Bicyclic compounds

Abstract

Provided herein are compounds useful for treating cancer, including those mediated by YAP / TAZ or regulated by the interaction between YAP / TAZ and TEAD, and pharmaceutical compositions containing the compounds.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 834,671, filed April 16, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] YAP and TAZ are transcriptional coactivators in the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP / TAZ translocation to the nucleus, where they interact with transcriptional enhancer-associated domain (TEAD) transcription factors and coactivate the expression of target genes, promoting cell proliferation. Hyperactivation of YAP and TAZ and / or mutations in one or more members of the Hippo pathway network are involved in many cancers. Described herein are inhibitors of YAP / TAZ or inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors that modulate the interaction between YAP / TAZ and TEAD. Summary of the Invention

[0003] Provided herein are bicyclic compounds and pharmaceutical compositions comprising the bicyclic compounds. In some embodiments, the subject compounds are useful for treating cancer.

[0004] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0005] [ka] During the ceremony, X 1 , X 4 , X 5 , and X 6 are each independently N or CR X and X 2 and X3 are each independently N or CR Y and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Y are each independently hydrogen, halogen, nitro, -CN, or -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and R 2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl or -NH2, and n is 0, 1, 2, 3, or 4.

[0006] In another aspect, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0007] [ka] During the ceremony, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently N or CR X and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and R 2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl or -NH2, and n is 0, 1, 2, 3, or 4.

[0008] In another aspect, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0009] [ka] During the ceremony, X 3 , X 5 , and X 6 are each independently N or CR X and X 4 is CR X and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and R 2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl or -NH2, and n is 0, 1, 2, 3, or 4.

[0010] Any combination of the groups described above in various variations is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

[0011] In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compounds disclosed herein have an IC of 10 μM or less. 50 Shows.

[0013] In some embodiments, the compounds disclosed herein have an IC of 3 μM or less. 50 Shows.

[0014] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, the present disclosure provides a method for treating cancer in a subject, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0016] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0017] Various aspects of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings in which: [Figure 1]1 illustrates a schematic diagram of the Hippo signaling network. Hippo pathway components shaded dark grey indicate components that inhibit YAP / TAZ activity. Hippo pathway components shaded light grey indicate components that promote YAP / TAZ activity. Pointed and blunt arrows indicate activating and inhibitory interactions, respectively. Abbreviations: α-CAT (α-catenin), AJUB (Ajuba), AMOT (Angiomotin), β-TRCP (β-transducin repeat-containing protein), CK1 (Casein kinase 1), CRB (Crumbs), E-CAD (E-cadherin), EX (Extended), GPCR (G protein-coupled receptor), HIPK (Homeodomain-interacting protein kinase), KIBRa (Kidney-brain), LATS (Large tumor suppressor), LGL (Lethal giant larvae), MASK (Multiple ankyrin single KH), MER (Merlin), MOB (Mups one binder), MST (Mammalian sterile 20) like), PALS (Lin-7-associated protein), PATJ (Pals1-associated tight junction protein), PP2A (protein phosphatase 2A), PTPN14 (tyrosine phosphatase protein non-receptor type 14), RASSF (Ras-associated factor), SAV (Salvador), SCRIB (Scribble), SIK (salt-inducible kinase), TAO (1001 amino acid protein), TAZ (transcriptional coactivator with PDZ-binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain-binding protein 2), YAP (Yes-associated protein), ZO (tight junction), ZYX (Zyxin). [Figure 2] FIG. 1 illustrates a schematic diagram of the Hippo signaling pathway regulated by Gα proteins. DETAILED DESCRIPTION OF THE INVENTION

[0018] Specific Terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. It is understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is non-limiting.

[0019] As used herein, in some embodiments, ranges and amounts are expressed as "about" a particular value or range. "About" includes the exact amount. Thus, "about 5 μL" also means "about 5 μL" and "5 μL." In general, the term "about" includes amounts that are expected to be within experimental error.

[0020] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0021] As used herein, the terms "individual," "subject," and "patient" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g., continuous or intermittent) of a medical professional (e.g., a physician, registered nurse, nurse practitioner, physician assistant, floor worker, or hospice worker).

[0022] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0023] "Amino" refers to the -NH2 radical.

[0024] "Cyano" refers to the -CN radical.

[0025] "Hydroxy" refers to the -OH radical.

[0026] "Nitro" refers to the -NO2 radical.

[0027] "Oxa" refers to the -O- radical.

[0028] "Oxo" refers to the =O radical.

[0029] "Thioxo" refers to the =S radical.

[0030] "Imino" refers to the =NH radical.

[0031] "Oximo" refers to the =N-OH radical.

[0032] "Alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl comprises 1 to 13 carbon atoms (e.g., C-C 13In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise stated in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O)t R f (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2); where R a are each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R f are each independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0033] "Amino-alkyl" refers to a radical of the formula: -alkyl-NH2.

[0034] "Hydroxyl-alkyl" refers to a radical of the formula: -alkyl-OH.

[0035] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0036] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains 2 to 8 carbon atoms. In other embodiments, an alkenyl contains 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specified in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2); where R a are each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R fare each independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0037] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise stated in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2); where R aare each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R f are each independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0038] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, e.g., methylene, ethylene, propylene, n-butylene, etc., which connects the rest of the molecule to a radical group, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon atom in the alkylene chain or any two carbon atoms within the chain. In certain embodiments, an alkylene contains 1 to 8 carbon atoms (e.g., a C1-C8 alkylene). In other embodiments, an alkylene contains 1 to 5 carbon atoms (e.g., a C1-C5 alkylene). In other embodiments, an alkylene contains 1 to 4 carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, an alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, an alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene contains 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene contains 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene contains 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(Ra )S(O) t R f (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R f (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2); where R a are each independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R f are each independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0039] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 5-18 carbon atoms, where at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups can be derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless specifically stated otherwise in this specification, the term "aryl" or the prefix "ar" (as in "aralkyl") is meant to include aryl radicals that are optionally substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -CN, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(Ra )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0040] "Aryloxy" refers to a radical attached through an oxygen atom of the formula -O-aryl, where aryl is as defined above.

[0041] "Aralkyl" has the formula -R c -refers to the aryl radical, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0042] "Aralkenyl" has the formula -R d -refers to the aryl radical, R dis an alkenylene chain as defined above. The aryl group part of the aralkenyl radical is optionally substituted as defined above for an aryl group. The alkenylene group part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0043] "Aralkynyl" has the formula -R e -refers to the aryl radical, R e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0044] "Carbocyclyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including, in some embodiments, fused or bridged ring systems having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. In some embodiments, a carbocyclyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl contains 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 7 carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 5 carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, cycloalkyl contains 3 to 4 carbon atoms (e.g., C3-C4 cycloalkyl). Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.Unless otherwise stated in this specification, the term "carbocyclyl" is meant to include carbocyclyl radicals optionally substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R. b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), and -R b -S(O) t N(Ra )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0045] A "carbocyclylalkyl" is a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0046] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0047] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0048] "Heterocyclyl" or "heterocycle" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which, in some embodiments, includes fused or bridged ring systems. The heteroatoms in a heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heterocyclyl radical is partially or fully saturated. In some embodiments, a heterocyclyl is attached to the rest of the molecule by any atom of the ring. In some embodiments, a heterocyclyl is saturated (i.e., contains only single bonds) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated heterocyclyl is also referred to as a "heterocycloalkyl." Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Unless otherwise stated in this specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above optionally substituted by one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -CN, -R. b -CN, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), and -R b-S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0049] "Heteroalkyl" refers to an alkyl group, as defined above, where one or more skeletal atoms of the alkyl is selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or a combination thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, the heteroalkyl contains 1, 2, or 3 heteroatoms. In some embodiments, the alkyl portion of the heteroalkyl radical is optionally substituted as defined for an alkyl group. Representative heteroalkyl groups include, but are not limited to, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2OH, -CHOCH3, -CH2CH2NH2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2CH2OH, -CH2CHOCH3, -CH2CHOCH2CH2NH2, or -CH2CHOCH2CH2OH.

[0050] "Heterocyclylalkyl" refers to a group of the formula -R c - refers to the heterocyclyl radical, R cis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0051] "Heterocyclylalkoxy" refers to a group of the formula -OR c - refers to a radical attached by an oxygen atom of a heterocyclyl, R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0052] "Heteroaryl" refers to a radical derived from a 3-18-membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, in some embodiments, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is bonded to the rest of the molecule through any atom in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 4-6 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a monocyclic heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the bicyclic heteroaryl is a C5-C9 heteroaryl. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloopta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl , 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,1 0,10a-Octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinol linyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term "heteroaryl" is meant to include heteroaryl radicals as defined above, optionally substituted by one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t R a(t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), where R a are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R b are each independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

[0053] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0054] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0055] "Heteroaryloxy" refers to a radical attached through an oxygen atom of the formula --O-heteroaryl, where heteroaryl is as defined above.

[0056] "Heteroarylalkyl" means a group of the formula -R c - refers to the heteroaryl radical, R cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0057] "Heteroarylalkoxy" means a heteroaryl group of the formula -OR c - refers to a heteroaryl radical attached by an oxygen atom, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0058] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are contemplated by the present disclosure. When the compounds described herein contain an alkene double bond, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans) unless otherwise specified. Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0059] "Tautomer" refers to a molecule that is capable of proton transfer from one atom of a molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0060] [ka]

[0061] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs and examples when it does not occur. For example, "optionally substituted aryl" means that the aryl radical may be substituted or unsubstituted, and that the description includes both substituted aryl radicals and aryl radicals that do not contain substitution.

[0062] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass all pharmaceutically suitable salt forms. Pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0063] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic, alkanediol, aromatic acids, and aliphatic and aromatic sulfonic acids, and with, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Additionally, salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)), which is incorporated herein by reference in its entirety.) In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0064] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0065] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, therapeutic utility and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic effect is achieved, in some embodiments, by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in a patient despite the patient still suffering from the underlying disease. For prophylactic benefit, in some embodiments, a composition is administered to a patient at risk of developing a particular disease or who has reported one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0066] The term "prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. In some embodiments, a prodrug is inactive when administered to a subject, but is converted to an active compound in vitro, for example, by hydrolysis. Prodrug compounds often have advantages of solubility, tissue compatibility, or delayed release in mammals (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 79, 21-24 (Elsevier, Amsterdam)).

[0067] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0068] The term "prodrug" is also meant to include any covalently bonded carrier, which releases the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of active compounds as described herein are prepared by modifying functional groups present in the active compound in such a way that the functional group modifications are cleaved, either by routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds where a hydroxy, amino, or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol or amine functional groups in the active compound, and the like.

[0069] compound In some embodiments, the compounds disclosed herein are bicyclic compounds.

[0070] In one aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0071] [ka] During the ceremony, X 1 , X 4 , X5 , and X 6 are each independently N or CR X and X 2 and X 3 are each independently N or CR Y and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Y are each independently hydrogen, halogen, nitro, -CN, or -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and R 2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl or -NH2, and n is 0, 1, 2, 3, or 4.

[0072] For any and all compounds of formula (I), substituents are selected from among a subset of the described alternatives. For example, in some embodiments, X 1 is N or CR X In another embodiment, X 1 is N. In some embodiments, X 1 is CR X is.

[0073] In some embodiments, X 1 is CR X and X 2 and X3 are CR Y In some embodiments, X 1 is N, and X 2 and X 3 are CR Y In some embodiments, X 1 is CR X and X 2 is CR Y and X 3 is N.

[0074] In some embodiments, X 4 , X 5 , and X 6 are CR X In some embodiments, X 4 is N, and X 5 and X 6 are CR X In some embodiments, X 4 and X 5 are CR X and X 6 is N.

[0075] In some embodiments, R X are each independently hydrogen, halogen, or -OR 3 , -SR 3 , -CN, -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C-C heterocycloalkyl. In some embodiments, R X are each independently hydrogen, halogen, or -OR 3 , -SR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C2-C4 alkynyl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0076] In some embodiments, R Xare each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH=CH2, -C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy aryl, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -C(=O)OH, -C(=O)OCH, -C(=O)OCHCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -NH, -NHCH, -N(CH), -NHC(=O)CH, -N(CH)C(=O)CH, -NHC(=O)OCH, -N(CH)C(=O)OCH, -S(=O)CH, -S(=O)CH, -NHS(=O)CH, or -N(CH)S(=O)CH. In some embodiments, R X are each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C≡CH, -OH, -OCH3, -OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, R X are each independently hydrogen, F, Cl, Br, I, -CH, -CHCH, cyclopropyl, -OH, -OCH, -OCHCH, -OCF, cyclopropyloxy, -NH, -NHC(=O)CH, -NHS(=O)CH, -S(=O)CH, or -S(=O)CH. In some embodiments, R Xare each independently hydrogen, F, Cl, Br, —CH, —OH, —OCH, or —OCF. In some embodiments, R X are each independently hydrogen, F, Cl, —CH, —OCH, or —OCF. In some embodiments, R X are each independently hydrogen, F, or —OCH. In some embodiments, R X are hydrogen atoms.

[0077] In some embodiments, R Y are each independently hydrogen, halogen, -CN, or -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C-C heterocycloalkyl. In some embodiments, R Y are each independently hydrogen, halogen, or -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C2-C4 alkynyl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0078] In some embodiments, R Y are each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH=CH2, -C≡CH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHC(=O)OCH3, -N(CH3)C(=O)OCH3, -S(=O)CH3, -S(=O)2CH3, -NHS(=O)2CH3, or -N(CH3)S(=O)2CH3. In some embodiments, R Y are each independently hydrogen, F, Cl, Br, I, -CH, -CHCH, cyclopropyl, -C≡CH, -NH, -NHC(=O)CH, -N(CH)C(=O)CH, -NHS(=O)CH, -N(CH)S(=O)CH, -S(=O)CH, or -S(=O)CH. In some embodiments, R Yare each independently hydrogen, F, Cl, Br, I, —CH, —CHCH, cyclopropyl, —NH, —NHC(═O)CH, —NHS(═O)CH, —S(═O)CH, or —S(═O)CH. In some embodiments, R Y are each independently hydrogen, F, Cl, or —CH. In some embodiments, R Y are each independently hydrogen or F. In some embodiments, R Y are hydrogen atoms.

[0079] In some embodiments, R 1 is a substituted or unsubstituted C1-C6 alkyl.

[0080] In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, or a C1-C6 alkyl substituted with -CN.

[0081] In some embodiments, R 1 HA-OR 3 and R 3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 It is cycloalkyl.

[0082] In some embodiments, R 1 is -C(=O)N(R 5 )2 or -N(R 5 )2 substituted C1-C6 alkyl, where R 5 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or -CN; or two R 5taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0083] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted C2-C7 heterocycloalkyl.

[0084] In some embodiments, R 1 is C1-C6 alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0085] In some embodiments, R 1 is C1-C6 alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0086] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted phenyl, wherein when the phenyl is substituted, the phenyl is optionally substituted with halogen, nitro, -CN, -OR 3 , -N(R 3 )2, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 fluoroalkyl; and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0087] In some embodiments, R 1 is a C1-C6 alkyl substituted with a 5-membered heteroaryl ring containing at least one nitrogen atom.

[0088] In some embodiments, R 1 is a C1-C6 alkyl substituted with a 5-membered heteroaryl ring selected from substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, and substituted or unsubstituted thiadiazolyl.

[0089] In some embodiments, R 1 teeth,

[0090] [ka] C1-C6 alkyl substituted with a 5-membered heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0091] In some embodiments, R 1 is a C-C alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C-C alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms. In some embodiments, R 1 is a C-C alkyl substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with pyridinyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with 2-pyridinyl.

[0092] In some embodiments, R 1 teeth,

[0093] [ka] C1-C6 alkyl substituted with a 6-membered heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0094] In some embodiments, R 1 is a C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R 1is a C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring selected from substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted isobenzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted indolizinyl, and substituted or unsubstituted imidazopyridinyl.

[0095] In some embodiments, R 1 teeth,

[0096] [ka] C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0097] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms. In some embodiments, R 1 is a C1-C6 alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring selected from substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pyridopyrimidinyl, substituted or unsubstituted pyridopyrazinyl, substituted or unsubstituted pyridopyridazinyl, substituted or unsubstituted pyrimidopyrimidinyl, and substituted or unsubstituted pteridinyl.

[0098] In some embodiments, R 1 teeth,

[0099] [ka] C1-C6 alkyl substituted with a 6 / 6 fused heteroaryl ring selected from where: R zare each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0100] In some embodiments, R 1 is C-C alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH, -NH, NHCH, N(CH), and pyridinyl. In some embodiments, R 1 is C-C alkyl substituted with one or two substituents each independently selected from -OH, -OCH, -NH, NHCH, N(CH), and pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R 1is C-C alkyl substituted with one or two substituents each independently selected from -NH and pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with one or two substituents each independently selected from -OH and -NH2. In some embodiments, R 1 is C1-C6 alkyl substituted with -OH. In some embodiments, R 1 is a C1-C6 alkyl substituted with -NH2.

[0101] In some embodiments, R z are each independently hydrogen, F, Cl, Br, -CH, -CHCH, -CHF, -CHF, -CF, -CN, -OH, -OCH, -OCHCH, -OCF, -NH, -NHCH, or -N(CH). z are each independently hydrogen, F, Cl, Br, —CH, —CN, —OCH, —NH, —NHCH, or —N(CH). In some embodiments, R z are each independently hydrogen, Cl, Br, —CH, —OCH, —NH, or —N(CH). In some embodiments, R z are hydrogen atoms.

[0102] In some embodiments, R 1 is halogen, -CN, -OR 3 , -SR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , -C(=O)N(R 3 )2, -CR=C(R 3 )2, -C≡CR3, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl or C1-C6 alkyl substituted with substituted or unsubstituted aryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0103] In some embodiments, R 1 is a substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 In some embodiments, R 1 is a C-C cycloalkyl or C-C heterocycloalkyl substituted with C-C alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. 1 is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl substituted with C1-C6 alkyl, phenyl, or pyridinyl.

[0104] In some embodiments, R is halogen, nitro, —CN, —OR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0105] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCHF, -OCHF, -OCF, -C(=O)CH, -C(=O)OCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -S(=O)CH, -S(=O)CH, -NHS(=O)CH, -N(CH)S(=O)CH, -NHC(=O)CH, -N(CH)C(=O)CH, -NHC(=O)OCH, -N(CH)C(=O)OCH, -CHF, -CHF, or -CF. In some embodiments, R is F, Cl, -CN, -OCF, -CHF, or -CF. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0106] In some embodiments, R 2 are each independently halogen, nitro, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0107] In some embodiments, R 2 are each independently F, Cl, Br, nitro, -CN, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -S(=O)CH, -NH, -NHCH, -N(CH), -C(=O)OCH, -CH, -CHCH, -CHF, -CHF, or -CF. 2 are each independently F, Cl, —CN, —OCH, —OCF, —C(═O)OCH, —CH, or —CF. In some embodiments, R 2 are each independently F, Cl, —OCF, or —CF. In some embodiments, R 2 are each independently F or Cl.

[0108] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0109] In another aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0110] [ka] During the ceremony, X 1 , X 4 , X 5 , and X 6 are each independently, CR X and X 2 and X 3 are each independently, CR Y and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R Y are each independently hydrogen, halogen, nitro, -CN, or -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R is halogen, nitro, —CN, or C1-C4 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl or a substituted or unsubstituted C3-C 10is cycloalkyl, R 2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C6 cycloalkyl; R 3 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl, and n is 0, 1, 2, 3, or 4.

[0111] In some embodiments, R X are each independently hydrogen, F, Cl, Br, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -OCF3, -OCF2CH3, or -OCH2CF3. In some embodiments, X 1 , X 4 , X 5 , and X 6 Each is CH. In some embodiments, R Y are each independently hydrogen, F, Cl, Br, -CH3, or -CH2CH3. In some embodiments, X 2 and X 3 Each is CH. In some embodiments, R 1 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 1 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R 1 is —CH3. In some embodiments, R 1 is -CH2CH3. In some embodiments, R 1 is -CH2CH2CH3. In some embodiments, R 1is —CH(CH). In some embodiments, R 1 is -CH2CH2CH2CH3. In some embodiments, R 1 is —CH(CH)CHCH. In some embodiments, R 1 is —CHCH(CH) In some embodiments, R 1 is —C(CH3)3. In some embodiments, R 1 is C-C alkyl substituted with 0, 1, 2, or 3 substituents each independently selected from F, -CN, -NH, -NH(C-C alkyl), -N(C-C alkyl), -OH, -O(C-C alkyl), C-C fluoroalkyl, amino-C-C alkyl, hydroxyl-C-C alkyl, C-C cycloalkyl, C-C heterocycloalkyl, or heteroaryl, where the C-C heterocycloalkyl has 1, 2, or 3 heteroatom ring members each independently selected from N, O, or S, and where the heteroaryl has 1, 2, or 3 heteroatom ring members each independently selected from N, O, and S. and wherein each instance of C-C cycloalkyl, C-C heterocycloalkyl, and heteroaryl is each substituted with 0, 1, 2, or 3 substituents independently selected from halogen, oxo, —CN, —NH, —NH(C-C alkyl), —N(C-C alkyl), —OH, —O(C-C alkyl), C-C alkyl, C-C fluoroalkyl, amino-C-C alkyl, hydroxyl-C-C alkyl, and C-C cycloalkyl. 1 is -N(R 3 )2 OR -OR 3 and R 3 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 1 is -N(R 3 )2 substituted C1-C6 alkyl, and R3 is hydrogen or C1-C6 alkyl. In some embodiments, R 1 HA-OR 3 and R 3 is hydrogen or C1-C6 alkyl. In some embodiments, R 1 is C-C alkyl substituted with -NH, -NHCH, -N(CH), -OH, or -OCH. In some embodiments, R 1 is C1-C6 alkyl substituted with -NH2. In some embodiments, R 1 is -CHNH, -CHCHNH, -CH(NH)CH, -CHCHCHNH, -CHCH(NH)CH, -CH(NH)CHCH, -CH(CH)CHNH, or -C(CH)NH. In some embodiments, R 1 is —CH 2 NH 2 . In some embodiments, R 1 is —CH(NH)CH. In some embodiments, R 1 is —CH2CH2CH2NH2. In some embodiments, R 1 is —CHCH(NH)CH. In some embodiments, R 1 is —CH(NH 2 )CH 2 CH 3 . In some embodiments, R 1 is —CH(CH)CHNH. In some embodiments, R 1 is —C(CH)NH. In some embodiments, R 1 is C1-C6 alkyl substituted with -NHCH3. In some embodiments, R 1 is -CHNHCH, -CHCHNHCH, -CH(NHCH)CH, -CHCHCHNHCH, -CHCH(NHCH)CH, -CH(NHCH)CHCH, -CH(CH)CHNHCH, or -C(CH)NHCH. In some embodiments, R 1 is —CHNHCH. In some embodiments, R 1 is —CH(NHCH)CH. In some embodiments, R1 is -CH2CH2CH2NHCH3. In some embodiments, R 1 is —CHCH(NHCH)CH. In some embodiments, R 1 is —CH(NHCH)CHCH. In some embodiments, R 1 is —CH(CH)CHNHCH. In some embodiments, R 1 is —C(CH)NHCH. In some embodiments, R 1 is C-C alkyl substituted with -N(CH). In some embodiments, R 1 is -CHN(CH), -CHCHN(CH), -CH(N(CH))CH, -CHCHCHN(CH), -CHCH(N(CH))CH, -CH(N(CH))CHCH, -CH(CH)CHN(CH), or -C(CH)N(CH). In some embodiments, R 1 is —CHN(CH). In some embodiments, R 1 is —CH(N(CH))CH. In some embodiments, R 1 is —CHCHCHN(CH)N. In some embodiments, R 1 is —CHCH(N(CH))CH. In some embodiments, R 1 is —CH(N(CH)CHCH. In some embodiments, R 1 is —CH(CH)CHN(CH). In some embodiments, R 1 is —C(CH)N(CH). In some embodiments, R 1 is C1-C6 alkyl substituted with -OH. In some embodiments, R 1 is -CHOH, -CHCHOH, -CH(OH)CH, -CHCHCHOH, -CHCH(OH)CH, -CH(OH)CHCH, -CH(CH)CHOH, or -C(CH)OH. 1 is —CHOH. In some embodiments, R1 is —CH(OH)CH. In some embodiments, R 1 is —CHCHCHOH. In some embodiments, R 1 is —CHCH(OH)CH. In some embodiments, R 1 is —CH(OH)CH2CH3. In some embodiments, R 1 is —CH(CH)CHOH. In some embodiments, R 1 is —C(CH)OH. In some embodiments, R 1 is C1-C6 alkyl substituted with -OCH3. In some embodiments, R 1 is —CH2OCH3, —CH2CH2OCH3, —CH(OCH3)CH3, —CH2CH2CH2OCH3, —CH2CH(OCH3)CH3, —CH(OCH3)CH2CH3, —CH(CH3)CH2OCH3, or —C(CH3)2OCH3. In some embodiments, R 1 is —CH2OCH3. In some embodiments, R 1 is —CH(OCH)CH. In some embodiments, R 1 is -CH2CH2CH2OCH3. In some embodiments, R 1 is —CHCH(OCH)CH. In some embodiments, R 1 is —CH(OCH)CH. In some embodiments, R 1 is —CH(CH)CHOCH. In some embodiments, R 1 is —C(CH)OCH. In some embodiments, R 1 is C1-C6 alkyl substituted with heteroaryl. In some embodiments, R 1 is a C1-C6 alkyl substituted with a 6-membered heteroaryl ring. In some embodiments, R 1is a C-C alkyl substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted pyridinyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with pyridinyl. In some embodiments, the pyridinyl is 2-pyridinyl. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is F. In some embodiments, R is Cl. In some embodiments, R is -CF3. In some embodiments, R 2 are each independently F, Cl, —OCF, or —CF. In some embodiments, R 2 are each independently F or Cl. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 1 or 2.

[0112] In another aspect, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0113] [ka] During the ceremony, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are each independently N or CR X and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and R2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl or -NH2, and n is 0, 1, 2, 3, or 4.

[0114] For any and all compounds of formula (II), substituents are selected from among a subset of the described alternatives. For example, in some embodiments, X 1 is N or CR X In another embodiment, X 1 is N. In some embodiments, X1 is CR X is.

[0115] In some embodiments, X 1 , X 2 , and X 3 are CR X In some embodiments, X 1 is N, and X 2 and X 3 are CR X In some embodiments, X and X 2 are CR X and X 3 is N.

[0116] In some embodiments, X 4 , X 5 , and X 6 are CR X In some embodiments, X 4 is N, and X 5 and X 6 are CR X In some embodiments, X 4 and X 5 are CR X and X 6 is N.

[0117] In some embodiments, R X are each independently hydrogen, halogen, or -OR 3 , -SR 3 , -CN, -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl; and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C-C heterocycloalkyl. In some embodiments, R X are each independently hydrogen, halogen, or -OR 3 , -SR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C2-C4 alkynyl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0118] In some embodiments, R Xare each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH=CH2, -C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy aryl, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -C(=O)OH, -C(=O)OCH, -C(=O)OCHCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -NH, -NHCH, -N(CH), -NHC(=O)CH, -N(CH)C(=O)CH, -NHC(=O)OCH, -N(CH)C(=O)OCH, -S(=O)CH, -S(=O)CH, -NHS(=O)CH, or -N(CH)S(=O)CH. In some embodiments, R X are each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C≡CH, -OH, -OCH3, -OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, R X are each independently hydrogen, F, Cl, Br, I, -CH, -CHCH, cyclopropyl, -OH, -OCH, -OCHCH, -OCF, cyclopropyloxy, -NH, -NHC(=O)CH, -NHS(=O)CH, -S(=O)CH, or -S(=O)CH. In some embodiments, R Xare each independently hydrogen, F, Cl, Br, —CH, —OH, —OCH, or —OCF. In some embodiments, R X are each independently hydrogen, F, Cl, —CH, —OCH, or —OCF. In some embodiments, R X are each independently hydrogen, F, or —OCH. In some embodiments, R X are hydrogen atoms.

[0119] In some embodiments, R 1 is a substituted or unsubstituted C1-C6 alkyl.

[0120] In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, or a C1-C6 alkyl substituted with -CN.

[0121] In some embodiments, R 1 HA-OR 3 and R 3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 It is cycloalkyl.

[0122] In some embodiments, R 1 is -C(=O)N(R 5 )2 or -N(R 5 )2 substituted C1-C6 alkyl, where R 5 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or -CN; or two R 5 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0123] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted C2-C7 heterocycloalkyl.

[0124] In some embodiments, R 1 is C1-C6 alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0125] In some embodiments, R 1 is C1-C6 alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0126] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted phenyl, wherein when the phenyl is substituted, the phenyl is optionally substituted with halogen, nitro, -CN, -OR 3 , -N(R 3 )2, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 fluoroalkyl; and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C 10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0127] In some embodiments, R 1is a C1-C6 alkyl substituted with a 5-membered heteroaryl ring containing at least one nitrogen atom.

[0128] In some embodiments, R 1 is a C1-C6 alkyl substituted with a 5-membered heteroaryl ring selected from substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, and substituted or unsubstituted thiadiazolyl.

[0129] In some embodiments, R 1 teeth,

[0130] [ka] C1-C6 alkyl substituted with a 5-membered heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0131] In some embodiments, R 1 is a C-C alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C-C alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms. In some embodiments, R 1 is a C-C alkyl substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with pyridinyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with pyridinyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with 2-pyridinyl.

[0132] In some embodiments, R 1 teeth,

[0133] [ka] C1-C6 alkyl substituted with a 6-membered heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0134] In some embodiments, R 1 is a C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R 1is a C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring selected from substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted isobenzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted indolizinyl, and substituted or unsubstituted imidazopyridinyl.

[0135] In some embodiments, R 1 teeth,

[0136] [ka] C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0137] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted bicyclic fused 6 / 6 heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms. In some embodiments, R 1 is a C1-C6 alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring selected from substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pyridopyrimidinyl, substituted or unsubstituted pyridopyrazinyl, substituted or unsubstituted pyridopyridazinyl, substituted or unsubstituted pyrimidopyrimidinyl, and substituted or unsubstituted pteridinyl.

[0138] In some embodiments, R 1 teeth,

[0139] [ka] C1-C6 alkyl substituted with a 6 / 6 fused heteroaryl ring selected from where: R zare each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0140] In some embodiments, R 1 is C-C alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH, -NH, NHCH, N(CH), and pyridinyl. In some embodiments, R 1 is C-C alkyl substituted with one or two substituents each independently selected from -OH, -OCH, -NH, NHCH, N(CH), and pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R 1is C-C alkyl substituted with one or two substituents each independently selected from -NH and pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with one or two substituents each independently selected from -OH and -NH2. In some embodiments, R 1 is C1-C6 alkyl substituted with -OH. In some embodiments, R 1 is a C1-C6 alkyl substituted with -NH2.

[0141] In some embodiments, R z are each independently hydrogen, F, Cl, Br, -CH, -CHCH, -CHF, -CHF, -CF, -CN, -OH, -OCH, -OCHCH, -OCF, -NH, -NHCH, or -N(CH). z are each independently hydrogen, F, Cl, Br, —CH, —CN, —OCH, —NH, —NHCH, or —N(CH). In some embodiments, R z are each independently hydrogen, Cl, Br, —CH, —OCH, —NH, or —N(CH). In some embodiments, R z are hydrogen atoms.

[0142] In some embodiments, R 1 is halogen, -CN, -OR 3 , -SR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , -C(=O)N(R 3 )2, -CR=C(R 3 )2, -C≡CR3, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl or C1-C6 alkyl substituted with substituted or unsubstituted aryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0143] In some embodiments, R 1 is a substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 In some embodiments, R 1 is a C-C cycloalkyl or C-C heterocycloalkyl substituted with C-C alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. 1 is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl substituted with C1-C6 alkyl, phenyl, or pyridinyl.

[0144] In some embodiments, R is halogen, nitro, —CN, —OR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0145] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCHF, -OCHF, -OCF, -C(=O)CH, -C(=O)OCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -S(=O)CH, -S(=O)CH, -NHS(=O)CH, -N(CH)S(=O)CH, -NHC(=O)CH, -N(CH)C(=O)CH, -NHC(=O)OCH, -N(CH)C(=O)OCH, -CHF, -CHF, or -CF. In some embodiments, R is F, Cl, -CN, -OCF, -CHF, or -CF. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0146] In some embodiments, R 2 are each independently halogen, nitro, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0147] In some embodiments, R 2 are each independently -CN, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -S(=O)CH, -NH, -NHCH, -N(CH), -C(=O)OCH, -CH, -CHCH, -CHF, -CHF, or -CF. 2 are each independently F, Cl, —CN, —OCH, —OCF, —C(═O)OCH, —CH, or —CF. In some embodiments, R 2 are each independently F, Cl, —OCF, or —CF. In some embodiments, R 2 are each independently F or Cl.

[0148] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0149] In another aspect, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0150] [ka] During the ceremony, X 3 , X 5 , and X 6 are each independently N or CR X and X 4 is CR X and R X are each independently hydrogen, halogen, nitro, -OR 3 , -SR 3 , -CN, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR 3 , -SR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl; R 1 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, a substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Heterocycloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, -CN, or -S(=O)2R 4 and R 2 are each independently halogen, nitro, -N3, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R 3are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl; R 4 is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C3-C 10 cycloalkyl or -NH2, and n is 0, 1, 2, 3, or 4.

[0151] For any and all compounds of formula (III), substituents are selected from among a subset of the described alternatives. For example, in some embodiments, X 5 is N or CR X In another embodiment, X 5 is N. In some embodiments, X 5 is CR X is.

[0152] In some embodiments, X 3 is CR X In some embodiments, X 3 is N.

[0153] In some embodiments, X 5 and X 6 are CR X In some embodiments, X 5 is N, and X 6 is CR X In some embodiments, X 5 is CR X and X 6 is N.

[0154] In some embodiments, R X are each independently hydrogen, halogen, or -OR 3 , -SR 3 , -CN, -S(=O)R 3 , -S(=O)2R 3 , -N(R 3)2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, or substituted or unsubstituted C1-C6 heteroalkyl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0155] In some embodiments, R X are each independently hydrogen, halogen, or -OR 3 , -SR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C2-C4 alkynyl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0156] In some embodiments, R X are each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2C(=O)OH, -CH2C(=O)OCH3, -CH2C(=O)OCH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2F, -CHF2, -CF3, -CH=CH2, -C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy aryl, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -C(=O)OH, -C(=O)OCH, -C(=O)OCHCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -NH, -NHCH, -N(CH), -NHC(=O)CH, -N(CH)C(=O)CH, -NHC(=O)OCH, -N(CH)C(=O)OCH, -S(=O)CH, -S(=O)CH, -NHS(=O)CH, or -N(CH)S(=O)CH. In some embodiments, R X are each independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -C≡CH, -OH, -OCH3, -OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH3, -N(CH3)C(=O)CH3, -NHS(=O)2CH3, -N(CH3)S(=O)2CH3, -S(=O)CH3, or -S(=O)2CH3. In some embodiments, R Xare each independently hydrogen, F, Cl, Br, I, -CH, -CHCH, cyclopropyl, -OH, -OCH, -OCHCH, -OCF, cyclopropyloxy, -NH, -NHC(=O)CH, -NHS(=O)CH, -S(=O)CH, or -S(=O)CH. In some embodiments, R X are each independently hydrogen, F, Cl, Br, —CH, —OH, —OCH, or —OCF. In some embodiments, R X are each independently hydrogen, F, Cl, —CH, —OCH, or —OCF. In some embodiments, R X are each independently hydrogen, F, or —OCH. In some embodiments, R X are hydrogen atoms.

[0157] In some embodiments, R 1 is a substituted or unsubstituted C1-C6 alkyl.

[0158] In some embodiments, R 1 is a substituted or unsubstituted C2-C6 alkenyl, a substituted or unsubstituted C2-C6 alkynyl, or a C1-C6 alkyl substituted with -CN.

[0159] In some embodiments, R 1 HA-OR 3 and R 3 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, or substituted or unsubstituted C3-C 10 It is cycloalkyl.

[0160] In some embodiments, R 1 is -C(=O)N(R 5 )2 or -N(R 5 )2 substituted C1-C6 alkyl, where R 5are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, or -CN; or two R 5 taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0161] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted C2-C7 heterocycloalkyl.

[0162] In some embodiments, R 1 is C1-C6 alkyl substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0163] In some embodiments, R 1 is C1-C6 alkyl substituted with oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0164] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted phenyl, wherein when the phenyl is substituted, the phenyl is optionally substituted with halogen, nitro, -CN, -OR 3 , -N(R 3 )2, -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 fluoroalkyl; and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C10 cycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0165] In some embodiments, R 1 is a C1-C6 alkyl substituted with a 5-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C1-C6 alkyl substituted with a 5-membered heteroaryl ring selected from substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, and substituted or unsubstituted thiadiazolyl.

[0166] In some embodiments, R 1 teeth,

[0167] [ka] C1-C6 alkyl substituted with a 5-membered heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0168] In some embodiments, R 1 is a C-C alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C-C alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms. In some embodiments, R 1 is a C-C alkyl substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with pyridinyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with 2-pyridinyl.

[0169] In some embodiments, R 1 teeth,

[0170] [ka] C1-C6 alkyl substituted with a 6-membered heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0171] In some embodiments, R 1 is a C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring. In some embodiments, R 1is a C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring selected from substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted isobenzofuranyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzisoxazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzisothiazolyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzoxadiazolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted indolizinyl, and substituted or unsubstituted imidazopyridinyl.

[0172] In some embodiments, R 1 teeth,

[0173] [ka] C1-C6 alkyl substituted with a bicyclic 6 / 5 fused heteroaryl ring selected from where: R z are each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0174] In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted bicyclic fused 6 / 6 heteroaryl ring containing at least one nitrogen atom. In some embodiments, R 1 is a C1-C6 alkyl substituted with a substituted or unsubstituted bicyclic 6 / 6 fused heteroaryl ring containing 1, 2, 3, or 4 nitrogen atoms. In some embodiments, R 1 is a C1-C6 alkyl substituted with a bicyclic 6 / 6 fused heteroaryl ring selected from substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted pyridopyrimidinyl, substituted or unsubstituted pyridopyrazinyl, substituted or unsubstituted pyridopyridazinyl, substituted or unsubstituted pyrimidopyrimidinyl, and substituted or unsubstituted pteridinyl.

[0175] In some embodiments, R 1 teeth,

[0176] [ka] C1-C6 alkyl substituted with a 6 / 6 fused heteroaryl ring selected from where: R zare each independently hydrogen, halogen, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and R 3 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0177] In some embodiments, R 1 is C-C alkyl substituted with 1, 2, or 3 substituents each independently selected from -OH, -OCH, -NH, NHCH, N(CH), and pyridinyl. In some embodiments, R 1 is C-C alkyl substituted with one or two substituents each independently selected from -OH, -OCH, -NH, NHCH, N(CH), and pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with 1 or 2 substituents each independently selected from -OH and pyridinyl. In some embodiments, R 1is C-C alkyl substituted with one or two substituents each independently selected from -NH and pyridinyl. In some embodiments, R 1 is C1-C6 alkyl substituted with one or two substituents each independently selected from -OH and -NH2. In some embodiments, R 1 is C1-C6 alkyl substituted with -OH. In some embodiments, R 1 is a C1-C6 alkyl substituted with -NH2.

[0178] In some embodiments, R z are each independently hydrogen, F, Cl, Br, -CH, -CHCH, -CHF, -CHF, -CF, -CN, -OH, -OCH, -OCHCH, -OCF, -NH, -NHCH, or -N(CH). z are each independently hydrogen, F, Cl, Br, —CH, —CN, —OCH, —NH, —NHCH, or —N(CH). In some embodiments, R z are each independently hydrogen, Cl, Br, —CH, —OCH, —NH, or —N(CH). In some embodiments, R z are hydrogen atoms.

[0179] In some embodiments, R 1 is halogen, -CN, -OR 3 , -SR 3 , -S(=O)R 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , -C(=O)N(R 3 )2, -CR=C(R 3 )2, -C≡CR3, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 heterocycloalkyl or C1-C6 alkyl substituted with substituted or unsubstituted aryl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0180] In some embodiments, R 1 is a substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 In some embodiments, R 1 is a C-C cycloalkyl or C-C heterocycloalkyl substituted with C-C alkyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or triazinyl. 1 is a C3-C6 cycloalkyl or C3-C5 heterocycloalkyl substituted with C1-C6 alkyl, phenyl, or pyridinyl.

[0181] In some embodiments, R is halogen, nitro, —CN, —OR 3 , -C(=O)R 3 , -C(=O)N(R 3 )2, -C(=O)OR 3 , -S(=O)R 3 , -S(=O)2R 3 , -NR 3 S(=O)2R 3 , -NR 3 C(=O)R 3 , -NR 3 C(=O)OR 3 or substituted or unsubstituted C1-C6 fluoroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0182] In some embodiments, R is F, Cl, Br, I, nitro, -CN, -OCHF, -OCHF, -OCF, -C(=O)CH, -C(=O)OCH, -C(=O)NH, -C(=O)NHCH, -C(=O)N(CH), -S(=O)CH, -S(=O)CH, -NHS(=O)CH, -N(CH)S(=O)CH, -NHC(=O)CH, -N(CH)C(=O)CH, -NHC(=O)OCH, -N(CH)C(=O)OCH, -CHF, -CHF, or -CF. In some embodiments, R is F, Cl, -CN, -OCF, -CHF, or -CF. In some embodiments, R is F, Cl, -OCF3, -CHF2, or -CF3. In some embodiments, R is F, Cl, or -CF3. In some embodiments, R is -OCF3. In some embodiments, R is -CF3.

[0183] In some embodiments, R 2 are each independently halogen, nitro, -CN, or -OR 3 , -SR 3 , -S(=O)2R 3 , -N(R 3 )2, -C(=O)OR 3 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 fluoroalkyl, and R 3are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C 10 Cycloalkyl or substituted or unsubstituted C2-C 10 heterocycloalkyl, or two R 3 are on the same nitrogen atom, two R 3 together with the nitrogen atom to which they are attached form a substituted or unsubstituted C3-C7 heterocycloalkyl.

[0184] In some embodiments, R 2 are each independently F, Cl, Br, nitro, -CN, -OH, -OCH, -OCHCH, -OCHCHOH, -OCHCN, -OCF, -S(=O)CH, -NH, -NHCH, -N(CH), -C(=O)OCH, -CH, -CHCH, -CHF, -CHF, or -CF. 2 are each independently F, Cl, —CN, —OCH, —OCF, —C(═O)OCH, —CH, or —CF. In some embodiments, R 2 are each independently F, Cl, —OCF, or —CF. In some embodiments, R 2 are each independently F or Cl.

[0185] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3 or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 1, 2, 3, or 4.

[0186] In another aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0187] [Table 1-1]

[0188] [Table 1-2]

[0189] [Table 1-3]

[0190] [Table 1-4]

[0191] [Table 1-5]

[0192] [Table 1-6]

[0193] [Table 1-7]

[0194] [Table 1-8]

[0195] [Table 1-9]

[0196]

Table 1-10

[0197]

Table 1-11

[0198]

Table 1-12

[0199]

Table 1-13

[0200]

Table 1-14

[0201]

Table 1-15

[0202]

Table 1-16

[0203]

Table 1-17

[0204]

Table 1-18

[0205]

Table 1-19

[0206]

Table 1-20

[0207]

Table 1-21

[0208]

Table 1-22

[0209]

Table 1-23

[0210]

Table 1-24

[0211]

Table 1-25

[0212]

Table 1-26

[0213]

Table 1-27

[0214]

Table 1-28

[0215]

Table 1-29

[0216]

Table 1-30

[0217] Preparation of compounds The compounds used in the reactions described herein are made by organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0218] Methods known to those skilled in the art can be identified from various literature sources and databases. Suitable references and articles detailing the synthesis of reactants useful for preparing the compounds described herein or referencing articles describing their preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC“Comprehensive Organic Transformations: A Guide to Functional Group Preparations”2nd Edition (1999)Wiley-VCH,ISBN:0-471-19031-4; March, J. “Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition (1992)John Wiley & Sons,ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 8 volumes of "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X; 55 volumes of "Organic Reactions" (1942-2000) John Wiley & Sons; and 73 volumes of "Chemistry of Functional Groups" John Wiley & Sons.

[0219] In some instances, specific similar reactants are identified through indexes of known chemicals prepared by the American Chemical Society's Chemical Abstract Service, available in most public and university libraries, and in online databases (contact the American Chemical Society in Washington, D.C., for details). Known but not cataloged chemicals are prepared by custom chemical synthesis companies, and many of the pharmaceutical supply companies (e.g., those listed above) offer custom synthesis services. For information on the preparation and selection of pharmaceutical salts of the compounds described herein, see P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts," Verlag Helvetica Chimica Acta, Zurich, 2002.

[0220] In some embodiments, the compounds disclosed herein are prepared as described in the Examples section.

[0221] Further isomers of the compound Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein contain one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein. In some circumstances, the compounds described herein contain one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, dissociable complexes (e.g., crystalline diastereomeric salts) are disclosed herein. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is recovered along with the resolving agent by any practical means that does not result in racemization.

[0222] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to the compounds listed herein, except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. In some embodiments, examples of isotopes incorporated into the compounds of the present disclosure are, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. 2Substitution with heavy isotopes, such as H, may confer certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives thereof are prepared by any suitable method.

[0223] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0224] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0225] In some embodiments, the compounds described herein possess acidic or basic groups and thus form pharmaceutically acceptable salts by reaction with any of a number of inorganic or organic bases and inorganic and organic acids. In some embodiments, these salts are prepared during the final isolation and purification of the compounds of the present disclosure, or in situ by separately reacting the purified compound in its base form with an appropriate acid or base and isolating the salt thus formed.

[0226] solvate In some embodiments, the compounds described herein exist as solvates. The present disclosure provides a method for treating a disease by administering such a solvate. The present disclosure further provides a method for treating a disease by administering such a solvate as a pharmaceutical composition.

[0227] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the process of crystallization using pharmaceutically acceptable solvents such as water or ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of the compounds described herein are suitably prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are suitably prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In some embodiments, the compounds provided herein exist in both solvated and unsolvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0228] Prodrug In some embodiments, the compounds described herein exist in prodrug form. The present disclosure provides methods for treating diseases by administering such prodrugs. The present disclosure provides methods for treating diseases by administering such prodrugs as pharmaceutical compositions.

[0229] In some embodiments, prodrugs comprise compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues is covalently linked via an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of the present disclosure. The amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, and further include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, prodrugs comprise compounds in which a nucleic acid residue or an oligonucleotide of two or more (e.g., 2, 3, or 4) nucleic acid residues is covalently linked to a compound of the present disclosure.

[0230] Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, metal salts, and sulfonate esters. In some embodiments, compounds with free amino, amide, hydroxy, or carboxyl groups can be converted into prodrugs. For example, free carboxyl groups are derivatized as amides or alkyl esters. In certain examples, all of these prodrug moieties incorporate groups including, but not limited to, ether, amine, and carboxylic acid functionalities.

[0231] Hydroxy prodrugs include, but are not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters, and disulfide-containing esters, ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews 1996, 19, 115.

[0232] Amine-derived prodrugs include, but are not limited to, the following groups and combinations of groups:

[0233] [ka] , as well as sulfonamides and phosphonamides.

[0234] In certain instances, any position on the aromatic ring moiety is susceptible to various metabolic reactions, and therefore, incorporation of appropriate substituents on the aromatic ring structure reduces, minimizes, or eliminates this metabolic pathway.

[0235] metabolite In some embodiments, the compounds described herein are highly susceptible to various metabolic reactions.Therefore, in some embodiments, incorporating suitable substituents into this structure reduces, minimizes, or eliminates metabolic pathways.In certain embodiments, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen or alkyl groups.

[0236] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism to produce metabolites that are used to produce a desired effect, including a desired therapeutic effect.

[0237] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration and standard pharmaceutical practice, for example, as described in "Remington: The Science and Practice of Pharmacy" (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)), the disclosure of which is incorporated herein by reference in its entirety.

[0238] Thus, provided herein are pharmaceutical compositions comprising at least one compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0239] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0240] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof.

[0241] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., contaminating intermediates or by-products produced in one or more of the steps of the synthetic method.

[0242] Such formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions are formulated as a unit dosage and / or formulated for oral or subcutaneous administration.

[0243] In some instances, typical pharmaceutical compositions are used in the form of pharmaceutical formulations, e.g., solid, semi-solid, or liquid forms, which contain one or more of the disclosed compounds as active ingredients in admixture with organic or inorganic carriers or excipients suitable for external, enteral, or parenteral use. In some embodiments, the active ingredient is compounded with a typically non-toxic, pharmaceutically acceptable carrier, for example, as a tablet, pellet, capsule, suppository, solution, emulsion, suspension, or other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect on the disease process or condition.

[0244] To prepare solid compositions such as tablets, in some instances, the primary active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When such a preformulation composition is referred to as homogeneous, it means that the active ingredient is evenly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0245] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules), the subject compositions are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerin; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) humectants, such as, for example, acetyl alcohol and glycerol monostearate; (8) kaolin and bentonite clay. (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions also, in some embodiments, contain buffering agents. Solid compositions of a similar type are used as fillers in soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0246] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, are optionally scored or prepared with coatings or shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

[0247] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0248] Suspensions optionally contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0249] In some embodiments, formulations for rectal or vaginal administration are presented as suppositories, which are prepared by mixing the subject compositions with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature, thereby melting in the body cavity and releasing the active agent(s).

[0250] Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required in some embodiments.

[0251] In some embodiments, ointments, pastes, creams, and gels comprise, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0252] In some embodiments, powders and sprays contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Propellants may also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0253] The compositions and compounds disclosed herein are optionally administered by aerosol. This is accomplished by preparing aqueous aerosols, liposomal preparations, or solid microparticles containing the compounds. Non-aqueous (e.g., fluorocarbon propellant) suspensions can be used. Sonic nebulizers are used in some embodiments to minimize drug shear, which can cause degradation of the compounds contained in the subject compositions. Aqueous aerosols are typically made by formulating an aqueous solution or suspension of the subject compositions with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic®, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0254] Pharmaceutical compositions suitable for parenteral application comprise the subject composition in combination with one or more pharmaceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders to be reconstituted immediately before use into sterile injectable solutions or dispersions, optionally containing antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0255] Examples of suitable aqueous and non-aqueous carriers for use in pharmaceutical compositions include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. In some embodiments, proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0256] Furthermore, enteral pharmaceutical formulations are contemplated, comprising the disclosed compounds and enteric materials, and pharmaceutically acceptable carriers or excipients. The enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach and predominantly soluble in intestinal fluids at a specific pH. The small intestine is the portion of the gastrointestinal tract (intestine) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the distal ileum is about 7.5. Accordingly, the enteric material is not soluble in water up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Typical enteric materials are cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose phthalate propionate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate, and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal collophorium. collophorium), as well as several commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric).The solubility of each of the above materials is known or can be readily determined in vitro. While the foregoing is a list of possible materials, those skilled in the art having the benefit of this disclosure will recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives of this disclosure.

[0257] In some embodiments, the dosage of a composition comprising at least one compound as described herein will vary depending on the condition of the patient (e.g., human), i.e., stage of disease, health status, age, and other factors used by one of skill in the art to determine dosage.

[0258] In some examples, pharmaceutical compositions can be administered in a manner appropriate for the disease being treated (or prevented), as determined by one skilled in the medical arts. The appropriate dosage and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. Generally, an appropriate dosage and treatment regimen provides the composition in an amount sufficient to result in a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome), such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a reduction in the severity of symptoms. Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends on the patient's body type, weight, or blood volume.

[0259] In some embodiments, oral dosages range from about 1.0 mg to about 1000 mg, typically 1-4 or more times per day.

[0260] Hippo signaling network The Hippo signaling network (also known as the Salvador / Warts / Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the primary function of the Hippo signaling network is to negatively regulate the transcriptional coactivator Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motifs (TAZ; also known as WWTR1) (Figure 1). The Hippo kinase cascade phosphorylates and inhibits YAP / TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth-promoting functions regulated under YAP / TAZ control. In the unphosphorylated / dephosphorylated state, YAP, also known as YAP1 or YAP65, is transported to the nucleus together with TAZ, where they interact with the TEAD family of transcription factors to upregulate genes that promote proliferation and migration and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and anti-apoptosis leads to the development of cancer. In some instances, overexpression of YAP / TAZ is associated with cancer.

[0261] Additional core members of the Hippo signaling pathway include the serine / threonine kinases MST1 / 2 (Hippo / Hpo homologs in Drosophila), Lats1 / 2 (Warts / Wts homologs), and their adaptor proteins Sav1 (Salvador / Sav homolog) and Mob (MOBKL1A and MOBKL1B; Mats homologs), respectively (Figure 1). Generally, MST1 / 2 kinases form a complex with the scaffolding protein Sav1, which phosphorylates and activates Lats1 / 2 kinases. Lats1 / 2 is also activated by the scaffolding protein Mob. Activated Lats1 / 2 then phosphorylates and inactivates YAP or its paralog TAZ. Phosphorylation of YAP / TAZ triggers its nuclear export, cytoplasmic retention, and degradation by the ubiquitin proteasome system.

[0262] In some examples, Lats1 / 2 phosphorylates YAP at the [HXRXXS] consensus motif. YAP contains five [HXRXXS] consensus motifs, where X represents any amino acid residue. In some examples, Lats1 / 2 phosphorylates YAP at one or more of the consensus motifs. In some examples, Lats1 / 2 phosphorylates YAP at all five of the consensus motifs. In some examples, Lats1 / 2 phosphorylates YAP at the S127 amino acid position. Phosphorylation of YAP S127 promotes 14-3-3 protein binding and causes cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0263] Further phosphorylation occurs at amino acid position S381 in YAP. Phosphorylation of YAP at S381 and the corresponding site in TAZ stimulates further phosphorylation of both proteins by CK1δ / ε in the degradation motif, which then signals their interaction with the β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0264] In some examples, Lats1 / 2 phosphorylates TAZ at the [HXRXXS] consensus motif. TAZ contains four [HXRXXS] consensus motifs, where X represents any amino acid residue. In some examples, Lats1 / 2 phosphorylates TAZ at one or more of the consensus motifs. In some examples, Lats1 / 2 phosphorylates TAZ at all four of the consensus motifs. In some examples, Lats1 / 2 phosphorylates TAZ at amino acid position S89. Phosphorylation of TAZ S89 promotes 14-3-3 protein binding and causes cytoplasmic sequestration of TAZ. Mutation of TAZ at position S89 thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.

[0265] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm and is expressed in the presence of SCF β-TRCPIn some instances, Skp, Cullin, and F-box-containing complexes (SCF complexes) are multiprotein E3 ubiquitin ligase complexes that contain F-box family member proteins (e.g., Cdc4), Skp1, bridging proteins, and RBX1, which contains a small RING finger domain that interacts with E2-ubiquitin conjugating enzymes. In some instances, the F-box contains more than 40 members, where exemplary members include F-box / WD repeat-containing protein 1A (FBXW1A, βTrCP1, Fbxw1, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated protein 2 (SKP2). In some embodiments, the SCF complex (e.g., SCF βTrCP1 ) interacts with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to YAP / TAZ substrates. Exemplary E1 ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, ubiquitinated YAP / TAZ is further processed for degradation via the 26S proteasome.

[0266] In some embodiments, the Hippo pathway is regulated upstream by multiple different families of regulators (Figure 1). In some instances, the Hippo pathway is regulated by G proteins and their coupled receptors, the Crumbs complex, upstream regulators of MST kinases, and adherens junctions.

[0267] YAP / TAZ interaction with TEAD In some embodiments, unphosphorylated and / or dephosphorylated YAP / TAZ accumulates in the nucleus, where it interacts with the TEAD family of transcription factors (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti-apoptosis and proliferation, such as CTFG, Cyr61, and FGF1.

[0268] In some embodiments, the compounds disclosed herein modulate the interaction between YAP / TAZ and TEAD, hi some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP / TAZ and TEAD.

[0269] G protein / GPCR-mediated regulation of YAP / TAZ In some embodiments, the Hippo pathway is regulated by proteins from the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) families (Figure 2). G proteins are molecular switches that transduce extracellular stimuli into the cell via GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes is the α(G α ), β(G β ), and γ(G γ ) subunits. In some cases, some classes of G α Subunit: G q / 11 α, G 12 / 13 α, G i / o α (G inhibitory, G other), and Gs α (G stimulatory).

[0270] In some instances, G i α (G inhibitory), G o α (G others), G q / 11 α, and G 12 / 13 α-coupled GPCRs activate YAP / TAZ and promote its nuclear translocation. s α (G-stimulated)-coupled GPCRs suppress YAP / TAZ activity, leading to YAP / TAZ degradation.

[0271] In some cases, G i α (G inhibitory), G o α (G others), G q / 11 α, and G 12 / 13 α-coupled GPCRs activate YAP / TAZ by suppressing Lats1 / 2 activity. In contrast, G s Alpha, in some embodiments, induces Lats1 / 2 activity, thereby promoting YAP / TAZ degradation.

[0272] G q Family G q α(G q / 11 Proteins (also known as ATP) mediate the release of calcium (Ca) from intracellular stores via the inositol triphosphate (IP3) signaling pathway and activation of phospholipase C (PLC). 2+ ) release. Activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and IP3. In some instances, IP3 diffuses through the cytoplasm into the ER or, in muscle cells, into the sarcoplasmic reticulum (SR), where it then releases Ca 2+ It binds to the inositol triphosphate receptor (InsP3R), a channel. In some cases, this binding occurs via Ca 2+ This causes the channel to open, thereby releasing Ca 2+ Increases release of into the cytoplasm.

[0273] In some embodiments, G qGPCRs that interact with alpha include, but are not limited to, 5-hydroxytryptamine receptors (5-HT receptors) types 5-HT2 and 5-HT3; alpha-1 adrenergic receptors; vasopressin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptors; histamine H1 receptors; metabotropic glutamate receptors (group I); muscarinic receptors M1, M3, and M5; and trace amine-associated receptor 1.

[0274] In some instances, multiple types of G q α:G q , G q / 11 , G q / 14 , and G q / 15 There is. G q The protein is encoded by GNAQ. q / 11 is encoded by GNA11. q / 14 is encoded by GNA14. q / 15 is encoded by GNA15.

[0275] In some instances, G q Mutations or modifications in the α gene have been linked to cancer. Indeed, studies have shown that q Mutations in GNAQ and / or GNA11 have been shown to promote uveal melanoma (UM) tumorigenesis. In some instances, approximately 80% of UM cases have been detected to contain mutations in GNAQ and / or GNA11.

[0276] In some instances, G q Mutations or modifications of the α gene have been associated with congenital disorders. q Mutations in GNAQ have been observed in congenital disorders such as port-wine stains and / or Sturge-Weber syndrome. In some instances, approximately 92% of cases of port-wine stains harbor mutations in GNAQ. In some instances, approximately 88% of cases of Sturge-Weber syndrome harbor mutations in GNAQ.

[0277] G 12 / 13 Family G12 / 13 GEFs regulate actin cytoskeleton remodeling in cells and control cellular processes through guanine nucleotide exchange factors. GEFs are involved in the activation of small GTPases, which act as molecular switches in various intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g., the Rho family, including Cdc42), which are involved in cell differentiation, proliferation, cytoskeletal organization, vesicle transport, and nuclear transport.

[0278] In some embodiments, G 12 / 13 GPCRs that interact with α include, but are not limited to, purinergic receptors (e.g., P2Y1, P2Y2, P2Y4, P2Y6); muscarinic acetylcholine receptors M1 and M3; thrombin receptors [protease-activated receptor (PAR)-1, PAR-2]; thromboxane (TXA2); sphingosine 1-phosphate (e.g., S1P2, S1P3, S1P4, and S1P5); lysophosphatidic acid (e.g., LPA1, LPA2, LPA3); angiotensin II (AT1); serotonin (5-HT2c and 5-HT4); somatostatin (sst5); endothelin (ETA and ETB); cholecystokinin (CCK1); V 1a These include vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; A1 adenosine receptors; α1 adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NK1 tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.

[0279] In some instances, G 12 / 13 α is G encoded by GNA12 and GNA13, respectively 12 Type and G 13 It is further subdivided into types.

[0280] G i / o Family G i / o α (G inhibitory, G other) (Gi / G0 or G i Proteins (also known as ATPase inhibitors) suppress the production of 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through the inhibition of adenylate cyclase activity, which converts ATP to cAMP.

[0281] In some embodiments, G i GPCRs that interact with α include, but are not limited to, 5-hydroxytryptamine receptors (5-HT receptors) type 5-HT1 and 5-HT5; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as A1 and A3; α 2A , α 2B , and α 2C apelin receptors; calcium-sensing receptors; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptors; dopamine D2, D3, and D4; GABAB receptors; glutamate receptors, e.g., metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors, e.g., H3 and H4 receptors; melatonin receptors receptors, such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as delta, kappa, and mu, and nociceptin receptors; prostaglandin receptors, such as prostaglandin E receptor 1 (EP1), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors sst1, sst2, sst3, sst4, and sst5; and trace amine-associated receptor 8.

[0282] In some instances, some types of G i α:G i α1, G i α2, Gi α3, G i α4, G o α, G t , G gust , and G z There is. G i α1 is encoded by GNAI1. i α2 is encoded by GNAI2. i α3 is encoded by GNAI3. o α (ao subunit) is encoded by GNAO1. t is encoded by GNAT1 and GNAT2. gust is encoded by GNAT3. z is coded by GNAZ.

[0283] G s Family G s α(G stimulatory, G s Alpha subunit, or G s G (also known as G protein) activates the cAMP-dependent pathway through activation of adenylate cyclase, which converts adenosine triphosphate (ATP) to 3',5'-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, G s GPCRs that interact with α include, but are not limited to, 5-hydroxytryptamine receptors (5-HT receptors) types 5-HT4, 5-HT6, and 5-HT7, adrenocorticotropic hormone receptors (ACTH receptors) (also known as melanocortin receptor 2 or MC2R), adenosine receptor A 2a Type and A 2btype, arginine vasopressin receptor 2 (AVPR2), beta-adrenergic receptors beta1, beta2, and beta3, calcitonin receptor, calcitonin gene-related peptide receptor, corticotropin-releasing hormone receptor, dopamine receptor D1-like family receptors such as D1 and D5, follicle-stimulating hormone receptor (FSH receptor), gastric inhibitory polypeptide receptor, glucagon receptor, histamine H2 receptor, luteinizing hormone / choriogonadotropin receptor, melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R, parathyroid hormone receptor 1, prostaglandin receptors type D2 and type I2, secretin receptor, thyrotropin receptor, and trace amine-related receptor 1, and box jellyfish opsin.

[0284] In some instances, two types of G s α:G s and G olf There is. G s is encoded by GNAS. olf is coded by GNAL.

[0285] Further regulators of the Hippo signaling network In some embodiments, a further regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex includes transmembrane CRB proteins that assemble into multiprotein complexes that function in cell polarity. In some instances, the CRB complex recruits members of the angiomotin (AMOT) family of adaptor proteins that interact with Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.

[0286] In some instances, additional regulators of the Hippo signaling pathway include regulators of the MST kinase family. MST kinases monitor the integrity of the actin cytoskeleton. In some instances, regulators include TAO kinase and cell polarity kinase PAR-1.

[0287] In some instances, additional regulators of the Hippo signaling pathway include molecules at adherens junctions. In some instances, E-cadherin (E-cad) suppresses YAP nuclear localization and activity through modulation of MST activity. In some embodiments, the E-cad-related protein α-catenin regulates YAP through sequestration of the YAP / 14-3-3 complex in the cytoplasm. In other instances, Ajuba protein family members interact with Lats1 / 2 kinase activity, thereby preventing YAP / TAZ inactivation.

[0288] In some embodiments, additional proteins that interact directly or indirectly with YAP / TAZ include, but are not limited to, merlin, protocadherin Fat1, MASK1 / 2, HIPK2, PTPN14, RASSF, PP2A, salt-inducible kinase (SIK), Scribble (SCRIB)1, Scribble-related protein Discs large (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1 / 2.

[0289] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivators with PDZ-binding motifs / Yes-associated protein transcriptional coactivators (TAZ / YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivators with PDZ-binding motifs / Yes-associated protein transcriptional coactivators (TAZ / YAP) or decrease the dephosphorylation of transcriptional coactivators with PDZ-binding motifs / Yes-associated protein transcriptional coactivators (TAZ / YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivators with PDZ-binding motifs / Yes-associated protein transcriptional coactivators (TAZ / YAP) or decrease the deubiquitination of transcriptional coactivators with PDZ-binding motifs / Yes-associated protein transcriptional coactivators (TAZ / YAP).

[0290] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by or associated with the Hippo pathway. In some examples, the one or more proteins include proteins shown in Figures 1 and / or 2. In some embodiments, the inhibitors of the Hippo pathway are inhibitors of G proteins and / or their coupled GPCRs. In some embodiments, the inhibitors of the Hippo pathway are inhibitors of G proteins. In some embodiments, the inhibitors of the Hippo pathway are inhibitors of G q , G q / 11 , G q / 14 , and ,G q / 15 G such as q α family protein; G 12 and G 13 Proteins such as G 12 / 13 α family; or G i α1, G i α2, G i α3, G i α4, G o α, G t , G gust , and ,G z Proteins such as G iIn some embodiments, the inhibitor of the Hippo pathway is an inhibitor of the G q In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q / 11 In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q / 14 In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q / 15 In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G 12 In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G 13 In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of α2. i In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of α4. o In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G t In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G gust In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G z is an inhibitor of

[0291] In some embodiments, the Hippo pathway inhibitor is an inhibitor of a Hippo pathway core protein. In some embodiments, the Hippo pathway inhibitor is an inhibitor of Sav1. In some embodiments, the Hippo pathway inhibitor is an inhibitor of Mob. In some embodiments, the Hippo pathway inhibitor is an inhibitor of YAP. In some embodiments, the Hippo pathway inhibitor is an inhibitor of TAZ. In some embodiments, the Hippo pathway inhibitor is an inhibitor of TEAD.

[0292] In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway, hi some embodiments, the inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g., the 26S proteasome).

[0293] In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of a protein in the Ra superfamily of proteins. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of a protein in the Rho family of proteins. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of Cdc42.

[0294] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, where family members are involved in diverse and important cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, the inhibitor of Cdc42 is a compound disclosed herein.

[0295] In some embodiments, the Hippo pathway inhibitor is an inhibitor of a deubiquitinase. In some embodiments, the Hippo pathway inhibitor is an inhibitor of a cysteine ​​protease or a metalloprotease. In some embodiments, the Hippo pathway inhibitor is an inhibitor of a ubiquitin-specific protease. USP47 is a member of the ubiquitin-specific protease (USP / UBP) superfamily of cysteine ​​proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.

[0296] Further embodiments provided herein include combinations of one or more of the specific embodiments set forth above.

[0297] disease cancer In some embodiments, compounds of Formula (I), Formula (II), or Formula (III) disclosed herein are useful for treating cancer. In some embodiments, provided herein are methods for treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds for use in treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating cancer.

[0298] In some embodiments, the cancer is mediated by activation of transcriptional coactivator with PDZ-binding motifs / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the cancer is mediated by modulation of YAP / TAZ interaction with TEAD. In some embodiments, the cancer is characterized by a mutant Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is G q In some embodiments, the mutant Gα-protein is G11. In some embodiments, the mutant Gα-protein is G1. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.

[0299] In some embodiments, the cancer is a solid tumor. In some instances, the cancer is a hematological malignancy. In some instances, the solid tumor is a sarcoma or carcinoma. In some instances, the solid tumor is a sarcoma. In some instances, the solid tumor is a carcinoma.

[0300] Exemplary sarcomas include, but are not limited to, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, desmoplastic small round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, nasal neuroblastoma, Ewing's sarcoma, extrarenal rhabdoid tumor, and extraskeletal myxoid chondrosarcoma. tumor, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastic tumor, Kaposi's sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma of bone (MFH), malignant mesenchymoma, malignant peripheral nerve sheath tumor, mesenchymal chondrosarcoma, myxofibrosarcoma, myxoinflammatory fibroblastic sarcoma fibroblastic sarcoma), neoplasm with perivascular epithelioid differentiation, osteosarcoma, parosteal osteosarcoma, neoplasm with perivascular epithelioid differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, pancreatic neuroendocrine tumor / extraskeletal Ewing's tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma.

[0301] Exemplary carcinomas include, but are not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., intrahepatic cholangiocarcinoma), bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, cancer of unknown primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastrointestinal cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some cases, the liver cancer is primary liver cancer.

[0302] In some examples, the cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. Optionally, the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. Optionally, the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. Optionally, the cancer is uveal melanoma. Optionally, the cancer is mesothelioma. Optionally, the cancer is esophageal cancer. Optionally, the cancer is liver cancer. Optionally, the cancer is primary liver cancer.

[0303] In some examples, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancy, or B-cell malignancy. In some examples, the hematological malignancy is a T-cell malignancy. Exemplary T-cell malignancies include, but are not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, hematoimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathic T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T lymphoma, and treatment-related T-cell lymphoma.

[0304] In some embodiments, the hematological malignancy is a B-cell malignancy. Exemplary B-cell malignancies include, but are not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, and non-CLL / SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt's lymphoma high-grade B-lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0305] In some instances, the cancer is a relapsed or refractory cancer. In some embodiments, the relapsed or refractory cancer is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory sarcoma or a relapsed or refractory carcinoma. In some embodiments, relapsed or refractory carcinomas comprise adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., intrahepatic cholangiocarcinoma), bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, cancer of unknown primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastrointestinal cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0306] In some examples, the relapsed or refractory cancer is selected from relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the relapsed or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the recurrent or refractory cancer is recurrent or refractory uveal melanoma. In some cases, the recurrent or refractory cancer is recurrent or refractory mesothelioma. In some cases, the recurrent or refractory cancer is recurrent or refractory esophageal cancer. In some cases, the recurrent or refractory cancer is recurrent or refractory liver cancer. In some cases, the recurrent or refractory cancer is recurrent or refractory primary liver cancer.

[0307] In some examples, the relapsed or refractory cancer is a relapsed or refractory hematological malignancy. In some embodiments, the relapsed or refractory hematological malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin's lymphoma, a relapsed or refractory Hodgkin's lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy. In some examples, the relapsed or refractory hematological malignancy is a relapsed or refractory T-cell malignancy. In some examples, the relapsed or refractory hematological malignancy is a relapsed or refractory B-cell malignancy, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt's lymphoma high-grade B-lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0308] In some examples, the cancer is a metastatic cancer. In some examples, the metastatic cancer is a metastatic solid tumor. In some examples, the metastatic solid tumor is a metastatic sarcoma or a metastatic carcinoma. In some embodiments, metastatic carcinomas include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., intrahepatic cholangiocarcinoma), bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, cancer of unknown primary (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastrointestinal cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, laryngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.

[0309] In some examples, the metastatic cancer is selected from metastatic uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, the metastatic cancer is metastatic uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, the metastatic cancer is metastatic uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the metastatic cancer is metastatic uveal melanoma. In some cases, the metastatic cancer is metastatic mesothelioma. In some cases, the metastatic cancer is metastatic esophageal cancer. In some cases, the metastatic cancer is metastatic liver cancer. In some cases, the metastatic cancer is metastatic primary liver cancer.

[0310] In some examples, the metastatic cancer is a metastatic hematologic malignancy. In some embodiments, the metastatic hematologic malignancy is a metastatic leukemia, a metastatic lymphoma, a metastatic myeloma, a metastatic non-Hodgkin's lymphoma, a metastatic Hodgkin's lymphoma, a metastatic T-cell malignancy, or a metastatic B-cell malignancy. In some examples, the metastatic hematologic malignancy is a metastatic T-cell malignancy. In some examples, the metastatic hematologic malignancy is a metastatic B-cell malignancy, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt's lymphoma high-grade B-lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

[0311] In some examples, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

[0312] Non-cancerous signs In some embodiments, compounds of Formula (I), Formula (II), or Formula (III) are useful for treating polycystic kidney disease. In some embodiments, compounds of Formula (I), Formula (II), or Formula (III) are useful for treating liver fibrosis. In some embodiments, provided herein are methods for treating polycystic kidney disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds for use in treating polycystic kidney disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating polycystic kidney disease. In some embodiments, provided herein are methods for treating liver fibrosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds for use in treating liver fibrosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating liver fibrosis.

[0313] congenital disease In some embodiments, compounds of Formula (I), Formula (II), or Formula (III) are useful for treating congenital diseases. In some embodiments, provided herein are methods for treating a congenital disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein are compounds for use in treating a congenital disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a congenital disease. In some embodiments, the congenital disease is mediated by activation of a transcriptional coactivator with a PDZ-binding motif / Yes-associated protein transcriptional coactivator (TAZ / YAP). In some embodiments, the congenital disease is characterized by a mutant Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is Gq. In some embodiments, the mutant Gα-protein is G11. In some embodiments, the mutant Gα-protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.

[0314] In some embodiments, the congenital disease is the result of a genetic abnormality, the intrauterine environment, an error associated with morphogenesis, an infection, an epigenetic modification on the parental germline, or a chromosomal abnormality. Exemplary congenital diseases include, but are not limited to, Sturgey-Weber syndrome, port-wine staining, Holtow-Aurum syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth disease (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart disease, congenital hypothyroidism, congenital muscular dystrophies, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, Fragile X syndrome, Friedreich's ataxia, galactosemia, hemochromatosis, Krabbe disease, limb-girdle muscular dystrophy, medium-chain acyl-CoA dehydrogenase deficiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunodeficiency (SCID), Stickler syndrome (or hereditary progressive arthrophthalmopathy), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disease is Sturgey-Weber syndrome or port-wine stain. In some embodiments, the congenital disease is Sturgey-Weber syndrome. In some embodiments, the congenital disease is port-wine stain. [Example]

[0315] These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims.

[0316] As used above, and throughout this disclosure, unless otherwise specified, the following abbreviations shall be understood to have the following meanings: ACN or MeCN acetonotrile Ac Acetyl BOC or Boc tert-butylcarbamate t-Bu tert-butyl ℃ Celsius DAST N,N-diethylaminosulfur trifluoride DBA or dba dibenzylidene acetone DCE Dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DIPEA or DIEA Diisopropylethylamine DMF Dimethylformamide DMSO dimethyl sulfoxide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EA or EtOAc Ethyl acetate Et Ethyl EtOH ethanol g grams(s) h, hr, hrs time (s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography Hz Hertz LAH Lithium Anhydrous LCMS Liquid Chromatography Mass Spectrometry m / z mass-to-charge ratio M molar concentration Me methyl MeOH Methanol mg milligram MHz Megahertz umol micromol(s) uL microliter(s) mL milliliter(s) mmol millimole (s) MS mass spectrometry NMR nuclear magnetic resonance PE Petroleum Ether Ph Phenyl prep HPLC Preparative High Pressure Liquid Chromatography prep TLC Preparative Thin Layer Chromatography Py Pyridine RT retention time TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography XPHOS 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0317] 1.Chemical synthesis Unless otherwise specified, reagents and solvents were used as obtained from commercial sources. Anhydrous solvents and oven-dried glassware were used for moisture- and / or oxygen-sensitive synthetic transformations. Yields were not optimized. Reaction times are approximate and not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise specified. In some embodiments, if there is a discrepancy between the reaction scheme and the written procedure, the written procedure should be followed.

[0318] Example 1: 5-(4-chlorophenoxy)-N-isopropyl-2-naphthamide (Compound 1)

[0319] [ka]

[0320] A mixture of 5-bromo-N-isopropyl-naphthalene-2-carboxamide (0.15 g, 0.51 mmol, 1 equivalent (eq)), 4-chlorophenol (99.0 mg, 0.77 mmol, 75.6 uL, 1.5 eq), CuI (19.5 mg, 0.10 mmol, 0.2 eq), CsCO (418.2 mg, 1.28 mmol, 2.5 eq), and 2-(dimethylamino)acetic acid (15.9 mg, 0.15 mmol, 0.3 eq) in DMSO (2 mL) was degassed and purged with N three times, and then the mixture was stirred at 140 °C under a N atmosphere in a microwave for 1 hour. HO (8 mL) was added to the solution. The mixture was then washed with ethyl acetate (15 mL). * The combined organic layers were washed with brine (25 mL). *2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. Compound 5-(4-chlorophenoxy)-N-isopropyl-naphthalene-2-carboxamide (14.5 mg, 42.6 umol, 8.3% yield) was obtained. LCMS (ESI): RT = 0.877 min, mass calc. for C 20 H 18 ClNO2339.10, m / z found 339.9 [M+H] +1 H NMR(400MHz,CDOD3)δ 8.36(d,J=1.5Hz,1H),8.13(d,J=8.8Hz,1H),7.85(dd,J=1.8, 8.8Hz,1H),7.75(d,J=8.3Hz,1H),7.46(t,J=8.0Hz,1H),7.34-7.30(m,2H),7.03-6.96(m,3H),4.23(s,1H),1.25(d,J=6.5Hz,7H).

[0321] Example 2: 5-(3-chlorophenoxy)-N-isopropyl-2-naphthamide (Compound 2)

[0322] [ka]

[0323] A mixture of 5-bromo-N-isopropyl-naphthalene-2-carboxamide (0.15 g, 0.51 mmol, 1 equiv.), 3-chlorophenol (99.0 mg, 0.77 mmol, 81.1 uL, 1.5 equiv.), CuI (19.6 mg, 0.10 mmol, 0.2 equiv.), CsCO (418.2 mg, 1.28 mmol, 2.5 equiv.), and 2-(dimethylamino)acetic acid (15.9 mg, 0.15 mmol, 0.3 equiv.) in DMSO (2 mL) was degassed and purged with N three times, then the mixture was stirred at 140 °C under a N atmosphere in a microwave for 1 hour. HO (8 mL) was added to the solution. The mixture was then washed with ethyl acetate (15 mL). * The combined organic layers were washed with brine (25 mL). *2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. Compound 5-(3-chlorophenoxy)-N-isopropyl-naphthalene-2-carboxamide (13.5 mg, 39.9 μmol, 7.7% yield) was obtained. LCMS (ESI): RT = 0.873 min, mass calc. for C 20 H 18 ClNO2339.10, m / z found 339.9 [M+H] + ; 1 H NMR(400MHz,CDOD3)δ 8.42(d,J=1.3Hz,1H),8.13(d,J=8.8Hz,1H),7.92-7.81(m,2H),7.54(t,J=8.0Hz, 1H),7.38-7.30(m,1H),7.16-7.10(m,2H),7.01(t,J=2.1Hz,1H),6.95(dd,J=1.8, 8.3Hz,1H),4.35-4.21(m,1H),1.30(d,J=6.5Hz,6H).

[0324] Example 3: 5-(3,4-Dichlorophenoxy)-N-isopropyl-naphthalene-2-carboxamide (Compound 3)

[0325] [ka]

[0326] A mixture of compound 5-bromo-N-isopropyl-2-naphthamide (140 mg, 0.5 mmol, 1 equiv.), compound 3,4-dichlorophenol (117.2 mg, 0.7 mmol, 27.1 uL, 1.5 equiv.), CuI (18.3 mg, 95.8 umol, 0.2 equiv.), CsCO (390.3 mg, 1.2 mmol, 2.5 equiv.), and N,N,N-dimethylglycine (14.8 mg, 0.1 mmol, 0.3 equiv.) in DMSO (3 mL) was placed in a microwave tube. The sealed microwave tube was heated at 140 °C in a microwave for 1 h. The residue was poured into HO (50 mL) and stirred for 5 min. The aqueous phase was extracted with EA (20 mL). *3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (58.6 mg, 0.2 mmol, 32.7% yield). LCMS (ESI): RT = 0.920 min, mass calc. for C 20 H 17 Cl2NO2373.1.1, m / z found 373.9 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.64-8.36(m,2H),8.16-7.84(m,3H),7.61(d,J=12.3Hz,2H),7.37(s,1H ),7.22(s,1H),7.01(d,J=5.8Hz,1H),4.15(s,1H),1.20(d,J=5.8Hz,6H).

[0327] Example 4: N-isopropyl-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 4)

[0328] [ka]

[0329] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (0.1, 0.30 mmol, 1 equiv) in DMF (2 mL) was added HATU (228.8 mg, 0.60 mmol, 2 equiv) and TEA (152.2 mg, 1.50 mmol, 0.20 mL, 5 equiv). The mixture was stirred at 25 °C for 0.5 h. Isopropylamine (35.5 mg, 0.60 mmol, 51.7 uL, 2 equiv) was added to the mixture, and the mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with HO (30 mL), and the mixture was extracted with EA (20 mL). * 3). The combined organic phases were washed with brine (20 mL * 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150* 25 mm*5 um; Mobile phase: [water (0.05% HCl)-ACN]; B%: 60%-90%, 9.5 min) to give the title compound (13.26 mg, 35.5 umol, 11.8% yield). LCMS (ESI): RT=0.881 min, mass calc. for: C 21 H 18 F3NO2373.37, m / z found 373.9; 1 H NMR(400MHz,METHANOL-d4) Shift=8.45(d,J=1.5Hz,1H),8.10(d,J=8.9Hz,1H),7.91(d,J=8.7Hz,2H),7.71-7.64(m,J=8.5Hz,2H),7.59(t,J=7.9Hz,1H),7.23(dd,J=0.8, 7.6Hz,1H),7.18-7.12(m,J=8.6Hz,2H),4.34-4.24(m,1H),1.31(d,J=6.6Hz,6H).

[0330] Example 5: N-(methylsulfonyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 5)

[0331] [ka]

[0332] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (0.05 g, 0.15 mmol, 1 equiv) in DMF (2 mL) was added CDI (29.2 mg, 0.18 mmol, 1.2 equiv). The mixture was stirred at 30 °C for 0.5 h. Methanesulfonamide (17.1 mg, 0.18 mmol, 1.2 equiv) and DBU (27.4 mg, 0.18 mmol, 27.2 uL, 1.2 equiv) were added to the mixture, and the mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with HO (30 mL), and the mixture was extracted with EA (20 mL). * 3). The combined organic phases were washed with brine (20 mL *3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8.3 mg, 20.3 umol, 13.5% yield). 1 H NMR(400MHz,METHANOL-d4) Shift=8.59(d,J=1.6Hz,1H),8.18(d,J=8.9Hz,1H),7.97(t,J=7.6Hz,2H),7 .73-7.62(m,3H),7.30(d,J=7.4Hz,1H),7.17(d,J=8.6Hz,2H),3.43(s,3H).

[0333] Example 6: 5-(3,4-dichlorophenoxy)-N-(methylsulfonyl)-2-naphthamide (Compound 6)

[0334] [ka]

[0335] To a solution of 5-(3,4-dichlorophenoxy)naphthalene-2-carboxylic acid (50.1 mg, 0.15 mmol, 1 equiv.) in DMF (2 mL) was added DBU (27.4 mg, 0.18 mmol, 27.2 uL, 1.2 equiv.). The mixture was stirred at 40° C. for 0.5 h. Methanesulfonamide (17.1 mg, 0.18 mmol, 1.2 equiv.) and CDI (29.2 mg, 0.18 mmol, 1.2 equiv.) were added to the mixture, and the mixture was stirred at 25° C. for 0.5 h. HO (6 mL) was added to the solution. The mixture was extracted with ethyl acetate (10 mL). * 3). The combined organic layers were washed with brine (15 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (9.1 mg, 21.6 μmol, 14.3% yield). LCMS (ESI): RT=0.881 min, mass calc. for C 18 H 13 Cl2NO4S 410.27, m / z found 409.8 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ=12.34(br s, 1H),8.68(s,1H),8.09(d,J=8.8Hz,1H),8.00-7.91(m,2H),7.65-7.58(m,2H),7.38(d,J=2.7Hz,1H),7.27(d,J=7.6Hz,1H),7.01(dd,J=2.8, 8.9Hz, 1H), 3.39(s, 3H).

[0336] Example 7: N-methyl-5-(4-(trifluoromethyl)phenoxy)naphthalene-2-sulfonamide (Compound 7)

[0337] [ka]

[0338] 5-Bromonaphthalene-2-sulfonyl chloride A mixture of 5-bromonaphthalene-2-sulfonic acid (900 mg, 3.13 mmol, 1 equiv.) and SOCl (745.8 mg, 6.27 mmol, 0.45 mL, 2 equiv.) in DMF (2 mL) was stirred for 1 h at 30 °C. The reaction mixture was diluted with HO (5 mL), and the mixture was extracted with EA (15 mL). * 3). The combined organic phases were washed with brine (10 mL * 6), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. Compound 5-bromonaphthalene-2-sulfonyl chloride (800 mg, 2.62 mmol, 83.5% yield) was obtained.

[0339] 5-Bromo-N-methylnaphthalene-2-sulfonamide Methylamine (2 M, 3.93 mL, 3 equiv.) was added dropwise to a mixture of 5-bromonaphthalene-2-sulfonyl chloride (800 mg, 2.62 mmol, 1 equiv.) in THF (1 mL) at 0° C. The mixture was stirred for 1 h at 25° C. The reaction mixture was diluted with HO (10 mL) and the mixture was extracted with EA (30 mL). * 3). The combined organic phases were washed with brine (20 mL* 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. Compound 5-bromo-N-methyl-naphthalene-2-sulfonamide (600 mg, 2.00 mmol, 76.3% yield) was obtained.

[0340] N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-sulfonamide A mixture of 5-bromo-N-methyl-naphthalene-2-sulfonamide (400 mg, 1.33 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (507.5 mg, 2.00 mmol, 1.5 equiv.), AcOK (261.5 mg, 2.67 mmol, 2 equiv.), and Pd(dppf)Cl (48.7 mg, 66.6 mmol, 0.05 equiv.) in dioxane (3 mL) was degassed and purged with N three times, after which the mixture was stirred at 90 °C under N atmosphere for 3 h. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography. The compound N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-sulfonamide (350 mg, 1.01 mmol, 75.6% yield) was obtained.

[0341] 5-Hydroxy-N-methylnaphthalene-2-sulfonamide A mixture of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-sulfonamide (350 mg, 1.01 mmol, 1 equiv.) and sodium;3-oxidedioxaborilane tetrahydrate (465.2 mg, 3.02 mmol, 0.58 mL, 3 equiv.) in THF (2 mL) and HO (1 mL) was stirred for 1 h at 30 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 3), dried over anhydrous NaSO, filtered and concentrated in vacuo to give compound 5-hydroxy-N-methyl-naphthalene-2-sulfonamide (250 mg, crude), which was used in the next step without further purification.

[0342] N-methyl-5-(4-(trifluoromethyl)phenoxy)naphthalene-2-sulfonamide A mixture of 5-hydroxy-N-methyl-naphthalene-2-sulfonamide (100 mg, 0.42 mmol, 1 equiv.), [4-(trifluoromethyl)phenyl]boronic acid (120.0 mg, 0.63 mmol, 1.5 equiv.), DIEA (217.8 mg, 1.69 mmol, 0.29 mL, 4 equiv.), and Cu(OAc) (153.1 mg, 0.84 mmol, 2 equiv.) in DCM (5 mL) was degassed and purged with O three times, after which the mixture was stirred under an O atmosphere at 20 °C for 16 h. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (20 mg, 51.9 μmol, 12.3% yield). LCMS (ESI): RT=0.828 min, mass calc. for C 18 H 14 F3NO3S 381.37, m / z found 382.06 [M+H] + ; 1H NMR(400MHz,METHANOL-d4)δ=8.51(d,J=1.5Hz,1H),8.26(d,J=8.8Hz,1H),7.97(d,J=8.3Hz,1H),7.88(dd,J=1.8, 8.8Hz,1H),7.72-7.65(m,3H),7.31(d,J=7.0Hz,1H),7.18(d,J=8.8Hz,2H),2.58(s,3H).

[0343] Example 8: 5-(3,4-difluorophenoxy)-N-isopropyl-2-naphthamide (Compound 8)

[0344] [ka]

[0345] To a solution of 5-(3,4-difluorophenoxy)naphthalene-2-carboxylic acid (70 mg, 0.23 mmol, 1 equiv) in DCM (1 mL) was added HATU (132.9 mg, 0.34 mmol, 1.5 equiv). The mixture was stirred for 1 hour at 15°C. DIEA (60.2 mg, 0.46 mmol, 81.2 uL, 2 equiv) and iso-propylamine (13.7 mg, 0.23 mmol, 20.0 uL, 1 equiv) were added to the solution. The reaction was stirred for 1 hour at 15°C. HO (6 mL) was added to the solution. The mixture was extracted with ethyl acetate (10 mL). * 3). The combined organic layers were washed with brine (15 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (10.5 mg, 30.8 umol, 13.2% yield). LCMS (ESI): RT=0.847 min, mass calc. for C 20 H 17 F2NO2341.35, m / z found 341.9 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ=8.51(s,1H),8.48-8.43(m,1H),8.11(d,J=8.8Hz,1H),7.98(dd,J=1.4, 8.9Hz,1H),7.87(d,J=8.3Hz,1H),7.56(t,J=7.9Hz,1H),7.52-7.42(m,1H) ,7.36-7.27(m,1H),7.15-7.09(m,1H),6.94-6.86(m,1H),4.16(qd,J=6.8, 13.7Hz,1H),1.22(d,J=6.5Hz,6H).

[0346] Example 9: 5-(3,4-dichlorophenoxy)-N-methylnaphthalene-2-sulfonamide (Compound 9)

[0347] [ka]

[0348] A mixture of 5-hydroxy-N-methyl-naphthalene-2-sulfonamide (80 mg, 0.33 mmol, 1 equiv), (3,4-dichlorophenyl)boronic acid (96.5 mg, 0.50 mmol, 1.5 equiv), Cu(OAc) (122.4 mg, 0.67 mmol, 2 equiv), and DIEA (174.3 mg, 1.35 mmol, 0.23 mL, 4 equiv) in DCM (3 mL) was degassed and purged with O three times, after which the mixture was stirred under O atmosphere for 16 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (5 mg, 12.8 umol, 3.8% yield). 1H NMR(400MHz,METHANOL-d4)δ=8.50(d,J=1.5Hz,1H),8.29(d,J=9.0Hz,1H),7.94(d,J=8.5Hz,1H),7.89(dd,J=1.8, 9.0Hz,1H),7.65(t,J=8.0Hz,1H),7.54(d,J=8.8Hz,1H),7.26-7.22(m,2H),7.01(dd,J=2.8, 8.8Hz,1H),2.58(s,3H).

[0349] Example 10: 5-(3,4-difluorophenoxy)-N-(methylsulfonyl)-2-naphthamide (Compound 10)

[0350] [ka]

[0351] To a solution of 5-(3,4-difluorophenoxy)naphthalene-2-carboxylic acid (70 mg, 0.23 mmol, 1 equiv.) in DMF (2 mL) was added CDI (45.3 mg, 0.27 mmol, 1.2 equiv.). The mixture was stirred for 1 hour at 40°C. DBU (42.5 mg, 0.27 mmol, 42.1 uL, 1.2 equiv.) and methanesulfonamide (26.6 mg, 0.27 mmol, 1.2 equiv.) were added to the solution. The mixture was stirred for 1 hour at 25°C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (5.9 mg, 15.6 umol, 6.7% yield). LCMS (ESI): RT=0.808 min, mass calc. for C 18 H 13 F2NO4S 377.36, m / z found 377.8; 1H NMR(400MHz,DMSO-d6)δ=8.56(s,1H),8.11(dd,J=1.3, 8.8Hz,1H),8.00(d,J=8.8Hz,1H),7.85(d,J=8.3Hz,1H),7.52-7.42(m,2H),7.35-7.26(m,1H),7.04(d,J=7.5Hz,1H),6.89(br s, 1H),2.90(s,3H).

[0352] Example 11: N-isopropyl-1-[4-(trifluoromethyl)phenoxy]isoquinoline-6-carboxamide (Compound 11)

[0353] [ka]

[0354] 1-[4-(trifluoromethyl)phenoxy]isoquinoline-6-carboxylic acid To a mixture of methyl 1-(4-(trifluoromethyl)phenoxy)isoquinoline-6-carboxylate (120 mg, 0.35 mmol, 1 equiv.) in MeOH (5 mL), THF (1.5 mL), and HO (1.5 mL) was added NaOH (2 M, 1.73 mL, 10 equiv.). The mixture was stirred for 1 h at 25 °C. The mixture was concentrated. The residue was diluted with HO (10 mL) and adjusted to pH = 6-7 with 1 N HCl. The mixture was extracted with EA (20 mL). * 3). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(4-(trifluoromethyl)phenoxy)isoquinoline-6-carboxylic acid (90 mg, crude).

[0355] N-Isopropyl-1-[4-(trifluoromethyl)phenoxy]isoquinoline-6-carboxamide A solution of 1-(4-(trifluoromethyl)phenoxy)isoquinoline-6-carboxylic acid (20 mg, 60.0 umol, 1 equiv) in DCM (2.5 mL), DIEA (31.0 mg, 0.24 mmol, 42 uL, 4 equiv) and HATU (34.2 mg, 90.0 umol, 1.5 equiv) was added. The mixture was stirred for 0.5 h at 25 °C. Isopropylamine (5.3 mg, 90.0 umol, 8 uL, 1.5 equiv) was added to the mixture. The mixture was stirred for 12 h at 25 °C. The mixture was diluted with HO (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (SiO2) to give the title compound (6.0 mg, 15.8 umol, 26.4% yield). LCMS (ESI): RT=0.968 min, mass calc. for C 20 H 17 F3N2O2 374.36, m / z found 375.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 8.45(d,J=8.6Hz,1H),8.21(s,1H),8.02(d,J=5.8Hz,1H),7.96(dd,J=1.4, 8.6Hz,1H),7.72(d,J=8.5Hz,2H),7.45-7.35(m,3H),6.14(br d,J=7.3Hz,1H),6.20-6.06(m,1H),4.37(qd,J=6.7, 13.7Hz,1H),1.33(d,J=6.5Hz,6H).

[0356] Example 12: N-[(1R)-2-hydroxy-1-methyl-ethyl]-1-[4-(trifluoromethyl)phenoxy]isoquinoline-6-carboxamide (Compound 12)

[0357] [ka]

[0358] To a solution of 1-(4-(trifluoromethyl)phenoxy)isoquinoline-6-carboxylic acid (20 mg, 60.0 μmol, 1 equiv) and (R)-2-aminopropan-1-ol (6.8 mg, 90.0 μmol, 7 μL, 1.5 equiv) in DCM (1 mL) was added DIEA (31.0 mg, 0.24 mmol, 42 μL, 4 equiv) and HATU (34.2 mg, 90 μmol, 1.5 equiv). The mixture was stirred for 12 h at 25 °C. The mixture was diluted with HO (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (5.5 mg, 14.2 μmol, 23.6% yield). LCMS (ESI): RT=0.882 min, mass calc. for C 20 H 17 F3N2O3390.36, m / z found 391.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 8.48(d,J=8.5Hz,1H),8.25(d,J=1.0Hz,1H),8.03(d,J=5.8Hz,1H),7.99(dd,J=1.5, 8.8Hz,1H),7.73(d,J=8.5Hz,2H),7.44(d,J=5.5Hz,1H),7.40(d,J=8.5Hz,2H),6. 57-6.44(m,1H),4.46-4.31(m,1H),3.93-3.81(m,1H),3.79-3.68(m,1H),2.40(br s, 1H),1.37(d,J=6.8Hz,3H).

[0359] Example 13: N-isopropyl-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 13)

[0360] [ka]

[0361] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 150.0 μmol, 1 equiv) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv) in DCM (1 mL) was added DIEA (77.6 mg, 0.6 mmol, 0.1 mL, 4 equiv). The mixture was stirred at 30° C. for 30 minutes. Isopropylamine (13.3 mg, 0.22 mmol, 19.3 μL, 1.5 equiv) was added to the mixture. The mixture was stirred at 30° C. for 12 hours. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (7.9 mg, 21.2 umol, 14.1% yield). LCMS (ESI): RT=0.802 min, mass calcd. for C 20 H 17 F3N2O2 374.12, m / z found 374.9[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.20(d,J=2.4Hz,1H),8.64(d,J=2.0Hz,1H),7.76(d,J=8.0Hz,1H),7.60-7.56(m,3H),7.35(d,J= 6.8Hz,1H),7.10(d,J=8.8Hz,2H),6.09(d,J=7.2Hz,1H),4.39-4.34(m,1H),1.32(d,J=6.4Hz,6H).

[0362] Example 14: N-[2-hydroxy-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 14)

[0363] [ka]

[0364] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 150.0 μmol, 1 equiv) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv) in DCM (2 mL) was added DIEA (96.9 mg, 0.75 mmol, 0.13 mL, 5 equiv) and 2-amino-2-pyridin-2-yl-ethanol (40 mg, 0.19 mmol, 1.3 equiv, 2HCl). The mixture was stirred at 30° C. for 12 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (15.7 mg, 34.7 umol, 23.1% yield). LCMS (ESI): RT=0.695 min, mass calcd. for C 24 H 18 F3N3O3453.13, m / z found 454.0[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.35(d,J=2.0Hz,1H),8.73(d,J=2.0Hz,1H),8.56(d,J=4.4Hz,1H),8.22(br d,J=6.8Hz,1H),7.78-7.76(m,2H),7.59-7.51(m,4H),7.36-7.34(m,2H),7.10( d,J=8.4Hz,2H),5.43-5.39(m,1H),4.20-4.16(m,1H),4.10-4.06(m,1H),2.7(br s, 1H).

[0365] Example 15: N-[(1R)-2-hydroxy-1-methyl-ethyl]-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 15)

[0366] [ka]

[0367] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 0.15 mmol, 1 equiv) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv) in DCM (2 mL) was added DIEA (77.6 mg, 0.60 mmol, 0.1 mL, 4 equiv) and (2R)-2-aminopropan-1-ol (16.9 mg, 0.23 mmol, 17.6 uL, 1.5 equiv). The mixture was stirred at 30 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (5.3 mg, 13.6 umol, 9.1% yield). LCMS (ESI): RT=0.733 min, mass calcd. for C 20 H 17 F3N2O3390.12, m / z found 390.9[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.26(d,J=2.0Hz,1H),8.67(d,J=2.0Hz,1H),7.74(d, J =7.2Hz,1H),7.73-7.57(m,3H),7.34(d,J=7.2Hz,1H),7.09(d,J=8.4Hz,2H),6.71(br d,J=7.2Hz,1H),4.44-4.37(m,1H),3.83-3.83(m,1H),3.72-3.68(m,1H),1.34(d,J=6.8Hz,3H).

[0368] Example 16: N-[(1R)-2-Methoxy-1-methyl-ethyl]-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 16)

[0369] [ka]

[0370] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 0.15 mmol, 1 equiv) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv) in DCM (2 mL) was added DIEA (96.9 mg, 0.75 mmol, 0.13 mL, 5 equiv) and (2R)-1-methoxypropan-2-amine (28.3 mg, 0.22 mmol, 17.6 uL, 1.5 equiv, HCl). The mixture was stirred at 30 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (16.9 mg, 41.9 umol, 27.9% yield). LCMS (ESI): RT=0.778 min, mass calcd. for C 21 H 19 F3N2O3404.13, m / z found 404.9[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.24(d,J=2.0Hz,1H),8.65(d,J=2.0Hz,1H),7.77(d,J=8.4Hz,1H),7.60-7.56(m,3H),7.36(d,J=8.4Hz,1H),7.10(d,J=8.8Hz,2H),6.58(br d,J=5.6Hz,1H),4.45-4.42(m,1H),3.58-3.54(m,1H),3.49-3.46(m,1H),3.41(s,3H),1.35(d,J=6.4Hz,3H).

[0371] Example 17: N-[(1R)-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 17)

[0372] [ka]

[0373] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv.) in DCM (2 mL) was added DIEA (77.6 mg, 0.60 mmol, 0.1 mL, 4 equiv.) and (1R)-1-(2-pyridyl)ethanamine (27.5 mg, 0.22 mmol, 17.55 uL, 1.5 equiv.). The mixture was stirred at 30° C. for 12 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (26.7 mg, 61.2 μmol, 40.8% yield). LCMS (ESI): RT=0.709 min, mass calcd. for C 24 H 18 F3N3O2437.14, m / z found 438.0[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.36(d,J=2.4Hz,1H),8.78(d,J=2.0Hz,1H),8.58(d,J=4.8Hz,1H),8.24(br d,J=6.4Hz,1H),7.81-7.79(m,2H),7.60-7.56(m,3H),7.38-7.35(m,2H),7.31 -7.27(m,1H),7.11(d,J=8.4Hz,2H),5.44-5.37(m,1H),1.65(d,J=6.8Hz,3H).

[0374] Example 18: N-[(1S)-2-Methoxy-1-methyl-ethyl]-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 18)

[0375] [ka]

[0376] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 0.15 mmol, 1 equiv) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv) in DCM (2 mL) was added DIEA (77.6 mg, 0.6 mmol, 0.1 mL, 4 equiv) and (2S)-1-methoxypropan-2-amine (20.1 mg, 0.22 mmol, 17.6 uL, 1.5 equiv). The mixture was stirred at 30 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (25.0 mg, 61.4 μmol, 40.9% yield). LCMS (ESI): RT=0.782 min, mass calcd. for C 21 H 19 F3N2O3404.13, m / z found 404.9[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.23(d,J=2.4Hz,1H),8.65(d,J=2.0Hz,1H),7.77(d,J=7.6Hz,1H),7.60-7.56(m,3H),7.36(d,J=6.4Hz,1H),7.10(d,J=8.4Hz,2H),6.59(br d,J=8.0Hz,1H),4.46-4.42(m,1H),3.58-3.54(m,1H),3.49-3.46(m,1H),3.41(s,3H),1.35(d,J=6.8Hz,3H).

[0377] Example 19: N-[(1S)-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxamide (Compound 19)

[0378] [ka]

[0379] To a solution of 8-[4-(trifluoromethyl)phenoxy]quinoline-3-carboxylic acid (50 mg, 0.15 mmol, 1 equiv) and HATU (62.8 mg, 0.16 mmol, 1.1 equiv) in DCM (2 mL) was added DIEA (77.6 mg, 0.6 mumol, 0.1 mL, 4 equiv) and (1S)-1-(2-pyridyl)ethanamine (27.5 mg, 0.22 mmol, 17.6 uL, 1.5 equiv). The mixture was stirred at 30 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL). * 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (19.6 mg, 44.9 umol, 29.9% yield). LCMS (ESI): RT=0.717 min, mass calcd. for C 24 H 18 F3N3O2437.14, m / z found 437.9[M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.36(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.57(d,J=4.8Hz,1H),8.16(br d,J=6.8Hz,1H),7.79(d,J=8.4Hz,1H),7.72(t,J=8.0Hz,1H),7.60-7.53(m,3H),7.36-7.34 (m,2H),7.26-7.21(m,1H),7.11(d,J=8.4Hz,2H),5.42-5.35(m,1H),1.63(d,J=6.8Hz,3H).

[0380] Example 20: N-(prop-2-yn-1-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 20)

[0381] [ka]

[0382] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and prop-2-yn-1-amine (9.9 mg, 0.18 mmol, 11.5 uL, 1.2 equiv.) in DMF (1 mL), HATU (114.4 mg, 0.3 mmol, 2 equiv.) and DIEA (77.7 mg, 0.6 mmol, 0.1 mL, 4 equiv.) were added. The mixture was stirred for 2 hours at 25 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (5.2 mg, 14.1 umol, 9.41% yield). LCMS (ESI): RT = 0.875 min, mass calculated for C 21 H 14 F3NO2369.34 m / z found 369.9 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6)δ 9.16(t,J=5.5Hz,1H),8.58(d,J=1.1Hz,1H),8.05-8.01(m,1H),8.01-7.94(m,2H),7.75(d,J=8 .8Hz,2H),7.64(t,J=7.9Hz,1H),7.34(d,J=7.1Hz,1H),7.18(d,J=8.6Hz,2H),4.12(dd,J=2.5, 5.5Hz,2H),3.17(t,J=2.5Hz,1H).

[0383] Example 21: N-(but-3-yn-1-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 21)

[0384] [ka]

[0385] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and but-3-yn-1-amine hydrochloride (10.4 mg, 98.5 mmol, 0.66 equiv.) in DMF (1 mL) was added HATU (114.4 mg, 0.3 mmol, 2 equiv.) and DIEA (77.7 mg, 0.6 mmol, 0.1 mL, 4 equiv.). The mixture was stirred for 2 h at 25 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12.6 mg, 33.1 umol, 22% yield). LCMS (ESI): RT = 0.878 min, mass calculated for C 22 H 16 F3NO2383.36 m / z found 383.9 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6)δ 8.88(t,J=5.5Hz,1H),8.55(s,1H),8.05-7.99(m,1H),7.99-7.92(m,2H),7.75(d,J=8.5Hz,2H),7.64(t,J=7.9H z,1H),7.33(d,J=7.0Hz,1H),7.17(d,J=8.5Hz,2H),3.48-3.41(m,2H),2.87(t,J=2.6Hz,1H),2.49-2.44(m,2H).

[0386] Example 22: N-(cyanomethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 22)

[0387] [ka]

[0388] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and 2-aminoacetonitrile (16.7 mg, 0.18 mmol, 1.2 equiv., HCl) in DMF (1 mL) was added HATU (114.4 mg, 0.3 mmol, 2 equiv.) and DIEA (77.7 mg, 0.6 mmol, 0.1 mL, 4 equiv.). The mixture was stirred for 2 h at 25 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm * Purification by HPLC using a 5 μL column (5 μM; mobile phase: [water (0.05% ammonium hydroxide vv)-ACN]; B%: 65%-95%, 7 min) gave the title compound (20.4 mg, 55.2 μmol, 36.7% yield). LCMS (ESI): RT =0.852 min, mass calculated for C 20 H 13 F3N2O2370.32 m / z found 370.8 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.51(d,J=1.4Hz,1H),8.14(d,J=8.8Hz,1H),7.96-7.89(m,2H),7.68(d,J=8.6Hz,2H), 7.61(t,J=7.9Hz,1H),7.25(d,J=7.1Hz,1H),7.15(d,J=8.6Hz,2H),4.44-4.39(m,2H).

[0389] Example 23: N-(2-cyanoethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 23)

[0390] [ka]

[0391] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and 3-aminopropanenitrile (12.6 mg, 0.18 mmol, 13.3 uL, 1.2 equiv.) in DMF (1 mL), HATU (114.4 mg, 0.3 mmol, 2 equiv.) and DIEA (77.7 mg, 0.6 mmol, 0.1 mL, 4 equiv.) were added. The mixture was stirred for 2 hours at 25 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (5.7 mg, 14.6 μmol, 9.7% yield). LCMS (ESI): RT = 0.843 min, mass calculated for C 21 H 15 F3N2O2384.35 m / z found 384.9 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6)δ 9.08(t,J=5.6Hz,1H),8.57(s,1H),8.08-8.02(m,1H),8.00-7.94(m,2H),7.75(d,J=8.8Hz,2H),7.65(t, J=7.9Hz,1H),7.34(d,J=7.4Hz,1H),7.18(d,J=8.6Hz,2H),3.57(q,J=6.3Hz,2H),2.83(t,J=6.5Hz,2H).

[0392] Example 24: (R)—N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 24)

[0393] [ka]

[0394] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.), DIPEA (77.7 mg, 0.6 mmol, 0.1 mL, 4 equiv.), and HATU (114.4 mg, 0.3 mmol, 2 equiv.) in DCM (1 mL) was stirred for 1 h at 25 °C. Then, (R)-2-aminopropan-1-ol (22.6 mg, 0.3 mmol, 23.9 uL, 2 equiv.) was added to the mixture, and the mixture was stirred for an additional 1 h. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm * Purification by HPLC (5 μm; mobile phase: [water (0.05% ammonium hydroxide vv)-ACN]; B%: 60%-88.4%, 5.6 min) gave the title compound (30 mg, 76.2 μmol, 50.6% yield). LCMS (ESI): RT=0.930 min, mass calculated for C 21 H 18 F3NO3389.37 m / z found 390.0 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6)δ 8.56(s,1H),8.33(d,J=7.9Hz,1H),8.01-7.94(m,3H),7.75(d,J=8.6Hz,2H),7.63(t,J=7.9Hz,1H),7.33(d,J=7.5Hz,1H) ,7.17(d,J=8.6Hz,2H),4.77(t,J=5.8Hz,1H),4.12-4.03(m,1H),3.55-3.46(m,1H),3.42-3.39(m,1H),1.19-1.15(m,3H).

[0395] Example 25: N-(2-hydroxy-1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 25)

[0396] [ka]

[0397] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (60 mg, 0.18 mmol, 1 equiv), HATU (102.9 mg, 0.27 mmol, 1.5 equiv), and DIPEA (70 mg, 0.54 mmol, 94.3 uL, 3 equiv) in DCM (2 mL) was stirred for 1 h at 25 °C. Then, 2-amino-2-pyridin-2-yl-ethanol (50 mg, 0.23 mmol, 1.31 equiv, 2HCl) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm * Purification by HPLC using a 5 μm column of HPLC (mobile phase: [water (0.05% ammonium hydroxide vv)-ACN]; B%: 60%-90%, 7.8 min) gave the title compound (32 mg, 70.7 μmol, 39.1% yield). LCMS (ESI): RT=0.868 min, mass calculated for C 25 H 19 F3N2O3452.34 m / z found 453.0 [M+H] + ; 1H NMR(400 MHz, DMSO-d6)δ 8.90(d,J=7.8Hz,1H),8.67(s,1H),8.58-8.53(m,1H),8.04-7.97(m,3H),7.80-7.73(m,4H),7.69-7.62(m,1H),7 .47(d,J=7.8Hz,1H),7.34(d,J=7.5Hz,1H),7.31-7.21(m,2H),7.18(d,J=8.5Hz,2H),5.26-5.18(m,1H),4.98(br s, 1H),3.85(br dd,J=5.8, 12.0Hz,2H).

[0398] Example 26: (R)—N-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 26)

[0399] [ka]

[0400] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 equiv), and HATU (85.8 mg, 0.22 mmol, 1.5 equiv) in DCM (2 mL) was stirred for 1 h at 25 °C. Then, (2R)-1-methoxypropan-2-amine hydrochloride (22.6 mg, 0.18 mmol, 1.2 equiv) was added to the mixture, and the mixture was stirred for 2 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm *5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 60%-90%, 7 min) to give the title compound (40 mg, 99.1 μmol, 65.9% yield). LCMS (ESI): RT=0.863 min, mass calculated for C 22 H 20 F3NO3403.39 m / z found 404.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.46(d,J=1.3Hz,1H),8.10(d,J=8.8Hz,1H),7.94-7.87(m,2H),7.68(d,J=8.5Hz,2H),7.60(t,J=7.9Hz,1H),7.26-7.20(m,1 H),7.15(d,J=8.5Hz,2H),4.40(sxt,J=6.5Hz,1H),3.59-3.53(m,1H),3.50-3.45(m,1H),3.42(s,3H),1.30(d,J=6.8Hz,4H).

[0401] Example 27: N-[(1R)-1-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (Compound 27)

[0402] [ka]

[0403] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 equiv), and HATU (85.8 mg, 0.22 mmol, 1.5 equiv) in DCM (3 mL) was stirred for 1 h at 25 °C. Then, (1R)-1-(2-pyridyl)ethanamine (22 mg, 0.18 mmol, 1.2 equiv) was added to the mixture, and the mixture was stirred for an additional 2 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL *2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm * 5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 65%-95%, 7 min) to give the title compound (30 mg, 68 μmol, 45.2% yield). LCMS (ESI): RT=0.891 min, mass calculated for C 25 H 19 F3N2O2436.43 m / z found 437.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.54(d,J=1.5Hz,2H),8.10(d,J=8.8Hz,1H),7.98-7.88(m,2H),7.83(dt,J=1.8, 7.7Hz,1H),7.66(d,J=8.6Hz,2H),7.59(t,J=7.9Hz,1H),7.52(d,J=8.0Hz,1H),7.32(ddd,J=0.9, 5.0, 7.5Hz,1H),7.23(d,J=7.0Hz,1H),7.13(d,J=8.6Hz,2H),5.34(q,J=7.0Hz,1H),1.64(d,J=7.1Hz,3H).

[0404] Example 28: (S)—N-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 28)

[0405] [ka]

[0406] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 equiv), and HATU (85.8 mg, 0.22 mmol, 1.5 equiv) in DCM (3 mL) was stirred for 1 h at 25 °C. Then, (2S)-1-methoxypropan-2-amine (16.1 mg, 0.18 mmol, 1.2 equiv) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm * Purification by HPLC (5 μm; mobile phase: [water (0.05% ammonium hydroxide vv)-ACN]; B%: 60%-90%, 7 min) gave the title compound (40 mg, 99.1 μmol, 65.9% yield). LCMS (ESI): RT=0.995 min, mass calculated for C 22 H 20 F3NO3403.39 m / z found 404.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.46(d,J=1.5Hz,1H),8.09(d,J=8.8Hz,1H),7.96-7.87(m,2H),7.66(d,J=8.8Hz,2H),7.58(t,J=7.9Hz,1H),7.22(d,J=7.6Hz,1H ),7.13(d,J=8.6Hz,2H),4.40(sxt,J=6.5Hz,1H),3.59-3.53(m,1H),3.50-3.45(m,1H),3.44-3.39(m,3H),1.30(d,J=6.8Hz,3H).

[0407] Example 29: (S)—N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 29)

[0408] [ka]

[0409] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv), DIPEA (58.3 mg, 0.45 mmol, 78.6 uL, 3 equiv), and HATU (85.8 mg, 0.22 mmol, 1.5 equiv) in DCM (3 mL) was stirred for 1 h at 25 °C. Then, (1S)-1-(2-pyridyl)ethanamine (22 mg, 0.18 mmol, 1.2 equiv) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Xtimate C 18 150 * 25mm * 5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 66%-76%, 8 min) to give the title compound (32 mg, 72.5 μmol, 48.2% yield). LCMS (ESI): RT=0.886 min, mass calculated for C 25 H 19 F3N2O2436.34 m / z found 437.0 [M+H] + ; 1H NMR(400 MHz, CD3OD δ 8.58-8.51(m,2H),8.12(d,J=8.8Hz,1H),7.99-7.90(m,2H),7.84(dt,J=1.6, 7.8Hz,1H),7.68(d,J=8.6Hz,2H),7.61(t,J=7.9Hz,1H),7.53(d,J=7.9Hz,1H),7.33(dd,J=5.1, 6.9Hz,1H),7.25(d,J=7.5Hz,1H),7.15(d,J=8.6Hz,2H),5.34(q,J=7.1Hz,1H),1.65(d,J=7.0Hz,3H).

[0410] Example 30: N-(2-(methylamino)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 30)

[0411] [ka]

[0412] A solution of tert-butyl N-methyl-N-[2-[[5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carbonyl]amino]ethyl]carbamate (20 mg, 40.9 umol, 1 eq) in HCl / dioxane (4 M, 51.1 uL, 5 eq) was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC to give the title compound (5.0 mg, 11.8 umol, 28.8% yield, HCl). LCMS (ESI): RT=0.742 min, mass calcd for C 21 H 19 F3N2O2388.38 m / z found 389.0 [M+H] + ; 1H NMR(400 MHz, CD3OD)δ 8.56(s,1H),8.14(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),7.93(d,J=8.3Hz,1H),7.68(d, J=8.5Hz,2H),7.62(t,J=7.9Hz,1H),7.26(d,J=7.5Hz,1H),7.15(d,J=8.5Hz,2H),3.79(br t,J=5.4Hz,2H),3.30(br s, 2H),2.80(s,3H).

[0413] Example 31: N-(2-(N-methylcyanamido)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 31)

[0414] [ka]

[0415] To a solution of N-[2-(methylamino)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (50 mg, 0.12 mmol, 1 equiv.) in DCM (1 mL) was added TEA (52.1 mg, 0.51 mmol, 71.6 uL, 4 equiv.) and BrCN (40.9 mg, 0.38 mmol, 28.4 uL, 3 equiv.). The mixture was stirred for 1 h at 0 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (2.8 mg, 6.6 umol, 5.1% yield). LCMS (ESI): RT=0.819 min, mass calculated for C 22 H 18 F3N3O2413.39 m / z found 435.9 [M+Na] + ; 1H NMR(400 MHz, CD3OD)δ 8.50(d,J=1.5Hz,1H),8.12(d,J=8.8Hz,1H),7.97-7.89(m,2H),7.68(d,J=8.5Hz,2H),7.61(t,J=7.9Hz, 1H),7.25(d,J=7.5Hz,1H),7.15(d,J=8.8Hz,2H),3.70(t,J=5.6Hz,2H),3.38-3.34(m,2H),3.00(s,3H).

[0416] Example 32: N-isopropyl-7-(4-(trifluoromethyl)phenoxy)benzo[b]thiophene-2-carboxamide (Compound 32)

[0417] [ka]

[0418] To a solution of 7-[4-(trifluoromethyl)phenoxy]benzothiophene-2-carboxylic acid (30 mg, 88.6 umol, 1.2 equiv) in DMF (1 mL) was added HATU (56.2 mg, 0.14 mmol, 2 equiv) and DIEA (38.2 mg, 0.29 mmol, 51.4 uL, 4 equiv). The mixture was stirred for 0.5 h at 25 °C. Isopropylamine (4.3 mg, 73.9 umol, 6.3 uL, 1 equiv) was added to the solution. The mixture was stirred for 0.5 h at 25 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (9.6 mg, 25.4 umol, 34.3% yield). LCMS (ESI): RT=0.889 min, mass calculated for C 19 H 16 F3NO2S 379.40 m / z found 379.9 [M+H] + ; 1H NMR(400 MHz, DMSO-d6)δ 8.60(d,J=7.6Hz,1H),8.20(s,1H),7.85(d,J=7.8Hz,1H),7.77(d,J=8.6Hz,2H),7.52(t,J=7.9Hz,1H),7.22(dd,J=2.3, 8.3Hz,3H),4.06(qd,J=6.7, 13.8Hz,1H),1.18(d,J=6.6Hz,6H).

[0419] Example 33: (R)—N-(1-hydroxypropan-2-yl)-7-(4-(trifluoromethyl)phenoxy)benzo[b]thiophene-2-carboxamide (Compound 33)

[0420] [ka]

[0421] To a solution of (2R)-2-aminopropan-1-ol (5.5 mg, 73.9 umol, 5.7 uL, 1 equiv) and 7-[4-(trifluoromethyl)phenoxy]benzothiophene-2-carboxylic acid (30 mg, 88.6 umol, 1.2 equiv) in DMF (1 mL) was added DIEA (38.2 mg, 0.29 mmol, 51.4 uL, 4 equiv) and HATU (56.2 mg, 0.14 mmol, 2 equiv). The mixture was stirred for 1 hour at 25 °C. HO (5 mL) was added to the solution. The mixture was extracted with ethyl acetate (8 mL). * 3). The combined organic layers were washed with brine (12 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (3.0 mg, 7.5 μmol, 10.2% yield). LCMS (ESI): RT = 0.803 min, mass calculated for C 19 H 16 F3NO3S 395.40 m / z found 395.9 [M+H] + , 1H NMR(400 MHz, CD3OD)δ 8.07(s,1H),7.80(d,J=7.5Hz,1H),7.70(d,J=8.5Hz,2H),7.49(t,J=7.9Hz,1H),7.19(d,J=8 .5Hz,2H),7.13(d,J=7.3Hz,1H),4.22-4.14(m,1H),3.67-3.58(m,2H),1.28(d,J=6.8Hz,3H).

[0422] Example 34: N-(3-(methylamino)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 34)

[0423] [ka]

[0424] A mixture of tert-butyl N-methyl-N-[3-[[5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carbonyl]amino]propyl]carbamate (0.02 g, 39.8 μmol, 1 eq) in HCl / EtOAc (4 M, 0.49 mL, 50 eq) was stirred for 1 h at 25° C. The mixture was concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC to give the title compound (8.5 mg, 19.3 μmol, 48.6% yield, HCl). LCMS (ESI): RT=0.745 min, mass calcd for C 22 H 21 F3N2O2402.41 m / z found 403.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.52(s,1H),8.13(d,J=8.8Hz,1H),7.92(d,J=8.4Hz,2H),7.68(d,J=8.6Hz,2H),7.62(t, J=7.9Hz,1H),7.26(d,J=7.5Hz,1H),7.15(d,J=8.5Hz,2H),3.58(t,J=6.6Hz,2H),3.11(br t,J=7.2Hz,2H),2.05(quin,J=7.0Hz,2H).

[0425] Example 35: N-(3-(N-methylcyanamid)propyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 35)

[0426] [ka]

[0427] A mixture of N-[3-(methylamino)propyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (0.048 g, 0.11 mmol, 1 equiv), TEA (48.2 mg, 0.47 mmol, 66.4 uL, 4 equiv), and BrCN (37.9 mg, 0.35 mmol, 26.3 uL, 3 equiv) in DCM (2 mL) was stirred at 25 °C for 1 h. The mixture was washed with brine (3 mL), dried over anhydrous NaSO, and concentrated in vacuo to give the crude product. The residue was purified by preparative HPLC to give the title compound (30.5 mg, 71.3 umol, 59.8% yield). LCMS (ESI): RT=0.957 min, mass calcd for C 23 H 20 F3N3O2427.42 m / z found 428.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.48(d,J=1.3Hz,1H),8.11(d,J=8.8Hz,1H),7.95-7.88(m,2H),7.68(d,J=8.6Hz,2H),7.60(t,J=7.9Hz,1H),7.24( d,J=7.4Hz,1H),7.15(d,J=8.5Hz,2H),3.55(t,J=6.9Hz,2H),3.17(t,J=7.1Hz,2H),2.93(s,3H),2.07-1.98(m,2H).

[0428] Example 36: N-(1-phenylcyclopropyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (Compound 36)

[0429] [ka]

[0430] Methyl 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylate To a solution of methyl 5-hydroxy-2-naphthoate (3.6 g, 17.80 mmol, 1 equiv.) and (4-(trifluoromethyl)phenyl)boronic acid (6.76 g, 35.61 mmol, 2 equiv.) in DCM (120 mL) under O was added DIEA (9.20 g, 71.21 mmol, 12.40 mL, 4 equiv.) and Cu(OAc) (6.47 g, 35.61 mmol, 2 equiv.). The mixture was degassed in vacuo and purged with O three times. The mixture was stirred for 12 h at 30 °C under O (15 psi). The mixture was filtered. The filtrate was diluted with HO (250 mL) and extracted with EA (500 mL). * 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give methyl 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylate (2.5 g, 7.22 mmol, 20.3% yield) and 1 (1.5 g, 7.42 mmol, 20.8% yield).

[0431] 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid To a mixture of methyl 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylate (200 mg, 0.58 mmol, 1 equiv.) in MeOH (1.5 mL), THF (0.5 mL), and HO (0.5 mL) was added NaOH (2 M, 2.89 mL, 10 equiv.). The mixture was stirred for 1 h at 30 °C. The mixture was concentrated. The residue was diluted with HO (20 mL) and adjusted to pH = 6-7 with 1 N HCl. The mixture was extracted with EA (40 mL). *3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (220 mg, crude).

[0432] N-(1-phenylcyclopropyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (30 mg, 90.3 umol, 1 equiv) in DCM (1 mL) was added DIEA (46.7 mg, 0.36 mmol, 63 uL, 4 equiv) and HATU (51.5 mg, 0.14 mmol, 1.5 equiv). The mixture was stirred for 0.5 h at 30 °C. 1-Phenylcyclopropan-1-amine (23.0 mg, 0.14 mmol, 1.5 equiv, HCl) was added to the mixture. The mixture was stirred for 1 h at 30 °C. The mixture was diluted with HO (10 mL) and extracted with EA (20 mL). * 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (16.6 mg, 36.9 umol, 40.8% yield). LCMS (ESI): RT=1.053 min, mass calc. for C 27 H 20 F3NO2447.14, m / z found 448.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 8.37(d,J=1.0Hz,1H),8.12(d,J=8.8Hz,1H),7.84(dd,J=1.6, 8.8Hz,1H),7.78(d,J=8.3Hz,1H),7.59(d,J=8.6Hz,2H),7.50(t,J=7.9Hz,1H),7.38-7.27(m,4H) ,7.24-7.17(m,1H),7.14(d,J=7.4Hz,1H),7.06(d,J=8.6Hz,2H),6.98(s,1H),1.47-1.35(m,4H).

[0433] Example 37: N-(3-phenyloxetan-3-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 37)

[0434] [ka]

[0435] 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid To a solution of compound methyl 5-(4-(trifluoromethyl)phenoxy)-2-naphthoate (2 g, 5.78 mmol, 1 equiv.) in MeOH (16 mL) and THF (4 mL) was added NaOH (2.31 g, 57.75 mmol, 10 equiv.) in HO (4 mL). The mixture was stirred at 25° C. for 1 h. The mixture was concentrated. 1N HCl was added to the residue until pH=6-7. The mixture was extracted with EA (20 mL). * 3) The organic layer was dried over Na2SO4, filtered, and concentrated to give compound 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (2.5 g, crude).

[0436] N-(3-phenyloxetan-3-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide To a solution of the compound 5-(4-(trifluoromethyl)phenoxy)-2-naphthoic acid (50.0 mg, 0.15 mmol, 1 equiv.), the compound 3-phenyloxetan-3-amine (22.5 mg, 0.15 mmol, 1 equiv.), and HATU (85.8 mg, 0.23 mmol, 1.5 equiv.) in DCM (0.5 mL) was added DIEA (38.9 mg, 0.30 mmol, 52 uL, 2 equiv.). The mixture was stirred at 25° C. for 2 hours. The mixture was diluted with water (5 mL). The mixture was extracted with EA (10 mL). * 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (2.0 mg, 4.4 umol, 2.9% yield). LCMS (ESI): RT=0.895 min, mass calc. for C27 H 20 F3NO3463.14, m / z found 464.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 8.45(d,J=1.4Hz,1H),8.17(d,J=8.9Hz,1H),7.89(dd,J=1.8, 8.8Hz,1H),7.81(d,J=8.4Hz,1H),7.61(br d,J=7.8Hz,4H),7.54(t,J=7.9Hz,1H),7.42(t,J=7.6Hz,2H),7.36-7.30(m,1H),7.17(d,J= 7.5Hz,1H),7.09(d,J=8.5Hz,2H),7.05(s,1H),5.21(d,J=6.8Hz,2H),5.08(d,J=6.9Hz,2H).

[0437] Example 38: (R)—N-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 38) and (S)—N-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 39) N-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0438] [ka]

[0439] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred for 1 h at 25 °C. Then, 1-cyclopropylethanamine (28.1 mg, 0.33 mmol, 1.1 equiv) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL* 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC.

[0440] The compounds N-(1-cyclopropylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (99 mg, 0.24 mmol, 82.3% yield) were obtained: (R)-N-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 38) and (S)-N-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 39). Racemic N-(1-cyclopropylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (99 mg, 0.24 mmol, 1 equiv.) was separated by SFC (column: DAICEL CHIRALPAK AS-H; mobile phase: [0.1% NH3HO ETOH]; B%: 30%-30%, min) to give compound 38 (20 mg, 49.6 µmol, 20% yield) (LCMS (ESI): RT = 1.042 min, mass calculated for C). 23 H 20 F3NO2399.41 m / z found 400.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.46(s,1H),8.09(br d,J=8.8Hz,1H),7.95-7.84(m,2H),7.69-7.54(m,3H),7.25-7.18(m,1H),7.14(br d,J=8.3Hz,2H),3.63-3.50(m,1H),1.37(d,J=6.8Hz,4H),1.07(dt,J=4.3, 8.7Hz,1H),0.65-0.37(m,3H),0.36-0.25(m,1H)) and compound 39 (20 mg, 49.6 umol, 20% yield) (LCMS (ESI): RT=1.036 min, mass calcd for C 23 H 20 F3NO2399.41 m / z found 400.0 [M+H] +; 1 H NMR(400 MHz, CD3OD)δ 8.45(s,1H),8.08(dd,J=4.1, 8.7Hz,1H),7.95-7.83(m,2H),7.68-7.52(m,3H),7.23-7.08(m,3H),3.62-3.49(m,1H ),1.37(d,J=6.8Hz,3H),1.13-1.01(m,1H),0.63-0.37(m,3H),0.36-0.23(m,1H)) were obtained.

[0441] Example 39: (R)—N-(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 40) and (S)—N-(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 41)

[0442] [ka]

[0443] N-(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred for 1 h at 25 °C. Then, 1-(oxetan-3-yl)ethanamine (33.4 mg, 0.33 mmol, 1.1 equiv) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC.

[0444] The compounds N-[1-(oxetan-3-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (66.2 mg, 0.15 mmol, 50.8% yield) were obtained: (R)-N-(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound 40) and (S)-N-(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (compound 41). The racemic compound N-[1-(oxetan-3-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (66.2 mg, 0.15 mmol, 1 equiv.) was purified by SFC (column: DAICEL CHIRALPAK AD-H; (250 mm * 30 mm, 5 μm; mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 30%-30%, min) to give compound 40 (10.8 mg, 25.6 μmol, 16.1% yield) (LCMS (ESI): RT=0.954 min, mass calculated for C 23 H 20 F3NO3415.41 m / z found 416.0 [M+H] + , 1 H NMR(400 MHz, CD3OD)δ 8.46(d,J=1.5Hz,1H),8.11(d,J=8.8Hz,1H),7.93-7.87(m,2H),7.70-7.57(m,3H),7.24(d,J=7.5Hz,1H),7.15(br d,J=8.5Hz,2H),4.67-4.51(m,5H),1.24(d,J=6.8Hz,3H)) and compound 41 (19.1 mg, 45.2 umol, 28.4% yield) (LCMS (ESI): RT=0.949 min, mass calcd for C 23 H 20 F3NO3415.41 m / z found 416.0 [M+H] + , 1H NMR(400 MHz, CD3OD)δ 8.34(s,1H),7.99(d,J=8.8Hz,1H),7.81-7.76(m,2H),7.56(br d,J=8.5Hz,2H),7.48(t,J=7.9Hz,1H),7.12(d,J=7.5Hz,1H),7.03(br d,J=8.5Hz,2H),4.55(s,1H),4.51-4.45(m,4H),4.43(t,J=6.1Hz,1H),1.15-1.05(m,4H)) were obtained.

[0445] Example 40: (R)-6-Methoxy-N-(1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxamide (Compound 42)

[0446] [ka]

[0447] 4-Methoxy-1-nitro-2-(4-(trifluoromethyl)phenoxy)benzene To a solution of compound 2-fluoro-4-methoxy-1-nitrobenzene (3.00 g, 17.53 mmol, 1.0 equiv.) and compound 4-(trifluoromethyl)phenol (3.13 g, 19.28 mmol, 1.1 equiv.) in DMF (1 mL) was added K2CO3 (4.85 g, 35.06 mmol, 2.0 equiv.). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL), and the resulting mixture was extracted with EA (30 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 4-methoxy-1-nitro-2-(4-(trifluoromethyl)phenoxy)benzene (5.2 g, 94.7% yield). 1H NMR(400 MHz,CDCl3)δ 8.13(d,J=9.3Hz,1H),7.62(d,J=8.6Hz,2H),7.08(d,J=8.5Hz,2H),6.82(dd,J=2.6, 9.3Hz,1H),6.58(d,J=2.6Hz,1H),3.86(s,3H).

[0448] 4-Methoxy-2-(4-(trifluoromethyl)phenoxy)aniline To a solution of the compound 4-methoxy-1-nitro-2-(4-(trifluoromethyl)phenoxy)benzene (5.20 g, 16.60 mmol, 1.0 equiv) in EtOH (50 mL) and HO (10 mL) was added Fe (9.27 g, 0.17 mol, 10 equiv) and NHCl (17.76 g, 0.33 mol, 20 equiv). The reaction mixture was stirred for 16 h at 80 °C. The reaction mixture was filtered and washed with EA (80 mL) and HO (40 mL). The suspension was separated, and the organic layer was then dried over NaSO, filtered, and concentrated under reduced pressure to give 4-methoxy-2-(4-(trifluoromethyl)phenoxy)aniline (4.6 g, crude).

[0449] 3-Bromo-6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline A mixture of compound 4-methoxy-2-(4-(trifluoromethyl)phenoxy)aniline (1.00 g, 3.53 mmol, 1.0 equiv.) and compound 2,2,3-tribromopropanal (2.08 g, 7.06 mmol, 2.0 equiv.) in AcOH (10 mL) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL), and then the suspension was basified with NaOH (1 M) until pH=10. The resulting mixture was extracted with EA (30 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline (230 mg, 16.3% yield).

[0450] Methyl 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylate To a solution of the compound 3-bromo-6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline (180.0 mg, 0.45 mmol, 1.0 equiv.) and TEA (183.0 mg, 1.81 mmol, 4.0 equiv.) in DMSO (3 mL) and MeOH (2.4 mL) was added Pd(dppf)Cl (33.1 mg, 45.2 mmol, 0.1 equiv.) under N. The suspension was degassed in vacuo and purged multiple times with CO. The mixture was stirred at 80 °C under CO (45 psi) for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was extracted with EA (30 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylate (140 mg, 82.0% yield).

[0451] 6-Methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylic acid To a solution of compound methyl 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylate (25.0 mg, 66.2 μmol, 1.0 equiv.) in THF (0.45 mL) and MeOH (0.15 mL), NaOH (1 M, 0.13 mL, 2.0 equiv.) was added. The reaction mixture was stirred for 2 h at 25° C. The suspension was adjusted to pH=5 with HCl (1 M), and then the resulting mixture was extracted with EA (10 mL). * 3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure to give 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylic acid (20 mg, crude).

[0452] (R)-6-Methoxy-N-(1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxamide To a solution of the compound 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylic acid (20.0 mg, 55.0 umol, 1.0 equiv.), the compound (R)-1-(pyridin-2-yl)ethan-1-amine (6.7 mg, 55.0 umol, 1.0 equiv.), and DIPEA (14.2 mg, 0.11 umol, 2.0 equiv.) in DCM (1 mL) was added HATU (31.4 mg, 82.5 umol, 1.5 equiv.). The reaction mixture was stirred for 2 hours at 25° C. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was extracted with EA (20 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (8.33 mg, 32.3% yield). LCMS (ESI): RT=0.840 min, mass calcd. for C 25 H 20 F3N3O3467.15, m / z found 468.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.21(d,J=2.0Hz,1H),8.67(s,1H),8.59(d,J=5.0Hz,1H),8.28-8.16(m,1H),7.82-7.74(m,1H),7.62(d,J=8.6Hz,2H),7.40(d,J=7.5Hz,1H), 7.34-7.28(m,1H),7.16(d,J=8.5Hz,2H),7.03(d,J=2.4Hz,1H),6.95(d,J=2.6Hz,1H),5.46-5.36(m,1H),3.94(s,3H),1.67(d,J=6.6Hz,3H).

[0453] Example 41: (S)-6-Methoxy-N-(1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxamide (Compound 43)

[0454] [ka]

[0455] To a solution of the compound 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylic acid (prepared as described in Example 40) (25.0 mg, 68.8 umol, 1.0 equiv.), the compound (S)-1-(pyridin-2-yl)ethan-1-amine (8.4 mg, 68.8 umol, 1.0 equiv.), and DIPEA (17.8 mg, 0.14 mol, 2.0 equiv.) in DCM (1 mL) was added HATU (39.2 mg, 0.10 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was extracted with EA (20 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (11.25 mg, 34.9% yield). LCMS (ESI): RT=0.843 min, mass calcd. for C 25 H 20 F3N3O3467.44, m / z found 468.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.20(d,J=1.9Hz,1H),8.62(d,J=1.9Hz,1H),8.57(d,J=4.6Hz,1H),8.14( d,J=6.6Hz,1H),7.76-7.68(m,1H),7.62(d,J=8.6Hz,2H),7.34(d,J=7.8H z,1H),7.27-7.23(m,1H),7.16(d,J=8.5Hz,2H),7.02(d,J=2.4Hz,1H),6. 95(d,J=2.5Hz,1H),5.44-5.34(m,1H),3.94(s,3H),1.63(d,J=6.8Hz,3H).

[0456] Example 42: (R)-6-Methoxy-N-(1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxamide (Compound 44)

[0457] [ka]

[0458] To a solution of the compound 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylic acid (prepared as described in Example 40) (25.0 mg, 68.8 umol, 1.0 equiv.), the compound (R)-1-methoxypropan-2-amine (8.6 mg, 68.8 umol, 1.0 equiv., HCl), and DIPEA (26.6 mg, 0.20 mmol, 3.0 equiv.) in DCM (1 mL) was added HATU (39.2 mg, 0.10 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was extracted with EA (20 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (11.71 mg, 38.7% yield). LCMS (ESI): RT=0.910 min, mass calcd. for C 22 H 21 F3N2O4434.15, m / z found 435.0 [M+H] + ; 1 H NMR(400 MHz,CDCl3)δ 9.07(d,J=2.0Hz,1H),8.54(d,J=1.9Hz,1H),7.61(d,J=8.5Hz,2H),7.15(d,J=8.5Hz,2H),7.00(d,J=2.5Hz,1H),6.94(d,J=2.5Hz,1 H),6.60(d,J=7.8Hz,1H),4.50-4.37(m,1H),3.93(s,3H),3.58-3.53(m,1H),3.51-3.45(m,1H),3.41(s,3H),1.35(d,J=6.8Hz,3H).

[0459] Example 43: (S)-6-Methoxy-N-(1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxamide (Compound 45)

[0460] [ka]

[0461] To a solution of 6-methoxy-8-(4-(trifluoromethyl)phenoxy)quinoline-3-carboxylic acid (prepared as described in Example 40) (25.0 mg, 68.8 umol, 1.0 equiv.), compound (S)-1-methoxypropan-2-amine (6.1 mg, 68.8 umol, 1.0 equiv.), and DIPEA (17.8 mg, 0.14 mol, 2.0 equiv.) in DCM (1 mL) was added HATU (39.2 mg, 0.10 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 hour at 25° C. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was extracted with EA (20 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (13.85 mg, 46.3% yield). LCMS (ESI): RT=0.906 min, mass calcd. for C 22 H 21 F3N2O4434.15, m / z found 435.0 [M+H] + ; 1H NMR(400 MHz,CDCl3)δ 9.07(d,J=1.9Hz,1H),8.54(d,J=1.6Hz,1H),7.62(d,J=8.5Hz,2H),7.15(d,J=8.5Hz,2H),7.00(d,J=2.4Hz,1H),6.95(d,J=2.4Hz,1 H),6.59(d,J=8.0Hz,1H),4.49-4.37(m,1H),3.93(s,3H),3.58-3.53(m,1H),3.51-3.46(m,1H),3.41(s,3H),1.35(d,J=6.8Hz,3H).

[0462] Example 44: (R)—N-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 46) and (S)—N-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 47) N-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide

[0463] [ka]

[0464] A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred for 1 h at 25 °C. Then, 1-pyrazin-2-ylethanamine (40.7 mg, 0.33 mmol, 1.1 equiv) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL *2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. Compound N-(1-pyrazin-2-ylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (22 mg, 49.7 μmol, 16.5% yield) was obtained.

[0465] (R)-N-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 46) and (S)-N-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 47) The racemic compound N-(1-pyrazin-2-ylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (22 mg, 50.30 μmol, 1 equiv.) was purified by SFC (column: REGIS(s,s) WHELK-O1 (250 mm * 30 mm, 5 μm; Mobile phase: [0.1% NH3HO ETOH]; B%: 50%-50%, min) to give compound 46 (6 mg, 13.6 μmol, 27.2% yield) (RT=0.970 min, mass calculated for C 24 H 18 F3N3O2437.41m / z found 438.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.75(s,1H),8.65-8.62(m,1H),8.56-8.51(m,2H),8.13(d,J=8.8Hz,1H),7.9 7-7.91(m,2H),7.68(d,J=8.5Hz,2H),7.61(t,J=7.9Hz,1H),7.25(dd,J=0.8, and compound 47 (5 mg, 11.4 umol, 22.6% yield) (LCMS (ESI): RT = 0.974 min, mass calcd for C 24 H 18F3N3O2437.41m / z found 438.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.75(br s, 1H),8.64(s,1H),8.54(d,J=1.5Hz,2H),8.12(d,J=8.8Hz,1H),7.98-7.90(m,2H),7.68(d,J=8.5Hz,2H),7.6 1(t,J=7.9Hz,1H),7.27-7.23(m,1H),7.15(d,J=8.5Hz,2H),5.42(q,J=7.0Hz,1H),1.70(d,J=7.0Hz,3H) were obtained.

[0466] Example 45: (R)—N-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 48) and (S)—N-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 49)

[0467] [ka]

[0468] N-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred for 1 h at 25 °C. Then, 1-(1H-imidazol-4-yl)ethanamine (60.9 mg, 0.33 mmol, 1.1 equiv, 2HCl) was added to the mixture, and the mixture was stirred for an additional 1 h at 25 °C. The reaction mixture was diluted with HO (10 mL), and the mixture was extracted with EA (10 mL). * 3). The combined organic phases were washed with brine (10 mL *2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. The compound N-[1-(1H-imidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (103 mg, 0.23 mmol, 79.6% yield) was obtained.

[0469] (R)—N-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 48) and (S)—N-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 49) The racemic compound N-[1-(1H-imidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (70 mg, 0.16 mmol, 1 equiv.) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 5 μm; mobile phase: [0.1% NH3HO IPA]; B%: 45%-45%, min) to give compound 48 (13 mg, 30.2 μmol, 18.3% yield) (LCMS (ESI): RT=0.860 min, mass calculated for C 23 H 18 F3N3O2425.40m / z found 426.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.34(s,1H),7.99(d,J=8.8Hz,1H),7.81-7.76(m,2H),7.56(br d,J=8.5Hz,2H),7.48(t,J=7.9Hz,1H),7.12(d,J=7.5Hz,1H),7.03(br and compound 49 (15 mg, 34.9 umol, 21.2% yield) (LCMS (ESI): RT=0.860 min, mass calcd for C 23 H18 F3N3O2425.40m / z found 426.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.37(d,J=1.5Hz,1H),7.96(d,J=8.9Hz,1H),7.84-7.73(m,2H),7.58-7.51(m,3H),7.45(t,J=7.9Hz,1H),7.09(dd,J=0.8, 7.6Hz,1H), 7.00(d,J=8.5Hz,2H),6.94(s,1H),5.26(q,J=6.9Hz,1H),1.52(d,J=6.9Hz,3H)) were obtained.

[0470] Example 46: (S)—N-(1-amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 50)

[0471] [ka]

[0472] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and HATU (68.6 mg, 0.18 mmol, 1.2 equiv.) in DCM (2 mL) was added DIPEA (77.7 mg, 0.60 mmol, 0.10 mL, 4 equiv.). After the addition, the mixture was stirred at 25° C. for 0.5 h, after which (8s)-2-aminopropanamide (19.8 mg, 0.15 mmol, 1.06 equiv., HCl) was added. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was added HO (50 mL) and extracted with EA (30 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the title compound (31 mg, 77.0 μmol, 51.2% yield). LCMS (ESI): RT=0.785 min, mass calcd for C 21 H 17F3N2O3402.37m / z found 425.1 [M+Na] + ; 1 H NMR(400 MHz, DMSO-d6)δ 8.68-8.58(m,2H),8.03-7.94(m,3H),7.74(d,J=8.8Hz,2H),7.64(t,J=8.0Hz,1H),7.43(br s, 1H),7.33(d,J=7.0Hz,1H),7.17(d,J=8.5Hz,2H),7.03(s,1H),4.47(quin,J=7.2Hz,1H),1.37(d,J=7.3Hz,3H).

[0473] Example 47: (R)—N-(1-amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 51)

[0474] [ka]

[0475] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and HATU (68.6 mg, 0.18 mmol, 1.2 equiv.) in DCM (2 mL) was added DIPEA (77.7 mg, 0.60 mmol, 0.10 mL, 4 equiv.). After the addition, the mixture was stirred at 25° C. for 0.5 h, after which (2R)-2-aminopropanamide (19.8 mg, 0.15 mmol, 1.06 equiv., HCl) was added. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was added to HO (20 mL) and extracted with EA (15 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the title compound (30.5 mg, 75.8 μmol, 50.3% yield). LCMS (ESI): RT=0.790 min, mass calcd for C 21 H 17F3N2O3402.37m / z found 425.1.0 [M+Na] + ; 1 H NMR(400 MHz, DMSO-d6)δ 8.69-8.57(m,2H),8.04-7.93(m,3H),7.74(d,J=8.8Hz,2H),7.63(t,J=7.9Hz,1H),7.43(br s, 1H),7.33(d,J=7.5Hz,1H),7.16(d,J=8.5Hz,2H),7.03(br s, 1H),4.47(quin,J=7.1Hz,1H),1.37(d,J=7.3Hz,3H).

[0476] Example 48: (S)—N-(1-(2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 52) and (R)—N-(1-(2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 53)

[0477] [ka]

[0478] N-(1-(2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (0.05 g, 0.15 mmol, 1 equiv) in DMF (3 mL) was added HATU (114.4 mg, 0.30 mmol, 2 equiv) and EtN (45.6 mg, 0.45 mmol, 62.8 uL, 3 equiv). The mixture was stirred at 25 °C for 0.5 h. 1-(2H-tetrazol-5-yl)ethanamine (34.0 mg, 0.30 mmol, 2 equiv) was added to the mixture. The mixture was stirred at 25 °C for 2.5 h. The mixture was quenched with HO (30 mL), and the mixture was extracted with EA (20 mL). * 3). The combined organic phases were washed with brine (20 mL *3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. The compound N-[1-(2H-tetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (30 mg, 70.2 μmol, 46.6% yield) was obtained.

[0479] (S)—N-(1-(2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 52) and (R)—N-(1-(2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 53) The racemic compound N-[1-(2H-tetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (0.02 g, 46.8 μmol, 1 equiv.) was purified by SFC (column: REGIS(s,s) WHELK-O1 (250 mm * Two separations on a 30 mm, 5 μm column (mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 40%-40%, min) gave compound 52 (1.1 mg, 2.6 μmol, 11.1% yield) (LCMS (ESI): RT=0.929 min, mass calculated for C 21 H 16 F3N5O2427.38 m / z found 428.1 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.44(s,1H),8.00(d,J=8.8Hz,1H),7.86(br d,J=8.6Hz,1H),7.80(d,J=8.3Hz,1H),7.56(d,J=8.6Hz,2H),7.49(t,J=7.9Hz,1H),7.13(d,J=7.4Hz,1H),7.03(d,J=8.6Hz,2H),5.54(br and compound 53 (3.2 mg, 7.6 umol, 32.5% yield) (LCMS (ESI): RT=0.923 min, mass calcd for C 21 H16 F3N5O2427.38 m / z found 428.0 [M+H] + ; 1 H NMR(400 MHz, CD3OD)δ 8.41(s,1H),7.96(d,J=8.6Hz,1H),7.87-7.72(m,2H),7.53(d,J=8.6Hz,2H) ,7.45(t,J=7.9Hz,1H),7.09(d,J=7.5Hz,1H),7.00(d,J=8.5Hz,2H),5.52(br s, 1H),1.61(br d,J=5.6Hz,3H) was obtained.

[0480] Example 49: N-(1-(pyridin-2-yl)cyclopropyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 54)

[0481] [ka]

[0482] To a solution of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 equiv.) and HATU (68.6 mg, 0.18 mmol, 1.2 equiv.) in DCM (2 mL) was added DIEA (77.7 mg, 0.60 mmol, 0.10 mL, 4 equiv.). After the addition, the mixture was stirred at 25° C. for 0.5 h, after which 1-(2-pyridyl)cyclopropanamine (121.1 mg, 0.22 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was added to HO (20 mL) and EA (15 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the title compound (17 mg, 37.9 μmol, 25.1% yield). LCMS (ESI): RT = 0.783 min, mass calcd for C 26 H 19 F3N2O2448.44 m / z found 449.1[M+H]+ ; 1 H NMR(400 MHz,DMSO-d6)δ9.47(s,1H),8.66(s,1H),8.48-8.44(m,1H),8.03-7.97(m,3H),7.75(d,J=8.5 Hz,2H),7.70-7.63(m,2H),7.40-7.34(m,2H),7.19-7.13(m,3H),1.61-1.55(m,2H),1.34-1.28(m,2H).

[0483] Example 50: (S)—N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 55) and (R)—N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 56)

[0484] [ka]

[0485] N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide To a solution of N-[1-(2H-tetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (0.2 g, 0.46 mmol, 1 equiv.) in DMF (3 mL) was added CHCl (132.8 mg, 0.93 mmol, 58.2 uL, 2 equiv.) and KCO (194.0 mg, 1.40 mmol, 3 equiv.). The mixture was stirred at 25 °C for 3 h. The reaction solution was added to HO (10 mL). The mixture was diluted with ethyl acetate (20 mL). * The combined organic phase was extracted with brine (20 mL *The mixture was washed with HCl, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give N-[1-(2-methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (20.9 mg, 47.3 μmol, 10.1% yield) and N-[1-(1-methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (20.8 mg, 47.3 μmol, 10.1% yield).

[0486] (S)-N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 55) and (R)-N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 56) Racemic N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (0.02 g, 45.3 μmol, 1 equiv.) was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm) * 30 mm, 5 μm; mobile phase: [0.1% NH3HO ETOH]; B%: 40%-40%, min) to give compound 55 (2.2 mg, 4.9 μmol, 21.9% yield) (LCMS (ESI): RT = 0.954 min, mass calcd for C 22 H 18 F3N5O2441.41 m / z found 442.0[M+H] + ; 1H NMR(400 MHz,CD3OD)δ8.40(s,1H),8.00(d,J=8.8 Hz,1H),7.85-7.74(m,2H),7.58-7.42(m,3H),7.14(d,J=7.5 Hz,1H),7.03(d,J=8.6 Hz,2H),5.54(q,J=7.2 Hz,1H),4.15-4.04(m,3H),1.69(d,J=7.0 Hz,3H)); and compound 56(2.6mg,6.0umol,26.9% yield)(LCMS(ESI):RT=0.957 min,mass calcd for C 22 H 18 F3N5O2441.41 m / z found 442.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.39(s,1H),8.00(d,J=8.8 Hz,1H),7.84-7.77(m,2H),7.56(d,J=8.6 Hz,2H),7.49(t,J=7.9 Hz,1H),7.13(d,J=7.5 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 5.54 (q, J = 7.0 Hz, 1H), 4.09 (s, 3H), 1.69 (d, J = 7.0 Hz, 3H)) were obtained.

[0487] Example 51: (R)—N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 57) and (S)—N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 58)

[0488] [ka]

[0489] (R)-N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 57) and (S)-N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 58) Racemic N-[1-(2-methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (prepared as described in Example 50) (0.02 g, 45.3 μmol, 1 equiv.) was subjected to SFC (column: Phenomenex-cellulose-2 (250 mm * Separation by HPLC using a HPLC-MS (LCMS (ESI): RT = 0.960 min, mass calcd for C) afforded compound 57 (4.8 mg, 10.8 umol, 48.0% yield). 22 H 18 F3N5O2441.41 m / z found 442.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.41(d,J=1.0 Hz,1H),8.00(d,J=8.8 Hz,1H),7.86-7.76(m,2H),7.56(d,J=8.6 Hz,2H),7.49(t,J=7.9 Hz,1H),7.13(d,J=7.6 Hz,1H),7.04(d,J=8.5 Hz,2H),5.50(q,J=7.1 Hz,1H),4.25(s,3H),1.63(d,J=7.1 Hz,3H)); and compound 58 (4.5 mg, 10.1 umol, 45.0% yield) (LCMS(ESI): RT=0.959 min, mass calcd for C 22 H 18 F3N5O2441.41 m / z found 442.0[M+H] + ; 1H NMR(400 MHz,CD3OD)δ8.41(s,1H),8.00(d,J=8.8 Hz,1H),7.86-7.75(m,2H),7.56(d,J=8.6 Hz,2H),7.48(t,J=7.9 Hz,1H),7.13(d,J=7.5 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 5.50 (q, J = 7.1 Hz, 1H), 4.30-4.20 (m, 3H), 1.63 (d, J = 7.1 Hz, 3H)) were obtained.

[0490] Example 52: (R)—N-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 59) and (S)—N-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 60)

[0491] [ka]

[0492] N-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred at 25 °C for 1 h. Then, 1-cyclobutylethanamine (44.9 mg, 0.33 mmol, 1.1 equiv, HCl) was added to the mixture, and the mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was diluted with HO (10 mL), and the mixture was diluted with EA (10 mL). * The combined organic phase was extracted with brine (10 mL *The mixture was washed with 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain the compound N-(1-cyclobutylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (91 mg, 0.21 mmol, 71.6% yield).

[0493] (R)-N-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide) (Compound 59) and (S)-N-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 60) The racemic compound N-(1-cyclobutylethyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (91 mg, 0.22 mmol, 1 equiv.) was purified by SFC (column: DAICEL CHIRALPAK AS-H (250 mm * Purification by LCMS (ESI): RT = 1.068 min, mass calcd for C 24 H 22 F3NO2413.43 m / z found 414.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.44(d,J=1.5 Hz,1H),8.10(d,J=8.8 Hz,1H),7.93-7.87(m,2H),7.72-7.55(m,3H),7.24(d,J=7.8 Hz,1H),7.15(br d,J=8.5 Hz,2H),4.23-4.13(m,1H),2.56-2.46(m,1H),2.15-2.04(m,2H),1.97-1.78(m,4H),1.18(d,J=6.5 Hz,3H)); and compound 60 (18.9 mg, 45.6 umol, 20.7% yield) (LCMS(ESI): RT=1.069 min, mass calcd for C 24 H 22F3NO2413.43 m / z found 414.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.44(d,J=1.5 Hz,1H),8.10(d,J=8.8 Hz,1H),7.90(td,J=1.9,8.7 Hz,2H),7.70-7.56(m,3H),7.24(d,J=7.5 Hz,1H), 7.15(d,J=8.8 Hz,2H),4.22-4.13(m,1H),2.57-2.45(m,1H),2.16-2.03(m,2H),1.97-1.80(m,4H),1.18(d,J=6.8 Hz,3H)).

[0494] Example 53: (R)—N-(but-3-yn-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 61) and (S)—N-(but-3-yn-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 62)

[0495] [ka]

[0496] N-(but-3-yn-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred at 25 °C for 1 h. Then, but-3-yn-2-amine hydrochloride (34.9 mg, 0.33 mmol, 1.1 equiv) was added to the mixture, and the mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was diluted with HO (10 mL), and the mixture was diluted with EA (10 mL). * The combined organic phase was extracted with brine (10 mL *The mixture was washed with 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the compound N-(1-methylprop-2-ynyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (112 mg, 0.29 mmol, 96.6% yield).

[0497] (R)-N-(but-3-yn-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 61) and (S)-N-(but-3-yn-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 62) Racemic compound N-(1-methylprop-2-ynyl)-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (98 mg, 0.25 mmol, 1 equiv.) was purified by SFC to give compound 61 (24.6 mg, 64.1 mmol, 25.1% yield) (LCMS (ESI): RT = 0.999 min, mass calcd for C). 22 H 16 F3NO2383.36 m / z found 384.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.48(d,J=1.5 Hz,1H),8.12(d,J=8.8 Hz,1H),7.95-7.89(m,2H),7.68(d,J=8.8 Hz,2H),7.60(t,J=7.9 Hz,1H),7.25(d,J=7.0 Hz,1H),7.15(d,J=8.5 Hz,2H),5.02(dd,J=2.4,6.9 Hz,1H),2.72(d,J=2.3 Hz,1H),1.56(d,J=7.0 Hz,4H)); and compound 62 (24.8 mg, 64.8 umol, 25.3% yield) (LCMS(ESI): RT=0.999 min, mass calcd for C 22 H 16 F3NO2383.36 m / z found 383.9[M+H] + ; 1H NMR(400 MHz,CD3OD)δ8.48(d,J=1.5 Hz,1H),8.12(d,J=8.8 Hz,1H),7.95-7.89(m,2H),7.68(d,J=8.8 Hz,2H),7.60(t,J=8.0 Hz,1H),7.25(d,J=7.5 Hz,1H),7.15(d,J=8.8 Hz,2H),5.02(dq,J=2.3,7.0 Hz,1H),2.72(d,J=2.5 Hz,1H),1.56(d,J=7.0 Hz,4H)).

[0498] Example 54: (S)—N-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 63) and (R)—N-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 64)

[0499] [ka]

[0500] N-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (100 mg, 0.30 mmol, 1 equiv), HATU (171.6 mg, 0.45 mmol, 1.5 equiv), and DIPEA (116.6 mg, 0.90 mmol, 0.15 mL, 3 equiv) in DCM (2 mL) was stirred at 25 °C for 1 h. Then, 1-(1H-imidazol-2-yl)ethanamine (48.8 mg, 0.33 mmol, 1.1 equiv, HCl) was added to the mixture, and the mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was diluted with HO (10 mL), and the mixture was diluted with EA (10 mL). * The combined organic phase was extracted with brine (10 mL *The mixture was washed with 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the compound N-[1-(1H-imidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (52 mg, 0.12 mmol, 40.2% yield).

[0501] (S)—N-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 63) and (R)—N-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 64) Racemic N-[1-(1H-imidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (52 mg, 0.12 mmol, 1 equiv.) was purified by SFC to give compound 63 (5.2 mg, 12.3 mmol, 10.1% yield) (LCMS (ESI): RT = 0.855 min, mass calcd for C). 23 H 18 F3N3O2425.40 m / z found 426.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.43(d,J=1.3 Hz,1H),8.00(d,J=8.8 Hz,1H),7.85(dd,J=1.8,8.8 Hz,1H),7.80(d,J=8.3 Hz,1H),7.56(d,J=8.8 Hz,2H),7.48(t,J=8.0 Hz,1H),7.16-7.10(m,1H),7.03(d,J=8.5 Hz,2H),6.89(s,2H),5.31(q,J=7.0 Hz,1H),1.58(d,J=7.0 Hz, 3H); and compound 64 (21.5 mg, 50.6 umol, 41.4% yield) (LCMS (ESI): RT = 0.855 min,mass calcd for C 23 H 18 F3N3O2425.40 m / z found 426.0[M+H] + ; 1H NMR(400 MHz,CD3OD)δ8.55(d,J=1.5 Hz,1H),8.11(d,J=8.8 Hz,1H),8.00-7.89(m,2H),7.68(d,J=8.5 Hz,2H),7.60(t,J=8.0 Hz,1H),7.24(dd,J=0.8,7.5 Hz,1H),7.15(d,J=8.5 Hz,2H),7.01(s,2H),5.43(q,J=7.0 Hz,1H),1.70(d,J=7.0 Hz,3H)).

[0502] Example 55: (S)—N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 65) and (R)—N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 66)

[0503] [ka]

[0504] 1-(4-Bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)ethanamine To a solution of 1-(6-bromo-2-pyridyl)ethanone (3.2 g, 16.00 mmol, 1 equiv.), (2,4-dimethoxyphenyl)methanamine (2.67 g, 16.00 mmol, 2.41 mL, 1 equiv.) in DCE (30 mL), HOAc (4.80 g, 79.99 mmol, 4.57 mL, 5 equiv.) was added and stirred at 25 °C for 1 h, followed by NaBH(OAc) (5.09 g, 24.00 mmol, 1.5 equiv.). The resulting mixture was stirred at 25 °C for 15 h. Then, ice-cold water (30 mL) was added, and the mixture was neutralized to pH = 9-10 with aqueous NaOH (2 M). The aqueous phase was diluted with EA (30 mL). *The resulting mixture was extracted with 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica chromatography. The compound 1-(6-bromo-2-pyridyl)-N-[(2,4-dimethoxyphenyl)methyl]ethanamine (1.6 g, 4.42 mmol, 27.6% yield) was obtained.

[0505] N-(1-(6-bromopyridin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide To a mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (473.0 mg, 1.42 mmol, 1 equiv.), HATU (1.08 g, 2.85 mmol, 2 equiv.) in DCM (10 mL) was added DIPEA (551.9 mg, 4.27 mmol, 0.74 mL, 3 equiv.) at 25° C. After the addition, the mixture was stirred at 25° C. for 1 h, and then 1-(6-bromo-2-pyridyl)-N-[(2,4-dimethoxyphenyl)methyl]ethanamine (500 mg, 1.42 mmol, 1 equiv.) in DCM (3 mL) was added. The resulting mixture was stirred at 25° C. for 15 h. The residue was poured into HO (50 mL) and stirred for 5 min. The aqueous phase was diluted with EA (30 mL). * The resulting mixture was extracted with 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica chromatography. The compound N-[1-(6-bromo-2-pyridyl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (650 mg, 0.97 mmol, 68.6% yield) was obtained.

[0506] N-(1-(6-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide To a solution of N-[1-(6-bromo-2-pyridyl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (590 mg, 0.88 mmol, 1 equiv.) in DCM (0.5 ml), TFA (9.09 g, 79.69 mmol, 5.90 ml, 89.88 equiv.) was added. The mixture was stirred at 25 °C for 3 h. After that, ice-cold water (30 ml) was added, and the mixture was neutralized to pH = 9-10 with aqueous NaOH (2 M). The aqueous phase was washed with EA (30 ml). * The crude product was obtained by extraction with 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica chromatography. The compound N-[1-(6-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (425 mg, 0.82 mmol, 93.0% yield) was obtained.

[0507] N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of N-[1-(6-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (150 mg, 0.29 mmol, 1 equiv.), CuO (41.6 mg, 0.29 mmol, 29.7 uL, 1 equiv.), and NH.HO (134.2 mg, 1.46 mmol, 0.14 mL, 38%, 5 equiv.) in dioxane (1 mL) was loaded into a sealed reaction tube. The reaction temperature was raised to 80 °C, and the reaction mixture was stirred at 80 °C for 16 h. The mixture was poured into HO (30 mL) and stirred for 5 min. The aqueous phase was diluted with EA (15 mL). * The resulting mixture was extracted with 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica chromatography. The compound N-[1-(6-amino-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (98 mg, 0.21 mmol, 74.5% yield) was obtained.

[0508] (S)—N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 65) and (R)—N-(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 66) The racemic compound N-[1-(6-amino-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (85 mg, 0.18 mmol, 1 equiv.) was purified by SFC to give compound 65 (20.2 mg, 42.0 mmol, 22.3% yield) (LCMS (ESI): RT = 0.776 min, mass calcd for C). 25 H 20 F3N3O2451.44 m / z found 452.1[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.51(s,1H),8.10(d,J=8.9 Hz,1H),7.98-7.87(m,2H),7.66(d,J=8.5 Hz,2H),7.58(t,J=8.0 Hz,1H),7.43(t,J=7.7 Hz,1H),7.23(d,J=7.6 Hz,1H),7.13(d,J=8.6 Hz,2H),6.66(d,J=7.3 Hz,1H),6.46(d,J=8.1 Hz,1H),5.18-5.07(m,1H),1.56(d,J=7.0 Hz, 3H); and compound 66 (17.6 mg, 37.4 μmol, 19.8% yield) (LCMS (ESI): RT = 0.773 min, mass calcd for C 25 H 20 F3N3O2451.44 m / z found 452.1[M+H] + ; 1H NMR(400 MHz,CD3OD)δ8.51(s,1H),8.10(d,J=8.8 Hz,1H),7.98-7.88(m,2H),7.66(d,J=8.5 Hz,2H),7.59(t,J=7.9 Hz,1H),7.42(t,J=7.8 Hz,1H),7.23(d,J=7.5 Hz,1H),7.13(d,J=8.4 Hz,2H),6.66(d,J=7.5 Hz,1H),6.46(d,J=8.3 Hz,1H),5.12(q,J=6.9 Hz,1H),1.56(d,J=6.9 Hz,3H)) was obtained.

[0509] Example 56: N-isopropyl-4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxamide (Compound 67)

[0510] [ka]

[0511] 7-Bromo-4-chloroquinoline POCl3 (1.03 g, 6.72 mmol, 7.53 equiv.) was added to a mixture of compound 7-bromoquinolin-4-ol (200.0 mg, 0.89 mmol, 1.0 equiv.) in dioxane (2 mL), and the mixture was stirred at 90 °C for 5 h. The reaction mixture was cooled to 25 °C. The mixture was poured into water (10 mL) and adjusted to pH = 8 with solid Na2CO3. The resulting mixture was diluted with EA (50 mL). * The resulting mixture was extracted with 3). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-4-chloroquinoline (170 mg, 78.5% yield). 1 H NMR(400MHz,CDCl3)δ8.81(d,J=4.5 Hz,1H),8.34(d,J=1.8 Hz,1H),8.13(d,J=9.0 Hz,1H),7.80-7.74(m,1H),7.76(dd,J=2.0,9.0 Hz,1H),7.53(d,J=4.8 Hz,1H).

[0512] 7-Bromo-4-(4-(trifluoromethyl)phenoxy)quinoline To a solution of compound 7-bromo-4-chloroquinoline (120.0 mg, 0.49 mmol, 1.0 equiv.) and compound 4-(trifluoromethyl)phenol (96.2 mg, 0.59 mmol, 1.2 equiv.) in DMF (1.5 mL) was added K2CO3 (136.7 mg, 0.98 mmol, 2.0 equiv.). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was diluted with EA (20 mL). * The resulting mixture was extracted with 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-4-(4-(trifluoromethyl)phenoxy)quinoline (52 mg, 27.6% yield). LCMS (ESI): RT = 0.894 min, mass calcd. for C16H9BrF3NO 366.98, m / z found 369.9 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ8.73(d,J=5.1 Hz,1H),8.36(d,J=1.3 Hz,1H),8.21(d,J=8.8 Hz,1H),7.77(d,J=8.6 Hz,2H),7.72(dd,J=1.8,8.8 Hz,1H),7.31(d,J=8.4 Hz,2H),6.65(d,J=5.1 Hz,1H).

[0513] Methyl 4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxylate To a solution of compound 7-bromo-4-(4-(trifluoromethyl)phenoxy)quinoline (50.0 mg, 0.13 mmol, 1.0 equiv.) and TEA (54.9 mg, 0.54 mmol, 4.0 equiv.) in MeOH (0.8 mL) and DMSO (1 mL), Pd(dppf)Cl (9.9 mg, 13.5 mmol, 0.1 equiv.) was added under N. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (45 psi) at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was diluted with EA (30 mL). * The resulting mixture was extracted with 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxylate (40 mg, 80.5% yield). LCMS (ESI): RT = 0.867 min, mass calcd. for C18H12F3NO3 347.08, m / z found 348.0 [M+H] + .

[0514] Methyl 4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxylate To a solution of compound methyl 4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxylate (25.0 mg, 72.0 μmol, 1.0 equiv.) in THF (0.6 mL) and MeOH (0.2 mL), NaOH (1 M, 0.14 mL, 2.0 equiv.) was added. The reaction mixture was stirred at 25° C. for 1 h. HO (5 mL) was added, and then the mixture was adjusted to pH=5 with HCl (1 M). The resulting mixture was diluted with EA (10 mL). * The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give methyl 4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxylate (20 mg, 83.3% yield).

[0515] N-Isopropyl-4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxamide To a solution of compound methyl 4-(4-(trifluoromethyl)phenoxy)quinoline-7-carboxylate (20.0 mg, 60.0 μmol, 1.0 equiv.), isopropylamine (3.6 mg, 60.0 μmol, 1.0 equiv.), and DIPEA (15.5 mg, 0.12 mmol, 2.0 equiv.) in DCM (1 mL) was added HATU (34.2 mg, 90.0 μmol, 1.5 equiv.). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was diluted with EA (20 mL). * The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (10.42 mg, 45.4% yield). LCMS (ESI): RT = 0.820 min, mass calcd. for C 20 H 17 F3N2O2374.12,m / z found 375.0[M+H] + ; 1 H NMR(400MHz,CDCl3)δ8.79(d,J=5.3 Hz,1H),8.42-8.35(m,2H),8.09-8.03(m,1H),7.76(d,J=8.5 Hz,2H),7.32(d,J=8.5 Hz,2H),6.69(d,J=5.0 Hz,1H),6.19(d,J=7.5 Hz,1H),4.43-4.30(m,1H),1.33(d,J=6.5 Hz,6H).

[0516] Example 57: (R)—N-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 68) and (S)—N-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 69)

[0517] [ka]

[0518] N-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide A mixture of 5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxylic acid (200 mg, 0.60 mmol, 1 equiv), DIPEA (233.3 mg, 1.81 mmol, 0.31 mL, 3 equiv), and HATU (343.3 mg, 0.90 mmol, 1.5 equiv) in DCM (2 mL) was stirred at 25 °C for 1 h. Then, 1-(1-methylimidazol-2-yl)ethanamine (90.4 mg, 0.72 mmol, 1.2 equiv) was added to the mixture, and the mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was diluted with HO (10 mL), and the mixture was diluted with EA (10 mL). * The combined organic phase was extracted with brine (10 mL * The mixture was washed with 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the compound N-[1-(1-methylimidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (90 mg, 0.20 mmol, 34.0% yield).

[0519] (R)-N-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 68) and (S)-N-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 69) N-[1-(1-methylimidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (90 mg, 0.20 mmol, 1 equiv.) was separated by SFC to give compound 68 (22.6 mg, 51.6 mmol, 25.2% yield) (LCMS (ESI): RT = 0.872 min, mass calcd for C 24 H 20F3N3O2439.43 m / z found 440.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.48(s,1H),8.08(d,J=8.8 Hz,1H),7.94-7.86(m,2H),7.65(d,J=8.8 Hz,2H),7.58(t,J=7.9 Hz,1H),7.22(d,J=7.5 Hz,1H),7.12(d,J=8.5 Hz,2H),7.03(s,1H),6.91(d,J=1.3 Hz,1H),5.50(q,J=7.0 Hz,1H),3.76(s,3H),1.69-1.64(m,1H),1.66(d,J=7.0 Hz, 2H); and compound 69 (10.5 mg, 23.8 μmol, 11.6% yield) (LCMS (ESI): RT = 0.872 min, mass calcd for C 24 H 20 F3N3O2439.43 m / z found 440.0[M+H] + ; 1 H NMR(400 MHz,CD3OD)δ8.46(d,J=1.5 Hz,1H),8.06(d,J=8.8 Hz,1H),7.92-7.83(m,2H),7.63(d,J=8.5 Hz,2H),7.55(t,J=8.0 Hz,1H),7.19(dd,J=0.8,7.5 Hz,1H),7.10(d,J=8.5 Hz,2H),7.01(d,J=1.3 Hz,1H),6.90(d,J=1.3 Hz,1H),5.49(q,J=6.9 Hz, 1H), 3.74 (s, 3H), 1.65 (d, J=7.0 Hz, 3H)) were obtained.

[0520] Example 58: N-isopropyl-5-(4-(trifluoromethyl)phenoxy)quinoline-2-carboxamide (Compound 70)

[0521] [ka]

[0522] 5-(4-(trifluoromethyl)phenoxy)quinoline To a solution of compound quinolin-5-ol (400.0 mg, 2.76 mmol, 1.0 equiv.), compound 1-iodo-4-(trifluoromethyl)benzene (899.4 mg, 3.31 mmol, 1.2 equiv.), CuI (524.8 mg, 2.76 mmol, 1.0 equiv.), and compound dimethylglycine (85.2 mg, 0.82 mmol, 0.3 equiv.) in dioxane (10 mL) was added CsCO (1.80 g, 5.51 mmol, 2.0 equiv.). The reaction mixture was stirred under N at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 mL), and the resulting mixture was diluted with EA (50 mL). * The resulting mixture was extracted with 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(4-(trifluoromethyl)phenoxy)quinoline (270 mg, 33.2% yield). LCMS (ESI): RT = 0.848 min, mass calcd. for C 16 H 10 F3NO 289.07,m / z found 290.0[M+H] + .

[0523] 5-(4-(trifluoromethyl)phenoxy)quinoline 1-oxide To a solution of compound 5-(4-(trifluoromethyl)phenoxy)quinoline (250.0 mg, 0.86 mmol, 1.0 equiv.) in DCM (5 mL) was added m-CPBA (350.9 mg, 1.73 mmol, 85%, 2.0 equiv.). The reaction mixture was stirred at 25° C. for 16 h. The mixture was diluted with NaOH (30 mL, 1 M), and the resulting mixture was diluted with DCM (50 mL). * The combined organic layers were washed with NaOH (25 mL, 1 M), brine (25 mL), dried over NaSO, filtered, and concentrated to dryness under reduced pressure to give 5-(4-(trifluoromethyl)phenoxy)quinoline 1-oxide (220 mg, 83.3% yield).

[0524] 5-(4-(trifluoromethyl)phenoxy)quinoline-2-carbonitrile To a solution of compound 5-(4-(trifluoromethyl)phenoxy)quinoline 1-oxide (100.0 mg, 0.32 mmol, 1.0 equiv.) in 1,2-dichloroethane (2 mL), TMSCN (35.7 mg, 0.36 mmol, 1.1 equiv.) and dimethylcarbamic chloride (35.2 mg, 0.32 mmol, 1.0 equiv.) were added. The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL), and the resulting mixture was diluted with EA (30 mL). * The resulting mixture was extracted with 3). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 5-(4-(trifluoromethyl)phenoxy)quinoline-2-carbonitrile (75 mg, 72.8% yield).

[0525] 5-(4-(trifluoromethyl)phenoxy)quinoline-2-carboxylic acid A mixture of compound 5-(4-(trifluoromethyl)phenoxy)quinoline-2-carbonitrile (40.0 mg, 0.12 mmol, 1.0 equiv) in concentrated HCl (1 mL) was stirred for 16 hours at 100° C. The reaction mixture was cooled to 25° C., and then the suspension was filtered to give 5-(4-(trifluoromethyl)phenoxy)quinoline-2-carboxylic acid (35 mg, crude).

[0526] N-Isopropyl-5-(4-(trifluoromethyl)phenoxy)quinoline-2-carboxamide To a solution of compound 5-(4-(trifluoromethyl)phenoxy)quinoline-2-carboxylic acid (35.0 mg, 94.6 μmol, 1 equiv., HCl), isopropylamine (6.7 mg, 0.11 mmol, 1.2 equiv.), and DIPEA (36.7 mg, 0.28 mmol, 3.0 equiv.) in DCM (1 mL) was added HATU (54.0 mg, 0.14 mmol, 1.5 equiv.). The reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL), and the resulting mixture was diluted with EA (20 mL). * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to give the title compound (5.81 mg, 16.2% yield). LCMS (ESI): RT = 1.048 min, mass calcd. for C 21 H 18 F4N2O3374.12,m / z found 375.0[M+H] + ; 1 H NMR(400MHz,CDCl3)δ8.61(d,J=8.6 Hz,1H),8.34(d,J=8.6 Hz,1H),8.09(d,J=7.8 Hz,1H),7.98(d,J=8.6 Hz,1H),7.71(t,J=8.1 Hz,1H),7.64(d,J=8.1 Hz,2H),7.13(d,J=8.0 Hz,3H),4.42-4.28(m,1H),1.37(d,J=6.5 Hz,6H).

[0527] Example 59: (S)—N-(1-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 71) and (R)—N-(1-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 72)

[0528] [ka]

[0529] N-(1-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide To a solution of N-[1-(4-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (200 mg, 0.38 mmol, 1 equiv.) in dioxane (1 mL) was added NH3.HO (2.73 g, 23.37 mmol, 3 mL, 30%, 60.21 equiv.), and Cu2O (55.53 mg, 0.38 mmol, 39.6 uL, 1 equiv.). The mixture was stirred in a sealed tube at 100 °C for 16 h. The mixture was added to HO (20 mL) and extracted with EA (15 mL). * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give N-[1-(4-amino-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenoxy]naphthalene-2-carboxamide (88 mg, 0.19 mmol, 49.7% yield).

[0530] (S)—N-(1-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide (Compound 71) and (R)—N-(1-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)ph...

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, X １ , X ４ , X ５ , and X ６ is CR Ｘ and X ２ and X ３ is CR Ｙ and R Ｘ are each independently hydrogen, halogen, nitro, -OR ３ , -SR ３ , -CN, -C(=O)R ３ , -C(=O)N(R ３ ) ２ , -C(=O)OR ３ , -S(=O)R ３ , -S(=O) ２ R ３ , -N(R ３ ) ２ , -NR ３ S (=O) ２ R ３ , -NR ３ C(=O)R ３ , -NR ３ C(=O)OR ３ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C ２ -C ４ Alkenyl, substituted or unsubstituted C ２ -C ４ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ２ -C １０ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R Ｙ are each independently hydrogen, halogen, nitro, -CN, or -C(=O)R ３ , -C(=O)N(R ３ ) ２ , -C(=O)OR ３ , -S(=O)R ３ , -S(=O) ２ R ３ , -N(R ３ ) ２ , -NR ３ S (=O) ２ R ３ , -NR ３ C(=O)R ３ , -NR ３ C(=O)OR ３ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C ２ -C ４ Alkenyl, substituted or unsubstituted C ２ -C ４ Alkynyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ２ -C １０ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is halogen, nitro, -CN, -OR ３ , -SR ３ , -C(=O)R ３ , -C(=O)N(R ３ ) ２ , -C(=O)OR ３ , -S(=O)R ３ , -S(=O) ２ R ３ , -N(R ３ ) ２ , -NR ３ S (=O) ２ R ３ , -NR ３ C(=O)R ３ , -NR ３ C(=O)OR ３ or substituted or unsubstituted C １ -C ６ is a fluoroalkyl; R １ teeth, a) C substituted with —OH １ -C ６ is alkyl, or b) C substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, and substituted or unsubstituted triazinyl. １ -C ６ is alkyl, or c) -OH, -OCH ３ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ C substituted with two or three substituents each independently selected from １ -C ６ is alkyl, R ２ each independently represents a halogen, nitro, or -N ３ , -CN, -OR ３ , -SR ３ , -S(=O) ２ R ３ , -N(R ３ ) ２ , -C(=O)OR ３ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ２ -C １０ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R ３ each independently represents hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, substituted or unsubstituted C ２ -C １０ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two R ３ On the same nitrogen atom, two R ３ are, together with the nitrogen atom to which they are attached, substituted or unsubstituted C ３ -C ７ forming a heterocycloalkyl, and, n is 0, 1, 2, 3, or 4; The compound, or a pharma- ceutically acceptable salt or solvate thereof.

2. R Ｘ are each independently hydrogen, F, Cl, Br, or -CH ３ , -OH, -OCH ３ , or -OCF ３ 2. The compound of claim 1, wherein:

3. R Ｘ 3. The compound of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein each is hydrogen.

4. R Ｙ are each independently hydrogen, halogen, or -S(=O)R ３ , -S(=O) ２ R ３ , -N(R ３ ) ２ , -NR ３ S (=O) ２ R ３ , -NR ３ C(=O)R ３ , substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ fluoroalkyl, or substituted or unsubstituted C ２ -C ４ alkynyl, and R ３ each independently represents hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ fluoroalkyl or substituted or unsubstituted C ３ -C １０ cycloalkyl; or two R ３ On the same nitrogen atom, two R ３ are, together with the nitrogen atom to which they are attached, substituted or unsubstituted C ３ -C ７ forming a heterocycloalkyl, 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

5. R Ｙ are each independently hydrogen, F, Cl, or -CH ３ 2. The compound of claim 1, wherein:

6. R Ｙ The compound of claim 5 , or a pharma- ceutically acceptable salt or solvate thereof, wherein each is hydrogen.

7. R １ is C substituted with -OH １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

8. R is halogen, nitro, -CN, -OR ３ , -C(=O)R ３ , -C(=O)N(R ３ ) ２ , -C(=O)OR ３ , -S(=O)R ３ , -S(=O) ２ R ３ , -NR ３ S (=O) ２ R ３ , -NR ３ C(=O)R ３ , -NR ３ C(=O)OR ３ or substituted or unsubstituted C １ -C ６ is fluoroalkyl, and R ３ each independently represents hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C １０ Cycloalkyl, or substituted or unsubstituted C ２ -C １０ heterocycloalkyl; or two R ３ On the same nitrogen atom, two R ３ are, together with the nitrogen atom to which they are attached, substituted or unsubstituted C ３ -C ７ forming a heterocycloalkyl, 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof.

9. R is F, Cl, -CN, -OCF ３ , -CHF ２ , or -CF ３ 9. The compound of claim 8, which is: or a pharma- ceutically acceptable salt or solvate thereof.

10. R is -CF ３ and n is 0, or a pharma- ceutically acceptable salt or solvate thereof.

11. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is selected from the following compounds: or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】

12. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is selected from the following compounds: or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 6】

13. A pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound according to any one of claims 1-12, or a pharma- ceutically acceptable salt or solvate thereof.

14. 13. Use of a compound of any one of claims 1-12 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject, wherein the cancer is selected from mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.

15. 17. Use of a compound of any one of claims 1-12, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating polycystic kidney disease or hepatic fibrosis in a subject.

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