.2, 2~(4~(3-(Piperidin-2-yl)pr0p&amp;xy)pkmyl}-N-(2-{thiitg0l~4-yi)tki0pk£n-3-yi)aceismiée |1M1549| The title compound was prepared from 2~(thiazol~4-yI)thiophen-3-an^ute and 2~M-{3~{p:pendm-4 yP3propoxy)phenyl)acetic acid using protocol X, Mothod[7], MS(F.Sl) 442.1 Retention time = 3.586 min; !H~NMR (300 MHz, CDCh) δ 10.8 (s, 3 H). 8.54 8,53 (m, IH), 8.13 - 8.11 (m, 1H), 7.33 7.30 (m, 2H), 7.25 - 7.17 (m, 2H), 6.90 (d, J- 8.8 Hzs 2H), 4.08 (t, J = 4.95 Hz, 2H), 3.74 (m, 3H), 3.28 -- 3.21 <m, 2H), 2.72 - 2.61 (m, 2H), 2.40 - 2.20 (m, 6FI), 2.05 - 1.91 (m, 3H). 2.10. Synthesis of A^-(femzo[d]thiazu!~2~yJ)~4-m£tljyMidophen-2~yI)~2-· ösö quin oh n~5~yl)acetis nude (51) [00550] The title compound was prepared from 2-4isoqiiinolin-5-yl)acetic acid and 3“(hcn/.ojd]thiazoi-2-yl)-4-n),ethylthiophen-2-amine using Protocol B except that triethylamine was also added. MS(ES1) 416.0 [M+H], Retention time = 2,86 min, JH-NMR (300 MHz, CDC1S) δ 9,40 (s, 1H), 8,57 (d, /= 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, IH% 7.55 - 7.51 (m, Hi), 7.42 -- 7,37 (m, 1.H), 6.56 (s, 1H), 4,39 ($, 2H), 2,56 (s, 3H). 2.11, Synthesis of j¥»(4-cyano-3~(thlazol~2~¥l)thiophea“2~yl)-2-{2-nxo~6~ (irïfiöoromethyl)qiiïnölliï-l(2/J)-yï)aeetamfd.e

2JIJ. (E)~Ethyi $-(2-m»ïne-$^triftu0romeikyl)pkenyl)aiïryl(ite [00551] To a mixture of 2-bromo-4-(ifjflaoromcthyl}annïnc (5g, 20.83 mmol), trieffayl amine (4.4 mL, 31.2 mmol) and P(o~tol}.; i'2.5 g, 8.33 mmol) 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 mmol). The tube was sealed and heated to 3 20 °C for 18 h. The resulting solution was concentrated under vacuum and purified by column chromatography. Retention time!min) - 2.532, method [I], MS(ESi) 260.1 (M-rHi. 2.12,2, 6~{Triflimmmeihyi)quinoUM~2{12S)~sme [00552] To a stirring mixture of (EVelbyl 3-(2-amiao-5- (trifluoromethyl)pheuyl)acrylate (4g, 15,4 mmol) in 4N HC1 in dioxane (20 mL) was added concentrated HC1 (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 MallCCL 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 titne(mm) - 1.849, method [1], MS(ESï) 214.0 (M+H). 2.1.0. Ethyl 2-(2-&amp;X4>-6-(inflmr&amp;meihyl)qmmiin-10H)~yl)sceiete [60553] To a stirring mixture of the above crude 6-{trifluoromethyl)quinolin-2(lH)-one in DMF/THF (0,5 M, 1:1) at rt was added NaH portionwise (1,2 g, 30.88 mmolj over 15 min. The reaction mixture was stirred at rt for additional 20 min before a solution ofbromo methyl acetate (4.73 g, 30.88 mmol) in THF was added. The resulting mixture was stirred at rt until the starting material was consumed. The mixture was slowly quenched with brine and extracted with EtOAc. The crude product mixture was purified by column chromatography (3.6 g„ 82% in two steps). Retention time (min) - 2,042, method [1], MS(ESl) 286.1 (Μ · H). 2,1L 4, 2~{2~Qxif~6~{Mfluoromethyl)quimiin~4{2H)-yi)acetie add [ÖÖ5S4] To a stirring solution of methyl 2~(2~oxo*6-(trifluoromcthyi)qninolin~ 1 (2H)-yl)acetate (4,8 g, 16.8 mmol) in THF/water (25 mL/5 mL, 5:1) was added LiOH-HhG (3,52 g, 84,2 mmol). The resulting mixture was stirred overnight, The crude mixture was slowly acidified with IN HC1 and then extracted with EtOAc. The organic phase was dried (MgSO<), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethyl)qtnaolin-1 (2H)-y l)acetie acid (4.,3 g). Retention time (min) = 3.005.. method [7], MS(ESI) 272.1 (M+H). 2,1 L 5, S~Nhr0~4~(thiiigei-2~yi)thwpkeiig-3‘-csrbtmii!riie [0Θ5551 A mixture of 4-bmmo-5"nitrathiophene-3--carbonitrile (0.5g, 2,1 mmol), 2'(tributylsta«myl)thiazole (1.2g, 3,2mmol)s dioxane (3.5mL)> and tetraktsitriphenylphosphine)pailadium(O) (0.23g, 0.21rnmol) was heated by microwave to 130 °C for 30 mm 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-Qitno-4<thiazoi~2-yl)thiopheQe-3-carboaitiile (IBikng) as an oil. LCMS of this material revealed an m/z of 238.0 with a retention time of 1.807mm method [1], 2, l L éi S~Amm(i~4~{ihiuzoi~2~yl)thmpkene--3~CiitbonitriL· [90556] A 30mL reaction via! was charged with 5-nitro~4-(thj<jzo!-2-y S Ithiopb.ene· 3 -co t’bon;; ri lc (.! 80mg, 0.7C«nmoi) and AeOH (3mL). A spatula tip of iron dust was added and the reaction vial was heated to 60 °C for 20min. The reaction mixture was cooled to 23 °C and partitioned between methylene chloride and sodium bicarbonate solution. The organic solution was dried over sodium sulfate and concentrated to give 5-mmo-4^tMazo)4-yi)thiophcne-3-carbonitriJe as a red solid. LCMS showed an m/z of 208.0 with a retention time of 2.016mm using method [1], 2» IL λ N-f4-Cym&amp;~3~($hmz&amp;i~2~yi)fki&amp;pkgn~2~yi)~2~(2~®xü-ë-{trifimmmeihyl)qiimt}Hn~ï{2H}-yl)ace$emide [0055?! [0005| The title compound was prepared from 5-amino~4~(thiazoi- 2-yl)thiophene-3-carhonitrile (271 mg, lmmol) and 2-(2~oxo~6~(trifluoromethyl)quinoIm-l(2H)-yl)acetic add (0.76mmol) according to protocol A. The crude product was purified by column chromatography (35%EtOAc/hcxancs) and HPLC to give N-(4-cyano-3-{thiazol~2-yl)thiophen-2-yi)-2-(2~oxo-6-(trifluorc>methyl)quinolin-l{2H)-yl)acetamide (24.mg) as a white solid with an m/z of 461.1 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 (4./=3.4¾ 1H), 7.46 (4/=8.8¾ 1H), 7.31 (d, /-3.3Hz, IB), 7.00 (4/=9.6¾ IB), 5.35 (s, 2H), i3C-NMR (75MHz, CDC13) 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, 1.15.9,115.0, 114.7, 106.0, 46.3. 2J2. Synthesis of A,-i4~eyano~3~(tlskzol-2.yI)thtophen-2-yï)~2-i2»oxo-3,4-di hyd rod ,5m ap hf h y ridlo-d (2//}~}1)aeetasx8 ide

[0Ö558J The title compound was prepared from 5-amino-4-(rbiazof-2* y!)thiop!jcnc-3-carboi3itrtle (67mg, 0.32mmoi) and 2-^2-ok.O'3,4-dihvdro-l .5- naphthyrldm·'!(2H)~yl)aeetie acid (löömg, 0.48tnmol) according to protocol A. The crude product was purified by column chromatography (2%metbano1/mcthylcne chloride) and HPLC to give N-(4-cyano-3-(0iiazo1-2-yl)ihiophcu-2"yl>2-(2-oxo-3,4-dihydro-l,5~· oaphihyridiu-1 (2H)-yl)acetamide (5.4mg) as a white solid. LCMS m/z 396.1, method [7] retention time 2,61 liuin. Ή-NMR (300MHz, CDCfr) δ 8.39 (d, /=4.1¾ 1H), 7.76 (4 J-3.3Hz, 2H), 7.62 tss IH)f 7.58 (d, /-7.4Hz, !H), 7.44 (m, 2H), 3.46 (1, /-7.1Hz, 2H), 3.02 (t, /==7,2¾ 2H).

Synthesis of JV~(4~bromO“3-(tblagol“2"yl)tMiephc4~diIwdrO"1,5" ïïspMlïyrM!iï~l(2ff)~yl)acetaiMlcle

2.13.1, 2A4~B?Q&amp;te~2~mt?othi0pheii~3-yl}ihkiz{ile [00559| A mixture of 3,4-dibromo-2-mlrotfaiopheae (242mgf 0.85mmol), 2-(tributyIstaimyl)thiazole (315mg, 0,84mmol), Pd(Ph3P)4 catalyst (194mg, 0.17mmol) and dioxane (0.9mL) was heated in the microwave to 130 °€ for 25mm. The reaction mixture was diluted with EtOAe 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-(4-bromo-2~nxtrothiophem3-yi)thiazok (210mg). LCMS mix of 289,1 /291.1 with a retention time of 2.043xnm on the [1 ] method. 2.13.2, 4-Bmm9-3-(thi®z@ï~2~}4)tkhtpken~2~&amp;Mim [00560] The title compound was prepaid from 2-(4-hromo-2-mtrothiopben-3~ yi)thiazole (120mg, 0.4] mmol) according to the procedures of Example 2,11,6 to give 4~ bromo-3-(thiazol-2-yl)thiophen-2-amine as a dark residue (90mg). LCMS m/z of 260.9/292.9 with a retention time of 6.0Q3mm in the [7] method. 2.13.3, i¥-(4-Bwffle-3~{tfe£@z&amp;$"2~yl}tki&amp;pkeft-2-yi)~2"(2~ex0~3,4-<$ifoyiiw~2i5-mphthyndm~l{2H)-y$}tgcetamide [00561] The title compound was prepared fern 4"hromo-3-(thiazo!~2-yl)thiophen-2~amine (90mg, 0.35mmoi) and 2~(2~oxo-3,4-dihydro-l,5"naphthyridm~ l{2H)-yl)aeetic acid (105mg, 0.52mmol) according to protocol A. The crude product was purified by HPLC to give AT-(4^omo-3-(thiaz»l-2-yl)tlibphiai~2~yl)-2-(2-oxo-3,4-dihydro4,5-naphthyridin-l(2ii)-yi)acetamide (24mg) as a white solid. LCMS m/z 449.0/451.0 and retention of 4.019min '«sing method [7], Ή-NMR (300 MHz, CDCis) S 8.39 (d, /-5.2Hz, 1H), 7:76 (d, J-3,3Hz; 1H), 7.70 (d, /=8.3Hz, 1H), 7.51 (dd, /=8.4,5.3Hz, 1H), 7.34 (d, /-3,4, 1H), 6.94 (s, 1H), 4.09 (s, 2H), 3.49 (t, /-7.2Hz, 2H), 3,00 (t,/=7.2Hz, 2H). 2.14, Synthesis of .<Y~(4« ch\ere-3~(thhzvi~2~yl}ihsophen-2-y I)~2~(2~oxO“3,4" dihydr0~l,5~n&amp;phttayr3dm-i (2/#)-yS)ace tnmide

2,14,1, 2‘‘{4~C'hi&amp;w~2~mtr&amp;ikiopken~3~yi)thiiïzi>i&amp; 1β0562| A mixture of 2-(4-hmmo-2-xiitrothiophen~3~yi.)thiazole (!20mg, G.dlmmoi), CuCl (240mg) in dioxane (1.5mL) and 5 drops of DMF was heated to I 10 °C for Hi by microwave. The reaction mixture was diluted with. fctOAc and washed with saturated, aqueous sodium bicarbonate and brine before drying over sodium sulfate. It wax concentrated under reduced pressure to give 2-(4-chioro-2“mtrothiophai-3~ y!)thiazoie as a yellow residue (lOÖmg), LCM.S m/z of246.9/249.0 with a retention, time of 3,994mm on the [7] method. 2,14.24‘€hi&amp;r&amp;~B~(ihimoï~2-yi)thhpketi~2~amme [005631 The title compound was prepared from 2-(4~chIoro-2-mtroth.iophen~3-yl)thiazole (lOOmg, 0.4mmol) according to the procedures of Example 2.11.6 to give 4-chIorO“3-(tMazoi-2-yi)thiophen-2-amine as a dark residue (90mg). LCMS m/z of 217.0/21 §.9 with a retention time oi2.426mra in the [1] method. 2,14.3. N-f&amp;Ckhm-S-ffhiazai^-yijikwpkm^-yi^-fê-exe-S^-dikydffl-^S-mphtk)^idin~l(2II)~j4}ecetamMe 1005641 The title compound was prepared from 4-cliloro-3-ühk?.el~2-yJHhiophen-2-amine (0.4mmol) and 2-{2-oxo~3,4~dihydr»-1,5-naphihyridjn·' 1 (2.11)-ylkeetic acid (165mg, O.fcrarnol) according to protocol A. The crude product was purified by column chromatography (4% meihanohmethyiette chloride) and HPLC to afford N“(4"Chloro-3~(thia2'.ol-2"yl)tliiophen-2-yl)-2-(2-oxo-3i4-dihydro-L5-naphthyridin-l(2H)-yi)aeetamide (2,lmg) as a white solid. LCMS m/z of 405.1/407.1 and retention of 3.670mk using the [?} LCMS method. !H~NMR (300MHz, CDCl?) δ 8.36 (d, /-4,9Hz, III), 7,71 (d,/=3.4Hz, 1H), 7.57 (d,J=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 (1,/-7.1Hz, 2H), 3.01 (t,/-7.1Hz, 2H). 2.15, Synthesis of iV"-(4-€hlorO”3~(tlslaK(tI-2~yl)ttóophen-2-yl)-2“(8-(trlffinoromafhyI)qnisioliii-5“yi)acetamido [005651 The title compound was prepared from 4-chloro-3-(lH”l^,4»triazol-5-yF)thiopl:cri' 2 -amine (ISOrog, 0.75τϊ«ηοΙ) and 2-(8-(tritliiomraeihyl)quinolin-5-yl)aceiic add (148mg, 0,58mmol) according to protocol A. The erode product was purified by column chromatography (35%EtOAc/hexaiies) to give N~(4-cMoro-3-(thiazol~2-yl)ihiophsn~2"yi)-2-(8~(trifluoromethy1)quinoSin-5-yl)acetamide (35mg) as a white solid. LCMS rn/z of 438.1/440.1 and retention, of 5.789min using the [7] LCMS method, NMR(300MHz, DMSO-d6) 6 9.06 (dd,/=4.2,1.6Hz, IB), 8.64 (dd,/=8.7,1.6Hz, 1H), 8.26(d,/=7.6Hz. IH), 7.83 (d,/=?.5Hz, 1H), 7.72 (dd, /===8.6,4.2Hz, IH), 7.13 (s, IH), 4.56 (s, 2H). 2.16, Synthesis of A-(4~eyMö”3-(thk;rol-4-yI)ihlöpta-2~yI)4M2"öxö“6--(trltlu or onset lsy!)q ssIroIIs-1 (2ff)~yl)ncetaroiile

2.16, L $~Niir&amp;~4~(ihiezi}l~4~yi}thiopkem~3-€ftrb&amp;iiitriii! [θ()566[ A microwave vial equipped with a stir bar was added 4-bromo-5-mtrothiophene-3-carbonitrüe ¢0.15 g, 0.66 mmole) and tetraids(triphenyiphosplime)palIadiuin (0) (0,077 g, 0.066 mmol) and then purged with N?. (g) inlet prior to addition of 4~(trihuiyistannyl)thiazole (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 -educed pressure. Purifk?*Hon by flash chromatography (silica. 50:50 ethyl acefetc/hexana) gave 5-niiro-4'(thjazol-4-yl)thiophene-3-carbonitrile (71 mgs, 45%) Retention time (mm) =1.656, method [4], MS(ESI) 238.0 (M+H), 2-16i 3» 5~i!mino~4~{•ijihiapkasw-S-earboHifrUe 100567] To a solution of 5-nitro-4-(thia2:.ol-4-yi)thiopherie-3--carbo™trile (0.07Ig, 0.31 mmol) In ethyl acetate (3 ml,) -was added tin (II) chloride dihydrate (0,29 g, 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-(thiazoM"yl)thiophene-3-carboniirüe (24 mgs, 38%) Retention time (min) =1.837, method [4), MS(ESI) 208.0 (M+H). AM.?. J4~{4~Cymm~3~{thmz0 i~4~y!)ikmphen~2~yl)~2~(2~ox&amp;-6~ (trip.mwmetkyi)qi4m&amp;im~l(2H)}4)iiceiumiée [00568 ] The title compound was prepared from 2-(2-oxo~6- (trifluoromethyi)qumolm-l(2.fii')-yl)acetic acid (0.047g, 0.17 mmol) and S-ammo-d- (thiazol-4-yI)thiophene"3-carbonitrile (G.024g, 0.12 mmol) according to protocol A, The desired product was submitted to prep HFLC for further purification. Retention time (min) = 7.57, method [7],MS(ESI) 461.1 (M+H). 3HNMR{CDCb) δ 12.73 (s, 1H), 8.60 (d, ./ = 2.4 Hz, IB), 8.14 (d, /= 2.4 Hz, IH), 7.92-7.89 (m, 2H), 7,89 (d, J = 9.3 Hz, 1H), 7.59 (s. IB), 7.48 (d, J= 8.9 Hz, IH), 6.96 (d, J= 9,3 Hz, IH), 5.30 (ss 2H). 2.17, Synthesis of A-(4~cyasi®-3-itlilazöl--5-yl)thIophea-2~yl)-2-(2-oxo-6'- (triflu®romethyl)qutaolto-l(2ii)-yl)Meetaroids

2J. Z L S~Nitr&amp;~4~(ikmz0i-~5~yi)fkwpkgm~3“mrb0mfriie

ProtocolR; [IM1S69] A microwave vial equipped with a stir bar was added 4-bromo-5-oitsOtMophene-d-carboriiLriie (0.24 g, 1,05 mmole) and tetraki<tripheny!phosphme>paliadiam (0) (0.14 g, 0.12 mmol), cupper iodide (0 028 g, 0 15 mmol) and then purged with M2 (g) inlet prior to addition of 5-(tributyistannyl.)tMazole (0.63 g, 1.67 mmol), dioxane (2.3 ml) and few drops of BMF, The reaction mixture was heated at 110'C for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-nitoo-4-(thiazoI-5~yl)thioph.ene-3-catbomirile (153 mgs. 61%) Retention time (min) - 1.715, method [4], MS(BSI) 238.0 (M+H). 2.17.2. 5-Amm&amp;~4~{ikiuzoi~5~yi)thi&amp;phene~3~mrbomiriie [00570] 5*Animo-4-(thiazol"5-yl)thiophene-3-carbomirile was prepared from 5-mtro-4-(thiazol-5-yl)th.iophcn.c-3-carbomtrilc (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~C)?aits~3~(thmz&amp;ï~S-y!)thwpke/i-2~yi)~2--(2-&amp;x&amp;~é~ {Mf!u&amp;romeihyi)qmn(ilm~J.{2H)--yl)aceUgmide [0(1571] The title compound was prepared from 2-(2-oxo~6-(trifluoromethyi)qnitiolin-1 (2/7)-yl)aeetic add (0,047 g, Q.17 mmol) and 5-amino-4-(thiazol-5-yl)thiophene-3~earbonitri1e (0.055, 0.26 mmol) according to protocol A. The crude product was purified by prep HPLC. Retention time (min) = 5,989, method [7], MS(ESl) 461.1 (M+H). 3H NMR (CDCJj) δ 9.95 (s, 1H), 7.91-7.85 (m, 4H) 7.78(d,/-8.7 Hz, 1H), 7.63 (s, IB), 6.84 (d,/= 8.7 Hz, 1H), 5.06 (s, 2H). 2.18. Synthesis of N~(3-(feenz® [d\ th!&amp;2ol-2-yi)~4~cyaMOtMoph©n-2“yI)-2~(2“OXO~ 1,5-Mph thyridsn-1 (2.H)~y l)aeef a mlde

2,18. L S~Nitm-4~(benz@[dJthiaz&amp;l~2-y!)ihi0pkme~3~cerbömÏriie [00572] 5-n.iiro-4-(benzo[£flthiazol-2-yl)ihiophene-3-carbonitrile was prepared from 4-bromo-5-nitrothiophene-3-earbonitrile (0.16 g, 0.67 mmol) and 2-(Uïbutvisianr y!Ybonze-[/]thlazole (0,45 g, 1,07 mmol) according to protocol R, Retention time (min) = 0.381, method [4], MS(ESI) 288.0 (M+H), 2,18.2. S~Amimi~4~{henz(iidi?kimM~2~yi}ihmphme-3~mrb&amp;mMie [005731 5-amino-4-(bcnzo[^|thiazol-2-yl)thiopliene~3-carbositrilc was prepared from 5-nitro-4-(benzo[i/]thiazol-2-yl)iMopliene-3-earbomtriie (0.27 g, 0.92 mmol) according to protocol Q. Retention time (min) = 2.579 method [4], MS(ES1) 258.0 (M+H). 2J8J. N~(3-@mwidjihiiK0i~2~yl)^cyafs(}tki0pken-2-}ii)~2~{2~ex&amp;-$>5-naphthjiri{iifi-1 (2M)~yi)&amp;cetiimide [00574] The title compound was prepared from 2-(2~oxo- .1,5-naphthyridin-l(2fl)-yl)acetic acid (0.040 g, 0.19 mmol) and 5-ammo-4-(beimo[/]ihiazol~2-yl)thiophene"3"Carbonitriie (Ö.Ö73 g, Ö.28 mmol.) according to protocol A, The cmde product was purified by prep HPLC. LCMS retention time (min) = 5.122» method [12], MS (ESI) 446.1 (M+H). 5HNMR (CDC13) δ 1338 (s, Hi), 8,32 (d, / = 5.6 Hz, 1H), 7-99(d, J = 7.5 Hz, 1H), 7.94 (d, /- 7.5 Hz, 1H), 7.62 (s, 1H), 7.58 (d,/= 8.4 Hz, 1H), 7.54 (d, J- 8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.35-7.30 (m, 1H)} 4.95 (s, 2H), 3.33-3.28 (m, 2H)} 2.99-2.94 (m, 2H). 2J 9. Synthesis of 2-(2-oio~6~(trifliioromefl5yl)quinoMti-l(2^)-yl)-A'-(2.(tl5iazol-4~yI)thiophen-3-yl)aeetamMe [00575] The title compound was prepared from 2-(tbiazd-4-yi)tMophen~3~ amine and 2-(2<sxo-6-(triiluoromethyl)qinnolin· I (2H)-y])acetic acid according to protocol A. Retention time (min) = 6.485, method [7], MS(TSI) 436.1 (M+H); jH NMR (300 MHz, CD3Ö) δ 11.32 (s, 1H), 8.51 (d,/= 1.5 Hz. 1H), 8.04 (d, /=5.5 Hz, Hi), 7.92 (d, /== 10,2 Hz, Hi), 7,90 (5,1H), 7.80 (d, /- 8.9 Hz, !H), 7.50 (d, /- 8.9 Hz, 1H), 7.22 (d,/= 1.4 Hz, 1H), 7.20 (d,/= 5.5 Hz, 1H), 7.03 (d, J = 9.7 Hz, Hi), 5.23 (s, 2H).

Synthesis of Thiophene Oxaxoles 3X Synthesis of 2-(4>nieihoAypbe}iy!)-A>(2*{exa2&amp;I>2>vl}tiitlephen>3>vI)acetan»dlc m)

' 3. L1, 2~{3~Nit?mhittpkfm--2"yi}oxazoie f§0576] 2-(3-mtrotMophea-2~yl azole was prepared from 2-(frtbutytsnmnyiloxazck· {0.94 g, 2.62 mmol) and 2-ehloro-3-nitrothiopiiene (0.429 g, 2.62 mmol) according to protocol E. Retention time (min) = 1.794, method [1], MS(ESI) 197.0 (M+H). 3, L 2. 2-{€hcsz®i~2~yl)ikiüphe}Ï~3~amme |.ΘΘ577| 2-(Oxazol~2~yl)tMopheo-3-amine was prepared from 2-(3-mtrotMophen-2-yl)oxazoIe (250 mg, 1,27 mmol)) according to protocol F. Retention time (min) = 1.388, method [1], MS(ESl) 167.0 (Mill). 3.1.3. 2~(4-Meikoxyphenyï)-N~{2~{i!xazül~2-yi}iM&amp;pken~3~yi)iicetamide [Ö05781 2-(4-meÜioxypheny!)-A-(2~(oxa2iof'2-yl)thiophen-3-yi)acetamide w«5 prepared fora 2-(4-meihoxyphenyl)acetic add 64 mg, 0.385 mmol) and 2-(oxazoi-2- yl)thiopSien-3-amioe (64 mg, 0.385 mmol) according to protocol A. Retention time (rain) - 6.845, method [7], MS(ESI) 315.1 (M+H); Ή NMR (300 MHz, CDCU) 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~(lsoqninoMo-5-yi)~iY“(2”(osa^;ol-2“yl)tMoplien-3-yl)acetasMMlc (S3) [00579] 2-(Isoqumolm~5-yl)-i¥-(2-(oxazol-2-yl)thioplien-3-yi)acetamide was prepared from 2-(isoquiriolin~5-yl)aeeiic acid (48 mg, 0.246 mmol) and 2-(oxazol-2-yl)tliiophen-3-amme (41 mg, Ö.246 mmol) according to protocol A. Retention time (min) - 2,206, method [7], MS(ESI) 336.1 (M+H); lIl NMR (300 MHz, CDCit) δ 10,79 (s, 1H), 9.71 (s, 1H), 8.59 (d, J = 6.5 Hz, 1H), 836 (d, 3 - 6.5 Hz, 1H). 8.28 id, 3-8.2 Hz, 1H), 8.07-8.13 (m, 2H), 7.95 (dd, 3- 8.3, 7.3 Hz, 1H), 7.55 (s, 1H), 7.36 (d, 3=53 Hz, 1H), 6.95 (s, 1H), 436 (s, 2H). 3.3. Synthesis of AH4~hromo~3.(oxiazol-2~yl)thiopta-2-yI)-2~C2Hixo-3,4-dihydro-l,5~MphihyridinM(272)~yl)acgtamide

5.3, /. 2-3'4~Brimo~2~ttit?f>ihktphett~3-yl)exüzoïe [β858Θ] A mixture of3,4-dibromfi-2-aitn>tisxophenc CO. 166 mg, 0,581 mmnl),

PdiPPlu h (67 mg. 0.0581 mmoi) and 2-(iribulyistannyl)oxazeic (350 rag, 0.698 mmoi) ia D>vlP (}.] ikL) was evacuated .and purged with nitrogen three times. The reaction mixture was heated io 90 UC for 18 h. and the resulting solution was cooled to room temperature arid dilated wnh Et;,0. The solution was washed with brine and the organic phase was separated, dried t ι4έρ80ί.|> futered, concentrated under vacuum and purified on a si lies gel column (duani hexane/elhyi acetate, 20/1 to l/Ι,ν/ν) to give 2-(4~bromo-2· rsitrothiophen-3-yi soxazole (107 mg, 67%). Retention time (tuin) = .1.948, method [1], MSCESI) 274.9 (M+H), 3.3.2, 4-Bmmo~3~(9xsz&amp;i-2~}>i)thkiph«m~2~amme 100581.] The title compound was prepared from 2 (4 bromo-2-m troth Iophers-3-y!)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-amme which was used without further purification. Retention time (min) = 2.131, method [I ], MS(ESJ) 244,9 (M+H). 5.3.3, N-(4-Brome-3^mzei-2~yl)thwphm-2-yf)~2--(2--ex&amp;-3i4-dihydr0-l!5-mphtkyndm~l(2II)~fi)ii£eMmiée 100582] The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-l(2/f)-yl)acetic acid (85 mg, 0.416 mmol) and 4-bromo-3-(oxazol”2« yI)thiophen-2-&amp;mine (51 mg, 0.208) mmol) according to protocol A, Retention time (min)

- 3.245, method [7], MS(ESI) 433.0 (Mill); Ή NMil (300 MHz, CDCh) S 8.39 (dd, J - 5.1,1.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d, J- 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-eyanO“3"{oMEOl~2-yl}tMophen~2~yl}-2~{2~oxo-6~ (triflooroisetliyl)qoiiioIIi5~l(2H)~yI)a«:etamide

3.4, h S~Almf"4~{üxazid~2~yl}shiophiSne~3~i:arbi}iiWiL· [ÖÖ5S31 The above titled compound (34 mg, 18%) was synthesized from 4-bromo-5-Bitrotliiophene-3-carbomtrile (203 mg, 0,87 mmol) and 2-tribuiylstannyioxazole (0.27 ml,, .1.29 mmol), tetrakis(iriphenylphosplurie}palladium(Ö) (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~Amwe~4~(oxes?&amp;l-2-yl)tki&amp;phem~3~csrbemtrUe [005841 The tide compound was prepared from 5-nit£O-4-(oxazoi~2-yl)thiophene-3-carbonitrile (34 mg, 0.15 mmol) using protocol Q. Flash chromatography (EtOAc/feexanes elution) gave desired product (20,8 mg, 71%): Rf- 0.84 (60% EtOAe/bexanes, silica); HPLC method [4], retention time::: 1.673 min; MS(ESI) 192,0 (MH+). 3.43. N~{4~€yumi~3-{exuz&amp;i-2~yi)iki&amp;phen~2~yi}~2~(2~iïxo~é~ (trifluora meihyi)qmn olm-I fêE)-yi)m;et&amp;mMe [0l)585| The title compound was synthesized trom 5~amIris>4~(oxazol~2~ ylidmvphene-S'Carhonitriie (21 mg, 0.11 mmol) and 2-(2-oxo-6-(trif1uoromethyl)qu8r;ohn-[(2n).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; MS(ESl) 445.0 fMiir); fK NMR (300 MHz, CD3OD) δ 8.19 (d, J - 9.8 Hz, 2H), 7.95-7.80 (m, 3Η), 7.85 (d.,; 1.8 Wz, IBs, 7.08 (d,J - 0.8 Wz, 1H), 6.90 id,./ -9.6 Hz, IH), 5.45 «s, 211). fcxampfr 4 .vnvkmmVAA.V'wwwv-v-t

SyRthesis of Thiophene Qxsdmzeles 4.1. Synthesis of 2-(4-meihoxyphessyl)~A~(3"(5"iïïethyHs2,4-oxadiazol~3“ yl)thlop!i ea-2-y l)aceiam 1de (54)

4.1. L fS/~{i~Cyan (Hhi&amp;phen-2~y!}~2~ {4~ffiefk&amp;xyphefsyl)ecêtMmide [005861 Ar-i3--cyanoihiophe5i-2-yl)~2--(4-iïïcihoxypheriyl)acetaimde was prepared from 2-(4-methoxyphenyl)acetic add (1.37 g, 8,29 mmol) and 2~ aminothiophen©-3-carix>nitrile (1,03 g, 8.29 mmol) according to protocol S. Retention time (min) = 2.150, method [1], MS(ESI) 273.0 (M+H). 43,2, N~{3~(N,~HydmxymrbsmimideyÏ}ihmphesi-~2~yl)~2~(4-meik&amp;xypkeftyi)~ acetamide [Θ05871 To a solution of A'~(3~eyanothiophen-2“yl)-2-(4-methoxyplienyl)aeetamide (234 mg, 0.859 mmo’} in a mixture of ethanol (5 ml,), methylene chloride (0.5 jkL) and triethykmine (202 pL, 1.46 mmol) was added hydroxylamine hydrochloride (90 mg, 1,29 mmol). The resulting solution was stirred at room temperature for 18 b and was subsequently diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried (NajSO^), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 7/3 to 2/8) to give A-(3~(A’?~hydroxyearbamimidoyl)thiophen~2"yl)-2-(4~methoxypb.enyl)acetamide. Retention time (min) ~ 1,161, method [1], MS(ESI) 306,1 (M+H). 4,13. 2~{4~Meth9xyphestyl)~N~{B~(S~mfiihy^-lf2s4~&amp;xadk(wl~3~yi}thi0phefi~2~ [995881 Ί o a solution of <V-<3-(Ai’-hydros>catOaniirnidoyl)ihiop3icn"2--yi.)-2"(4·· rnelhoxyphcsjyO-acetarnide (104 mg, 0.34] mmol) in acetonitrile (2 mL) was added DÏPKA (127 mg, 0.987 mmol) and acetyl chloride (48 pL, 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. The organic phases were combined, dried (Na2S04), filtered, concentrated under vacuum and purified by preparative HPLC to give 2-(4-metboxyphenyl)-A-(3-(3~methyl"l52,4-oxadiazol-3~ yUthiophen-2-yi)acetamide, Retention time (min) - 6.733, method [7], MS(ESI) 330.1 H NjVlk (3v0 MHz, C IX 1,)8 10.63 (s, 1H), 7.30-/,33 (m. JH), '7.00 id,,/--' 9.2 Hz, 2H), 6.89 (d, ./- 6.2 Hz, JI-I), 3.86 (s, 3H), 3..80 (s, 2H), 2.50 (s, 3H). 4.2, Synthesis of' j¥-{2-(1 ,3,4~0xadlazol-2-yl)tt5lopfeen-3-yl)-2-»(naphiliaieii-l~ yl)ae£iasnide (55) [08589] To a solution of (isocyajjoimino)triphenylphosphorane (978 mg, 3.24 mmol) in anhydrous CH2CI2 (30 mL) was added dropwise a solution of 3-{2-(napfathaien~ 1 -yI)acctamidoHbiophea3e-2-carboxylic add (340 rug, i .09 mmol) in anhydrous CH2CI2 (27 mL). The rests Hing mixture was stirred at room temperature under nitrogen overnight and evaporated under reduced pressure. Purification by flash, chromatography (silica, .50:70 ethyl aestate/hsxas.©) gave W2-( 1,3,4-oxsdiaaiol-2-yl)thiophsii-3-yl)-2-(naphlhalen-1 -yllacetamIdc (45mg, 12%), Method [7] m/s 357.9 (M-KNa): retention time

- 5.919. 5H-MMR (COCK) S 8.18 (d,J- 1.1 Hz, ! H), 8.16 (d, J= 1.4 Hz, 1H), 8.05 (d,J - 8.3 Hz, 1H), 7.88 (d, J= 8.0 Hz, 2H), 7.61-7.41 (m, 5H), 4.27 (s, 2H). 4.3. Synthesis of 2-(4-rnethwwphen}4)-/\M2-{5-imethyl-1 3,4~o x&amp;dsa zn 1-2-yI)fhiophei8~3-yl)aeetaiwide (56)

Ό,Ι. Methyi 3-(2~{4~ifieth(ïxypheiïyi}(u;etamido'ithiephem-2~carh(txyï&amp;se [00590] The title compound was prepared from 4-methoxyphcnyl acetic acid (6,65 g, 40.2 mmol) and methyi-3-amiao-2-thiophene earboxykte ¢6,30 g, 40,08 mmol) using protocol Λ to afford (he coupled iniermediate (?.40g, 60%). Method 17] m/z 306.0 (M+H); retention tune ~ 5.9Ö7. 'H-MMR (CDCj?) δ 10.04 (broad s, 1.H), 8.07 (d. J— 5,5 Hz, 1H), 7.38 (d, J 5.5 Hz, ill), 7,22 (d, J - 8,3 Hz, 2H,), 6.88 (d, J8.3 Hz, 2H)„ 3.76 (s, 3H), 3.75 (a, 3H), 3.65 (s, 2H). 4.5,2. 3~(2~{4~Methexypkmyi}iicetamide)thwphene~2~carè&amp;xyUc acid [ÖÖ5911 A 3M lithium hydroxide elution (80 mL) was added to methyl~3~(2-(4-methoxyphenyi)acetamido)thiopheiie~2~cari3oxylate (7.30 g, 23.91 mmol) dissolved in methanol. The reaction, mixture was refluxed for 2 k, 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] m/z 291.9 (M+H); retention time = 3.827. JH-NMR (CD3OD) δ 8.0 (d, J~-5,3 Hz, IH), 7.61 (d,./-5,3 Hz, !H), 7.26 (d, ./=8.3 Hz, 2H), 6,91 (d,J=8.3Hzs 2H), 3,76 (s, 3H), 3,70 (s, 2H), 43,3, N-{2~(2~A£et}'>lhydrisziïïig(‘®$’h&amp;ïïyii)ïMi}phen~3-yï)~2~{4~meihiixypheftyl)~ acetamide 100592] The title compound was prepared horn 3-(2- (4-n3etb.oxypbetiyl)acerami.do)-thiophene-2-carboxylic acid (500 mg, 1.72 mmol) arid acctyjhydrazide (I 0 g, 13.50 mmol) according to protocol B to give 14-(2-(2-acctyihydrazinecarboT!y1)thiophc:i-3-y.i}--2-i4-rrseihoxypheriyl)acciamide which was used without further puriheation (300 mg, 50%). Method [4] m/z 370.0 (M+Na); retention time - i. 3 86. 4.3,4, 2~{4~Methaxypkeiii}4)-N~{2-(S~mefha4~3f3f4o.wdm7M~2~yi}ihicphgn~3~ yi)aceiamide |00593] To a solution of Ar-(2~(2~acetylhydrazmecar!xnryl)thiophen-3-yl)-2-C4-methoxyphenyl)acetamide (300 mg, 0.86 mmol) in anh. acetonitrile (6 mL) was added diisopropylsihylamme (0.8 mL, 4.84 mmol) and tripheny(phosphine (396 mg, 1.51 mmol). After 5 min, hexachioroeihaae (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 acetate/hexane) gave 2~ (4-mel:hoxyphenyi)~Af~(2~(5“m.ethyl~.1 }3,4»oxadiazol”2^4)thiophen-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, 3B-NMR (CDC13) δ 10.15 .(broad s, IE), 8.18 (d, /= 5.4 Hz, 1H), 7.43 (d,/=5.4 Hz, 1H), 7.31 (d,J= 7.6 Hz, 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-isopropyl"1 J,4~oxadsarol~2-yl)thloplieïS”3“yI)“2"(4-5nethoxyphesyl)aceiamide (ST)

4.4. L N~{2~(2~Mfhutyryihfdmzmeeurbonyi)thmphen-3-yi)~2~(4-me4kt>xvpheny4)~ ueetumiéë |00594| Ar-(2-(2-isobutyry]hydrazinecarbony])thiopheri'3-y1)“2-(4- metlioxypheuyl)aceiamide (443 mg, 34%) was prepared from 3-(2-(4-methoxypheny])aceuinüdo)lhiophene-2«carboxy1ic acid and isobotyrohydrazine according to essentially the same procedure as described above in Example 4,3.3. and was purified by flash column chromatography (silica, 50:50 ethyl acetate/hexane).

Method [4] m/z 398.0 (M+Na); retention time = 1.453. 4.4,2, N~{2~{5~httpmpy!~! 3,4-ox(uium)l-2--}4}thksphsn~3~}i}~2~{4~*netkoxypke&amp;y!)~ acetamide ί(ΜΙ595| Ar-(2~(S-isopropyld,3,4~oxadiazol-2~y!)lhiop!ien-3-yi)-2-(4-methoxyphenyi)acetamide (339 mgs, 81%) was prepared from N-Q-(2-isobutyryihydra2inecarbonyl)thiophen-3-yl)"2-(4-TnetlK)xyphenyl)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-M-I); retention time - 6,683, Vl-NMfr (CDCfe) δ 10.21 (broads, 1H), 8.15 (d, J-5.2 Hz, 1H), 7.40 (4 5.2 Hz, Hi), 7.29 (d, .7- 8.2 Hz, 2H), 6.89 (d J= 8.2 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 2H), 3.24*3.14 (m, 1 H).L42 (s, 3H). 1.40 (s, 3H). 4,5. Synthesis of 6;-{2-(5"roeth34“l J,4“Ozadbiza82*>1)Odoplïesi"3--yl)~2~ (lïiip hthalen-l ~yl)a€etarmde (58)

-/,5,/. N^(2~(2-Acetylhydrazinecarbeny!)ikmphen~3~yi}~2~{nephthelen~l~yi)acetismide [ÖÖ596J The title compound was prepared from 3~(2~(naphthaiene--1 -yi)aeetamido)thiophene-2-carfeoxy3ie add (32 i mg, 1.03 mmol) and methyl keto hydrazine (609 mg, 8.22 mmol) using protocol B to give the desired 19-(2-(2-acelylhydrazitieciirbonyl)thiophen-3-yl)-2-(naptahaien-l-yl)aeetamide, which was used without further purification (250 mg, 66%). 4.5.2. N~{2~{$~Msihyi~l,3f4-&amp;xadiaz&amp;!~2~yi)thi&amp;phem~3~)>i}~2-{mphthsien~l~ yij&amp;cetmmie [ÖÖ597] Λ-(2-(5 -methyl -1,3,4-oxadi azol ~2-yl)thiophen-3 -y i)-2-(iiaphtliaIen-1 -y!)acetamMe (105 mgs, 44%) was prepared from iV-(2~(2-acetylhydrazinecarbonyl)thiophen-3-yl)-2-(naphthalen-1 -yl)acetamide (250 mg, 0.68 mmol) according to essentially the same prodecnre as described in Example 4,3.4.. Method [7] m/z 371.9 (M+Na); retention time = 6.243. ‘H-NMR (CDCla) δ 10,08 (s, 1H), 8.12 (d, 7=5.4 Hz, 1H), 8.03(4/-8,1 Hz, 1H), 7.83 (d,J-8.1 Hz, 2H), 7.577.40 (m, 4H), 7.33 (4/-5.4 Hz, 1H), 4.21 (s, 2H), 2,45 (s, 3H). 4.6, Synthesis of 77-(4- ns ethyl-3- (3-ei ethyl-1 s2,4~os:adiazoI-5-yl)thloplsen-2-y l)~2~ (naphflmlen-l-ylHeeiamide (59)

4. &amp;. 1, Methyl 4~meihyl~2~{2~(naphthaïen·-!~yi}acei{imêée}ihmphem~3csrh(ixyiate [¢05981 The title compound was prepared from 2-(naj>ktba!cn-1 -y!)acetic acid (10 g, 54 mmol) and methyl 2-amino-4-metbyltbiophene-3-csrboxylatc (9.2 g, 54 mmol) according to protocol A (15.4 g, 85%) as a white solid. *H NMR (CDC13) 31.1.0 (s, 1H), 8.05-7.85 (m, 3H), 7.63-7.50 (m, 411), 6.36 (s, ÏH), 4.29 (s, 2H), 3.57 (s, 3H), 2.28 (s, 3H); 53CNMR(CDC!3) £168.3, 165.6, 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. 4.6.2. N^4~methyi~3~{3~meihyi-l,2,4~&amp;xmf.mz^i~S~}'i}ihmphm~2~yi)~2~{nup.hthaim^?-yl}aceMmkie [005991 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»methyl-2-(2-(naphtliaIen-1 “yl)acetamido)tliiophene~3~carboxylate (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 NaCl solution, The organic layer was dried (MgS&amp;j), filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexaaes elution), and then triturated from acetonitrile to afford the desired product (58 mg) as a white solid. Method [7]; rt = 9.42 min; }HNMR (CDCh) £1 1.3 (s, 1H), 8.02-7.89 (m, 3H), 7.63-7.50 (m, 4H), 6.48 (s,

Hi), 4.35 (s, 2H), 2.42 (s, 3H), 2.08 (s, 3H); l3C NMR (CDCla) 3112.1, 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, Π4.0, 106.9,42.1, 16.9,11.4; MH+364.1. 47. Synthesis of A^4~mcthyi~3~(3-m£thyl-l ,2,4~©.sadiagoi-S-yl)thioplien-2-yl)-2-(4-ipyrsdm-4-y1)pl5enyl)acetamide (66)

4.7. 1. Methyl 2~{2~(4~faé0phenyi)aceiamid0}-4~meihylihfaphme-$-carh&amp;xyiate [ÖOéOÖJ The title compound was synthesized in 87% yield according to protocol A from 2-44 >iodophenyi)acetic acid and methyl 2-amino-4”methylthtophene-3-carboxylate. ,3CNMR(CDCb) «5167.5, 166.6, 149.8, 138,1,134.8,133.1,131.4,113.0, 112.3, 93.2,51.5,43.3,17.8; MH+ 416.0. 4.7. Z Methyl 4~Metkyl~2-{2-(4~{pyrMm~4-yl)phenyl)®e0&amp;mido}tkhpkem~3~ ewhexylate 1006011 Methyl 2-{2-(4-iödöphenyi)aeetamido)-4-methy!thiöpherte-3~ carboxylate (420.4 mg, 1,01 mmol), 4-pyridylboronic acid (Aldrich, 167 mg, 1.36 mmol), tetrakis(triphenyiphosphine)palkdium(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 b, The reaction mixture was cooled to rt, then partitioned between EtOAc and water, The organic layer was separated, washed (brine), dried (NajSO-i), filtered and concentrated under reduced pressure. Flash chromatography (EiQAcvhexan.es) afforded the titled compound. lHNMR (CDCI3) <5113 (s, 1H), 8.67 (dd, J = 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); °CNMR (CDClj) <5167.7, 166.6, .150.3, 149,9, 147.8, 137.4, 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~}mthyï~3~(3-metkyi-2f2s4-&amp;x&amp;émml~5~yï}thk!phm-2~yi)~2~{4~{pyTidm~4~ yi)phenyl}memmkle [60602] Acetamide oxime (66 mg, 0.89 mmol) was taken up in dry THF (1 rnL) at rt, and sodium hydride (6034 dispersion in mineral oil, 55 mg, 1,4 mmol) was added. After hydrogen evolution ceased, methyl 4~meihyl-2-(2-(4-(pyridin-4-yi)phenyl)acetamido)tMophene~3~earhoxylate (82 rag, 0,22 mmol) was added, in one portion. The reaction was stirred at rt for 90 min, then at 50 °C 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 (MgSCTj), filtered and concentrated. HPLC purification of the crude residue afforded the title compound as a trifluoroacetk acid salt, Ή NMR (CDÖ3) S 11.6 (s, 1H), 8.86 (dd, J = 5,3, 1.4 Η, 2H), 7.94 (dd, /= 5.3, 1,4 Η, 2H), 7.77 (d, / = 8.2 Has, 2H), 7.61 (d,J-8.2 Hz, 2H), 6.54 (s, 1H), 3.99 (s, 2H), 2.51 (ss 3H), 2.34 (s, 3H); MH+ 407.1. 4.8. Synthesis of A^2~(3~metliyl-l,2,4-dxa€tI&amp;2ol-5-yl)tlri©pheM~3-yl)~2~ (n&amp;ph thaien-1 -yïjmemmMe (61)

41 S. L Methyl S-(2~(naphthaien~l ~yi)ecet&amp;mid&amp;)tkwpkme-2-cerb0xyi&amp;te [00603} Methyl 3-{2-(oaphthalen-l -yf)aceiamido)tbiophene-2«carboxylaie was prepared from methyl J-a-ï-inoihiophene-2-carboxyhite (A .30 g, 27.3 mmol) and 2-(naphihaieii-l-yl)acetie 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,2,4-0X(idimeI-5-yi)tki&amp;pkm-3-yl)-2~{nephtkaiett-l~ }2}immmide [00604] 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 was stirred at room temperature for 10 minutes after which a solution of methyl 3-(2-(naphthalen-l-yl)acetamido)thiophene>2-carboxylate (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 (NazSCV). filtered and concentrated ander vacuum. The residue was dissolved in THF (1 mL) an d HC1 (1 mL of a 10% aqueous solution) was added. The mixture was stirred for 20 minutes after which ethyl acetate (10 xnL) was added. The resulting soiut-en was washed with brine (5 m!.) and the organic phase was then dried (Nu^SO-s), filtered, concentrated under vacuum and the residue was purified by preparative HPLC to give A*(2-(3-methyl-1,2,4~oxadiazol-5-yi)thiophen-3-3d)-2-(naphthalen-l-yl)aceiamide. Retention time (min) - 9.533, method [7], MS(ESi) 350.1 (M+H). *HNMR (300MHz, CDChs o 10.10 (s, 1H), 8.26(d,/-5.4 Hz, IB), 8.03 (d, J = 9.3 Hz, 2H), 7.59-7.49 (m, 5H), 4.27 (s, 2H), 2,14 (s, 30).

Synthesis of7V-(3"(l,2,4-oxadta2»l~3-yi)thiophen”2-yl>-2-(6,7~difliioro~2~oxoqnlnolin-l(2/i)-y!)acetamide

4.9J. N~(JMmof2,3-4]pyrimidin--4~yi)hydr<>x}4amim [60605] 4-chIorothienoj 2,3-t/Tpyrimidine (340 mg, 1.99 mmol), hydroxylamine-hydrogen chloride (550 mg, 7,91 mmol), and diisopropylethylamme (1 ml) in absolute ethanol (5 ml) was placed into a preheated oil bath at 75UC. After stirring for 6 h, the solution was concentrated under reduced pressure. 4. #,2. { }.{} I'ihyi AT~ 3-{lt2f4~{/xs4mz&amp;i~3~yi)ikmpkeii~2~ylfs}rmimklMie 1Θ06Θ61 Af-(thieno[2,3 -/]pyrimidm-4-y1)hydroxyiamine and triethyloithoformate (10 ml) in ethanol (10 ml) was placed into a preheated oil bath at 100°€ for 4 h. The solution was concentrated to yield (£)~ethyi //-3-(1,2,4-oxadiazol-3-yl)thiophen-2-ylformimidate. Method [8] retention time 4,08 rniu by HPLC (M+-224). /.9,3, 3~(l,2f4-Oxa4mz&amp;i-S-yi)£ki&amp;pkefi~2~amim 100607] (E)-Ethyi ,V-3-(l,2s4~oxadiazQl-3-yl)thiophen-2-yIfGrmimidaie (82 mg, 365 nmol) and Mmethylethane-l,2-diamine (0.30 ml, 3,40 mmol) in methanol (2 ml) was placed inio a preheated oil bath at 60"'€. After stirrmg ib? i 5 min, the solution was concentrates undeor reduced pressure and the residue was flash chfOTnotraphed with 9:1, 4:1, 7:3, and 3:2 hexanetethyi acetate as the eluant to afford IS mg (5.4% yield over three steps) of 3»(l,2>4-oxadiazol-3»yl)thiophen"-2-atnme. Method [6] retention time 4.08 min by HPLC (Ml 168). *Η NMR (300 MHz, CDCh) δ 8.70 (s, 1H), 7.22 (d, >5.4 Hz, IB), 6.45 (d, >5.4 Hz, IB). 4.9L 4. N~{3~(lf2s 4~&amp;xadia^fl~3~yi)tkkipken-2~yl)~2~(6f 7~dsfiuom~2”isxsqumeim- 1 (2H}-yï}acëtamide 100608! The title compound was prepared from 3-(l,2,4~oxadiazol-3-yl)thiophen-2-amine (18 mg, 108 uraol) and 2-(6,7-difluoro-2-oxoq«inolin-l(2//)-yl)aeetie acid (32 mg, 234 nmol) using protocol A. The crude product was purified by HPLC to yield //-(3-(1,2,4-ox.adiazol-3-yl)thiophen-2-yl)-2-(6,7-difliKm>-2-oxoquinolm~ l(2i-/)-yi)8cetainide. Method. [7] retention time 5.34 min by HPLC (M-H=389) and (M+Na=4Jl). !H NMR (300 MBz, CDCI3) δ 11.06 (s, IB), 8.69 (s, 111), 7.74 (d, >9.9 Hz, lid), 7.42 (m, 2H), 7.35 (m, III), 6.98 (d, >5.4 Hz, 1H), 6.86 (d, 3==9.3 Hz, 1H), 5.22 (s, 2H).

Exnmnle 5

Synthesis ef Thlaznie Triazoles 5,1< Symhmh orA''-{4-(l//-Ij)2j>4-triazol''5-y.l)thSazol-5-y!)-2-(lsoqnlno3ia-5- yliiscehimide (62)

J.I.l, Methyl S~(diphenylmethyimeamm)thüm)le-4~carboxylate I0Ö609] A mixture of methyl 5-bromothiazole-4-cafboxykte (3,51 g, 15,8 mmol), diphenylmedianimine (4.0 mi, 23.9 mmol), cesium carbonate (10.98 g„ 33.7 mmol), PdjfdbafrCHCi.i (876 mg, 957 urnol.j, and 4,5~bis(diphenyJphosphino)-9,9~

dsmethylxanthene (Xantphos, 1.67 g, 2.89 mmol) in toluene (30 ml) was heated at 80°C fbr 18 h. Theheterogeneous mixture was directly flash chromatographed with 9:1« 4:1, 7:3, 3:2 and 1:1 hexane:elhyl acetate as the eluant to yield 4.30 g (84% yield) of methyl 5-(diphenylrnethylen.eamiiio)thiazole-4"carboxylate as a yellow oil Retention time (min) = 6.41, method [7], MS(ESi) 323.0 (M+H). 5.1.2, Methyl 5~amm&amp;thiaz£>le~4-carhoxyi&amp;te {@@610| Aqueous 3N HC1 (1 m'L) was added to a solution of methyl 5-(dipheaylmethyleneamino)thia25ole-4~carboxylate (1.22g, 3.81 mmol) in THF (5 mL), The reaction mixture was stirred for 1 h and the -white solid which had formed was isolated by filtration to give methyl 5-ammothiazoie-4-caiboxylate (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~(isitqmmflm-5~yl)aeetamM&amp;}ihmz&amp;le~4-carhexyiate [006111 Methyl 5-(2-(isoqninolin-5-y])acetamido)thiazoie~4-carboxykte was prepared from methyl 5-aminothiazole-4-catboxylaie (0.132 g, 0.834 mmol) and 2--(isoqurö.oim-5-yl)aeeiic acid (Ö.163 g, 0.834 mmol) according to protocol A, Retention time (min) = 2.400, method [3], MS(ESI) 328.0 (M tH). 5. L 4. 5~{2~(Is&amp;qmmlm~5~yl)acetmmd&amp;}ihmzf>le~4~earhexiimiie [00612] [0S06] 5 «(2-{Isoqniaoiin~5 ~y l)ac etamido)thi azoSe-4-carhox am i de was prepared from methyl 5-(2-(isoquinolin-5“yl)acetamido)thiazole-4-carboxykte (210 mg, 0.64 mmol) according to protocol H. Retention time (min) ::: 2.507, method [3], MS(ESI) 313.0 (M+H). 5. A 5. N-(4-(2ff-l,2f4-tmiml-S-yi)ihi&amp;zel~5~yl}~2-(ssoqmmlm-5-yi)acetamMe [@0613] ,¥-(4-( Iff-1,2,4-triazol"5“yl)thiazol“5“yi)-2--(isoqninoiin~5~yl)acetanude was prepared from 5-(2-(isoquinolin-5-yl)aectamido)tMazole-4"carboxamide (124 nig, 0.396 mmol) according to protocol 1. Retention time (min) = 4.890, method [8], MS(ES1) 337.1 (M+H); htt NMR(300 MHz, CD3OD) δ 9.75 (s, 1H), 8.43-8.59 (m, 4H), 8.29-8,31 (m, HI), 8.05-8.14 (m, 2H), 4.63 (s, 2H). 5.2, Synthesis of 2»(lsoqn!s5oIln-5~yl)~.¥~(4-(l"metliyl-lif~l»2,4-trinzol-5-yl)thiazol"5-yl)acetamide (63) [0Θ6141 2*(IsoqumoIin-5-yl)-ALi4-(]-metliyl-l//-l,2s44riaEoI-5-y!)tliia2oi-5-yljacetamide was prepared from 5-{2-(Isoqiiinoliii"5-"yi)acetamido}thiazole-4-carboxamide (Example 5,1.4., 197 mg, 0.631 mmol) according to protocol J. Retention time (min) -1.] 96, method [7], MS(ESI) 351.1 (M+H); Ti NMR (300 MHz, CD,3OD) S 9.75 (s, 1H)„ 8 45-8.60 (m, 4Π). 8.28 (d, J= 7.6 Hz, LH), 8.07 (dd, J= 8.8, 7.6 Hz, 1H), 7.73 (s, 1H), 4.61 (s, 2H), 4.27 (s, 3H).

Example 6 »xoxoxoxwnxwnxw

Synthesis of 2-(2-pyrMyl)»3~(i-napMhylaeetylamHio)tliloplseise (64)

6, L 2~Iod0~3~ftiirt~hHti}xyciirhotiyi&amp;Mim)ihk}phe&amp;e [00615] A vial was charged with 199 mg (1.0 mmol) 3 -{ferf-b»toxycarbonyiammo)thiophene, 164mg (2.0 mmol) NaOAc, 4,0 ml.. HOAc, and a stir bar. The mixture was stirred at mom temperature, giving a homogeneous solution “A”.. A second vial was charged with 162 mg (1.0 mmol) iodine monochloridc and 2 0 ml. glacial acetic acid, 'I he second mixture was swirled at room temperature. This second homogeneous solution "Ή'’ was added to solution “A” dropwise over three minutes, A white solid began to precipitate immediately. After the addition, the mixture was showed to stand overnight, at which time the white solid had separated from the brown supernatant. With stirring, 200 uL sat. Na^SjCMHiO was added, decolorizing the mixture .tVo-n 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 EtOAe and H?0, and the separated EtOAe phase was washed (sat. NaHCOj, then sat, NaCl).

The EtOAe phase- was filtered, and concentrated to give 262 mg (8J%) of the title compound as light brown crystals. !H NMR (CDC13, 300 MHz) δ 7.49 (bs, 1H), 7,45 (d, J = 5.4 Hz, 1H), 6.50 (bs, 1H), 1.54 (s, 9H). Method [5]: rt - 1.40 min; mlz ------ 269,9 (MH.+ minus isobutylene). 6.2» 2~(2~P}Tsdyihi~{ï~^iïphihyku:etyïa}tdm)}thhphene

[00616] A vial was charged with 253 mg (0.783 mmol) 2-iodo-3-(ieri-b«toxycarbonylamino>thiophene, 467 mg (1.27 mmol) 2-(trihutylstanrw1)pyridine, 18 mg (0.015 mmol) PdfPPh.ih, and 2 mL toluene. The vial was Poshed with mitogen. The vial was shaken at 95 C for 24 h. The cooled vial was opened, and TLC indicated consumption of 2-iodo~3-(terf-butoxycarbonylan3ino){hiophene and formation of a complex product mixture. The toluene was evaporated, and the residue was treated with 3 mL CF.CO2H. After 5 h at rt, the CF3CÖ2H was evaporated, and the residue was partitioned between 1 M H2SO4 and toluene. The aqueous phase was made baste by adding solid NaHCOj, and then the mixture was extracted with EtOAc. Evaporation of the EtOAc extracts provided 75 mg of a 2:1 mixture of 2-(2-pyridmyi)-3-aminothiophene and 2-{3-aminothiophenC“2-yl)-3-amii3.othiophene, as determined by HPLCMS, [00617] The title compound was prepared from the above mixture and 1 -naphthylacetic acid (230 mg, 1.23 mmol) according to protocol A. The residue was purified by flash chromatography using EtOAc/hexanes on silica gel, affording 40 mg (15%) of the title compound as a white solid. jH NMR (CDCI>, 300 MHz) δ 11.92 (bs, 1H), 8.26 (d, J - 5.4, 1H), 8.08 (dd, J = 1.8 Hz, i = 6.9 Hz, 1H), 7.93-7.88 (m, 2H), 7.597.46 (m, 6H), 7.27 (d, 3 = 8.1 Hz, 1H), 7.20 (d, J - 6.3 Hz, !R), 6.84 (dd, J - 4.8 Hz, 3 - 7,2 Hz, 1H), 4.24 (s, 2Β), UC NMR (COCI3, 75 MHz) δ 153.5, 147.L 138.3,136.7, 134.0,132.6, 130.9,128.9,128.6,128.4, 126.8,126.1, 125.6, 124.4,124.1,123.9,120.1, 119.8,116.9, 43.2. Method [5]: rt - 1.67 min; MH+ 345,2. ΕχΙΜβΜΙ

Synthesis of Thiophene Pyrazoles 7J, Synthesis of jV-<2-UjSr~pyra£ol>l>y!)thiophen'-3~yi)>2>f4-aiethoxyphenyl)* acetamide (65)

7.1.1, 1 ~{S~NUr(iihU}phen~2~yi)~! Ηψ}ψαζ/βΪ€ |006fS| Potassium rm-butoxide (2.28 g, 20.3 mmol) and lif-pyrazole (2.02 g. 29.7 mnio!) in DMF (50 ml) was stirred for 30 min. 2-chloro~3»nitrothiopliene (2.56 g, 15.6 mmol) was added and the solution was placed into a preheated oil bath, at !GG°C. After stirring for i L, the solution was diluted with brine and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, tillered and concentrated under reduced pressure, I he residue was flash chromatographed with 9:1, 4:1,7:1.3:2. and 1.:1 hexane:eihyi acetate as the eluant to yield impute 1 -(3-niüx)thiophcü”2*y] }-iH~pyrazoie. Method j 1 ] Retention time 1.52 min by HPLC (MH-i 196). 7.1.2, 2-{lH-Pymzoi~l~yt)thiopken-3-%mine [00619j The title compound was prepared from l“(3-mtrothiophen-2~yl)-li?-pyrazole using protocol Q to yield Impure 2-( 1H-pyrazoi-1 -yl)thiophen~3~amirie. Method [3] Retention time 1.55 min by HPLC (MH+ 166). 7,1 J, N~(2-(lH~Pymz&amp;i-l-yi)ihwpken-3-yi}-2-{4~metkmypkenyi)aeet&amp;ftiide [ÖÖ62ÖJ The title compound was prepared from 2»(lH-pyrazol-l-yl)tliIophen-3-amine and 2-(4~methoxyphenyl)acetic acid using protocol B. The solution was directly purified by HPLC to yield /9-(2--0 ILpyraeol--I --yijthiophen -5-y 1)-2-(4--metIioxyphenyl)aceiarnide. Method [7] Retention time 5,22 min by HPLC (MH+ 314). 1H NMR (300 MHz, CDCI3) δ 9.94 (broad s, 1H), 8,00 (d, 3=-5.7 Hz, 1H), 7,61 (d, J=2.7 Hz, 1H), 7.39 (d, J~1.8 Hz, UTi, 7,27 (m, 2H), 6.94 (m, 3H), 6.35 (t, j-2.4 Hz, 1H), 3.87 (s. 3H), 3.71 (s,2H). 7,2. Synthesis of 2A4-meihoxyphenyl)-A-{2d4~methyMJ^i>ra/oM» yl)thlophen-3-yJ)aeetamlde (66)

7.2.1. 4-Methyi-i-{5-mtwihiopken~2~yi)-ni~pyrezele [0062 ij Potassium reri-buioxide (2 78 g, 24.8 mmol) and 4-metbyl417-pyrazole (3.0 mi g, 37.3 mmol) in DMF (50 ml) was stirred for 30 min. 2-chloro-3-nilrotaiophêiie (3,08 g» 18.7 mmol) was added and the solution was placed into a preheated oil bath at 100'X.l 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:ethyl acetate as the eluant to yield 4--methyH-(3-nitrothiophen-2-yl)-li7“pyrazole. Method [I] Retention time 1,80 min by HPLC (MH+ 210). 7.2.2. 2-{4-Meihyl-lH-pymz8i~ï~yï)ihk}phen~3~amim [08622] 4-Mcthyl"l~(3“nitn>thiophcn-2»yl)- i /-/-pyraxosc was treated with protocol Q to yield impure 2 (4 -nietoyMH-pyrazol~1 -ydlthiophenA-amme, Method [3] Retention time 2.6! min by HPLC (MH+ 180), 7.2.3. 2-{4-Meth&amp;xyphenyi)~N~(2~(4~ffle$hyl~lH-pwa?M~l-yl)ihisfph€fs~3'-yijacemmide [60623] The title compound was prepared from 2-(4-methyi-lH-pyrazol-l-yi)tbiophen~3-amine and 2-(4-methoxypheöyl)aceli.c add using protocol B and purified by HPLC. Method [7] Retention time 6.16 min by HPLC (MH+ 328). Ή NMR (300 MHz, CDC13) 6 9.93 (broad s, 1H), 7.97 (d, 1-6.0 Hz, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 7.27 (d, 1=8.7 Hz, 2H), 6.96 (d, J-8.7 Hz, 2H), 6.90 id, >6.0 Hz, 1H), 3.87 {», 3H), 3.70 (s, 2H). 2.11 (s, 3H i. 7.3o Synthesis of /9-(3-(I /f-pyrazol-3-y]l)ihf©pheii~3~yll)“2~iu&amp;phfhaleji-l~ y!)acetar»ute (67)

7.3J, iii)~N-{2J3~fötmeihyfaMm0faayloyt}thwpken-$-yi)-2~(mtpk$t(tim-l- yi}ac(tmshie f00624j A solution of N"(2~a€etyfthiophen-3~yij-2-( naphthalan·· i -yi (acetamide (165 mg, G.53 mmol) in J^JV-dimethylfomamide dimethyl acetal (0.2 mL, 1.50 mmol) was heated at 80 UC for 2 h. The reaction mixture was partitioned between ethyl acetate and H20. The organic layer was washed with H20, dried (sodium sulfate), filtered and concentrated under reduced pressure to give the desired N-(2-(3-(dimethylamino)acry] oyl)ihiophen-3-yl)-2-(naphthalai-1 -yl)acetamide (185 mg, 95%) which was used without further purification. Method [4] na/z 387.0 (M+Na); rt = 2.199 min, 73,2. N~{2~{lM~P}’mz&amp;i~3~fi}ihmphm~3~ji}~2~{naphthsien~l-yi)meÏamée [ÖÖ62SJ To a solution of (£0-Ai-(2-(3-(dimethyiamino)aerjdoyl)thiopheEe~3-yl)-2>(naphtiiaien-l-yl)acetamide (185 mg, 0.51 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate (0.2ml, 4.11 mmol) and acetic add (0.5 mL, 8,73 mmol). The reaction mixture was stirred at room temperature o vernight under N2 (g) inlet 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 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-(naphthalcn-]-yl)acetamide (50 mg, 30%). Method [7] m/z 334.0 (M+H); retention time ~ 5.887. :ίΗ-NMR (DMSO-de) δ 12.92 (broad s, 1H), 10.37 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.92 (d, /= 6,9 Hz, 2H), 7,86 (d, J = 7.7 Hz, 1H), 7.77 (s, 1H), 7.66 (d,/= 5.3 Hz, 1H), 7.61-7.47 (m, 4H), 7.36 (d, /= 5.3 Hz, !H)S 6.36 (d, J= 2.4 Hz, 1H), 4,19 (s, 2H). 7,4. Synthesis of N-(2~(i~methyMi/-pyrazoi-3-yi)tlMopI^n"3-y!)~2"(naphthalen- l~yl)acetamide (68) [00626] To a solution of (i;)“A'r-(2-(3-(dimethyIamirio)aciy!oyi)thiopl'sen"3-yl)-2~(naphthalen4-yi)acetamide (Example 7.3.] 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 Nï(g) inlet and rhen concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H20. The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20:80 ethyl aeetate/hexaae) yielded N-(2-(l~methyHH-pyrazol-3-yl)ihiophen-3-yl)~2~(naphthalen-l~yl)acet;i.:mide (27 mgs, 20%). Method [7] m/z 348,0 (M+H); retention time - 5.328. lH~NMR (CDClj) δ 7.96 (d, J- 5.2 Hz, 2H), 7.94-7.91 (m, Hi), 7.86 (0,,/-7.8 Hz, 1H), 7.56-7.53 (m, 2H), 7.41 (d,J~ 7.8 Hz, 1H), 7.36 (d, J - 9.1 Hz, 1H), 7.32 (d, J~ 5.2 Hz, 1H), 7.,15 (s, 1H), 7.09 (d,J= 1.9 Hz, IH), 5.17 (d, J= 1,9 Hz, 1H), 4.13 (s, 2H), 3.45 (s, 3H). 7.5. Synthesis ofAH2K5~methyl-lj9-pyra2ol~3~yI)thk>phen~3~yl)«2-(i5aphthaJm~ I»yl)acetamide (69)

yfyscefizmiile [0062 7| A sol ution of N-(2-aceEylthioplien-3-yl)-2 -(naphth a j en-1 -yi)acetamide ¢197 mg, 0.64 mmol) in A(A-dimethyia.cetamide dimethyl acetal (0.3 mL, 2.05 mmol) was heated at 80 °C for 2 h. The reaction mixture was partitioned between ethyl acetate and HjO. The organic layer was washed with (1--0, dried (sodium sulfate), filtered and concentrated to give tire desired Ar-(2~(3-(dimet.hy]atnmo)but-2"enoyl)thiophen~3-yl)-2-(naphthalenfi-yl)acd:amide (139 mg, 58%) which was used without further purification., 7.5J, N~(2~{5-meihyi~lM~pymz&amp;i~3~}i)tMopheH~3~yi)~2~{nnphthulen~2~yi}aceiamMe [00628] To a solution of (E)-Ar-(2-(3-(dimethylamino)bui-2-cnoyl)thiophc.n~3~ yI)-2-(naphthafen-l-yl)ac-e4axnide (139 mg, 0.37 mmol) in abs. ethanol (2 mL) was added hydrazine hydrate (1 mt, 62,91 mmol) and acetic acid (0,5 mi, 8.73 mmol). The reaction mixture was stirred at room temperature overnight under 1¾ (g) inlet and then concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and H2O. The or; ame layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. Panfication by flash column chromatography (.silica, 20:80 ethyl aceiaie/liexane) yielded M{2«(5“methyl·· 1 f/-pyraaol~3“yl)0iiopher5-3-yl)-2-(tjaphtfcal.ai-l-yi)aeetamide ('20 mgs, 16%), Method {7] m/z 348.1 (M-f-Na); retention time = 6.791, lH-NMR (CDCU) S 10.28 (broad $,1H), 8.07 id, J = 5.8 Hz, 2H), 7,91 (d, /= 4.5 Hz, 2H), 7.53 (d,,/= 5.8 Hz, 2H), 7.53 (s, IB), 7.50 (d, J= 4.5 Hz, 2H), 7.08 (d, ,/ = 5.2 Hz, 1H), 5.88 (s, IK), 4.23 is. 2H), 2.19 (s, 3H). .Example 8

Thsophene TetraaoU1 Analogs 8.1. Synthesis 0f A-(3'(2if-tetra®ol-S-yl)flsiophen-2-yl)-2-(4-nsetIicjxyphenyl)~ acetamide (70)

8.1. L 2~{4~Melhox}’phei!ji)~N~(2~{4~methyl~lH~pjmz(fI.’-l~y$ihwphem~3~}flkicetamide |00629[ The title compound was synthesized from 2~(4-snethoxyphenyl)aeetic acid and 2-srninothiophetm-3<;arboni!rtle using protocol B. The crude product was purified using normal phase chromatography with 9:1, 4:1, 7:3, and 3:2 hexane:ethyi acetate as the eluant to yield JV-(3-cyaaothiophen-2-yJ.)-2-(4-methoxypheny!)ace{amide. Method [1] Retention time 1.81 min by HPLC (MH+ 307). 8.L2, N~{3~(2II-Tetmz&amp;i-5~}i)tki&amp;phe?i~2~yi)"2~{4~Meihaxypheiiy$)~&amp;£etiimid£ |09S30j JV“(3-cyanoihiophen-2~yI)-2-(4-methoxyphenyl)acetamide (285 mg,

1.05 mmol), and azidotributylstannane (614 mg , 1.85 mmol) in toluene (10 ml) was placed into a preheated oil hath at löö°C. After stirring for 6 h, The solution was concentrated and directly purified by HPLC to yield iV~(3-(2ii-tetrazol-5-yl)thiophcn-2» yl)-2-(4-methoxyphenyi)acetamide. Method [7] Retention time 4.92 min by HPLC (MH+ 316), ’H NMR (300 MHz, DMSO) 5 11.05 (s, 1H), 7.37 (d, i=6.0 Hz, 1H), 7,30 (d, >8.4 Hz, 2H), 7.23 (d, 3=6.0 Hz, 1H), 6.94 (d, 3=8.4 Hz, 2H), 3.88 (s, 2H), 3,76 (s, 3H). 8.2. Synthesis oi 2-{4-ïMethox>'pheisyI)-Ar-{3-(2»SBetlïyI-2lï~teS;ra/,ol~S-y l)ih ioph en~2~y Queetamide (71) [088311 lodomethane (0.20 ml, 3.21 mmol) was added ίο a heterogeneous mixute of//-(3-(2//-tetraz»l-5-yi)thiophea-2-yl)-2-(4-inethoxyphenyl}acetainide (.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 under reduced pressure. The residue was directly purified by HPLC to yield 2-(4-metboxyplienyl)-A,-(3“(2-methyl*2i;/-tetraz:oi-5-yl)thioplien-2-yl)acetamide. Method [7] Retention time 6.03 min by HPLC (MH+ 330). iII NMR (300 MHz, COCK) δ 10.59 (s, JH). 7.34 (d5 3=6.0 Hz, HI), 7.33 (d, 3=8.7 Hz, i*, -00 (d, 1=8,7 Hz, 21-1), 6.91 (d, 3=6.0 Hz, 1H), 4,28 (e, 3H)S 3.89 (s, 3H), 3.86 (s, 2.H). 8.3, Synthesis ofiV-(3-(2-(meihosymethyI)-2//-tetrMoI~5-yl)tSilophen~2"yl>-2-(4-methoxyphesyl)acetamlde (72) [00632] Cliloromethyi methyl ether (Ö.20 ml. 2.63 mmol) wait added to a heterogeneous mixture ofAL{3-(2/f-teirazol-S-yl)thïöphen~2-yl>-2"(4·-msthoxyphenyDacetaniide (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 to yield A'.(3~(2~(ru<uhoxynmihyl)"2i:/”tetrazol-5-yl)thiophen-2-yl)-2-(4-methoxyphenyl)-ac«taimde. Method [7] Retention time 6,60 min by HPLC (MPH 360). ÉH NMR (300 MHz, CDC13) 8 10.58 (s, 1H), 7.47 (d, 3===5.7 Hz, 1H), 7.33 (d, 3=8.4 Hz, 2H), 7.00 (d. .1=8,4 Hz, 2H), 6.93 (d, 3=5.7 Hz, 1H), 5.77 (s, 2H), 3.87 (s, 3H), 3.86 (s, 2H), 3.37 (s, 3H). 8.4 Synthesis of Ar-i3”(l~iïiiechC9symeiïiyi)-i//~ietr«xo.l~5-yï)ihiopIiCïï-2-y!)-2-(4·-meth®xyphOTyl)acetamitte (72¾)

[00633] The title compound was isolated during the purification of N-G-(2-(methoxymcthyl)-2iiMetrazol"S"yl)thiopliea>2-yl)-2-(4-inethox>'phcny.l)acetamide, above. Method [7] Retention time 6.60 min by HPLC (MH+ 660).

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Synthesis of Thiophene Irnidimdes 9.L Synthesis of /V»(2-(l-methyl-lJi»isnidMol~2~yl)ihiopheii-3-yl)-2-(saphtl8oiei5-l»yI)acetemWe (73)

.¾ L1, 2~{Naphihsiien~l~yl)~N~(thii>phen-3-yl)scctamide 1606341 2-(naphthalen~l -y])acetami<k (14.00 g, 75.6 mmol), 3-iodothiophene (10.15 g, 48,3 mmol), tom-wl^diaminocydohexaiie ( 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 18 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 chlorideretbyl acetate as the eluant to yield 12.26 g (95% yield) of 2-(naphihalen"i~yi)-A’"(thiophen-3"yl)acetamide as a brown solid. Method [7] Retention time 2.07 min by HPLC (MH+ 268). 9Λ.2, N~(2~S&amp;dotM&amp;phm.~‘i~yl)~2~(nepkthalen~l~yl)asets,mlde [00635] 2-(naphtb.alsr!~l~yI)-Ar-(tbioplien-3-yI)acetamide (7,50 g, 28.1 mmol) and Nriodosuecmiroide (7.12 g, 31.6 mmol) in acetonitrile (1ÖÖ 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 chloride:ethyl acetate as the eluant to yield impure jV~(2-iodothiophen-3-yl)-2-(naphthalesi-l-yl)acetamide. Method [1] .Retention time 2,32 min by HPLC (MHt 394). yi)aeeiamide [0Ö636] This molecule was synthesized from N-(2-todoihiophen-3-yi)-2-(naphthalen~]-yi)ace!amide and ]-methyl-2-(tributylstannyI)-lH-imidazole according to protocol E. The residue was directly purified by HPLC to yield #-(2-( 1 -methyl-1//-iii»dazoi-2-yi)thtophen-3-yi)-2-(naphthalert-l-yi)acetamide. Method [7] Retention lime 3.41 min by HPLC (MH+ 348). i t NMR (300 MHz, CDCh) δ 10.27 (s, 1H), 7.87 (m, 3H), 7.51 (m, 6H), 6.91 (d, JMLS hz, 1H), 6.82 (d, J===1.5 Hz, IB), 4..15 (s, 3H), 3.68 (s, 2.H), 9.2. Synthesis of 2“(4~mottioiypheisyl)~j¥~(2-(I-m£thyMM-ïmida®0i-4-yl)thiophen-3"yi)acetaïnide (74)

9.2,1. I~Metkyl-4~{tnbutylstmn}4)-lE-imMuzoi8 1006.17] 3 M Ethyl magnesium bromide in THF (11.0 ml, 33.0 mmol) was added dropwise to a solution of 4-iodo-l-methyl-J//-imidazole (5.61 g, 27.0 mmol) in THF (50 ml) at -78¾. After stirring for 2 h, tributyltin chloride (8,0 ml, 29.5 mmol) was added. After stirring for an additional 2 h, the solution was concentrated under reduced pressure. The residue wens flash chromatographed (hexanetethyf acetate) to yield I-rnctbyl-4"<iribulylsia£Wiyl}-l//-in)idazo3c. Method {?] Retention time 7,34 min by HPLC (MH+ 373). 9.2.2, 2-Meihyi-4-(3~ftitroihwphe»-2-yl^IH-imMaz&amp;ie [IICI63SJ The title compound was prepared from, 2~eh3.oro-3~nitrothiophcne (2.57 g. 15.7 mmol) and l-methyM^tnT>utylstannyl)4ii?-imidaz»ie (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 Hash chromatography (hexane ethyl acetate). Method [1] Retention time 0.57 min by HPLC (MH+ 210). 9.2.3, 2~iI~Methyl~lH4myez&amp;l~4~yl}ihi&amp;pken"3^mmm [Ö0639J 1 -mcUiyl^-(3-nitFothiophen-2-yl)-lF-imi.dazole was reduced according to protocol F to yield 2-('l-niethyl-li:/-ixnidazoi-4~yl)thiophen~3-amine.

Method [6] Retention time 0.35 min bv HPLC (MH+ 180), 9.2.4, 2~(4-Metk&amp;x}iphenyi)~N~(2~(l~meihyï~ÏH~imidazol~4-yl}ihiopkm~3~ $i)aeekmide [00640] The title compound was prepared from. 2-(1 -methyi-1 H-injidazoi-4- y!)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid using protocol B and was purified by HPLC. Method [8j Retention time 3.55 min by HPLC (MH+ 328). 3Ii NMR (300 MHz, DMSO) 8 10.37 (s> HI), 8.33 (s, 1H), 7.48 (3m, H), 7.26 (d, J=8.4 Hz, 2H), 6.92 (d, 3—8.4 Hz, 2H), (s, 6H), 3,60 (s, 2H). 9,3, Synthesis of Ak(2“(l/f~lmfdaz©1-4-yl)thiopImn-3“yI)-2-(4“methoxypbemd)~ acetamide (75)

9.3.1, [00641] 3 M Ethyl magnesium bromide in THE (5.0 ml, 15.0 mmol) was added dropwise to a solution or 4~iodo~i~tr:tyl i//· imidazole (4,44 g, 10.2 mmol) in THF (100 ml) at -78¾. After stirring for 2 ft, tributyltm. chloride (5.0 ml, 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 hexanexthyi acetate as the eluant to yield 7.72 g of impure 4~(tributylstamiyl)-l -triiy 1-1//-imidazole as a yellow .solid. Method [7] Retention time 10.89 min by HPLC (MH+ 601). 9.3.2. 4-(3-Nitmtki&amp;phe&amp;~2~yl)~I~triiyl~lff-midawie 1006421 The title compound was prepared from 2”Chioro-3-nitrothiophene and 4>jiTibuiyIstasi.n.y 1)-.1 -!n.iy 1-1//-imidazole according to Protocol. E. Yield: 2.43 u (56% over 2 steps from 4-iod.o-ltniyl-1 //-imidazole) of 4 (3 -rsiirothiophen~2'-yi)·- l.-trity! IH-imidazole as a greenish-yellow .solid. Method [7] Retention time 9.92 min by HPLC (M+Na=460). 9.3.3. 2~{l»Trtfyï~lH~imidaz&amp;if~4~y$}thii?pkeïi~3~@mim [0®é431 The title compound was prepared from 4-(3-nitrothiophen-2-yi)-l-trityl-,1 H-imidazoie using protocol F (1,27 g, 95% yield) as a red viscous liquid. Method [7] Retention rime 5.51 min by HPLC (M+Na=43Ö). 9.3.4. 2-{4~Mstlwxyphe!nyl)~iy~{'2~(l-tH^i~2H~imid&amp;ZiSi~4~yi)tkwphe^-3~yi}aeeasmide ]00644] [0007] The title compound was prepared from 2-(l~trityMH- irmdazol.-4-yl)thiophen-3-anïine and 2-(4-metfeoxyphen.yl)acetic acid using protocol B ¢561 mg, 59%) as a brown solid. Method [7] Retention rime 9.46 min by HPLC (MH+ 536), 9.3.5. N-(2~{lH-lMid8zo!-4-yl)fkiopkefi-3-yl)~2~(4~&amp;tethi)X¥pheHyi)&amp;ceMiiiide [0064S] 2"(4-Methoxyphenyl)~.Y-(2~(l-trityl-lH-imida2ol-4~yl)thioplien"3" yiiacctamidc (561 mg, 1.01 mmol) in T.FA (10 ml) was stirred for 1 h. The solution was concentrated under reduced pressure and the residue was directly purified by HPLC to yield jY-(2-(li7-imidazol-4-yI)thiophen-3”y!)-2-(4-meihoxyphenyl)acetamide. Method 18] Retention time 3.37 min by HPLC (MH+ 314). Tl NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 8.60 (s, IH), 7,59 (s, IH), 7.53 (ds 3=5.7 Hz, IH), 7,49 (d, 1=5,7 Hz, IH), 7.23 (d, 3=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 3.73 (s, 3H). 9.4, Synthesis ofA-(2-{lff-lnïsdazol-4-y!)ihiophe!ï-3-yl>“2-{2“<)xo»3i4" dïhyclroq«lwollM~.1.(2i#>-yl}ace4anilcle (76)

9.4.1. 2~(2^x0~3>4^ikydr0qitiit0lM~l(2H)-yi)-N-(2-(l-fiityi-2B-§mMaz0i-4- yf)tkiifpheiïS-yi}eesföttiiiïe [U06461 The title compound was prepared trom 2-(1 -trityl-!H-imidazol~4-y1)th iopheo.-3-amine and 2-(2-oxo~3,4-dihydroquinoiin~ 1 (2H)-yl)acetie add using protocol B (269 mg. 32%), Method [7] Retention time 9,32 min by HPLC (MH+ 593), 9.4.2. N«(2-{lH-imühziïi-4~yi}ihiiïpk&amp;ft"3"}i}"2-{2~(Km-3t4~dikydp^4m&amp;im~l{2ff)~ yi)ecetamide [0064η The title compound was prepared from 2~(2~oxo-3,4-dihydroqumo!ii!-](2ii)~yl)-iV-(2~(l-trityl-li:/-imidazol-4~yl)tbiop3tei3~3~yl)aeetarnide (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) 6 10.58 (s, 1H), 8.52 (s, 1H), 7.65 is. 1H), 7.54 (s, 2H), 7.22 (m, 2H), 6.99 <m, 2H), 4.68 (s5 2H), 2.95 (m, 2H), 2,66 (m, 2H). 9.5. Synthesis of 2-(4-nseiboxypimïiyl)--,¥-(2-(2-rnethyl-IiI--smldazi>L4--yI)thsopheR»3-yl)acetamide (77)

9.5.1. 2-Metkyi-4~{tributyki8tiftyih1 -witpi-Hï-mhlezoie [606481 3 M Ethyl magnesium bromide in THF (6.0 ml, 18.Ö mmol) was added dropwise to a solution or 4-iodO"2"mdhyi-l-tnTyl-l//-imidsi»le (5.30 g, 11.8 mmol) in THF (i00 ml) at -78°C. After stirring tor 2 h, tributyhin chloride (5,0 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 sedate, filtered and concentrated under reduced pressure to yield 8,49 g of impure 2“meth.y{*4-(tributyl.stam3yl)-l-tHtyi-t /7-imidazoie as a orange liquid. Method |71 Retention time .11.32 min by HPLC (MH+ 615). 9.5.2. 2-Metkyl~4~{3~nity®thiophen-2-yl)-I-t?iiyï~lH-ifflid&amp;z&amp;ïe [9(}649| The title compound was prepared from 2-merhyi-4-(tributylstamiyl)-I~ trityl- IH-imidazolc and 2-ch1oro-3-nitrothiophenc using protocol E (3.43 g, 76% over 2 steps). Method [7] Retention time 8.87 min by HPLC (M+Na=474), 9.53. 2-(2-Methyi~l~Mtyi~lIl~imisiisz&amp;i~4~yi)thmpken~3~umiBe [ÖÖ6S0] The title compound was prepared from 2-methyi-4-(3*nitroihiophen~2~ yl)-l -trityl-lH-inndazole using protocol F (1.33 g, 100% yield). Method [7] Retention time 5.42 min by HPLC (M+Na=444). 9.5.4. 2^4-Meih&amp;xypkmyi}~N~(2-(2~metk)?l-2-tnti?i~Hf~iMM&amp;ze!-4~y4}tki&amp;pkm-3- vljaceiamide [906511 The title compound was prepared from 2-(2-meib.yl-1 -trityl-1H-imidazoi"4-yl)thiophen~3~amine and 2-(4-methoxyphenyl)aeetic add using protocol B (540 mg, 57%), Method [7] Retention time 7.42 min by HPLC (MH+ 570). 9.5.5. 2~(4~AIeikexyphmyi)~N~(2~{2~methyi~lH~imidszoi-4'-yl)thiophm~3- yihiceiamide [00652! 2-(4“mcthoxyphenyr)-A-(2-(2~methyl-1 -trityl- l#"imidazol-4-yt)thiophen-3-yl)acetaraidc (540 mg, 948 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 2-(4-raethoxvpheiiyl5-uV-i2-(2-mcthyi·- li/-imidazol~4-yl)thiopknj~3~ yl)aceiamide. Method [8] Retention time 3.52 min by HPLC (MH+ 328). 43 NMR (300 MHz, DMSÖ) δ 10.02 (s, 1H), 7.60 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.40 (d, 1=5,4 Hz, 1H), 7.23 (d, 3-8.7 Hz. 2 Hi, 6.89 (d, .1-8.9 Hz, 2H), 3.73 (,s, 3H).

Synthesis of A^2^2~raethy!~1^4mida:mi"4-yI)thtGphcn-3~yli-2^2~öx©-3,4” dlhvdroi|nm«lln»l (2/f)yyI)&amp;cetamiik (78)

9.6. L Ν-(2~(2~ΜβΐΗγΙ~1~(ίΗνί-1Η·4ηίϊΦχζοίΦχί)ίΗί&amp;ρΗ€»-3^ϊ)~2~(2~οχο-3,4- dihydrvqmnoim~l(2H)~\'i}aceiiimid>> 100653\ The tide compound was prepared from 2-t'2-meth.y[-14niv!~]B~ iinidajK)l-4-yl)tiiiophea-3-anwne and 2~(2-oso-3,4”dihydroqumolki"I(2It)-yI)aeeiic acid using protocol B (123 mg). Method [7] Retention time 7,33 min by HPLC {MTB- 609), [006541 iV-(2~(2-methyl-1 -trityl-1 /7~imidazoi-4”yl)tliiophen-3~y])~2~(2~oxo-3 .4-dihydroqumolinH(2i/)--yl)acetaniids (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 A'~(2·-(2--methyl-li7-imidazol-4-yl)thiopheti~3~yI)-2~(2~oxo-3,4-dihydroquinolirt-1 (2i7s~yl)acetamide, Method [8] Retention time 4,05 min by HPLC (MH+ 367), lH NMR (300 MHz, DMSO) δ 10.28 (s, 1H), 7.57 (m, 2H), 7.43 (d, 3-4.8 Hz, 2H), 7.22 (xb, 2H), 6.99 (m, 2H), 4.68 (s, 2H), 2.92 (m, 2H), 2.59 (m, 2H), 2.46 (s, 3B), 9.7. Synthesis of i¥»(2Tl£f~teMaz0l“1~yJ)thiophen"3~yI)2Rti&amp;pMh&amp;l£is~l~ yl)aeetamsde (79)

9.7.L J~(3-Nitmthkiphen~2~yi}-III~mM(iz&amp;le [00655] Imidazole (860 mg, 12,63 mmol) was added to a solution of 2-chioro-3-nilKwhiophcne (Ig, 6.10 mmol) m abs. ethanol (20 mL). T he 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/hexane) gave 1-(3-rJtrot.biophen-2-yl)-l//rimida2ole (540 rug, 45%), See Erker, T, I et aL, J. Heterocylk. Chem. 39 (2002) 857-861, Method [3] m/z 195,9 (M+H); retention time - 0.615. 9,7,2. 2~{lH»hnidazi>i~l~yi}ihhpketi~3~amme ΙΘ0656] The title compound was prepared flora 1 -(3-nitrothiophen-2-yl)-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 166.0 (M+H); retention time = 0.227.

[00657] To a mixture of 1-naphthyl acetic acid and 2-(l/f-imidazol-l-y0d.riopheii-3~amine in anhydrous CH;CI; was added 0-(7-«izabcnzotriazoi-1 -yl)-,tV,iV,A%v;-tetramethyl uranium hexafluorophosphate and 4-methymoipholhse. A small amount of DMF was added to help starting material reagents go into solution. The reaction mixture was stirred overnight under hi.; (g) miei and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica, 10:90 methanol/methytene chloride) to afford iV-(2-(l//-imidazol-]-yl)thioplien-3-yl)2-(naphlhaleri~l~yj-acetamide (209 mg, 33%), The desired product was purified by preparative HPLC, Method [8] m/z 334.1 (M+H); retention time = 4,885. lH-NMR (CD3OD) δ 8.83 (8,.111), 7.89-7.80 (m, 2H), 7.77 (d, ./=== 7.8 Hz, 1H), 7,51 (d, J = 6.3 Hz, 211), 7.48-7.52 (m, 5H), 7.17 (d, J- 6.3 Hz, 2H), 4.08 (s, 2H). 9,8. Synthesis of of 2-(4“ïnethc5xyphenyI)-A~(2-(4~iTsethyl-t//”imic!azoI-l~ yI)thiopheu-3-yl)aeefamidc (80)

9.8. L 4~Methyl~I~(3-mir*t&amp;iophm~2-yi)-lfi-imléfiz®te [00658] 4-methyl-1 -(3-mtrothiophen-2-yl)-1 ff-irnidazole was prepared from 2-chloro-3*nitrothiophene and 4-mcüiyl-] H~hmdazof e according to the procedure described in Example 9,7.1,, above. Purification by flash column chromatography (silica, 40:60 ethyl acetafce/hexane) gave the nitro intermediair (i .26 g, 49%), *H-NMR (CDClj) 6 7.67 (§,10), 7.59 id, J------ 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“Methyi~lM~imidaz(.fi~l~}?i)thiophm~3~amine [00659] 2-(4-methyI-li7-imidazoM-yI)thiophen-3-amine was prepared from 4-Tnethyl-1 -(3-nitrothiopheo-2-yl)-1 H-imidassole 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~Mefhoi^phenyi)~N-(2-(4-m^hyl~lH-imM&amp;z0i-i~yi)ihiephen-3-yi)aeetamide [ΘΘ66Θ] 2-(4-methoxyphenyi}-A~(2~(4--methyl-Ii7-imidazoM-yl)ihiophen-3-yl)acetamide was prepared from 2-(4-meihoxyphenyl)acetie acid and 2-(4-methyl-1H~ tmidazoH-yl)Ü3iophen-3-amine according to the procedure described in Example 9.7.3., above, Purification by flash column chromatography afforded the final product (silica, 75:25 ethyl acetate/hexane) (77 mg, 6%). Method [7] m/z 328,0 (M+H); retention time - 1.001. *H-NMR (CDCI3) δ 8.00 (broad s, IH), 7.77 (d, /= 6,4 Hz, 1H), 7.16 (s, IH), 7.13 (d, J~ 8.7 Hz, 2H), 6.85 (d,/= 8.7 Hz, 2H)S 6.50 (s, IH), 3.81 (s, 3H)S 3.65 (s, 2H), 2.15(6, /=0.9 Hz, 2H).

Example 10

Thiophene Pyraztae Analogs 10.1. Synthesis of 2-(4-3iMetl}0xyplteey.l>r'V>(2"<pyra2ln-'2-yi)thiephen<3> yi (acetamide (81)

10.1, L 2~0~Nitmthiepkm~2~y$)pymz£ne [086611 The tiije compound was prepared from 2-(tribiitylstannyl^pyrazi«e and 2-eMoro~3~mtroihiQphene 'using protocol E and was purified by flash chromatograpy (hexane:ethyl acetate). Method [7] Retention time 2,38 min by HPLC (MH+ 208), 10. /.2 2~{Pymzift~2~vl)?ki(q}kïm~3~smsm IÖÖ662J The title compound was prepared from 2-(3-nitrotliiopben«2· yl)pyrazine using protocol F. Method [8] Retention time 2.17 min by HPLC (MH+ 178 ï. 10, J. 3. 2-(4-Methoxffihmy4)~N^~(pyrezitt-2-yi)thi0pkeit~3~yi)eceiimMe (00663] The title compound was prepared from 2-(pyrazin-2-yi)tliiophen-3-amine and 2-{4-methoxyphenyl)aeetic acid according to protocol B and was purified by HPLC. Method [7] Retention time 5,91 min by HPLC (MH+ 326). !i.i NMR (300 MHz, DMSO) δ s (1 L02s IE), 8.81 (d, JM>.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, .1=8,7 Hz, 2H), 3.78 (s, 3H), 3,72 (s, 2H). 1 Θ.2. Synthesis of j¥-(4-cyan®-3-(pyrazin~2-y!}th!of)h£n~2~yI)-2~(qn!n0Mn~5” yl)acetamide

ί δ, 21. 4-Bromo-5-nitrothfflphem--3~ciirhtfmtrMe [ÖÖ664J The title compound (2.8 g, 71 %) was prepared from 4-bromoÜiiophene-3-carbonitrile (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); lH NMR (300 MHz, CDCh) S 8.12 (s, M). 1 &amp;, 2,2, 5"NitF0~4~{pymziït~2~yï)tkiepkeiie-’3-carèmifriie [00665} To a solution of 4»broiTsO-5-nitrothii>phene-3-carix)nitri{c (312 mg, .1.34 mrnob in dioxsne (4 mL) was add*,d tetrakis(triphenylphosphine)palladiiuri{0) (154 mg, 0.133 mmol) and irihuiyisbmnylpyrazine (794 mg, 2.15 mmol). This was heated by microwave irradiation to 140°C for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography to afford the titled compound (166 mg, 53%); Rf= 0,33 (20% EtOAc/hexanes; silica); HPLC metkod [4], retention time = 1.45 min; MS(ESï) 233.0 (MER). 1 ϋ, 2,S~A mhw~4~{pwttzw~2~}4}thwphemi™3^aï"b{mitriie [00666} To 5"mtro-4-ÖJ>Tazia-2"yl)thiophene»3-cafbo«itrilc (166 mg, 0,72 mmol) in cone HC1 (3 mL) at it was added tin(li) chloride (327 mg, 1.7 mmol). This was stirred at rt for 2 h, whereupon the reaction mixture was basified with aqueous NaOH and extracted with EtOAc. The combined organic extract?. were dried (N^SO.·), filtered and concentrated to give a brown oil (31 mg, 21%), HPLC method [4], retention lime = 1.458 min; MS (ESI) 203.1 (MH+). 1 (l 2.4, !y-i4~Cyim&amp;-3-(pymzm~2~fi)iki&amp;phen~2~yi)~2-(qmnoUn~5~ji}(icet{mtide [60667] The title compound was synthesized from 5~amino-4~(pyrazm-2-yl)thiophenc-3-earbomtrile (30.5 mg, 0,15 mmol) and 2-(quinolffl-5-yl)aeetic add hydrochloride (36 mg, 0,16 mmol) according to protocol A. The product was purified by HPLC method [4], retention time - 1.393 min; MS(ESi) 372.1 (MH.+); ‘H NMR (300 MHz, CDjOD) δ 9.30 (d, J = 1.5 Hz, IH), 9.06 (dd, 4.8, 1.3 Hz, j H), 8.99 (d, /= 8.5

Hz. 1H). 8,51 (d, J- 2.6Hz, HI), 8.29 (i,/- 1.9Hz, 1H), 8.20id,/ 8.6 Hz, 1H), 8.09 (dd,/= 8.6, 7.1 Hz, 1H), 7.95 (s, IB), 7.93 (d, J= 6.7 Hz, IHh 7.86 (dd, J = 8.6,4.9 Hz, 1H), 4.55 (s, 2H).

ExamBle 11

SyMbesis of 2"(!soquMiolIn-5-yJ>-IV-(4-{pyr&amp;ziM~2~yI)tMaz0l-5"yJ)aeetamide (82)

ILL tert-Butyl l-brmmithmioi-S-jlmrhamsfe [00668] To a solution of tertebutyl thiazo1~S~yicarbamate (WO 2007/071955) (607 mg, 3,0 mmol) in cMorofonn (50 mL) was added A-bromosuccini mide (542 mg, 3 0-! mmol) at 0 °C. After 1 h, reaction was quenched by addition of saturated NaHCCb solution (50 mL), The layers were separated, and the mixture extracted with CHOU (3 x 50 mL), The combined organic extracts were dried (MgSChf), filtered arid concentrated. *H NMR (CDCfi) d’S.37 (d,,/- 0.6 Hz, 1H), 7.05 (br s, 1H), 1.35 (s, 9H); MTit· 278.9, .11.-2, iert-Buiyi 4-(pym^-2-yS)thmzol-S-yi€arhamisUe

[006691 A mixture of teri-butyl 4-bromothiazol-5-ylcarbamaic (420 nig, 1.5 mmol), tetrakia(tripher?ylpl:o.splnne)palladium(0) (170 mg, 0,15 mmol) and 2-tnbutyL staaaylpyrazine (930 mg, 2.5 mmol) in anhydrous dioxane (4 nil,) was heated to 140 °€ in a microwave reactor for 2 h. The reaction mixture was then concentrated in vacuo and purified by flash chromatography (EtOAe/hexanes) to give the desired product (260 mg, 62/¾). lH NMR(CDCh) cHIJO (s, 1H), 9.47 (d,./=1.4 Hz, 1H), 8.52 (t,/=2.0 Hz, 1H), 8.45 (d, J= 2.7 Hz, 1H), 8.40 (s, 1H), 1.58 (s, 9H); MHr 279,0. 11.3. 2-0mqmneUn~S-yi)-N~{4~(pytii^ti~2~yl)ihmz&amp;LS~yl)sieeiamide [09670] To a solution of ieri-bulyl 4-(pyi^m-2-yi)thiazol-5~ylcarbamate (260 mg, 0,94 mmol) in CB^Cl·?. (1 mL) at 0 °C -was added irifluoroacetic acid (1 mL) and the mixture was allowed to warm to rt over 1 h. The solvent was removed in vacuo and the exude product was used without further purification.

[00671] The crude 4-(jpyrazin-2-yi)thiazol-5-amme was coupled with 2-(isoquinolin~5~yl)acetic acid hydrochloride using procedure A and was purified by BPLC purified to afford desired material as a white irifiuoroacetie acid salt (107 mg), Method [8]: rt - 3.71 min; ?B NMR (CDClj) δ i 2.; 6 (s, 1H). 9.80 is, i H), 9,48 (d, J™ 12 Hz, 1H), 8,64 (d, J -- 6.4 Hz, 1 H), 8.47 (s, 1H), 8.45 <d,,/==== 2.7 Hz, )H), 8.39 (d, J8.5 Hz, ΪΗ). 8.31 (d.,/- 6.5 Hz, IK), 8.15 (d, J =~ 7.2 Hz, IB), 8.10-7.98 (m, 2H), 4.45 (s, 2B); MH+ 348.0.

Essiablfi 12

Synthesis of JV-C^’-bithiazoi-S-yl^-^lsoquinolm-S-yllaeetamlde (83)

if./.· ieM-Butyl 4f4*-Mtkmml~5~ylca?b®maie £00672] A mixture of fen-butyl 4 bio met h i azo 1 - 5 -y 1 e ar bam ate (590 mg, 2,1 mmol), tetrakis(tripheïiyiphösphme}pa!iadium(0) (240 mg, 0,21 mmol) and 4-tributylstannylthiazofe (1.18 g, 3.2 mmol) is anhydrous dioxane (5 ml,) was heated to 140 °C in a microwave reactor for I !i. The 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. 2 2,2, N~{4,4

[006731 Corn. version of tert-Butyl d^'-bithiaznl-S-ylc-arb&amp;m&amp;ie to the above titled compound was performed according to the procedure detailed for the synthesis of 2-(isoquinolm-5"y!)~N~(4“(pyrazm-2-yl)-hiazol~5-yl)aceta.miide. Met hod [4]: it-1.22 min; MMR (έΑ-MeOD) ¢59,73 (s, 1H), 8.79 (d, J~ 2.0 Hz, 1H), 8.63-8.45 (m, 4H), 830(4,/--- 7.1 Hz, 1H), 8.09(1,/- 7.8Hz, 1 Η), 736(4/-2.01¼ 11-1),4.58(42H>; MEf 353.1,

Exmin>ic 13

Synthesis of 2-(4-rsiethoxyplieiiyl)-Af-(2-(2-oi;iii>xaz©IIiliii-3~yl)«;htophefi~3- yl}acetarnide (84)

13J, 3~(3-NimHkmpken-2~yi)<fxaz(>Ud'sf!~2~ime {006741 Potassium fcrf-butoxide (1.86 g, 16.6 mmol) and oxazolidin-2-one (1.90 g, 21.8 mmol) irt DMF (50 ml) was stirred for 30 min, l-cMoro-S-nitrothiopbene (1.64 g, 10.0 mmol) was added and after 1 h, the solution was placed into a preheated oil bath at 10G°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 hexane:ethyl acetate as the eluant to yield impure 3-(3mitrothiophen-2'-yi)o,\azolidm-2-one, Method [3] Retention time 2,50 min by HPLC (MH+ 215) and (M+Na-237). 15.2, 3~(3~A mimrthmpkm-2-yl)oxazoUfUn-2~ene [00675] The title compound was prepared from 3-(3-niirotitiophen~2~ yi)oxazoiidin-2-one according to the procedures of Example 1.97.2. Method [7] Retention-time 0,85 min by HPLC (MH+ 185). 13.3. 2~{4~Metk&amp;xyphesiyi)~N~(2~(2~&amp;xmxmoUdm~3-yi)iM&amp;phes-i~3~yi)u€etamiée [0(16761 The title compound was prepared from 3-(3-aminothiophen-2--yi)oxazolidin-2-ons and 2-(4-methoxy,phenyl)aeetic 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), !H NMR (300 MHz, CDCb) δ 8.14 (broad s, 1H), 7.39 id. .1-5,7 Hz, 1Η), 7.27 (d, J-9.0 Hz, 2H), 7.06 (d, 1===5.7 Hz, IH). 6.92 (d, 3=9,0 Hz, 2H), 4.47 (m, 2H), 3,89 (m, 2H), 3.83 (s, 3H), 3.64 (s, 2H). 7.3.319.9 ^ ^ i 9

Beter min alum of Kinase Activities

Abbreviations j0067?I [0008] DTI: DL-dithiothreitof; DMSÖ: dimethyl sulfoxide; BSA: bovine serum albumin; ATP: adenosine triphosphate; MARK: mitogen-activated protein kinase; EDTA: ethylenediaminetetraacetic acid; HEPES: (4-(2-hydmxyethyl)-1 -piperazineetlianesulfbmc acid),

Materials EPIW-1

Biotin-Jun-Jun 50mer {BIOTIN-I.C-Asn-Pro-Lys-Ile-Leu-Lys-Gin-Ser-Met-'T'hr-Ix’u-Asn-Leu-Ala-Asp-Pro-Val-Giy-Ser-Leu-Lys-Pro-His-Leu-Aig-Ala-Lys-Asn-Ser-Asp-Leu«Leu-Thr~Ser-Pro-Aiq5-Yal-Gly-.Leu-Leu-.Lys-Lei3-Aia-Ser-Pio-Glu-Atg~Giu-Arg-

Leu-OH) EPIG-1

Biotin- ELK-1 45mer (BlOTIN-LC~PnvGln-Lys«GIy-Arg-Lys~Pro~Arg~Asp~Leij~Glii-

Leu-Pro-Lcu-Ser-Pro-Ser-LemLen-Gly-Gly-Pro-Gly-Pto-gk-Thr-Leu-Ser-Pro-Ile-Ak-

Pro-Arg-Ser-Pro-Ala-Lys-Leu-Ser-Phe-Gln-Phe-Pro-Ser-Ser-OH)

Biotin-ATF-2 35mer (BIOTIN-LC^Leu-Ala-Val-His-Lys-His-Lys-His-Glu-Met-Thr-l^u-

Lys-Phe-Giy-Pro-Aia-Arg-Asn-Asp-Ser-Val-IIe-Val-AIa-Asp-Ghi-Thr-Pto-Thr-Pro-Thr-A rg-Ph e-Leu-0 H) aP38b (Upstate Biotech); aP385 (Ceil Signaling Technology); SA-XL (High grade XL665-conjugated streptavidin SA-Xient, CIS Bio International); Eu-ELK-l-Ab (Phosplio- ELK.-1 antibody 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 from Ceil Signaling Technology labeled by Perkin Elmer with Lance Bit W1024); Eu-Ser-73-Ab (Phospho-e-Jun (Ser?3) 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 En WÏÖ24); aJNKl/SAPKlc, aJNK2/SAPKla, aJNK3/SAPKlb, «JNKl/SAPKlc, «JNK2/SAPK1 a, iUNK3/SAPKlb, MKK4/SKK1 active, MKK7bl active, uMAPK2/Etfc2, MEK1 (active), up38ct/SAPK2a and MKK6/SKK3 (active) from Upstate Cell Signaling Solutions; K252a (A.G, Scientific); 506126 (Calbiochem).

Reagents

,\W\W\W\\V».W\W\WV |0067S| Reagents were prepared and stored as specified below. JNK buffer stock solution: 2'; n>M HEPES (free acid), .1 mM hfgCfi. pH 7.0« prepared by media kitchen and .stored, at 4°C. ννίΛ.'! v.v 50 mM HEPES, 0.1% BSA, 400mM Nad, stored at. 4°C.

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

1 ATP 275.6 mg of ATP (MW 551.2) were dissolved In 500 mL DI H20 and stored at ~20°C. 14,L Active MAFK TR-FMET Assay Procedure (1) Assay buffer #1 was prepared (JNK. buffer stock solution, 0.0025% Tween, ImM DTT). (2) Assay buffet #2 was prepared (assay buffer #1, 0.025% BSA), (3) Test compound solution preparation: 5X compound solution was prepared using assay butler #1 with 5% DMSO. The compound solution (ΙΟμί/weÜ) was added to a 384-well plate. (4) aMAPK preparation: aMA.PK stock (I OOug/rni) was thawed from 80l'C on ice, and &amp;MAPK (lÖüg/köpfoG.Sug/pl) solution using assay buffer #2 was prepared. The aMAPK solution (2Gpi/weli) 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/SÖnM ELK-1) was prepared using assay buffer #1. The ATP/substrate f20|j.i/we!l) was added to the plate. The plate was shaken and incubated at 30°C for Ihr. (6) EDTA preparation: 30mM EDTA was prepared using C1.3M EDTA stock and assay buffer #1. The EDTA (1 Ομΐ/well) wras added to the plate to quench the enzyme reaction, and the plate -was shaken well. (7) Detection reagent preparation: Eu-ELK-1 -Ab and SA-XL stocks were thawed on ice. 4X Eu-Anti-ELK-I /SA-XL (2nM Eu-Anti-ELK-l/ 9.4nM SA-XL) using INK detection buffer was prepared. The 4X Eu-Anti-HLK-1/SA-XL solution (2tkd/weil) was added to the plate. The plate was shaken and incubated at RT for Ihr before reading the plate on LJL using ratiomeirie method named HTRF. £4,2, Activep38 TR-FRETAssay

Procedures (1) Assay buffer #i with 0.0025% '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 Duffer //1 with 5% DMsO. The compound solution (lOuiAvell) was added to a 384-wcU plate (Coming, Cat No. 3654). (4) aP38 preparation: aF38 stock {lOOug/rnl) at -8G°C was thawed on lee and a P38 (3{big/20pi=l,5ng/(ui) solution using assay buffer v2 was prepared. The P38 solution (20rul/well) was added to the plate. The plate was shaken and the enzyme was incubated with compound at RT for 10 min. (5) ΛΤΡ/substrate solution preparation: ATP and substrate stocks were thawed on ice. 2.5X ATP/substrate (7SpM ATP/5QnM ATF-2) was prepared using assay buffet #1. The A fP/substralc (lOtii/weli) was added to the plate, the plate was shaken, and the plate was incubate at 30°C for 3 hr. (6) EDTA preparation: 3QmM EDTA was prepared using 0.5M EDTA stock and assay buffer #i. The EDTA (ΙΟμΙ/well) 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-ATF-2/SA-XL (2nM Eu-Aati-ATF-2 / 9,4nM SA-XL) was prepared using INK detection buffer. The Eu-Ant AdΓΕ-2/SA-XL solution (2Ggl/well) was added to ibe plate. The plate was shaker; and incubated at RT for Ihr before reading the plate on LJL using ratiometric method named HTRF. Μ X A ctive JNM 1,2 ami 3 TR-FRET Assay Procedures (1) Assay buffer # 1 with 0.0025% Tween and 1 mM 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/wcll) was added to a 384-well plate (Coming, Cat No. 3654), (4) aJNKI, 2 or 3 preparation: aJNK stock (!Q0ug/ml) at-80¾ was thawed on ice and an aJNK (Lóng/mi) solution was prepared «.sing assay buffer 42. The aiNK". solution (20pl'weH) was added to the plate and the plate was shaken. The enzyme was incubated with the compound ai RT for 10 min. (5} ATIYsubstrate solution preparation: ATP arid substrate stocks were thawed on ice. 2.5X ATP/substrate (e,g., 25μΜ or 2,5 mM ATP/50nM EPIW-1) was prepared using assay buffer #1.7 he ATP/substrate (20gl/well) was added to the plate and the plate was shaken. The plate was incubated at RT for 15min. Note; In an exemplary assay, the final ATP concentration was about .1 mM. (6) ED IA preparation: 3ÖmM EDTA was prepared rising 0.5M EDTA stock and assay buffer #1, The EDTA (ΙΟμΙ/weli) 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 tee. 4X Eu-63/SA-XL (2nM Eu-63 / 9.4nM SA-XL) was prepared using JNK detection buffer. The Eu-63/SA-XL solution (20ph'well) was added to the plate and the plate was shaken. The plate was incubated at RT for I hr before reading the plate on LJL using raiiometric method named HTRF. 14.4. Cmpied JNK ïf2 mui 3 TR-FKET Asmy Procedures (1) Assay buffer with 0.0025% Tween, 0.01% BSA, and ImM DTT was prepared 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) uJNK 1,2, or 3 activation reaction preparation: uJNK activation solution was prepared using assay buffer (!.6ng/ml MfCK4s 1.óng/ml MKK7, 16ng/mi uJNK, and 20uM ATP final). Ί he uJNK. activation solution (SSpl/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-Jun substrate solution preparation: 50nM EPIW-1., c-Jtin peptide, was prepared using assay butter (15nM final). The EPIW-1 solution (1Spl/well) was added to the plate, the plate was shaken and incubated at 3G°C for 60 min. (5) EDTA preparation: 30mM EDTA was prepared using 0.5NI EDTA stock and assay buffer, f he EDTA (ΙΟμΙ/well) was added to the plate to quench the enzyme reaction and the plate was shaken well. (6) Detection reagent preparation: Eu-73 and SA-XL stocks were thawed on ice. 4X Eu-73/SA-XL (2nM Eu-73 / 9.4uM SA-XL) were prepared using INK detection buffer, f he Eu-73/SA-XL solution (2Gpl/weil) was added to the plate. The plate was shaken and incubated at RT for 1far before reading ihe plate on LIL using ratiometrie method named HTRF. 14,5. Coupled MA PK2/Erk2 TR-FRET Amir

Procedures (1) Assay buffer with 0.0025% Tween. 0,01 % BSA, and ImM DTT was prepared using JNK buffer stock solution, (2) '] est. compound solution preparation: 5.X compound solution, including EDTA background, was prepared using assay buffer with 5% DMSO, The compound solution ΟΟμΙ/welO w&amp;< added to a 384-wclJ plate- (Corning, Cat No. 3654). ¢3) uMAPK/JirkS activation reaction preparation: uMAPK activation solution was prepared using assay buffer (!6ng/ml MEK1, I60ng/ml uMAPK2'Erk2, and 60u.M ATP final).· The uMAPK activation solution (35pj/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) ELK-1 substrate solution preparation: 50nM ELK-1 peptide was prepared using assay buffer (15nM final). The ELK-1 peptide solution (ISpI/weil) was added to the plate. The plate was shaken and incubated at 30°C for 60 min. (5) EDTA. preparation: 30m.M 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: £u-ELK~l>Ab and SA-XL stocks were thawed on ice. 4X Eu-Anti-ELK-l/SA-XL (2uM Eu-Anti«ELK-l/ 9.4nM SA-XL) was prepared using JNK detection buffer. The Eu-Anti-ELK-l/SA-XL solution (20pi/wel1) was added to the plate. The plate was shaken and incubated at RT for óömin. before reading the plate on LJL using ratiometric method named HTRF. 14.6. Coupled ρ38α^ΑΡΚ2α TR-FRET Assay

Procedures NWm\vww\\w\\w\\w\\vw\t (1) Assay ouder with 0,0025% Tween, 0.01% QSA, and ImM D IT was prepared using JNK buffer stock solution. (2) Test contpound solution preparation 5X compound solution, including EDTA background, was prepared using assay buffer with 5% DMSO. The compound solution (ΙΟμΙ/weli) was added to a 384-well plate (Corning, Cat No, 3654). (3) up38a/SAPK2a activation reaction preparation: up38a activation solution was prepared using assay buffer (48ng/m! MKK6,480ng/ml up38a and 60uM ATP final). The up38a activation solution (35ul/wcl!) was added to the plate. The plate was shaken and the reaction mixture was incubated with compound at 30°C for 60 min. (4) ATF-2 substrate solution preparation: SÖnM ATF-2 peptide was prepared using assay butter (15nM final). The ATF-2 peptide solution. (15pf/well) was added to the plate, the plate was shaken, and the plate was incubate at 30°C for 60 min. (5) EDTA preparation: 30mM EDT.A was prepared using 0.5M EDTA stock and assay buffer. The EDTA (ΙΟμΙ/wdl) 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-ATF-2/SA-XL (2nM Eu-Anti-ATF-2 / 9.4nM SA-XL) was prepared using INK detection buffer. The Eu-Anti-ATF-2/SA-XL solution (20pl/well.) was added to the plate. The plate 'was shaken and incubated at RT for Ihr before reading the plate on IJL using ratiomctric method named HTRF,

Example 1S inhshsikm of Kalme Add Imdoeed Fhospho-eJiia UpreguMion in Mice Hippocampi [006791 Exei to toxic cell death can be induced experimentally by the administration of kainic acid, a potent agonist of the kainate class of glutamate rceen\>'’s. Peripheral injection of kainic acid results in recurrent seizures and degeneration of select populations of neurons in the hippocampus. Acti vation ofjrsk is observed after kainic acid treatment in vivo (see, e.g., Jeon S. H. et ai., Experimental and Molecular Medicine 2000, 32(4): 227-230 and Kim Y.-H. et al. 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-ejun) and hippocampal neuronal apotosis (see e.g., Yang D.D. et a)., Nature 1997, 389: 865-870). Phosphorylated c-jan in wildtype mice is upregnlated after kamie acid administration aad have demonstrated that this uprcguiaHon is inhibited by certain compounds of the present disclosure.

Methods [9Θ68Θ] Female, FVB/N mice (Taconic) were treated by oral, gavage (PO) with one 300 mg/kg dose ofN~(4 -chloro~3-(l H-l ,2^--triazoi“5-yi)ihiophen~2-y1)--2~ iisoqurnohn~,>y!}acetarmde or vehicle (0.9¾ saline) at a 5 ml/kg dose volume. Control animals were dosed with vehicle, Thirty minutes later animals were treated imerperi.ioneally with 25 mg/kg of kainic acid or saline at a 10 ml/kg dose volume. Kamie acid was formulated in 0.9% saline. Font hours after kainic acid administration animals were euthanized by carbon dioxide and were transcardialiy perfused with 0.9% saline. Brains were removed, and separated into left and right hemispheres. The hippocampus was dissected from the right hemisphere, frozen on dry ice and kept at -8Ö °C until used for quantitation of p-ejnn levels.

[00681] Preweighed hippocampus tissues were homogenized in cold cell extraction buffer (CEB) containing 1% Triton X-100, 0.1% SD8, 0.5% deoxycholate, 20mM Na4P207, 2 mM Na,V04,0.1% SOS and protease inhibitors (PI, 2 mg/mL aprorinin and 1 mg/mL icupeptin) at a ratio of 9:1 CEB to wet tissue weight. Homogenized samples were analyzed using PathScan Phospho-c-Jun (Ser63) Sandwich ELISA Kit II from Cell Signaling Technology. Sampler were diluted 1:10 in sample diluent provided in the kit. An 8-poinr. standard curve was prepared by diluting a 10 ng/mL phos-c-Jun standard I ;3 in 10% CEB/PI in sample diluent, Samples and standards were added at I Oil uL per well to prewetted ELISA plates which contain a phos-c-jun(ser63)-specifle 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-Iim detection antibody and the plate was incubated at 37 °C for 1 hour. The plate was washed litres times in TTBS, then 100 μΕ per well of an anti-mouse IgG HRP-linked antibody was added. The plate was incubated at 37 °C for 30 minutes and was then washed three times m TTBS. To each well were added 100 pL ofTMB 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,

Mas til is [086821 Treatment with. 300 mg/kg of N”(4-chloro-3~( 1 H~ l ,2.4-triaaol-5-yi}thiopheii-2-yl)~2--(isoquinolin.-5-yljaociamide resulted in a statisticaliy significant (unpaired t-test) 51% reduction ofp-ejun in the hippocampus of FV.8 mice 4 hours after treatment with kainic acid. The results are summarized in Table 2, below'.

Table 2; N-{4"£hïoro-3-(IH“i,2,4-trlax©l~S-yl)fhlophe!i-2-yI)-2“(lsoqu!BöSia~S~yl)aceiaiHicie

Inhibits K&amp;iisk Add Induced Fhospho-eJun Upregulntino in Msec

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-cycloalkyl, Βίο 8-membered heterocycloalkyl, aryl, 5- or 6-membered heteroaryl, CM, halogen, OR12, SR12, NR12R13, C(0)R14, C(0)NR12R13, 0C(0)NR12R13, C(Q)QR12, NR15C(0)R14, NR15C(0)0R12, NR15C(0)NR12R13, NR15C(S)NR12R13, NR15S(0)2R14, S(0)2NR12R13, S{0)R14 and S(0)2R14, wherein R12, R " cr>d R15 are independently chosen from H, acyl, Ci-Ce-alkyl, 2- to 6-membered heteroalkyl, aryl, 5- or 6-membered heteroaryl, C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, 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-aikyl, 2-- to 6~rnembered heteroalkyL aryl, 5- or 6~membered heteroaryl. Cs-Cg cycloalkyl and 3-to 8-membered heterocycloaikyl; 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, heterocycloaikyl, aryl, heteroaryl, -R3, -OR®, -SR3, =0, =NRa, =N-0Ra, ~NRaRb, -halogen, ~SiRaRbRc, ~0C{0)Ra, -C(0)Re, -C(0)0Ra, -C{G)NRaRb, -0G(0)NRaRb, ~NRcC(0)Re, -NRcC(0)NRaRb, ~NRcC(S)NRaRb, -NRcC(0)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)alkyi, 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, C1-C24 heteroalkyl, C3-C10 heterocycloaikyl, 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 Gi-Ce 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, alkynyi, haloaikyi, heferoaikyl, Cs-Cs-cyofoaikyi, 3* to 8~membered heterocyctealkyli aryl, 5.- or 6~membered heteroaryi, CN, halogen, OR42, SR42, NR42R4l QÖ)R44, C{0)NR42R43 0C{0)NR42R43, CiOjGR42, 'NR45C{0)R44, NR45C(O)0R42, NR45C(0)NR42R43, N R45C{SIN R42R4 3s MR4SS(O%R44, S(0)2NR42R43i S(0}R44, and SCO^R44, wherein R42, R43 and R46' are members Independently chosen from H, acyl, Ci-Ce^alkyl, 2- to 6~membered heieroalkyi aryl, 5·· or (h-membered heteroaryi Cg-Os cycloalkyl and 3- to 8-membered heterocycloaikyl, wherein R42 and R43 together with the nitrogen atom to which they are hound are optionally joined to form a 5~ to T-membered heterocyclic ring; and R44 Is Independently chosen from acyl, Cr-Ca-aikyl 2~ to; 6~ memhered heteroalkyi, aryl, 5- or 8-membered heteroaryl, Cs-Cs cycloalkyl and 3» to 8-rrtembered heterocycioalkyf; Cy Is chosen from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the cycloalkyl, heterocycloaikyl, aryl or heteroaryl Is optionally substituted with 1 - δ substituents independently chosen from substituted or unsubsisfuied alkyl,, substituted or unsubstltuted alkenyl, substituted or unsubstltuted alkynyi, haioalkyl, substituted or unsubslituted heteroalkyl, substituted or unsubstltuted cycloalkyl, substituted or unsubstltuted heterocycloaikyl., substituted or unsubstltuted aryl, substituted-or unsubstltuted heteroaryl, CM, halogen, OR32, SR32 *0, NRS2R53, C(0)R54, C(0)MR5SR53, 0C(0)NR52R53, C(Ö)ÖR52, NR55C(Ö)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 6-membered heteroalky], aryl, 5- or 6-membered heteroaryl, Ca-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-aikyl, 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, Ca-Cio 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)QRa, -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, Ca-Cio 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-, 8-, 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, -ORas -SRa, =0, ~NRaf =N-ORa, -NRaRb, -halogen, -SiRaRbRc, -0C(0)Ra, ~C(0)Re, ~C(0)ORa, -C(0)NRaRb, -0C(0)NRaRb, .. NRcC(0)R®, -NRcC(ö)NRsRb, ~NRcC(S)NRaRb, -NRcC(0)0Ra,, NRcC(NRaRb)-NRd, -S{0)Re, -S(0)2Re, ~S(0)2NRaRb, -NRcS(0)2Ra, ~CN, -N02, -Ns, ~CH{Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci- Chalky I, In a number from one to the total number of open valences on the aromatic ring system, wherein Ra rcs Rd ancj are eac^ independently hydrogen, C1-C24 alkyl, C3-C10 cydoalkyl, 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 be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring; wherein the aryl g xjps are chosen from 5~, 8~ or 7-membered, 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 aromatic moiety 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) ; (VI) ; 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

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, qumolin-2-one, 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 ~ 6 substituents independently chosen from Ci-Ce-alkyl, Ci-Ce-alkenyl, Ci-Ce-alkynyl, C-i-Ce-haloalkyl, 2~ to 6-membered heteroalkyl, Cs-Ce-cycloalkyi, 3- to 8-merrsbered heterocycloalkyl, aryl, 5- or8~membered heteroaryl, CN, halogen, OR52, SR52, NR52R53, C(0)R54! C(0)NR52R53, 0G{0)NR52R53, C(0)ORS2, NR55C(0)R54s NR55C(0)0R52s 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 claim 7, wherein Cy is optionally substituted quinolin- 2-one.

11. The compound of claim 10, wherein the Cy is quinolin-2-one substituted with at least 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)0R52s NR55C{0)R54, NR55C(0)0R52, NR5SC{0)NR52R53, NR55C(S)NR52R53, NR55S{0)2R54, S(0)2NR52R53, S(0)Rm 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.