EA046394B1 - BICYCLIC COMPOUNDS - Google Patents

Description

BACKGROUND OF THE INVENTION

YAP and TAZ are transcriptional coactivators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes nuclear translocation of YAP/TAZ, with YAP/TAZ interacting with transcription enhancer associated domain (TEAD) transcription factors and coactivating the expression of target genes and promoting cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous forms of cancer. Described herein are inhibitors associated with one or more members of the Hippo pathway network, such as YAP/TAZ inhibitors or inhibitors that modulate the interaction between YAP/TAZ and TEAD.

Brief Description of the Present Invention

The present invention provides bicyclic compounds and pharmaceutical compositions containing these compounds. In some embodiments, the subject compounds are useful for treating cancer.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

But

CF ₃

Formula (I) wherein X ¹ and X ² are each independently N, NRX, C(=O) or CRX;

each X ³ and X ⁴ independently represents N, NRX, C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two R ^x are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each RX independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted ^-^heterodi^l, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -Cl ₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ¹ represents substituted or unsubstituted Cl-C ₆ alkyl, substituted or unsubstituted Cl-C ₆ haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C2C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl or -S(=O)2R ⁴ ;

each ^R2 is independently -N3, -CN, ^-OR3 , ^-SR3 , -S(=O) ^2R3 , -N( ^R3 )2, -C(=O) ^OR3 , substituted or unsubstituted^ -^alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, 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;

each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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 ⁴ represents substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or -NH2;

each - independently represents a single or double bond; And

- 1 046394 n represents 0, 1, 2, 3 or 4.

According to another aspect, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

R ^x H O

R ⁵

Formula (1a) where each R ^X independently represents hydrogen, halogen, -OH, -NH ₂ , -CH ₃ , -CH ₂ CH ₃ , cyclopropyl, -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , cyclopropyloxy or -OCF ₃ ;

R ¹ is substituted or unsubstituted C1- _C6 alkyl, wherein if C1- _C6 alkyl is substituted, then it is substituted with 1 or 2 substituents, each independently selected from -OH, -NH2, azetidinyl, pyridyl and aminopyridyl;

R ² represents F;

R ⁵ is -CF ₃ and n is 0 or 1.

According to another aspect, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

where each X ¹ and X ² independently represents N, NR ^X , C(=O) or CR ^X ;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CR ^X ; or if the two X ³ and X ⁴ are each independently NR ^X or CR ^X , then the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, OR ³ , -SR ³ , -CN, -C(=O)R ² , -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-C _b haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted C1-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 ¹ is substituted or unsubstituted C1- _C6 alkyl, substituted or unsubstituted C1- _C6 haloalkyl, substituted or unsubstituted C1- _C6 heteroalkyl, substituted or unsubstituted _C3 - _C10 cycloalkyl, substituted or unsubstituted C2 _{- C10} heterocycloalkyl , substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

each R ² is independently -N3, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted C1 -C6alkyl, substituted or unsubstituted C ₁ -C _b haloalkyl, substituted or unsubstituted C1-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 whelped aryl or substituted or unsubstituted heteroaryl;

each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-C ₆ heteroalkyl,

- 2 046394 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;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

According to another aspect, the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

CF ₃

Formula (III) wherein X ¹ and X ² are each independently N, NR ^X , C(=O) or CR ^X ;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NR ^X or CR ^X , then the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 C ₁ -C ₆ haloalkyl, 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 ¹ represents substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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;

each R ² is independently -N ³ , -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted ^-^alkyl, substituted or unsubstituted ^-^haloalkyl, 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;

each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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 ⁴ represents substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or -NH2;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

According to another aspect, the present invention relates to a compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

- 3 046394

Formula (IV) wherein X ¹ , X ² , X ⁵ and X ⁶ are each independently N, NR ^X , C(=O) or CR ^X ;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two RX are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 C^^haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted C1-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;

each R ² is independently -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , -N ₃ , F, substituted or unsubstituted C^C^alkyl, substituted or unsubstituted C^^haloalkyl, substituted or unsubstituted C1-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;

each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-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 ⁵ represents F, -SF5, substituted C1- _C6 alkyl, substituted or unsubstituted C1- _C6 haloalkyl, substituted C1- _C6 alkyloxy or substituted C1- _C6 alkylthio;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

According to another aspect, the present invention relates to a compound of formula (V) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

O

X ³ '''y HEI

X< X ^x ⁶

Ύ' V ¹ (R ² )-(- Z ) ^r5 ,

Formula (V) wherein X ¹ , X ² , X ⁵ and X ⁶ are each independently N, NRX, C(=O) or CRX;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 haloalkyl, 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

- 4 046394 or unsubstituted C2-C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

ring Z is a substituted monocyclic 5-membered heterocyclic ring containing at least one N, O or S atom, or a substituted monocyclic 6-membered heterocyclic ring containing at least one N atom;

each R2 is independently -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , -N ₃ , substituted or unsubstituted C1 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C^Cdeteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C2-C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

each R ³ independently represents hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C 1 -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ⁵ represents F, -SF5, substituted C1- _C6 alkyl, substituted or unsubstituted C1- _C6 haloalkyl, substituted C1- _C6 alkyloxy or substituted C1- _C6 alkylthio;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

Any combination of the groups described above for the various variables is contemplated in the present invention. Throughout the description, groups and their substituents are selected by one skilled in the relevant field to provide stable moieties and compounds.

According to another aspect, the present invention relates to a compound or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein the compound is a compound from Table. 1 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

According to another aspect, the present invention relates to a compound or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein the compound is a compound from Table. 2 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

According to another aspect, the present invention relates to a compound or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein the compound is a compound from Table. 3 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

In some embodiments, a compound disclosed herein exhibits an IC ₅₀ of no more than 3 μM.

In some embodiments, a compound disclosed herein exhibits an IC ₅₀ of no more than 1 μM.

According to another aspect, the present invention relates to a pharmaceutical composition containing a pharmaceutically acceptable excipient and a compound disclosed herein or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

According to another aspect, the present invention provides a method of treating cancer in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

Incorporation by reference

All publications, patents and patent applications mentioned in this specification are incorporated by reference in the present invention to the same extent as if each individual publication, patent or patent application had been specifically and separately designated as being incorporated by reference.

Brief description of graphic materials

Various aspects of the present invention are specifically set forth in the accompanying claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description, which sets forth illustrative embodiments employing the principles of the present invention, and the accompanying drawings.

In fig. Figure 1 shows a schematic representation of the Hippo signaling network. Hippo pathway components shaded in dark gray indicate components that inhibit YAP/TAZ activity. Hippo pathway components shaded in light gray indicate components that contribute to YAP/TAZ activity. Pointed and blunt arrows indicate activating and inhibitory interactions, respectively. Abbreviations: α-CAT (α-catenin),

- 5 046394

AJUB (Ajuba), AMOT (angiomotin), β-TRCP (β-transducing 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 and single KH domain), MER ( Merlin), MOB (Mps one binder), MST (mammalian sterile 20-like protein), PALS (Lin-7 associated protein), PATJ (Palsl-associated tight junction protein), PP2A (protein phosphatase 2A), PTPN14 ( non-receptor protein tyrosine phosphatase type 14), RASSF (Ras-related factor), SAV (Salvador), SCRIB (Scribble), SIK (Salt-inducible kinase), TAO (Thousand and one amino acid protein), TAZ (transcription coactivator with PDZ- binding motif), TEAD (TEADomain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain binding protein 2), YAP (Yes-associated protein), ZO (Zonula occludens), ZYX (Zyxin).

In fig. Figure 2 schematically represents the Hippo signaling pathway regulated by Gα proteins.

Detailed Description of the Present Invention

Certain terminology.

Unless otherwise noted, all technical and scientific terms used in this specification have the same meaning as would be commonly understood by one skilled in the art to which the claimed subject matter belongs. It is understood that the above general description and the following detailed description are illustrative and explanatory only and do not limit any of the claimed subject matter. In the present invention, the use of the singular form includes the plural form unless specifically stated otherwise. It should be noted that when the singular form is used in the specification and appended claims, it includes references to the plural unless the context clearly indicates otherwise. In the present invention, the use of or means and/or, unless otherwise noted. Moreover, the use of the term including, as well as other forms such as include, includes and included, is not limited.

As used in the present invention, in some embodiments, ranges and amounts are expressed as an approximate fixed value or range. Approximately also includes the exact quantity. So approximately 5 µl means approximately 5 µl as well as 5 µl. Generally, the term approximates the amount that can be expected to be within experimental error.

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

As used herein, the terms individual(s), subject(s) and patient(s) refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is non-human. None of such terms require or are limited to situations that are characterized by supervision (e.g., ongoing or intermittent) by a health care professional (e.g., physician, registered nurse, auxiliary nurse, physician assistant, ancillary staff, or hospice worker).

As used in the specification and claims, unless otherwise stated, the following terms have the meanings set forth below.

Amino refers to the -NH ₂ radical.

Cyano refers to the -CN radical.

Nitro refers to the -NO2 radical.

Oxa refers to the -O- radical.

Oxo refers to the = O radical.

Thioxo belongs to the = S radical.

Imino refers to the = N-H radical.

Oximo refers to the = N-OH radical.

Alkyl refers to a radical with a straight or branched hydrocarbon chain consisting only of carbon and hydrogen atoms, without unsaturation, that contains from one to fifteen carbon atoms (for example, C ₁ -C ₁₅ alkyl). In certain embodiments, alkyl contains from one to thirteen carbon atoms (eg, C1- _C13 alkyl). In certain embodiments, alkyl contains from one to eight carbon atoms (eg, C1-C8 alkyl). In other embodiments, alkyl contains from one to five carbon atoms (eg, Cj-C5 alkyl). In other embodiments, alkyl contains from one to four carbon atoms (eg, C1-C4 alkyl). In other embodiments, alkyl contains from one to three carbon atoms (eg, Cj-C ₃ alkyl). In other embodiments, alkyl contains one to two carbon atoms (eg, C ₁ -C ₂ alkyl). In other embodiments, alkyl contains one carbon atom (eg, C1 alkyl). In other embodiments, alkyl contains from five to fifteen carbon atoms (for example, C ₅ -C ₁₅

- 6 046394 alkyl). In other embodiments, alkyl contains from five to eight carbon atoms (eg, C5-C8 alkyl). In other embodiments, alkyl contains from two to five carbon atoms (eg, C2-C5 alkyl). In other embodiments, alkyl contains three to five carbon atoms (eg, C ₃ -C ₅ alkyl). In other embodiments, the 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 (mpembutyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless specifically stated otherwise in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halogen, 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)ORf , -OC(O)- NR ^a Rf, N(R ^a )C(O)Rf, -N(R ^a )S(O)tRf (where t represents 1 or 2), -S(O)tOR ^a (where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl and each R ^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

Alkoxy refers to a radical linked through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

Alkenyl refers to a straight-chain or branched-chain radical group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and containing from two to twelve carbon atoms. In certain embodiments, alkenyl contains from two to eight carbon atoms. In other embodiments, alkenyl contains from two to four carbon atoms. Alkenyl is attached to the remainder of the molecule by a single bond, for example, ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, pent-1-enyl, penta-1,4- dienyl, etc. Unless specifically stated otherwise in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halogen, 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)tR ^f (where t represents 1 or 2), -S (O)tOR ^a (where t is 1 or 2), -S(O)tR ^f (where t is 1 or 2) and -S(O)tN(R ^a ) ₂ (where t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl and each R ^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

Alkynyl refers to a straight or branched chain radical group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, containing from two to twelve carbon atoms. In certain embodiments, the alkynyl contains from two to eight carbon atoms. In other embodiments, the alkynyl contains two to four carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise in the specification, an alkynyl group is optionally substituted with one or more of the following substituents: halogen, 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)tR ^f (where t represents 1 or 2), -S(O )tOR ^a (where t is 1 or 2), -S(O)tR ^f (where t is 1 or 2) and -S(O)tN(R ^a )2 (where t is 1 or 2) wherein each R ^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl and each R ^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

Alkylene or alkylene chain refers to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group consisting only of carbon and hydrogen, containing no unsaturation and containing from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene and so on. The alkylene chain is attached to the remainder 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 remainder of the molecule and to the radical group are through one carbon atom in the alkylene chain or through any two carbon atoms in the chain. In certain embodiments, the alkylene contains from one to eight carbon atoms (eg, C1-C5 alkylene). In other embodiments, the alkylene contains from one to five carbon atoms (eg, Cj-C ₅ alkylene). In other embodiments, the alkylene contains from one to four carbon atoms (eg, C1- _C4 alkylene). In other embodiments, the alkylene contains from one to three carbon atoms (eg, C-C3 alkylene). In other embodiments, the alkylene contains one to two carbon atoms (eg, C ₁ -C ₂ alkylene). In other embodiments, the alkylene contains one carbon atom (for example,

- 7 046394

C1 alkylene). In other embodiments, the alkylene contains from five to eight carbon atoms (eg, C5-C8 alkylene). In other embodiments, the alkylene contains from two to five carbon atoms (eg, C2-C5 alkylene). In other embodiments, the alkylene contains three to five carbon atoms (eg, C3-C5 alkylene). Unless specifically stated otherwise in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, 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)ORf, - OC(O)-NR ^a Rf, -N(R ^a )C(O)Rf, -N(R ^a )S(O)tRf (where t represents 1 or 2), -S(O)tOR ^a ( where t is 1 or 2), -S(O)tRf (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl and each R ^f is independently alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

Aryl refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from the ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only a hydrogen atom and five to eighteen carbon atoms, where at least one of the rings in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n+2) ts-electron system according to Hückel's theory. The ring system from which the aryl groups are derived includes, but is not limited to, benzene, fluorene, indane, indene, tetraline and naphthalene. Unless specifically stated otherwise in the specification, the term aryl or the prefix ar- (as in aralkyl) is intended to include aryl radicals, optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, 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(R ^a )C(O)R ^a , -R ^b -N( R ^a )S(O)tR ^a (where t represents 1 or 2), -R ^b -S(O)tOR ^a (where t represents 1 or 2), -R ^b -S(O)tR ^a ( where t is 1 or 2) and -R ^b -S(O)tN(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halogen groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R ^b independently represents a straight link or straight or branched alkylene or alkenylene chain and R ^c represents a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

Aryloxy refers to a radical linked through an oxygen atom of the formula -O-aryl, where aryl is as defined above.

Aralkyl refers to a radical of the formula Rc-aryl, wherein ^Rc represents an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical is optionally substituted, as described above for the aryl group.

Aralkenyl refers to the radical of the formula -Rd-aryl. where Rd represents an alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted, as described above for the aryl group. The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for the alkenylene group.

Aralkynyl refers to a radical of the formula -I ^e -aryl, where R ^e represents an alkynylene chain as defined above. The aryl portion of the aralkynyl radical is optionally substituted as described above for the aryl group. The alkynylene chain portion of the aralkynyl radical is optionally substituted as defined above for the alkynylene chain.

Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting of only carbon and hydrogen atoms, and in some embodiments includes fused or bridged ring systems containing from three to fifteen carbon atoms. In certain embodiments, the carbocyclyl contains from three to ten carbon atoms. In other embodiments, the carbocyclyl contains from five to seven carbon atoms. The carbocyclyl is attached to the remainder of the molecule by a single bond. In some embodiments, the carbocyclyl is saturated (ie, containing only C-C single bonds) or unsaturated (ie, containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also called a cycloalkyl. Examples of monocyclic cycloalks

- 8 046394 compounds include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In certain embodiments, cycloalkyl contains from three to eight carbon atoms (eg, C ₃ -C ₅ cycloalkyl). In other embodiments, cycloalkyl contains from three to seven carbon atoms (eg, C3-C7 cycloalkyl). In other embodiments, cycloalkyl contains from three to six carbon atoms (eg, C ₃ -C ₆ cycloalkyl). In other embodiments, cycloalkyl contains three to five carbon atoms (eg, C ₃ -C ₅ cycloalkyl). In other embodiments, cycloalkyl contains three to four carbon atoms (eg, C ₃ -C ₄ cycloalkyl). An unsaturated carbocyclyl is also called a cycloalkenyl. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Unless specifically stated otherwise in the specification, the term carbocyclyl is intended to include carbocyclyl radicals that are optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, 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)tR ^a (where t is 1 or 2), -R ^b -S(O)tOR ^a (where t is 1 or 2), -R ^b -S(O)tR ^a (where t is 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R ^b independently represents a straight link or straight or branched alkylene or alkenylene chain, and R ^c represents a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise noted.

Carbocyclylalkyl refers to a radical of the formula -K ^c -carbocyclyl, where R ^c represents an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

Halo or halogen refers to bromide, chloride, fluoride or iodide substituents.

Fluoroalkyl refers to an alkyl radical as defined above that is substituted with one or more fluoro radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl moiety of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

Heterocyclyl or heterocycle refers to a stable 3-18 membered non-aromatic ring radical that contains from two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which includes fused ring systems and bridged ring systems in some embodiments. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. In some embodiments, the heterocyclyl is attached to the remainder of the molecule through any atom of the ring(s). In some embodiments, the heterocyclyl is saturated (ie, containing only single bonds) or unsaturated (ie, containing one or more double bonds or triple bonds). A fully saturated heterocyclyl radical is also called 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, 2oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyr rolidinil, oxazolidinyl, piperidinyl, piperazinil , 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tritianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl and 1,1dioxothiomorpholinyl. Unless specifically stated otherwise in the specification, the term heterocyclyl is intended to include heterocyclyl radicals as defined above which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, 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

- 9 046394 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)tR ^a (where t represents 1 or 2), -R ^b -S(O)tOR ^a (where t represents 1 or 2), -R ^b -S(O)tR ^a (where t represents 1 or 2) and -R ^b -S(O)tN(R ^a )2 (where t represents 1 or 2) wherein each R ^a independently represents hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R ^b independently represents a straight link or straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

Heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from an atom other than carbon, i.e. oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. The heteroalkyl is attached to the moiety of the molecule at the carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is ^-^heteroalkyl. In some embodiments, the alkyl moiety of the heteroalkyl radical is optionally substituted as defined for an alkyl group.

Heterocyclylalkyl refers to a radical of the formula ^-heterocyclyl, wherein R ^c represents an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

Heterocyclylalkoxy refers to a radical linked through an oxygen atom of the formula -OR ^c heterocyclyl, where R ^c represents an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclyl alkoxy radical is optionally substituted as defined above for a heterocyclyl group.

Heteroaryl refers to a radical derived from a 3 to 18 membered aromatic ring radical that contains from two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, in some embodiments, a teroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is completely unsaturated, i.e. it contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory.

Heteroaryl includes fused ring systems or bridged ring systems. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, 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^]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2 -a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta-pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3d]pyrimidinyl, 5,6-dihydrobenzo[Cchinazolinyl, 5,6-dihydrobenzo[Ccinnolinyl, 6,7 -dihydro-5Hbenzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctapyrimidinyl . ,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5.6.6a.7.8.9.10.1()a-octahydrobenzo[11| quinazolinil. 1phenyl-III-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3.4ch1|pyrimidinyl. pyridinyl, pyrido[3.2ch1|pyrimidinyl. pyrido[3,4d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8tetrahydrobenzo[4,5]thieno[ 2,3d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3d]pyrimidinyl, thieno[3.2ch1|pyrimidinyl. thieno[2,3-c]pyridinyl and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, the term heteroaryl is intended to include heteroaryl radicals as defined above which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, fluoro

- 10 046394 kilo, 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, substituted heterocyclylalkyl, optional 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)tR ^a (where t represents 1 or 2), -R ^b -S(O)tOR ^a (where t represents 1 or 2), -R ^b - S(O)tR ^a (where t is 1 or 2) and -R ^b S(O)tN(R ^a ) ₂ (where t is 1 or 2), where each R ^a independently represents hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R ^b independently represents a straight link or straight or branched alkylene or alkenylene chain, and R ^c represents a straight or branched alkylene or alkenylene chain, and where each of the above substituents are unsubstituted unless otherwise indicated.

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

C-heteroaryl refers to a heteroaryl radical as defined above, and where the point of attachment of the heteroaryl radical to the remainder 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.

Heteroaryloxy refers to a radical linked through an oxygen atom of the formula -O-heteroaryl, where heteroaryl is as defined above.

Heteroarylalkyl refers to a radical of the formula -^-heteroaryl wherein R ^c represents an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of a heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

Heteroarylalkoxy refers to a radical linked through an oxygen atom of the formula -OR ^c heteroaryl, where R ^c represents an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus result in enantiomers, diastereomers, and other stereoisomeric forms that are defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise noted, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present invention. When the compounds described herein contain alkene double bonds, and unless otherwise stated, the present invention is intended to include both E and Z geometric isomers (eg, cis or trans). Likewise, it is also intended that all possible isomers are included, as well as their racemic and optically pure forms, and all tautomeric forms. The term geometric isomer refers to the E or Z geometric isomers (eg, cis or trans) of an 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.

A tautomer refers to a molecule in which a proton shift is possible from one atom of the molecule to another atom of the same molecule. The compounds provided herein according to certain embodiments exist as tautomers. In cases where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

- 11 046394

Optional or optional means that the event or circumstance further described may or may not occur and that the description includes cases in which the event or circumstance occurs and cases in which it does not occur. For example, optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and unsubstituted aryl radicals.

The pharmaceutically acceptable salt includes both acid addition and base addition salts. The pharmaceutically acceptable salt of any of the compounds described herein is intended to include any and all pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts of the compounds described herein are optionally pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

Pharmaceutically acceptable acid addition salt refers to those salts that maintain the biological effectiveness and properties of free bases that are not biologically or otherwise undesirable and that are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts which are formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedionic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like, and include, 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 acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates , malonates, succinates, suberates, sebacates, fumarates, maleates, mandelic acid salts, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Amino acid salts such as arginates, gluconates and galacturonates have also been considered (see, for example, Berge S. M. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66:1-19 (1997), which is incorporated herein by reference throughout completeness). In some embodiments, acid addition salts of base compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to form the salt according to methods and techniques with which one skilled in the art is familiar.

Pharmaceutically acceptable base addition salt refers to those salts that maintain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. Such salts are prepared by adding an inorganic base or an 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 and the like salts. Salts obtained from organic bases

- 12 046394 include, without limitation, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2 -dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, ^^dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylene dianiline, N-methylglu amine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al. higher.

As used herein, the terms treatment or implementation of treatment, or temporary relief or reduction in intensity are used interchangeably in the present invention. These terms refer to a technique for obtaining beneficial or desired results, including, without limitation, therapeutic utility and/or prophylactic utility. Therapeutic benefit refers to the elimination or reduction of the underlying disease being treated. In addition, therapeutic benefit is achieved by eliminating or reducing the intensity of one or more physiological symptoms associated with the underlying disorder such that the patient experiences improvement despite the patient still suffering from the underlying disorder, according to some embodiments. For prophylactic utility, the compositions in some embodiments are administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of that disease has not been established.

A prodrug is intended to mean a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described in the present invention. Thus, the term prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some embodiments, the prodrug is inactive when administered to a subject, but is converted in vivo to the active compound, for example, by hydrolysis. The prodrug often has advantages regarding solubility, histocompatibility or sustained release in mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

For a discussion of prodrugs, see Higuchi, T., et al., Pro-drugs as Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14 and in 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.

The term prodrug is also intended to include any covalently linked carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. In some embodiments, prodrugs of an active compound as described herein are prepared by modifying functional groups present in the active compound such that the modifications are cleaved, either by routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is linked to any group that, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in active compounds and the like.

Connections.

In some embodiments, the compounds disclosed herein are bicyclic compounds.

In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

CF ₃

Formula (I) wherein X ¹ and X ² are each independently N, NRX, C(=O) or CR ^X ;

- 13 046394 each X ³ and X ⁴ independently represents N, NRX, C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NR ^X or CR ^X , then the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 haloalkyl, substituted or unsubstituted _C2 - _C4 alkenyl, substituted or unsubstituted _C2 - _C4 alkynyl, substituted or unsubstituted _C1 - _C6 heteroalkyl, substituted or unsubstituted ^-Cscycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ¹ represents substituted or unsubstituted C^alkyl, substituted or unsubstituted C ₁ -C6haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ C ₁₀ heterocycloalkyl, substituted or unsubstituted C ^ heteroalkyl or -S(=O) ₂ R ⁴ ; each R ² is independently -N3, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ ) ₂ , -C(=O)OR ³ , substituted or unsubstituted^ -^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted ^-^sdicloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted whelped aryl or substituted or unsubstituted heteroaryl;

each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C6 haloalkyl, 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 ⁴ represents substituted or unsubstituted C^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted ^-^scycloalkyl or -NH ₂ ;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

In some embodiments of the compound of formula (I), X ¹ and X ² are each CR ^X . In some embodiments of the compound of Formula (I), X ¹ is N and X ² is CR ^X . In some embodiments of a compound of formula (I), X ¹ is CR ^X and X ² is N. In some embodiments of a compound of formula (I), X ¹ and X ² are each N.

In some embodiments of the compound of formula (I), X ³ and X ⁴ are each CR ^X . In some embodiments of the compound of formula (I), X ³ is N and X ⁴ is CR ^X . In some embodiments of the compound of formula (I), X ³ is CR ^X and X ⁴ is N. In some embodiments of the compound of formula (I), X ³ and X ⁴ are each N.

In some embodiments of the compound of formula (I), each R ^X is independently hydrogen, halogen, -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-C ₆ alkyl, substituted or unsubstituted C ₁ C ₆ haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ C ₄ alkynyl or substituted or unsubstituted C 1 -C 6 heteroalkyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C-dicloalkyl, or substituted or unsubstituted C2-C10 heterocycloalkyl. In some embodiments of the compound of formula (I), each R ^X is independently hydrogen, halogen, -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 C| -Cgi alkyl, substituted or unsubstituted C1 -C6 haloalkyl or substituted or unsubstituted C ₂ -C ₄ alkynyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1Silkyl, substituted or unsubstituted C1-C6haloalkyl, or substituted or unsubstituted C3^ocycloalkyl. In some embodiments of the compound of formula (I), each R ^X is independently hydrogen, F, Cl, Br, I, -CH3, -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH2CN, CH2CO2H , -CH2CO2CH3, -CH2CO2CH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, CH ₂ NH ₂ , -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH=CH ₂ , -C^CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN , -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, -CO2H, -CO2CH3, -CO2CH2CH3, -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 of the compound of formula (I), each R ^x is independently hydrogen, F, Cl, Br, I, -CH ₃ , -CH ₂ CH ₃ , cyclopropyl,

- 14 046394

-CHC'H, -OH, -OCH3, -OCH2CH3, -OCF3, -SCH3, cyclopropyloxy, -NH2, -NHC(=O)CH ₃ , -N(CH ₃ )C(=O)CH ₃ , -NHS (=O)2CH ₃ , -N(CH ₃ )S(=O)2CH ₃ , -S(=O)CH ₃ or -S(=O)2CH ₃ . In some embodiments of the compound of formula (I), each R ^x independently represents hydrogen, halogen, -OCH3, -OCH2CH3, cyclopropyloxy, or -OCF3. In some embodiments of the compound of Formula (I), each R ^X is independently hydrogen or halogen. In some embodiments of the compound of Formula (I), each R ^X is independently hydrogen, F, or Cl. In some embodiments of the compound of formula (I), each R ^X is hydrogen.

In some embodiments of the compounds of formula (I), X ³ and X ⁴ are each independently NR ^X or CR ^X , where the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring. According to some embodiments of a compound of formula (I), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

- 15 046394

each R ^Z is independently hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C1C ₆ haloalkyl, substituted or unsubstituted ^-^heteroalkyl, substituted or unsubstituted C ₃ ^cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroαalkyl, substituted or unsubstituted ^-^cycloalkyl, or substituted or unsubstituted C2^ heterocycloalkyl.

According to some embodiments of a compound of formula (I), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

each R ^z independently represents hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C1C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ ^^ic^alk^, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroαalkyl, substituted or unsubstituted ^-^cycloalkyl, or substituted or unsubstituted C2^ heterocycloalkyl.

According to some embodiments of a compound of formula (I), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

each R ^z independently represents hydrogen, F, Cl, -CN or -NH2.

According to some embodiments of a compound of formula (I), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

- 16 046394

In some embodiments of the compound of formula (I), R ¹ is substituted or unsubstituted ^-^ alkyl. In some embodiments of the compound of formula (I), R ¹ is ^-^alkyl substituted with substituted or unsubstituted C3C ₁₀ cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl. In some embodiments of a compound of formula (I), R ¹ is a ^^alkyl substituted with a 5-membered heterocyclic ring containing at least one N atom. In some embodiments of a compound of formula (I), R ¹ is a V-Cbalkyl substituted with a 5-membered heterocyclic ring 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 any triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiazolyl and substituted or unsubstituted dithiazolyl. In some embodiments of the compound of formula (I), R ¹ is C ₁ C6alkyl substituted with a 5-membered heterocyclic ring selected from:

- 17 046394

hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, C1-C ₆ alkyl, substituted or unsubstituted C1, each R ^z independently represents -C( =O)OR ³ , substituted or unsubstituted

C ₆ haloalkyl, 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; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

In some embodiments of a compound of formula (I), R ¹ is a C1C6 alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one N atom. In some embodiments of a compound of formula (I), R ¹ is a C1-C6 alkyl , substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing 1 or 2 N atoms. In some embodiments of the compound of formula (I), R ¹ is a C1-C6 alkyl substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl or substituted or unsubstituted pyridazinyl. In some embodiments of the compound of formula (I), R ¹ is a C1-C6 alkyl substituted with a 6-membered heteroaryl ring,

- 18 046394 selected from

each R ^Z is independently hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted C^^alkyl, substituted or unsubstituted C1C ₆ haloalkyl, 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 displaced aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted C^^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

In some embodiments of the compound of formula (I), R ¹ is a C1C6alkyl substituted with 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 ³ =C(R ³ )2, -C=CR ³ , substituted or unsubstituted C3-C ₁₀ cycloalkyl, substituted or unsubstituted

C ₂ -C ₁₀ heterocycloalkyl or substituted or unsubstituted aryl; each R ³ independently represents hydrogen, substituted or unsubstituted C^^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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.

In some embodiments of a compound of formula (I), n is 0, 1, 2, or 3. In some embodiments of a compound of formula (I), n is 0, 1, or 2. In some embodiments of a compound of formula (I), n is 1 or 2. In some embodiments of the compound of formula (I), n is 0 or 1. In some embodiments of the compound of formula (I), n is 0.

According to another aspect, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

where each R ^x independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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 ¹ represents substituted or unsubstituted C^^alkyl, substituted or unsubstituted C^C^haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl , substituted or unsubstituted C2C ₁₀ heterocycloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl or -S(=O)2R ⁴ ;

- 19 046394 each R ² independently represents -N3, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , F , substituted or unsubstituted C^C^alkyl, substituted or unsubstituted Cl-C6halorealkyl, substituted or unsubstituted C1-C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted ralkyl , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ Cl ₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ⁴ represents substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or -NH ₂ ;

R ⁵ represents F, -SF ₅ , substituted C^C^alkyl, substituted or unsubstituted C1C ₆ haloalkyl, substituted C1-C ₆ alkyloxy or substituted C1-C ₆ alkylthio;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

In some embodiments of the compound of formula (Ia), each R ^X is independently hydrogen, halogen, -OH, -NH ₂ , -CH ₃ , -CH ₂ CH ₃ , cyclopropyl, -CF ₃ , -OCH ₃ , -OCH ₂ CH ₃ , cyclopropyloxy or -OCF ₃ ;

R ¹ represents substituted or unsubstituted C1-C ₆ alkyl, and if C1-C ₆ alkyl is substituted, then it is substituted with 1 or 2 substituents, each independently selected from -OH, -NH2, azetidinyl, pyridyl and aminopyridyl;

R ² represents F;

R ⁵ is -CF3; and n is 0 or 1.

In some embodiments of the compound of formula (Ia), each R ^X is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, cyclopropyl, -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 of the compound of formula (Ia), each R ^X is independently hydrogen, F, Cl, -CH3, -CH ₂ CH ₃ , cyclopropyl, -OH, -OCH ₃ , -OCH2CH3, -OCH2F, -OCHF2, -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 of the compound of formula (Ia), each R ^X is independently hydrogen, halogen, -OH, NH2, -CH3, -CH2CH3, cyclopropyl, -CF3, -OCH3, -OCH2CH3, cyclopropyloxy, or -OCF3. In some embodiments of the compound of formula (Ia), each R ^X is independently hydrogen, F, Cl, -CN, -CH3, -OH, -OCH3, -OCH2F, -OCHF2, or -OCF3. In some embodiments of the compound of formula (Ia), each R ^X is independently hydrogen, halogen, -OCH3, -OCH2CH3, cyclopropyloxy, or -OCF3. In some embodiments of the compound of formula (Ia), each R ^X is independently hydrogen, F, Cl, or -CH3. In some embodiments of the compound of formula (Ia), each R ^X is hydrogen.

In some embodiments of a compound of formula (Ia), R ¹ is a substituted or unsubstituted C1-C6 alkyl. In some embodiments of a compound of formula (Ia), R ¹ is a C1-C6 alkyl substituted with a substituted or unsubstituted C ₃ C ₁₀ cycloalkyl or a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl. In some embodiments of a compound of formula (Ia), R ¹ is a C1-C6 alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing at least one N atom. In some embodiments of a compound of formula (Ia), R ¹ is C1 -C6alkyl substituted with a substituted or unsubstituted monocyclic 6-membered heteroaryl ring containing 1 or 2 N atoms. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6alkyl substituted with a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl or substituted or unsubstituted pyridazinyl. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6 alkyl substituted with substituted or unsubstituted pyridinyl. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6alkyl substituted with substituted or unsubstituted pyridin-2-yl, substituted or unsubstituted pyridin-3yl, or substituted or unsubstituted pyridin-4-yl. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6 alkyl substituted with pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6 alkyl substituted with substituted or unsubstituted pyridin-2-yl or substituted or unsubstituted pyridin-3-yl. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6 alkyl substituted with pyridin-2-yl or pyridine

- 20 046394

3-yl substituted with 1, 2 or 3 substituents, each independently selected from F, Cl, -OH, -CN and -NH ₂ . In some embodiments of the compound of formula (Ia), R ¹ is C1C alkyl. substituted with pyridin-2-yl or pyridin-3-yl substituted with -OH, -CN or -NH2. In some embodiments of the compound of formula (Ia), R ¹ is C1-C6 alkyl substituted with pyridin-2-yl or pyridin-3-yl substituted with -Nft. In some embodiments of the compound of formula (Ia), R ¹ is C1- _C6 alkyl substituted with 6-aminopyridin-2yl or 2-aminopyridin-3-yl.

In some embodiments of the compound of formula (Ia), R ¹ is C1C6 alkyl substituted with 1, 2, 3, or 4 substituents, each independently selected from halogen, -CN, -OR ³ , -N(R ³ )2, -C(= O)OR ³ , -C(=O)N(R ³ )2, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C10 heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; where each R ³ independently represents hydrogen, substituted or unsubstituted C1-C-alkyl, substituted or unsubstituted C1-C-Dalogenalkyl or substituted or unsubstituted ^-^heteroalkyl, substituted or unsubstituted C3-C ₁₀ cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl. In some embodiments of the compound of formula (Ia), R ¹ is ^-^alkyl substituted with 1, 2, 3, or 4 substituents, each independently selected from F, Cl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, pyridinyl, pyrimidinyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH3OH, -OCH2CN, -OCF3, -CO2H, -CO2CH3, -CO2CH2CH3, -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(=ObCH3, -NHS(=O)2CH3 or -N(CH3)S(=O)2CH3 In some embodiments of the compound of formula (Ia), R ¹ is a substituted or unsubstituted C1-C ₆ alkyl, wherein if C-C alkyl is substituted, then it is substituted with 1 or 2 substituents, each independently selected from -OH, -NH2 , azetidinyl, pyridyl, and aminopyridyl. In some embodiments of the compound of formula (Ia), R ¹ is ^-^alkyl substituted with 1, 2, or 3 substituents, each independently selected from F, Cl, azetidinyl, pyridinyl, -CN, -OH. , -OCH3, -OCF3 or -NH2. In some embodiments of the compound of formula (Ia), R ¹ is ^-^ alkyl substituted with azetidinyl, -OH, or -NH2. In some embodiments of the compound of formula (Ia), R ¹ is Cj-^alkyl substituted with -OH or -NH2. In some embodiments of the compound of formula (Ia), R ¹ is ^-^ alkyl substituted with azetidinyl. In some embodiments of the compound of formula (Ia), R ¹ is ^-^ alkyl substituted with substituted or unsubstituted pyridinyl and -OH. In some embodiments of the compound of formula (Ia), R ¹ is Cl-C ₆ alkyl substituted with pyridinyl and -OH. In some embodiments of the compound of formula (Ia), R ¹ is ^-^alkyl substituted with pyridin-2yl and -OH.

In some embodiments of the compound of formula (Ia), each R ² is independently F, -CH3, -CH2CH3, -OH, or -OCH3. In some embodiments of the compound of formula (Ia), each R ² is independently F or -OCF3. In some embodiments of the compound of formula (Ia), each R ² is F.

In some embodiments of the compound of Formula (Ia), R ⁵ is -F or -SF5. In some embodiments of the compound of formula (Ia), R ⁵ is -F. In some embodiments of the compound of formula (Ia), R ⁵ is -SF5. In some embodiments of a compound of formula (Ia), R ⁵ is a substituted or unsubstituted C1-C4 haloalkyl, a substituted C1- _C4 alkyloxy, or a substituted _C1C4 alkylthio. In some embodiments of the compound of formula (Ia), R ⁵ is a C1-C6 haloalkyl, substituted C-C alkyloxy, or substituted C1-C6 alkylthio. In some embodiments of the compound of formula (Ia), R ⁵ is a C1-C4 haloalkyl. In some embodiments of the compound of formula (Ia), R ⁵ is C1C4alkyloxy or C1-C4alkylthio, each independently substituted with one or more F. In some embodiments of the compound of formula (Ia), R ⁵ is -CH2F, -CHF ₂ , -CF ₃ , -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCF2CH3, -OCH2CF3, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, - SCF2CH3 or -SCH2CF3. In some embodiments of the compound of formula (Ia), R ⁵ is -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ , -SCHF 2 or -SCF3. In some embodiments of the compound of Formula (Ia), R ⁵ is -CF3.

In some embodiments of a compound of formula (Ia), n is 0, 1, 2, or 3. In some embodiments of a compound of formula (Ia), n is 0, 1, or 2. In some embodiments of a compound of formula (Ia), n is 1 or 2. In some embodiments of the compound of formula (Ia), n is 0 or 1. In some embodiments of the compound of formula (Ia), n is 0.

- 21 046394

According to another aspect, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

where each X ¹ and X ² independently represents N, NR ^X , C(=O) or CRX;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CR ^X ; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two RX are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -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-C ₆ haloalkyl, 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 ¹ represents substituted or unsubstituted C^^alkyl, substituted or unsubstituted C1- _C6 haloalkyl, substituted or unsubstituted C1- _C6 heteroalkyl, substituted or unsubstituted _C3 - _C10 cycloalkyl, substituted or unsubstituted _C2 - _C10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

each R ² is independently -N3, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted C1 -C6alkyl, substituted or unsubstituted C1- _C6 haloalkyl, substituted or unsubstituted C1- _C6 heteroalkyl, substituted or unsubstituted _C3 - _C10 cycloalkyl, substituted or unsubstituted _C2 - _C10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted puppy aril or substituted or unsubstituted heteroaryl;

each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-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 ⁴ represents substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or -NH2;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

In some embodiments of a compound of formula (II), X ¹ and X ² are each CRX. In some embodiments of a compound of formula (II), X ¹ is N and X ² is CRX. In some embodiments of a compound of formula (II), X ¹ is is CRX and X ² is N. In some embodiments of the compound of formula (II), X ¹ and X ² are each N.

In some embodiments of a compound of formula (II), X ³ and X ⁴ are each CRX. In some embodiments of a compound of formula (II), X ³ is N and X ⁴ is CRX. In some embodiments of a compound of formula (II), X ³ is is CRX and X ⁴ is N. In some embodiments of a compound of formula (II), X ³ and X ⁴ is each N. In some embodiments of a compound of formula (II), X ³ is NR ^X and X ⁴ is C( =O).

In some embodiments of the compound of formula (II), each R ^X is independently hydrogen, halogen, -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 C1C ₆ haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ C ₄ alkynyl or substituted or unsubstituted C 1 -C ₆ heteroalkyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1

- 22 046394

Sbhaloalkyl, 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. In some embodiments of the compound of formula (II), each R ^X is independently hydrogen, halogen, -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 haloalkyl or substituted or unsubstituted C2-C4 alkynyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, or substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments of the compound of formula (II), each RX is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2C (=O)NH2, -CH2C(=O)NHCH3, -CH ₂ C(=O)N(CH ₃ ) ₂ , -CH2NH2, -CH2NHCH3, -CH2N(CH ₃ )2, -CH2F, -CHF2, - CF ₃ , -CH=CH ₂ , -C CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, - OCF3, -СО2Н, -CO2CH3, -CO2CH2CH3, -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) ₂ CH ₃ , -NHS(=O) ₂ CH ₃ or -N(CH ₃ )S(=O) ₂ CH ₃ . In some embodiments of the compound of formula (II), each R ^X is independently hydrogen, Cl, -CH3, -CH2CH3, -OH, or OCH3. In some embodiments of the compound of formula (II), each R ^X is independently hydrogen, halogen, -OCH3, -OCH ₂ CH ₃ , cyclopropyloxy, or -OCF ₃ . In some embodiments of the compound of Formula (II), each R ^X is independently hydrogen or halogen. In some embodiments of the compound of Formula (II), each R ^X is independently hydrogen, F, or Cl. In some embodiments of the compound of Formula (II), each R ^X is hydrogen.

In some embodiments of the compound of formula (II), X ³ and X ⁴ are each independently NR ^X or CR ^X , wherein the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring. According to some embodiments of a compound of formula (II), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

- 23 046394

each R ^z independently represents hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted ^ -^Alkyil, replaced or unnoticed by C1^HALONALENALLECHIL, replaced or unnoticed with ₁ -c ₆ heteroalkil, replaced or unnoticed with ₃ ^cycloilkil, explosive or unnoticed with ₂ -c ₁₀ heterocyclicl, explosive or unnoticed arallkil, substituted or unnecessary ail or an arile substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

According to some embodiments of a compound of formula (II), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

- 24 046394

each R ^z independently represents hydrogen, halogen, -CN, -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 C1C ₆ haloalkyl, substituted or unsubstituted C1-C ₆ heteroalkyl, substituted or unsubstituted C3C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

According to some embodiments of a compound of formula (II), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

each R ^z independently represents hydrogen, F, Cl, -CN or -NH2.

According to some embodiments of a compound of formula (II), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

In some embodiments of the compound of formula (II), R ¹ is a substituted or unsubstituted C1-C ₆ alkyl. In some embodiments of the compound of formula (II), R ¹ is -CH3, -CH2CH3, -CH2CH3CH3, -CH(CH3), -CH2CH2CH2CH3, -CHCH(CH3)2, -CH(CH3)(CH2CH3), -C (CH3)3, -CH2CH3OH, -CHTN3OCH3 or -CH2CF3.

In some embodiments of a compound of formula (II), n is 0, 1, 2, or 3. In some embodiments of a compound of formula (II), n is 0, 1, or 2. In some embodiments of a compound of formula (II), n is 1 or 2. In some embodiments of the compound of formula (II), n is 0 or 1. In some embodiments of the compound of formula (II), n is 0.

According to another aspect, the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

- 25 046394

CF ₃

Formula (III) wherein X ¹ and X ² are each independently N, NR ^X , C(=O) or CR ^X ;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -S(=O)R ³ , - S(=O^R 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 C^C^alogenalkyl, 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 ¹ represents substituted or unsubstituted C^^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted Cr^heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl;

each R ² is independently -N3, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted C1 -C6alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C1-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 displaced aryl or substituted or unsubstituted heteroaryl;

each R ³ independently represents hydrogen, substituted or unsubstituted C1- _C6 alkyl, substituted or unsubstituted _C1 - _C6 haloalkyl, substituted or unsubstituted C1- _C6 heteroalkyl, substituted or unsubstituted _C3 - _C10 cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ⁴ represents substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or -NH2;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

In some embodiments of the compound of formula (III), X ¹ and X ² are each CR ^X . In some embodiments of the compound of Formula (III), X ¹ is N and X ² is CR ^X. In some embodiments of a compound of formula (III), X ¹ is CR ^X and X ² is N. In some embodiments of a compound of formula (III), X ¹ and X ² are each N.

In some embodiments of the compound of formula (III), X ³ and X ⁴ are each CR ^X . In some embodiments of the compound of formula (III), X ³ is N and X ⁴ is CR ^X . In some embodiments of a compound of formula (III), X ³ is CR ^X and X ⁴ is N. In some embodiments of a compound of formula (III), X ³ and X ⁴ are each N. In some embodiments of a compound of formula (III) X ³ represents NR ^X and X ⁴ represents C(=O).

In some embodiments of the compound of formula (III), each R ^X is independently hydrogen, halogen, -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 C1C ₆ haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ C ₄ alkynyl or substituted or unsubstituted C 1 -C ₆ heteroalkyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1- _C6 alkyl, substituted or unsubstituted _C1C6 haloalkyl, substituted or unsubstituted C1- _C6 heteroalkyl, substituted or unsubstituted _C3C10 cycloalkyl _, or substituted or unsubstituted _C2 -C ₁₀ heterocycloalkyl. In some embodiments of the compound of formula (III), each R ^X is independently hydrogen, halogen, -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 haloalkyl or substituted or unsubstituted C2-C4 alkynyl; and each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, or substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments of the compound of formula (III), each R ^X is independently hydrogen, F, Cl, Br, I, -CH3, -CH2CH3. -CH2OH, -CH2CH2OH, CH2CN, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2C(=O)NH2, -CH2C(=O)NHCH3, CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CHN(CH3)2, -CHF, -CHF2, -CF3, -CH=CH2, -C CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, -CN, -OH, - OCH3, -OCH2CH3, -OCH2CH3OH, OCH2CN, -OCF3, -CO2H, -CO2CH3, -CO2CH2CH3, -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 of the compound of formula (III), each R ^X is independently hydrogen, Cl, -CH3, -CH2CH3, -OH, or -OCH3. In some embodiments of the compound of formula (III), each R ^X is independently hydrogen, halogen, -OCH3, _-OCH2CH3 , _{cyclopropyloxy} , or _-OCF3 . In some embodiments of the compound of Formula (III), each R ^X is independently hydrogen or halogen. In some embodiments of the compound of Formula (III), each R ^X is independently hydrogen, F, or Cl. In some embodiments of the compound of Formula (III), each R ^X is hydrogen.

According to some embodiments of a compound of formula (III), X ³ and X ⁴ are each independently NR ^X or CR ^X , where the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring. According to some embodiments of a compound of formula (III), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

- 27 046394

each R ^z independently represents hydrogen, halogen, -CN, -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 _C1C6 haloalkyl, substituted or unsubstituted _C1 - _C6 heteroalkyl, substituted or unsubstituted _{C3 C10} cycloalkyl, substituted or unsubstituted _C2 - _C10 heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted displaced aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

According to some embodiments of a compound of formula (III), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

- 28 046394

each R ^Z is independently hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C1C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ ^cycloalkyl, substituted or unsubstituted ^-^heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted ^-^haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

According to some embodiments of a compound of formula (III), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

each R ^Z is independently hydrogen, F, Cl, -CN or -NH2.

According to some embodiments of a compound of formula (III), when two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

In some embodiments of the compound of formula (III), R ¹ is substituted or unsubstituted ^-^ alkyl. In some embodiments of the compound of formula (III), R ¹ is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH _; )2, -CH2CH2CH2CH3, CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ )(CH ₂ CH ₃ ), -C(CH ₃ ) ₃ , -CH2CH2OH, -CH ₂ CH ₂ OCH ₃ or -CH2CF3.

In some embodiments of a compound of formula (III), n is 0, 1, 2, or 3. In some embodiments of a compound of formula (III), n is 0, 1, or 2. In some embodiments of a compound of formula (III), n is 1 or 2. In some embodiments of the compound of formula (III), n is 0 or 1. In some embodiments of the compound of formula (III), n is 0.

According to another aspect, the present invention relates to a compound of formula (IV) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

- 29 046394

Formula (IV) wherein X ¹ , X ² , X ⁵ and X ⁶ are each independently N, NRX, C(=O) or CRX;

each X ³ and X ⁴ independently represents N, NRX, C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two RX are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each RX independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -S(=O)R ³ , -S (=OhR 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 -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, substituted or unsubstituted ^-^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;

each R ² is independently -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , -N ₃ , F, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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;

each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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 ⁵ represents F, -SF5, substituted ^-^alkyl, substituted or unsubstituted C1^haloalkyl, substituted ^-^alkyloxy or substituted ^-^alkylthio;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

In some embodiments, the compound of formula (IV) is not 4(4-(trifluoromethyl)phenyl)quinazoline-7-carboxylic acid.

According to another aspect, the present invention relates to a compound of formula (V) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

O x ³ ηρ <en

X ² -^X (R ² ) -Η Z ) η \1

^R5 ,

Formula (V) wherein X ¹ , X ² , X ⁵ and X ⁶ are each independently N, NRX, C(=O) or CRX;

each X ³ and X ⁴ independently represents N, NR ^X , C(=O) or CRX; or if the two X ³ and X ⁴ are each independently NRX or CRX, then the two R ^X are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring;

each R ^X independently represents hydrogen, halogen, nitro, oxo, thioxo, imino, oximo, -OR ³ , -SR ³ , -CN, -C(=O)R ² , -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 haloalkyl, substituted

- 30 046394 substituted or unsubstituted C2-C ₄ alkenyl, substituted or unsubstituted C2-C ₄ alkynyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C2-C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

ring Z is a substituted monocyclic 5-membered heterocyclic ring containing at least one N, O or S atom, or a substituted monocyclic 6-membered heterocyclic ring containing at least one N atom;

each R2 independently represents -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , -N ₃ , substituted or unsubstituted C -^alkyl, substituted or unsubstituted C-^haloalkyl, substituted or unsubstituted C-^heteroalkyl, substituted or unsubstituted C^C^cyclolkyl, substituted or unsubstituted pure heteroaryl ;

each R ³ independently represents hydrogen, substituted or unsubstituted C-^alkyl, substituted or unsubstituted C-^haloalkyl, substituted or unsubstituted C-^heteroalkyl, substituted or unsubstituted C^C^cyclolkyl, substituted or unsubstituted C2C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R ⁵ represents F, -SF5, substituted C-^alkyl, substituted or unsubstituted C1^haloalkyl, substituted C-^alkyloxy or substituted C-^alkylthio;

each - independently represents a single or double bond; and n is 0, 1, 2, 3 or 4.

In some embodiments of a compound of formula (V), when X ¹ , X ³ , X ⁵ and X ⁶ are CH; and X ² and X ⁴ are N, then ring Z is not a pyrazole.

In some embodiments of a compound of formula (V)

R ⁵ is a substituted monocyclic 5-membered heterocyclic ring containing at least one N, O or S atom. In some embodiments, the compound of formula (V) is a substituted monocyclic 5-membered heterocyclic ring containing 1-4 N atoms, 0-2 O atoms and 0-2 S atoms. In some embodiments of the compound of formula (V) (R ² ), p

R ⁵ is substituted pyrrolidinyl, substituted imidazolidinyl, substituted pyrazolidinyl, substituted oxazolidinyl, substituted oxazolidinyl, substituted thiazolidinyl, or substituted isothiazolidinyl. In some embodiments, the compounds of formula (V) (R ² );

R ⁵ is substituted furanyl, substituted pyrrolyl, substituted thiophenyl, substituted imidazolyl, substituted pyrazolyl, substituted oxazolyl, substituted isoxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted triazolyl, substituted tetrazolyl, substituted oxadiazolyl, substituted thiadiazolyl or substituted dithiazolyl. In some embodiments, a compound of formula (V) (R ² ), p

R ⁵ is substituted furanyl, substituted thiophenyl, substituted imidazolyl, substituted oxazolyl, substituted isoxazolyl, substituted thiazolyl, substituted isothiazolyl, substituted oxadiazolyl, substituted thiadiazolyl or substituted dithiazolyl. In some embodiments of a compound of formula (V)

is a substituted thiophenyl, substituted thiazolyl or substituted thiadiazolyl. In some embodiments of a compound of formula (V)

is a substituted monocyclic 6-membered heteroaryl ring containing at least one N atom. In some embodiments of a compound of formula (V),

is a substituted monocyclic 6-membered heteroaryl ring containing 1, 2 or 3 N atoms. In some embodiments of a compound of formula (V)

is substituted pyridinyl, substituted pyrazinyl, substituted pyrimidinyl, substituted pyridazinyl or substituted triazinyl. In some embodiments, a compound of formula (V) is

In some embodiments of a compound of formula (V)

- 32 046394 represents

In some embodiments, a compound of formula (V) has a structure of formula (Va) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

ABOUT

Formula (Va) where A is -S-, -CH=N- or -N=CH-.

In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ¹ and X ² are each CR ^X . In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ¹ is N and X ² is CR ^X . In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ¹ is CR ^X and X ² is N. In some embodiments of a compound of formula (IV), formula (V), or formula (Va ) X ¹ is CR ^X and X ² is N. In some embodiments of a compound of Formula (IV), Formula (V), or Formula (Va), X ¹ and X ² are each N.

In some embodiments of a compound of Formula (IV), Formula (V), or Formula (Va), X ⁵ and X ⁶ are each CRX. In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ⁵ is N and X ⁶ is CR ^X . In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ⁵ is CR ^X and X ⁶ is N. In some embodiments of a compound of formula (IV), formula (V), or formula (Va ) each X ⁵ and X ⁶ represents N.

In some embodiments of a compound of Formula (IV), Formula (V), or Formula (Va), X ³ and X ⁴ are each CRX. In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ³ is N and X ⁴ is CR ^X . In some embodiments of a compound of formula (IV), formula (V), or formula (Va), X ³ is CR ^X and X ⁴ is N. In some embodiments of a compound of formula (IV), formula (V), or formula (Va ) X ³ represents NR ^X and X ⁴ represents C(=O).

In some embodiments, a compound of formula (IV) has a structure of formula (IVa):

Formula (IVa).

In some embodiments, a compound of formula (IV) has the structure of formula (IVb):

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Formula (IVb).

In some embodiments, a compound of formula (Va) has a structure of formula (Vb), or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof:

Formula (Vb).

In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ^X is independently hydrogen, halogen, -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 haloalkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl or substituted or unsubstituted C1-C6 heteroalkyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, 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. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ^X is independently hydrogen, halogen, -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-C6alkyl, substituted or unsubstituted C1-C6haloalkyl or substituted or unsubstituted C2-C4alkynyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, or substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments of a compound of formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb), each R ^X independently represents hydrogen, Cl, or -OH. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ^X is independently hydrogen, Cl, -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ^X is independently hydrogen, -OCH3, -OCH2CH3, -OCH2CH2CH3 or -OCH(CH ₃ ) ₂ , -OCF ₃ , -OCH2CF3 , cyclopropyloxy or cyclobutyloxy. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each RX is independently hydrogen, -OCH ₃ , -OCH2CH3, -OCF ₃ or cyclopropyloxy. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each RX is independently hydrogen or halogen. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ^X is independently hydrogen, F, or Cl. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ^X is hydrogen.

In some embodiments, compounds of formula (IV) or formula (V) each

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X ³ and X ⁴ are independently NRX or CRX, where the two RX are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring. In some embodiments of a compound of formula (IV) or formula (V), when two RX are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

each R ^z independently represents hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , substituted or unsubstituted C ₁ -C ₆ αlkyl, substituted or unsubstituted C1C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ ^^i^^alkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl , substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C2C ₁₀ heterocycloalkyl.

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In some embodiments of a compound of formula (IV) or formula (V), when two R ^Xs are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

independently represents hydrogen, halogen, -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, each R ^z

-C(=O)OR ³ , substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C1C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ ^cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and each R ³ independently represents hydrogen, substituted or unsubstituted ^-^alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C2^heterocycloalkyl.

In some embodiments of a compound of formula (IV) or formula (V), when two R ^Xs are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

each R ^z independently represents hydrogen, F, Cl, -CN or -NH2.

In some embodiments of a compound of formula (IV) or formula (V), when two R ^Xs are taken together with the intermediate atoms to which they are attached to form a 5-membered heterocyclic ring, the 5-membered heterocyclic ring is selected from:

In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), R ⁵ is -F or -SF5. In some embodiments of a compound of formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb), R ⁵ is -F. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), R ⁵ is -SF5. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), R ⁵ is substituted or unsubstituted C1-C6haloalkyl, substituted ^-^alkyloxy or substituted ^-^alkylthio. In some embodiments of a compound of formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb), R ⁵ is a ^^haloalkyl, substituted C1-C ₆ alkoxy, or substituted ^-^alkylthio. In some embodiments, compounds of formula (IV), formula (IVa), formula (IVb), formula (V), for

- 36 046394 mules (Va) or formula (Vb) R ⁵ is C1-C6alkyloxy or C1-C6alkylthio, each of which is independently substituted with one of several F. In some embodiments, compounds of formula (IV), formula (IVa), formula (IVb), Formula (V), Formula (Va) or Formula (Vb) R ⁵ is -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CF2CH3, -CH2CF3, -OCH2F, -OCHF2, - OCF3, -OCH2CH2F, -OCH2CHF2, -OCF2CH3, -OCH2CF3, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCF ₂ CH ₃ or -SCH ₂ CF ₃ . In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), R ⁵ is -CHF2, -CF3, -OCHF2, -OCF3, -SCHF2 or -SCF3. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), R ⁵ is a C1-C6 haloalkyl. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), R ⁵ is -CF3.

In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ² is independently -CN, -OR ³ , -SR ³ , -S(=O)2R ³ , -N(R ³ )2, -C(=O)OR ³ , -N3, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C-Cheteroalkyl. substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl; and each R ³ independently represents hydrogen, substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C1-C ₆ haloalkyl, substituted or unsubstituted C1-C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, or substituted or unsubstituted C2C1 ₀ heterocycloalkyl.

In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ² is independently -CH3, CH2CH3, -CH2OH, -CH2CH2OH , -CH2CN, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2C(=O)NH2, CH2C(=O)NHCH3, -CH2C(=O)N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2N(CH3 )2, -CH2F, -CHF2, -CF3, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2OH, -OCH2CN, -OCF3, CO2H , -СО2СН3, -СО2СН2СН3, -NH2, -NHCH3, -N(CH3)2 or -S(=O)2CH3. In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ² is independently -CH3, -CH ₂ CH ₃ , - OH or -OCH ₃ . In some embodiments of a compound of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), each R ² is -CH3. In some embodiments of a compound of formula (IV), formula (IVa), or formula (IVb), each R ² is F.

In some embodiments of a compound of formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va), or formula (Vb), n is 0, 1, 2, or 3. In some embodiments of the compound Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) n is 0, 1, or 2. In some embodiments of a compound of Formula (IV), Formula ( IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb) n is 1 or 2. In some embodiments, compounds of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or Formula (Vb), n is 0 or 1. In some embodiments, compounds of Formula (IV), Formula (IVa), Formula (IVb), Formula (V), Formula (Va), or formula (Vb) n represents 0.

According to another aspect, the present invention relates to a compound or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein the compound is a compound from Table. 1 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

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Table 1

Connection no. Structure Name 1 ⁰ 1 LL 1] n 0 F^F M-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 2 o o _h Jk 's'' LL II η ⁰ 0 ^F T ^F ]Ch-(methylsulfonyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 3 0 ^Η ζτχ'° 0 F^F M-methyl-5-(4-(trifluoromethyl)phenyl) naphthalene-2-sulfonamide 4 ο=ζ \At the eyes- M-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide 5 0 ⁿ QJ'° 0 ^F T ^F M-ethyl-5-(4-(trifluoromethyl)phenyl) naphthalene-2-sulfonamide 6 o n Aj'° 0 ^F F ^F M-isopropyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide 7 ⁰ 1 LL IJ h Q ^f O M-isopropyl-4-[4-(trifluoromethyl) phenyl]quinoline-7-carboxamide

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8 Bg O I L II J n 0 ^F F ^F 8-bromo-M-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 9 \7 /=° O \ methyl 1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxylate 10 Cl 0 ^N Tf° ^z 0 ^F F ^F methyl 1-chloro-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate AND ⁰ 1 ί ^!ί#χ γ ^:ί >Τ' ^Ν ' ^Λχ ' ⁿ 0 F^F N-isopropyl-1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxamide 12 NHBoc 0 I |l JL J ^H 0 FT'F tert-butyl(7-(isopropylcarbamoyl)-4(4-(trifluoromethyl)phenyl)naphthalene-1yl)carbamate 13 Cl 0 I L II Ί h 0 F^F 8-chloro-X-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 14 \7 /=°o \ methyl-1-oxo-4-[4- (trifluoromethyl)phenyl]-2H-isoquinoline7-carboxylate

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15 0 0 ό ^р b methyl-2-methyl-1-okco-4-[4- (trifluoromethyl)phenyl]isoquinoline-7carboxylate 16 ΝΗ ₂ 0 1 [Afu τ ⁴ ^1 JJ ^Η 0 ^f f ^F 8-amino-M-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 17 0 0 1 |IJJ ⁿ ό F^F 8-acetamido-U-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 18 S''' 0 I Ι^ιΤ^Γ Ν' ⁴ '' · L II J h 0 F^F M-isopropyl-8-methylsulfanyl-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 19 1 ⁰ 1 L 11 J ^H 0 ^F T ^F ]H-isopropyl-8-methyl-5-[4- (trifluoromethyl)phenyl]naphthalene-2carboxamide 20 1 ⁰ 1 uQ^ ό ^F T ^F 8-ethynyl-1H-isopropyl-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 21 v ⁰ 1 L II J h 0 ^F f ^F 8-ethyl-M-isopropyl-5-[4- (trifluoromethyl)phenyl]naphthalene-2carboxamide

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22 Y ⁰ 1 ί ^ί ιΙ ^Χ %Γ L II \ η 0 FYF 8-cyclopropyl-M-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 23 ο=^ X Ο \ <ο \ / M-isopropyl-8-(methylsulfonamido)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide 24 0 ^Ν<ί4 ψ ^:?χ |ρ' ^ο ' ^χ 0 F'T'F F methyl-4-[4- (trifluoromethyl)phenyl]isoquinoline-7carboxylate 25 ⁰ 1 L I. I| h 0 fYf M-isopropyl-4-[4- (trifluoromethyl)phenyl]isoquinoline-7carboxamide 26 0 0 I NN l M ^H 0 f-Yf M-isopropyl-2-methyl-1-oxo-4-(4(trifluoromethyl)phenyl)-1,2d ihydroisoquinoline-7-carboxamide 27 V° 0 1 0 F'T'F F M-isopropyl-8-methylsulfinyl-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 28 1 O=S=O O I AIZ A L II \ H 0 fYf H-isopropyl-8-methylsulfonyl-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide

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29 kyu v) 2=0 ο- _ζ Τ N-sulf amoyl-5-(4(trifluoromethyl)phenyl)-2-naphthamide thirty Ο j o ΜHrv M-isopropyl-8-(]H-methylacetamido)-5(4-(trifluoromethyl)phenyl)-2-naphthamide 31 NH ₂ 0 1 LI J ^H 0 ^F F ^F 8-amino-7-bromo-M-isopropyl-5-(4(trifluoromethyl)phenyl)-2-naphthamide 32 CD o )=o _ 7-bromo-M-isopropyl-5-[4- (trifluoromethyl)phenyl]naphthalene-2carboxamide 33 o ^04=^ o )=o 8-amino-7-chloro-M-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 34 o=/ to O\<.O\/ N-ii3onponiw-8-(N- methylmethylsulfonamido)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 35 Ν=Ν 0 1 o _x 1 11 1 Г II ^Ν [ II J n 0 ^F T ^F M-isopropyl-5-[4- (trifluoromethyl)phenyl]benzo[e][1.2.3]be nzoxadiazole-8-carboxamide

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36 О ήμ5 О /=° 7-xnop-N-H3onponHn-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 37 ^X o O I L II J h 0 ^F T ^F M-isopropyl-8-methoxy-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 38 -M>d O 2=° ZE^ 7-ethyl-M-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 39 \ ABOUT O 2=0 IZ^ N-isopropyl-7-methoxy-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 40 -H>Q O 2=0 IZ ( o o t °=c N-(2-(2-(2- acetami d oethoxy)ethoxy)ethyl)- 5 -(4(trifluoromethyl)phenyl)-2-naphthamide 41 ⁰ 1 L II J h 0 ^F F ^F ]H-isopropyl-7-methyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 42 ° 1 L II J h 0 F'T'F F ]H-isopropyl-7-(methylthio)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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43 l ° 1 7-cyclopropyl-M-isopropyl-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide Ί03 0 F^F H _H2N ⁰ 1 x^'N'^>X H 7-amino-]H-isopropyl-5-[4- 44 0 F^F (trifluoromethyl)phenyl]naphthalene-2carboxamide O II Q O 1 I ^1H M-isopropyl-7-methylsulfinyl-5-[4- 45 0 ^F T ^F (trifluoromethyl)phenyl]naphthalene-2carboxamide q _w p ⁰ 1 8 0\ x^N^H M-isopropyl-7-methylsulfonyl-5-[4- 46 0 ^F T ^F (trifluoromethyl)phenyl]naphthalene-2carboxamide ⁰ 1 47 XQO x'^'N'' ⁴ '· h 7-ethyl-1H-isopropyl-5-(4- 0 F'T'F F (trifluoromethyl)phenyl)-2-naphthamide H Οχ,Ν,^χ i T T ⁰ 1 ^ϊ =ΐ<'Ν' ^Αχ J ^H J.Q. 7-acetamido-M-isopropyl-5-(4- 0 fXf (trifluoromethyl)phenyl)-2-naphthamide 0 Jh -^0^ ₀ x^N _T 0^ 0 ¹ tert-butyl(2-(2-(2-(5-(4-(trifluoromethyl) 49 ό F'f'F phenyl)-2-naphtamido)ethoxy)ethoxy)ethyl)carbamate

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50 0 A .0. .NH ₂ [ II J n 0 f+f M-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-5(4-(trifluoromethyl)phenyl)-2-naphthamide 51 1 U 1 Υυ^αλ IL IL J ^H 0 ^F T ^F N-isopropyl-?-A ^methyl C ^etami D°) ^_ 5(4-(trifluoromethyl)phenyl)-2-naphthamide 52 . _H 9 1 Ο π % .к .-^ A. A .s' r TAr A ° kJM ^H 0 ^F F ^F ]H-isopropyl-7-(methylsulfonamido)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide 53 I 9 I .s' gAtA '° UU ^H 0 F^F N-isopropyl-?-(N- methylmethylsulfonamido)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 54 О r IT ^N T< _c UU ^H F ^F 0 fAf F M-(2,2,2-trifluoroethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 55 ⁰ Λ r^Ar'Ar ^N L II J h 0 F Af F M-cyclopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 56 o _r ^0H A^on G IT ^N L JIJ ^H 0 F^F N-(1,3-dihydroxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

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57 MM) w )=о о \ U-(2-(2-methoxyethoxy)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 58 0 ^nZX/ ° ^x L II J n ό ^F A ^F U-(2-methoxyethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 59 ⁰ 1 ^^Α4,Λ^νη ₂ g ιι ΜΓ ^Ν L 11 J ^H 0 ^F A ^F (S)-N-( 1 -aminopropan-2-yl)- 5 -(4- (trifluoromethyl)phenyl)-2-naphthamide 60 ο Ξ AA^nh, [ II J n 0 ^F A ^F (R)-N-(1-aminopropan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 61 o < ^0H L II Ί and Q ^F F ^F N-(1-fluoro-3-hydroxypropan-2-yl)-5 (4-(trifluoromethyl)phenyl)-2-naphthamide 62 ⁰ f ^F A A l fYY NL II J h 0 F^F N-(1,3-difluoropropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 63 h ₂ n An o I s. AAA YN UJ ^H 0 A ^F 2-amino-M-isopropyl-5-(4(trifluoromethyl)phenyl)naphtho[1,2- <1]thiazole-8-carboxamide

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64 9 1 1 X ,N. ΓΥΥ Ν L II Ί η 0 ^F A ^F (S)-N-(l -(dimethylamino)propan-2-yl)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide 65 η ^Ξ ι ^Ν - L II _| η Q ^F A ^F (R)-N-(l-(dimethylamino)propan-2-yl)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide 66 ⁰ I GA L II Ί η Q F^F (S)-N-(l -(pyrrolidin-1 -yl)propan-2yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide 67 ° = ΓΑ L II Ί η ό F^F (R)-N-( 1 -(pyrrolidin-1 -yl)propan-2yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide 68 /=Ν 0 ι s _x 1 _ 11 1 Π ^Ν J ^Η 0 ^F f ^F L'G-isopropyl-5-(4(trifluoromethyl)phenyl)naphtho[1,2<1]thiazol-8-carboxamide 69 ⁰ ι A ^ΑΛ'^ L II \ η 0 F^F (8)-M-(1-morpholinopropan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 70 0 3 |^Ο I^IIJ ⁿ 0 fAf (R)-N-(1-morpholinopropan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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71 /=N O I o _x 1 11 1 π ί ίτ ^ν II ^Η 0 X N-isopropyl-5 -(4(trifluoromethyl)phenyl)naphtho[1,2<1]oxazole-8-carboxamide 72 f ° 1 ^f vVV'n^ [1 JJ n 0 5,6-difluoro-M-isopropyl-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide ^F T ^F 73 F θ O O ?si P ΊΊΤ ^Ν Η \ \ Η 0 5,6-difluoro-H-(methylsulfonyl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide ^F T ^F 74 O O I X O O XX 1 II 1 n n 0 ^F T ^F tert-butyl(1-oxo-1-(5-(4(trifluoromethyl)phenyl)naphthalene-2-yl)5,8,11 -1rioxa-2-azatridecan-13yl)carbamate 75 II n ABOUT A tert-butyl(1-oxo-1-(5-(4(trifluoromethyl)phenyl)naphthalene-2-yl)5,8,11,14-tetraoxa-2-azahexadecan-16yl)carbamate 76 Η n UU ⁿ about 0 N-(4-okco-2,8,1 1-trioxa-5azatridecan-13 -yl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide FM'F F 77 fy/l Clz )=° IZ o o' ZI 7 o / T4-(5-oxo-2,9,12-trioxa-6azatetradecan-14-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

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78 o AA/K''/ ϋ JL J ^H 0 ^F f ^F M-(ethylsulfonyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 79 0 °\'° rrV'N'V MJ ^H 1 0 ^F A ^F M-(isopropylsulfonyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 80 ( o K>6 =O )=o 6-ethoxy-A-isopropyl-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 81 ( o ΉΛό =О 2=° ^ΧΖ χ,Ο ωί / θ 6-ethoxy-L-(methylsulfonyl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 82 ο.? ><ζ>°'' _Ζ χ ο=/ ΛΑ (ΜΗ M-(cyclopropylsulfonyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 83 0 °w° UU ^Η F 0 ^F F ^F 5-(4-(trifluoromethyl)phenyl)A((trifluoromethyl)sulfonyl)-2naphthamide 84 ⁰ 1 Λ A .on g ιΐ ^Ν L II \ η 0 ^F A ^F (8)-M-(1-hydroxypropan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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85 0 Ξ Г II ^Ν L II Ί η 0 F^F (R)-N-(1-hydroxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 86 0 A ·χ\Υ>Η G ιΓ ίΓ ^N L II J n 0 ^F T ^F N-(2-hydroxyethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 87 ^f 4 ^f o , ί<Αγ^γΧ _Ν >\ L II Ί and 0 ^F T ^F N-isopropyl-8-(trifluoromethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 88 ^{1 0} 1 1 II J ^H 0 ^F T ^F 8-iodo-X-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 89 ⁰ 1 AA >xr >r ίΓ ^N L II J h 0 fTf F (S)-N-(l -methoxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 90 ⁰ 1 AA_n. Γ Υ VNV > L II J η II] 0 ^F T ^F (S)-N-(l -(pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 91 0 = L 11 J ^H L IJ 0 F^F (C)-X-(1-(pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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92 / IZ ο=ζ oh sky Ν-(1 -(methylamino)propan-2-yl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide 93 o Ξ L II J n Q ^F T ^F (R)-N-(1-methoxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 94 o=< ^z o 5,6-Dichloro-7U-isopropyl-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 95 OH 0 I II JL J ^H 0 ^F f ^F 7-amino-8-hydroxy-]H-isopropyl-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 96 ci 9 °\/° ^C| ^4/^AA Τι ίΓ Ν [1 Ί \ η γΉ 0 f+f 5,6-dichloro-7U-(methylsulfonyl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 97 ο=ζ \-3 ^ζ rchm- —ο 7U-isopropyl-6-methoxy-8-[4(trifluoromethyl)phenyl]quinoline-3 carboxamide 98 τ ο ζι °=/ \-3 ^ζ —ο N-[(1R)-2-hydroxy-1-methylethyl]-6methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide

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99 0 Ξ A Α/ΟΗ il ^Ν LA J ^{Η Ν} 0 ^F A ^F (7?)A-(1-hydroxypropan-2-yl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 100 0 = AAA'” ⁴ '' ⁰ ' ⁴ LA 2 ⁿ Ν 0 ^F F ^F (7?)A-(1-methoxypropan-2-yl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 101 0 Ξ A Ar Y ^N Г 31 kA J ^H kJ N 0 fAf (7?)-A(1-(pyridin-2-yl)ethyl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 102 o IA -A-cl <«γ ^N LA J ^H YN 0 fAf (5)-A(1-methoxypropan-2-yl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 103 ⁰ 1 AA ,n. Af Y ^N V 31 kA J ^H kJ N 0 fAf (5)-A(1-(pyridin-2-yl)ethyl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 104 ψ 0 νΆΑ LA J ^{H N} 0 _F A _f 7U-isopropyl-6-(trifluoromethoxy)-8-[4(trifluoromethyl)phenyl]quinoline-3 carboxamide 105 \ o ΉαΑ A )=° IZ N-[2-hydroxy-1-(2-pyridyl)ethyl]-6methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide

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106 \o =O 2=° IZ d 6-methoxy-L-[(17?)-1 -(2-pyridyl)ethyl] 8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide 107 o— =O 2=0 IZ / 6-methoxy-Λ-[(17?)-2-methoxy-1 methylethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 108 \ O K>6 =O 2=° IZ 6-methoxy-A-[(15)-1-(2-pyridyl)ethyl]8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide 109 O- =Ο 2=0 IZ/ b-methoxy-TV- [(15)-2-methoxy-1 - methylethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 110 o < ^he k YV ^N r L II J η II] 0 ]H-(2-hydroxy-1 -(pyr id in-2-yl)ethyl)-5 (4-(trifluoromethyl)phenyl)-2-naphthamide ^4F 111 f ZI o=^ O SNU Ν-(προπ-2-ΗΗ-1 -yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide ^F F ^F 112 0 κ'Ή L II h 0 F^F Ν-(6γτ-3 -in-1 -yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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FROM ζι ο=ζ O SNM ]Ch-(cyanomethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 114 A Α ^ν QQi n 0 M-(2-cyanoethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 115 That- ABOUT ο=ζ ΛΑ SNM HNi-(disulfandiylbis(ethane-2,1 diyl))bis(5-(4-(trifluoromethyl)phenyl)2-naphthamide) 116 ⁰ 1 \Υ°Λ ^: Λ ^: Υ ^ζ1 ^ ^Ν V || Ί Ί η γ^Ύ 0 f+f 6-cyclopropoxy-7U-isopropyl-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 117 9 1 / Α ,Ν. ,0./ ΛΡΑ t l 0 ^F Y ^F tert-butylmethyl(2-(5-(4(trifluoromethyl)phenyl)-2naphtamido)ethyl)carbamate 118 0 0 ι X Λ J<f /ΥΧ'Ν^^'Ν 0^ ⁿ ι 0 ^F F ^F tert-butylmethyl(3-(5-(4(trifluoromethyl)phenyl)-2naphtamido)propyl)carbamate

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119 ABOUT fYf T4,T4'-(disulfandiylbis(propane-3,1 diyl))bis(5-(4-(trifluoromethyl)phenyl)2-naphthamide) 120 oh oh L II J n 1 II 1 0Q S-(3 -(5 -(4-(trifluoromethyl)phenyl)-2naphtamido)propyl)5-(4-(trifluoromethyl)phenyl)naphthalene-2-carbothiolate 121 ⁰ V7 L II J h |l| 0 ^F T ^F N-(1-phenylcyclopropyl)-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 122 ^=° ωί / Ό b-cyclopropoxy-TU-(methylsulfonyl)8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide 123 0 0,,0 ^F F IL JJ ^H ό ^F F ^F ]Ch-(methylsulfonyl)-6- (trifluoromethoxy)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide 124 ABOUT /=° / ]Ch-(2-(methylamino)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 125 N about i|i G ΥΥ N L II J h 0 F F F M-(2-(M-methylcyanamido)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

According to another aspect, the present invention relates to a compound or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein the compound is a compound from Table. 2 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

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table 2

Compound No. Structure o _Gon 11 hs) to ιΤ ν''Γύ-'L YM ^{n N} \--NH ^{130 O F f F o Gon} _Η N V?NH ¹³¹ X O FJ'F Name JV-[(1S)-1-(azetidin-3-yl)-2-hydroxyethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide A-[(1K)-1-(azetidin-3-yl)-2-hydroxyethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 126 Oh n n' 1 II 1 n n 0 F^F N-(3 -(methylamino)propyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide 127 O UU ^N ill 1 N 0 ^F F ^F M-(3-(M-methylcyanamido)propyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 128 z ZI o=^ about lkH (S)-N-(l -(6-aminopyridin-2-yl)ethyl)-5(4-(trifluoromethyl)phenyl)-2-naphthamide 129 ΉΜ) О 2=0 4 z (R)-N-( 1 -(6-aminopyrid in-2-yl)ethyl)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide

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132 o ( 7 ji \<5>J AA^NyVNH; 1 II J η h 0 fXf 7U-[(3K)-4-(aminomethyl)tetrahydrofuran-3-yl]-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 133 o ^H N 'ΤΤν'Ά Ш HU^ _0H 0 ^F F ^F (R)-A-(l -(1 -(2-hydroxyethyl) azetide in-3 -yl)ethyl)-5 -(4- (trifluoromethyl)phenyl)-2-naphthamide 134 o < ^0H reagent grade. A. LI J h hCn, Boc 0 ^F f ^F tert-butyl-3-[(18)-2-hydroxy-1-[[5[4-(trifluoromethyl)phenyl]naphthalene-2carbonyl] amino]ethyl] azetide in-1 carboxylate 135 ΛΑ_ΛΑ О )=° IZ Γ\ θ z-^ CD O o tert-butyl-3 -[(1 K)-2-hydroxy-1 -[[5 [4-(trifluoromethyl)phenyl]naphthalene-2carbonyl] amino]ethyl] azetide in-1 carboxylate 136 o N/ LJLX ^H Q ^F f ^F N-[(1S)-1-(1-cyclopropylazetidin-Zyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 137 o ^H |*Ш| NffAr—\ Ϊ LI|J h Un^M _f 0 ^F F ^F (7?)-7V-(l-(1 -(2,2-difluoroethyl)azetidine- 3 -yl)ethyl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide 138 0 N/ MMr ⁿ AM\ UM η Un___U _F 0 fTf F N-[(1S)-1-[1 -(2,2-difluoroethyl) azetide in-3 -yl]ethyl]-5 - [4(trifluoromethyl)phenyl]naphthalene-2carboxamide

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139 He, / LJLJ ^Η o F^F N-[(1S)-1-[1 -(2-fluoroethyl)azetidin-3 yl]ethyl]-5 -[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 140 0 N/ L II J h H/Ύ he 0 ^F T ^F N-[(1S)-1-[1 -(2-hydroxyethyl) azetide in-3 -yl]ethyl]-5 - [4(trifluoromethyl)phenyl]naphthalene-2carboxamide 141 0H _? AyA^n'tAnh IL AL. ⁿ but γ ^N ό fTf F (R)-7V-( 1 -(3-hydroxyazetidin-3 yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide 142 0 ^H - ^? АФт^Ау LiAA ⁿ an^ 0 ^F T ^F N-[(1R)-1-(1-isopropylazetidin-3 yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 143 O N/ AAAAr ⁴ n Αυλ LiL^A ^H 0 ^F f ^F 7V-[( 15)-1 -(1-isopropylazetidin-3 yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 144 L^JAAA o /=° F (7?)-7V-(l-(1 -(2-fluoroethyl)azetidin-3yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 145 O * Η AAAAr' ν Axjn η ΙΑ А ⁿ ηο^ Ν ό F^F N-[(lS)-l-(3-hydroxyazetide in-3 yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide

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146 n ⁿ 7 |ldd H VN^xy ⁴ n | 0 ^F T ^F N-[(17?)-1-(1-isopropylazetidin-3 yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 147 o H * [Id d H V-Ν^χ Ίγ~ ^ν T 0 ^F A ^F N-[(1S')-1-(1-isopropylazetidin-3 yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 148 He _? MJ H V-N___<- 0 ^F T ^F N-[(17?)-1 -(1-ethyl azetide in-3-yl)ethyl] 5 - [4-(trifluoromethyl)phenyl]naphthalene2-carboxamide 149 O N/ ΑϊΥτ nYh ι i|d ^H '-n^ 0 ^F A ^F N-[(1S)-1 -(1-ethylazetidin-3-yl)ethyl] 5 - [4-(trifluoromethyl)phenyl]naphthalene2-carboxamide 150 o ^H [Id d H V-Ν^χ ΥΥή 0 ^F F ^F N-[(17?)-1 -(1-ethyl azetide in-3 -yl)ethyl] 8-[4-(trifluoromethyl)phenyl]quinoline3-carboxamide 151 О Н/ [AAr nYh [1 dd HU^/ γΉ 0 ^F f ^F N-[(1S)-1-(1-ethylazetidin-3-yl)ethyl] 8-[4-(trifluoromethyl)phenyl]quinoline3-carboxamide 152 O N/ ΐΥΥτΝ ®Y\ ϋ JL J ^H 0 ^F f ^F N-[(1S)-1-(1-methylazetidin-3 yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

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153 ο ^Η Η JJ ^Η 0 ^F f ^F K-[(1K)-1-(1-methylazetidin-3yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 154 0 Η _? UU ^Η A 0 A (R)-7V-( 1 -(3-hydroxyazetidin-3 yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 155 0 N/ νη TsDL ^{n n} A 0 ^F T ^F (S)-7V-( 1 -(3-hydroxyazetidin-3 yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 156 o ⁿ (ΑΑ ^χΧ4:ϊ Γ' ^Ν 'ίΑγ\ |l JJ n Υν^ 0 ^F A ^F 7V-[(17?)-1 -(1-methylazetidin-3 yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 157 0 N/ [1 JJ Η γΉ 0 ^F f ^F 7V-[( 1S)-1-(1-methylazetidin-3 yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 158 w >€ ο=ζ O OA>A 7U-[(17?)-1-(azetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3carboxamide 159 He/ [1 J J n V-NH 0 A A-[(15)-1-(azetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3 carboxamide

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160 OH ⁰ 1 NH LA / ^H N 0 fYf JV-(1,5-dihydroxypentan-3-yl)-8-(4(trifluoromethyl)phenyl)quinoline-3 carboxamide 161 OH ⁰ 1 L II J h 0 f-Yf 7V-(1,5-dihydroxypentan-3-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 162 o r ^0H CO O ό fYf N-[(l 8)-2-hydroxy-1-(2pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 163 o < ^0H CC· haq 0 fYf N-[(l th)-2-hydroxy-1-(2pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 164 OH CO ^Li h) 0 fYf (5)-7V-(3-hydroxy-1-(pyridin-2yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 165 OH CCA^O 0 ^F F ^F (7?)-7V-(3 -hydroxy-1 -(pyridin-2yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

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166 he ίι ίΓ ^ν g J. J ⁿ ό ^F ^F N-[(1S)-3-hydroxy-1-methylpropyl] 5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide 167 OH O CO^' ^H 0 ^f f ^F N-[(1R)-3-hydroxy-1-methylpropyl]5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide 168 nh ₂ O ^^chL^A-n ίι ^Ν g |l JL J ^H ό Fb (5)-A-(4-aminobutan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 169 nh ₂ 0 QQi n ^l 0 ^F r ^F (7?)-L-(4-aminobutan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 170 0 Ν '^γ· ^Ν F UU ^H W 0 ^F T ^F 7U-((2-(fluoromethyl)pyrimidin-4yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 171 0 ^Ύυ'ν'^Ά ^H N^N T LX) ⁰ ΓΊ °^ ^{N F} ^F 7U-((2-((isoxazol-3-yloxy)methyl)pyrimidin-4-yl)methyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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172 0 ⁿ n¥n A 1 HA Aa T Ϊ J ^F F ^F A((2-((2,6-difluorophenoxy)methyl)pyrimidin-4-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 173 O><U ' ZI g o=/ o CH>A A[(1C)-1-(3N-benzimidazol-4yl)ethyl]-5 - [4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 174 0 < N (GAgAg ^Ν τίΆ M J n II 1 ^Η ~Ν ^=Ν Q f-Af A[(18)-1-(3N-benzimidazol-4yl)ethyl]-5 - [4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 175 0 < Η |Ι J. J ^Η HI 0 F^F 7U-[(75) ^_1_ (benzothiophen-7 ^- yl)ethyl]-5[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 176 'HW o /=° ΙΖ ω E/Ά Ο=\ V.A. 7V-[(77?)-1 -(benzothiophen-7-yl)ethyl]-5 [4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 177 0 o _g Η ^Η 'Ν |1 ϋ JL J ^Η L У ό ^F A ^F N-[(1R)-1-(2-okco-1 H-quinolin-8yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 178 l ^h Zj0 Q3* ^th аЦ1 ό ^F T ^F N-[(1S)-1-(2-okco-1H-xiihc«ihh-8yl)ethyl]-5 - [4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

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179 0 ^Η iAn Ж III Μ] Ν ^F A ^F A-((2-cyanopyrimidin-4-yl)methyl)5-(4-(trifluoromethyl)phenyl)-2naphthamide 180 0 kUAJ ^Η Ν^>Ν ^ci Ο ^F A ^F A-((2-chloropyrimidin-4-yl)methyl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide 181 0 r=\ ιι je A Ρ ΑϊΑ'Υ Ν —0 ν L II J η ό ^F f ^F A-[(E)-5-isoxazol-3-yloxypent-3enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 182 ο '-. ^Η Η \ \ Η II 1 ^Ν=/ Ο ^F A ^F N-[(1R)-1 -(1 H-indazol-7-yl)ethyl]-5 [4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 183 ο * Η |Ι J \ Η II 1 ^Η ~Ν^Ι ^Ν=/ Ο ^F A ^F N-[(1S)-1-(1 H-ind azol-7-yl)ethyl]-5 [4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 184 0 Γ ιι n » Ά AAA N~ _s ^z ΝΗ ₂ 0 CF ₃ 3-((5-(4-(trifluoromethyl)phenyl)-2naphtamido)methyl)-1,2,4-thiadiazol-5carboxamide 185 0 ^ν ΑΑ1 ^Η ν^ν 0 ^F A ^F H-(pyrimidin-4-ylmethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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186 0 UJJJ ^H kJ U ¹¹ kJ ^{N F} T ^F ]Ch-((2-cyanopyridin-4-yl)methyl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide 187 0 UU ^H U ΓΊ] i I IJ f-Nf M-((6-((2,6-difluorophenoxy)methyl)pyridin-2-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 188 ⁰ ? L II J h 0 F^F N-[3-hydroxy-1-(2-pyridyl)propyl] 5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide 189 o ^F YJ π JI N ^/χ ^^Ο ^/ γ UM ^H F ό ^F F ^F 7U-[(E)-5-(2,6-difluorophenoxy)pent-3enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 190 About UU ^H U J\ ^F and F'f'F ]Ch-((6-fluoropyridin-2-yl)methyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 191 0 UU ^H nU JJ II U ^N fTf F ]Ch-((6-cyanopyridin-2-yl)methyl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide 192 0 L II J η [II T T JZ ,o Zll O N F^F N-(3 -((isoxazol-3-yloxy)methyl)benzyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide

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193 OS 0 CF ₃ 0 j N~ _s A-((1,2,4-thiadiazol-3-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 194 OS 0 F^F 0 J ^H IL A Ό K/LF TA M-(3-((2,6-difluorophenoxy)methyl)benzyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 195 ss 0 ^F f ^F 0 . H ') ^H #=/ (S)-N-(1-(1-methyl-1H-imide azol-4yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 196 OS 0 ^f C ^f o ⁿ t J ^N N=/ (R)-N-(l-(l-methyl-1H-imidazol-4yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 197 OS 0 ^F T ^F -HE 1 ϊ jO 1 Η T4-(1-hydroxy-3-(pyridin-2yl)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 198 OS 0 ^f O 0 11 ___^J ^E >^ ο Η ' / '> Ν~ο A-[(E)-6-isoxazol-3-yloxyhex-4enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 199 OS 0 ^F F ^F O I _? ^% T ^< n'(r7v3 Η ν-Ν^χ 0 (R)-N-( 1 -(1-acetyl azetide in-3 yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide

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200 0 N/ ° Q ^F F ^F (S)-N-(l-(1-acetylase etidin-3yl)ethyl)-5-(4-(trifluoromethyl)phenyl)- 2-naphthamide 201 ⁰ 1 Il 1 T n and LAX Ns' ΝΗ ₂ 0 CF ₃ 3-(1-(5 -(4-(trifluoromethyl)phenyl)-2naphtamido)ethyl)-1,2,4-thiadiazol-5carboxamide 202 0 X ,ΝΗ, ^but about ό F^F A-[(E)-6-amino-6-oxo-hex-4-enyl]-5[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 203 ^He ? ^ILJ ^H L-nh 0 ^F f ^F (R)-N-(l -(azetidin-3-yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 204 0 Hy L{J ^H ^ ^NH 0 ^F F ^F (S)-N-( 1 -(azetidin-3 -yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 205 0 < H |l J A η II 1 0 f+f (S)-N-(l-(2-chlorophenyl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 206 9 ^H .-= N XPrXX [1 JJ η II 1 Q F^F (R)-N-(l -(2-chlorophenyl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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207 0 F AA Fil ίΓ N Π Ί L II J n II J 0 ^F A ^F A-[(E)-6-(2,6-difluorophenoxy)hex-4enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 208 0 QC0^Q Λ °^°- ^F A ^F M-(3-(2-methoxyethoxy)benzyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 209 o 0 ___ A ^lA ΌΗ L II J h 0 ^F A ^F (E)-5-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]pent-2enoic acid 210 0 ^H Xi>N A. o _x О F^F A((2-methoxypyridin-4-yl)methyl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide 211 O UU ^H *U .XF Q F'l'F A((2-fluoropyridin-4-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 212 °\/ L II Λ h 0 f+f 7V-(1-methoxy-2-methylpropan-2-yl)-5 (4-(trifluoromethyl)phenyl)-2-naphthamide 213 0H _? A LS^g-h^mn, r if NiRjY^Y ^z UU ^H and 0 ^F T ^F (R)-N-(l -(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide

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214 OH/ A ,nh ₂ |ΑτΥ NiS/YY ² UU ⁿ and 0 fAf (S)-N-(l-(4-aminopyridin-2-yl)ethyl)5-(4-(trifluoromethyl)phenyl)-2naphthamide 215 0 AAr ^N AA L II J n [II Ж ill kJ ^N FA f M-(3-cyanobenzyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 216 0 ΑΆ^^Ά UU ^H II 1 N 0 fAf A-[(2)-4-cyanobut-3-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 217 AA kJLJ ^H 0 fAf A-[(£)-4-cyanobut-3-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 218 o ^H .-AAg ν AA L II J η II 1 η ₂ ι\γ n 0 fAf (C)-A-[1-(2-amino-3-pyridyl)ethyl]-5[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 219 O N/ AbkAAA L II A and II J h ₂ n^n 0 fAf (S)-N-(1 -(2-aminopyridin-3-yl)ethyl)5-(4-(trifluoromethyl)phenyl)-2naphthamide 220 0 Lx/xL _K , N ίι νΓ NT* \ hjjh ' // ΑγΑΑ ^s ~n 0 CF ₃ A-((1,2,4-thiadiazol-5-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

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221 0 H \ \ h ' // ^S ~N 0 CF ₃ A-((3-methyl-1,2,4-thiadiazol-5yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 222 0 0 L II A h ² ό ^F F ^F N-[(E)-5-amino-5-oxopent-3-enyl]-5 [4-(trifluoromethyl)phenyl]naphthalene-2carboxamide 223 He _? | A. .n. Г IT ^{N ίΒ} Υ if UU ^H M 0 F'T'F F (R)-N-(l -(4-(dimethylamino)pyridin2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 224 o H * I /¾. A Г IT ΊΓ N (Spy^ X UU ^H and 0 ^F f ^F (8)-M-(1-(4-(dimethylamino)pyridin2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 225 ⁰ 1 /XA xL^?x.^Br r IT ΊΓ ^N riT UU ^H and 0 ^F T ^F M-(1-(4-bromopyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 226 o A /X r it GG N UU ^H ° 0 f4f A-[(E)-5-methylsulfonylpent-4enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide 227 o 0 ^F F ^F N-[(E)-5-cyanopent-4-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide

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228 N 0 Ψ Οσ n 0 F^F 7U-[(2)-5-cyanopent-4-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 229 0 UU ^Η Μ 0 F Yf F ]Ch-(pyridin-4-ylmethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 230 0 0 ΥΤΥΥ^Ν^— L II J η 0 F'Y methyl (E)- 5 - [ [ 5 - [4- (trifluoromethyl)phenyl]naphthalene-2carbonyl]amino]pent-2-enoate 231 0 HE 0 F F F N-(5-cyano-5-hydroxypentyl)-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 232 0 . H/0. _AK , XN. ^x YN fsJY [1 Ί \ η [| Ί fYx Tj ^F F ^F (5)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-A'-(1 -(pyr idin-2yl)ethyl)quinoline-3-carboxamide 233 0H _? A..JK ,oh ' Y^TN (K)^ Η Ί \ h M f+f (7?)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-7U-(1-hydroxypropan-2-yl)-6methoxyquinoline-3-carboxamide 234 0 r ^i! Y<Yr ^Ν ΎίΎ L IL J ⁿ |l J cp ° f-Xf N-(3 -(3-methoxypropanamido)benzyl)5-(4-(trifluoromethyl)phenyl)-2naphthamide

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235 o 1 II J h 111 Jx NH ₂ Q ^F A ^F T\G-(3-aminobenzyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 236 w )=o TZ O tert-butyl(3-((5-(4- (trifluoromethyl)phenyl)-2- naphtamido)methyl)phenyl)carbamate 237 0 L II J η [II Jx HN_.O Q ' ^F T ^F M-(3-acetamidobenzyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 238 0 ΥτΥ ^Λ Ν' ^/χ/Χζ ^0Η L 11 J h ό F^F M-(5-hydroxypentyl)-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 239 0 UU ^H nJ 0 fTf F 1H-(pyridin-2-ylmethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 240 0 1 II Ί η [II ABOUT f+f N-(3-methoxybenzyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 241 0 L II J η [| Ί 0 Af F M-benzyl-5-(4-(trifluoromethyl)phenyl)2-naphthamide

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242 ^He ? UU ⁿ hnA 0 fYf (R)-N-( 1 -(1 H-imide azol-2-yl)ethyl)-5 - (4-(trifluoromethyl)phenyl)-2-naphthamide 243 0 N/ N Ύτ* ^N \ UU ^H HN~Z 0 fUf (S)-N-(1-(1H-imide azol-2-yl)ethyl)-5 - (4-(trifluoromethyl)phenyl)-2-naphthamide 244 ft ^H -/ A Г r rt Nfspr^T] UU ^H U 0 fYf (S)-N-( 1 -(pyr idin-2-yl)ethyl)-5 -(4(trifluoromethyl)phenyl)quinoline-2carboxamide 245 0 yyY _N ^/X/ T _| L II J ⁿ 1 OH 0 fYf M-[(E)-5-hydroxypent-3-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2carboxamide 246 ft H _Z ^i\,N___λ,ΑΑ K IT ^N LL l| h 0 fYf (S)-N-(1-methoxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)quinoline-2carboxamide 247 ft H g JL.X___-OH YYN (RT^ L JL JI ^H ό fUf (7?)-7U-(1-hydroxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)quinoline-2carboxamide 248 ⁰ 1 LJL II ^H 0 fYf LChtzopropyl-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide

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249 OS O f4-F 0 " A γ N 1 n U-(4-chlorobutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 250 OS O ^F F ^{F 0} р>Ψ'νίΓ' 0 Ν-(1 -(pyr id in-2-yl)cyclopropyl)-5 (4-(trifluoromethyl)phenyl)-2-naphthamide 251 OS 0 O ^F 0 N/ γ ν ΑγΤ J n vJ (S)-N-(l-cyclobutylethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 252 OS 0 O ^f o ⁿ V nAh 1 and \A (8)-U-(1-cyclobutylethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 253 OS 0 ^f O O N/ A ^N _ζ Ν-? (S)-N-(1-(1-methyl-1H-imide azol-2yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 254 OS 0 o o ⁿ A ^N _χ Ν-~/ (R)-N-(l-(l-methyl-1 H-imide azol-2yl)ethyl)-5-(4-(τpiφτopmethyl)φenyl)2-naphthamide 255 OS O O O 1 n D2-(4-hydroxybutyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

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256 _ ϊ ,χ- To ιΓ Ν Ν L II J η 0 fAf F Ν-(3-azide oppropyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 257 Ο V7 L/ ^OH g π ίΓ ^ν L II J Η 0 fAf N-( 1 -(hydroxymethyl)cyclopropyl)-5 (4-(trifluoromethyl)phenyl)-2-naphthamide 258 0 Η _{? k} , Λ____ Ν Η ₂ g ιΓ ^Ν (ΆτΓ UU ^Η ο ό ^F T ^F (R)-N-(l -amino-1-oxopropan-2-yl)-5 (4-(trifluoromethyl)phenyl)-2-naphthamide 259 0 Н/ „, χΑ, Ν Η ₂ Г II ΊΓ ^ν ΑΓ UU ^Η ο 0 ^F F ^F (S)-N-(1-amino-1-oxopropan-2-yl)-5(4-(trifluoromethyl)phenyl)-2-naphthamide 260 o < ^he mA 0 fAf A-[2-hydroxy-1-(2-pyridyl)ethyl]-8[4-(trifluoromethyl)phenyl]quinoline-3carboxamide 261 0 g 7Γ Ar ^Ν Ά. 1 II 1 η ν 0 ^F F ^F A-(2-azidoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 262 °\/ L II Ί η || Ί 0 fAf A-(2-(pyridin-2-yl)propan-2-yl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide

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263 ⁰ \/ χΑχΟΗ L II J h 0 fXf N-(1-hydroxy-2-methylpropan-2-yl)5-(4-(trifluoromethyl)phenyl)-2naphthamide 264 ⁰ 1 L II A h 0 f+f 7U-(tert-butyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 265 0 Άγ\ ^Α Ν ^ζχ - ^/χ α LI J ^H 0 ^F F ^F N-(3-chloropropyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 266 sO-Q z z // /=o <c/~ (S)-N-( 1 -(pyr idin-2-yl)ethyl)-5 -(4(trifluoromethyl)phenyl)quinoxaline-2carboxamide 267 ο Ξ ^nUI^OH η ίΓ π ^N |l JJ h 0 CF ₃ (7?)-7U-(1-hydroxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)quinoxaline-2carboxamide 268 α ^Ν /Λ 0 CF ₃ 7U-isopropyl-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide 269 O N/ r ^i! Ur ^x% V^ ^N '(sbrA L IL J h Uo 0 f+f (S)-N-( 1 -(oxetan-3 -yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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270 about and _? L II J h Vo 0 ^F A ^F (C)-U-(1-(oxetan-3-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 271 z z \\ // /=° Ξ (D (S)-N-(1-methoxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)quinoxaline-2carboxamide 272 0 ~ U (st Г IT ΊΓ ^N L II J h 0 ^F F ^F 1 rH (8)-1U-(pent-3-in-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 273 0 । U(R). Г II ΊΤ ^N L II J h 0 ^F T ^F ς'Η (R)-N-(neHT-3-HH-2-iin)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 274 O * H L II J ^H 0 ^F A ^F (8)-T4-(but-3-in-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 275 О /=° IZ 3/4 / ¹ (R)-N-(6yT-3-iiH-2-iin)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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276 0 N/ (S)-N-(1-(1H-imide azol-4-yl)ethyl)-5 - (4-(trifluoromethyl)phenyl)-2-naphthamide OS O ^f f ^f J ^H N=sZ 277 OS O ^F T ^F 0 ⁿ T n'W^nh (R)-N-( 1 -(1 H-imide azol-4-yl)ethyl)-5 - (4-(trifluoromethyl)phenyl)-2-naphthamide 278 OS 0 ^F f ^F O . N ⁿ =N (8)-H-(1-(2-methyl-2H-tetrazol-5yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 279 OS 0 ^F F ^F o ⁿ t 1W ^N ' _N - J №n (R)-N-(l -(2-methyl-2H-tetrazol-5- yl)ethyl)-5-(4-(trifluoromethyl)phenyl)- 2-naphthamide 280 OS 0 F't'F O * Η 1 T y A ^N n ') ⁿ NA' (8)-H-(1-(1-methyl-1H-tetrazol-5yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 281 OS 0 ^f C ^f about and _? 1 tA% n~ _n (R)-N-(l -(1 -methyl-1H-tetra azol-5 yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 282 OS 0 ^F F ^F ABOUT . N D ^N nA (8)-18G-(1-(pyrazin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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283 ο ^Η UU ^Η 0 fTf (K)-H-(1-(pyrazin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 284 O N/ Ofj ηΟ* ^{Ν 'ν- η ν} ~ν ό ^F T ^F (8)-H-(1-(2H-tetrazol-5-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 285 Η ^g - ^Η ν= _ν ' 0 ^F T ^F (R)-N-( 1 -(2H-tetrazol-5 -yl)ethyl)-5 - (4-(trifluoromethyl)phenyl)-2-naphthamide 286 He? I Hch /X Α .N. r ιΐ ^Ν < ^R >r ιΓ L II \ η [^Η 0 fA _F ^)-H-(1-(6-(dimethylamino)pyridin2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 287 ο Η f 1 Α Α,Ν. _N. Γ Υ V ^ν < ^s >V II L II λ η [1] ό ^F ? _F (8)-H-(1-(6-(dimethylamino)pyridin2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 288 ⁰ ΰ 0 ^F T ^F N-(3-phenyloxetan-3-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide 289 HE/ L II L n V 0 f+f (8)-H-(1-cyclopropylethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide

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290 o ⁿ .-- IYLJ ^H v 0 ^F A ^F (R)-N-(l -cyclopropylethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide 291 o G ^he MeO. A„, AN. h Ύ N g, <1 IIJJ ^H C 0 CF ₃ A-(2-hydroxy-1 -(pyridin-2-yl)ethyl)7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthamide 292 ⁰ I MeO. A„/L.N. ΪΙ ^N η Ί MJ ^H 0 CF ₃ (N) ^- 7-MeT0KCH-N-( 1 -(pyridin-2yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 293 e ο=ζ oh oh ω (7?)-7-methoxy-T4-(1-(pyridin-2yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide 294 ⁰ 1 MeO. // //. Α.Λ,ΟΜβ U JL J ⁿ 0 CF ₃ (5)-7-methoxyA-(1-methoxypropan-2yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide 295 <: f o /=° IZ ?..... o f (/?)-7-methoxy-M-P-methoxypropan-2yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide 296 ⁰ I MeSK // A,, Αχ.ΟΗ Τι ΊΓ ^ν U JL J ⁿ 0 CF ₃ (S)-N-(1-hydroxypropan-2-yl)-7methoxy-5-(4-(trifluoromethyl)phenyl)2-naphthamide

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297 MeCL J v) 2=0 IZ )..... ^OH (R)-N-(l-hydrox ipropan-2-yl)-7methoxy-5-(4-(trifluoromethyl)phenyl)2-naphthamide 0 flj HN^ A ^, -isopropyl-6-(4-(trifluoromethyl) 298 0 CF ₃ phenyl)-[1.2.4]triazolo[5,1- a] isoquinoline-9-carboxamide 0 13 HN^ Co A ^, -Isopropyl-6-(4-(trifluoromethyl) 299 0 CF ₃ phenyl)imidazo[2,1-a]isoquinoline-9carboxamide 0 N=\ J.M. HN'''”' ⁴ .^X/N^ ( J J A ^, -isopropyl-5-(4-(methyl trifluoro) 300 0 CF ₃ phenyl)-[1.2.4]triazole o[1,5-a]quinoline8-carboxamide °U nn _l JI 'n HN | \ Ij A ^, -methyl-6-(4-(trifluoromethyl)phenyl) 301 0 CF ₃ tetrazolo[5,1-a]isoquinoline-9sulfonamide 0 r=-^\ HN^ i J J A ^, -isopropyl-5-(4-(methyl trifluoro) 302 0 CF ₃ phenyl)imidazo[1,2-a]quinoline-8carboxamide Ύ HN Η \ 4 N-N N A ^, -methyl-6-(4-(trifluoromethyl)phenyl)- 303 0 CF ₃ [1,2.4]triazolo[3,4-a]isoquinoline-9sulfonamide

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304 1 ⁰ A'N'gf n H ν~ν ^Α > Ν 0 CF ₃ Aisopropyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4a]isoquinoline-9-carboxamide ¹⁰ ν-ν JI 'ν Ύ) Η Aisopropyl-6-(4-(trifluoromethyl) 305 0 CF ₃ phenyl)tetrazolo[5,1-a]isoquinoline-9carboxamide ¹⁰ 1 'Ά^Α η 1 Χ^χΝχ^ ⁰ JJ TV-isopropyl-1-methyl-2-oxo-4-(4- 306 0 CF ₃ (trifluoromethyl)phenyl)-1,2- d ihydroquinoline-7-carboxamide 1° /A Μ > Ν ⁿ L /χ _ζ Ν ₄ λ ^ιν And isopropyl-5-(4-(methyl trifluoro) 307 0 CF ₃ phenyl)-[1.2.4]triazolo[4,3-a]quinoline8-carboxamide 1 ⁰ AA ⁿ L ν=ν Aisopropyl-5-(4-(trifluoromethyl) 308 0 CF ₃ phenyl)tetrazolo[1,5-a]quinoline-8carboxamide nA ΗΝ Π\11^ α ^ν > Amethyl-5-(4-(trifluoromethyl)phenyl)- 309 0 CF ₃ [1.2.4]triazolo[4,3-a]quinoline-8sulfonamide nA ΗΝ ]| \Α* ν=ν Amethyl-5-(4-(trifluoromethyl) 310 0 CF ₃ phenyl)tetrazolo[1,5-a]quinoline-8sulfonamide

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311 o p AA/' _ν ^s a h ii ^H ° 0 CF ₃ (£)-U-(4-(methylsulfonyl)but-3-en-1 yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide 312 О JI,p AAA MM ^H ° 0 CF ₃ (£)-U-(3-(methylsulfonyl)allyl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide 313 ^0H ? MM ^{H 1} ό O ^f 7V-[(17?)-3 -(dimethylamino)-1 methylpropyl]-5-[4-(trifluoromethyl) phenyl]naphthalene-2-carboxamide 314 o N/ [1 JJ η t_N___xx -pY ^F 0 O ^f N-[(1S)-1-[1-(2-fluoroethyl)azetidin-3 yl]ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide 315 0 N/ AAynAh Η \ \ h U ₄ Ax VV -/-oh 0 ^F f ^F N-[(1S)-1-[1 -(2-hydroxyethyl) azetidin-3-yl]ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3 carboxamide 316 o ^H ΑΑτ' NN ^~—· [I 1 1 η h —pN·^ 0 f-Af 7V-[( 17?)-3 -(ethylamino)-1 methylpropyl]-8-[4-(trifluoromethyl) phenyl]quinoline-3-carboxamide 317 ^9H ? [ί'Ά''Ά'''ΆΆγ\ l [1 JJH Vn _v _>x _c -ρ·Ν ^F 0 f-Af (7?)-7V-(l-(1 -(2,2-difluoroethyl)azetidin3-yl)ethyl)-8-(4-(trifluoromethyl) phenyl)quinoline-3-carboxamide

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318 ^{o n} ΐ/Αζ-γΥ'Ν'Υγ'Λ VV ¹ 0 ^F F ^F (7?)-7V-(l-(1 -(2-fluoroethyl)azetidin-3yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide 319 0 ^H ιί'ΆΑ'^τ' ^{4 N} n ' |l JJ h | γΆ 0 fAf 7V-[( 17?)-3 -(dimethylamino)-1 methylpropyl]-8-[4-(trifluoromethyl) phenyl]quinoline-3-carboxamide 320 o =( SNI (R)-7V-(1 -(1-cyclopropyl azetide in-3 yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide

According to another aspect, the present invention relates to a compound or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, wherein the compound is a compound from Table. 3 or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

Table 3

Connection no. Structure Name 321 \ -p O =O /=° about t 8-(2-fluoro-4-(trifluoromethyl)phenyl)-6methoxyquinoline-3-carboxylic acid 322 0 0 fAf 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid

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323 ABOUT 2=ο o I 6-cyclopropoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid 324 A o =Q 2=° O I 6-(trifluoromethoxy)-8-[4(trifluoromethyl)phenyl]quinoline-3 carboxylic acid 325 G o ο=ζ oh oh \ 6-methoxy-8-(4-(trifluoromethyl) phenyl)quinoline-3-carboxylic acid fTf F 326 Cl 0 ^ci yW° ^h 0 ^F T ^F 5,6-dichloro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid 327 ABOUT ^θΥΎΎ^θπ ό 6-ethoxy-8-(4-(trifluoromethyl) phenyl)quinoline-3-carboxylic acid fJ 328 F O ^F 3iTJr ^<0H 0 5,6-difluoro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid ^F F ^F 329 0 0 5 - [4-(pentafluorosulph anil)phenyl] naphthalene-2-carboxylic acid SF ₅

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330 o 0 ^F T ^F 5 - [4-(trifluoromethyl)phenyl]naphthalene2-carboxylic acid 331 0 [GAAg' ⁰¹⁴ Gn uA ^F T ^F 5 -(b-(trifluoromethyl)pyr idin-3-yl)-2naphthoic acid 332 0 GL) ^he \ ^s A ^F FF 5-[5-(trifluoromethyl)-2-thienyl]naphthalene-2-carboxylic acid 333 0 0 ^F f ^F 5-(4-(trifluoromethyl)phenyl)quinoline-2carboxylic acid 334 τ O O=/ About Z Z 5-(4-(trifluoromethyl)phenyl) quinoxaline-2-carboxylic acid 335 he o r^on 0 ^F f ^F 1-Hydroxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid 336 -HW about /=o o I 4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylic acid

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337 -P 2=°o 2-methyl-1-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-7carboxylic acid 338 \7 2=0 O 1 -(4-(trifluoromethyl)phenyl) isoquinoline-6-carboxylic acid 339 0 (ΎΧΛ ^0Η 0 FfF 8-(4-(trifluoromethyl)phenyl)quinoline-3carboxylic acid

Receiving connections.

The compounds used in the reactions described in the present invention were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or from compounds described in the chemical literature. Commercially available chemicals were obtained from standard commercial sources, including

Acros Organics (Pittsburgh, RA), 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, U.K.), 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, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co.

Ltd. (Cornwall, U.K.), 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).

Methods known to one skilled in the art have been identified from various reference publications and databases. Suitable reference works and treatises that detail the synthesis of reagents useful in the preparation of the compounds described herein, or that provide references to articles that describe the preparation, include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York; S. R. Sandier 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 reference works and treatises detailing the synthesis of reagents useful in the preparation of the compounds described herein include: or which provide references to articles that describe the preparation 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, R. V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. Comprehensive Organic Transformations: A Guide to Functional Group Preparations ^2nd Edition (1999) WileyVCH, 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, J.C., Intermediate Organic Chemistry ^2nd Edition (1993)

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Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, in over 55 volumes; and Chemistry of Functional Groups John Wiley & Sons, in 73 volumes.

In some cases, specific and similar reagents are identified through the American Chemical Society's Chemical Abstracts Service indexes of known chemicals, which are available in most public and university libraries and online databases (for more detailed information contact the American Chemical Society, Washington , D.C). Chemicals that are known but not commercially available in catalogs were obtained from standard chemical suppliers, with many of the standard chemical suppliers (such as those listed above) providing custom synthesis services. A reference to the preparation and selection of pharmaceutical salts of the compounds described in the present invention is P. H. Stahl & C. G. Wermuth Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002.

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

Additional forms of the compounds disclosed herein.

Isomers.

Moreover, 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, cross-linked (E) and cross-linked (Z) isomers, as well as their respective mixtures. In some situations, compounds exist as tautomers. The compounds described in the present invention include all possible tautomers within the formulas described in the present invention. In some situations, the compounds described in the present invention have one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, as well as appropriate mixtures thereof. In additional embodiments of the compounds and methods of the present invention, mixtures of enantiomers and/or diastereoisomers obtained from a single preparative step, combination or interconversion are useful for the applications described in the present invention. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and reducing the optically pure enantiomers. In some embodiments, those disclosed herein are disintegrating complexes (eg, crystalline diastereomeric salts). In some embodiments, diastereomers have different physical properties (eg, melting points, boiling points, solubility values, reactivity, etc.) and are separated using such differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, separation/resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then reduced simultaneously with the cleavage agent by any practical means that do not result in racemization.

Labeled compounds.

In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotope-labeled compounds. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such isotope-labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except that one or more atoms are replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number , commonly found in nature. In some embodiments, examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ^2H , ^3H , ^13C , ^14C , ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. The compounds described herein and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives that contain the above isotopes and/or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, such as those containing radioactive isotopes such as ^3H and ^14C ,

- 88 046394 are applicable in tissue distribution assays of a drug and/or substrate. Tritium, i.e., ^3H and carbon-14, i.e., ^14C , isotopes are particularly preferred for ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium, e.g. ^2H , provides certain therapeutic benefits derived from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof are prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts.

In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

In some embodiments, the compounds described herein contain acidic or basic groups and thus react with any number of inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds of the present invention, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

Solvates.

In some embodiments, the compounds described herein exist as solvates. The present invention relates to methods for treating diseases by administering such solvates. The present invention further relates to methods of treating diseases by administering such solvates in the form of pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is alcohol. In some embodiments, solvates of the compounds described herein are readily prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are readily 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 unsolvated as well as solvated forms. In addition, solvated forms are considered equivalent to non-solvated forms for purposes of the compounds and methods provided herein.

Prodrugs.

In some embodiments, the compounds described herein exist in prodrug form. The present invention provides methods for treating diseases by administering such prodrugs. The present invention further provides methods for treating diseases by administering such prodrugs in the form of pharmaceutical compositions.

In some embodiments, prodrugs include compounds wherein an amino acid residue or polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked via an amide or ester bond to a free amino, hydroxy, or carboxylic acid moiety of the compounds of the present invention. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone . In other embodiments, prodrugs include compounds wherein a nucleic acid residue or oligonucleotide of two or more (eg, two, three, or four) nucleic acid residues is covalently linked to a compound of the present invention.

Pharmaceutically acceptable prodrugs of the compounds described herein also 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.

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In some embodiments, compounds containing free amino, amido, hydroxy, or carboxylic acid groups are converted into prodrugs. For example, free carboxyl groups are derivatized as amides or alkyl esters. In certain cases, all such prodrug moieties include groups, including, without limitation, ester, amine and carboxylic acid functional groups.

Hydroxyprodrugs include esters such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, sulfonate esters, sulfate esters and disulfide esters, esters, amides , carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.

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

as well as sulfonamides and phosphonamides.

In certain cases, sites on any part of the aromatic ring are sensitive to various metabolic reactions, so the inclusion of appropriate substituents in the aromatic ring structures reduces, minimizes or eliminates such a metabolic pathway.

Metabolites.

In some embodiments, the compounds described herein are sensitive to various metabolic reactions. Thus, in some embodiments, the inclusion of appropriate substituents in the structure will reduce, minimize, or eliminate a metabolic pathway. In certain embodiments, a suitable substituent for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions is, by way of example only, a halogen or an alkyl group.

In additional or further embodiments, the compounds described herein are metabolized upon administration into the body to form a metabolite, which is then used to obtain the desired effect, including the desired therapeutic effect.

Pharmaceutical compositions.

In certain embodiments, a compound as described herein is administered as a pure chemical. In other embodiments, a compound as described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) excipient) carrier) selected based on the selected route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, ^21st Ed. Mack Pub. Co., Easton, PA (2005)), disclosure which is hereby incorporated by reference in its entirety.

Accordingly, the present invention provides a pharmaceutical composition containing at least one compound described in the present invention, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate or N-oxide, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) are acceptable or suitable if the carrier is consistent with the other ingredients of the composition and is not harmful to the recipient (ie, the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), formula (Ia), formula (II), formula (III), formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va) or formula (Vb) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

Another embodiment relates to a pharmaceutical composition consisting mainly

- 90 046394 of a pharmaceutically acceptable carrier and a compound of formula (I), formula (Ia), formula (II), formula (III), formula (IV), formula (IVa), formula (IVb), formula (V), formula (Va) or formula (Vb) or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof.

In certain embodiments, a compound as described herein is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% other organic small molecules, such as unreacted intermediates compounds or by-products that were formed, for example, during one or more steps of the synthesis process.

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 appropriate form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions are formulated as a single dose and/or formulated for oral or subcutaneous administration.

In some cases, the exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, solid, semi-solid or liquid form, which includes one or more of the disclosed compounds as an active ingredient in admixture with an organic or inorganic carrier or excipient, suitable for external, enteral or parenteral administration. In some embodiments, the active ingredient is mixed, for example, with conventional non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active end compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect as a result of the course or condition of the disease.

To prepare solid compositions, such as tablets in some cases, the main active ingredient is mixed with a pharmaceutical carrier, for example, traditional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums , and other pharmaceutical diluents, for example, water, to form a solid composition before giving it a dosage form containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt or non-toxic pharmaceutically acceptable solvate thereof. When such compositions are referred to as homogeneous before dosage forming, it is intended that the active agent be uniformly dispersed throughout the composition so that the composition is readily subdivided into equal, effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the claimed composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or dry diluents such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retardants such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions also contain buffering agents in some embodiments. Solid compositions of this type have also been used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars and high molecular weight polyethylene glycols and the like.

In some cases, the tablet is made by compression or molding, optionally with one or more additional ingredients. Compressed tablets are prepared using a binder (eg, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactant or dispersant. Molded tablets were prepared by molding in a suitable apparatus a mixture of the claimed composition moistened with an inert liquid diluent. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, are optionally made with a break line or prepared with coatings and coatings, such as enteric coatings and other coatings well known in the field of pharmaceutical formulations.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceuticals

- 91 046394 commercially acceptable aqueous or organic solvents or mixtures and powders thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the claimed composition, liquid dosage forms optionally contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, cyclodextrins and mixtures thereof.

Suspensions, in addition to the claimed composition, optionally contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and sorbitan, microcrystalline cellulose, aluminum metahydroxide, bentonite, agaragar and tragacanth and mixtures thereof.

In some embodiments, the compositions for rectal or vaginal administration are provided in the form of a suppository that is prepared by mixing the claimed composition with one or more suitable non-irritating excipients or carriers containing, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the body cavity and release the active agent.

Dosage forms for topical or transdermal administration of the claimed composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient is optionally mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that are necessary in some embodiments.

According to some embodiments, ointments, pastes, creams and gels contain, in addition to the claimed composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica acid, talc and zinc oxide or mixtures thereof.

According to some embodiments, the powders and sprays contain, in addition to the claimed composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The compositions and compounds disclosed herein are alternatively administered by aerosol. This was achieved by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (eg, fluorocarbon propellant) suspension may be used. Ultrasonic nebulizers were used because they minimize exposure of the agent to shear, which leads to breakdown of the compounds contained in the claimed compositions in some embodiments. Typically, an aqueous aerosol has been prepared by formulating an aqueous solution or suspension of the claimed composition together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary with the requirements of the particular composition claimed, but typically include nonionic surfactants (Tweens, Pluronics or polyethylene glycol), safe proteins such as serum albumin, sorbitan esters, butyric acid, lecithin, amino acids such as glycine , buffers, salts, sugars or sugar alcohols. Aerosols were usually obtained from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administration contain the claimed composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, which are formulated into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers used in pharmaceutical compositions include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrins. In some embodiments, proper fluidity is maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

Also considered are enteric pharmaceutical formulations, including the disclosed compound and the enteric substance; and a pharmaceutically acceptable carrier or excipient thereof. Enteric solubles refer to polymers that are essentially insoluble in the acidic environment of the stomach and that are predominantly soluble in intestinal juice at specific pH values. The small intestine is the part of the gastrointestinal tract (intestines) between the stomach and large intestine and includes the duodenum, small intestine, and ileum. The pH value of the duodenum is approximately 5.5, the pH value of the small intestine is approximately 6.5, and the pH value of the ileum is approximately 7.5. Accordingly, enteric soluble substances are insoluble, for example, up to a pH value of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, approximately 6.4, approximately 6.6, approximately 6.8, approximately 7.0, approximately 7.2, approximately 7.4, approximately 7.6, approximately 7.8, approximately 8.0, approximately 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. Exemplary enteric solubles include cellulose acetate phthalate (CAP), hydroxypropyl methyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methyl cellulose succinate, cellulose acetyl hexahydrogen succinate, cellulose talate, Cellulose propionate phthalate, cellulose acetyl maleate, cellulose acetobutyrate, cellulose acetopropionate, methyl methacrylic acid-methyl methacrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, methyl vinyl ether-maleic anhydride copolymer (Gantrez ES series), ethyl methacrylate copolymer methyl methacrylate-chlorotrimethylammonium ethyl acrylate, natural resins such as zein , shellac and gum, rosin, and 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 substances is either known or easily determined in vitro. The above is a list of possible substances, but one skilled in the art will recognize by virtue of the disclosure that it is not exhaustive and that there are other enteric substances that meet the purposes of the present invention.

In some embodiments, dosages of a composition comprising at least one compound as described herein differ depending on the patient's (e.g., human) condition, condition, namely, the extent of the disease, general health, age, and other factors, which the medical professional will use to determine the dose.

In some cases, pharmaceutical compositions have been administered in a manner appropriate to the disease being treated (or prevented) as determined by those skilled in the medical field. The appropriate dose and appropriate duration and frequency of administration will be determined based on factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the route of administration. In general, the appropriate dosage and course of treatment will provide the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., improved clinical outcome such as increased complete or partial remissions, or longer disease-free and/or overall survival, or a decrease in the severity of symptoms). Optimal dosages have generally been determined using experimental samples and/or clinical studies. In some embodiments, the optimal dose depends on the patient's body weight, weight, or blood volume.

In some embodiments, oral dosages typically range from about 1.0 mg to about 1000 mg one to four times or more per day.

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 pathway is to negatively regulate the transcriptional coactivators Yes-associated protein (YAP) and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ; also known as WWTR1) (Fig. 1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ, promoting its retention and degradation in the cytoplasm, thereby inhibiting the growth promotion function regulated under the control of YAP/TAZ. In the unphosphorylated/dephosphorylated state, YAP, also known as YAP1 or YAP65, along with TAZ are transported into the nucleus where they interact with the TEAD family of transcription factors to upregulate genes that promote proliferation and migration and inhibit apoptosis. In some cases, unregulated activation of these genes involved in proliferation, migration and anti-apoptosis leads to the development of cancer. In some cases, overexpression of YAP/TAZ is associated with cancer.

Additional core members of the Hippo signaling pathway include the serine/threonine kinases MST1/2 (Drosophila homologs of Hippo/Hpo), Lats1/2 (homologues of Warts/Wts), and their adapter proteins Sav1 (homolog of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; Mats homologues), respectively (Fig. 1). Typically, MST1/2 kinase forms complexes with the scaffold protein Sav1, which, in

- 93 046394, in turn, phosphorylates and activates the Lats1/2 kinase. 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 leads to their nuclear export, retention in the cytoplasm, and degradation by the ubiquitin proteasome system.

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

Additional phosphorylation occurs at amino acid position S381 in YAP. Phosphorylation of YAP at position S381 and the corresponding site in TAZ primes both proteins for further phosphorylation events by CKA/i; at the degradation motif, which then signals interaction with the ubiquitin ligase e-TRCPE3, leading to polyubiquitination and degradation of YAP.

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

In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm and undergoes SCFβ ^-TRCP -mediated ubiquitination and subsequent proteasomal degradation. In some cases, the Skp, Cullin, F-box complex (SCF complex) is a ubiquitin ligase complex with several E3 proteins that includes an F-box family member protein (e.g., Cdc4), Skp1, a bridging protein, and RBX1. which contains a small RING Finger domain that interacts with the ubiquitin-conjugating enzyme E2. In some cases, the F-box family includes more than 40 members, examples of which include F-box/WD repeat-containing protein 1A (FBXW1A, eTrCP1, Fbxw1, hsSlimb, plkappaBalpha-IA receptor subunit) and associated kinase S -phase protein 2 (SKP2). In some embodiments, the SCF complex (eg, SCFe ^TrCP1 ) interacts with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to a YAP/TAZ substrate. 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 UBE2FC.

In some embodiments, the ubiquitinated YAP/TAZ is further subjected to degradation through the 26S proteasome.

In some embodiments, the Hippo pathway is regulated at previous steps by several different families of regulators (FIG. 1). In some cases, the Hippo pathway is regulated by the G protein and its associated receptors, the Crumbs complex, upstream regulators of MST kinases, and the adhesion junction.

Interaction of YAP/TAZ with TEAD.

In some embodiments, unphosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ 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, for example, CTFG, Cyr61 and FGF1.

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

G-protein/GPCR-mediated regulation of YAP/TAZ.

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In some embodiments, the Hippo pathway is regulated by a family of G protein-coupled receptor (GPCR) and G protein proteins (also known as guanine nucleotide binding proteins) (FIG. 2). G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some cases, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some cases, the latter class of complexes consists of alpha (Ga), beta (Ge) and gamma (Gy) subunits. In some cases, there are several classes of Ga subunits: Gq/11a, G ₁₂ / ₁₃ a, Gi/ _o a (inhibitory G, other G) and G _s a (stimulatory G).

In some cases, Gia (inhibitory G), Goa (other G), G _q/11 a and G _12/13 a coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other cases, G _s a (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, resulting in YAP/TAZ degradation.

In some cases conjugated with Gia (inhibitory G), Goa (another G), G _q/11 a and G _12/13 a. GPCRs activate YAP/TAZ by repressing Lats1/2 activity. Conversely, in some embodiments, G _s a induces Lats1/2 activity, thereby promoting YAP/TAZ degradation.

Gq family.

Gqa (also known as G _q/11 protein) is involved in the inositol triphosphate (IP3) signaling pathway and the release of calcium (Ca ²⁺ ) from intracellular storage through activation of phospholipase C (PLC). Activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and IP3. In some cases, IP3 then diffuses through the cytoplasm into the ER or sarcoplasmic reticulum (SR) in the case of muscle cells and then binds to the inositol triphosphate receptor (InsP3R), which is a Ca ²⁺ channel. In some cases, binding triggers the opening of the Ca ²⁺ channel and thereby increases the release of Ca ²⁺ into the cytoplasm.

In some embodiments, GPCRs that interact with G _q a include, but are not limited to, the 5-hydroxytryptamine receptor (5-HT receptor) of the 5-HT ₂ and 5-HT3 types; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and 1B; angiotensin II receptor type 1; calcitonin receptor; histamine H1 receptor; metabotropic glutamate receptor, group I; muscarinic receptors M1, M3 and _M5 and trace amine receptor 1.

In some cases, there are several types of Gqa: Gq, Gq/11, Gq _/14 and Gq _/15 . The Gq protein is encoded by GNAQ. G _q /n is encoded by GNA11. Gq _/14 is encoded by GNA14. Gq/15 is encoded by GNA15.

In some cases, mutations or modifications of Gqa genes have been linked to cancer. Indeed, studies have shown that mutations in Gqa contribute to the tumorigenesis of uveal melanoma (UM). In some cases, approximately 80% of UM cases have been found to contain mutations in GNAQ and/or GNA11.

In some cases, mutations or modifications of Gqa genes have been associated with congenital diseases. In some cases, Gqa mutations have been observed in congenital diseases such as capillary hemangioma and/or Sturge-Weber syndrome. In some cases, approximately 92% of capillary hemangioma cases contain a mutation in GNAQ. In some cases, approximately 88% of Sturge-Weber syndrome contain a mutation in GNAQ.

Family G12/13.

G12/1301 modulates actin cytoskeleton remodeling in cells and regulates cellular processes through guanine nucleotide exchange factors (GEFs). GEFs are involved in the activation of small GTPa3s, which act as molecular switches in multiple intracellular signaling pathways. Examples of small GTPa3s include the Ras-related GTPa3 superfamily (e.g., the Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.

In some embodiments, GPCRs that interact with G12/1301 include, but are not limited to, purinergic receptors (eg, P2Y1, P2Y2, P2Y4, P2Y6); muscarinic acetylcholine receptors M1 and M3; thrombin receptors [protease-activated receptors (PAR)-1, PAR-2]; thromboxane (TXA2); sphingosine-1-phosphate (eg, S1P ₂ , S1P3, S1P4 and S1P5); lysophosphatidic acid (eg LPA, LPA2, LPA3); angiotensin II (AT1); serotonin (5-HT _2c and 5HT ₄ ); somatostatin (sst ₅ ); endothelium (ETA and ETB); cholecystokinin (CCK ₄ ); vasopressin V _1a receptors; dopamine D5 receptors; formyl peptide receptors fMLP; galanin receptors GAL2; prostanoid receptors EP3; adenosine A1 receptors; adrenergic receptors he; bombesin BB2 receptors; bradykinin B ₂ receptors, calcium-sensing receptors; chemokine receptors KSHVORF74; tachykinin NK1 receptors and thyroid stimulating hormone (TSH) receptors.

In some cases, G12/1301 is further subdivided into G12 and G13 types, which are coded GNA12 and GNA13, respectively.

Family Gi _/o .

G _i/o a (inhibitory G, other G) (also known as Gi/G _o or Gi protein) suppresses the production of 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP) by inhibiting adenium

- 95 046394 lath cyclase activity, which converts ATP to cAMP.

In some embodiments, GPCRs that interact with Gia include, but are not limited to, the 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT1 and 5-HT ₅ ; muscarinic acetylcholine receptors such as M2 and _M4 ; adenosine receptors such as A1 and _A3 ; adrenergic receptors such as _a2A , a2B and _a2C ; apelin receptors; calcium sensing receptor; cannabinoid receptors CB1 and CB2; chemokine receptor CXCR4; dopamines D2, D3 and _D4 ; GABAB receptor; glutamate receptors such as 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 such as H3 and _H4 receptors; melatonin 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 δ, κ, μ and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EP1), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP) and thromboxane receptor (TR); somatostatin receptors sst1, sst2, sst3, sst4 and sst5 and trace amine receptor 8.

In some cases, there are several types of Gia: Gia1, G _i a2, G _i a3, G _i a4, Goa, G _t , G _gust and G _z . Gia1 is encoded by GNAI1. Gia2 is encoded by GNAI2. Gia3 is encoded by GNAI3. Goa, a ₀ subunit, is encoded by GNAO1. G _t is encoded by GNAT1 and GNAT2. _Gust is encoded by GNAT3. G _z is encoded by GNAZ.

G _S family.

G _s a (also known as stimulatory Gs, Gs alpha subunit or Gs 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, GPCRs that interact with G _s a include, but are not limited to, the 5-hydroxytryptamine receptor (5-HT receptor) of the 5-HT4, 5-HT6, and 5-HT7 types; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptors types A _2a and A2b; arginine vasopressin receptor 2 (AVPR2); β-adrenergic receptors β1, β2 and β3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin releasing hormone receptor; dopamine receptor-like D1 receptor families such as D1 and _D5 ; follicle-stimulating hormone receptor (FSH receptor); gastric 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 types D ₂ and I ₂ ; secretin receptor; thyrotropin receptor; Trace amine receptor 1 and box jellyfish opsin.

In some cases, there are two types of G _s a: G _s and G _olf . G _s is encoded by GNAS. Go _lf is encoded by GNAL.

Additional regulators of the Hippo signaling network.

In some embodiments, an additional 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 cases, the Crumbs complex includes transmembrane CRB proteins that assemble multiprotein complexes that function according to cell polarity. In some cases, CRB complexes recruit members of the angiomotin (AMOT) family of adapter proteins, which interact with components of the Hippo pathway. In some cases, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.

In some cases, an additional regulator of the Hippo signaling pathway includes regulators of the MST family of kinases. MST kinases control the integrity of the actin cytoskeleton. In some cases, regulators include TAO kinases and cell polarity kinase PAR-1.

In some cases, an additional regulator of the Hippo signaling pathway involves adhesion molecules. In some cases, E-cadherin (E-cad) suppresses the nuclear localization and activity of YAP by regulating MST activity. In some embodiments, the E-cad-associated protein α-catenin regulates YAP by sequestering YAP/14-3-3 complexes in the cytoplasm. In other cases, members of the Ajuba family of proteins interact with Lats1/2 kinase activity, thereby preventing YAP/TAZ inactivation.

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

In some embodiments, the compounds described herein are transcriptional coactivator inhibitors of the transcriptional coactivator PDZ-binding motif α/Yes-associated protein (TAZ/YAP). In some embodiments, compounds described herein increase phosphorylation of a transcriptional coactivator

- 96 046394 with the transcriptional coactivator of the PDZ-binding motif/Yes-associated protein (TAZ/YAP) or reduce the dephosphorylation of the transcriptional coactivator with the transcriptional coactivator of the PDZ-binding motif/Yes-associated protein (TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of the transcriptional coactivator with the transcriptional coactivator PDZ-binding motif/Yes-associated protein (TAZ/YAP) or decrease the deubiquitination of the transcriptional coactivator with the transcriptional coactivator PDZ-binding motif/Yes-associated protein (TAZ/YAP). .

In some embodiments, compounds disclosed herein are inhibitors of one or more proteins included in or associated with the Hippo pathway. In some cases, one or more proteins include the protein shown in FIG. 1 and/or 2. In some embodiments, the Hippo pathway inhibitor is an inhibitor of a G protein and/or its associated GPCR. In some embodiments, the Hippo pathway inhibitor is a G protein inhibitor. In some embodiments, the Hippo pathway inhibitor is an inhibitor of Gqa family proteins such as Gq, Gq _/11 , Gq _/14 , and Gq _/15 ; the G _12/13 a family of proteins, such as G ₁₂ and G ₁₃ ; or the Gia family of proteins such as Gia1, Gia2, Gia3, Gia4, Goa, Gt, Ggust and _Gz . In some embodiments, the Hippo pathway inhibitor is a Gq inhibitor. In some embodiments, the Hippo pathway inhibitor is a G _q/11 inhibitor. In some embodiments, the Hippo pathway inhibitor is a G _q/14 inhibitor. In some embodiments, the Hippo pathway inhibitor is a G _q/15 inhibitor. In some embodiments, the Hippo pathway inhibitor is a G ₁₂ inhibitor. In some embodiments, the Hippo pathway inhibitor is a G ₁₃ inhibitor. In some embodiments, the Hippo pathway inhibitor is a Gia1 inhibitor. In some embodiments, the Hippo pathway inhibitor is a Gia2 inhibitor. In some embodiments, the Hippo pathway inhibitor is a Gia3 inhibitor. In some embodiments, the Hippo pathway inhibitor is a Gia4 inhibitor. In some embodiments, the Hippo pathway inhibitor is a Goa inhibitor. In some embodiments, the Hippo pathway inhibitor is a G _t inhibitor. In some embodiments, the Hippo pathway inhibitor is a Ggust inhibitor. In some embodiments, the Hippo pathway inhibitor is a G _z inhibitor.

In some embodiments, the Hippo pathway inhibitor is a Hippo pathway core protein inhibitor. In some embodiments, the Hippo pathway inhibitor is a Sav1 inhibitor. In some embodiments, the Hippo pathway inhibitor is a Mob inhibitor. In some embodiments, the Hippo pathway inhibitor is a YAP inhibitor. In some embodiments, the Hippo pathway inhibitor is a TAZ inhibitor. In some embodiments, the Hippo pathway inhibitor is a TEAD inhibitor.

In some embodiments, a Hippo pathway inhibitor is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, the Hippo pathway inhibitor is an inhibitor of a proteasomal degradation pathway protein (eg, the 26S proteasome).

In some embodiments, the Hippo pathway inhibitor is a protein inhibitor of the Ras superfamily of proteins. In some embodiments, the Hippo pathway inhibitor is a protein inhibitor of the Rho family of proteins. In some embodiments, the Hippo pathway inhibitor is a Cdc42 inhibitor.

Cdc42 is a member of the Ras superfamily of small GTPases. In particular, Cdc42 belongs to the Rho family of GTPases, members of which are involved in diverse and critical cellular processes such as gene transcription, cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some cases, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, the Cdc42 inhibitor is a compound described herein.

In some embodiments, the Hippo pathway inhibitor is a deubiquitinating enzyme inhibitor. In some embodiments, the Hippo pathway inhibitor is a cysteine protease or metalloproteinase inhibitor. In some embodiments, the Hippo pathway inhibitor is a ubiquitin-specific protease inhibitor. USP47 is a member of the cysteine protease superfamily of ubiquitin-specific proteases (USP/UBP). In some embodiments, compounds disclosed herein are USP47 inhibitors.

Additional embodiments provided herein include combinations of one or more of the specific embodiments set forth above.

Diseases.

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Cancer.

In some embodiments, compounds disclosed herein are useful for treating cancer. In some embodiments, cancer is mediated by transcriptional coactivator activation of the PDZ-binding motif/Yes-associated protein (TAZ/YAP) transcriptional coactivator. In some embodiments, cancer is mediated by modulating the interaction of YAP/TAZ with TEAD. In some embodiments, the cancer is characterized by a mutant Ga protein. In some embodiments, the mutant Ga protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga protein is G12. In some embodiments, the mutant Ga protein is G13. In some embodiments, the mutant Ga protein is Gq. In some embodiments, the mutant Ga protein is G11. In some embodiments, the mutant Ga protein is Gi. In some embodiments, the mutant Ga protein is Go. In some embodiments, the mutant Ga protein is Gs.

In some embodiments, the cancer is a solid tumor. In some cases, the cancer is a hematologic malignancy. In some cases, the solid tumor is a sarcoma or carcinoma. In some cases, the solid tumor is a sarcoma. In some cases, the solid tumor is a carcinoma.

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

Exemplary carcinoma includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor brain, breast cancer, cervical cancer, colon cancer, cancer of unknown primary site (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, cancer oral cavity, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer and vulvar cancer. In some cases, liver cancer is a primary liver cancer.

In some cases, 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, squamous cell carcinoma of the esophagus, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer and meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, stomach cancer, medulloblastoma, ovarian cancer, squamous cell carcinoma of the esophagus, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer or meningioma. In some cases, the cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the cancer is uveal melanoma. In some cases, the cancer is mesothelioma. In some cases, the cancer is esophageal cancer. In some cases, the cancer is liver cancer. In some cases, the cancer is primary liver cancer.

In some cases, the cancer is a hematologic malignancy. In some embodiments, a hematologic malignancy

- 98 046394 is a leukemia, lymphoma, myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, T-cell malignancy or B-cell malignancy. In some cases, the hematologic 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, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma ( ATLL), blast NK cell lymphoma, enteropathic type T cell lymphoma, gamma delta T cell lymphoma of the liver and spleen, lymphoblastic lymphoma, nasal NK/T cell lymphomas and treatment-associated T cell lymphomas.

In some cases, hematologic malignancies are Bcellular malignancies. 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), Waldenström's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, marginal zone cells, Burkitt's lymphoma, poorly differentiated non-Burkitt B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, B-lymphoblastic progenitor cell leukemia, 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.

In some cases, the cancer is recurrent 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, the relapsed or refractory carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, breast cancer, cervical cancer, colon cancer, cancer of unknown primary site (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma , oral cancer, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer and vulvar cancer.

In some cases, 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, squamous cell esophageal carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer and meningioma. In some cases, recurrent 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, squamous cell carcinoma of the esophagus, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer or meningioma. In some cases, the recurrent or refractory cancer is relapsed or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, the recurrent or refractory cancer is relapsed or refractory uveal melanoma. In some cases, the recurrent or refractory cancer is relapsed 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 relapsed or refractory liver cancer. In some cases, the recurrent or refractory cancer is a relapsed or refractory primary liver cancer.

In some cases, the relapsed or refractory cancer is a relapsed or refractory hematologic malignancy. In some embodiments, the relapsed or refractory hematologic malignancy is relapsed or refractory leukemia, relapsed or refractory lymphoma, relapsed or refractory myeloma, relapsed or refractory non-Hodgkin's lymphoma, relapsed or refractory Hodgkin's lymphoma, relapsed

- 99 046394 or refractory T-cell malignancy or relapsed or refractory B-cell malignancy. In some cases, the relapsed or refractory malignancy is a relapsed or refractory T-cell malignancy. In some cases, the relapsed or refractory malignancy is a relapsed or refractory B-cell malignancy, such as, for example, 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), Waldenström's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, marginal zone cells, Burkitt's lymphoma, poorly differentiated non-Burkitt B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, B-lymphoblastic progenitor cell leukemia, 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.

In some cases, the cancer is a metastatic cancer. In some cases, the metastatic cancer is a metastatic solid tumor. In some cases, the metastatic solid tumor is a metastatic sarcoma or metastatic carcinoma. In some embodiments, the metastatic carcinoma includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor brain, breast cancer, cervical cancer, colon cancer, cancer of unknown primary site (CUP), esophageal cancer, eye cancer, fallopian tube cancer, gastroenterological cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, cancer oral cavity, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer and vulvar cancer.

In some cases, 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, 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, squamous cell carcinoma of the esophagus, 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, 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 a metastatic primary liver cancer.

In some cases, the metastatic cancer is a metastatic hematologic malignancy. In some embodiments, the metastatic hematologic malignancy is a metastatic leukemia, metastatic lymphoma, metastatic myeloma, metastatic non-Hodgkin's lymphoma, metastatic Hodgkin's lymphoma, metastatic T-cell malignancy, or metastatic B-cell malignancy. In some cases, the metastatic malignancy is a metastatic T-cell malignancy. In some cases, the metastatic malignancy is a metastatic B-cell malignancy, such as, for example, 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), Waldenström's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, marginal zone cells, Burkitt's lymphoma, poorly differentiated non-Burkitt B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, B-lymphoblastic progenitor cell leukemia, B-cell prolymphocytic leukemia

- 100 046394 goats, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large cell lymphoma, primary effusion lymphoma or lymphomatoid granulomatosis.

In some embodiments, the cancer is selected from malignant peripheral nerve sheath tumor (MPNST), schwannoma, and cutaneous neurofibromas.

Congenital diseases.

In some embodiments, compounds disclosed herein are useful for treating a congenital disorder. In some embodiments, the congenital disease is mediated by activation of a transcriptional coactivator with transcriptional coactivator PDZ-binding motif/Yes-associated protein (TAZ/YAP). In some embodiments, the congenital disorder is characterized by a mutant Ga protein. In some embodiments, the mutant Ga protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Ga protein is G12. In some embodiments, the mutant Ga protein is G13. In some embodiments, the mutant Ga protein is Gq. In some embodiments, the mutant Ga protein is G11. In some embodiments, the mutant Ga protein is Gi. In some embodiments, the mutant Ga protein is Go. In some embodiments, the mutant Ga protein is Gs.

In some embodiments, the congenital disease is the result of a genetic abnormality, the intrauterine environment, errors associated with morphogenesis, infection, epigenetic modifications of the parental germline, or a chromosomal abnormality. Examples of congenital disorders include, but are not limited to, Sturge-Weber syndrome, capillary hemangioma, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth amyotrophy (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, fragile X syndrome, Friedreich muscular ataxia, galactosemia, hemoglobinopathies, Krabbe disease, pelvic-brachial 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 disorder is Sturge-Weber syndrome or capillary hemangioma. In some embodiments, the congenital disorder is Sturge-Weber syndrome. In some embodiments, the congenital disease is a capillary hemangioma.

Examples

Such examples are presented for illustrative purposes only and do not limit the scope of the claims presented herein.

List of abbreviations.

As used above and throughout the invention, the following abbreviations, unless otherwise noted, are to be understood as having the following meanings:

ACN or MeCN - acetonitrile;

Ac - acetyl;

Bn - benzyl;

BOC or Boc - tert-butyl carbamate;

tert-Bu - tert-butyl;

Cy - cyclohexyl;

°C - degrees Celsius;

DBA or dba - dibenzylideneacetone;

DCE - dichloroethane (C1CH ₂ CH ₂ C1);

DCM - dichloromethane (CH2C12);

DIAD - diisopropyl azodicarboxylate;

DIPEA or DIEA - diisopropylethylamine;

DMAP - 4-(XNdimethylamino)pyridine;

DMF - dimethylformamide;

DMA - N.N-dimethylacetamide;

DMSO - dimethyl sulfoxide;

Dppf or dppf - 1,1'-bis(diphenylphosphino)ferrocene;

EA or EtOAc - ethyl acetate;

eq. - equivalent(s);

- 101 046394

Et-ethyl;

Et2O - diethyl ether;

EtOH - ethanol g - gram(s);

h - hour(s);

HPLC - high performance liquid chromatography;

Hz - hertz;

LAH - lithium aluminum hydride;

LCMS - liquid chromatography-mass spectrometry;

m/z is the ratio of mass to charge;

M - molar;

Me - methyl;

MeI - methyl iodide;

MeOH - methanol;

mg - milligram(s);

MHz - megahertz;

µmol - micromole(s);

µl - microliter(s);

ml - milliliter(s);

mmol - millimole(s);

MS - mass spectroscopy;

MsCl - methanesulfonyl chloride;

MW - microwave irradiation;

NCS - N-chlorosuccinimide;

NMM - N-methylmorpholine;

NMP - Nmethylpyrrolidin-2-one;

NMR - nuclear magnetic resonance;

PE - petroleum ether;

Ph - phenyl;

Prep.-HPLC - preparative high pressure liquid chromatography;

Prep.-TLC - preparative thin layer chromatography;

Ru - pyridine;

RP-HPLC - reverse phase high pressure liquid chromatography;

RT - retention time;

TEA - triethylamine;

TFA - trifluoroacetic acid;

THF - tetrahydrofuran;

TLC - thin layer chromatography;

TMSCl - trimethylsilyl chloride;

Xantphos - 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

XPhos - 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl;

XPhos Pd GII - chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'biphenyl)]palladium (II).

I. Chemical synthesis.

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture- and/or oxygen-sensitive synthesis reactions. Outputs have not been optimized. Reaction times are approximate and have not been optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Some compounds may have a different note.

Example 1: N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 1)

Step 1: 5-bromo-2-naphthoic acid

To a boiling solution of compound 1-1 (4 g, 23.23 mmol, 1 eq.) in AcOH (20 ml) was added Br ₂ (3.71 g, 23.23 mmol, 1.20 ml, 1 eq.), containing I2 (117.9 mg, 0.46 mmol, 93 µl, 0.02 eq.). After addition, the solution was refluxed at 120°C for 0.5 hours. During cooling,

- 102 046394 a white precipitate fell out. The mixture was filtered, washed with acetic acid (15 ml) and then with water (15 ml). The collected filter cake was triturated in methanol (50 ml) and filtered, dried in vacuo to give compound 1-2 (2.4 g, 9.56 mmol, 41.15% yield) as a white solid, which was used immediately without cleaning. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J=1.5 Hz, 1H), 8.21 (t, J=8.0 Hz, 2H), 8.17 - 8 .11 (m, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H).

Step 2: 5-bromo-K-isopropyl-2-naphthamide

To a solution of compound 1-2 (1 g, 3.98 mmol, 1 eq.) in DMF (5 mL) was added DIPEA (1.03 g, 7.97 mmol, 1.39 mL, 2 eq.) and HATU ( 1.67 g, 4.38 mmol, 1.1 eq.) at 30°C. After stirring for 10 min, propan-2-amine (282.5 mg, 4.78 mmol, 0.41 mL, 1.2 eq.) was added and the solution was stirred at 30°C for 16 h. Observed by LCMS that 47% of the required product has been identified. The solution was diluted with 50 ml EA, washed with 0.5 M HCl (20 mlx2) and saline (20 ml) twice in turn, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/0 - 2:1) to obtain compound 1-3 (0.6 g, 2.05 mmol, 51.56% yield) as a white solid . ¹ H NMR (400 MHz, CDCl3) δ 8.35 - 8.25 (m, 2H), 7.95 - 7.84 (m, 3H), 7.41 (t, J=7.8 Hz, 1H ), 6.09 (br s, 1H), 4.38 (qd, J=6.6, 13.7 Hz, 1H), 1.35 (d, J=6.5 Hz, 6H).

Step 3: K-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 1-3 (0.2 g, 0.68 mmol, 1 eq.), compound 1-3a (195.0 mg, 1.03 mmol, 1.5 eq.), Pd(dppf)Cl ₂ ( 25.04 mg, 34.2 µmol, 0.05 eq.) and KOAc (201.5 mg, 2.05 mmol, 3 eq.) in dioxane (5 ml) were bubbled with nitrogen for 1 min, capped and stirred at 100°C for 8 hours. 48% of desired product formed was observed by LCMS. The mixture was filtered and concentrated to obtain a residue. The residue was purified by pre-HPLC. The desired fractions were collected and most of the organic solvent was removed in vacuo. The remaining mixture was lyophilized to dryness to obtain the title compound (176.88 mg, 0.49 mmol, 71.48% yield) as a white solid. LCMS (ESI): RT=0.826 min, mass, calc. for C ₂₁ H ₁₈ F ₃ NO 357.13, m/z obtained 358.0 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H ), 7.97 - 7.90 (m, 3H), 7.80 (d, J=8.5 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.59 (d, J=7.0 Hz, 1H), 4.24 - 4.07 (m, 1H), 1.22 (d, J=6.5 Hz, 6H).

Example 2: K-(methylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 2)

Step 1: 5-bromo-K-(methylsulfonyl)-2-naphthamide

A mixture of compound 2-1 (0.3 g, 1.19 mmol, 1 eq.) and SOCl ₂ (1.42 g, 11.95 mmol, 0.87 mL, 10 eq.) in DCM (5 mL) was stirred at 70°C for 2 hours. The solution was then concentrated to obtain a residue, which was quickly dissolved in DCM (5 ml). After cooling to 0°C, TEA (362.7 mg, 3.58 mmol, 0.50 L, 3 eq.) and methanesulfonamide (227.3 mg, 2.39 mmol, 2 eq.) were added and the resulting mixture was treated at 25°C for 16 hours. Using LCMS it was observed that 46% of the required product was determined. The mixture was quenched with water (5 ml), diluted with EA (60 ml) and separated. The organic layer was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was triturated with a 1:1 ethyl acetate:petroleum ether solution (20 mL) to give 2-2 (0.4 g, crude) as a white solid, which was used immediately without further purification. It was observed by 1H NMR that this was a 1:1 mixture of starting material and desired product. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.47 (s, 1H), 8.24 8.16 (m, 2H), 8.11 - 8.01 ( m, 4H), 7.88 (dd, J=7.4, 11.7 Hz, 2H), 7.43 (q, J=8.2 Hz, 2H), 2.89 (s, 3H).

Step 2: K-(methylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 2-2 (0.3 g, 0.91 mmol, 1 eq.), compound 2-2a (260.4 mg, 1.37 mmol, 1.5 eq.), Pd(dppf)Cl ₂ ( 33.4 mg, 46 µmol, 0.05 eq.) and AcOA (269.1 mg, 2.74 mmol, 3 eq.) in dioxane (10 ml) were bubbled with nitrogen for 1 min, sealed and stirred at 100° C for 16 hours. Completion of the reaction was observed by LCMS and 40% of the desired product was formed. The reaction mixture was filtered and concentrated to obtain a residue. The residue was purified by pre-HPLC to give the crude product (20 mg). It was then purified again by pre-HPLC to give the title compound (5.31 mg, 12.27 µmol, 1.34% yield) as a white solid. LCMS (ESI): RT=1.411 min, mass, calc. for C ₁₉ H ₁₄ F ₃ NO ₃ S 393.06, m/z obtained 394.0 [M+1] ⁺ ; 1H NMR (400 MHz, CD3OD) δ 8.63 (d, J=1.5 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 8.03 - 7.97 (m , 1H), 7.89 - 7.80 (m, 3H), 7.72 7.62 (m, 3H), 7.59 - 7.54 (m, 1H), 3.30 (s, 3H) , 3.23 (s, 1H).

- 103 046394

Example 3: Amethyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (compound 3)

Step 1: 5-bromonaphthalene-2-sulfonyl chloride

SOCl ₂ (248.6 mg, 2.09 mmol, 0.15 ml, 2 eq.). The reaction mixture was then stirred at 30°C for 1.5 hours. The mixture was poured into ice water (20 ml) and then extracted with EA (20 ml x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-2 (310 mg, 1.01 mmol, 97.1% yield) as a yellow solid substance that was used in the next stage.

Step 2: 5-Bromo-Amethylnaphthalene-2-sulfonamide

To a solution of MeNH ₂ (2.0 M in THF, 1.52 ml, 3 eq.) in THF (1 ml) at 30°C, compound 3-2 (310 mg, 1.01 mmol, 1 eq.) was added dropwise. ) in THF (2 ml). The reaction mixture was stirred at 30°C for 16 hours. The mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 3-3 (270 mg, 0.81 mmol, 79.8% yield) as a yellow solid substances. LCMS (ESI): RT=0.706 min, mass, calc. for C _n H ₁₀ BrNO ₂ S 298.96, m/z obtained 299.7 [M+1]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J=1.8 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 7.91 7.84 (m , 3H), 7.40 (t, J=7.8 Hz, 1H), 4.38 (d, J=4.8 Hz, 1H), 2.64 (d, J=5.5 Hz, 3H ).

Step 3: Amethyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide

A mixture of compound 3-3 (100 mg, 0.33 mmol, 1 eq.), compound 3-3a (82.3 mg, 0.43 mmol, 1.3 eq.), Pd(dppf)Cl ₂ (12, 2 mg, 16.7 µmol, 0.05 eq.) and Na ₂ CO ₃ (70.6 mg, 0.67 mmol, 2 eq.) in dioxane (5 ml) and water (1 ml) at 30 ° C degassed and purged with N2 3 times and then stirred at 100°C under _N2 for 16 hours. Complete consumption of the starting material was observed by LCMS and 72% of the desired product was formed. The mixture was concentrated to obtain a residue. The residue was purified by pre-TLC (PE:EA=1:1) to obtain the title compound (90.9 mg, 0.24 mmol, 73.2% yield) as a white solid. LCMS (ESI): RT=0.810 min, mass, calc. for C ₁₈ H ₁₄ F ₃ NO ₂ S 365.07, m/z obtained 365.9[M+1]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J=1.5 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.98 - 7, 90 (m, 3H), 7.84 - 7.74 (m, 4H), 7.69 (d, J=7.0 Hz, 1H), 7.63 (brs, 1H), 2.45 (s , 3H).

Example 4: Aisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 4)

Step 1: 8-bromo-Aisopropylquinoline-3-carboxamide

To a solution of compound 4-1 (100 mg, 0.40 mmol, 1 eq.) in DCM (2 ml) was added HATU (226.3 mg, 0.60 mmol, 1.5 eq.), DIEA (102.5 mg, 0.80 mmol, 0.14 ml, 2 eq.) and compound 4-1a (46.9 mg, 0.80 mmol, 68 μl, 2 eq.). The mixture was stirred at 25°C for 16 hours. It was observed by LCMS that 66% of the desired product was detected. The reaction mixture was diluted with EA (20 ml). The organic phase was washed with brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1/0-9:1). Compound 4-2 (55 mg, 0.18 mmol, 47.3% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCM δ 9.33 (d, J=2.26 Hz, 1H), 8.58 (d, J=2.02 Hz, 1H), 8.15 (dd, J=7, 40, 1.13 Hz, 1H), 7.90 (dd, J=8.16, 1.13 Hz, 1H), 7.49 (t, J=7.92 Hz, 1H), 6.08 ( br s, 1H) 4.28 - 4.46 (m, 1H), 1.34 (d, J=6.52 Hz, 7H).

Step 2: Aisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 4-2 (50 mg, 0.17 mmol, 1 eq.) in THF (3 ml) and H ₂ O (0.5 ml) was added Pd(PPh ₃ ) ₄ (19.7 mg, 17 µmol , 0.1 eq.), K ₂ CO ₃ (35.36 mg, 0.25 mmol, 1.5 eq.) and compound 4-2a (48.6 mg, 0.25 mmol, 1.5 eq. ). The mixture was stirred at 90°C for 2 hours. It was observed by LCMS that 42% of the desired product was determined. The reaction mixture was filtered and the filter was concentrated in vacuo. The crude product was purified by pre-HPLC. The title compound (25.14 mg, 70.15 µmol, 41.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.786 min, mass of races

- 104 046394 count. for C ₂₀ H ₁₇ F ₃ N2O, 358.13 m/z, 359.0 [M+H]+ was obtained; 1H NMR (400 MHz, CDC13) δ 9.26 (d, J=2.26 Hz, 1H), 8.66 (d, J=2.26 Hz, 1H), 7.99 (dd, J=8 .02, 1.25 Hz, 1H), 7.81 - 7.87 (m, 3H), 7.76 - 7.80 (m, 2H), 7.70 7.75 (m, 1H), 6 .08 (br d, J=6.27 Hz, 1H), 4.35 - 4.44 (m, 1H), 1.35 (d, J=6.52 Hz, 6H).

Example 5: Methyl 5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (compound 5)

Step 1: 5-bromonaphthalene-2-sulfonyl chloride

To a solution of compound 5-1 (500 mg, 1.74 mmol, 1.0 eq.) in DMF (5 ml) was added SOCl ₂ (517.9 mg, 4.35 mmol, 0.31 ml, 2. 5 equiv.) at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with DCM (20 ml x 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-2 (500 mg, crude) as a yellow oil, which was used in the next step without further purification.

Step 2: 5-bromo-methylnaphthalene-2-sulfonamide

To a solution of compound 5-2 (200 mg, 0.65 mmol, 1.0 eq.) in THF (5 mL) was added TEA (132.4 mg, 1.31 mmol, 0.18 mL, 2.0 eq. ) and compound 5-2a (295.0 mg, 6.55 mmol, 0.43 ml, 10.0 eq.). The mixture was stirred at 25°C for 16 hours. Using LCMS, it was observed that reagent 2 was completely consumed and 50% of the required MS was determined. The reaction mixture was poured into water (10 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-3 (150 mg, crude) as a yellow solid, which was used in the next step without further purification . LCMS (ESI): RT=0.734 min, mass calc. for C ₁₂ H ₁₂ BrNO ₂ S 312.98, m/z obtained 313.8 [M+H]+.

Step 3: Methyl 5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide

To a solution of compound 5-3 (150 mg, 0.48 mmol, 1.0 eq.) in H2O (1 ml) and THF (5 ml) was added Pd(dppf)Cl ₂ (34.9 mg, 47.7 µmol , 0.1 eq.), Na ₂ CO ₃ (101.2 mg, 0.95 mmol, 2.0 eq.) and compound 5-3a (181.3 mg, 0.95 mmol, 2.0 eq. ). The mixture was stirred at 100°C for 16 hours. Using LCMS, it was observed that reagent 5-3 was completely consumed, and ~50% of the required MS was determined. The reaction was monitored using HPLC. The reaction mixture was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (19.52 mg, 51.5 µmol, 10.8% yield) as a white solid. LCMS (ESI): RT=0.828 min, mass calc. for C ₁₉ H ₁₆ F ₃ NO ₂ S 379.09, m/z obtained 379.9 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J=1.8 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.95 (d, J= 8.8 Hz, 1H), 7.84 - 7.76 (m, 3H), 7.73 - 7.66 (m, 1H), 7.64 - 7.57 (m, 3H), 4.41 (br d, J=5.8 Hz, 1H), 3.13 3.03 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).

Example 6: Misopropyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (compound 6)

Step 1: 5-bromonaphthalene-2-sulfonyl chloride

To a solution of compound 6-1 (500 mg, 1.74 mmol, 1.0 eq.) in DMF (5 ml) was added SOCl ₂ (517.9 mg, 4.35 mmol, 0.31 ml, 2. 5 equiv.) at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (20 ml) and extracted with DCM (20 ml x 3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without further purification. Compound 6-2 (500 mg, crude) was obtained as a yellow oil.

Step 2: 5-bromo-misopropylnaphthalene-2-sulfonamide

To a solution of compound 6-2 (200 mg, 0.65 mmol, 1.0 eq.) in THF (5 mL) was added TEA (132.4 mg, 1.31 mmol, 0.18 mL, 2.0 eq. ) and compound 6-2a (386.9 mg, 6.55 mmol, 0.56 ml, 10.0 eq.). The mixture was stirred at 25°C for 16 hours. Complete consumption of the reagent was observed using LCMS, and 50% of the required MS was determined. The reaction mixture was poured into water (10 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ ,

- 105 046394 filtered and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without further purification. Compound 6-3 (160 mg, crude) was obtained as a yellow solid. LCMS (ESI): RT=0.765 min, mass calc. for C ₁₃ H ₁₄ BrNO2S 326.99, m/z obtained 329.7 [M+H]+.

Step 3: N-isopropyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide

To a solution of compound 6-3 (160 mg, 0.49 mmol, 1.0 eq.) in H2O (1 ml) and THF (5 ml) was added Pd(dppf)Cl ₂ (35.6 mg, 48.75 µmol , 0.1 eq.), Na ₂ CO ₃ (103.3 mg, 0.97 mmol, 2.0 eq.) and compound 6-3a (185.1 mg, 0.97 mmol, 2.0 eq. ). The mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (27.02 mg, 68.68 µmol, 14.1% yield) as a white solid. LCMS (ESI): RT=0.849 min, mass calc. for C^H^NO^ 393.10, m/z obtained 393.9 [M+H]+; ¹ H NMR (400 MHz, CDCf) δ 8.54 (d, J=1.8 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.94 (d, J= 9.0 Hz, 1H), 7.84 - 7.76 (m, 3H), 7.73 - 7.66 (m, 1H), 7.64 7.56 (m, 3H), 4.40 ( br d, J=7.3 Hz, 1H), 3.61 - 3.49 (m, 1H), 2.78 (s, 1H), 1.11 (d, J=6.5 Hz, 6H) .

Example 7: N-isopropyl-4-[4-(trifluoromethyl)phenyl]quinoline-7-carboxamide (compound 7)

Step 1: 4-chloroquinoline-7-carboxylic acid

To a solution of compound 7-1 (0.2 g, 0.82 mmol, 1 eq.), COAc (323.7 mg, 3.30 mmol, 4 eq.) and DPPF (91.4 mg, 0.16 mmol , 0.2 eq.) in DMSO (4 ml) was added Pd(OAc) ₂ (9.2 mg, 41.2 µmol, 0.05 eq.) under N ₂ atmosphere. The suspension was degassed in vacuum and purged with CO several times. The mixture was stirred under a CO atmosphere (15 psi) at 65°C for 3 hours. Using LCMS, it was observed that 30% of the desired product was determined. The reaction mixture was diluted with EA (40 ml) and washed with saline (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was triturated with EA (20 mL) and filtered to give 7-2 (98 mg, 0.46 mmol, 55.92% yield) as a pink solid.

Step 2: 4-chloro-Ni-isopropylquinoline-7-carboxamide

Propan-2-amine was added to a solution of 7-2 (98 mg, 0.47 mmol, 1 eq.) and HATU (269.2 mg, 0.70 mmol, 1.5 eq.) in DCM (5 mL). (33.4 mg, 0.56 mmol, 48.6 μl, 1.2 eq.) and DIEA (122 mg, 0.94 mmol, 0.16 ml, 2 eq.). The reaction mixture was stirred at 25°C for 16 hours. Using LCMS it was observed that 93% of the desired product was determined. The reaction mixture was diluted with DCM (20 ml) and washed with water (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:1 - 1:0) to give compound 7-3 (40 mg, 0.16 mmol, 33.02% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (d, J=4.4 Hz, 1H), 8.40 (d, J=1.2 Hz, 1H), 8.31 (d, J =8.8 Hz, 1H), 8.12 (dd, J=8.8, 1.6 Hz, 1H), 7.57 (d, J=4.8 Hz, 1H), 6.19 (br , 1H), 4.40 -4.25 (m, 1H), 1.33 (d, J=6.8 Hz, 6H).

Step 3: N-isopropyl-4-[4-(trifluoromethyl)phenyl]quinoline-7-carboxamide

To a solution of compound 7-3 (40 mg, 0.16 mmol, 1 eq.) in DME (2.4 ml) was added Pd(PPh ₃ ) ₄ (9.2 mg, 8.0 μmol, 0.05 eq. ). And then Na ₂ CO ₃ (34.0 mg, 0.32 mmol, 2 eq.) in H2O (0.6 ml) and [4(trifluoromethyl)phenyl]boronic acid (38.1 mg, 0.2 mmol) was added , 1.25 eq.). The suspension was degassed in vacuo and purged with N ₂ several times. The mixture was stirred under N ₂ atmosphere at 110° C. for 16 hours. It was observed by LCMS that 30% of the starting material remained and that 16% of the desired product was determined. The reaction mixture was diluted with EA (15 ml) and washed with water (2x6 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by pre-HPLC to give the title compound (2.03 mg, 5.66 µmol, 3.52% yield) as a white solid. LCMS (ESI): RT=0.709 min, mass calc. for C ₂₀ H ₁₇ F ₃ N ₂ O 358.13, m/z obtained 359.0 [M+H]+; ^1H NMR (400 MHz, CHLOROFORM-d) δ 9.05 (d, J=4.2 Hz, 1H), 8.47 (d, J=1.5 Hz, 1H), 8.02 (dd, J= 8.6, 1.6 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 7.43 (d, J=4.2 Hz, 1H), 6.20 (d, J=7.6 Hz, 1H), 4.32 4.43 (m, 1H ), 1.35 (d, J=6.5 Hz, 6H).

Example 8: 8-bromo-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 8)

- 106 046394

Step 1: 5-bromo-N-isopropyl-2-naphthamide

To a mixture of compound 8-1 (11 g, 43.81 mmol, 1 eq.) in DMF (10 ml) was added HATU (33.32 g, 87.62 mmol, 2 eq.) and Et ₃ N (4.43 g, 43.81 mmol, 6.10 ml, 1 eq.). The mixture was stirred for 0.5 h at 25°C. Propan-2-amine (3.11 g, 52.57 mmol, 4.52 mL, 1.2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched by adding H ₂ O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 - 5:1). Compound 8-2 (11 g, 37.65 mmol, 85.9% yield) was obtained as a yellow solid.

Step 2: Aisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 8-2 (1 g, 3.42 mmol, 1 eq.), compound 8-2a (975.0 mg, 5.13 mmol, 1.5 eq.), KOAc (1.01 g, 10. 2 mmol, 3 eq.), Pd(dppf)Cl ₂ (125.2 mg, 0.17 mmol, 0.05 eq.) in dioxane (15 ml) was degassed and purged with N ₂ 3 times, and then the mixture was stirred at 100°C for 3 hours in N ₂ atmosphere. The residue was poured into H2O (50 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (30 mlx3). The combined organic phase was washed with brine (50 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product. The residue was purified by flash chromatography on silica gel. Compound 8-3 (920 mg, 2.57 mmol, 75.2% yield) was obtained as a white solid.

Step 3: 8-bromo-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 8-3 (150 mg, 0.41 mmol, 1 eq.) in HOAc (5 ml) was added NBS (298.8 mg, 1.68 mmol, 4 eq.). The mixture was stirred at 80°C for 3 hours. The mixture was cooled to room temperature. Ice water (20 ml) was then added and the mixture was neutralized to pH=7.5 with aq. NaOH (2 M). The aqueous phase was extracted with ethyl acetate (15 mlx3). The combined organic phase was washed with brine (30 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (42.7 mg, 96.9 µmol, 23% yield) as a white solid. LCMS (ESI): RT=0.938 min, mass calc. for C ₂₁ H ₁₇ BrF ₃ NO 436.26, m/z obtained 437.7 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J=1.3 Hz, 1H), 8.64 (d, J=7.5 Hz, 1H), 8.07 (d, J=7.5 Hz, 1H), 8.01 (dd, J=1.5, 8.8 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.83 ( d, J=8.8 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.50 (d, J=7.8 Hz, 1H), 4.18 (qd, J=6.7, 13.8 Hz, 1H), 1.22 (d, J=6.5 Hz, 6H).

Example 9: Methyl 1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxylate (compound 9)

- - _Br NaOAc (2.03KB.),PPh ₃ (0.25 eq.) ______XOOMe ^y^- ^COOMe

AVV Pd(OAc) ₂ (Q.25 3KB.),CO(50psi) ATA' ^С °° ^Ме m-CPBA (1.4 eq.)_ ΑΊΑΥ РОС!з (10.0 eq.) CDD

DMF, MeOH, 80=0.16 h DCM, k.t., 16 h θθ θ θ ₅ T

9-1 9-2 9-3 9-4

HE

Step 1: Methylisoquinoline-6-carboxylate

To a solution of compound 9-1 (2 g, 9.6 mmol, 1 eq.), NaOAc (1.58 g, 19.2 mmol, 2 eq.) and PPh ₃ (630.3 mg, 2.4 mmol, 0.25 eq.) in DMF (20 ml) and MeOH (20 ml) was added Pd(OAc) ₂ (539.5 mg, 2.4 mmol, 0.25 eq.). The suspension was degassed in vacuum and purged with CO several times. The mixture was stirred in atmosphere

- 107 046394 CO sphere (50 psi) at 80°C for 16 hours. Using LCMS, it was observed that 76% of the required product was determined. MeOH was removed. The residue was diluted with EA (30 ml) and washed with saline (2x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was used immediately in the next step. Compound 9-2 (1.6 g, 8.55 mmol, 88.91% yield) was obtained as a yellow solid.

Step 2: Methyl 2-oxidoisoquinoline-2-ium-6-carboxylate

To a solution of compound 9-2 (1.3 g, 6.9 mmol, 1 eq.) in DCM (15 ml) m-CPBA (1.95 g, 9.6 mmol, 1.38 eq.) was added portionwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. Using LCMS it was observed that 40% of the desired product was determined. The reaction mixture was diluted with EA (50 ml) and washed with us. Na ₂ CO ₃ (3x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. Compound 9-3 (0.7 g, 2.72 mmol, 39.19% yield) was used immediately in the next step as a yellow solid. The LCMS confirmed that the required product was obtained.

Step 3: Methyl 2-oxidoisoquinoline-2-ium-6-carboxylate

Compound 9-3 (0.7 g, 3.4 mmol, 1 eq.) was added to POCl ₃ (3 ml) portions and the reaction was heated at 80°C for 0.5 h. LCMS observed that 29% the required product has been determined. The reaction mixture was poured into water (10 ml), and the pH was adjusted to 7 sat. NaHCO ₃ and extracted with EA (2x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA: PE=1:10-1:5) to give compound 9-4 (260 mg, 0.94 mmol, 17.03% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J=1.25 Hz, 1H), 8.44 - 8.35 (m, 2H) 8.27 (dd, J=8.78 , 1.51 Hz, 1H), 7.72 (d, J=5.52 Hz, 1H).

Step 4: Methyl 1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxylate

A mixture of compound 9-4 (60 mg, 0.27 mmol, 1 eq.), [4-(trifluoromethyl)phenyl]boronic acid (61.7 mg, 0.32 mmol, 1.2 eq.), Na ₂ CO ₃ (57.3 mg, 0.54 mmol, 2 eq.) and Pd(PPh ₃ ) ₄ (31.8 mg, 27 μmol, 0.1 eq.) in DME (3 ml) were degassed and then heated at 85°C for 4 hours in N2 atmosphere. Using LCMS, it was observed that 28% of the required product was identified. The reaction was concentrated. The residue was diluted with EA (20 ml) and washed with saline (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by pre-HPLC to give the title compound (12 mg, 35.35 µmol, 13.06% yield) as a white solid. LCMS (ESI): RT=0.815 min, mass calc. for C ₁₈ H ₁₂ F ₃ NO ₂ 331.08, m/z obtained 331.9 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (s, 1H), 8.75 (d, J=5.52 Hz, 1H), 8.17 (d, J=5.77 Hz, 1H), 8.12 (s, 2H), 7.90 - 8.00 (m, 4H), 3.96 (s, 3H).

Example 10: Methyl 1-chloro-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate (compound 10)

Step 1: Methyl 1-hydroxyisoquinoline-7-carboxylate

To a solution of compound 10-1 (0.5 g, 2.23 mmol, 1 eq.), Et ₃ N (564.5 mg, 5.58 mmol, 0.77 ml, 2.5 eq.) and DPPP ( 55.2 mg, 0.13 mmol, 0.06 eq.) in DMF (5 ml) and MeOH (5 ml) was added Pd(OAc) ₂ (20 mg, 89.26 μmol, 0.04 eq.) in atmosphere N2. The suspension was degassed in vacuum and purged with CO several times. The mixture was stirred under a CO atmosphere (50 psi) at 80°C for 16 hours. Using LCMS, it was observed that 94% of the desired product was determined. The reaction mixture was filtered and MeOH was removed. The residue was diluted with EA (40 ml) and washed with saline (3x20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. Compound 10-2 (400 mg, 1.97 mmol, 88.21% yield) was used immediately in the next step as an off-white solid. It was observed by NMR that the desired product was obtained. 1H NMR (400 MHz, CDCl ³ ) δ 11.08 (br s, 1H), 9.08 (d, J=1.76 Hz, 1H), 8.28 (dd, J=8.41, 1, 88 Hz, 1H), 7.61 (d, J=8.28 Hz, 1H), 6.58 (d, J=7.28 Hz, 1H), 4.02 - 3.87 (m, 3H) .

Step 2: Methyl 4-bromo-1-hydroxyisoquinoline-7-carboxylate

A mixture of Br ₂ (220.2 mg, 1.38 mmol, 71.04 µl, 1 eq.) and HOAc (2 ml) was added dropwise to a mixture of compound 10-2 (280 mg, 1.38 mmol, 1 eq. ) and HOAc (10 ml) and stirred at 25°C for 30 min. Using LCMS, it was observed that 53% of the starting material remained and that 45% of the desired product was detected. The reaction mixture was diluted with water (20 ml) and filtered. Compound 10-3 (350 mg, 1.24 mmol, 89.95% yield) was obtained as a yellow solid, which was used

- 108 046394 immediately at the next stage without additional cleaning.

Step 3: Methyl 1-hydroxy-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate

To a solution of compound 10-3 (330 mg, 1.17 mmol, 1 eq.), compound 10-3a (244.40 mg, 1.29 mmol, 1.1 eq.) and K ₂ CO ₃ (323.3 mg, 2.34 mmol, 2 eq.) in THF (8 ml) and H ₂ O (2 ml) was added Pd(dppf)Cl ₂ (85.6 mg, 0.11 mmol, 0.1 eq.) in atmosphere N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 atmosphere at 90° C. for 4 hours. It was observed by LCMS that 36% of the desired product was consumed. The reaction was concentrated. The residue was diluted with EA (15 ml) and washed with water (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA: PE=1:10~1:5) to obtain compound 10-4 (70 mg, 177.37 μmol, 15.16% yield) as a white solid.

Step 4: Methyl 1-chloro-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate

A solution of compound 10-4 (70 mg, 0.2 mmol, 1 eq.) in POCl ₃ (1.5 ml) was heated at 80°C for 2 hours. Using LCMS, it was observed that 81% of the desired product was determined. The reaction mixture was poured into water (5 ml), the pH was adjusted to 7 sat. NaHCO ₃ and extracted with EA (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (EA: PE=1:10) to obtain the title compound (46 mg, 0.12 mmol, 59.90% yield) as a white solid. LCMS (ESI): RT=0.946 min, mass calc. for C ₁₈ H11ClF ₃ NO ₂ 365.04, m/z obtained 365.9 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.19 (d, J=1.00 Hz, 1H), 8.38 - 8.30 (m, 2H), 7.90 (d, J=8.78 Hz, 1H), 7.85 (d, J=8.03 Hz, 2H), 7.64 (d, J=8.03 Hz, 2H), 4.06 (s, 3H).

Example 11: N-isopropyl-1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxamide (compound 11)

Step 1: 1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxylic acid

NaOH (16.3 mg, 0.4 mmol, 3 equiv) was added to a solution of compound 11-1 (45 mg, 0.13 mmol, 1 eq.) in MeOH (3 mL) and H2O (3 mL). The reaction mixture was stirred at 25°C for 2 hours. Using

LCMS observed that 90% of the required product was identified. The reaction was concentrated. The residue was adjusted to pH 4-5 with 1N aq. HCl and extracted with EA (20 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. Compound 11-2 (40 mg, 0.11 mmol, 83.5% yield) as a white solid was used immediately in the next step.

Step 2: N-isopropyl-1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxamide

Isopropylamine (14.9 mg, 0.25 mmol, 22 µl, 2 eq.). The reaction mixture was stirred at 25°C for 16 hours. It was observed by LCMS that 71% of the desired product was detected. The reaction mixture was diluted with EA (30 ml) and washed with saline (3x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by pre-HPLC to give the title compound (14.67 mg, 40.94 µmol, 32.47% yield) as a white solid. LCMS (ESI): RT=0.737 min, mass calc. for C ₂₀ H ₁₇ F ₃ N ₂ O 358.13, m/z obtained 359.0 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J=5.52 Hz, 1H), 8.62 (d, J=7.78 Hz, 1H), 8.54 (s, 1H ), 8.05 - 8.00 (m, 3H), 7.94 (q, J=8.28 Hz, 4H), 4.26 - 4.10 (m, 1H), 1.22 (d, J=6.53 Hz, 6H).

Example 12: tert-butyl (7-(isopropylcarbamoyl)-4-(4-(trifluoromethyl)phenyl)naphthalene-1yl)carbamate (compound 12) he

To a solution of compound 12-1 (220 mg, 0.54 mmol, 1 eq.) in dioxane (2 ml) was added Pd(dppf)Cl ₂ (19.8 mg, 27.0 μmol, 0.05 eq.), AsOK (159.0 mg, 1.62 mmol, 3 equiv.) and compound 12-1a (153.9 mg, 0.81

- 109 046394 mmol, 1.5 eq.). The mixture was stirred at 100°C for 16 hours. It was observed by LCMS that the starting material was completely consumed and that 70% of the desired product was detected. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with EA (20 ml), washed with brine (5 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 4:1). The title compound (300 mg, 0.55 mmol, 53.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.935 min, mass calc. for C ₂₆ H ₂₇ F ₃ N ₂ O ₃ , 472.20 m/z, 495.1 [M+Na]+ was obtained; ¹ H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (s, 1H), 8.07 (br d, J=7.78 Hz, 1H), 7.86 (d, J=8.78 Hz , 1H), 7.75 (d, J=8.04 Hz, 2H), 7.64 (d, J=9.04 Hz, 1H), 7.57 (d, J=8.04 Hz, 2H ), 7.48 (d, J=8.04 Hz, 1H), 7.13 (br s, 1H), 6.07 (br d, J=8.28 Hz, 1H), 4.36 (dq , J=13.62, 6.76 Hz, 1H), 1.59 (s, 9H), 1.32 (d, J=6.54 Hz, 6H).

Example 13: 8-chloro-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 13)

To a solution of compound 13-1 (300 mg, 0.83 mmol, 1 eq.) in HOAc (5 mL) was added NCS (336.2 mg, 2.52 mmol, 3 eq.). The mixture was stirred at 80°C for 16 hours. Ice water (20 ml) was then added and the mixture was neutralized to pH=7.5 aq. NaOH (2 M), The aqueous phase was extracted with ethyl acetate (15 mlx3). The combined organic phase was washed with brine (30 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to obtain 85 mg of crude product. And then the crude product was purified by chiral SFC to obtain the title compound (51.8 mg, 0.13 mmol, 15.7% yield) as a white solid. LCMS (ESI): RT=0.934 min, mass, calc. for C ₂₁ H ₁₇ ClF ₃ NO 391.1, m/z obtained 391.9 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (d, J=1.5 Hz, 1H), 8.66 (d, J=7.8 Hz, 1H), 8.02 (dd , J=1.8, 8.8 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.86 (dd, J=8.4, 13.9 Hz, 2H) , 7.73 (d, J=8.0 Hz, 2H), 7.57 (d, J=7.8 Hz, 1H), 4.23 - 4.10 (m, 1H), 1.22 ( d, J=6.5 Hz, 6H), 1.16 (d, J=6.5 Hz, 1H).

Example 14: Methyl 1-oxo-4-[4-(trifluoromethyl)phenyl]-2H-isoquinoline-7-carboxylate (compound 14)

Step 1: Methyl 1-hydroxyisoquinoline-7-carboxylate

To a solution of compound 14-1 (0.5 g, 2.23 mmol, 1 eq.), Et ₃ N (564.5 mg, 5.58 mmol, 0.8 ml, 2.5 eq.) and DPPP ( 55.2 mg, 0.13 mmol, 0.06 eq.) in DMF (5 ml) and MeOH (5 ml) was added Pd(OAc) ₂ (20 mg, 89.3 μmol, 0.04 eq.) in atmosphere N ₂ . The suspension was degassed in vacuum and purged with CO several times. The mixture was stirred under 50 psi CO at 80°C for 16 hours. It was observed by LCMS that 94% of the desired product was detected. The reaction mixture was filtered and MeOH was removed. The residue was diluted with EA (40 ml) and washed with brine (3 x 20 ml). The organic layer was dried over Na2SO4 and concentrated. Compound 14-2 (400 mg, 1.97 mmol, 88.2% yield) was used immediately in the next step as an off-white solid. NMR confirmed that the desired product was obtained. 1H NMR (400 MHz, CHLOROFORM-d) 11.08 (br s, 1 H), 9.08 (d, J=1.76 Hz, 1H), 8.28 (dd , J=8.41, 1.88 Hz, 1H), 7.61 (d, J=8.28 Hz, 1H), 6.58 (d, J=7.28 Hz, 1H), 4.02 - 3.87 (m, 3H).

Step 2: Methyl 4-bromo-1-hydroxyisoquinoline-7-carboxylate

A mixture of Br ₂ (220.2 mg, 1.38 mmol, 71 μl, 1 eq.) and HOAc (2 ml) was added dropwise to a mixture of compound 14-2 (280 mg, 1.38 mmol, 1 eq.) and HOAc (10 ml) and stirred at 25°C for 30 min. Using LCMS, it was observed that 53% of the remaining material remained and that 45% of the desired product was determined. The reaction mixture was diluted with water (20 ml) and filtered. Compound 14-3 (350 mg, 1.24 mmol, 89.9% yield) was used immediately in the next step as a yellow solid.

Step 3: Methyl 1-oxo-4-[4-(trifluoromethyl)phenyl]-2H-isoquinoline-7-carboxylate

To a solution of compound 14-3 (1.9 g, 6.74 mmol, 1 eq.), compound 14-4a (1.41 g, 7.41 mmol, 1.1 eq.) and K ₂ CO ₃ (1 .86 g, 13.47 mmol, 2 eq.) in THF (40 ml) and H ₂ O (10 ml) was added Pd(dppf)Cl ₂ (492.8 mg, 0.67 mmol, 0.1 eq. ) in an N2 atmosphere. The suspension was degassed under vacuum and purged with N2 several times. Mixture

- 110 046394 was stirred under N2 atmosphere at 90° C. for 4 hours. It was observed by LCMS that 36% of the desired product was consumed. The reaction was concentrated. The residue was diluted with EA (100 ml) and washed with water (2x30 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA: PE=1:10~1:5) to obtain the title compound (480 mg, 1.24 mmol, 18.47% yield) as a white solid. LCMS (ESI): RT=0.802 min, mass calc. for C ₁₈ H ₁₂ F ₃ NO ₃ 347.08, m/z obtained 347.9 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br, 1H), 8.89 (s, 1H), 8.20 (dd, J=8.4, 1.0 Hz, 2H) , 7.88 (d, J=8.0 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7 .40 (s, 1H), 3.92 (s, 3H).

Example 15: methyl 2-methyl-1-oxo-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate (compound 15) he o oo

CsjCO, (1.5 eq.)

J Mel (1.3 eq.) J dmf, 50°C, W h f| η

15-ή Connection

F ^F F ^F

_{MeI (} 26.5 mg, 0.18 mmol, 11.6 µl, 1.3 eq.). The reaction was heated at 50°C for 3 hours. Using LCMS, it was observed that the desired product was determined, and using HPLC, it was observed that 80% of the desired product was determined. The reaction mixture was diluted with EA (15 ml) and washed with saline (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by pre-HPLC to give the title compound (25 mg, 69.19 µmol, 48% yield) as a white solid. LCMS (ESI): RT=0.837 min, mass, calc. for C ₁₉ H ₁₄ F ₃ NO ₃ 361.09, m/z obtained 362.1 [M+1]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.20 (d, J=2.0 Hz, 1H), 8.23 (d, J=8.4, 2.0 Hz, 1H), 7.77 ( d, J=8.4 Hz, 2H), 7.60 - 7.50 (m, 3H), 7.18 (s, 1H), 3.99 (s, 3H), 3.70 (s, 3H ).

Example 16: 8-amino-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 16)

To a solution of compound 16-1 (20 mg, 42.3 μmol, 1 eq.) in dioxane (0.5 ml) was added HCl/dioxane (4 M, 0.1 ml, 10 eq.). The mixture was stirred at 20°C for 32 hours. It was observed by LCMS that the starting material was completely consumed and that 76% of the desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC. The title compound (8 mg, 21.5 µmol, 50.8% yield) was obtained as a light yellow solid. LCMS (ESI): RT=0.826 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O, 372.14 m/z, 372.9 [M+H] ⁺ was obtained; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.48 (s, 1H) 7.78 (d, J=8.76 Hz, 1H) 7.66 (br d, J=7.88 Hz, 2H) 7.61 (br d, J=8.88 Hz, 1H) 7.48 (br d, J=7.88 Hz, 2H) 7.26 (d, J=7.64 Hz, 1H) 6.96 (d, J=7.50 Hz, 1H) 6.12 (br d, J=7.38 Hz, 1H) 4.20 - 4.30 (m, 1H) 1.21 (d, J=6, 50 Hz, 6H).

Example 17: 8-Acetamido^-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 17)

To a solution of compound 17-1 (50 mg, 0.14 mmol, 1 eq.) in DCM (1 ml) was added TEA (27.2 mg, 0.27 mmol, 37.4 μl, 2 eq.) and acetyl acetate ( 20.6 mg, 0.2 mmol, 18.9 µl, 1.5 eq.). The mixture was stirred at

- 111 046394

20°C for 1 hour. Using LCMS it was observed that 85% of the required product was determined. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC. The title compound (28 mg, 64.9 µmol, 48.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.787 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ , 414.16 m/z, 437.0 [M+Na]+ was obtained; ^1H NMR (400 MHz, CHLOROFORM-d) δ 8.49 (s, 1H), 7.91 - 8.12 (m, 2H), 7.70 - 7.82 (m, 3H), 7.60 (br s, 1H), 7.51 (br d, J=7.76 Hz, 2H), 7.44 (br d, J=7.76 Hz, 1H), 6.24 (br d, J= 7.64 Hz, 1H), 4.33 (dq, J=13.59, 6.74 Hz, 1H), 2.39 (s, 3H), 1.32 (d, J=6.50 Hz, 6H).

Example 18: N-isopropyl-8-methylsulfanyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 18)

A mixture of compound 18-1 (100 mg, 0.23 mmol, 1 eq.), NaSMe (24.1 mg, 0.34 mmol, 21.9 μl, 1.5 eq.), Xantphos (13.2 mg, 22.9 µmol, 0.1 eq.), Pd ₂ (dba) ₃ (20.9 mg, 22.9 µmol, 0.1 eq.) and DIPEA (59.2 mg, 0.46 mmol, 79. 8 µl, 2 eq) in toluene (10 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 110°C for 3 hours under N2. The residue was poured into H2O (50 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (30 mlx3). The combined organic phase was washed with brine (50 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (42.8 mg, 0.11 mmol, 46.2% yield) as a white solid. LCMS (ESI): RT=0.927 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NOS 403.1, m/z obtained 404.0 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J=1.4 Hz, 1H), 8.56 (d, J=7.6 Hz, 1H), 7.98 (dd , J=1.6, 8.9 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.83 (d, J=8.9 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 7.59 - 7.52 (m, 2H), 4.17 (q, J=6.7, 13.8 Hz, 1H), 2.69 ( s, 3H), 1.22 (d, J=6.6 Hz, 6H).

Example 19: N-isopropyl-8-methyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 19)

To a mixture of compound 19-1 (0.05 g, 0.11 mmol, 1 eq.) and compound 19-1a (28.7 mg, 0.22 mmol, 32 μl, 2 eq.) in dioxane (5 ml) and H2O (1 ml), KOAc (33.7 mg, 0.34 mmol, 3 eq.), Pd(dppf)Cl ₂ (4.1 mg, 5.7 µmol, 0.05 eq.) was added under N2 atmosphere . The mixture was stirred for 3 hours at 100°C. Completion of the reaction was monitored using LCMS. The mixture was quenched with EA (30 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (6.38 mg, 17.1 µmol, 14.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.915 min, mass, calc. for: C ₂₂ H ₂₀ F ₃ NO 371.40, m/z obtained 372.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 7.90 - 7.82 (m, 4H), 7.67 (d, J=8.1 Hz, 2H), 7, 52 (d, J=7.3 Hz, 1H), 7.45 (d, J=7.1 Hz, 1H), 4.35 - 4.26 (m, 1H), 2.85 (s, 3H ), 1.33 (d, J=6.6 Hz, 6H).

Example 20: 8-ethynyl-Nisopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 20)

- 112 046394

To a mixture of compound 20-1 (0.03 g, 66.1 μmol, 1 eq.) in DCM (1 ml) was added TBAF (1 M, 66.1 μl, 1 eq.). The mixture was stirred for 10 minutes at 25°C. The completion of the reaction was monitored using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (8.9 mg, 23.3 µmol, 35.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.908 min, mass, calc. for: C ₂₃ H ₁₈ F ₃ NO 381.39, m/z obtained 382.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 7.91 - 7.85 (m, 5H), 7.70 (br d, J=7.9 Hz, 2H), 7 .54 (d, J=7.4 Hz, 1H), 4.30 (td, J=6.6, 13.2 Hz, 1H), 4.14 (s, 1H), 1.32 (d, J=6.6 Hz, 6H).

Example 21: 8-ethyl-Nisopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound

21)

Step 1: 5-bromonaphthalene-2-carboxylic acid

To a mixture of compound 21-1 (5 g, 29.04 mmol, 1 eq.) in AcOH (50 ml) was added I ₂ (368.5 mg, 1.45 mmol, 0.29 ml, 0.05 eq.) and Br ₂ (4.64 g, 29.04 mmol, 1.50 ml, 1 eq.) under N2 atmosphere. The mixture was stirred for 0.5 h at 120°C. The mixture was quenched with H2O (100 ml) and the mixture was filtered and the filter cake was washed with PE (100 ml x 3). The crude product was used in the next step without further purification. Compound 21-2 (18 g, crude) was obtained as a white solid.

Step 2: 5-bromo-Ni-isopropylnaphthalene-2-carboxamide

To a mixture of compound 21-2 (9 g, 35.85 mmol, 1 eq.) in DMF (10 ml) was added HATU (16.36 g, 43.01 mmol, 1.2 eq.) and Et ₃ N (10 .88 g, 107.54 mmol, 14.97 ml, 3 eq.). The mixture was stirred for 0.5 h at 25°C. Propan-2-amine (2.54 g, 43.01 mmol, 3.70 mL, 1.2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 5:1). Compound 21-3 (20 g, 51.34 mmol, 71.6% yield) was obtained as a white solid.

Step 3: N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

To a mixture of compound 21-3 (6 g, 20.54 mmol, 1 eq.) and [4-(trifluoromethyl)phenyl]boronic acid 21-3a (5.85 g, 30.80 mmol, 1.5 eq.) in dioxane (5 ml) add KOAc (6.05 g, 61.61 mmol, 3 eq.),

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Pd(dppf)Cl ₂ (751.3 mg, 1.03 mmol, 0.05 eq.) under N2 atmosphere. The mixture was stirred for 10 hours at 100°C. The mixture was quenched with EA (30 ml) and the mixture was filtered and the filter cake was washed with EA (20 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 10:1) to obtain a residue. Compound 21-4 (6.12 g, 17.13 mmol, 27.8% yield) was obtained as a white solid.

Step 4: 8-bromo-H-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

To a mixture of 21-4 (2.5 g, 7.0 mmol, 1 eq) in AcOH (10 mL) was added NBS (2.49 g, 13.99 mmol, 2 eq) under N2. The mixture was stirred for 10 hours at 80°C. The mixture was quenched with NaOH (4 M, 100 ml) and the mixture was extracted with EA (30 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 5:1). Compound 21-5 (3 g, 6.8 mmol, 48.6% yield) was obtained as a yellow solid.

Step 5: N-isopropyl-5-[4-(trifluoromethyl)phenyl]-8-(2-trimethylsilylethynyl)naphthalene-2carboxamide

To a mixture of compound 21-5 (0.2 g, 0.45 mmol, 1 eq.) and ethynyl(trimethyl)silane 21-5a (135.0 mg, 1.3 mmol, 0.19 ml, 3 eq.) in dioxane (2 ml) was added Pd(dppf)Cl ₂ (33.5 mg, 45.8 mmol, 0.1 eq.), CuI (8.7 mg, 45.8 μmol, 0.1 eq.) and DIPEA (296.2 mg, 2.2 mmol, 0.39 ml, 5 eq.). The mixture was stirred for 10 hours at 100°C. LCMS monitored the completion of the reaction. The mixture was quenched with EA (30 ml) and the mixture was filtered and the filter cake was washed with EA (20 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 8:1). Compound 21-6 (0.15 g, 0.33 mmol, 72.1% yield) was obtained as a yellow solid.

Step 6: 8-ethynyl-N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

To a mixture of compound 21-6 (0.1 g, 0.22 mmol, 1 eq.) in DCM (1 mL) was added TBAF (1 M, 0.22 mL, 1 eq.). The mixture was stirred for 10 minutes at 25°C. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 8:1). Compound 21-7 (61 mg, 0.15 mmol, 72.5% yield) was obtained as a yellow solid.

Step 7: 8-ethyl-N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

To a solution of compound 21-7 (30 mg, 0.078 mmol, 1 eq.) in MeOH (2 ml) was added Pd/C (30 mg, 10% wet) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25°C for 8 hours. Completion of the reaction was monitored by LCMS. The reaction solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (9.5 mg, 24.6 µmol, 31.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.939 min, mass, calc. for: C ₂₃ H ₂₂ F ₃ NO 385.17, m/z obtained 386.0 [M+H]+; 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.50 (d, J=7.6 Hz, 1H), 7.96 - 7.88 (m, 3H), 7.81 (d, J=8.9 Hz, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.58 - 7.47 (m, 2H), 4.19 (br d, J =7.1 Hz, 1H), 3.24 (q, J=7.4 Hz, 2H), 1.39 (t, J=7.4 Hz, 3H), 1.23 (d, J=6 ,6 Hz, 6H).

Example 22: 8-cyclopropyl-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 22)

A mixture of compound 22-1 (100 mg, 0.22 mmol, 1 eq.), cyclopropylboronic acid (23.6 mg, 0.27 mmol, 1.2 eq.), K ₃ PO ₄ (145.9 mg, 0 .68 mmol, 3 eq.), H ₂ O (4.1 mg, 0.22 mmol, 4.13 μl, 1 eq.) and Pd(dppf)Cl ₂ (16.77 mg, 22.9 μmol, 0.1 eq.) in THF (5 ml) was stirred at 90°C for 1 hour under N ₂ atmosphere with microwave irradiation. Detection of the desired compound was observed using LC-MS and HPLC. The reaction mixture was diluted with H2O (5 ml) and the mixture was extracted with EA (6 ml x 3).

The combined organic phase was washed with brine (6 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (35 mg, 87.1 µmol, 38.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.953 min, mass, calc. for C ₂₄ H ₂₂ F ₃ NO 397.17, m/z obtained 398.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ=0.82 - 0.86 (m, 2H) 1.13 - 1.18 (m, 2H) 1.23 (d, J=6.50 Hz, 6H ) 2.59 - 2.65 (m, 1H) 4.15 - 4.22 (m,

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1H) 7.38 (d, J=7.50 Hz, 1H) 7.45 - 7.49 (m, 1H) 7.70 (d, J=8.00 Hz, 2H) 7.81 (d, J=8.88 Hz, 1H) 7.88 -7.98 (m, 3H) 8.49 (d, J=7.75 Hz, 1H) 8.98 (s, 1H).

Example 23: N-isopropyl-8-(methylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamcd (compound 23)

To a solution of compound 23-1 (30 mg, 80.6 µmol, 1 eq.) in DCM (1 ml) was added TEA (24.5 mg, 0.24 mmol, 34 µl, 3 eq.) and methanesulfonyl chloride (0. 34 g, 2.97 mmol, 0.2 ml, 36 eq.) at 0°C. The mixture was stirred at 20°C for 4 hours. It was observed by LCMS that the starting material was completely consumed and that ~50% of the required mass was determined. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC. The title compound (10 mg, 22.2 µmol, 27.5% yield) was obtained as a light yellow solid. LCMS (ESI): RT=0.819muh, mass calc. for C ₂₂ H ₂ iF ₃ N ₂ O ₃ S, 450.12 m/z, 473.0 [M+Na]+ was obtained; ^1H NMR (400 MHz, CDCl3) δ 8.73 8.76 (m, 1H) 7.88 - 7.92 (m, 1H) 7.77 - 7.84 (m, 4H) 7.59 (d , J=8.00 Hz, 2H) 7.52 (d, J=7.75 Hz, 2H) 6.29 (br d, J=7.50 Hz, 1H) 4.31 - 4.40 (m , 1H) 3.14 (s, 3H) 1.32 (d, J=6.50 Hz, 6H).

Example 24: Methyl 4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate (compound 24)

24-1 Connection 24

To a solution of compound 24-1 (140 mg, 0.38 mmol, 1 eq.) in MeOH (3 ml) was added Pd/C (50 mg, 50% purity) under N2 atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25° C. for 3 hours. It was observed by LCMS that 84% of the desired product was detected. The reaction mixture was filtered and concentrated. 20 mg of crude product was purified by pre-HPLC to give the title compound (4.42 mg, 12.67 µmol, 3.3% yield) as a white solid. LCMS (ESI): RT=0.786 min, mass calc. for C ₁₈ H ₁₂ F ₃ NO ₂ 330.08, m/z obtained 331.9 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ 9.43 (s, 1H), 8.85 (d, J=1.38 Hz, 1H), 8.61 (s, 1H), 8.30 (dd , J=8.88, 1.75 Hz, 1H), 7.92 (d, J=8.88 Hz, 1H), 7.85 (d, J=8.00 Hz, 2H), 7.67 (d, J=8.00 Hz, 2H), 4.00 - 4.09 (m, 3H).

Example 25: N-isopropyl-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxamide (compound 25)

Isopropylamine (27, 9 mg, 0.47 mmol, 41 μl, 3 eq.), followed by HATU (89.8 mg, 0.24 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 16 hours. It was observed by LCMS that 45% of the desired product was detected. The reaction mixture was diluted with DCM (15 ml) and washed with water (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by pre-HPLC to give the title compound (2.33 mg, 6.24 µmol, 3.9% yield) as

- 115 046394 white solid. LCMS (ESI): RT=0.722 min, mass calc. for C ₂₀ H ₁₇ F ₃ N ₂ O 358.13, m/z obtained 359.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.41 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.09 (dd, J=8.91, 1 .63 Hz, 1H), 7.92 (d, J=8.78 Hz, 1H), 7.84 (d, J=8.03 Hz, 2H), 7.67 (d, J=8.03 Hz, 2H), 6.09 (s, 1H), 4.33 - 4.47 (m, 1H), 1.36 (d, J=6.53 Hz, 6H).

Example 26: H-isopropyl-2-methyl-1-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-7 carboxamide (compound 26)

HATU ( 21.3 mg, 56.1 µmol, 1.5 eq.) and DIEA (14.5 mg, 0.11 mmol, 19.5 µl, 3 eq.). The reaction mixture was stirred at 25°C for 16 hours. It was observed by LCMS that 58% of the desired product was detected. The reaction mixture was diluted with EA (20 ml) and washed with saline (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by pre-HPLC to give the title compound (3.15 mg, 8.11 µmol, 21.6% yield) as a white solid. NMR and LCMS confirmed that the desired product was obtained. LCMS (ESI): RT=0.782 min, mass, calc. for C ₂₁ H ₁₉ F ₃ N ₂ O ₂ 388.14, m/z obtained 389.1 [M+1] ⁺ ; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.76 (d, J=1.88 Hz, 1H), 8.23 (dd, J=8.51, 2.00 Hz, 1H), 7.78 (d, J=8.13 Hz, 2H), 7.58 (dd, J=12.26, 8.38 Hz, 3H), 7.18 (s, 1H), 6.26 (br d, J =6.63 Hz, 1H), 4.30 - 4.41 (m, 1H), 3.72 (s, 3H), 1.33 (d, J=6.63 Hz, 6H).

Example 27: N-isopropyl-8-methylsulfinyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 27)

To a solution of compound 27-1 (120 mg, 0.3 mmol, 1 eq.) in DCM (3 ml) was added m-CPBA (47.1 mg, 0.3 mmol, 0.9 eq.). The mixture was stirred at 20°C for 2 hours. It was observed by LCMS that the reagent was completely consumed and that ~83% of the desired compound was detected (m/z=441.9; RT: 0.78 min). The reaction mixture was diluted with DCM (30 ml). This solution was washed successively with saturated Na ₂ SO ₃ (20 mlx2), NaHCO ₃ (20 mlx2) and saline (30 ml). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (65.8 mg, 0.2 mmol, 52.7% yield) as a white solid. lCmS (ESI): RT=0.790 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₂ S 419.1, m/z obtained 442.0 [M+Na]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J=7.6 Hz, 1H), 8.48 (d, J=1.3 Hz, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.06 (dd, J=1.6, 9.0 Hz, 1H), 7.99 - 7.89 (m, 3H), 7.86 - 7.74 (m, 3H), 4.17 (m, 1H), 2.93 (s, 3H), 1.23 (dd, J=2.6, 6.6 Hz, 6H).

Example 28: N-isopropyl-8-methylsulfonyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 28)

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To a solution of compound 28-1 (120 mg, 0.3 mmol, 1 eq.) in DCM (3 ml) was added m-CPBA (104.8 mg, 0.6 mmol, 2 eq.). The mixture was stirred at 20°C for 2 hours. It was observed by LCMS that the reagent was completely consumed and that ~72% of the desired compound was detected (m/z=436.0; RT: 0.82 min). The reaction mixture was diluted with DCM (30 ml). This solution was washed successively with saturated Na ₂ SO ₃ (20 mlx2), NaHCO ₃ (20 mlx2) and saline (30 ml). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (45.8 mg, 0.1 mmol, 35.4% yield) as a white solid. LCMS (ESI): RT=0.825 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₃ S 435.1, m/z obtained 436.0 [M+H]+; ^1H NMR (400 MHz, D\lSO-d6) δ 9.14 (d, J=1.3 Hz, 1H), 8.58 (d, J=7.6 Hz, 1H), 8.38 ( d, J=7.6 Hz, 1H), 8.06 (dd, J=1.6, 8.9 Hz, 1H), 8.00 - 7.91 (m, 3H), 7.78 (t , J=7.5 Hz, 3H), 4.26 - 4.10 (m, 1H), 3.49 (s, 3H), 1.23 (d, J=6.6 Hz, 6H).

Example 29: Nsulfamoyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 29)

Step 1: 5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid

To a mixture of compound 29-1 (0.5 g, 1.99 mmol, 1 eq.), [4-(trifluoromethyl)phenyl]boronic acid (453.9 mg, 2.39 mmol, 1.2 eq.) and Na ₂ CO ₃ (633.2 mg, 5.97 mmol, 3 eq.) in dioxane (7 ml) and H2O (1.3 ml) was added Pd(dppf)Cl ₂ (72.9 mg, 99 µmol, 0 .05 eq.) at 20°C. The mixture was degassed and recharged three times with nitrogen and then stirred at 90°C for 16 hours. It was observed by LCMS that no starting material remained and 48% of the desired product was determined. The mixture was concentrated to remove the organic solvent, diluted with water (10 ml), pH adjusted to ~11 with 1 M NaOH and extracted with EA (15 mlx2). The separated aqueous layer was adjusted to pH~2 with 1 M HCl and extracted with EA (25 mlx3). However, the combined organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to give only 50 mg of residue. The above parts were then combined, concentrated, diluted with 7:1 DCM:MeOH (30 ml) and filtered. The filtrate was concentrated to obtain a residue. The residue was purified by pre-HPLC to give 29-2 (0.21 g, 0.66 mmol, 33.3% yield) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.21 (d, J=8.1 Hz, 1H), 8.00 (dd, J=1.6, 8.8 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.9 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.62 (d, J=6.5 Hz, 1H).

Step 2: ^sulfamoyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A solution of compound 29-2 (80 mg, 0.25 mmol, 1 eq.) and SOCl ₂ (6.02 g, 50.59 mmol, 3.7 mL, 200 eq.) was heated at 80°C for 2 h and then concentrated in vacuo to give a residue, which was quickly dissolved in DCM (3 ml). The resulting solution was added dropwise to a solution of sulfamide (48.6 mg, 0.51 mmol, 30 μl, 2 eq.) and DIPEA (81.7 mg, 0.63 mmol, 0.1 ml, 2.5 eq.) in DCM (3 ml) at 0°C. The resulting mixture was then stirred at 15°C for 16 hours. It was observed by LCMS that no starting material remained and 53% of the desired product was determined. The mixture was quenched with 1 ml of water and then concentrated to obtain a residue. The residue was purified by pre-HPLC to give the title compound (28.1 mg, 69 µmol, 27.3% yield) as a white solid. LCMS (ESI): RT=1.615 min, mass, calc. for C ₁₈ H ₁₃ F ₃ N ₂ O ₃ S 394.06, m/z obtained 395.0 [M+H]+. 1H NMR (400 MHz, DMSO-de) δ 12.08 (s, 1H), 8.70 (d, J=1.3 Hz, 1H), 8.36 (s, 1H), 8.16 (d , J=8.3 Hz, 1H), 7.99 - 7.92 (m, 3H), 7.85 (d, J=9.0 Hz, 1H), 7.78 -7.71 (m, 3H), 7.67 - 7.56 (m, 3H).

Example 30: N-isopropyl-8-(N-methylacetamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 30)

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Step 1: tert-butyl(7-(isopropylcarbamoyl)naphthalene-1-yl)carbamate

To a solution of compound 30-1 (2.0 g, 5.11 mmol, 1 eq.) in DMF (20 mL) was added TEA (1.03 g, 10.22 mmol, 1.4 mL, 2 eq.) PPh ₃ (134.0 mg, 0.51 mmol, 0.1 eq.), Pd(OAc)2 (57.4 mg, 0.26 mmol, 0.05 eq.) and propan-2-amine (604 .1 mg, 10.22 mmol, 0.88 ml, 2 eq.). The reaction mixture was purged with CO, then heated to 60°C and stirred for 16 hours in a CO atmosphere. Using LCMS it was observed that 45% of the required product was detected. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with EA (20 ml) and washed with brine (5 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 4:1). Compound 30-2 (700 mg, 2.07 mmol, 40.5% yield) was obtained as a white solid. ^1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.98 (br d, J=7.04 Hz, 1H), 7.86 (d, J=8.54 Hz, 1H ), 7.70 (dd, J=8.54, 1.25 Hz, 1H), 7.62 (d, J=8.28 Hz, 1H), 7.50 - 7.56 (m, 1H) , 7.12 (br s, 1H), 6.18 (br d, J=7.04 Hz, 1H), 4.29 - 4.42 (m, 1H), 1.57 (s, 9H), 1.31 (d, J=6.54 Hz, 6H).

Step 2: tert-butyl(4-bromo-7-(isopropylcarbamoyl)naphthalene-1-yl)carbamate

To a solution of compound 30-2 (500 mg, 1.52 mmol, 1 eq.) in MeCN (5 ml) was added NBS (325.2 mg, 1.83 mmol, 1.2 eq.). The mixture was stirred at 25°C for 1.5 hours. It was observed by LCMS that 97% of the desired product was detected. The reaction mixture was concentrated in vacuo. The residue was diluted with EA (20 ml), washed with brine (5 mlx2) and the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 4:1). Compound 30-3 (420 mg, 1.03 mmol, 67.7% yield) was obtained as a yellow solid.

Step 3: tert-butyl(7-(isopropylcarbamoyl)-4-(4-(trifluoromethyl)phenyl)naphthalene-1-yl)carbamate

To a solution of compound 30-3 (220 mg, 0.54 mmol, 1 eq.) in dioxane (2 ml) was added Pd(dppf)Cl ₂ (19.8 mg, 27.0 μmol, 0.05 eq.), AcOK (159.0 mg, 1.62 mmol, 3 eq.) and compound 30-3a (153.9 mg, 0.81 mmol, 1.5 eq.). The mixture was stirred at 100°C for 16 hours. Using LCMS, it was observed that the starting material was completely consumed and 70% of the desired product was determined. The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with EA (20 ml), washed with brine (5 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 - 4:1). Compound 30-4 (300 mg, 0.55 mmol, 53.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.935 min, mass calc. for C ₂₆ H ₂₇ F ₃ N ₂ O ₃ , 472.20 m/z, 495.1 [M+Na]+ was obtained; 1H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 8.07 (br d, J=7.78 Hz, 1H), 7.86 (d, J=8.78 Hz, 1H ), 7.75 (d, J=8.04 Hz, 2H), 7.64 (d, J=9.04 Hz, 1H), 7.57 (d, J=8.04 Hz, 2H), 7.48 (d, J=8.04 Hz, 1H), 7.13 (br s, 1H), 6.07 (br d, J=8.28 Hz, 1H), 4.36 (dq, J =13.62, 6.76 Hz, 1H), 1.59 (s, 9H), 1.32 (d, J=6.54 Hz, 6H).

Step 4: 8-amino-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

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To a solution of compound 30-4 (20 mg, 42.3 μmol, 1 eq.) in dioxane (0.5 ml) was added HCl/dioxane (4 M, 0.1 ml, 10 eq.). The mixture was stirred at 20°C for 32 hours. Using LCMS, it was observed that the starting material was completely consumed and 76% of the desired product was determined. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC. Compound 30-5 (8 mg, 21.5 µmol, 50.8% yield) was obtained as a light yellow solid. LCMS (ESI): RT=0.826 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O, 372.14 m/z, 372.9 [M+H]+ was obtained; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H) 7.78 (d, J=8.76 Hz, 1H) 7.66 (br d, J=7.88 Hz, 2H) 7.61 (br d, J=8.88 Hz, 1H) 7.48 (br d, J=7.88 Hz, 2H) 7.26 (d, J=7.64 Hz, 1H) 6.96 (d, J=7.50 Hz, 1H) 6.12 (br d, J=7.38 Hz, 1H) 4.20 - 4.30 (m, 1H) 1.21 (d, J=6, 50 Hz, 6H).

Step 5: 8-acetamido-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 30-5 (50 mg, 0.14 mmol, 1 eq.) in DCM (1 ml) was added TEA (27.2 mg, 0.27 mmol, 37.4 μl, 2 eq.) and acetyl acetate ( 20.6 mg, 0.2 mmol, 18.9 µl, 1.5 eq.). The mixture was stirred at 20°C for 1 hour. It was observed by LCMS that 85% of the desired product was detected. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC. Compound 30-6 (28 mg, 64.9 µmol, 48.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.787 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ , 414.16 m/z obtained 437.0 [M+Na]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 1H), 7.91 - 8.12 (m, 2H), 7.70 -7.82 (m, 3H), 7.60 (br s, 1H), 7.51 (br d, J=7.76 Hz, 2H), 7.44 (br d, J=7.76 Hz, 1H), 6.24 (br d, J=7, 64 Hz, 1H), 4.33 (dq, J=13.59, 6.74 Hz, 1H), 2.39 (s, 3H), 1.32 (d, J=6.50 Hz, 6H) .

Step 6: N-isopropyl-8-(N-methylacetamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 30-6 (5 mg, 12.1 µmol, 1 eq.) in DMF (0.2 ml) was added K2CO3 (8.34 mg, 60.3 µmol, 5 eq.) and MeI (0.89 g, 6.27 mmol, 0.39 ml, 520 eq.). The mixture was stirred at 20°C for 4 hours. It was observed by LCMS that 56% of the desired product was detected. The reaction mixture was filtered. The crude product was purified by pre-HPLC. The title compound (3.5 mg, 8.2 µmol, 67.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.824 min, mass calc. for C ₂₄ H ₂₃ F ₃ N ₂ O ₂ , 428.17 m/z, 429.1 [M+H]+ was obtained; 1H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 7.93 (s, 2H), 7.81 (d, J=8.00 Hz, 2H), 7.62 (d, J=7.88 Hz, 2H), 7.51 (q, J=7.50 Hz, 2H), 6.19 (br d, J=7.63 Hz, 1H), 4.30 - 4.43 (m, 1H), 3.44 (s, 3H), 1.87 (s, 3H), 1.34 (d, J=6.63 Hz, 6H).

Example 31: 8-amino-7-bromo-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 31)

A mixture of compound 31-1 (0.41 g, 0.74 mmol, 1 eq.) in HCl/EtOAc (4 M, 7.44 mL, 40 eq.) was stirred at 25°C for 2 h. Using LCMS completion of the reaction was observed. The mixture was concentrated in vacuo to give the crude product (0.35 g, crude, HCl) as a white solid. The crude product was used in the next step without further purification. The crude product (40 mg) was purified by pre-HPLC to give the title compound (14.7 mg, 30.1 μmol, HCl) as a white solid. LCMS (ESI): RT=1.069 min, mass, calc. for C21H18BrF ₃ N2O 450.06, m/z obtained 453.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=1.3 Hz, 1H), 8.28 (d, J=7.6 Hz, 1H), 7.91 (dd, J =1.5, 8.9 Hz, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.9 Hz, 1H), 7.67 (d , J=8.0 Hz, 2H), 7.53 (s, 1H), 4.17 (qd, J=6.8, 13.8 Hz, 1H), 1.24 (d, J=6, 5 Hz, 6H).

Example 32: 7-bromo-N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 32)

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To a solution of compound 32-1 (650 mg, 1.44 mmol, 1 eq.) in EtOH (2 ml) was added H ₂ SO ₄ (1.20 g, 12.19 mmol, 0.65 ml, 8.47 eq. .) and sodium nitrite (298.1 mg, 4.32 mmol, 3 eq.). The mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with H2O (5 ml) and the mixture was extracted with EA (5 mlx3). The combined organic phase was washed with brine (5 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1 - 1:1) to obtain the crude product (180 mg, 0.30 mmol, 20.9% yield) as a white solid. 40 mg of the crude product was purified by pre-HPLC to give the title compound (26 mg) as a white solid. LCMS (ESI): RT=0.949 min, mass, calc. for C ₂₁ H ₁₇ BrF ₃ NO 435.04, m/z obtained 437.7 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 1.08 - 1.29 (m, 1H) 1.21 (d, J=6.53 Hz, 5 H) 4.15 (dq, J=13, 80, 6.69 Hz, 1H) 7.67 - 7.79 (m, 1H) 7.71 (d, J=2.01 Hz, 1H) 7.76 (d, J=8.53 Hz, 2H ) 7.89 - 7.99 (m, 3H) 8.39 - 8.52 (m, 3H).

Example 33: 8-amino-7-chloro-Misopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 33)

To a mixture of compound 33-1 (0.05 g, 0.13 mmol, 1 eq) in THF (2 ml) was added NCS (21.5 mg, 0.16 mmol, 1.2 eq) under N2. The mixture was stirred for 0.5 h at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with HCl (4 M, 20 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (6.8 mg, 15.2 µmol, 11.3% yield, HCl) as a light yellow solid. LCMS (ESI): RT=0.903 min, mass, calc. for C ₂₁ H ₁₈ ClF ₃ N ₂ O 406.83, m/z obtained 406.9 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 7.93 - 7.80 (m, 5H), 7.66 (br d, J=8.0 Hz, 2H), 7, 48 (s, 1H), 7.51 - 7.46 (m, 1H), 4.29 (td, J=6.6, 13.2 Hz, 1H), 1.33 (d, j=6, 5 Hz, 7H).

Example 34: Misopropyl-8-(N-methylmethylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 34)

Step 1: Misopropyl-8-(methylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 34-1 (120 mg, 0.32 mmol, 1 eq.) in DCM (1 ml) was added TEA (163 mg, 0.64 mmol, 0.2 ml, 5 eq.) and methanesulfonyl chloride (0. 07 g, 4.02 mmol, 50 µl, 2 eq.) at 0°C. The mixture was stirred at 20°C for 1.5 hours. Using LCMS, it was observed that the starting material was completely consumed, and 20% of the required product was determined. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC. Compound 34-2 (14 mg, 31.08 µmol, 9.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.813 min, mass calc. for C ₂₂ H ₂₁ F ₃ N ₂ O ₃ S, 450.12 m/z, 473.0 [M+Na]+ was obtained.

Step 2: N-isopropyl-8-(Mmethylmethylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 34-2 (14 mg, 31 µmol, 1 equiv.) in DMF (1 ml) was added K ₂ CO ₃ (12.9 mg, 93 µmol, 3 equiv.) and MeI (2.5 mg, 15 µmol, 5 eq.). The mixture was stirred at 20°C for 4 hours. Using LCMS, it was observed that the starting material was completely consumed and 82% of the desired product was determined. The reaction mixture was filtered and concentrated in vacuo. The crude product was purified by pre-HPLC. The title compound (5 mg, 10.33 µmol, 33.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.829 min, mass calc. for C ₂₃ H ₂₃ F ₃ N ₂ O ₃ S, 464.14 m/z, 487.0 [M+Na]+ was obtained; 1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 7.87 (s, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.65 (d, J=7.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.51 (d, J=7.5 Hz, 1H), 6.14 (br d, J =7.3 Hz, 1H), 4.40 4.30 (m, 1H), 3.49 (s, 3H), 3.13 (s, 3H), 1.37 -1.31 (m, 6H ).

Example 35: Misopropyl-5-[4-(trifluoromethyl)phenyl]benzo[e][1.2.3]benzoxadiazole-8-carboxamide (compound 35)

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To a solution of compound 35-1 (500 mg, 1.11 mmol, 1 eq.) in EtOH (5 mL) was added _H2SO4 (184.0 mg, 1.84 mmol, 0.1 mL, 1.66 eq.) and sodium nitrite (229.3 mg, 3.32 mmol, 3.0 eq.). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 ml) and the mixture was adjusted to pH 8 with NaOH (4 M). The mixture was extracted with EA (30 mlx3). The combined organic phase was washed with brine (20 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 - 3:1) to obtain the title compound (210 mg, 0.52 mmol, 47.4% yield) as a red solid. LCMS (ESI): RT=0.785 min, mass, calc. for C ₂₁ H ₁₆ F ₃ N ₃ O ₂ 399.12, m/z obtained 400.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.23 (d, J=6.53 Hz, 6 H) 4.20 - 4.30 (m, 1H) 5.91 (br d, J=7, 03 Hz, 1H) 6.63 (s, 1H) 7.32 - 7.40 (m, 2H) 7.45 (d, J=8.03 Hz, 2H) 7.71 (d, J=8, 03 Hz, 2H) 7.80 (d, J=1.25 Hz, 1H).

Example 36: 7-chloro-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 36)

Step 1: 8-amino-7-chloro-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a mixture of compound 36-1 (0.05 g, 0.13 mmol, 1 eq.) in THF (3 ml) was added NCS (17.9 mg, 0.13 mmol, 1 eq.). The mixture was stirred for 0.5 h at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with HCl (4 M, 10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 5:1). Compound 36-2 (30 mg, 73.3 µmol, 54.6% yield) was obtained as a yellow solid.

Step 2: 7-chloro-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a mixture of compound 36-2 (0.02 g, 49.1 µmol, 1 eq.) in EtOH (2 ml) and H ₂ SO ₄ (4.9 mg, 49.1 µmol, 2.67 µl, 1 eq. .) NaNO ₂ (16.9 mg, 0.24 mmol, 5 eq.) and H2O (4.4 mg, 0.24 mmol, 4.4 µl, 5 eq.) were added. The mixture was stirred for 0.5 h at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (2.7 mg, 7.0 µmol, 14.3% yield) as a white solid. LCMS (ESI): RT=0.933 min, mass, calc. for C ₂₁ H ₁₇ ClF ₃ NO 391.81, m/z obtained 391.9 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J=1.5 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.92 - 7.85 (m , 3H), 7.85 - 7.80 (m, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.56 (d, J=2.0 Hz, 1H), 4 .35 - 4.23 (m, 1H), 1.31 (d, J=6.5 Hz, 6H).

Example 37: Aisopropyl-8-methoxy-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 37)

To a solution of compound 37-1 (200 mg, 0.5 nmol, 1 eq.) and CuBr (72.3 mg, 0.5 mmol, 15.4 μl, 1.1 eq.) in DMF (3 ml) CH ₃ ONa (0.13 M, 5.3 ml, 1.5 eq.). The mixture was stirred at 120°C for 16

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h. Using LCMS, complete consumption of the reagent was observed, and ~74% of the desired compound was determined (m/z=388.0; RT: 0.89 min). Ice water (20 ml) was then added and the mixture was neutralized to pH=4~5 with aq. HCl (2 M), The aqueous phase was extracted with ethyl acetate (25 mlx3). The combined organic phase was washed with brine (40 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (61.6 mg, 0.2 mmol, 34.7% yield) as a white solid. LCMS (ESI): RT=0.900 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.1, m/z obtained 388.0 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.53 (d, J=7.0 Hz, 1H), 7.99 - 7.86 (m, 2H), 7.79 (d, J=8.5 Hz, 1H), 7.70 (d, J=7.3 Hz, 2H), 7.52 (d, J=8.0 Hz, 1H), 7. 16 (d, J=8.0 Hz, 1H), 4.22 - 4.13 (m, 1H), 4.16 (m, 1H), 4.08 (s, 3H), 1.21 (d , J=6.0 Hz, 6H).

Example 38: 7-ethynyl-K-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 38)

Step 1: K-isopropyl-5-(4-(trifluoromethyl)phenyl)-7-((trimethylsilyl)ethynyl)-2-naphthamide

Mixture of compound 38-1 (50 mg, 0.11 mmol, 1 eq.), ethynyl(trimethyl)silane (33.7 mg, 0.34 mmol, 47.6 μl, 3 eq.), Pd(dppf)Cl ₂ (8.3 mg, 11.4 µmol, 0.1 eq.), CuI (2.1 mg, 11.4 µmol, 0.1 eq.) and DIPEA (74.0 mg, 0.57 mmol, 99.8 µl, 5 eq) in dioxane (2 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 100°C for 3 hours under N2. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 38-2 (80 mg, crude) was obtained as a yellow solid, which was used in the next step without further purification.

Step 2: 7-ethynyl-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 38-2 (80 mg, 0.17 mmol, 1 eq.) in THF (5 mL) was added TBAF (1 M, 0.17 mL, 1.0 eq.). The mixture was stirred at 25°C for 10 minutes. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (5 mg, 12.9 µmol, 7.3% yield) as a white solid. LCMS (ESI): RT=0.909 min, mass, calc. for C ₂₃ H ₁₈ F ₃ NO 381.39, m/z obtained 381.9 [M+H] ⁺ ; ¹ H NMR (400 MHz, CD3OD) δ 8.43 (d, J=1.6 Hz, 1H), 8.21 (s, 1H), 7.94 - 7.81 (m, 4H), 7, 70 (d, J=8.0 Hz, 2H), 7.58 (d, J=1.5 Hz, 1H), 4.33 - 4.24 (m, 1H), 3.71 (s, 1H ), 1.31 (d, J=6.6 Hz, 6H).

Example 39: N-isopropyl-7-methoxy-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 39)

To a solution of compound 39-1 (100 mg, 0.2 mmol, 1 eq.) and CuBr (36.2 mg, 0.3 mmol, 8 μl, 1.1 eq.) in DMF (2 ml) was added CH ₃ ONa (0.13 M, 2.6 ml, 1.5 eq.). The mixture was stirred at 120°C for 16 hours. Complete consumption of the reagent was observed by LCMS and ~67% of the desired compound was detected (m/z=388.0; RT: 0.89 min). Ice water (20 ml) was then added and the mixture was neutralized to pH=4~5 with aq. HCl (2 M), The aqueous phase was extracted with ethyl acetate (25 mlx3). The combined organic phase was washed with brine (40 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (26.7 mg, 68.9 µmol, 30.1% yield) as a white solid. LCMS (ESI): RT=0.901 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.1, m/z obtained 388.0 [M+H] ⁺ ; ¹ H NMR (400 MHz,

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CD3OD) δ 8.33 (s, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.74 - 7.61 (m, 4H), 7.43 (d, J=2 .3 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 4.27 (m, 1H), 4.01 - 3.94 (m, 1H), 3.97 (s , 2H), 1.29 (d, J=6.8 Hz, 6H).

Example 40: N(2-(2-(2-acetamidoethoxy)ethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 40)

Step 1: tert-butyl(2-(2-(2-(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)ethoxy)ethoxy)ethyl)carbamate

To a solution of compound 40-1 (0.05 g, 0.16 mmol, 1 eq.) and tert-butyl-H-[2-[2-(2aminoethoxy)ethoxy]ethyl]carbamate (47.1 mg, 0. 19 mmol, 1.2 eq.) in DCM (2 ml) was added HATU (90.2 mg, 0.24 mmol, 1.5 eq.) and DIEA (30.7 mg, 0.24 mmol, 41.3 µl, 1.5 eq.). The mixture was stirred at 25°C for 2 hours. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. To prepare the reaction, H ₂ O (25 ml) was added to the solution. The mixture was extracted with ethyl acetate (30 mlx3). The combined organic layers were washed with brine (60 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 -=0:1). Compound 40-2 (0.3 g, crude) was obtained as a white solid.

Step 2: N(2-(2-(2-aminoethoxy)ethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

HCl/dioxane (3 mL) was added to a solution of compound 40-2 (0.3 g, 0.55 mmol, 1 eq.). The mixture was stirred at 25°C for 2 hours. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. The reaction mixture was concentrated in vacuo to obtain the crude product. The reaction mixture was used in the next step without purification. Compound 40-3 (0.2 g, 0.45 mmol, 81.6% yield) was obtained as a white solid.

Step 3: N(2-(2-(2-acetamidoethoxy)ethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 40-3 (0.06 g, 0.13 mmol, 1 eq.) in DCM (2 ml) was added Ac ₂ O (20.6 mg, 0.20 mmol, 18.9 μl, 1.5 eq.), DMAP (16.4 mg, 0.13 mmol, 0.1 eq.) and TEA (40.8 mg, 0.40 mmol, 56.1 μl, 3 eq.). The mixture was stirred at 25°C for 1 hour. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. H ₂ O (20 ml) was added to the solution. The mixture was extracted with ethyl acetate (25 mlx3). The combined organic layers were washed with brine (40 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (19.9 mg, 40.9 µmol, 30.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.794 min, mass, calc. for C ₂₆ H ₂₇ F ₃ N ₂ O ₄ 488.5, m/z obtained 389.1 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 8.77 (br t, J=5.4 Hz, 1H), 8.57 (s, 1H), 8.12 (d, J=8.3 Hz , 1H), 7.92 (d, J=8.0 Hz, 3H), 7.81 (d, J=9.0 Hz, 1H), 7.77 - 7.77 (m, 1H), 7 .78 - 7.67 (m, 2H), 7.60 (d, J=7.3 Hz, 1h), 3.60 - 3.55 (m, 5H), 3.55 - 3.52 (m , 2H), 3.51 - 3.44 (m, 2H), 3.40 (t, J=5.9 Hz, 2H), 3.21 - 3.12 (m, 1H), 3.21 - 3.12(m, 1H), 1.78(s, 3H).

Example 41: N-isopropyl-7-methyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 41)

A mixture of compound 41-1 (50 mg, 0.11 mmol, 1 eq.), compound 41-1a (28.7 mg, 0.22 mmol, 32 μl, 2

- 123 046394 eq.), KOAc (33.7 mg, 0.34 mmol, 3 eq.) and Pd(dppf)Cl ₂ (4.1 mg, 5.7 µmol, 0.05 eq.) in dioxane ( 5 ml) and H2O (1 ml) were degassed and purged with N2 3 times, and then the mixture was stirred at 100°C for 2 h under an N2 atmosphere. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (20 ml) and the mixture was adjusted to pH 4 with HCl (4 M). The mixture was extracted with EA (30 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (6 mg, 15.9 µmol, 13.9% yield) was obtained as a white solid. LCMS (ESI): RT=1.037 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO 371.4, m/z obtained 372.1 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.88 - 7.80 (m, 4H), 7.79 (s, 2H), 7.68 (d, J=8 .0 Hz, 2H), 7.42 (d, J=1.3 Hz, 1H), 4.28 (td, J=6.6, 13.2 Hz, 1H), 4.36 - 4.21 (m, 1H), 2.59 (s, 3H), 1.31 (d, J=6.5 Hz, 6H).

Example 42: Schisopropyl-7-(methylthio)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 42)

A mixture of compound 42-1 (50 mg, 0.11 mmol, 1 eq.), sodium methanethiolate (12 mg, 0.17 mmol, 10.9 μl, 1.5 eq.), Pd ₂ (dba) ₃ (10 .5 mg, 11.4 µmol, 0.1 eq.), Xantphos (6.6 mg, 11.4 µmol, 0.1 eq.) and DIPEA (29.6 mg, 0.22 mmol, 39.9 µl, 2 eq.) in toluene (3 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 100°C for 3 hours under N ₂ atmosphere. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (20 ml) and the mixture was extracted with EA (30 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (4.3 mg, 10.7 µmol, 9.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.925 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NOS 403.46, m/z obtained 403.9 [M+H]+; 1H NMR (400 MHz, CD3OD) 5 8.36 (s, 1H), 7.89 - 7.82 (m, 3H), 7.81 - 7.73 (m, 2H), 7.69 (br d , J=7.8 Hz, 2H), 7.42 (d, J=1.8 Hz, 1H), 4.28 (td, J=6.6, 13.2 Hz, 1H), 2.66 (s, 3H), 1.31 (d, J=6.5 Hz, 8H).

Example 43: 7-cyclopropyl-N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 43)

A mixture of compound 43-1 (50 mg, 0.11 mmol, 1 eq.), cyclopropylboronic acid (11.8 mg, 0.13 mmol, 1.2 eq.), Pd(dppf)Cl ₂ (8.3 mg , 0.01 mmol, 0.1 eq.), H2O (2.0 mg, 0.11 mmol, 2.0 µl, 1 eq.) and K ₃ PO ₄ (72.9 mg, 0.34 mmol, 3 eq.) in THF (5 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 90°C for 1 hour under N2. It was observed by LC-MS and HPLC that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC and SFC. The title compound (5 mg, 12.4 µmol, 10.8% yield) was obtained as a white solid. LCMS (ESI): RT=1.054 min, mass, calc. for C ₂₄ H ₂₂ F ₃ NO 397.43, m/z obtained 398.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 0.73 - 0.80 (m, 2H), 0.96 - 1.03 (m, 2H), 1.19 (d, J=6.53 Hz, 6 H ), 2.00 - 2.11 (m, 1H), 4.12 - 4.20 (m, 1H), 7.17 (d, J=1.76 Hz, 1H), 7.56 (d, J=8.03 Hz, 2H), 7.62 - 7.67 (m, 3H), 7.73 (d, J=8.03 Hz, 2H), 8.24 (s, 1H).

Example 44: 7-amino-N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 44)

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Step 1: 7-('bsnhydrylideneamino)-U-isopropyl-5-[4-('trifluoromethyl)phenyl|naphtha.lin-2-carboxamide

A mixture of compound 44-1 (140 mg, 0.32 mmol, 1 eq.), diphenylmethanimine (69.7 mg, 0.38 mmol, 64.6 μl, 1.2 eq.), tert-BuONa (46.2 mg, 0.48 mmol, 1.5 eq.), Pd(dppf)Cl ₂ (23.4 mg, 0.03 mol, 0.1 eq.) and BINAP (19.9 mg, 0.03 mol, 0.1 eq.) in DMF (3 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 100°C for 30 min with microwave irradiation. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx5), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 4:1). Compound 44-2 (140 mg, 0.14 mmol, 44.7% yield) was obtained as a yellow solid. LCMS (ESI): RT=1.008 min, mass, calc. for C ₃₄ H ₂₇ F ₃ N ₂ O 536.59, m/z obtained 537.0 [M+H]+.

Step 2: 7-amino-M-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide

To a solution of compound 44-2 (140 mg, 0.26 mmol, 1 eq.) in THF (3 ml) was added HCl (12 M, 0.14 ml, 6.44 eq.) and the mixture was stirred at 25°C in for 3 hours. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (2 ml) and the pH of the mixture was adjusted to 7 with NaHCO ₃ . The mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1) and prep-HPLC. The title compound (65 mg, 0.17 mmol, 66.2% yield) was obtained as a red solid. LCMS (ESI): RT=0.778 min, mass, calc. for C ₂₁ H ₁₉ F ₃ N ₂ O 372.38, m/z obtained 373.0 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 1.21 (d, J=6.63 Hz, 6H) 2.29 -2.40 (m, 1H) 4.10 - 4.19 (m, 1H ) 7.19 (s, 1H) 7.16 - 7.18 (m, 1H) 7.40 (br s, 1H) 7.57 - 7.73 (m, 4H) 7.92 (d, J= 8.13 Hz, 2H) 8.30 (s, 1H) 8.36 (brd, J=7.75 Hz, 1H).

Example 45: N-isopropyl-7-methylsulfinyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 45)

A mixture of compound 45-1 (15 mg, 0.03 mmol, 1 eq.) and m-CPBA (6.4 mg, 0.02 mmol, 0.8 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. It was observed by LCMS that the desired compound was detected. The reaction mixture was diluted with H2O (6 ml) and the mixture was extracted with EA (8 ml x 3). The combined organic phase was washed with brine (8 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (2 mg, 4.7 µmol, 12.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.780 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₂ S 419.46, m/z obtained 420.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 1.21 (d, J=6.53 Hz, 6H) 2.85 (s, 3H) 4.18 (quin., J=6.59 Hz, 1H) 7, 61 - 7.71 (m, 2H) 7.68 - 7.69 (m, 1H) 7.76 7.85 (m, 3H) 7.87 - 7.95 (m, 1H) 8.33 (s , 1H) 8.48 (d, J=1.26 Hz, 1H).

Example 46: N-isopropyl-7-methylsulfonyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 46)

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A mixture of compound 46-1 (15 mg, 0.03 mmol, 1 eq.) and m-CPBA (16.0 mg, 0.07 mmol, 2 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. It was observed by LCMS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (6 ml) and the mixture was extracted with EA (8 ml x 3). The combined organic phase was washed with brine (8 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (7 mg, 15.9 µmol, 42.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.828 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₃ S 435.46, m/z obtained 436.0 [M+H]+; ^1H NMR (400 MHz, CD3OD) δ 1.31 - 1.34 (m, 1H) 1.32 - 1.32 (m, 1H) 1.32 - 1.32 (m, 1H) 3.29 ( s, 3H) 4.24 - 4.33 (m, 1H) 7.77 (d, J=8.03 Hz, 2H) 7.92 (d, J=8.03 Hz, 2H) 7.97 ( d, J=8.78 Hz, 1H) 8.01 (d, J=1.76 Hz, 1H) 8.10 (dd, J=8.78, 1.76 Hz, 1H) 8.55 (br d, J=7.28 Hz, 1H) 8.67 (d, J=1.51 Hz, 1H) 8.75 (s, 1H).

Example 47: 7-ethyl-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 47)

A mixture of compound 47-1 (80 mg, 0.20 mmol, 1 eq.), Pd/C (35 mg, 10%, 1.00 eq.) and H ₂ (0.42 mg, 0.20 mmol, 1 eq.) in MeOH (5 ml) was degassed and purged with H ₂ 3 times, and then the mixture was stirred at 25°C for 1 hour in an atmosphere of H 2 . It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (9 mg, 23.1 µmol, 11.0% yield) was obtained as a white solid. LCMS (ESI): RT=1.072 min, mass, calc. for C23H22F3NO 385.42, m/z obtained 386.1 [M+H]+; 1H NMR (400 MHz, CD3OD) δ=8.40 (s, 1H), 7.85 (br d, J=9.3 Hz, 3H), 7.80 (s, 2H), 7.69 (d , J=7.8 Hz, 2H), 7.46 (d, J=1.5 Hz, 1H), 4.29 (td, J=6.6, 13.1 Hz, 1H), 2.91 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.5 Hz, 3H), 1.33 - 1.33 (m, 1H), 1.32 (d, J= 6.8 Hz, 5H).

Example 48: 7-acetamido-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 48)

48-1 Connection 48

A mixture of compound 48-1 (20 mg, 53.7 µmol, 1 eq.), TEA (10.9 mg, 0.10 mmol, 14.9 µl, 2 eq.) and Ac ₂ O (8.22 mg, 80.5 µmol, 7.55 µl, 1.5 eq) in DCM (1 ml) was stirred at 25°C for 30 min. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (12 mg, 28.9 µmol, 53.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.803 min, mass, calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ 414.42, m/z obtained 415.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=2.0 Hz, 1H), 8.36 (s, 1H), 8.37 8.33 (m, 1H), 7.85 ( d, J=8.3 Hz, 2H), 7.77 (s, 1H), 7.77 (br d, J=19.6 Hz, 1H), 7.69 (d, J=8.0 Hz , 2H), 7.64 (d, J=2.0 Hz, 1H), 7.65 - 7.62 (m, 1H), 4.27 (quin., J=6.6 Hz, 1H), 2.21 (s, 3H), 1.30 (d, J=6.5 Hz, 6H).

- 126 046394

Example 49: 1ret-Butyl(2-(2-(2-(5-(4-(1fluoromethyl)phenyl)-2-naphthamdo)ethoxy)ethoxy)ethyl)carbamate (compound 49)

To a solution of compound 49-1 (50 mg, 0.16 mmol, 1 equiv.) and tert-butyl-H-[2-[2-(2aminoethoxy)ethoxy]ethyl]carbamate (47.1 mg, 0.19 mmol , 1.2 eq.) in DCM (1 ml) were added HATU (90.2 mg, 0.24 mmol, 1.5 eq.) and DIEA (30.7 mg, 0.24 mmol, 41.3 μl, 1.5 eq.). The mixture was stirred at 25°C for 2 hours. Using LCMS, it was observed that the starting material was consumed and the required mass was determined. H ₂ O (30 ml) was added to the solution. The mixture was extracted with ethyl acetate (35 mlx3). The combined organic layers were washed with brine (60 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (16.8 mg, 30.6 µmol, 19.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.889 min, mass, calc. for C ₂ 9H33F ₃ N ₂ O ₅ 546.58, m/z obtained 569.1 [M+Na]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (br t, J=5.5 Hz, 1H), 8.56 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.15 - 8.09 (m, 1H), 7.96 - 7.90 (m, 3H), 7.81 (d, J=8.8 Hz, 1H), 7.77 - 7.67 (m, 3H), 7.60 (d, J=7.0 Hz, 1H), 6.76 (br s, 1H), 3.62 - 3.46 (m, 8H), 3 .41 - 3.35 (m, 3H), 3.05 (q, J=5.9 Hz, 2H), 1.36 (s, 9H).

Example 50: N(2-(2-(2-aminoethoxy)ethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 50)

Compound 50-1 (50 mg, 91.5 µmol, 1 eq.) was added to HCl/dioxane (4 ml). The reaction mixture was stirred at 25°C for 1 hour. Using LCMS, it was observed that the starting material was consumed and that the required mass was determined. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by pre-HPLC. The title compound (7.72 mg, 17.3 µmol, 18.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.727 min, mass, calc. for C ₂₄ H ₂₅ F ₃ N ₂ O ₃ 446.46, m/z obtained 447.0 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (br t, J=5.4 Hz, 1H), 8.60 (d, J=1.3 Hz, 1H), 8.12 (d , J=8.3 Hz, 1H), 8.04 -8.00 (m, 1H), 7.98 7.89 (m, 4H), 7.81 (d, J=8.8 Hz, 1H ), 7.77 - 7.67 (m, 3H), 7.62 - 7.58 (m, 1H), 3.63 - 3.59 (m, 8H), 3.54 - 3.48 (m , 2H), 2.94 (br d, J=5.3 Hz, 2H).

Example 51: N-isopropyl-7-(N-methylacetamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 51)

To a solution of compound 51-1 (66 mg, 0.15 mmol, 1 eq.) in DMF (5 ml) was added NaH (12.7 mg, 0.31 mmol, 60%, 2 eq.) at 0°C. The mixture was stirred at 0°C for 30 minutes. MeI (0.42 g, 2.96 mmol, 0.18 mL, 18.6 eq.) was then added to the mixture and the mixture was stirred at 40°C for 1 hour. It was observed by LC-MS that the required compound. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The indicated compound (12 mg, 27.4 µmol, 17.2% yield) was obtained in vitro

- 127 046394 de white solid. LCMS (ESI): RT=0.808 min, mass, calc. for C ₂₄ H ₂₃ F ₃ N ₂ O ₂ 428.45, m/z obtained 429.0 [M+H]+; ^1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.04 (br s, 1H), 7.97 - 7.86 (m, 4H), 7.75 (br d, J =7.8 Hz, 2H), 7.55 (d, J=1.8 Hz, 1H), 4.29 (td, J=6.6, 13.2 Hz, 1H), 3.41 (br s, 1H), 3.43 - 3.38 (m, 1H), 3.43 - 3.37 (m, 1H), 2.07 - 1.90 (m, 3H), 1.32 (d, J=6.5 Hz, 6H).

Example 52: N-isopropyl-7-(methylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 52)

Methanesulfonyl chloride (9.23 mg, 80.5 µmol, 6.2 µl, 1 eq.) was added to a mixture of compound 52-1 (30 mg, 80.5 µmol, 1 eq.) and TEA (24.46 mg, 0 .24 mmol, 33.6 μl, 3 eq.) in DCM (1 ml) at 0°C, then the mixture was stirred at 20°C for 3 hours. Using LC-MS, it was observed that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (15 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (10 mg, 21.9 µmol, 27.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.808 min, mass, calc. for C ₂₂ H ₂₁ F ₃ N ₂ O ₃ S 450.47, m/z obtained 451.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.69 - 7.67 (m, 2H), 7.59 (d, J=8.0 Hz, 2H), 7.32 (d, J=2.3 Hz, 1H), 4.16 (quin ., J=6.5 Hz, 1H), 2.98 (s, 3H), 1.19 (d, J=6.8 Hz, 6H).

Example 53: N-isopropyl-7-(N-methylmethylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 53)

Mel (36.8 eq.), Cs ₂ CO ₃ (3.0 eq.)

DMF, 50 °C, 1 h

To a solution of compound 53-1 (38 mg, 84.3 µmol, 1 eq.) in DMF (2 ml) was added Cs ₂ CO ₃ (82.4 mg, 0.25 mmol, 3 eq.) and MeI (0. 44 g, 3.10 mmol, 0.19 ml, 36.8 eq.). The mixture was stirred at 50°C for 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (10 mg, 21.5 µmol, 25.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.844 min, mass, calc. for C ₂₃ H ₂₃ F ₃ N ₂ O ₃ S 464.50, m/z obtained 465.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.93 - 7.82 (m, 4H), 7, 73 (d, J=8.0 Hz, 2H), 7.67 (d, J=2.3 Hz, 1H), 4.29 (q, J=6.6 Hz, 1H), 3.49 ( s, 2H), 3.46 (s, 1H), 3.00 (s, 1H), 3.04 - 2.93 (m, 1H), 3.06 - 2.93 (m, 1H), 3 .05 - 2.89 (m, 1H), 1.32 (d, J=6.5 Hz, 4H), 1.34 - 1.28 (m, 1H), 1.35-1.28 (m , 1H).

Example 54: N(2,2,2-trifluoroethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 54)

To a mixture of compound 54-1 (0.05 g, 0.15 mmol, 1 eq.) in DMF (2 ml) was added HATU (120.2 mg, 0.31 mmol, 2 eq.) and Et ₃ N (47 .9 mg, 0.47 mmol, 66 µl, 3 eq.). The mixture was stirred for 0.5 h at 25°C. 2,2,2-Trifluoroethanamine (31.3 mg, 0.31 mmol, 24.8 μL, 2 eq.) was then added to the mixture. Stir the mixture

- 128 046394 leave for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H ₂ O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (19 mg, 48 µmol, 30.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.895 min, mass, calc. for: C ₂₀ Hi ₃ F ₆ NO 397.31, m/z obtained 397.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.33 (t, J=6.3 Hz, 1H), 8.63 (d, J=1.5 Hz, 1H), 8.16 (d, J =8.0 Hz, 1H), 7.99 - 7.91 (m, 3H), 7.85 (d, J=9.0 Hz, 1H), 7.77 - 7.70 (m, 3H) , 7.63 (dd, J=1.0, 7.0 Hz, 1H), 4.22 - 4.12 (m, 2H).

Example 55: N-cyclopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 55)

To a mixture of compound 55-1 (0.05 g, 0.15 mmol, 1 eq.) in DMF (2 ml) was added HATU (120.2 mg, 0.31 mmol, 2 eq.) and Et ₃ N (47 .9 mg, 0.47 mmol, 66 µl, 3 eq.). The mixture was stirred for 0.5 h at 25°C. Cyclopropanamine (18 mg, 0.31 mmol, 21.9 μL, 2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (23 mg, 64.9 µmol, 41.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.854 min, mass, calc. for: C21H16F3NO 355.35, m/z obtained 355.9 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (br d, J=3.5 Hz, 1H), 8.52 (s, 1H), 8.11 (br d, J=8.0 Hz, 1H), 7.92 (br d, J=8.5 Hz, 3H), 7.83 - 7.66 (m, 4H), 7.58 (br d, J=6.8 Hz, 1H ), 2.92 (td, J=3.5, 7.0 Hz, 1H), 0.80 0.68 (m, 2H), 0.63 (br d, J=3.0 Hz, 2H) .

Example 56: N(1,3-dihydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 56)

To a mixture of compound 56-1 (0.05 g, 0.15 mmol, 1 eq.) in DMF (2 ml) was added HATU (120.2 mg, 0.31 mmol, 2 eq.) and Et ₃ N (47 .9 mg, 0.47 mmol, 66.0 µl, 3 eq.). The mixture was stirred for 0.5 h at 25°C. 2-Aminopropane-1,3-diol (28.8 mg, 0.31 mmol, 2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (5.9 mg, 15.1 µmol, 9.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.756 min, mass, calc. for: C ₂ iH ₁₈ F ₃ NO ₃ 389.37, m/z obtained 390.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.94 - 7.84 (m, 4H), 7.72 - 7.65 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 4.25 (t, J=5.6 Hz, 1H), 3.80 (d, J= 5.8 Hz, 4H).

Example 57: N(2-(2-methoxyethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 57)

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To a mixture of compound 57-1 (0.05 g, 0.15 mmol, 1 eq.) in DMF (2 ml) was added HATU (120.2 mg, 0.31 mmol, 2 eq.) and Et ₃ N (47 .9 mg, 0.47 mmol, 66.0 µl, 3 eq.). The mixture was stirred for 0.5 h at 25°C. 2-(2-methoxyethoxy)ethanamine (37.6 mg, 0.31 mmol, 2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (9.56 mg, 22.9 µmol, 14.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.843 min, mass, calc. for: C ₂₃ H ₂₂ F ₃ NO ₃ 417.42, m/z obtained 440.0 [M+Na]+; ¹ H NMR (400 MHz, DMSO-δΑ δ 8.75 (t, J=5.8 Hz, 1H), 8.59 - 8.55 (m, 1H), 8.12 (d, J=8, 3 Hz, 1H), 7.96 - 7.90 (m, 3H), 7.83 - 7.68 (m, 4H), 7.60 (d, J=7.0 Hz, 1H), 3, 61 - 3.54 (m, 4H), 3.52 -3.44 (m, 4H), 3.24 (s, 3H).

Example 58: N(2-methoxyethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 58)

To a mixture of compound 58-1 (0.05 g, 0.15 mmol, 1 eq.) in DMF (2 ml) was added HATU (120.2 mg, 0.31 mmol, 2 eq.) and Et ₃ N (47 .9 mg, 0.47 mmol, 66.0 µl, 3 eq.). The mixture was stirred for 0.5 h at 25°C. 2-Methoxyethanamine (23.7 mg, 0.31 mmol, 27.4 μL, 2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (21.1 mg, 56.5 µmol, 35.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.840 min, mass, calc. for: C ₂₁ H ₁₈ F ₃ NO ₂ 373.37, m/z obtained 373.9 [M+H]+; 1H NMR (400 MHz, CD ₃ OD) δ 8.49 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.91 - 7.83 (m, 4H), 7 .74 - 7.65 (m, 3H), 7.58 (dd, J=1.0, 7.0 Hz, 1H), 3.64 (s, 4H), 3.42 (s, 3H).

Example 59: ^)A-(1-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 59) and ^)A-(1-aminopropan-2-yl)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 60)

Step 1: tert-butyl(2-(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)propyl)carbamate

To a mixture of compound 59-1 (0.1 g, 0.31 mmol, 1 eq.) in DMF (10 ml) was added HATU (240.4 mg, 0.63 mmol, 2 eq.) and Et ₃ N (159 .9 mg, 1.58 mmol, 0.22 ml, 5 eq.). The mixture was stirred for 0.5 h at 25°C. Tert-butyl-N(2-aminopropyl)carbamate (66.1 mg, 0.37 mmol, 1.2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 1:1). Compound 59-2 (0.08 g, 0.16 mmol, 53.5% yield) was obtained as a yellow solid.

Step 2: ^)A-(1-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and (R)-N-(1

- 130 046394 aminopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 59-2 (80 mg, 0.16 mmol, 1 eq.) in MeOH (1 mL) was added HCl/dioxane (4 M, 3.00 mL, 70.87 eq.). The mixture was stirred for 1 hour at 25°C. LCMS monitored the completion of the reaction. The mixture was quenched with H ₂ O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the racemic compounds (61 mg). Racemic compounds were separated by the SFC method. Compound 59 (18.8 mg, 50.6 µmol, 29.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.727 min, mass, calc. for: C ₂₁ H ₁₉ F ₃ N ₂ O 372.38, m/z obtained 373.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.81 7.70 (m, 4H), 7.59 - 7.53 (m, 3H), 7.45 (d, J=6.9 Hz, 1H), 4.13 (d, J=6.8 Hz, 1H), 2.73 (d, J= 6.5 Hz, 2H), 1.19 (d, J=6.8 Hz, 3H). Compound 60 (16.1 mg, 43.2 µmol, 25.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.735 min, mass, calc. for: C ₂₁ H ₁₉ F ₃ N ₂ O 372.38, m/z obtained 373.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.81 - 7.70 (m, 4H), 7.60 - 7.53 (m, 3H), 7.45 (d, J=6.8 Hz, 1H), 4.12 (q, J=6.7 Hz, 1H), 2.72 (d, J= 6.3 Hz, 2H), 1.19 (d, J=6.8 Hz, 3H).

Example 60: N(1-fluoro-3-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 61) and N(1,3-difluoropropan-2-yl)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 62)

Step 1: N(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide

To a solution of compound 61-1 (1.86 g, 4.78 mmol, 1 eq.) in DCM (5 ml) was added imidazole (325.3 mg, 4.78 mmol, 1 eq.) and TBDPSCl (1.31 g, 4.78 mmol, 1.23 ml, 1 eq.). The mixture was stirred for 3 hours at 25°C. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was used in the next step without further purification. Compound 61-2 (1.6 g, 2.55 mmol, 53.3% yield) was obtained as a yellow oil.

Step 2: N(1-((tert-butyldiphenylsilyl)oxy)-3-fluoropropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide

To a solution of compound 61-2 (0.8 g, 1.27 mmol, 1 eq.) in DCM (5 mL) was added BAST (2.82 g, 12.74 mmol, 2.79 mL, 10 eq.). The mixture was stirred for 3 hours at 25°C. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was used in the next step without further purification. Compound 61-3 (0.81 g, crude) was obtained as a yellow oil.

Step 3: N(1-fluoro-3-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 61-3 (0.6 g, 0.95 mmol, 1 eq.) in THF (1 mL) was added TBAF (1 M, 4.76 mL, 5 eq.). The mixture was stirred for 3 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 - 1:1). Compound 61 (0.212 g, 0.54 mmol, 56.8% yield) was obtained as a yellow oil. LCMS (ESI): RT=0.768 min, mass, calc. for: C ₂₁ H ₁₇ F ₄ NO ₂ 391.36, m/z obtained 372.0 [M-FH] ⁺ ; 1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.07 (d, J=7.7 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.86 (d, J=8.3 Hz, 3H), 7.73 - 7.66 (m, 3H), 7.59 (d, J=6.8 Hz, 1h), 4.67 - 4 .58 (m, 1H), 4.53 - 4.42 (m, 2H), 3.77 (t, J=4.8 Hz, 2H).

Step 4: N-(1,3-difluoropropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 61 (0.1 g, 0.25 mmol, 1 eq) in DCM (5 mL) was added BAST (565.3 mg, 2.56 mmol, 0.55 mL, 10 eq). The mixture was stirred for 3 hours at 25°C. Completion of the reaction was observed using LCMS and HPLC. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). Unite

- 131 046394 The resulting organic phase was washed with saline (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. Compound 62 (4.38 mg, 10.5 μmol, 4.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.885 min, mass, calc. for: C ₂ iHi ₆ F ₅ NO 393.35, m/z obtained 373.9 [M-FH] ⁺ ; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.58 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.99 (dd, J=1.5, 9 .0 Hz, 1H), 7.91 -7.80 (m, 3H), 7.74 - 7.64 (m, 3H), 7.59 (d, J=6.3 Hz, 1H), 4 .75 - 4.46 (m, 5H), 3.30 - 3.25 (m, 1H), 3.22 (s, 1H).

Example 61: 2-amino-N-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2^]thiazol-8-carboxamide (compound 63)

To a solution of compound 63-1 (50 mg, 0.13 mmol, 1 eq.) and potassium thiocyanate (52.2 mg, 0.54 mmol, 52.2 μl, 4 eq.) in HOAc (2 ml) was added Br ₂ (21.5 mg, 0.13 mmol, 6.9 µl, 1 eq.). The mixture was stirred at 19°C for 16 hours. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. H2O (15 ml) was added to the solution. The mixture was extracted with ethyl acetate (25 mlx3). The combined organic layers were washed with brine (30 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (1.67 mg, 3.6 µmol, 2.6% yield, HCl) was obtained as a white solid. LCMS (ESI): RT=0.821 min, mass, calc. for C ₂₂ H ₁₈ F ₃ N ₃ OS 429.46, m/z obtained 430.0 [M+H] ⁺ ; ^1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 7.96 - 7.93 (m, 3H), 7.90 - 7.87 (m, 1H), 7.88 (d , J=7.8 Hz, 1H), 7.72 (d, J=8.0 Hz, 2H), 4.30 (q, J=6.6 Hz, 1H), 1.33 (d, J =6.6 Hz, 7H).

Example 62: ^)-N-(1-(dimethylamino)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 64) and ^)-N-(1-(dimethylamino )propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 65)

To a mixture of compound 64-1 (0.2 g, 0.63 mmol, 1 eq.) in DMF (10 ml) was added HATU (480.8 mg, 1.26 mmol, 2 eq.) and Et ₃ N (319 .9 mg, 3.16 mmol, 0.44 ml, 5 eq.). The mixture was stirred for 0.5 h at 25°C. Na/N1-dimethylpropane-1,2-diamine (77.5 mg, 0.75 mmol, 1.2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the racemic compounds (51 mg). Racemic compounds were separated by the SFC method. Compound 64 (10.8 mg, 27.1 µmol, 4.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.747 min, mass, calc. for: C ₂₃ H ₂₃ F ₃ N ₂ O 400.44, m/z obtained 401.0 [M+H] ⁺ ; ¹ H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.96 (br d, J=8.0 Hz, 1H), 7.82 - 7.71 (m, 4H), 7 .60 - 7.52 (m, 3H), 7.48 - 7.43 (m, 1H), 4.30 (td, J=6.2, 8.3 Hz, 1H), 2.57 (dd , J=9.0, 12.5 Hz, 1H), 2.25 (dd, J=5.4, 12.7 Hz, 1H), 2.23 - 2.19 (m, 6H), 1, 17 (d, J=6.5 Hz, 3H). Compound 65 (13.8 mg, 34.6 µmol, 5.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.736 min, mass, calc. for: C ₂₃ H ₂₃ F ₃ N ₂ O 400.44, m/z obtained 401.0 [M+H] ⁺ ; ^1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.95 (t, J=6.5 Hz, 1H), 7.82 - 7.69 (m, 4H), 7, 60 - 7.51 (m, 3H), 7.45 (br t, J=6.8 Hz, 1H), 4.30 (br d, J=8.3 Hz, 1H), 2.60 2, 52 (m, 1H), 2.27 - 2.23 (m, 1H), 2.22 (d, J=3.5 Hz, 6H), 1.17 (d, J=6.5 Hz, 3H ).

Example 63: ^)-N-(1-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 66) and ^)-N-( 1-(pyrrolidin-1-yl)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 67)

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To a mixture of compound 66-1 (0.12 g, 0.37 mmol, 1 eq.) in DMF (10 ml) was added HATU (288.5 mg, 0.75 mmol, 2 eq.) and Et ₃ N (191 .9 mg, 1.90 mmol, 0.26 ml, 5 eq.). The mixture was stirred for 0.5 h at 25°C. 1-pyrrolidin-1-ylpropan-2-amine (58.3 mg, 0.45 mmol, 1.2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the racemic compounds (42 mg). Racemic compounds were separated by the SFC method. Compound 66 (4.8 mg, 11.2 µmol, 2.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.768 min, mass, calc. for: C ₂₅ H ₂₅ F ₃ N ₂ O 426.47, m/z obtained 427.1 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.43 - 8.38 (m, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.82 - 7.71 (m, 4H ), 7.61 - 7.53 (m, 3H), 7.46 (d, J=6.5 Hz, 1H), 4.35 - 4.26 (m, 1H), 2.73 (dd, J=8.7, 12.4 Hz, 1H), 2.62 - 2.54 (m, 2H), 2.51 (br dd, J=1.9, 6.9 Hz, 2H), 2, 45 - 2.40 (m, 1H), 1.71 (br s, 4H), 1.19 (d, J=6.5 Hz, 3H). Compound 67 (6.2 mg, 14.1 µmol, 3.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.757 min, mass, calc. for: C ₂₅ H ₂₅ F ₃ N ₂ O 426.47, m/z obtained 427.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J=1.5 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.82 - 7.72 (m , 4H), 7.61 - 7.53 (m, 3H), 7.46 (d, J=6.7 Hz, 1H), 4.35 - 4.26 (m, 1H), 2.73 ( dd, J=8.8, 12.3 Hz, 1H), 2.62 - 2.55 (m, 2H), 2.54 - 2.47 (m, 2H), 2.44 (dd, J= 5.3, 12.3 Hz, 1H), 1.71 (br s, 4H), 1.19 (d, J=6.5 Hz, 3H).

Example 64: Aisopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2A]thiazole-8-carboxamide (compound 68)

Step 1: 2-amino-X-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2A]thiazole-8-carboxamide

To a solution of compound 68-1 (0.2 g, 0.53 mmol, 1 eq.) and potassium thiocyanate (208.7 mg, 2.15 mmol, 0.20 mL, 4 eq.) in HOAc (2 mL) Br ₂ (85.8 mg, 0.53 mmol, 27.6 µl, 1 eq.). The mixture was stirred at 19°C for 16 hours. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. H2O (5 ml) was added to the solution. The mixture was extracted with ethyl acetate (10 mlx3). The combined organic layers were washed with brine (15 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Compound 68-2 (200 mg, 0.46 mmol, 86.7% yield) was obtained as a white solid.

Step 2: Aisopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2A]thiazole-8-carboxamide

To a solution of compound 68-2 (0.15 g, 0.34 mmol, 1 eq.) in THF (3 mL) was added isopentyl nitrite (81.8 mg, 0.69 mmol, 94.0 μl, 2 eq.). The mixture was stirred at 19°C for 2 hours. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. H2O (30 ml) was added to the solution. The mixture was extracted with ethyl acetate (35 mlx3). The combined organic layers were washed with brine (60 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (36.27 mg, 87.5 µmol, 25.0% yield) was obtained as a brown solid. LCMS (ESI): RT=0.879 min, mass, calc. for C ₂₂ H ₁₇ F ₃ N ₂ OS 414.44, m/z obtained 415.0 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 9.37 (d, J=1.5 Hz, 1H), 8.70 (d, J=7.8 Hz, 1H), 8.34 (s, 1H), 8.05 (dd, J=1.8, 8.8 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7, 88 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 4.21 (qd, J=6.7, 13.9 Hz, 1H), 1.24 (d, J=6.5 Hz, 7H).

Example 65: ^)-X-(1-morpholinopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 69) and ^)-X-(1-morpholinopropan-2-yl) )-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 70)

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To a mixture of compound 69-1 (0.2 g, 0.63 mmol, 1 eq.) in DMF (3 ml) was added HATU (480.8 mg, 1.26 mmol, 2 eq.) and Et ₃ N (319 .9 mg, 3.16 mmol, 0.44 ml, 5 eq.). The mixture was stirred for 0.5 h at 25°C. 1-morpholinopropan-2-amine (109.4 mg, 0.75 mmol, 1.2 eq.) was then added to the mixture. The mixture was stirred for 1.5 hours at 25°C. Completion of the reaction was observed using LCMS and HPLC. The mixture was quenched with H ₂ O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the racemic compounds (50 mg). Racemic compounds were separated by the SFC method. Compound 69 (12.5 mg, 26.9 µmol, 4.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.751 min, mass, calc. for: C ₂₅ H ₂₅ F ₃ N ₂ O ₂ 442.47, m/z obtained 443.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.97 (br d, J=8.1 Hz, 1H), 7.82 - 7.70 (m, 4H), 7, 65 - 7.52 (m, 3H), 7.51 - 7.42 (m, 1H), 3.61 (br s, 4H), 3.55 - 3.41 (m, 1H), 3.35 - 3.26 (m, 1H), 2.81 (br d, J=6.5 Hz, 1H), 2.67 - 2.45 (m, 4H), 1.09 - 0.99 (m, 3H). Compound 70 (10.2 mg, 23.0 µmol, 3.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.760 min, mass, calc. for: C ₂₅ H ₂₅ F ₃ N ₂ O ₂ 442.47, m/z obtained 443.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.09 (br d, J=8.0 Hz, 1H), 7.95 - 7.80 (m, 4H), 7 .78 - 7.65 (m, 3H), 7.63 - 7.57 (m, 1H), 3.81 - 3.68 (m, 4H), 3.61 (dd, J=8.0 7 ,1, 13.6 Hz, 1H), 3.42 (br dd, J=8.0 6.5, 13.6 Hz, 1H), 2.93 (br d, J=8.0 6.9 Hz, 1H), 2.81 -2.58 (m, 4H), 1.19 - 1.11 (m, 3H).

Example 66: N-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2^]oxazole-8-carboxamide (compound 71)

Step 1: 8-amino-Nisopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 71-1 (200 mg, 0.44 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl1,3,2-dioxaborolane-2 -yl)-1,3,2-dioxaborolane (168.8 mg, 0.66 mmol, 1.5 eq.) in dioxane (2 ml) was added AcOK (86.9 mg, 0.88 mmol, 2 eq. ) and Pd(dppf)Cl ₂ (16.2 mg, 22.1 µmol, 0.05 eq.). The mixture was stirred at 90°C for 2 hours. It was observed by LCMS that the starting material was consumed and the required weight was determined. H ₂ O (15 ml) was added to the solution. The mixture was extracted with ethyl acetate (25 mlx3). The combined organic layers were washed with brine (40 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). Compound 71-2 (100 mg, crude) was obtained as a yellow oil.

Step 2: 8-amino-7-hydroxy-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 71-2 (100 mg, 0.20 mmol, 1 eq.) in THF (2 ml) was added sodium 3oxydioxaborirane tetrahydrate (92.6 mg, 0.60 mmol, 0.11 ml, 3 eq.) and H2O (0.5 ml). The mixture was stirred at 25°C for 1 hour. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. H ₂ O (15 ml) was added to the solution. The mixture was extracted with ethyl acetate (25 mlx3). The combined organic layers were washed with brine (50 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. Compound 71-3 (90 mg, crude) was obtained as a brown solid.

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Step 3: Y-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2-1|oxazole-8-carboxamide

TsOH (3.9 mg, 23 .1 µmol, 0.1 equiv.). The mixture was stirred at 60°C for 1 hour. Using LCMS, it was observed that the starting material was consumed and the required weight was determined. H2O (3 ml) was added to the solution. The mixture was extracted with ethyl acetate (5 mlx3). The combined organic layers were washed with brine (6 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the product (5 mg). HPLC observed that ~54% of the desired product was detected. The product was purified by the SFC method. The title compound (1 mg, 2.4 µmol, 1.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.856 min, mass, calc. for C ₂₂ H ₁₇ F ₃ N ₂ O ₂ 398.38, m/z obtained 399.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 8.60 (s, 1H), 7.84 (s, 3H), 7.78 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 4.20 (quin., J=6.6 Hz, 1H), 1.22 (d, J=6.6 Hz, 8H ).

Example 67: 5,6-difluoro-Aisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 72)

Step 1: 8-bromo-5,6-difluoroquinoline-3-carboxylic acid

A solution of compound 72-1 (140 mg, 0.46 mmol, 1.0 eq.) in MeOH (2 mL) and THF (2 mL) was added dropwise with a solution of NaOH (1 M, 0.93 mL, 2.0 eq. ). The reaction mixture was stirred at 25°C for 2 hours. The pH of the reaction mixture was adjusted to 2 with HCl (1 M), and then the resulting mixture was extracted with EA (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 72-2 (120 mg, 89% yield) as a white solid.

Step 2: 8-bromo-5,6-difluoro-Aisopropylquinoline-3-carboxamide

To a solution of compound 72-2 (30 mg, 0.10 mmol, 1.0 eq.), DIPEA (27 mg, 0.20 mmol, 2.0 eq.) and compound 72-2a (12.3 mg, 0 .20 mmol, 2.0 eq.) HATU (47.5 mg, 0.12 mmol, 1.2 eq.) was added to DCM (2 mL). 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 (20 ml) and the resulting mixture was extracted with EA (30 ml x 3).

The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to give compound 72-3 (30 mg, 87% yield) as a white solid.

Step 3: 5,6-difluoro-Aisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 72-3 (30 mg, 91 µmol, 1.0 eq.), compound 72-3a (21 mg, 0.11 mmol, 1.2 eq.) and Na ₂ CO ₃ (19 mg, 0. 18 mmol, 2.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (3.3 mg, 4.6 µmol, 0.05 eq.) under N2 atmosphere . The reaction mixture was stirred at 100°C for 2 under N2 atmosphere. Complete consumption of the starting material was observed by LC-MS and one major peak with the required MS was identified. 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 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (12.80 mg, 35% yield) as a white solid. LCMS (ESI): RT=0.890 min, mass calc. for C ₂₀ H ₁₅ F ₅ N ₂ O 394.11, m/z obtained 394.9 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 7.77 (s, 4H ), 7.72 (dd, J=8.5, 10.8 Hz, 1H), 6.11 (d, J=7.3 Hz, 1H), 4.44 - 4.32 (m, 1H) , 1.35 (d, J=6.5 Hz, 6H).

Example 68: 5,6-difluoro-A(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 73)

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Step 1: 8-bromo-5,6-difluoro-U-(methyls-ulfonyl)quinoline-3-carboxamide

To a solution of compound 73-1 (20 mg, 69 μmol, 1.0 eq.) in DMF (0.5 ml) was added CDI (12 mg, 76 μmol, 1.1 eq.). The reaction mixture was stirred at 40°C for 30 minutes. The reaction was cooled to 25°C and then DBU (13 mg, 83 μmol, 1.2 eq.) and compound 73-1a (8 mg, 83 μmol, 1.2 eq.) were added. The reaction mixture was stirred at 25°C for 2 hours. Using LC-MS, it was observed that the starting material was completely consumed, and one major peak was detected with the required MS. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 73-2 (22 mg, crude) as a yellow solid.

Step 2: 5,6-difluoro-N(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 73-2 (30 mg, 82 µmol, 1.0 eq.), compound 73-2a (16 mg, 82 µmol, 1.0 eq.) and Na ₂ CO ₃ (17.4 mg, 0.0 eq.) 16 mmol, 2.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (3.0 mg, 4.1 µmol, 0.05 eq.) under N2 atmosphere . The reaction mixture was stirred at 90°C for 16 hours under N ₂ atmosphere. Using LC-MS, it was observed that the starting material was completely consumed and one major peak was identified with the required MS. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (2.66 mg, 6.9% yield, HCl) as a white solid. LCMS (ESI): RT=0.946 min, mass calc. for C18H11F5N2O3S 430.04, m/z obtained 431.0 [M+H]+; ¹ H NMR (500 MHz, DMSO^) δ 9.29 (dd, J=2.1, 12.7 Hz, 2H), 8.25 (dd, J=8.5, 11.3 Hz, 1H) , 7.90 (s, 4H), 3.47 - 3.45 (m, 1H), 3.46 (s, 4H).

Example 69: tert-butyl(1-oxo-1-(5-(4-(trifluoromethyl)phenyl)naphthalene-2-yl)-5,8,11-trioxa-2azatridecan-13-yl)carbamate (compound 74)

A mixture of compound 74-1 (50 mg, 0.15 mmol, 1 eq.), HATU (90.1 mg, 0.23 mmol, 1.5 eq.) and DIEA (30.6 mg, 0.23 mmol, 41.3 µl, 1.5 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then tert-butyl-N[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl ]carbamate (46.2 mg, 0.15 mmol, 1 eq.) was added to the mixture and the mixture was stirred at 25°C for 1 hour. It was observed by LC-MS and HPLC that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (30 mg, 50.7 µmol, 32.1% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.828 min, mass, calc. for C ₃₁ H ₃₇ F ₃ N ₂ O ₆ 590.63, m/z obtained 613.1 [M+Na]+; 1H NMR (400 MHz, CD3OD) δ 1.33 - 1.46 (m, 9 H), 3.17 (t, J=5.57 Hz, 2H), 3.45 (t, J=5.50 Hz, 2H), 3.54 - 3.59 (m, 2H), 3.62 (br s, 1H), 3.63 - 3.69 (m, 1H), 3.63 - 3.68 (m , 1H), 3.63 - 3.68 (m, 1H), 3.70 - 3.71 (m, 2H), 3.71 3.75 (m, 2H), 4.78 - 4.95 ( m, 9 N), 7.58 (dd, J=7.07, 0.94 Hz, 1H), 7.65 - 7.72 (m, 3H), 7.82 -7.93 (m, 1H ), 7.83 - 7.91 (m, 3H), 8.08 (d, J=8.26 Hz, 1H), 8.50 (s, 1H).

Example 70: tert-butyl(1-oxo-1-(5-(4-(trifluoromethyl)phenyl)naphthalene-2-yl)-5,8,11,14-tetraoxa-2azahexadecan-16-yl)carbamate (compound 75)

A mixture of compound 75-1 (50 mg, 0.15 mmol, 1 eq.), DIEA (30.6 mg, 0.23 mmol, 41.3 μl, 1.5 eq.) and HATU (90.1 mg, 0.23 mmol, 1.5 eq.) in DCM (1 ml) was stirred at 25°C for 1 hour. Then tert-butyl-N[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy ]ethoxy]ethyl]carbamate (53.1 mg, 0.15 mmol, 1 eq.) was added to the mixture and the mixture was stirred at 25°C for 1 hour. It was observed by LC-MS and HPLC that the desired compound was detected . The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with saline (10 ml x 3),

- 136 046394 dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (25 mg, 39.3 µmol, 24.9% yield) was obtained as a yellow oil. LCMS (ESI): RT=0.886 min, mass, calc. for C ₃₃ H ₄₁ F ₃ N ₂ O ₇ 634.68, m/z obtained 657.1 [M+Na]+; 1H NMR (400 MHz, CD3OD) δ 1.43 (s, 9 H), 3.18 (t, J=5.52 Hz, 2H), 3.44 (t, J=5.52 Hz, 2H) , 3.49 - 3.54 (m, 2H), 3.54 - 3.59 (m, 2H), 3.59 - 3.63 (m, 2H), 3.64 - 3.68 (m, 4 H), 3.69 (s, 3H), 3.71 - 3.76 (m, 2H), 7.59 (d, J=7.03 Hz, 1H), 7.64 - 7.74 ( m, 3H), 7.81 - 7.94 (m, 4H), 8.09 (d, J=8.28 Hz, 1H), 8.51 (s, 1H).

Example 71: M(4-oxo-2,8,11-trioxa-5-azatridecan-13-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 76)

A mixture of compound 76-1 (50 mg, 0.11 mmol, 1 eq.), 2-methoxyacetyl chloride (14.5 mg, 0.13 mmol, 12.2 μl, 1.2 eq.) and DIEA (57.9 mg, 0.44 mmol, 78.0 μl, 4 eq.) in DCM (3 ml) was stirred at 25°C for an additional 2 hours. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (12 mg, 22.6 µmol, 20.2% yield) was obtained as a yellow oil. LCMS (ESI): RT=0.828 min, mass, calc. for C ₂₇ H ₂₉ F ₃ N ₂ O ₅ 518.52, m/z obtained 519.2 [M+H]+; ^1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.90 7.83 (m, 4H), 7.72 - 7.65 (m, 3H), 7.58 (dd, J=0.9, 7.1 Hz, 1H), 3.84 (s, 2H), 3.75 - 3.71 (m, 2H ), 3.70 - 3.65 (m, 6H), 3.61 - 3.56 (m, 2H), 3.44 - 3.39 (m, 2H), 3.37 (s, 3H), 3.33 (td, J=1.6, 3.3 Hz, 5H).

Example 72: M(5-oxo-2,9,12-trioxa-6-azatetradecan-14-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 77) o

A mixture of 3-methoxypropanoic acid (17.4 mg, 0.16 mmol, 15.7 μl, 1.5 eq.), HATU (63.8 mg, 0.16 mmol, 1.5 eq.) and DIEA (57 .9 mg, 0.44 mmol, 78.0 μl, 4 eq.) in DCM (2 ml) was stirred at 25°C for 1 h. Then compound 77-1 (50 mg, 0.11 mmol, 1 eq. .) was added to the mixture and the mixture was stirred for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (30 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (10 mg, 18.5 µmol, 16.6% yield) was obtained as a yellow oil. LCMS (ESI): RT=0.899 min, mass, calc. for C ₂₈ H ₃₁ F ₃ N ₂ O ₅ 532.56, m/z obtained 533.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.50 (d, J=1.3 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.89 -7.83 (m , 4H), 7.72 - 7.67 (m, 1H), 7.66 (s, 1H), 7.72 - 7.65 (m, 1H), 7.58 (dd, J=1.1 , 7.1 Hz, 1H), 3.76 - 3.63 (m, 8H), 3.61 - 3.54 (m, 1H), 3.57 (td, J=5.9, 7.5 Hz, 3H), 3.36 (t, J=5.5 Hz, 2H), 3.34 - 3.32 (m, 3H), 3.29 (s, 3H), 2.41 (t, J =6.1 Hz, 2H).

Example 73: M(ethylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 78)

EDCI (90.9 mg, 0.47 mmol, 1.5 eq.) and DMAP (96.5 mg, 0.79 mmol, 2.5 eq.). The mixture was stirred at 19°C for 1 hour. Using LCMS and HPLC, it was observed that the initial

- 137 046394 the substance has been consumed. H2O (8 ml) was added to the solution. The mixture was extracted with ethyl acetate (10 mlx3). The combined organic layers were washed with brine (15 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the crude product (18 mg). The residue was purified by the SFC method. The title compound (7.2 mg, 17.7 µmol, 5.6% yield) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.07 - 8.02 (m, 1H) , 7.91 (d, J=8.0 Hz, 2H), 7.77 - 7.71 (m, 3H), 7.64 (s, 1H), 7.54 (s, 1H), 3, 18 (q, J=7.1 Hz, 2H), 1.15 (t, J=7.4 Hz, 3H).

Example 74: K-(isopropylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 79)

To a solution of compound 79-1 (50 mg, 0.15 mmol, 1 eq.) and propane-2-sulfonamide (29.2 mg, 0.23 mmol, 1.5 eq.) in DCM (2 ml) was added EDCI (45.4 mg, 0.23 mmol, 1.5 eq.) and DMAP (48.2 mg, 0.39 mmol, 2.5 eq.). The mixture was stirred at 19°C for 1 hour. It was observed by LCMS that the starting material was consumed. H ₂ O (10 ml) was added to the solution. The mixture was extracted with ethyl acetate (10 mlx3). The combined organic layers were washed with brine (12 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (12.3 mg, 29.2 µmol, 18.4% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.28 -12.20 (m, 1H), 8.75 (s, 1H), 8.20 (d, J=7.8 Hz, 1H), 7 .98 - 7.92 (m, 3H), 7.86 (s, 1H), 7.75 (d, J=7.8 Hz, 3H), 7.69 - 7.65 (m, 1H), 3.92 - 3.83 (m, 1H), 1.35 (d, J=6.8 Hz, 6H).

Example 75: 6-Ethoxy-K-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound

80)

Step 1: 8-bromo-6-ethoxyquinoline-3-carboxylic acid

To a solution of compound 80-1 (150 mg, 0.484 mmol, 1.0 eq.) in THF (1.5 ml) and MeOH (1.5 ml), a solution of NaOH (2 M, 0.48 ml, 2 ,0 eq.). The reaction mixture was stirred at 25°C for 2 hours. Complete consumption of the starting material was observed by LC-MS, and one major peak with the required MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 ml) and then the pH of the residue was adjusted to 6 with HCl (1 M). The resulting mixture was extracted with EA (40 ml x 3 ). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 80-2 (130 mg, 90% yield) as a white solid. LCMS (ESI): RT=0.829 min, mass, calc. C ₁₂ H ₁₀ BrNO ₃ 294.98, m/z obtained 296.0 [M+H]+.

Step 2: 8-bromo-6-ethoxy-N-isopropylquinoline-3-carboxamide

To a solution of compound 80-2 (40.0 mg, 0.13 mmol, 1 eq.), compound 80-2a (9.6 mg, 0.16 mmol, 1.2 eq.) and DIPEA (52.3 mg , 0.40 mmol, 3.0 eq.) HATU (61.6 mg, 0.16 mmol, 1.2 eq.) was added to DCM (2 mL). The reaction mixture was stirred at 25°C for 0.5 h. Complete consumption of the starting material was observed by LC-MS and one major peak with the required MS was detected. The mixture was diluted with water (10 ml) and the resulting mixture was extracted with DCM (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. Remainder

- 138 046394 was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:1) to obtain compound 80-3 (40 mg, 87% yield) as a white solid.

Step 3: 6-ethoxy-U-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 80-3 (40 mg, 0.12 mmol, 1.0 eq.), compound 80-3a (23 mg, 0.12 mmol, 1.0 eq.) and Na ₂ CO ₃ (25 mg, 0.24 mmol, 2.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (4.3 mg, 5.9 µmol, 0.05 eq.). The reaction mixture was stirred at 90°C for 2 hours under N2 atmosphere. Complete consumption of the starting material was observed by LC-MS and one major peak with the required MS was identified. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (20.00 mg, 41% yield) as a white solid. LCMS (ESI): RT=1.008 min, mass calc. for C ₂₂ H ₂₁ F ₃ N ₂ O ₂ 402.16, m/z obtained 403.1 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (d, J=2.3 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 7.83 - 7.78 (m, 2H), 7.78 - 7.73 (m, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H) , 6.05 (d, J=7.5 Hz, 1H), 4.43 - 4.32 (m, 1H), 4.21 (q, J=6.9 Hz, 2H), 1.53 ( t, J=6.9 Hz, 3H), 1.33 (d, J=6.5 Hz, 6H).

Example 76: 6-ethoxy-N(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 81)

Step 1: 8-bromo-6-ethoxy-N(methylsulfonyl)quinoline-3-carboxamide

To a solution of compound 81-1 (40 mg, 0.14 mmol, 1 eq.) in DMF (1 ml) was added CDI (24 mg, 0.15 mol, 1.1 eq.). The reaction mixture was stirred at 40°C for 30 minutes. The reaction was cooled to 25°C and then DBU (25 mg, 0.16 mmol, 1.2 eq) and compound 81-1a (15 mg, 0.16 mmol, 1.2 eq) were added. The reaction mixture was stirred at 25°C for 5.5 hours. The reaction mixture was concentrated under reduced pressure. The pH of the reaction mixture was adjusted to 4 with HCl (1 M). The mixture was diluted with water (10 ml) and the resulting mixture was extracted with EA (30 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=1:0 - 10:1) to give compound 81-2 (40 mg, crude) as a white solid.

Step 2: 6-ethoxy-N(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 81-2 (40 mg, 0.11 mmol, 1 eq.), compound 81-2a (20 mg, 0.11 mmol, 1.0 eq.) and Na ₂ CO ₃ (34 mg, 0. 32 mmol, 3.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) Pd(dppf)Cl ₂ (3.9 mg, 5.4 µmol, 0.05 eq.) was added. The reaction mixture was stirred at 90°C for 16 hours under N2 atmosphere. Complete consumption of the starting material was observed by LC-MS and one major peak with the required MS was identified. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (5 ml) and then the pH of the residue was adjusted to 5 with HCl (1 M). The resulting mixture was extracted with EA (20 ml x 3 ). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (10.10 mg, 19% yield) as a white solid. LCMS (ESI): RT=0.959 min, mass calc. for C ₂₀ H ₁₇ F ₃ N ₂ O ₄ S 438.09, m/z obtained 439.0 [M+H]+; 1H NMR (400 MHz, DMSO-de) δ 12.54 (br s, 1H), 9.08 (d, J=2.1 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 7.92 - 7.82 (m, 4H), 7.63 - 7.59 (m, 2H), 4.27 (q, J=7.0 Hz, 2H), 3.45 (s , 3H), 1.45 (t, J=6.9 Hz, 3H).

Example 77: N(cyclopropylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 82)

EDCI (45.4 mg, 0.23 mmol, 1.5 eq.) and DMAP (48.2 mg, 0.39 mmol, 2.5 eq.). The mixture was stirred at 19°C for 1 hour. It was observed by LCMS that

- 139 046394 the active substance has been used up. H2O (10 ml) was added to the solution. The mixture was extracted with ethyl acetate (15 mlx3). The combined organic layers were washed with brine (15 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. It was observed by HPLC that ~100% of the required mass was determined. The residue was purified by pre-HPLC. The title compound (14.6 mg, 34.9 µmol, 22.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.874 min, mass, calc. for C ₂₁ H ₁₆ F ₃ NO ₃ S 419.42, m/z obtained 419.8 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J=1.5 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.99 (dd, J=1.8, 8.9 Hz, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.82 (d, J=8.9 Hz, 1H), 7.75 ( d, J=8.1 Hz, 2H), 7.73 - 7.68 (m, 1H), 7.65 - 7.60 (m, 1H), 3.19 - 3.09 (m, 1H) , 1.16-1.01 (m, 4H).

Example 78: 5-(4-(trifluoromethyl)phenyl)-C-((trifluoromethyl)sulfonyl)-2-naphthamide (compound 83)

EDCI (45.4 mg, 0.23 mmol, 1.5 eq.) and DMAP (48.2 mg, 0.39 mmol, 2.5 eq.). The mixture was stirred at 19°C for 1 hour. Using LCMS, it was observed that the starting material was consumed. H ₂ O (9 ml) was added to the solution. The mixture was extracted with ethyl acetate (12 mlx3). The combined organic layers were washed with brine (15 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (6.0 mg, 13.4 µmol, 8.4% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 - 8.78 (m, 1H), 8.61 (d, J=1.3 Hz, 1H), 8.15 (d, J=8, 0 Hz, 1H), 8.02 (dd, J=1.6, 8.9 Hz, 1H), 7.91 (d, J=8.3 Hz, 2H), 7.79 - 7.71 ( m, 3H), 7.69 - 7.60 (m, 1H), 7.55 (d, J=6.0 Hz, 1H), 7.26 - 6.94 (m, 1H).

Example 79: ^)-K-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 84)

A mixture of compound 84-1 (60 mg, 0.18 mmol, 1 eq.), HATU (108.2 mg, 0.28 mmol, 1.5 eq.) and DIEA (73.5 mg, 0.56 mmol, 99.1 µl, 3 eq.) in DCM (3 ml) was stirred at 25°C for 1 hour. Then (2S)-2aminopropan-1-ol (14.2 mg, 0.18 mmol, 14.7 µl , 1 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (15 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (50 mg, 0.13 mmol, 69.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.931 min, mass calc. for C2iHi ₈ F3NO2 373.37, m/z obtained 374.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=1.5 Hz, 1H), 8 .34 (d, J=8.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.96 - 7.90 (m, 3H), 7.81 (d, J=8.8 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.62 - 7.56 (m, 1H), 4.12 - 4.04 (m, 1H), 3 .52 (br dd, J=5.9, 10.7 Hz, 1H), 2.45 (br s, 1H), 1.18 (d, J=6.8 Hz, 3H).

Example 80: ^)-K-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 85)

- 140 046394

A mixture of compound 85-1 (70 mg, 0.22 mmol, 1 eq.), HATU (126.2 mg, 0.33 mmol, 1.5 eq.) and DIEA (85.8 mg, 0.66 mmol, 0.11 ml, 3 eq.) in DCM (3 ml) was stirred at 25°C for 1 hour. Then 2-aminopropan-1-ol (19.9 mg, 0.26 mmol, 21.1 µl, 1.2 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (52 mg, 0.13 mmol, 62.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.924 min, mass calc. for C21H18F3NO2 373.37, m/z obtained 374.1 [M+H]+, ¹ H NMR (400 MHz, DMSO40 δ 8.57 (s, 1H), 8.34 (d, J=8.0 Hz , 1H), 8.11 (s, 1H), 7.96 - 7.90 (m, 3H), 7.81 (d, J=8.8 Hz, 1H), 7.76 - 7.67 ( m, 3H), 7.59 (d, J=6.5 Hz, 1H), 4.11 - 4.03 (m, 1H), 4.12 (s, 1H), 3.57 - 3.47 (m, 1H), 3.52 (dd, J=5.8, 10.5 Hz, 1H), 3.41 (br s, 1H), 1.18 (d, J=6.8 Hz, 3H ).

Example 81: N(2-hydroxyethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 86)

A mixture of compound 86-1 (70 mg, 0.22 mmol, 1 eq.), HATU (126.2 mg, 0.33 mmol, 1.5 eq.) and DIEA (85.8 mg, 0.66 mmol, 0.11 ml, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then 2-aminoethanol (16.2 mg, 0.26 mmol, 16.0 μl, 1.2 eq.) was added to the mixture and the mixture was stirred for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (36 mg, 0.10 mmol, 45.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.898 min, mass calc. for C20H16F3NO2 359.34, m/z obtained 360.1 [M+H] ⁺ , 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br t, J=5.5 Hz, 1H), 8, 58 (d, J=1.5 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.98 - 7.89 (m, 3H), 7.81 (d, J =8.8 Hz, 1H), 7.77 - 7.67 (m, 3H), 7.59 (dd, J=1.0, 7.0 Hz, 1H), 4.78 (br s, 1H ), 3.61 - 3.51 (m, 2H), 3.45 - 3.39 (m, 2H).

Example 82: Schizopropyl-8-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 87) and 8-iodo-N-isopropyl-5-(4-(trifluoromethyl)phenyl)-2 -naphthamide (compound 88)

- 141 046394

Step 1: N-isopropyl-8-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a mixture of compound 87-1 (0.4 g, 0.91 mmol, 1 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolane -2-yl)-1,3,2-dioxaborolane (465.6 mg, 1.83 mmol, 2 eq.) in dioxane (3 ml) was added Cs ₂ CO ₃ (896.2 mg, 2.75 mmol, 3 equiv.) and Pd(dppf)Cl ₂ (67.0 mg, 91.6 µmol, 0.1 equiv.) at 25°C in an N2 atmosphere. The mixture was heated to 90°C and stirred for 6 hours. Using LCMS, it was observed that the starting material was completely consumed and one major peak with the required mass. The reaction mixture was filtered and the filtrate was concentrated to give the crude compound. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 - 3:1) to give compound 87-2 (250 mg, 0.20 mmol, 22.5% yield) as a yellow solid.

Step 2: (7-(isopropylcarbamoyl)-4-(4-(trifluoromethyl)phenyl)naphthalene-1-yl)boronic acid

To a solution of compound 87-2 (0.2 g, 0.41 mmol, 1 eq.) in dioxane (2 ml) was added HCl/dioxane (1 M, 2.07 ml, 5 eq.) at 25°C. The mixture was stirred at 25°C for 12 hours. Using LCMS, it was observed that the starting material was completely consumed and one major peak with the required mass. The reaction mixture was quenched by adding water (10 ml) and extracted with EA (20 mlx2). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 - 0:1) to give compound 87-3 (50 mg, 53.5 μmol, 12.9% yield) as a yellow oil.

Step 3: N-isopropyl-8-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and 8-iodo-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a mixture of compound 87-3 (20 mg, 49.8 µmol, 1 equiv.) and compound 87-3a (24.6 mg, 74.7 µmol, 1.5 equiv.) in 1-methoxy-2-(2 -methoxyethoxy)ethane (1 ml) was added 1,10-phenanthroline (0.89 mg, 4.9 µmol, 0.1 eq.), CuI (0.94 mg, 5 µmol, 0.1 eq.) and K ₂ CO ₃ (20.6 mg, 0.15 mmol, 3 eq.) at 25°C in an N2 atmosphere. The mixture was heated to 35°C and stirred for 16 hours. Using LCMS, it was observed that the starting material was completely consumed and one major peak with the required mass. The reaction mixture was quenched by adding water (10 ml) and extracted with EA (20 mlx2). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to leave a residue. The residue was purified by pre-HPLC. Compound 87 (4 mg, 9.4 µmol, 18.8% yield) as a white solid. LCMS (ESI): RT=0.929 min, mass, calc. for C22H17F6NO, 425.37, m/z obtained 425.9[M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.60 (br d, J=7.6 Hz, 1H), 8.16 (d, J=7.6 Hz , 1H), 8.09 (dd, J=1.3, 8.9 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.90 (d, J=8, 9 Hz, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.71 (d, J=7.6 Hz, 1H), 4.17 (qd, J=6.9, 13.9 Hz, 1H), 1.21 (d, J=6.5 Hz, 6H). Compound 88 (3.5 mg, 7.0 µmol, 14.0% yield) as a white solid. LCMS (ESI): RT=0.949 min, mass, calc. for C ₂₁ H ₁₇ F ₃ INO, 483.27, m/z obtained 483.8 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 - 8.56 (m, 2H), 8.31 (d, J=7.5 Hz, 1H), 7.96 (dd, J=1 ,4, 8.8 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.72 (br d, J=7.9 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 4.17 (qd, J=6.7, 13.7 Hz, 1H), 1.22 ( d, J=6.5 Hz, 6H).

Example 83: ^)-N-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 89) and ^)-H-(1-methoxypropan-2-yl) )-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 93)

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A mixture of compound 89-1 (200 mg, 0.63 mmol, 1 eq.), TEA (63.9 mg, 0.63 mmol, 88 μl, 1 eq.) and HATU (360.6 mg, 0.94 mmol , 1.5 eq.) in DCM (5 ml) was stirred at 25°C for 1 h. Then 1methoxypropan-2-amine (67.6 mg, 0.75 mmol, 80 μl, 1.2 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1) to obtain compound 89-2 (90 mg) as a white solid, which was further separated by SFC to obtain the above compounds. Compound 89 (28 mg, 70.8 µmol, 11.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.991 min, mass calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.39, m/z obtained 388.1 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J=1.5 Hz, 1H), 8.46 (d, J=8.1 Hz, 1H), 8.13 (d , J=8.3 Hz, 1H), 7.96 - 7.90 (m, 3H), 7.81 (d, J=8.9 Hz, 1H), 7.77 7.72 (m, 2H ), 7.69 (d, J=8.1 Hz, 1H), 7.60 (dd, J=0.9, 7.1 Hz, 1H), 4.27 (spt, J=6.9 Hz , 1H), 3.49 - 3.42 (m, 1H), 3.35 (br s, 1H), 3.30 (s, 3H), 1.19 (d, J=6.8 Hz, 3H ). Compound 93 (18 mg, 46.4 µmol, 72.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.875 min, mass calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.39, m/z obtained 388.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.77 7.72 (m, 4H), 7.60 - 7.53 (m, 3H), 7.47 - 7.44 (m, 1H), 4.29 (sextet, J=6.4 Hz, 1H), 3.47 - 3.41 (m, 1H) , 3.39 3.33 (m, 1H), 3.30 (s, 3H), 1.18 (d, J=6.8 Hz, 3H).

Example 84: ^)-Na(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 90) and (K)-Na(1-(pyridin- 2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 91)

Step 1: N(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 90-1 (200 mg, 0.63 mmol, 1 eq.), HATU (360.6 mg, 0.94 mmol, 1.5 eq.) and DIEA (326.9 mg, 2.53 mmol, 0.44 ml, 4 eq.) in DCM (3 ml) was stirred at 25°C for 1 hour. Then 1-(2pyridyl)ethanamine (92.7 mg, 0.75 mmol, 1.2 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). Compound 90-2 (200 mg, 0.46 mmol, 72.9% yield) was obtained as a yellow oil.

Step 2: ^)-N(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and (R)-N-(1(pyridin-2-yl) ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

Compound 90-2 (90 mg, 0.21 mmol, 1 eq.) was purified by SFC.

Compound 90 (20 mg, 47.5 µmol, 22.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.881 min, mass calc. for C ₂₅ H ₁₉ F ₃ N ₂ O 420.43, m/z obtained 421.1 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.56 - 8.51 (m, 2H), 8.08 (d, J=8.3 Hz, 1H), 7.93 - 7.78 (m, 5H) , 7.72 - 7.63 (m, 3H), 7.56 (d,

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J=6.1 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.31 (dd, J=4.8, 6.6 Hz, 1H), 5.32 ( q, J=7.0 Hz, 1H), 1.63 (d, J=7.0 Hz, 3H). Compound 91 (30 mg, 71.3 µmol, 33.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.896 min, mass calc. for C ₂₅ H ₁₉ F ₃ N ₂ O 420.43, m/z obtained 421.1 [M+H]+; ^1H NMR (400 MHz, CD3OD) δ 8.57 - 8.54 (m, 2H), 8.08 (d, J=7.9 Hz, 1H), 7.95 - 7.81 (m, 4H ), 7.95 -7.79 (m, 1H), 7.70 - 7.64 (m, 2H), 7.71 - 7.64 (m, 1H), 7.61 - 7.55 (m , 1H), 7.58 (t, J=7.9 Hz, 1H), 7.40 (dd, J=5.5, 6.8 Hz, 1H), 5.37 5.28 (m, 1H ), 1.65 (d, J=7.5 Hz, 3H).

Example 85: Y-(1-(methylamino)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 92)

Step 1: tert-butyl(2-(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)propyl)carbamate

To a solution of compound 92-1 (0.5 g, 1.58 mmol, 1 eq.) in DMF (2 ml) was added HATU (1.20 g, 3.16 mmol, 2 eq.) and TEA (799.8 mg, 7.90 mmol, 1.10 ml, 5 eq.). The mixture was stirred for 0.5 h at 25°C. Tert-butyl-N(2-aminopropyl)carbamate (330.5 mg, 1.90 mmol, 1.2 eq.) was added to the mixture and the mixture was stirred for 0.5 h at 25°C. Completion of the reaction was observed using LCMS. The mixture was quenched with H2O (15 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (15 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was used in the next step without further purification.

Compound 92-2 (0.650 g, crude) was obtained as a yellow oil.

Step 2: N(1-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 92-2 (0.65 g, 1.38 mmol, 1 eq.) in MeOH (3 mL) was added HCl/dioxane (4 M, 2.60 mL, 7.56 eq.). The mixture was stirred for 1 hour at 25°C. The mixture was quenched with H2O (25 ml) and adjusted to pH 8 with NaOH (4 M). The mixture was extracted with EA (15 mlx3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 - 0:1). Compound 92-3 (0.45 g, 1.21 mmol, 87.8% yield) was obtained as a yellow solid.

Step 3: ^(1-formamidopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a mixture of compound 92-3 (0.1 g, 0.26 mmol, 1 eq.) was added ethyl formate (198.9 mg, 2.69 mmol, 0.21 mL, 10 eq.) and the mixture was stirred for 48 h at 80°C. Using LCMS, it was observed that the reaction had the desired MS. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 - 0:1) to give compound 924 (0.01 g, 24.9 μmol, 9.3% yield) as a yellow solid.

Step 4: N-(1 -(methylamino)propan-2-yl)-5-(4 -(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 92-4 (0.02 g, 49.9 µmol, 1 eq.) in THF (1 ml) was added LiAlH ₄ (9.4 mg, 0.24 mmol, 5 eq.). The mixture was stirred for 16 hours at 25°C. LCMS monitored the completion of the reaction. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The compound (8 mg) was obtained as a yellow solid. The residue was purified by pre-HPLC. The title compound (1.2 mg, HCl) was obtained as a colorless oil. LCMS (ESI): RT=0.738 min, mass calc. for C ₂₂ H ₂₁ F ₃ N ₂ O 386.41, m/z obtained 387.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.10 ( d, J=8.0 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.93 - 7.83 (m, 3H), 7.74 - 7.66 (m , 3H), 7.65 - 7.58 (m, 1H), 3.28 - 3.13 (m, 2H), 2.82 - 2.75 (m, 3H), 1.43 (d, J =6.8 Hz, 3H), 1.20 (s, 1H).

Example 86: 5,6-dichloro-Nisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 94)

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Step 1: (2E)-X-(4,5-dichloro-2-iodophenyl)-2-(hydroxyimino)acetamide

To a solution of compound 94-1 (8.0 g, 28 mmol, 1.0 eq.) in H ₂ O (160 ml) was added conc. HCl (1.28 ml), Na ₂ SO ₄ (39.5 g, 0.28 mol, 10 eq.), chloral hydrate (9.2 g, 55.5 mmol, 2.0 eq.) and hydroxylamine hydrochloride ( 7.7 g, 111 mol, 4.0 eq.). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was extracted with EA (100 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to give compound 94-2 (1.7 g, 17% yield) as a brown solid.

Step 2: 4,5-dichloro-7-iodindoline-2,3-dione

Compound 94-2 (1.7 g, 4.74 mmol, 1.0 eq.) was added to 90% aqueous H2SO4 (20 mL) in portions at 70°C. The mixture was stirred at 90°C for 16 hours. The reaction mixture was poured into ice water, and then the resulting mixture was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 943 (1.5 g, crude) as a red solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.25 (s, 1H), 8.20 (s, 1H).

Step 3: 2-amino-5,6-dichloro-3-iodobenzoic acid

A solution of compound 94-3 (1.5 g, 4.4 mmol, 1.0 eq), NaCl (564 mg, 9.65 mmol, 2.2 eq) and NaOH (420 mg, 0.70 mmol, 2.4 eq.) in H2O (75 ml) was stirred at 25°C for 0.5 hour. H ₂ O ₂ (2.61 mL, 27.2 mmol, 30%, 6.2 eq.) was added slowly, followed by aqueous NaOH (420 mg NaOH in H2O (75 mL)). The reaction mixture was stirred at 25°C for 3 hours. The pH of the reaction mixture was adjusted to 5 with HCl (1 M). The suspension was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 94-4 (920 mg, crude) as a gray solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.92 (s, 1H).

Step 4: (2-amino-5,6-dichloro-3-iodophenyl)methanol

To a solution of compound 94-4 (920 mg, 2.77 mmol, 1.0 eq.) in THF (1.0 ml) was added BH ₃ -THF (1 M, 14 ml, 5.0 eq.) at 25° WITH. The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to 0°C and then MeOH (20 ml) was added. The mixture was stirred for 10 minutes and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 - 3:1) to give compound 94-5 (750 mg, 85% yield) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 4.97 (s, 2H).

Step 5: 2-amino-5,6-dichloro-3-iodobenzaldehyde

To a solution of compound 94-5 (750 mg, 2.36 mmol, 1.0 eq) in DCM (10 mL) was added MnO ₂ (2.05 g, 23.59 mmol, 10 eq). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure to obtain compound 94-6 (720 mg, 96% yield) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 10.39 (s, 1H), 7.91 (s, 1H).

Step 6: Methyl 5,6-dichloro-8-iodoquinoline-3-carboxylate

A mixture of compound 94-6 (720 mg, 2.28 mmol, 1.0 eq.), compound 94-6a (230 mg, 2.73 mmol, 1.2 eq.) and L-proline (131 mg, 1.0 eq.) 14 mmol, 0.5 eq.) in EtOH (10 ml) was stirred at 80°C for 16 hours. Complete consumption of the starting material was observed by LC-MS and one major peak was detected with the required MS. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 ml) and the resulting mixture was extracted with DCM (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The remainder is cleared

- 145 046394 by column chromatography over silica gel (petroleum ether:ethyl acetate = 1:0 - 5:1) to obtain compound 94-7 (800 mg, 91% yield) as a yellow solid.

Step 7: 5,6-dichloro-8-iodoquinoline-3-carboxylic acid

To a solution of methyl compound 94-7 (300 mg, 0.78 mmol, 1.0 eq.) in THF (2 mL) and MeOH (2 mL), a solution of NaOH (1 M, 1.6 mL, 2 eq.) was added dropwise. ). The reaction mixture was stirred at 25°C for 2 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. The reaction mixture was acidified with HCl (1 M) to pH=5, and then the suspension was extracted with EA (25 mlx3). The combined organic layers were concentrated under reduced pressure to give compound 94-8 (270 mg, 97% yield) as a yellow solid.

Step 8: 5,6-dichloro-8-iodoquinoline-3-carboxylic acid

To a solution of compound 94-8 (50.0 mg, 0.14 mmol, 1.0 eq.), DIPEA (35.1 mg, 0.27 mmol, 2.0 eq.) and compound 94-8a (16 mg , 0.272 mmol, 2.0 eq.) HATU (62.0 mg, 0.16 mmol, 1.2 eq.) was added to DCM (2 mL). The reaction mixture was stirred at 25°C for 16 hours. Using LC-MS, it was observed that the starting material remained and one major peak was detected with the required MS. 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 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0-1:1) to give compound 94-9 (45 mg, 80% yield) as a light yellow solid.

Step 9: 5,6-dichloro-Nisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 94-9 (45.0 mg, 0.11 mmol, 1 eq.), compound 94-9a (20.9 mg, 0.11 mmol, 1.0 eq.) and Na ₂ CO ₃ (23 .3 mg, 0.22 mmol, 2.0 eq.) in dioxane (2.5 ml) and H2O (0.5 ml) was added Pd(dppf)Cl ₂ (4.0 mg, 5.5 µmol, 0 .05 eq.) in an N2 atmosphere. The reaction mixture was degassed in vacuo and purged with N ₂ several times. The mixture was stirred under N ₂ atmosphere at 80° C. for 4 hours. Complete consumption of the starting material was observed by LC-MS and one major peak with the required MS was detected. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (5 ml) and the resulting mixture was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (17.5 mg, 35% yield) as a white solid. LCMS (ESI): RT=1.075 min, mass calc. for C ₂₀ H ₁₅ Cl ₂ F ₃ N ₂ O 426.05, m/z obtained 427.0 [M+H]+; ^1H NMR (400 MHz, CDCl3) δ 9.28 (d, J=2.3 Hz, 1H), 8.96 (d, J=2.3 Hz, 1H), 7.88 (s, 1H) , 7.77 (s, 4H), 6.16 (d, J=7.0 Hz, 1H), 4.44 - 4.33 (m, 1H), 1.36 (d, J=6.5 Hz, 6H).

Example 87: 7-Amino-8-hydroxy-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound

95)

Step 1: 8-bromo-Nisopropyl-7-nitro-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 95-1 (210 mg, 0.48 mmol, 1 eq.) in TFA (3 ml) was added HNO ₃ (93.3 mg, 0.96 mmol, 67 μl, 65%, 2 eq.). The mixture was stirred at 15°C for 16 hours. Ice water (30 ml) was then added and the mixture was neutralized to pH=9-10 with NaOH (4 M). The aqueous phase was extracted with ethyl acetate (20 mlx3). The combined organic phase was washed with brine (30 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. Compound 95-2 (91.4 mg, 0.18 mmol, 39.4% yield) was obtained as a white solid.

Step 2: 7-amino-8-bromo-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 95-2 (85 mg, 0.17 mmol, 1 eq.), Fe (49.3 mg, 0.88 mmol, 5 eq.), NH ₄ Cl (47.2 mg, 0.88 mmol, 31 µl, 5 eq.) in a mixture of EtOH (5 ml) and H2O (1 ml) was stirred at 80°C for 3 hours. React

- 146 046394 the mixture was filtered and the cake was washed with EtOH (10 mlx3), the filtrate was concentrated in vacuo to obtain the crude product. The crude product was used in the next step without further purification. Compound 95-3 (76.4 mg, crude) was obtained as a yellow solid.

Step 3: 7-amino^-isopropyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 95-3 (75 mg, 0.16 mmol, 1 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolane-2- yl)-1,3,2-dioxaborolane (63.3 mg, 0.24 mmol, 1.5 eq.), KOAc (48.9 mg, 0.49 mmol, 3 eq.), Pd(dppf)Cl ₂ (6.08 mg, 8.3 µmol, 0.05 eq.) in dioxane (5 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 110°C for 3 hours under _N2 . The residue was poured into H2O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (10 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Compound 95-4 (68 mg, 0.11 mmol, 71.4% yield) was obtained as a yellow solid.

Step 4: 7-amino-8-hydroxy-Nisopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

To a solution of compound 95-4 (50 mg, 0.10 mmol, 1 eq.) in THF (1 ml) and H2O (0.5 ml) was added sodium 3oxydioxaborirantetrahydrate (46.3 mg, 0.30 mmol, 58 μl, 3 eq.). The mixture was stirred at 10°C for 1 hour. The residue was poured into H ₂ O (20 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (10 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (23.8 mg, 54.9 µmol, 54.7% yield, HCl) was obtained as a white solid. LCMS (ESI): RT=0.765 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O ₂ 388.38, m/z obtained 398.2 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.48 (br s, 1H), 8.54 (s, 1H), 8.23 (br d, J=8.0 Hz, 1H), 7 .88 (d, J=8.0 Hz, 2H), 7.70 - 7.61 (m, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 1H), 6.66 (s, 1H), 4.12 (qd, J=6.5, 13.6 Hz, 1H), 1.22 -1.12 (m, 1H ), 1.17 (d, J=6.5 Hz, 5H).

Example 88: 5,6-dichloro-Mmethylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 96)

Step 1: 5,6-dichloro-8-iodo-Mmethylsulfonyl)quinoline-3-carboxamide

To a solution of compound 96-1 (50.0 mg, 0.13 mmol, 1.0 eq) in DMF (1 ml) was added CDI (24.2 mg, 0.14 mmol, 1.1 eq). The reaction mixture was stirred at 40°C for 30 minutes. The reaction was cooled to 25°C and then DBU (24.8 mg, 0.16 mmol, 1.2 eq) and compound 96-1a (15.5 mg, 0.16 mmol, 1.2 eq) were added. . The reaction mixture was stirred at 25°C for 2 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was triturated with DCM (2 ml) and filtered to give compound 96-2 (35 mg, 57% yield) as a white solid.

Step 2: 5,6-dichloro-N(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 96-2 (35 mg, 78 mmol, 1.0 eq.), compound 96-2a (15 mg, 78 mmol, 1.0 eq.) and Na ₂ CO ₃ (25.0 mg, 0.0 eq.) 23 mmol, 3.0 eq.) in dioxane (2 ml) and H ₂ O (0.4 ml) was added Pd(dppf)Cl ₂ (2.9 mg, 3.9 µmol, 0.05 eq.) in atmosphere N2. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred under N2 at 80°C for 4 hours. Complete consumption of the starting material was observed by LC-MS and one major peak with the required MS was detected. The pH of the suspension was adjusted to 5 with HCl (1 M). The mixture was diluted with water (5 ml) and the resulting mixture was extracted with EA (20 ml x 3 ). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (9.6 mg, 24% yield) as a white solid. LCMS (ESI): RT=1.011 min, mass calc. for C18H11Q2F3N2O3S 461.98, m/z obtained 462.9 [M+H]+; 1H NMR (400 MHz, DMSOd6) δ 9.33 (d, J=2.3 Hz, 1H), 9.27 (d, J=2.0 Hz, 1H), 8.23 (s, 1H), 7.89 (s, 4H), 3.45 (s, 3H)

Example 89: N-isopropyl-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 97)

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F

Step 1: 8-bromo-6-methoxyquinoline-3-carboxylic acid

LiOH _{-H2O (} 340 mg, 8.1 mmol, 12.0 eq.). The mixture was stirred at 80°C for 16 hours. The desired product was observed by LCMS. The pH of the mixture was adjusted to 7 with citric acid. The mixture was extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. Compound 97-2 (140 mg, 63.9% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.681 min, mass calc. for C ₁₁ H ₈ BrNO ₃ , 280.97 m/z, 283.7 [M+H]+ was obtained.

Step 2: 8-bromo-Ni-isopropyl-6-methoxyquinoline-3-carboxamide

HATU (60 .7 mg, 0.16 mmol, 1.5 eq.). The mixture was stirred at 20°C for 1 hour. Compound 97-2a (12.6 mg, 0.213 mmol, 2.0 eq.) was added. The mixture was stirred at 20°C for 15 hours. The desired product was observed by LCMS. The mixture was diluted with H ₂ O (10 ml) and extracted with DCM (20 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under pressure to obtain a residue. The residue was purified by flash chromatography on silica gel. Compound 97-3 (13 mg, 37.1% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.700 min, mass calc. for C ₁₄ H ₁₅ BrN ₂ O ₂ , 322.03 m/z, 324.8 [M+H]+ was obtained.

Step 3: N-isopropyl-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide

To a mixture of compound 97-3 (13 mg, 40 µmol, 1.0 eq.), compound 97-3a (11.5 mg, 60 µmol, 1.5 eq.), H ₂ O (0.5 ml) and Na ₂ CO ₃ (12.8 mg, 0.12 mmol, 3.0 eq.) in dioxane (2 ml) was added with Pd(dppf)Cl ₂ (3.0 mg, 4 μmol, 0.1 eq.). The mixture was degassed and purged with N2 3 times. The mixture was stirred at 90°C for 16 hours under N2 atmosphere. The desired product was observed using LCMS. The mixture was filtered. The filtrate was diluted with H2O (2 ml) and extracted with EA (5 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (10.86 mg, 69.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.845 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O ₂ , 388.14 m/z, 388.9 [M+H]+ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 8.98 (s, 1H), 8.47 (s, 1H), 7.73 - 7.67 (m, 4H), 7.40 (s, 1H), 7.13 (s, 1H), 5.99 (d, J=7.2 Hz, 1H), 4.33 - 4.23 (m, 1H), 3.96 - 3.88 (m, 3H) , 1.28 - 1.23 (m, 6H).

Example 90: N-[(1R)-2-hydroxy-1-methylethyl]-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide (compound 98)

Step 1: 8-bromo-N[(^)-2-hydroxy-1-methylethyl]-6-methoxyquinoline-3-carboxamide

To a mixture of compound 98-1 (80 mg, 0.284 mmol, 1.0 eq.), DIEA (110 mg, 0.851 mmol, 3.0 eq.) and compound 98-1a (42.6 mg, 0.567 mmol, 2. 0 eq.) to DCM (2 mL) was added HATU (216 mg, 0.567 mmol, 2.0 eq.). The mixture was stirred at 20°C for 16 hours. The desired product was observed by LCMS. The mixture was diluted with H ₂ O (10 ml) and extracted with EA (20 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel. Compound 98-2 (66 mg, 63.81% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.638 min, mass calc. for C ₁₄ H ₁₅ BrN ₂ O ₃ , 338.03 m/z, 340.8 [M+H]+ was obtained.

Step 2: N-[(1R)-2-hydroxy-1-methylethyl]-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide

To a mixture of compound 98-2 (60 mg, 0.177 mmol, 1.0 eq.), compound 98-2a (50.4 mg, 0.265 mmol, 1.5 eq.), Na ₂ CO ₃ (56.2 mg, 0.531 mmol, 3.0 eq.) and H ₂ O (0.5 ml) in dioxane (2 ml) was added Pd(dppf)Cl ₂ (13 mg, 18 µmol, 0.1 eq.). The mixture was degassed and purged with N2 3 times. The mixture was stirred at 90°C for 16 hours under N ₂ atmosphere. The desired product was observed using LCMS and HPLC. The mixture was diluted with H ₂ O (10 ml) and extracted with EA (20 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified

- 148 046394 Tod. Rev.-HPLC. The title compound (8.28 mg, 10% yield) was obtained as a light yellow solid. LCMS (ESI): RT=0.775 min, mass calc. for C ₂ iHi9F3N2O3, 404.13 m/z, 404.9 [M+H]+ was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.11 (d, J=2 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H), 7.83 - 7.76 (m , 4H), 7.50 (d, J=2.8 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.51 - 6.49 (m, 1H), 4 .39 (m, 1H), 4.01 (s, 3H), 3.89 - 3.86 (m, 1H), 3.75 - 3.71 (m, 1H), 2.43 (m, 1H ), 1.39 - 1.36(m, 3H).

Example 91: ^)-N-(1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 99)

Step 1: 8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid

To a solution of compound 99-1 (500.0 mg, 1.88 mmol, 1.0 eq.), compound 99-1a (356.8 mg, 1.88 mmol, 1.0 eq.) and Na ₂ CO ₃ (398.3 mg, 3.76 mmol, 2.0 eq.) in dioxane (7.5 ml) and H2O (1.5 ml) was added Pd(dppf)Cl ₂ (68.7 mg, 93 µmol, 0 .05 eq.). The reaction mixture was stirred at 100°C for 16 hours under N2 atmosphere. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was identified. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 ml) and the resulting mixture was extracted with EA (40 ml). The aqueous layers were acidified with HCl (1 M) to pH 5 and then the suspension was extracted with EA (40 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 99-2 (550 mg, crude) as a brown solid.

Step 2: (R)-N-(1-hydroxypropan-2-yl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 99-2 (50.0 mg, 0.15 mmol, 1.0 eq.), compound 99-2a (14.2 mg, 0.18 mmol, 1.2 eq.) and DIPEA (40, 7 mg, 0.31 mmol, 2.0 eq.) to DCM (3 mL) was added HATU (89.9 mg, 0.23 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (17.41 mg, 29% yield) as a white solid. LCMS (ESI): RT=0.870 min, mass calc. for C ₂₀ H ₁₇ F ₃ N ₂ O ₂ 374.12, m/z obtained 375.0 [M+H]+; ¹ H NMR (400 MHz,

CDCl ₃ ) δ 9.27 (d, J=2.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 7.96 (dd, J=1.1, 8, 2 Hz, 1H), 7.85 - 7.73 (m, 5H), 7.73 7.68 (m, 1H), 6.59 (d, J=7.0 Hz, 1H), 4.45 - 4.32 (m, 1H), 3.92 - 3.80 (m, 1H), 3.76 - 3.63 (m, 1H), 2.59 (s, 1H), 1.36 (d , J=6.8 Hz, 3H).

Example 92: ^)-N-(1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 100)

To a solution of compound 100-1 (50.0 mg, 0.15 mmol, 1.0 eq.), compound 100-1a (23.7 mg, 0.18 mmol, 1.2 eq.) and DIPEA (61, 1 mg, 0.47 mmol, 3.0 eq.) to DCM (3 mL) was added HATU (89.9 mg, 0.23 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (19.7 mg, 32% yield) as a white solid. LCMS (ESI): RT=0.930 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O ₂ 388.13, m/z obtained 389.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.4 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 7.99 (dd, J =1.4, 8.1 Hz, 1H), 7.85 - 7.75 (m, 5H), 7.74 - 7.68 (m,

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1H), 6.61 (d, J=7.5 Hz, 1H), 4.49 - 4.39 (m, 1H), 3.60 - 3.55 (m, 1H), 3.51 -3 .47 (m, 1H), 3.42 (s, 3H), 1.37 (d, J=6.9 Hz, 3H).

Example 93: ^)-N-(1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 101)

To a solution of compound 101-1 (50.0 mg, 0.15 mmol, 1.0 eq.), compound 101-1a (23.1 mg, 0.18 mmol, 1.2 eq.) and DIPEA (40, 7 mg, 0.31 mmol, 2.0 eq.) to DCM (3 mL) was added HATU (89.9 mg, 0.23 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (27.8 mg, 41% yield) as a white solid. LCMS (ESI): RT=0.841 min, mass calc. for C ₂₄ H ₁₈ F ₃ N ₃ O 421.14 m/z, 422.1 [M+H]+ was obtained; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (d, J=2.3 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.60 (d, J =4.5 Hz, 1H), 8.22 (br d, J=6.8 Hz, 1H), 8.02 (dd, J=1.3, 8.0 Hz, 1H), 7.87 - 7.82 (m, 3H), 7.81 - 7.77 (m, 2H), 7.77 - 7.69 (m, 2H), 7.35 (d, J=7.8 Hz, 1H) , 7.28 - 7.25 (m, 1H), 5.41 (quin., J=6.8 Hz, 1H), 1.67 (s, 3H).

Example 94: ^)-N-(1-methoxypropan-2-yl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 102)

To a solution of compound 102-1 (50.0 mg, 0.15 mmol, 1.0 eq.), compound 102-1a (16.8 mg, 0.18 mmol, 1.2 eq.) and DIPEA (40, 7 mg, 0.31 mmol, 2.0 eq.) to DCM (3 mL) was added HATU (89.9 mg, 0.23 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (18.9 mg, 30% yield) as a white solid. LCMS (ESI): RT=0.940 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O ₂ 388.13, m/z obtained 389.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=2.3 Hz, 1H), 8.67 (d, J=2.3 Hz, 1H), 7.99 (dd, J= 1.3, 8.0 Hz, 1H), 7.86 - 7.74 (m, 5H), 7.74 - 7.68 (m, 1H), 6.60 (d, J=8.0 Hz , 1H), 4.50 - 4.39 (m, 1H), 3.59 - 3.54 (m, 1H), 3.51 -3.46 (m, 1H), 3.42 (s, 3H ), 1.37 (d, J=6.8 Hz, 3H).

Example 95: ^)-N-(1-(pyridin-2-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 103)

To a solution of compound 103-1 (50.0 mg, 0.15 mmol, 1.0 eq.), compound 103-1a (23.1 mg, 0.18 mmol,

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1.2 eq.) and DIPEA (40.7 mg, 0.31 mmol, 2.0 eq.) in DCM (3 ml) was added HATU (89.9 mg, 0.23 mmol, 1.5 eq.) . The reaction mixture was stirred at 25°C for 1 hour. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (26.2 mg, 39% yield) as a white solid. LCMS (ESI): RT=0.846 min, mass calc. for C ₂₄ H ₁₈ F ₃ N ₃ O 421.14 m/z, 422.1 [M+H]+ was obtained; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.42 (d, J=2.3 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.60 (d, J =4.5 Hz, 1H), 8.22 (br d, J=7.0 Hz, 1H), 8.03 (dd, J=1.3, 8.3 Hz, 1H), 7.87 - 7.77 (m, 5H), 7.77 - 7.70 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 7.28 - 7.25 (m, 1H) , 5.41 (quin., J=6.8 Hz, 1H), 1.66 (d, J=6.8 Hz, 3H).

Example 96: N-isopropyl-6-(trifluoromethoxy)-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 104)

Step 1: 8-bromo-6-(trifluoromethoxy)quinoline-3-carboxylic acid

To a mixture of compound 104-1 (380 mg, 1.1 mmol, 1.0 eq.) and H2O (2 ml) in MeOH (8 ml) was added NaOH (434.1 mg, 10.8 mmol, 10 eq.) . The mixture was stirred at 80°C for 2 hours. The desired product was observed by LCMS. The mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in H2O (5 ml). The pH value of the mixture was adjusted to 6 us. citric acid, extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. Compound 104-2 (330 mg, 0.98 mmol, 90.5% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.769 min, mass, calc. for C11H ₅ BrF ₃ NO ₃ 334.94, m/z obtained 335.8 [M+H]+.

Step 2: 8-bromoA-isopropyl-6-(trifluoromethoxy)quinoline-3-carboxamide

HATU ( 113.1 mg, 0.29 mmol, 2 eq.). The mixture was stirred at 25°C for 1 hour. Propan-2-amine (17.5 mg, 0.29 mmol, 25.5 μl, 2 eq.) was added. The mixture was stirred at 25°C for 2 hours. The desired product was observed by LCMS. The mixture was diluted with H ₂ O (10 ml) and extracted with EA (20 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel. Compound 104-3 (55 mg, 0.14 mmol, 94.0% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.787 min, mass, calc. for C ₁₄ H ₁₂ BrF ₃ N ₂ O ₂ 377.16, m/z obtained 378.8 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.35 (m, 1H), 8.58 (m, 1H), 8.03 (m, 1H), 7.74 (s, 1H), 6.08 ( s, 1H), 4.42 - 4.33 (m, 1H), 1.35 - 1.32 (m, 6H).

Step 3: Aisopropyl-6-(trifluoromethoxy)-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide

To a mixture of compound 104-3 (50 mg, 0.13 mmol, 1 eq.), [4-(trifluoromethyl)phenyl]boronic acid (30.2 mg, 0.15 mmol, 1.2 eq.), H2O ( 1 ml) and Na ₂ CO ₃ (28.1 mg, 0.26 mmol, 2 eq.) in dioxane (4 ml) was added Pd(dppf)Cl ₂ (4.8 mg, 6.6 µmol, 0.05 eq.). The mixture was degassed and purged with N2 3 times. The mixture was stirred at 90°C for 16 hours under N ₂ atmosphere. The desired product was observed using LCMS. The mixture was filtered. The filtrate was diluted with H2O (10 ml) and extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (21 mg, 47.5 µmol, 35.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.915 min, mass, calc. for C ₂₁ H ₁₆ F ₆ N ₂ O ₂ 442.35, m/z obtained 442.9 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.26 (m, 1H), 8.62 (m, 1H), 7.83 - 7.77 (m, 5h), 7.69 - 7.68 (m , 1H), 6.07 - 6.06 (m, 1H), 4.42 - 4.34 (m, 1H), 1.35 - 1.33 (m, 6H).

Example 97: N[2-hydroxy-1-(2-pyridyl)ethyl]-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 105)

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Step 1: 6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxylic acid

To a mixture of compound 105-1 (500.0 mg, 1.7 mmol, 1.0 eq.), compound 105-1a (384.8 mg, 2.0 mmol, 1.2 eq.), Na ₂ CO ₃ (715.8 mg, 6.7 mmol, 4.0 eq.) and H ₂ O (2 ml) in dioxane (10 ml) was added Pd(dppf)Cl ₂ (61.8 mg, 84 µmol, 0.05 eq.). The mixture was degassed and purged with N2 3 times. The mixture was stirred at 90°C for 16 hours under N2 atmosphere. The desired product was observed using LCMS. The pH value of the mixture was adjusted to 6 us. citric acid. The mixture was diluted with H2O (10 ml) and extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. Compound 105-2 (780 mg, crude) was obtained as a black solid. LCMS (ESI): RT=0.831 min, mass, calc. for Ci ₈ Hi ₂ F ₃ NO ₃ 347.08, m/z obtained 347.9 [M+H]+.

Step 2: N[2-hydroxy-1-(2-pyridyl)ethyl]-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide

To compound 105-2 (50.0 mg, 0.144 mmol, 1.0 eq.) and DIEA (55.8 mg, 0.432 mmol, 3.0 eq.) in DCM (3 ml) was added HATU (82.1 mg , 0.216 mmol, 1.5 eq.). The mixture was stirred at 25°C for 1 hour. Compound 105-2a (24.0 mg, 0.114 mmol, 0.8 eq, 2 HCl) was added. The mixture was stirred at 25°C for 2 hours. The desired product was observed by LCMS. The mixture was diluted with H ₂ O (10 ml) and extracted with EA (20 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (15.7 mg, 23.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.731 min, mass, calc. for C ₂₅ H ₂₀ F ₃ N ₃ O ₃ 467.15, m/z obtained 468.0 [M+H]+; ^1H NMR (400 MHz, CDCl ₃ ) δ 9.23 (m, 1H), 8.64 (m, 1H), 8.59 - 8.58 (m, 1H), 8.17 (m, 1H) , 7.83 - 7.76 (m, 5H), 7.54 - 7.50 (m, 2H), 7.32 (m, 1H), 7.24 (m, 1H), 5.44 - 5 .41 (m, 1H), 4.20 - 4.16(m, 3H), 4.10 - 4.02 (m, 3H).

Example 98: 6-methoxy-H-[(III)-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 106)

HATU (114.9 mg, 0.30 mmol, 1.5 eq.). The mixture was stirred at 25°C for 1 hour. Compound 106-1a (29.5 mg, 0.24 mmol, 1.2 eq.) was added. The mixture was stirred at 25°C for 2 hours. The desired product was observed by LCMS. The mixture was diluted with H ₂ O (10 ml) and extracted with EA (20 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (33.5 mg, 36.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.756 min, mass, calc. for C ₂₅ H ₂₀ F ₃ N ₃ O ₂ 451.15, m/z obtained 452.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.23 (m, 1H), 8.66 (m, 1H), 8.58 (m, 1H), 8.44 (m, 1H), 7.82 - 7.75 (m, 2H), 7.73 - 7.72 (m, 3H), 7.48 (m, 1H), 7.35 - 7.33 (m, 1H), 7.25 - 7, 24 (m, 2H), 5.43 - 5.36 (m, 1H), 4.00 (s, 3H), 1.65 - 1.63 (m, 3H).

Example 99: 6-methoxy-H-[(III)-2-methoxy-1-methylethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 107)

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HATU was added to a mixture of compound 107-1 (70.0 mg, 0.20 mmol, 1.0 eq.) and DIEA (104.2 mg, 0.80 mmol, 4.0 eq.) in DCM (3 mL). (114.9 mg, 0.30 mmol, 1.5 eq.). The mixture was stirred at 25°C for 1 hour. Compound 107-1a (21.5 mg, 0.24 mmol, 1.2 eq.) was added. The mixture was stirred at 25°C for 2 hours. The desired product was observed by LCMS. The mixture was diluted with H2O (10 ml) and extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (26.9 mg, 31.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.832 min, mass, calc. for C ₂₂ H ₂ iF ₃ N ₂ O ₃ 418.15, m/z obtained 419.0 [M+H]+; ^1H NMR (400 MHz, CDCl ₃ ) δ 9.10 (m, 1H), 8.57 (m, 1H), 7.81 - 7.75 (m, 4H), 7.48 (m, 1H) , 7.22 (m, 1H), 6.60 - 6.58 (m, 1H), 4.46 - 4.43 (m, 1H), 4.00 (s, 3H), 3.58 - 3 .55 (m, 1H), 3.50 - 3.46 (m, 1H), 3.42 (s, 3H), 1.36 - 1.35 (m, 3H).

Example 100: 6-methoxy-N-[(^)-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 108)

HATU was added to a mixture of compound 108-1 (70.0 mg, 0.20 mmol, 1.0 eq.) and DIEA (104.2 mg, 0.80 mmol, 4.0 eq.) in DCM (3 mL). (114.9 mg, 0.30 mmol, 1.5 eq.). The mixture was stirred at 25°C for 1 hour. Compound 108-1a (29.5 mg, 0.24 mmol, 1.2 eq.) was added. The mixture was stirred at 25°C for 2 hours. The desired product was observed by LCMS. The filtrate was diluted with H2O (10 ml) and extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (20.4 mg, 22.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.753 min, mass, calc. for C ₂₅ H ₂₀ F ₃ N ₃ O ₂ 451.15, m/z obtained 452.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.23 (m, 1H), 8.66 (m, 1H), 8.58 (m, 1H), 8.44 (m, 1H), 7.82 - 7.75 (m, 2H), 7.73 - 7.72 (m, 3H), 7.48 (m, 1H), 7.34 - 7.32 (m, 1H), 7.25 - 7, 24 (m, 1H), 5.43 - 5.36 (m, 1H), 4.00 (s, 3H), 1.65 - 1.63 (m, 3H).

Example 101: 6-methoxy-N-[(^)-2-methoxy-1-methylethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 109)

HATU was added to a mixture of compound 109-1 (70.0 mg, 0.20 mmol, 1.0 eq.) and DIEA (104.2 mg, 0.80 mmol, 4.0 eq.) in DCM (3 mL). (114.9 mg, 0.30 mmol, 1.5 eq.). The mixture was stirred at 25°C for 1 hour. Compound 109-1a (21.5 mg, 0.24 mmol, 1.2 eq.) was added. The mixture was stirred at 25°C for 2 hours. The desired product was observed by LCMS. The mixture was diluted with H2O (10 ml) and extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound (9.8 mg, 11.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.831 min, mass, calc. for C ₂₂ H ₂₁ F ₃ N ₂ O ₃ 418.15, m/z obtained 419.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.10 (m, 1H), 8.56 - 8.55 (m, 1H), 7.81 - 7.74 (m, 4H), 7.48 - 7 .47(m, 1H), 7.21 - 7.20 (m, 1H), 6.61 - 6.59 (m, 1H), 4.46

- 153 046394

- 4.43 (m, 1H), 3.99 (s, 3H), 3.57 - 3.54 (m, 1H), 3.49 - 3.46 (m, 1H), 3.42 (s , 3H), 1.36 - 1.35(m, 3H).

Example 102: N(2-hydroxy-1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 110)

A mixture of compound 110-1 (60 mg, 0.18 mmol, 1 eq.), TEA (57.5 mg, 0.56 mmol, 79.2 μl, 3 eq.) and HATU (108.2 mg, 0. 28 mmol, 1.5 eq.) in DCM (2 ml) was stirred at 25°C for 1 h. Then 2-amino-2-pyridin-2-ylethanol (50 mg, 0.36 mmol, 1.9 eq. 2 HCl) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (50 mg, 0.11 mmol, 60.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.865 min, mass calc. for C ₂₅ H ₁₉ F ₃ N ₂ O ₂ 436.43 m/z obtained 437.1 [M+H]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (d, J=7, 8 Hz, 1H), 8.68 (d, J=1.5 Hz, 1H), 8.55 (d, J=4.0 Hz, 1H), 8.16 (d, J=8.3 Hz , 1H), 7.99 (dd, J=1.8, 8.8 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.83 (d, J=8, 8 Hz, 1H), 7.81 - 7.69 (m, 4H), 7.62 - 7.59 (m, 1H), 7.47 (d, J=8.0 Hz, 1H), 7, 28 (dd, J=4.9, 6.7 Hz, 1H), 5.25 - 5.18 (m, 1H), 5.00 (t, J=5.9 Hz, 1H), 3.93 - 3.80 (m, 2H).

Example 103: N(prop-2-yn-1-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 111)

A mixture of compound 111-1 (50 mg, 0.15 mmol, 1 eq.), DIPEA (61.2 mg, 0.47 mmol, 82.6 μl, 3 eq.) and HATU (90.1 mg, 0. 23 mmol, 1.5 eq.) in DMF (2 ml) was stirred at 25°C for 1 hour. Then prop-2in-1-amine (10.4 mg, 0.18 mmol, 12.1 µl, 1 .2 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS and HPLC that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (8 mg, 22.4 µmol, 14.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.859 min, mass calc. for C ₂₁ H ₁₄ F ₃ NO 353.34 m/z, 353.9 [M+H]+ was obtained; 1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.92 - 7.82 (m, 4H), 7.72 - 7.66 (m, 3H), 7.59 (d, J=6.4 Hz, 1H), 4.24 (d, J=2.4 Hz, 2H), 2.65 (t, J= 2.5 Hz, 1H).

Example 104: N(but-3-yn-1-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 112)

A mixture of compound 112-1 (50 mg, 0.15 mmol, 1 eq.), HATU (90.1 mg, 0.23 mmol, 1.5 eq.) and DIPEA (61.2 mg, 0.47 mmol, 82.6 µl, 3 eq.) in DMF (2 ml) stirred at 25°C for 1 h. Then but-3in-1-amine (20 mg, 0.18 mmol, 1.2 eq., HCl) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS and HPLC that the desired compound was detected. Reactionary

- 154 046394 the mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC.

The title compound (10 mg, 27.2 µmol, 17.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.879 min, mass calc. for C ₂₂ Hi ₆ F ₃ NO 367.36 m/z, 367.9 [M+H]+ was obtained; ¹ H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J=5.7 Hz, 1H), 8.61 (d, J=1.3 Hz, 1H), 8.18 (d, J=8.3 Hz, 1H), 8.02 - 7.95 (m, 3H), 7.87 (d, J=8.9 Hz, 1H), 7.82 - 7.71 (m, 3H ), 7.65 (d, J=6.5 Hz, 1H), 3.55 - 3.45 (m, 3H), 2.92 (t, J=2.6 Hz, 1H), 2.54 - 2.50 (m, 2H).

Example 105: N(cyanomethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 113)

ABOUT

A mixture of compound 113-1 (50 mg, 0.15 mmol, 1 eq.), DIPEA (61.2 mg, 0.47 mmol, 82.6 μl, 3 eq.) and HATU (90.1 mg, 0. 23 mmol, 1.5 eq.) in DMF (1 ml) was stirred at 25°C for 1 h. Then 2-aminoacetonitrile (17.5 mg, 0.18 mmol, 1.2 eq., HCl) was added to the mixture and the mixture was stirred for another 1 hour. It was observed by LC-MS and HPLC that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (32 mg, 89.4 µmol, 56.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.958 min, mass calc. for C ₂₀ H ₁₃ F ₃ N ₂ O 354.33 m/z, 355.0 [M+H]+ was obtained; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.82 (d, J =8.9 Hz, 1H), 7.73 - 7.67 (m, 3H), 7.59 - 7.44 (m, 4H), 6.67 (br t, J = 5.4 Hz, 1H ), 4.40 (d, J=5.8 Hz, 2H).

Example 106: N(2-cyanoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 114)

A mixture of compound 114-1 (50 mg, 0.15 mmol, 1 eq.), DIPEA (61.2 mg,

0.47 mmol, 82.6 µl, 3 eq.) and HATU (90.1 mg, 0.23 mmol, 1.5 eq.) in DMF (1 ml) were stirred at 25°C for 1 hour. Then 3-Aminopropanonitrile (13.3 mg, 0.18 mmol, 14 μL, 1.2 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. It was observed by LC-MS and HPLC that the required compound. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (27 mg, 73.3 µmol, 46.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.960 min, mass calc. for C ₂₁ H ₁₅ F ₃ N ₂ O 368.35 m/z, 369.0 [M+H]+ was obtained; 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (t, J=5.6 Hz, 1H), 8.58 (d, J=1.3 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.98 - 7.89 (m, 3H), 7.84 (d, J=8.9 Hz, 1H), 7.77 - 7.68 (m, 3H ), 7.61 (d, J=6.4 Hz, 1H), 3.60 - 3.59 (m, 1H), 3.59 - 3.54 (m, 1H), 3.55 - 3, 53 (m, 1H), 3.59 - 3.53 (m, 1H), 3.57 (q, J=6.3 Hz, 1H), 2.83 (t, J=6.4 Hz, 2H ).

Example 107: ^^-(disulfandiylbis(ethane-2,1-diyl))bis(5-(4-(trifluoromethyl)phenyl)-2-naphthamide) (compound 115)

- 155 046394

Step 1: Y-(2-mercaptoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of compound 115-1 (50 mg, 0.15 mmol, 1 eq.), HATU (90.1 mg, 0.23 mmol, 1.5 eq.) and DIPEA (61.2 mg, 0.47 mmol, 82.6 µl, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 h. Then 2-aminoethanethiol (19.7 mg, 0.17 mmol, 1.1 eq., HCl) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. It was observed by LC-MS that the desired compound was detected. Compound 115-2 (59 mg, crude) was used in the next step without further purification.

Step 2: ^Ni-(disulfandiylbis(ethane-2,1-diyl))bis(5-(4-(trifluoromethyl)phenyl)-2-naphthamide)

A mixture of compound 115-2 (59 mg, 0.15 mmol, 1 eq.) in DCM (2 ml) was stirred at 25°C for 48 hours. It was observed by LC-MS and HPLC that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (20 mg, 25.3 µmol, 16.1% yield) was obtained as a yellow solid. LCMS (ESI): RT=1.165 min, mass calc. for C40H30F6N2O2S2 748.80 m/z, 748.9[M+H]+ was obtained; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (br t, J=5.4 Hz, 2H), 8.55 (s, 2H), 8.10 (d, J=8.3 Hz, 2H), 7.96 - 7.86 (m, 6H), 7.79 (d, J=8.8 Hz, 2H), 7.75 - 7.64 (m, 6H), 7.58 (d, J=6.8 Hz, 2H), 3.65 (q, J=6.2 Hz, 4H), 3.01 (br t, J=6.8 Hz, 4H).

Example 108: 6-cyclopropoxy-Nisopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 116)

Step 1: Methyl 5-cyclopropoxy-2-nitrobenzoate

To a solution of compound 116-1a (577.4 mg, 9.9 mmol, 1.1 eq.) in DMF (15 ml) was added NaH (433.8 mg, 10.8 mmol, 60%, 1.2 eq. ) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. After compound 116-1 (1.8 g, 9.0 mmol, 1.0 eq.) in DMF (3 mL) was slowly added dropwise, the reaction mixture was stirred at 25°C for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (20 ml) and the resulting mixture was extracted with EA (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to give compound 116-2 (1.1 g, 53% yield) as a yellow oil.

Step 2: Methyl 2-amino-5-cyclopropoxybenzoate

To a solution of compound 116-2 (1.5 g, 6.3 mmol, 1.0 eq.) in EtOH (30 ml) and H2O (6 ml) was added Fe (3.53 g, 63.2 mmol, 10 eq. .) and NH4Cl (6.77 g, 126 mmol, 20 eq.). The reaction mixture was stirred at 80°C for 4 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. The suspension was filtered, washed with EA (50 ml) and water (30 ml). The filtrate was separated and then the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 116-3 (1.2 g, 91% yield) as yellow

- 156 046394 th oil.

Step 3: Methyl 2-amino-3-bromo-5-cyclopropoxybenzoate

To a solution of compound 116-3 (1.2 g, 5.8 mmol, 1.0 eq) in DMF (10 ml) was added NBS (1.13 g, 6.4 mmol, 1.1 eq) at 0 °C. The reaction mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (20 ml) and the resulting mixture was extracted with EA (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0-10:1) to give compound 116-4 (790 mg, 47% yield) as a colorless oil. LCMS (ESI): RT=0.959 min, mass calc. for CnHi ₂ BrNO ₃ 285.00, m/z obtained 287.9 [M+H]+.

Step 4: (2-amino-3-bromo-5-cyclopropoxyphenyl)methanol

To a solution of compound 116-4 (790.0 mg, 2.76 mmol, 1.0 eq.) in THF (12 ml) was added LiBH ₄ (601.4 mg, 27.6 mmol, 10 eq.) at 0° WITH. The reaction mixture was stirred at 25°C for 4 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. The reaction mixture was poured into H2O (30 ml) and then the mixture was extracted with EA (50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to give compound 116-5 (700 mg, 97% yield) as a white solid.

Step 5: 2-amino-3-bromo-5-cyclopropoxybenzaldehyde

To a solution of compound 116-5 (700.0 mg, 2.71 mmol, 1.0 eq) in DCM (15 ml) was added MnO ₂ (2.36 g, 27.1 mmol, 10 eq). The reaction mixture was stirred at 25°C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 10:1) to give compound 116-6 (480 mg, 69% yield) as a yellow oil.

Step 6: Methyl 8-bromo-6-cyclopropoxyquinoline-3-carboxylate

To a solution of compound 116-6 (480.0 mg, 1.87 mmol, 1.0 eq.) and compound 116-6a (189.0 mg, 2.25 mmol, 1.2 eq.) in EtOH (8 ml ) L-proline (108.8 mg, 0.937 mmol, 0.5 eq.) was added. The reaction mixture was stirred at 80°C for 16 hours. 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 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to give compound 116-7 (560 mg, 92% yield) as a light yellow solid.

Step 7: 8-bromo-6-cyclopropoxyquinoline-3-carboxylic acid

To a solution of compound 116-7 (150 mg, 0.47 mmol, 1.0 eq.) in THF (1.5 ml) and MeOH (0.5 ml), NaOH (2 M, 0.46 ml, 2.0 eq.). The reaction mixture was stirred at 25°C for 2 hours. The pH of the reaction mixture was adjusted to 6 with HCl (1 M), and then H2O (5 ml) was added. The suspension was extracted with EA (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 116-8 (140 mg, 97% yield) as a light yellow solid.

Step 8: 8-bromo-6-cyclopropoxy-N-isopropylquinoline-3-carboxamide

To a solution of compound 116-8 (40.0 mg, 0.13 mmol, 1.0 eq.), compound 116-8a (11.5 mg, 0.195 mmol, 1.5 eq.) and DIPEA (33.5 mg , 0.26 mmol, 2.0 eq.) HATU (74.0 mg, 0.15 mmol, 1.5 eq.) was added to DCM (1 ml). The reaction mixture was stirred at 25°C for 2 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 ml) and the resulting mixture was extracted with EA (50 mlx3). 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 (petroleum ether:ethyl acetate=1:0 to 3:1) to give compound 9 (40 mg, 88% yield) as a white solid.

Step 9: 6-cyclopropoxy-N-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 116-9 (40.0 mg, 0.11 mmol, 1.0 eq.), compound 116-9a (26.1 mg, 0.14 mmol, 1.2 eq.) and Na ₂ CO ₃ (24.2 mg, 0.23 mmol, 2.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (4.1 mg, 5.7 µmol, 0 .05 eq.). The reaction mixture was stirred at 90°C for 16 hours under N ₂ atmosphere. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was identified. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (6.86 mg, 14% yield) as a white solid. LCMS (ESI): RT=1.024 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ 414.16, m/z obtained 415.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3 Hz, 1H), 7.84

- 157 046394

-7.73 (m, 4H), 7.55 (d, J=2.8 Hz, 1H), 7.49 (d, J=2.8 Hz, 1H), 6.07 (d, J= 7.1 Hz, 1H), 4.45 -4.33 (m, 1H), 3.97 3.91 (m, 1H), 1.34 (d, J=6.5 Hz, 6H), 0 .97 - 0.89 (m, 4H).

Example 109: tert-butylmethyl (2-(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)ethyl)carbamate (compound 117)

A mixture of compound 117-1 (0.03 g, 94.8 µmol, 1 eq), HATU (54.1 mg, 0.14 mmol, 1.5 eq) and DIPEA (36.7 mg, 0.28 mmol, 49.5 µl, 3 eq.) in DMF (1 ml) was stirred at 25°C for 1 hour. Tert-butyl-U-(2-aminoethyl)-U-methylcarbamate (19.8 mg) was added to the reaction , 0.11 mmol, 20.3 µl, 1.2 eq.). The mixture was stirred at 25°C for another 1 hour. Completion of the reaction was observed using LCMS. The mixture was partitioned between EA (5 ml) and saline (5 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product. The crude product was purified by pre-HPLC. The title compound (6 mg, 12.5 µmol, 13.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.878 min, mass calc. for C26H27F3N2O3. ¹ H NMR (400 MHz, CD=OD) δ 8.48 (br d, J=14.6 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.93 - 7 .82 (m, 4H), 7.74 - 7.64 (m, 3H), 7.59 (d, J=6.5 Hz, 1H), 3.64 - 3.58 (m, 1H), 3.58 - 3.54 (m, 1H), 3.65 - 3.51 (m, 2H), 2.97 (br s, 3H), 1.39 (br d, J=18.8 Hz, 9H).

Example 110: tert-butylmethyl (3-(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)propyl)carbamate (compound 118)

A mixture of compound 118-1 (0.03 g, 94.8 µmol, 1 eq.), DIPEA (36.7 mg, 0.28 mmol, 49.5 µl, 3 eq.) and HATU (54.1 mg, 0.14 mmol, 1.5 eq.) in DMF (1 ml) was stirred at 25°C for 1 hour. Then tert-butyl-U-(3-aminopropyl)-U-methylcarbamate (21.4 mg, 0.11 mmol, 1.2 eq.) was added to the mixture and the mixture was stirred for another 1 hour. Completion of the reaction was observed by LC-MS and HPLC. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx4), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (7 mg, 14.2 µmol, 15% yield) was obtained as a brown solid. LCMS (ESI): RT=1.069 min, mass calc. for C27H29F3N2O3 486.53 m/z 487.1[M+H]+ was obtained; 1H NMR (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.82 - 7.72 (m, 4H), 7 .64 - 7.55 (m, 3H), 7.48 (d, J=7.0 Hz, 1H), 3.37 (t, J=6.9 Hz, 2H), 3.30 (t, J=7.1 Hz, 2H), 2.82 (br s, 3H), 1.82 (br s, 2H), 1.37 (br d, J=8.9 Hz, 9H).

Example 111: Al-(disulfandiylbis(propan-3,1-diyl))bis(5-(4-(trifluoromethyl)phenyl)-2naphthamide) (compound 119)

Step 1: 3,3'-disulfandiylbis(propan-1-amine)

A mixture of compound 119-1 (50 mg, 391.74 µmol, 1 eq., HCl) in DCM (2 ml) was stirred at 25°C in

- 158 046394 for 48 hours in an O2 atmosphere. Compound 119-2 (crude) was used in the next step without further purification.

Step 2: XNi-(disulfandiylbis(propan-3,1-diyl))bis(5-(4-(trifluoromethyl)phenyl)-2-naphthamide)

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (55.8 mg, 0.17 mmol, 1 eq.), HATU (100.6 mg, 0.26 mmol, 1.5 eq. ), compounds 119-2 (35 mg, 0.19 mmol, 1.1 eq.) and DIPEA (68.4 mg, 0.52 mmol, 92.2 μl, 3 eq.) in DCM (2 ml) were stirred at 25°C for 2 hours. It was observed by LC-MS and HPLC that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (10 mg, 12.7 µmol, 7.2% yield) was obtained as a white solid. LCMS (ESI): RT=1.172 min, mass calc. for C ₄₂ H ₃₄ F ₆ N ₂ O ₂ S ₂ 776.85 m/z, 777.0 [M+H]+ was obtained; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (br s, 2H), 8.55 (s, 2H), 8.12 (d, J=8.3 Hz, 2H), 7.94 - 7.88 (m, 6H), 7.80 (d, J=8.9 Hz, 2H), 7.76 - 7.66 (m, 6H), 7.59 (br d, J=7, 0 Hz, 2H), 3.43 (br d, J=5.8 Hz, 4H), 2.85 (t, J=7.1 Hz, 4H), 2.06 - 1.91 (m, 5H ).

Example 112: S-(3-(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)propyl)-5-(4(trifluoromethyl)phenyl)naphthalene-2-carbothiolate (compound 120)

A mixture of compound 120-1 (50 mg, 0.15 mmol, 1 eq.), 3-aminopropane-1-thiol (22.2 mg, 0.17 mmol, 1.1 eq., HCl), HATU (90, 1 mg, 0.23 mmol, 1.5 eq.) and DIPEA (61.2 mg, 0.47 mmol, 82.6 µl, 3 eq.) in DCM (2 ml) were stirred at 25°C for 2 h. Using LC-MS and HPLC, it was observed that the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was washed with MeCN (5 ml) and filtered. The filter cake was concentrated in vacuum. The title compound (10 mg, 14.4 µmol, 9.1% yield) was obtained as a white solid. LCMS (ESI): RT=1.225 min, mass calc. for Q9H27F6NO2S 687.69 m/z, 688.0[M+H]+ was obtained; ^1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J=5.6 Hz, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.58 (d, J=1.3 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.98 7.86 (m , 7H), 7.82 (d, J=8.8 Hz, 1H), 7.77 - 7.70 (m, 5H), 7.71 - 7.65 (m, 2H), 7.59 ( d, J=6.0 Hz, 1H), 3.48 (q, J=6.5 Hz, 2H), 3.22 (t, J=7.0 Hz, 2H), 2.04 - 1, 93 (m, 2H).

Example 113: N(1-phenylcyclopropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 121)

F

To a solution of compound 121-1 (20 mg, 63.2 µmol, 1 eq.) in DCM (1 ml) was added DIEA (32.7 mg, 0.25 mmol, 44 µl, 4 eq.) and HATU (36, 1 mg, 94.8 µmol, 1.5 eq.). The mixture was stirred at 30°C for 0.5 h. Compound 121-1a (16.1 mg, 94.8 μmol, 1.5 eq., HCl) was added to the mixture. The mixture was stirred at 30°C for 2 hours. The desired compound was determined by LCMS. The mixture was diluted with H ₂ O (10 ml), extracted with EA (20 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated. The residue was checked by HPLC. The residue was purified by pre-HPLC to give the title compound (24.2 mg, 56.1 µmol, 88.7% yield) as a white solid. LCMS (ESI): RT=1.056 min, mass, calc. for C ₂₇ H ₂₀ F ₃ NO 431.15, m/z obtained 432.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=1.4 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.90 - 7.74 (m, 4H), 7.64 - 7.57 (m, 3H), 7.50 (dd, J=1.1, 7.1 Hz, 1H), 7.38 - 7.28 (m, 4H ), 7.23 - 7.18 (m, 1H), 6.97 (s, 1H), 1.48 - 1.40 (m, 4H).

Example 114: 6-cyclopropoxy-N-(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide (compound 122)

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Step 1: 8-bromo-6-cyclopropoxy-U-('methyls-ulfonyl)quinoline-3-carboxamide

To a solution of compound 122-1 (50.0 mg, 0.16 mmol, 1.0 eq) in DMF (1 ml) was added CDI (31.5 mg, 0.19 mmol, 1.2 eq). The reaction mixture was stirred at 40°C for 30 minutes. The reaction was cooled to 25°C and then DBU (29.6 mg, 0.19 mmol, 1.2 eq) and compound 122-1a (18.5 mg, 0.19 mmol, 1.2 eq) were added. . The reaction mixture was stirred at 25°C for 2 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=20:1) to give compound 122-2 (35 mg, 53% yield) as a white solid. LCMS (ESI): RT=0.831 min, mass calc. for C ₁₄ H ₁₃ BrN ₂ O ₄ S 383.98, m/z obtained 386.8 [M+H]+.

Step 2: 6-cyclopropoxy-N(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinnoline-3-carboxamide

To a solution of compound 122-2 (35.0 mg, 90 µmol, 1.0 eq.), compound 122-2a (20.7 mg, 0.11 mmol, 1.2 eq.) and Na ₂ CO ₃ (28 .8 mg, 0.27 mmol, 3.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (3.3 mg, 4.5 µmol, 0.05 eq.) in an N2 atmosphere. The reaction mixture was stirred at 90°C for 16 hours under N2 atmosphere. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was identified. The pH of the reaction mixture was adjusted to 5 with HCl (1 M). The resulting mixture was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (2.23 mg, 5% yield, HCl) as a white solid. LCMS (ESI): RT=0.979 min, mass calc. for C ₂₁ H ₁₇ F ₃ N ₂ O ₄ S 450.09, m/z obtained 451.0 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (d, J=2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H), 7.92 - 7, 81 (m, 5H), 7.63 (d, J=2.8 Hz, 1H), 4.14 - 4.06 (m, 1H), 3.44 (s, 3H), 0.99 - 0 .88 (m, 2H), 0.85 - 0.76 (m, 2H).

Example 115: N(methylsulfonyl)-6-(trifluoromethoxy)-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide (compound 123)

123-2a (1.2 eq.C

Pd(dppf}CI ₂ (0.05 eq.)

Na ₂ CO ₃ (3.0 eq.) Dioxane/H ₂ O, 90 °C, 16 h

Step 1: 8-bromo-N(methylsulfonyl)-6-(trifluoromethoxy)quinoline-3-carboxamide

To a solution of compound 123-1 (80.0 mg, 0.24 mmol, 1.0 eq) in DMF (1 ml) was added CDI (46.3 mg, 0.28 mmol, 1.2 eq). The reaction mixture was stirred at 40°C for 30 minutes. The reaction was cooled to 25°C and then DBU (43.4 mg, 0.28 mmol, 1.2 eq) and compound 123-1a (27.1 mg, 0.28 mmol,

1.2 eq.). The reaction mixture was stirred at 25°C for 3 hours. Using LC-MS, it was observed that the starting material remained and one peak with the required MS was determined. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (3 ml) and the pH of the mixture was adjusted to 5 with HCl (1 M). The resulting mixture was extracted with EA (20 ml x 3 ). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=10:1) to give compound 123-2 (80 mg, crude) as a yellow oil.

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Step 2: N(methylsulfonyl)-6-(trifluoromethoxy)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide

To a solution of compound 123-2 (80.0 mg, 0.19 mmol, 1.0 eq.), compound 123-2a (44.1 mg, 0.23 mmol, 1.2 eq.) and Na ₂ CO ₃ (61.5 mg, 0.58 mmol, 3.0 eq.) in dioxane (2 ml) and H ₂ O (0.4 ml) was added Pd(dppf)Cl ₂ (7.0 mg, 9.7 µmol , 0.05 eq.) in an N2 atmosphere. The reaction mixture was stirred at 90°C for 16 hours under N2 atmosphere. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was identified. The pH of the reaction mixture was adjusted to 5 with HCl (1 M). The resulting mixture was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (19.45 mg, 19% yield, HCl) as a light yellow solid. LCMS (ESI): RT=0.993 min, mass calc. for C ₁₉ H ₁₂ F ₆ N ₂ O ₄ S 478.04, m/z obtained 478.9 [M+H]+; 1H NMR (400 MHz, DMSC-d ₆ ) δ 9.29 (d, J=2.3 Hz, 1H), 9.15 (d, J=2.3 Hz, 1H), 8.31 (d, J=1.3 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.95 - 7.85 (m, 4H), 3.44 (s, 3H).

Example 116: N(2-(methylamino)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 124)

A mixture of compound 124-1 (0.02 g, 42.3 µmol, 1 eq.) in HCl/dioxane (4 M, 0.52 ml, 50 eq.) was stirred at 25°C for 1 h. Using LC -MS and HPLC observed that the desired compound was detected. The mixture was concentrated in vacuo to give the crude product. The crude product was purified by pre-HPLC. The title compound (5 mg, 12.2 µmol, 28.8% yield, HCl) was obtained as a white solid. LCMS (ESI): RT=0.850 min, mass calc. for C21H1 ₉ F ₃ N2O 372.38 m/z, 373.0 [M+H]+ was obtained; ¹ H NMR (400 MHz, CD3OD) δ 8.46 (d, J=1.5 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.86 - 7.81 ( m, 1H), 7.79 - 7.71 (m, 3H), 7.61 - 7.55 (m, 3H), 7.51 - 7.46 (m, 1H), 3.67 (t, J=5.7 Hz, 2H), 3.21 - 3.17 (m, 3H), 2.71 - 2.63 (m, 3H).

Example 117: N(2-(Nmethylcyanamido)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 125)

A mixture of compound 125-1 (40 mg, 0.10 mmol, 1 eq.), TEA (43.4 mg, 0.42 mmol, 59.8 μl, 4 eq.) and BrCN (34.1 mg, 0. 32 mmol, 23.7 μl, 3 eq.) in DCM (2 ml) was stirred at 0°C for 1 hour. Using LC-MS and HPLC, it was observed that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (6 mg, 14.9 µmol, 13.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.946 min, mass calc. for C ₂₂ H ₁₈ F ₃ N ₃ O 397.39 m/z, 398.0 [M+H]+ was obtained; 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.93 7.83 (m, 4H), 7.73 - 7.65 (m, 3H), 7.58 (d, J=6.3 Hz, 1H), 3.70 (t, J=5.7 Hz, 2H), 3.36 (t, J=5 .8 Hz, 2H), 3.00 (s, 3H).

Example 118: N(3-(methylamino)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 126)

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A mixture of compound 126-1 (0.05 g, 0.10 mmol, 1 eq.) in HCl/dioxane (4 M, 1.28 ml, 50 eq.) was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was partitioned between EA (5 ml) and saturated NaHCO ₃ (5 ml). The organic layer was washed with brine (5 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (SiO ₂ , EA:PE=1:0 - 1:1). The title compound (38 mg, 96.3 µmol, 93.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.845 min, mass calc. for C ₂₂ H ₂₁ F ₃ N ₂ O 386.41 m/z, 387.0 [M+H]+ was obtained; 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.95 - 7.83 (m, 4H), 7.73 - 7.66 (m, 3H), 7.60 (d, J=6.5 Hz, 1H), 3.63 - 3.55 (m, 2H), 3.12 (t, J=7.3 Hz, 2H), 2.77 (s, 3H), 2.06 (quin, J=6.9 Hz, 2H).

Example 119: N(3-(Nmethylcyanamido)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 127)

A mixture of compound 127-1 (100 mg, 0.25 mmol, 1 eq.), BrCN (82.2 mg, 0.77 mmol, 57.1 μl, 3 eq.) and TEA (104.7 mg, 1 eq. 04 mmol, 0.14 ml, 4 eq.) in DCM (2 ml) was stirred at 0°C for 1 hour. Using LC-MS and HPLC, it was observed that the desired compound was detected. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The title compound (18 mg, 43.3 µmol, 16.7% yield) was obtained as a brown solid. LCMS (ESI): RT=0.960 min, mass calc. for C ₂₃ H ₂₀ F ₃ N ₃ O 411.42 m/z, 412.0 [M+H]+ was obtained; δNMR (400 MHz, CD3OD) δ 8.47 (d, J=1.5 Hz, 1H), 8.07 8.03 (m, 1H), 7.88 - 7.80 (m, 5H), 7 .67 - 7.61 (m, 3H), 7.55 - 7.51 (m, 1H), 3.54 (t, J=6.9 Hz, 2H), 3.37 - 3.31 (m , 1H), 3.16 (t, J=7.0 Hz, 2H), 2.91 (s, 3H), 2.01 (quin., J=7.0 Hz, 2H).

Example 120: ^)-No(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 128) and ^)-No(1-(6 -aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 129)

Step 1: 1-(6-bromopyridin-2-yl)ethanamine

To a solution of compound 128-1 (9.5 g, 51.91 mmol, 1 eq.) in dry THF (150 ml) was added dropwise MeMgBr (3 M, 25.96 ml, 1.5 eq.) at 0° C in N2 atmosphere. After addition, the reaction mixture was stirred at 25°C for 0.5 h. The suspension was then treated with MeOH (31.34 g, 978.16 mmol, 39.58 ml, 18.84 eq.) and NaBH ₄ (5.89 g, 155.73 mmol, 3 equiv.). The reaction mixture was stirred at 25°C for 2.5 hours. The reaction mixture was poured into NaOH (120 ml, 2 M) at 0°C and stirred for 5 minutes. The aqueous phase was extracted with EA (60 mlx3). The combined organic phase was washed with brine (100 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.

Compound 128-2 (1.1 g, 3.99 mmol, 7.6% yield) was obtained as a yellow oil.

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Step 2: Y-(1-(6-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

A mixture of 5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1.51 g, 4.77 mmol, 1.2 eq.), HATU (3.03 g, 7.96 mmol, 2 eq. ) in DMF (15 ml) was added DIPEA (1.54 g, 11.94 mmol, 2.08 ml, 3 eq.) at 25°C. After addition, the mixture was stirred at 25°C for 1 hour, and then compound 128-2 (800 mg, 3.98 mmol, 1 eq.) (in DMF (3 ml)) was added. The resulting mixture was stirred at 25°C for 15 hours. The residue was poured into H2O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Compound 128-3 (386 mg, 0.74 mmol, 18.8% yield) was obtained as a yellow solid.

Step 3: ^)-N(1-(6-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and (R)-N-(1(6-aminopyridin- 2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide

Mixture of compound 128-3 (300 mg, 0.60 mmol, 1 eq.), NH3-H2O (842.2 mg, 6.01 mmol, 0.92 ml, 25%, 10 eq.), Cu ₂ O ( 85.9 mg, 0.60 mmol, 61.4 µl, 1 eq.) in ethylene glycol (2 ml) was loaded into a stoppered reaction tube. The reaction temperature was raised to 70°C and the reaction mixture was stirred at 70°C for 16 hours. The residue was poured into H ₂ O (20 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (10 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to obtain 152 mg of product. The product was purified by chiral SFC. Compound 128 (48.6 mg, 0.10 mmol, 18% yield) was obtained as a white solid. LCMS (ESI): RT=0.768 min, mass calc. for C ₂₅ H ₂₀ F ₃ N ₃ O 435.44 m/z, 436.0 [M+H]+ was obtained; ¹ H NMR (400 MHz, DMSO-de) δ 8.85 (d, J=7.8 Hz, 1H), 8.63 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.00 - 7.89 (m, 3H), 7.81 (d, J=9.0 Hz, 1H), 7.77 - 7.67 (m, 3H), 7.59 (d , J=6.3 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 6.55 (d, J=7.3 Hz, 1H), 6.31 (d, J =8.3 Hz, 1H), 5.89 (s, 2H), 5.01 (quin., J=7.2 Hz, 1H), 1.48 (d, J=7.0 Hz, 3H) .

Compound 129 (47.4 mg, 0.10 mmol, 18.1% yield) was obtained as a white solid. LCMS (ESI):RT=0.774 min, mass calc. for C ₂₅ H ₂₀ F ₃ N ₃ O 435.44 m/z, 436.0 [M+H]+ was obtained; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (d, J=7.8 Hz, 1H), 8.63 (s, 1H), 8.15 (d, J=8.0 Hz , 1H), 8.00 - 7.89 (m, 3H), 7.81 (d, J=9.0 Hz, 1H), 7.77 - 7.67 (m, 3H), 7.59 ( d, J=6.3 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 6.55 (d, J=7.3 Hz, 1H), 6.31 (d, J=8.3 Hz, 1H), 5.89 (s, 2H), 5.01 (quin., J=7.2 Hz, 1H), 1.48 (d, J=7.0 Hz, 3H ).

Example 121: A[(^)-1-(azetidin-3-yl)-2-hydroxyethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 130) and tert-butyl-3-[( ^)-2-hydroxy-1-[[5-[4-(trifluoromethyl)phenyl]naphthalene2-carbonyl]amino]ethyl] azetidine-1-carboxylate (compound 134)

tert-Butyl-3-[(1R)-2-benzyloxy-1-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2carbonyl]amino]ethyl]azetidine-1-carboxylate and tert-butyl-3-[ (^)-2-benzyloxy-1-[[5-[4(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]ethyl]azetidine-1-carboxylate.

The separation of compound 121-6a (150 mg, 0.24 mmol, 1 eq.) was carried out by the SFC method. The product was tested by LCMS. The racemate was separated by chiral SFC (column: DAICEL CHIRALCEL OD-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; V%: 25%-25%, min). Compound 121-8 (65 mg, 0.10 mmol, 42.4% yield) was obtained as a colorless oil. Compound 121-9 (65 mg, 0.10 mmol, 42.9% yield) was obtained as a colorless oil.

1ret-Butyl-3-[(^)-2-hydroxy-1-[[5-[4-(lfluoromethyl)phenyl]naphthalene-2-carbonyl]amino]ethyl]azetidine 1-carboxylate (compound 134).

To a solution of compound 121-9 (65 mg, 0.10 mmol, 1 eq.) in MeOH (2 ml) was added Pd(OH) ₂ (7.5 mg, 10.7 μmol, 20%, 0.1 eq. ) and TFA (12.2 mg, 0.10 mmol, 8 μl, 1 eq.). The mixture was degassed, purged with H ₂ 3 times and stirred at 25°C for 2 hours under H ₂ (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by pre-TLC method (PE/EA=1/2). The desired compound (43 mg, 82.7 µmol, 76.9% yield) was obtained as white

- 163 046394 solids. LCMS (ESI): RT=0.982 min, mass calc. for C ₂₈ H ₂₉ F ₃ N ₂ O ₄ , 514.21 m/z, 515.3 [M+H]+ was obtained. ¹ HNMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J=1.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.90 - 7.85 ( m, 1H), 7.83 - 7.75 (m, 3H), 7.65 - 7.58 (m, 3H), 7.52 (dd, J=0.9, 6.9 Hz, 1H) , 6.71 (br d, J=8.5 Hz, 1H), 4.49 (td, J=4.3, 8.4 Hz, 1H), 4.06 (td, J=8.6, 11.2 Hz, 2H), 3.93 (dd, J=5.8, 8.8 Hz, 1H), 3.88 - 3.74 (m, 3H), 3.05 - 2.88 (m , 1H), 2.52 - 2.30 (m, 1H), 1.43 (s, 9H).

^[(^)-1-(azetidin-3-yl)-2-hydroxy-ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 130).

To a solution of compound 134 (35 mg, 68.0 μmol, 1 eq.) in DCM (2 ml) was added TFA (232.6 mg, 2.04 mmol, 0.15 ml, 30 eq.). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was quenched with saturated aq. NaHCO ₃ (5 ml), extracted with EA (10 mlx3). The combined organic phase was washed with H ₂ O (5 ml), brine (5 ml) and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was tested by LCMS, HPLC and purified by pre-HPLC. Compound 130 (4.0 mg, 8.8 µmol, 13.0% yield, HCl) was obtained as a colorless oil. LCMS (ESI): RT=0.748 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ , 414.16 m/z, 415.0 [M+H] ⁺ was obtained. ¹ H NMR (400 MHz, CD3OD) δ 8.57 (d, J=1.3 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.96 - 7.83 ( m, 4H), 7.76 - 7.66 (m, 3H), 7.63 - 7.57 (m, 1H), 4.53 (td, J=5.5, 8.7 Hz, 1H) , 4.22 - 4.08 (m, 4H), 3.79 - 3.63 (m, 2H), 3.46 - 3.35 (m, 1H).

Example 122: N[(^)-1-(azetidin-3-yl)-2-hydroxyethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 131), N-[(3R) -4-(aminomethyl)tetrahydrofuran-3-yl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 132) and tert-butyl-3-[(1K.)-2-hydroxy-1- [[5[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]ethyl]azetidine-1-carboxylate (compound 135)

2-Nitroethoxymethylbenzene.

To a solution of compound 122-1 (5 g, 54.91 mmol, 3.88 ml, 1 eq.) and compound 122-1a (15.25 g, 60.40 mmol, 11.3 ml, 1.1 eq. ) in DCM (80 ml) and cyclohexane (160 ml) was added trifluoromethanesulfonic acid (824.0 mg, 5.49 mmol, 0.48 ml, 0.1 eq.). The mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered and the filtrate was washed with saturated aq. NaHCO ₃ (20 ml), H ₂ O (20 ml) and dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash column, gradient 0~10% ethyl acetate/petroleum ether eluent approximately 40 ml/min). NMR confirmed that compound 122-2 (11.2 g, 61.81 mmol, 56.2% yield) was obtained as a colorless oil. ^1H NMR (400 MHz, CDCl3) δ 7.41 - 7.28 (m, 5H), 4.58 (s, 2H), 4.57 -4.51 (m, 2H), 4.03 - 3 .94 (m, 2H).

tert-Butyl-3-(2-benzyloxy-1-nitroethyl)-3-hydroxyazetidine-1-carboxylate.

To the TBAF mixture (1 M, 23.37 mL, 2 eq.) was added compound 122-2 (4.23 g, 23.37 mmol, 2 eq.) at 0°C and the mixture was stirred at 0°C for 1 h. Then compound 122-2a (2 g, 11.68 mmol, 1 eq.) in THF (30 ml) was added to the mixture and stirred at 0°C for 4 hours. The reaction mixture was quenched with saturated NH ₄ Cl (20 ml ), extracted with EA (15 mlx3). The combined organic phase was washed with H ₂ O (10 ml) and brine (10 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, 0~20% ethyl acetate/petroleum ether eluent gradient approximately 35 ml/min). Compound 122-3 (1.5 g, 4.26 mmol, 36.4% yield) was obtained as a colorless oil.

tert-Butyl 3-(2-benzyloxy-1-nitroethylidene)azetidine-1-carboxylate.

To a solution of compound 122-3 (500 mg, 1.42 mmol, 1 eq.) in DCM (20 mL) was added DAST (343.0 mg, 2.13 mmol, 0.28 mL, 1.5 eq.) at 0°C. The mixture was then stirred at 0°C for 0.5 hours with H2O (10 ml) and

- 164 046394 saturated aq. NaHCO ₃ (10 ml) was added to the reaction mixture with stirring until the product was bubble-free. The mixture was extracted with DCM (15 mlx3). The combined organic phase was washed with H2O (10 ml), brine (10 ml) and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Compound 122-4 (815 mg, 2.44 mmol, 85.8% yield) was obtained as a yellow oil.

tert-Butyl-3-(1-amino-2-benzyloxyethyl)azetidine-1-carboxylate.

To a solution of compound 122-4 (800 mg, 2.39 mmol, 1 eq.) in THF (5 ml) was added Pd/C (381.9 mg, 0.36 mmol, 10%, 0.1 eq.). The mixture was degassed and purged with H2 3 times and stirred at 25°C for 16 hours under H2 (40 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was used immediately in the next step. Compound 122-5 (610 mg, crude) was obtained as a yellow oil.

tert-Butyl-3 - [2-benzyloxy-1-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2 carbonyl]amino]ethyl]azetidine-1-carboxylate.

To a solution of compound 122-5a (227.0 mg, 0.72 mmol, 1.1 eq.) in DCM (3 mL) was added HATU (409.5 mg, 1.08 mmol, 1.5 eq.), mixture compounds 122-5 (220 mg, 0.72 mmol, 1 eq.) and DIEA (185.5 mg, 1.44 mmol, 0.25 ml, 2 eq.). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was then diluted with EA (15 mlx3), washed with H2O (10 ml) and brine (10 mlx2), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. The crude product was then purified by pre-HPLC (column: Welch Xtimate C18 150x25mmx5µm; mobile phase: [water (0.05%HCl)-ACN]; B%: 65%-95%, 8.5 min). Compound 122-6a (110 mg, 0.17 mmol, 24.8% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H) , 7.82 - 7.75 (m, 3H), 7.67 - 7.59 (m, 3H), 7.52 (d, J=6.8 Hz, 1H), 7.40 - 7.29 (m, 5H), 6.67 (br d, J=9.0 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.59 4.48 (m, 2H), 4, 06 -3.90 (m, 3H), 3.80 - 3.71 (m, 1H), 3.67 - 3.58 (m, 2H), 3.07 - 2.94 (m, 1H), 1.42(s,9H).

tert-Butyl-3-[(III)-2-benzyloxy-1-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2carbonyl]amino]ethyl]azetidine-1-carboxylate.

The separation of compound 122-6a (150 mg, 0.24 mmol, 1 eq.) was carried out by the SFC method. The product was tested by LCMS. The racemate was separated by chiral SFC (column: DAICEL CHIRALCEL OD-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; V%: 25%-25%, min). Compound 122-8 (65 mg, 0.10 mmol, 42.4% yield) was obtained as a colorless oil.

tert-butyl-3-[(III)-2-hydroxy-1-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2carbonyl]amino]ethyl]azetidine-1-carboxylate (compound 135)

To a solution of compound 122-8 (65 mg, 0.10 mmol, 1 eq.) in MeOH (2 ml) was added Pd(OH) ₂ (7.5 mg, 10 μmol, 20%, 0.1 eq.) and TFA (122.5 mg, 1.07 mmol, 79 µl, 10 eq.). The mixture was degassed and purged with H ₂ 3 times and stirred at 25°C for 2 hours under an atmosphere of H ₂ (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by pre-TLC (PE/EA=1/2). Compound 135 (42 mg, 81.6 μmol, 75.9% yield) was confirmed to be obtained as a white solid by LCMS and NMR. LCMS (ESI): RT=0.927 min, mass calc. for C28H2 ₉ F ₃ N2O4, 514.21 m/z obtained 515.1 [M+H]+ 1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.91 - 7.85 (m, 1H), 7.84 - 7.76 (m, 3H), 7.67 -7.59 (m, 3H), 7.52 (d, J=7.0 Hz, 1H), 6.67 (br d, J=8.4 Hz, 1H), 4.56 - 4.44 (m, 1H), 4.07 (td, J =8.7, 11.3 Hz, 2H), 3.93 (dd, J=5.7, 8.8 Hz, 1H), 3.87 - 3.75 (m, 3H), 3.05 - 2.92 (m, 1H), 2.33 (brs, 1H), 1.43 (s.9H).

N[(U)-1-(Azetidin-3-yl)-2-hydroxy-ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 131) and N-[(3R)- 4-(aminomethyl)tetrahydrofuran-3-yl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (compound 132).

To a solution of compound 135 (30 mg, 58.3 µmol, 1 eq.) in DCM (2.5 ml) was added TFA (385 mg, 3.38 mmol, 0.25 ml). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo. The pH of the residue was adjusted to 8 with saturated aq. NaHCO ₃ , extracted with EA (15 mlx3). The combined organic phase was washed with H2O (10 ml), brine (10 ml) and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was tested by LCMS, HPLC and purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HC1)-ACN]; B%: 20%-50%, 8 ,5 minutes). Compound 132 (6.6 mg, 14.1 µmol, 24.2% yield, HCl) was obtained as a colorless oil. LCMS (ESI): RT=0.724 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ , 414.16 m/z, 415.1 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.47 (d, J=1.8 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.00 (d, J=9 .0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.80 - 7.72 (m, 2H), 7.72 - 7.67 (m, 3H), 3 .98 - 3.92 (m, 1H), 3.91 -3.85 (m, 2H), 3.85 - 3.74 (m, 2H), 3.74 - 3.61 (m, 2H) , 2.57 - 2.45 (m, 1H). ¹³ C NMR (101 MHz, CD3OD) δ 160.80, 143.68, 138.90, 132.99, 132.94, 130.33, 129.70, 129.28, 129.03, 127.03, 126.57, 126.10, 125.22, 125.18, 123.19, 60.56, 59.27, 52.63, 48.09, 47.88, 47.66, 40.46, 34, 16. Compound 131 (2.8 mg, 6.2 µmol, 10.7% yield, HCl) was obtained as a colorless oil. LCMS (ESI): RT=0.741 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ , 414.16 m/z, 415.0 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.54 (d, J=1.5 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.94 -7.81 (m , 4H), 7.72 - 7.65 (m, 3H), 7.58 (dd, J=0.8, 7.0 Hz, 1H), 4.51 (td,

- 165 046394

J=5.5, 8.9 Hz, 1H), 4.21 - 4.07 (m, 4H), 3.77 - 3.64 (m, 2H), 3.43 - 3.33 (m, 1H). ¹³ C NMR (101 MHz, CD ₃ OD) δ 169.23, 138.63, 133.10, 132.52, 131.23, 130.31, 129.24, 128.73, 128.26, 126, 17, 125.44, 125.10, 125.06, 124.23, 61.83, 53.22, 49.27, 49.07, 48.24, 47.88, 34.35.

Example 123: (R)-N-(1-(1-(2-hydroxyethyl)azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 133)

To a solution of compound 123-1 (50.0 mg, 0.13 mmol, 1.0 eq.) and K ₂ CO ₃ (52.0 mg, 0.38 mmol, 3.0 eq.) in ACN (1 ml ) compound 123-1a (23.5 mg, 0.19 mmol, 13 μl, 1.5 eq.) was added at 30°C. The reaction mixture was stirred at 60°C for 1 hour. The reaction was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC: (column: Welch Xtimate C18 150x25 mmx5 μm; mobile phase: [water (0.05% HC1 )-ACN]; B%: 20%-50%, 8.5 min]; B%: 65%-95%, 7.8 min) to give compound 133 (2.8 mg, 6 µmol, 4.8 % yield, HCl) as a yellow solid. LCMS (ESI): RT=0.862 min, mass, calc. for C ₂₅ H ₂₅ F ₃ N ₂ O ₂ 442.19, m/z obtained 443.3 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 11.01 - 10.23 (m, 1H), 8.61 (brs, 1H), 8.53 (brd, J=7.4r Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.97 (dd, J=1.8, 8.9 Hz, 1H), 7.89 (d, J=8.1 Hz, 2H ), 7.79 (d, J=8.8 Hz, 1H), 7.73 - 7.67 (m, 3H), 7.57 (dd, J=1.0, 7.0 Hz, 1H) , 4.53 - 4.29 (m, 1H), 4.27 - 3.95 (m, 4H), 3.88 (brs, 1H), 3.64 (brd, J=4.3 Hz, 2H ), 3.07 - 2.99 (m, 2H), 1.22 - 1.13 (m, 3H).

Example 124: N-[(1S)-1-(1-cyclopropylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 136)

Cu( OAc) ₂ (54.7 mg, 0.30 mmol, 2 eq.) and DIPEA (38.9 mg, 0.30 mmol, 52.5 μl, 2 eq.) in one serving at 25°C. The suspension was degassed under vacuum and purged with O2 several times. The mixture was stirred under O2 (15 psi) at 25°C for 18 hours. The reaction mixture was filtered and the cake was washed with EA (10 mlx2). The filtrate was concentrated in vacuo to obtain the crude product. The crude product was purified by pre-HPLC (column: Waters Xbridge C18 150x50 mmx10 µm; mobile phase: [water (0.04%NH ₃ H ₂ O)-ACN]; B%: 54%-84%, 11 min) to give compound 136 (5.6 mg, 12.5 µmol, 8.3% yield) as a white solid. LCMS (ESI): RT=0.804 min, mass calc. for C ₂₆ H ₂₅ F ₃ N ₂ O 438.19, m/z obtained 439.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=1.0 Hz, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.11 (d, J =8.3 Hz, 1H), 7.91 (d, J=8.0 Hz, 3H), 7.80 (d, J=8.8 Hz, 1H), 7.77 - 7.65 (m , 3H), 7.58 (d, J=6.3 Hz, 1H), 4.31 - 4.14 (m, 1H), 3.32 - 3.22 (m, 2H), 3.02 ( t, J=6.5 Hz, 1H), 2.93 (t, J=6.7 Hz, 1H), 2.48 - 2.42 (m, 1H), 1.80 (m, 1H), 1.10 (d, J=6.8 Hz, 3H), 0.28 (m, 2H), 0.17 (m, 2H).

Example 125: (R)-N-(1-(1-(2,2-difluoroethyl)azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 137)

To a solution of compound 125-1 (50 mg, 0.13 mmol, 1 eq.), KI (2.1 mg, 12.6 µmol, 0.1 eq.) and K ₂ CO ₃ (52.0 mg, 0 .38 mmol, 3 equiv.) in ACN (3 ml) at 30°C was added compound 125-1a (27.3 mg, 0.19 mmol, 1.5

- 166 046394 eq.) and the mixture was stirred at 70°C for 16 hours. The reaction mixture was filtered to remove solids and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 μm; mobile phase: [water (0.04% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN]; B%: 58%- 88%, 11 min) to give compound 137 (31.1 mg, 67.4 µmol, 53.7% yield) as a white solid. LCMS (ESI): RT=0.783 min, mass, calc. for C25H23F5N2O 462.17, m/z obtained 463.1 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₀ ) δ 8.52 (d, J=1.1 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.12 (d , J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 3H), 7.81 (d, J=8.9 Hz, 1H), 7.73 (d, J =8.0 Hz, 2H), 7.69 (t, J=7.7 Hz, 1H), 7.58 (d, J=6.6 Hz, 1H), 6.11 - 5.74 (m , 1H), 4.34 - 4.19 (m, 1H), 3.39 (br d, J=8.0 Hz, 2H), 3.07 (t, J=6.8 Hz, 1H), 2.99 (t, J=6.8 Hz, 1H), 2.76 (dt, J=4.1, 16.1 Hz, 2H), 2.62 - 2.56 (m, 1H), 1 ,10 (d, J=6.5 Hz, 3H).

Example 126: N[(^)-1-[1-(2,2-difluoroethyl)azetidin-3-yl]ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (compound 138)

To a solution of compound 126-1 (60 mg, 0.15 mmol, 1 eq.) in MeCN (3 ml) was added K2CO3 (52.0 mg, 0.38 mmol, 2.5 eq.) and compound 126-1a ( 32.7 mg, 0.23 mmol, 1.5 eq.). The mixture was stirred at 70°C for 16 hours. The reaction mixture was diluted with H2O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 mmx5 µm; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 60%-90%, 7.8 min) to give compound 138 (10.6 mg, 22.9 µmol, 15.2% yield) as a white solid. LCMS (ESI): RT=0.808 min, mass calc. for C ₂₅ H ₂₃ F ₅ N ₂ O 462.17, m/z obtained 463.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=1.5 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 8.12 (d, J =8.0 Hz, 1H), 7.91 (d, J=8.5 Hz, 3H), 7.81 (d, J=9.0 Hz, 1H), 7.76 - 7.66 (m , 3H), 7.58 (dd, J=1.0, 7.0 Hz, 1H), 6.10 5.75 (m, 1H), 4.32 - 4.20 (m, 1H), 3 .44 - 3.38 (m, 1H), 3.12 - 2.94 (m, 2H), 2.76 (m, 2H), 2.63 - 2.55 (m, 1H), 1.10 (d, J=6.8 Hz, 3H).

Example 127: N[(^)-1-[1-(2-fluoroethyl)azetidin-3-yl]ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 139)

To a solution of compound 127-1 (60 mg, 0.15 mmol, 1 eq.) in MeCN (3 ml) was added K2CO3 (52.0 mg, 0.38 mmol, 2.5 eq.) and 1-bromo-2 -fluoroethane (28.68 mg, 0.23 mmol, 1.5 eq.). The mixture was stirred at 70°C for 16 hours. The reaction mixture was diluted with H2O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge C18 150x50 mmx10 μm; mobile phase: [water (0.04% NH ₃ H ₂ O)-ACN]; B%: 48-78%, 11 min) to obtain compound 139 (11.2 mg, 24.7 µmol, 16.4% yield) as a yellow solid. LCMS (ESI): RT=0.788 min, mass calc. for C ₂₅ H ₂₄ F ₄ N ₂ O 444.18, m/z obtained 445.3 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J=1.1 Hz, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.96 -7.88 (m, 3H), 7.81 (d, J=8.9 Hz, 1H), 7.76 - 7.66 (m, 3H ), 7.58 (d, J=6.4 Hz, 1H), 4.43 (t, J=4.8 Hz, 1H), 4.36 - 4.21 (m, 2H), 3.35 - 3.27 (m, 2H), 2.99 (t, J=6.6 Hz, 1H), 2.90 (t, J=6.8 Hz, 1H), 2.66 (t, J= 4.8 Hz, 1H), 2.62 - 2.53 (m, 2H), 1.11 (d, J=6.6 Hz, 3H).

Example 128: N[(^)-1-[1-(2-hydroxyethyl)azetidin-3-yl]ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 140)

- 167 046394

To a solution of compound 128-1 (60 mg, 0.15 mmol, 1 eq.) in DMF (2 ml) was added K ₂ CO ₃ (52.0 mg, 0.38 mmol, 2.5 eq.) and 2- bromoethanol (28.2 mg, 0.23 mmol, 16.0 µl, 1.5 eq.). The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 8.5 min) to obtain the compound 140 (14.6 mg, 30.5 µmol, 20.2% yield, HCl) as a white solid. LCMS (ESI): RT=0.783 min, mass calc. for C ₂₅ H ₂₅ F ₃ N ₂ O ₂ 442.19, m/z obtained 443.2 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.00 - 7.85 (m, 3H), 7.80 (d, J=8.8 Hz, 1H), 7.75 - 7.65 (m, 3H), 7.58 (d , J=7.3 Hz, 1H), 4.36 (m, 1H), 4.26 - 3.75 (m, 4H), 3.64 (s, 2H), 3.38 - 3.19 ( m, 3H), 1.17 (d, J=6.0 Hz, 1H), 1.23 - 1.10 (m, 1H), 1.23 - 1.10 (m, 1H).

Example 129: (R)-N-(1-(3-hydroxyazetidin-3-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3 carboxamide (compound 141)

To a solution of compound 129-1 in DCM (1 ml) at 30°C was added TFA (154.0 mg, 1.4 mmol, 0.1 ml, 12.2 eq.). The mixture was stirred at 30°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was made alkaline with NH3-H2O to pH 9 and concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (column: Waters Xbridge C18 150x50 mmx10 µm; mobile phase: [water (0.04% NH ₃ H2O + 10 mM NH4HCO3)ACN]; V%: 33%-63%, 11 min) to obtain compound 141 (14.9 mg, 35 µmol, 32.0% yield) as a white solid. LCMS (ESI): RT=0.825 min, mass, calc. for C ₂₂ H ₂₀ F ₃ N ₃ O ₂ 415.15, m/z obtained 416.2 [M+H]+; ¹ H NMR (400 MHz, D\lSO)-d6) δ 9.25 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.48 (brd, J=8.8 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.95 -7.89 (m, 2H), 7.87 (d, J= 8.6 Hz, 4H), 7.82 - 7.78 (m, 1H), 5.59 (brs, 1H), 4.49 - 4.40 (m, 1H), 3.44 (brs, 2H ), 3.32 (brs, 2H), 1.16 (d, J=6.8 Hz, 3H).

Example 130: N-[(1R)-1-(1-isopropylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2 carboxamide

N-[(1S)-1-(1-isopropylazetidin-3-yl)ethyl]-5-[4(compound

142) and

(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 143)

N[(2,4-Dimethoxyphenyl)methyl]-N-[1-(1-isopropylazetidin-3-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

- 168 046394

To a solution of compound 130-1 (200 mg, 0.36 mmol, 1 eq.) in MeOH (15 ml) was added acetone (264.2 mg, 4.55 mmol, 0.33 ml, 12.4 eq.) and Pd/C (150 mg, 10%). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 130-2 (200 mg, 0.33 mmol, 92.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.969 min, mass calc. for C ₃₅ H ₃₇ F ₃ N ₂ O ₃ 590.28 m/z, 591.2 [M+H]+ was obtained.

N[1-(1-Isopropylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 130-2 (260 mg, 0.44 mmol, 1 eq.) in DCM (2 mL) was added TFA (7.8 g, 68.5 mmol, 5.0 mL, 155.7 eq.). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 40%-70%, 5 min) to give compound 130 -3 (90 mg, 0.20 mmol, 46.4% yield) as a white solid. LCMS (ESI): RT=0.881 min, mass calc. for C ₂₆ H ₂₇ F ₃ N ₂ O 440.21 m/z, 441.1 [M+H]+ was obtained.

N-[(1R)-1-(1-Isopropylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 142) and N-[(1S)-1- (1-isopropylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 143).

Compound 130-3 (90 mg) was purified by pre-SFC method (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; V%: 20% -20%, min) to obtain compound 143 (14.5 mg, 32.7 µmol, 16.0% yield) and compound 142 (17.2 mg, 38.7 µmol, 18.9% yield) as two white solids. Compound 143 LCMS (ESI): RT=0.883 min, mass calc. for C ₂₆ H ₂₇ F ₃ N ₂ O 440.21 m/z, 441.1 [M+H]+ was obtained. ^1H NMR (400 MHz, CD3OD) δ 8.50 - 8.40 (m, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.88 - 7.80 (m, 4H ), 7.69 - 7.63 (m, 3H), 7.55 (dd, J=1.0, 7.1 Hz, 1H), 4.38 - 4.21 (m, 1H), 3, 57 3.46 (m, 2H), 3.07 (t, J=7.8 Hz, 1H), 2.95 (t, J=7.8 Hz, 1H), 2.72 - 2.58 ( m, 1H), 2.43 (spt, J=6.2 Hz, 1H), 1.22 1.18 (m, 3H), 0.95 (dd, J=4.0, 6.3 Hz, 6H). Compound 142 LCMS (ESI): RT=0.883 min, mass calc. for C26H27F3N2O 440.21 m/z, 441.1 [M+H] ⁺ was obtained. ¹ H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.90 - 7.80 (m, 4H), 7, 70 -7.64 (m, 3H), 7.56 (dd, J=1.0, 7.1 Hz, 1H), 4.47 - 4.34 (m, 1H), 3.97 - 3, 82 (m, 2H), 3.63 (br t, J=8.4 Hz, 1H), 3.51 (br t, J=8.5 Hz, 1H), 2.97 (td, J=6 ,3, 12.6 Hz, 1H), 2.85 (sextet, J=8.3

Hz, 1H), 1.25(d, J=6.8 Hz, 3H), 1.11 (dd, J=1.3, 6.4 Hz, 6H).

Example 131: ^)-No(1-(1-(2-fluoroethyl)azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 144)

Benzyl 3-(hydroxymethyl)azetidine-1-carboxylate.

To a solution of compound 131-1 (5 g, 21.26 mmol, 1 eq.) in THF (50 ml) at 0°C was added BH ₃ -Me ₂ S (10 M, 2.55 ml, 1.2 eq. ) dropwise and the mixture was stirred at 30°C for 2 hours. The mixture was quenched at 0°C with saturated NH ₄ Cl (50 ml) and then combined with that indicated on page ES8223-963. The combined mixture was diluted with water (100 ml) and extracted with EA (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (ISCO®; 80 g SepaFlash® Silica Flash column, 0~100% ethyl acetate/petroleum ether eluent gradient approximately 60 mL/min) to give compound 131-2 (8.5 g, 38. 42 mmol,

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90.7% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 - 7.29 (m, 5H), 5.10 (s, 2H), 4.08 (t, J=8.6 Hz, 2H), 3 .84 -3.72 (m, 4H), 2.82 - 2.69 (m, 1H), 1.81 (br s, 1H).

Benzyl-3-formyl azetidine-1-carboxylate.

_DMSO (847.5 mg, 10.85 mmol, 0.85 ml, 1.2 eq.) dropwise and the mixture was stirred at -78°C for 0.5 h. And then compound 131-2 (2 g, 9.04 mmol, 1 eq.) in DCM (10 ml) and TEA (2.74 g, 27.12 mmol, 3.77 ml, 3 eq.) were sequentially added to the above mixture at -78°C. The resulting mixture was stirred at 30°C for 0.5 hours. The mixture was slowly poured into water (100 ml) at 0°C and then extracted with EA (100 ml x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 131-3 (3.96 g, 18.06 mmol, 100.00% yield) as yellow oil, which was used in the next step.

(b)-Benzyl-3 -(((tert-butylsulfinyl)imino)methyl)azetidine-1-carboxylate.

To a solution of compound 131-3 (1.98 g, 9.03 mmol, 1 eq.) and compound 131-3a (1.31 g, 10.84 mmol, 1.2 eq.) in DCM (100 ml) at At 30°C, CuSO ₄ (3.17 g, 19.87 mmol, 3.05 ml, 2.2 eq.) was added dropwise and the mixture was stirred at 30°C for 16 hours. The mixture was filtered through celite to remove solids . The filtrate was concentrated to obtain a residue. The residue was purified by silica gel flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash column, 0~50% ethyl acetate/petroleum ether eluent gradient approximately 40 mL/min) to give compound 131-4 (4.8 g, 14.89 mmol , 82.4% yield) as a colorless oil.

Benzyl-3 -((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)azetidine-1-carboxylate.

To a solution of compound 131-4 (2.4 g, 7.44 mmol, 1 eq.) in DCM (30 ml) at -78°C was added MeMgBr (3 M, 6.20 ml, 2.5 eq.) at drops and the mixture was stirred at -78°C for 0.5 h, and then at 30°C for another 1.5 h. The mixture was quenched with a saturated solution of NH ₄ Cl (10 ml) at 0°C, then diluted with water (40 ml ), and then extracted with EA (50 mlx3). The combined organic layers were washed with brine (40 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, 0~100% ethyl acetate/petroleum ether eluent gradient approximately 35 mL/min) to obtain 2.4 g of the desired product as a mixture of isomers. 2.4 g of the desired product was further purified by prep-HPLC (column: YMC-Triart Prep C18 150x40 mmx7 μm; mobile phase: [water (0.04% NH ₃ H ₂ O+10 mM NH4HCO ₃ )-ACN]; B%: 43%-43%, 10 min) to give compound 131-5 (1.7 g, 4.72 mmol, 31.7% yield) as a colorless oil.

(K)-Benzyl-3-(1-aminoethyl)azetidine-1-carboxylate.

To a solution of compound 131-5 (1.7 g, 5.02 mmol, 1 eq.) in MeOH (20 ml) at 30°C was added HCl/MeOH (4 M, 3.77 ml, 3 eq.) dropwise and the mixture was stirred at 30°C for 5 hours. Na2CO3 powder (2 g) was added to the mixture, and then the mixture was diluted with EA (20 ml) and then filtered to remove the solid. The filtrate was concentrated under reduced pressure to give compound 1316 (1.10 g, 4.69 mmol, 93.5% yield) as a colorless oil, which was used in the next step.

(C)-Benzyl-3 -(1 -(5-(4-(trifluoromethyl)phenyl)-2-naphtamido)ethyl)azetidine-1-carboxylate.

To a solution of compound 131-6a (300 mg, 0.95 mmol, 1 eq.), compound 131-6 (266.7 mg, 1.14 mmol, 1.2 eq.) and HATU (468.9 mg, 1 .23 mmol, 1.3 eq.) in DMF (3 ml) at 30°C was added TEA (288.0 mg, 2.85 mmol, 0.40 ml, 3 eq.) and the mixture was stirred at 30°C in for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). 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 silica gel flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, 0~60% ethyl acetate/petroleum ether eluent gradient approximately 30 mL/min) to give compound 7 (450 mg, 0.80 mmol, 84 .6% yield) as a white solid. LCMS (ESI): RT=0.994 min, mass, calc. for C ₃ iH ₂₇ F ₃ N ₂ O ₃ 532.20, m/z obtained 533.1 [M+H]+.

^)-N-(1-(Azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 131-7 (400 mg, 0.75 mmol, 1 eq.) and NH3-H2O (1.05 g, 7.51 mmol, 1.16 ml, 25% solution, 10 eq.) in EtOH ( 10 ml) at 30°C, Pd/C (79.9 mg, 75.1 µmol, 10%, 0.1 eq.) was added and the mixture was purged and degassed with H ₂ 3 times and then stirred at 30°C under H ₂ (15 psi) for 1 hour. The reaction mixture was filtered to remove Pd/C and the filtrate was concentrated under reduced pressure to give compound 131-8 (290 mg, 0.68 mmol, 91.1% yield) as a white solid which was used in the next step. LCMS (ESI): RT=0.756 min, mass, calc. for C ₂₃ H ₂₁ F ₃ N ₂ O 398.16, m/z obtained 399.0 [M+H]+.

(R)-N-(1-(1-(2-Fluoroethyl)azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 131-8 (50 mg, 0.13 mmol, 1 eq.) and K2CO3 (52.0 mg, 0.38 mmol, 3 eq.) in ACN (3 ml) at 30°C was added compound 131- 8a (23.9 mg, 0.19 mmol, 1.5 eq.) and the mixture was stirred at

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70°C for 16 hours. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 8.5 min) to obtain the compound 144 (31.8 mg, 64.7 µmol, 51.5% yield, HCl) as a white solid (hygroscopic). LCMS (ESI): RT=0.792 min, mass, calc. for C ₂₅ H ₂₄ F ₄ N ₂ O 444.18, m/z obtained 445.0 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J=1.3 Hz, 1H), 8.45 (d, J=7.8 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.95 (dd, J=1.9, 8.9 Hz, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.80 ( d, J=8.8 Hz, 1H), 7.74 - 7.68 (m, 3H), 7.59 (dd, J=1.3, 7.0 Hz, 1H), 4.80 - 4 .76 (m, 1H), 4.69 - 4.63 (m, 1H), 4.41 (brs, 1H), 4.23 - 3.93 (m, 4H), 3.63 - 3.45 (m, 2H), 3.05 - 3.04 (m, 1H), 1.19 (br d, J=6.8 Hz, 3H).

Example 132: M[(^)-1-(3-hydroxyazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 145)

tert-Butyl-3-hydroxy-3-(1-(8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamido)ethyl)azetidine-1 carboxylate.

To a solution of compound 132-1 (90.0 mg, 0.28 mmol, 1 eq.) and HATU (161.8 mg, 0.43 mmol, 1.5 eq.) in DMF (1 ml) at 20°C compound 132-1a (61.4 mg, 0.28 mmol, 1.0 eq.) and TEA (86.1 mg, 0.85 mmol, 0.12 mL, 3.0 eq.) were added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with water (20 ml x 2) and brine (20 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash column, gradient 0~75% ethyl acetate/petroleum ether eluent approximately 20 ml/min) to give compound 132-2 (82.0 mg, 0.14 mmol, 49.9% yield) was obtained as a colorless oil. LCMS (ESI): RT=0.910 min, mass calc. for C ₂₇ H ₂₈ F ₃ N ₃ O ₄ 515.20, m/z obtained 516.1 [M+H]+.

^)-tert-Butyl-3-hydroxy-3-(1-(8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamido)ethyl)azetidine 1-carboxylate.

Compound 132-2 (82.0 mg, 0.16 mmol, 1.0 eq.) was purified by SFC: (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH ]; V%: 30%-30%, min) to obtain compound 132-3 (38.0 mg, 72 µmol, 45.5% yield) and compound 132-4 (40.0 mg, 57 µmol, 35. 6% yield) as a white solid. LCMS (ESI): RT=0.908 min, mass calc. for C ₂₇ H ₂₈ F ₃ N ₃ O ₄ 515.20, m/z obtained 516.1 [M+H] ⁺ .

M[(^)-1-(3-Hydroxyazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of compound 132-3 (38.0 mg, 73.7 µmol, 1 eq.) in DCM (0.6 ml) at 20°C was added TFA (0.50 mg, 4.42 µmol, 3.27 e- 1 µl, 0.06 eq.). The mixture was stirred at 30°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was basified with NH3-H2O to pH 9. The residue was purified by pre-HPLC: (column: Waters Xbridge C18 150x50 mmx10 μm; moving phase: [water (0.04% NH3H2O 10 mM NH4HCO ₃ )-ACN]; B%: 32%-62%, 11 min) to give compound 145 (9.8 mg, 23.7 µmol, 32.1% yield) in the form of a colorless oil. LCMS (ESI): RT=0.738 min, mass calc. for C ₂₂ H ₂₀ F ₃ N ₃ O ₂ 415.15, m/z obtained 416.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.28 (d, J=1.8 Hz, 1H), 8.66 (d, J=1.5 Hz, 1H), 7.92 (brd, J= 8.0 Hz, 1H), 7.82 - 7.71 (m, 5H), 7.69 7.64 (m, 1H), 7.22 (brd, J=8.5 Hz, 1H), 4 .71 (brs, 1H), 4.62 - 4.51 (m, 1H), 3.96 - 3.56 (m, 4H), 1.30 (br d, J=6.8 Hz, 3H) .

Example 133: M[(^)-1-(1-Isopropylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 146) and M[(^)-1-( 1-isopropylazetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 147)

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H-[(2.4-Dimethoxyphenyl)methyl| -N-[1-(1-isopropylazetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide.

Pd/C (200 mg, 10%). The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 133-2 (90 mg, crude) was obtained as a white solid. LCMS (ESI): RT=0.944 min, mass calc. for C3 ₄ H3 ₆ F3N ₃ O3 591.27 m/z, 592.2 [M+H]+ was obtained.

N-[1-(1-Isopropylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of compound 133-2 (170 mg, 0.28 mmol, 1 eq.) in DCM (2 mL) was added TFA (5.1 g, 44.76 mmol, 3.31 mL, 155.7 eq.). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%-50%, 8.5 min) to obtain the compound 3 (60 mg, 47.3% yield) as a white solid.

LCMS (ESI): RT=0.842 min, mass calc. for C ₂₅ H ₂₆ F ₃ N ₃ O 441.20 m/z, 442.1 [M+H]+ was obtained.

N-[(1R)-1-(1-Isopropylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 146) and N[(^)-1-( 1-isopropylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 147).

Compound 133-3 (60 mg) was purified by pre-SFC method (column: DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 25% - 25%, min) to obtain compound 147 (3.7 mg, 8.3 µmol, 6.1% yield) and compound 146 (4.4 mg, 9.8 µmol, 7.2% yield) in as two white solids. Compound 147 LCMS (ESI): RT=0.853 min, mass calc. for C ₂ 5H ₂₆ F ₃ N ₃ O 441.20 m/z, 442.1 [M+H]+ was obtained. 1H NMR (400 MHz, CD ₃ OD) δ 9.24 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 8.13 (dd, J =1.2, 8.2 Hz, 1H), 7.92 (dd, J=1.3, 7.2 Hz, 1H), 7.85 - 7.76 (m, 5H), 4.49 ( s, 1H), 4.30 - 4.18 (m, 2H), 4.16 - 4.08 (m, 1H), 4.02 (t, J=9.2 Hz, 1H), 3.53 - 3.35 (m, 1H), 3.11 - 2.93 (m, 1H), 1.30 (d, J=6.9 Hz, 3H), 1.25 (d, J=6.5 Hz, 6H). Compound 146 LCMS (ESI): RT=0.856 min, mass calc. for C ₂ 5H ₂₆ F ₃ N ₃ O 441.20 m/z, 442.1 [M+H]+ was obtained. 1H NMR (400 MHz, CD ₃ OD) δ 9.21 (d, J=2.3 Hz, 1H), 8.82 (d, J=2.3 Hz, 1H), 8.11 (dd, J =1.3, 8.1 Hz, 1H), 7.91 (dd, J=1.4, 7.1 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.81 - 7.76 (m, 3H), 4.62 (s, 1H), 4.45 -4.26 (m, 1H), 3.68 (q, J=8.4 Hz, 2H), 3.20 (t, J=8.0 Hz, 1H), 2.80 - 2.60 (m, 2H), 1.23 (d, J=6.6 Hz, 3H), 1.02 (dd, J= 3.3, 6.3 Hz, 6H).

Example 134: N-[(1R)-1-(1-ethyl azetidin-3 -yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 148) and N[(^)-1- (1-ethylazetidin-3-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 149)

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N - [(2,4-Dimethoxyphenyl)methyl]-N-[1-(1-ethylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2 carboxamide.

To a solution of compound 134-1 (150 mg, 0.27 mmol, 1 eq.) in MeOH (15 mL) was added acetaldehyde (150.3 mg, 3.4 mmol, 0.19 mL, 12.48 eq.) and Pd/C (150 mg, 10%). The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H2 (15 psi) at 25°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 134-2 (160 mg, crude) was obtained as a white solid. LCMS (ESI): RT=0.946 min, mass calc. for C ₃₄ H ₃₅ F ₃ N ₂ O ₃ 576.26 m/z, 577.2 [M+H]+ was obtained.

N[1-(1-Ethylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 134-2 (200 mg, 0.34 mmol, 1 eq.) in DCM (2 mL) was added TFA (6.16 g, 54.03 mmol, 4 mL, 155.7 eq.). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl) - ACN]; V%: 22% - 52%, 9.5 min) to obtain the compound 134-3 (40 mg, 93 µmol, 27.04% yield) as a white solid. LCMS (ESI): RT=0.873 min, mass calc. for C ₂₅ H ₂₅ F ₃ N ₂ O 426.19 m/z, 427.1 [M+H]+ was obtained.

No.[(^)-1-(1-Ethylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 148) and No.[(^)-1-(1 -ethyl azetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 149)

Compound 134-3 (40 mg) was purified by pre-SFC method (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 25% - 25%, min) to obtain compound 149 (6.6 mg, 15.4 µmol, 16.5% yield) LCMS (ESI): RT=0.785 min, mass calc. for C ₂₅ H ₂₅ F ₃ N ₂ O 426.19 m/z, 427.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CD3OD) δ 8.51 (d, J=1.0 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.92 -7.82 ( m, 4H), 7.67 (td, J=3.5, 8.0 Hz, 3H), 7.58 (dd, J=1.0, 7.0 Hz, 1H), 4.50 (s , 1H), 4.33 - 3.94 (m, 4H), 3.25 (q, J=6.9 Hz, 2H), 3.11 (sextet, J=8.4 Hz, 1H), 1 .28 (d, J=6.8 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H) and compounds 148 (8.3 mg, 19.5 µmol, 20.8% yield) LCMS (ESI): RT=0.895 min, mass calc. for C ₂₅ H ₂₅ F ₃ N ₂ O 426.19 m/z, 427.0 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.88 - 7.80 (m, 4H), 7.70 - 7.62 (m, 3H), 7.56 (dd, J=1.0, 7.0 Hz, 1H), 4.39 - 4.27 (m, 1H), 3.55 3.41 ( m, 2H), 3.04 (t, J=7.7 Hz, 1H), 2.92 (t, J=7.7 Hz, 1H), 2.76 - 2.64 (m, 1H), 2.51 (q, J=7.1 Hz, 2H), 1.20 (d, J=6.8 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

Example 135: N-[(1R)-1-(1-Ethylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide (compound 150) and N[(^)-1 -(1-ethylazetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 151)

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U-[(2,4-Dimethoxyphenyl)methyl| -N-[1-(1-ethylazetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of compound 135-1 (150 mg, 0.27 mmol, 1 equiv.) in MeOH (5 ml) was added Pd/C (50 mg, 10%), H2 and acetaldehyde (60.1 mg, 1.3 mmol , 76.5 µl, 5 eq.). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. LCMS (ESI): RT=0.920 min, mass calc. for C ₃₃ H ₃₄ F ₃ N ₃ O ₃ 577.26 m/z, 578.1 [M+H]+ was obtained.

N-[1-(1-Ethylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of compound 135-2 (160 mg, 0.27 mol, 1 eq.) in DCM (0.5 mL) was added TFA (4.81 g, 42.17 mmol, 3.12 mL, 152.2 eq. ). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl) - ACN]; V%: 20%-50%, 8.5 min) to obtain compound 135-3 (40 mg, 93.58 µmol, 33.78% yield) as a white solid. LCMS (ESI): RT=0.842 min, mass calc. for C ₂₄ H ₂₄ F ₃ N ₃ O 427.19 m/z, 728.1 [M+H]+ was obtained.

Y-[(1I)-1-(1-Ethylazetidin-3-yl)ethyl|-8-[4-(trifluoromethyl)phenyl|quinoline-3-carboxamide (compound 150) and Y-[(1I)-1- (1-ethylazetidin-3-yl)ethyl|-8-[4-(trifluoromethyl)phenyl|quinoline-3-carboxamide (compound 151).

Compound 135-3 (40 mg) was purified by the prep-SFC method (column: DAICELCHIRALPAKAD-H (250 mmx30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OETOH|; V%: 25%- 25%, min) to obtain compound 151 (10.2 mg, 23.8 µmol, 25.5% yield) and compound 150 (13.1 mg, 30.7 µmol, 32.9% yield) as two white solids. Compound 151 LCMS (ESI): RT=0.761 min, mass calc. for C ₂₄ H ₂₄ F ₃ N ₃ O 427.19 m/z, 428.0 [M+H|+] was obtained. 1H NMR (400 MHz, CD3OD) δ 9.20 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.10 (dd, J=1 ,1, 8.2 Hz, 1H), 7.89 (dd, J=1.3, 7.3 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.80 -7, 74 (m, 3H), 4.40 - 4.29 (m, 1H), 3.61 - 3.47 (m, 2H), 3.09 (t, J=7.7 Hz, 1H), 2 .97 (t, J=7.7 Hz, 1H), 2.80 - 2.67 (m, 1H), 2.54 (q, J=7.1 Hz, 2H), 1.21 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H). Connection 150 LCMS (ESI): RT=0.759 min, mass calc. for C ₂₄ H ₂₄ F ₃ N ₃ O 427.19 m/z, 428.0 [M+H| ⁺ . 1H NMR (400 MHz, CD3OD) δ 9.24 (d, J=2.0 Hz, 1H), 8.90 (d, J=1.8 Hz, 1H), 8.13 (dd, J=1 ,1, 8.2 Hz, 1H), 7.91 (dd, J=1.4, 7.2 Hz, 1H), 7.85 7.81 (m, 2H), 7.81 - 7.75 (m, 3H), 4.51 (s, 1H), 4.33 - 3.68 (m, 4H), 3.27 (s, 2H), 3.17 - 3.09 (m, 1H), 1.29 (d, J=7.0 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H).

Example 136: N-[(1S)-1-(1-methylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 152) and N-[(1R)-1 -(1-methylazetidin-3-yl)ethyl]-5-[4(trifluoromethyl)phenyl|naphthalene-2-carboxamide (compound 153)

N-[1-(1-Methylazetidin-3-yl)ethyl| -5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

HOAc ( 67.8 mg, 1.13 mmol, 64.6 µl, 3 eq.) and stirred at 25°C for 1 hour, and then added NaBH(OAc) ₃ (159.6 mg, 0.75 mmol, 2 eq.). The resulting mixture was stirred at 25°C for 15 hours. Then ice water (30 ml) was added and the pH value of the mixture was neutralized

- 174 046394 li up to 9-10 aq. NaOH (2 M). The aqueous phase was extracted with EA (20 mlx3). The combined organic phase was washed with brine (30 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to leave a residue. The residue was purified by silica gel flash chromatography (12 g SepaFlash® Silica Flash column, EA/PE: 0~30%) to obtain 106 mg of crude product. And the crude product was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 11.5 min) with yielding compound 136-2 (32 mg, 77.6 µmol, 20.6% yield) as a white solid.

N-[(1R)-1-(1-Methylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 153) and N[(^)-1-( 1-methylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 152).

The compound N-[1-(1-methylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (30 mg, 72.7 μmol, 1 eq.) was separated by SFC ( column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 5 µm); mobile phase: [01% NH ₃ H ₂ O IPA]; V%: 35%-35%, min) to obtain compound 153 (5.4 mg , 12.7 µmol, 17.5% yield) as a yellow solid. LCMS (ESI): RT=0.787 min, mass calc. for C ₂₄ H ₂₃ F ₃ N ₂ O 412.18, m/z obtained 413.2 [M+H]+. ¹ H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.90 - 7.81 (m, 4H), 7, 71 - 7.64 (m, 3H), 7.58 (dd, J=1.1, 7.1 Hz, 1H), 4.50 (s, 1H), 4.34 (s, 2H), 4 .16 - 3.88 (m, 2H), 3.17 - 3.09 (m, 1H), 2.93 (s, 3H), 1.29 - 1.24 (m, 3H) and compounds 152 ( 5.2 mg, 12.5 µmol, 17.2% yield) as a yellow solid. LCMS (ESI): RT=0.794 min, mass calc. for C24H23F3N2O 412.18, m/z obtained 413.1 [M+H] ⁺ ; 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.88 - 7.82 (m, 4H), 7.71 - 7.64 (m, 3H), 7.57 (dd, J=1.1, 7.0 Hz, 1H), 4.45 - 4.34 (m, 1H), 3.68 (m, 2H ), 3.39 -3.33 (m, 1H), 3.25 (t, J=8.1 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.47 (s, 3H), 1.90 (s, 1H), 1.21 (d, J=6.8 Hz, 3H).

Example 137: N)A-(1-(3-hydroxyazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 154) and N)A-(1-(3 -hydroxyazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 155)

tert-Butyl-3-ethylidene azetidin-1-carboxylate.

A solution of compound 137-1a (3.25 g, 8.76 mmol, 2.5 eq.) and tert-BuOK (983.2 mg, 8.76 mmol, 2.5 eq.) in THF (10 ml) at 20°C was purged and degassed with N2, and then stirred at 20°C for 1 hour. Then compound 137-1 (600.0 mg, 3.50 mmol, 1 eq.) was added to the reaction mixture at 20°C and purged and degassed with N2 and then stirred at 35°C for 4.5 hours. The residue was diluted with water (20 ml) and then extracted with EA (20 ml x 3). The combined organic layers were washed with water (20 mlx2) and brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue, which was purified by silica gel flash chromatography (ISCO®; 20 g SepaFlash ® Silica Flash column, gradient 0~20% ethyl acetate/petroleum ether eluent approximately 35 mL/min) to give compound 137-2 (288.0 mg, 1.57 mmol, 44.8% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.37 - 5.28 (m, 1H), 4.46 - 4.40 (m, 4H), 1.56 -1.53 (m, 3H), 1.46(s,9H).

tert-Butyl-2-methyl-1-oxa-5-azaspiro[2,3]hexane-5-carboxylate.

To a solution of compound 137-2 (150.0 mg, 0.82 mmol, 1 eq.) in CHCl = (2 ml) at 20°C was added mCPBA (581.7 mg, 2.86 mmol, 85%, 3. 5 eq.), and then stirred at 20°C for 3 hours. The reaction mixture was diluted with Na ₂ SO ₃ (4 ml) and DCM (50 ml), and then washed with saturated Na ₂ CO ₃ solution (14 mlx4). The combined organic layers were washed with H2O (20 mlx2) and saline (20 ml), dry

- 175 046394 over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 137-3 (174.0 mg, crude) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ) δ 4.19 4.08 (m, 4H), 3.10 (q, J=5.3 Hz, 1H), 1.47 (s, 9H), 1.25 (d, J=5.3 Hz, 3H).

tert-Butyl-3-(1-aminoethyl)-3-hydroxyazetidine-1-carboxylate.

To a solution of compound 137-3 (150.0 m 0.75 mmol, 1 equiv.) in MeOH (2 ml) at 20°C was added NH3-H2O (910.0 mg, 6.49 mmol, 1 ml, 25% solution, 8.6 eq.), and then the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was concentrated under reduced pressure to give compound 137-4 (130.0 mg, 0.60 mmol, 79.8% yield) as a white solid.

tert-Butyl-2-methyl-1-oxa-5-azaspiro[2,3]hexane-5-carboxylate.

To a solution of compound 137-4a (95.1 mg, 0.30 mmol, 1 eq.) and HATU (171.4 mg, 0.45 mmol, 1.5 eq.) in DMF (1 ml) at 20°C compound 137-4 (130.0 mg, 0.60 mmol, 2 eq.) and TEA (91.2 mg, 0.90 mmol, 0.13 mL, 3 eq.) were added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC: (column: Welch Xtimate C18 150x25 mmx5 μm; mobile phase: [water (0.05% HCl )-ACN]; B%: 45%-75%, 8.5 min) to give compound 137-5 (27.0 mg, 50 µmol, 16.7% yield) as a white solid. LCmS (ESI): RT=0.955 min, mass, calc. for C ₂₈ H ₂₉ F ₃ N ₂ O ₄ 514.21, m/z obtained 515.1 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H ), 7.79 (brd, J=8.0 Hz, 3H), 7.66 - 7.60 (m, 3H), 7.55 - 7.51 (m, 1H), 6.58 (brs, 1H), 4.43 (brs, 1H), 4.05 (d, J=9.3 Hz, 1H), 3.98 (brd, J=9.3 Hz, 1H), 3.85 (brd, J=11.0 Hz, 2H), 1.45 (s, 9H), 1.40 (brd, J=6.5 Hz, 3H).

N(1-(3-Hydroxyazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 137-5 (17.0 mg, 33. µmol, 1 eq.) in DCM (0.6 ml) at 20°C was added TFA (92.4 mg, 0.81 mmol, 60 µl, 24. 5 eq.). The mixture was stirred at 20°C for 1 hour. The reaction mixture was combined with ES10388-363. The reaction was concentrated under reduced pressure to obtain a residue, which was purified by prep-HPLC (column: Waters Xbridge C18 150x50 mmx10 μm; mobile phase: [water (0.04% NH3H2O 10 mM NH ₄ HCO ₃ )-ACN]; B% : 43%-73%, 11 min) to give compound 137-6 (22.0 mg, 51 µmol, 77.9% yield) as a white solid. LCMS (ESI): RT=0.773 min, mass, calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ 414.16, m/z obtained 415.0 [M+H]+.

(S)-N-(1-(3-Fhydroxyazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 155) and ^)-N-(1-(3 -hydroxyazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 154).

Compound 137-6 (20.0 mg, 48.26 µmol, 1 eq.) was separated by SFC (column: PhenomenexCellulose-2 (250 mmx30 mm, 10 µm); mobile phase: [0.1% NH3H2O MEOH]; B %: 50%-50%, min) to obtain 6 mg of sample and 5 mg of sample. 6 mg of sample was purified by prep-HPLC: (column: Waters Xbridge C18 150x50 mmx10 µm; mobile phase: [water (0.04% NH3H2O+10 mM NH ₄ HCO ₃ )-ACN]; V%: 43%-73 %, 11 min) to obtain compound 154 (2.7 mg, 6 µmol, 12.7% yield) as a white solid. LCMS (ESI): RT=0.771 min, mass, calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ 414.16, m/z obtained 415.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.98 (brd, J=8.3 Hz, 1H), 7.88 - 7.84 (m, 1H), 7, 81 - 7.76 (m, 3H), 7.63 - 7.57 (m, 3H), 7.50 (brd, J=6.8 Hz, 1H), 6.95 (brd, J=8, 1 Hz, 1H), 4.61 - 4.49 (m, 1H), 3.88 - 3.74 (m, 2H), 3.61 (brdd, J=8.8, 16.2 Hz, 2H ), 1.33 (brd, J=6.5 Hz, 3H). 5 mg of sample was purified by pre-HPLC method: (column: Waters Xbridge C18 150x50 mmx10 µm; mobile phase: [water (0.04% NH3H2O+10 mM NH4HCO ₃ )-ACN]; V%: 43%-73%, 11 min) to give compound 155 (1.5 mg, 4 µmol, 7.5% yield) as a white solid. LCMS (ESI): RT=0.774 min, mass, calc. for C ₂₃ H ₂₁ F ₃ N ₂ O ₂ 414.16, m/z obtained 415.0 [M+H]+; 1H NMR (400 MHz, CDC13) δ 8.38 (s, 1H), 7.99 (brd, J=8.3 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.82 - 7.76 (m, 3H), 7.63 - 7.57 (m, 3H), 7.53 - 7.49 (m, 1H), 6.93 (brd, J=7.5 Hz, 1H ), 4.60 - 4.50 (m, 1H), 3.89 - 3.73 (m, 2H), 3.68 - 3.54 (m, 2H), 1.34 (brd, J=6 ,6 Hz, 3H).

Example 138: N-[( 1R)-1-( 1 -methylazetidin-3 -yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide (compound 156) and H-|(1K)- 1-(1-methylazetidin-3-yl)ethyl|-8-|4(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 157)

- 176 046394

H-[(2.4-Dimstoxy(|>enyl)methyl|-N-[1-(1-methylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline3-carboxamide.

To a solution of compound 138-1 (150 mg, 0.27 mmol, 1 eq.) in MeOH (5 ml) was added Pd/C (50 mg, 10%) and formaldehyde (4.90 g, 60.44 mmol, 4 .50 ml, 221.4 eq.). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H ₂ (15 psi) at 25° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , ethyl acetate: methanol=100/1 - 1/2) to give compound 138-2 (70 mg, 0.12 mmol, 45.5% yield) as a white solid. LCMS (ESI): RT=0.839 min, mass calc. for C32H32F3N3O3 563.24 m/z, 564.1 [M+H]+ was obtained.

N-[1-(1-Methylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of compound 138-2 (70 mg, 0.12 mmol, 1 eq.) in DCM (0.5 mL) was added TFA (2.16 g, 18.91 mmol, 1.40 mL, 152.2 eq. ). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; V%: 20%-50%, 8.5 min) to obtain the compound 138-3 (20 mg, 48.3 µmol, 38.9% yield) as a white solid. lCmS (ESI): RT=0.825 min, mass calc. for C3 ₂ H ₂₂ F3N ₃ O 413.17 m/z, 414.1 [M+H]+ was obtained.

N-[(1S)-1-(1-Methylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 157) and N[(^)-1-( 1-methylazetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 156).

Compound 138-3 (30 mg) was purified by pre-SFC method (column: DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; V%: 25%-25 %, min) to obtain compound 157 (6.5 mg, 15.4 µmol, 21.3% yield) and compound 156 (10.8 mg, 25.2 µmol, 34.7% yield) as two white solids substances. Compound 157 LCMS (ESI): RT=0.824 min, mass calc. for C ₂₃ H ₂₂ F ₃ N ₃ O 413.17 m/z, 414.1 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 9.22 (d, J=2.3 Hz, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.11 (dd, J=1 ,1, 8.1 Hz, 1H), 7.91 (dd, J=1.2, 7.2 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.80 -7, 76 (m, 3H), 4.52 4.40 (m, 1H), 4.01 (q, J=8.8 Hz, 2H), 3.90 - 3.82 (m, 1H), 3, 74 (t, J=8.9 Hz, 1H), 3.04 - 2.91 (m, 1H), 2.75 (s, 3H), 1.26 (d, J=6.6 Hz, 3H ). Compound 156 LCMS (ESI): RT=0.830 min, mass calc. for C ₂₃ H ₂₂ F ₃ N ₃ O 413.17 m/z, 414.0 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 9.20 (d, J=2.1 Hz, 1H), 8.80 (d, J=2.3 Hz, 1H), 8.10 (d, J=7 .5 Hz, 1H), 7.92 - 7.87 (m, 1H), 7.86 - 7.81 (m, 2H), 7.80 - 7.74 (m, 3H), 4.46 - 4.27 (m, 1H), 3.62 (q, J=8.5 Hz, 2H), 3.27 (t, J=7.8 Hz, 1H), 3.16 (t, J=7 .8 Hz, 1H), 2.81 - 2.68 (m, 1H), 2.42 (s, 3H), 1.22 (d, J=6.6 Hz, 3H).

Example 139: N-[(1R)-1-(Azetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 158) and N[(^)-1- (azetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 159)

- 177 046394

(2-Amino-3-bromophenyl)methanol.

To a solution of compound 139-1 (1.2 g, 5.55 mmol, 1 eq.) in THF (5 ml) was added BH3-THF (1 M, 8.33 ml, 1.5 eq.) at 0°C . The mixture was stirred in an atmosphere at 70°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 - 1/1) to give compound 139-2 (1.1 g, 5.44 mmol, 98% yield) as a white solid. LCMS (ESI): RT=0.699 min, mass calc. for C ₇ H ₈ BrNO 200.98 m/z, 203.0 [M+H]+ was obtained.

2-Amino-3-bromobeschaldehyde.

To a solution of compound 139-2 (1.10 g, 5.44 mmol, 1 eq.) in DCM (15 mL) was added MnO ₂ (4.73 g, 54.44 mmol, 10 eq.). The mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give compound 139-3 (1 g, crude) as a black oil.

Methyl 8-bromoquinoline-3-carboxylate.

To a solution of compound 139-3 (1.0 g, 5.00 mmol, 1 eq.) in EtOH (10 ml) was added L-proline (287.7 mg, 2.50 mmol, 0.5 eq.) and compound 139-3a (546.3 mg, 6.5 mmol, 0.54 ml, 1.3 eq.). The mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 - 3/1) to give compound 139-4 (1.2 g, 4.51 mmol, 90% yield) as a light yellow solid .

Methyl 8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxylate.

Pd(dppf)Cl ₂ (192.4 mg, 0.26 mmol, 0.1 eq.), compound 139-4a (599.5 mg, 3.16 mmol, 1.2 eq.) and Na ₂ CO ₃ (836.4 mg, 7.89 mmol, 3.0 eq. .). The mixture was stirred at 90°C for 16 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 -5/1) to give methyl compound 139-5 (800 mg, 2.25 mmol, 85.3% yield) as a white solid. LCMS (ESI): RT=1.029 min, mass calc. for C ₁₈ H ₁₂ F ₃ NO ₂ 331.08, m/z obtained 332.0 [M+H]+.

8-[4-(Trifluoromethyl)phenyl]quinoline-3-carboxylic acid.

To a solution of compound 139-5 (800 mg, 2.41 mmol, 1 eq.) in MeOH (6 ml) was added a solution of NaOH (386.3 mg, 9.66 mmol, 4.0 eq.) in H2O (3 ml ). The mixture was stirred at 25°C for 1 hour. The pH of the reaction mixture was adjusted with HCl (2 M) to 4 ~ 5. The mixture was concentrated under reduced pressure to remove MeOH, then diluted with H2O (20 ml) and extracted with EtOAc (20 ml x 3 ). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 139-6 (750 mg, crude) was obtained as a white solid.

Benzyl 3-[1-[(2,4-dimethoxyphenyl)methyl-[8-[4-(trifluoromethyl)phenyl]quinoline-3carbonyl]amino]ethyl]azetidine-1-carboxylate.

To a solution of compound 139-6 (0.6 g, 1.89 mmol, 1 eq.) in DCM (6 ml) was added HATU (1.08 g, 2.84 mmol, 1.5 eq.), DIPEA (488 .8 mg, 3.78 mmol, 0.65 ml, 2.0 eq.) and compound 139-6a (799.8 mg, 2.08 mmol, 1.1 eq.). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 - 1/1) to give compound 139-7 (1.2 g, 1.56 mmol, 82.6% yield) as a colorless oil. LCMS (ESI): RT=1.096 min, mass calc. for C ₃₉ H ₃₆ F ₃ N ₃ O ₅ 683.26 m/z, 684.1 [M+H]+ was obtained.

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N-[1-(Azetidin-3-yl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide.

To a solution of compound 139-7 (0.7 g, 1.0 mmol, 1 eq.) in MeOH (30 ml) was added Pd/C (0.3 g, 10%) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without further purification. Compound 139-8 (540 mg, crude) was obtained as a white solid. LCMS (ESI): RT=0.903 min, mass calc. for C3|H3 ₀ F3N3O3 549.22 m/z, 550.1 [M+H]+ was obtained.

N-[1 -(Azetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of compound 139-8 (200 mg, 0.36 mmol, 1 eq.) in DCM (0.5 mL) was added TFA (10.27 g, 90.04 mmol, 6.67 mL, 247.4 eq. ). The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl) - ACN]; V%: 20% 50%, 8.5 min) to obtain compound 139 -9 (30 mg, 75.11 µmol, 20.64% yield) as a white solid. LCMS (ESI): RT=0.820 min, mass calc. for C ₂₂ H ₂₀ F ₃ N ₃ O 399.16 m/z, 400.1 [M+H]+ was obtained.

N[(^)-1-(Azetidin-3-yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 158) and N[(^)-1-(azetidine-3 -yl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 159).

Compound 139-9 (40 mg) was purified by pre-SFC method (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH3H2O IPA]; V%: 40% - 40%, min) to give compound 159 (4.0 mg, 10.1 µmol, 10.1% yield) and compound 158 (4.1 mg, 10.2 µmol, 10.2% yield) as two white solids. Compound 159 LCMS (ESI): RT=0.826 min, mass calc. for C ₂₂ H ₂₀ F ₃ N ₃ O 399.16 m/z, 400.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CD3OD) δ 9.23 - 9.18 (m, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.11 (dd, J=1.1 , 8.2 Hz, 1H), 7.90 (dd, J=1.3, 7.3 Hz, 1H), 7.85 - 7.82 (m, 2H), 7.80 - 7.76 ( m, 3H), 4.51 4.40 (m, 1H), 3.77 - 3.65 (m, 3H), 3.60 (t, J=8.2 Hz, 1H), 3.08 - 2.92 (m, 1H), 1.22 (d, J=6.5 Hz, 3H). Compound 158 LCMS (ESI): RT=0.824 min, mass calc. for C ₂₂ H ₂₀ F ₃ N ₃ O 399.16 m/z, 400.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CD3OD) δ 9.21 (d, J=2.3 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.10 (dd, J= 1.1, 8.2 Hz, 1H), 7.90 (dd, J=1.3, 7.0 Hz, 1H), 7.85 - 7.81 (m, 2H), 7.81 - 7 .77 (m, 3H), 4.52 - 4.41 (m, 1H), 3.75 (d, J=7.3 Hz, 3H), 3.69 - 3.61 (m, 1H), 3.08 - 2.92 (m, 1H), 1.23 (d, J=6.5 Hz, 3H).

Example 140: N-(1,5-dihydroxypentan-3-yl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide (compound 160)

Compound 140-1 (13.5 mg, 0.11 mmol, 1.2 eq.) and TEA (28.7 mg, 0.28 mmol, 39 µl, 3 eq.). The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated to obtain a residue, which was purified by pre-HPLC (column: Xtimate C18 100x30 mmx3 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 8.5 min) to give compound 160 (3.9 mg, 9 µmol, 9.6% yield) as a colorless oil. LCMS (ESI): RT=0.841 min, mass, calc. for C22H21F ₃ N2O ₃ 418.15, m/z obtained 419.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 9.31 (q, J=2.2 Hz, 2H), 8.34 (dd, J=1.3, 8.3 Hz, 1H), 8.11 - 8.05 (m, 1H), 8.02 - 7.96 (m, 1H), 7.92 -7.86 (m, 2H), 7.84 (d, J=8.3 Hz, 2H) , 4.43 (tt, J=4.7, 9.0 Hz, 1H), 3.73 - 3.65 (m, 4H), 1.98 -1.82 (m, 4H).

Example 141: N(1,5-dihydroxypentan-3-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 161)

- 179 046394

To a solution of compound 141-1a (120.0 mg, 0.38 mmol, 1 eq.) and HATU (216.4 mg, 0.57 mmol, 1.5 eq.) in DMF (1 ml) at 20°C compound 141-1 (54.3 mg, 0.46 mmol, 1.2 eq.) and TEA (115.2 mg, 1.14 mmol, 0.16 mL, 3 eq.) were added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated to obtain a residue, which was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 μm; mobile phase: [water (0.05% HCl)-ACN] ;B%: 35%-65%, 8.5 min) to give compound 161 (10.2 mg, 24 µmol, 6.4% yield) as a white solid. LCMS (ESI): RT=0.886 min, mass, calc. for C ₂₃ H ₂₂ F ₃ NO ₃ 417.16, m/z obtained 418.0 [M+H]+; ¹ H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.86 (s, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.69 - 7.64 (m, 3H), 7.56 (dd, J=1.0, 7.0 Hz, 1H), 4.40 (tt, J =4.6, 9.0 Hz, 1H), 3.72 - 3.66 (m, 4H), 1.97 -1.81 (m, 4H).

Example 142: Na[(^)-2-hydroxy-1-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 162) and Na[(^)-2-hydroxy -1-(2-pyridyl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 163)

2-(2-Pyridyl)ethyl-2,2,2-trichloroethanimidate

A mixture of 2-(2-pyridyl)ethanol (200 mg, 1.62 mmol, 0.18 ml, 1 eq.), 2,2,2-trichloroacetonitrile (351.7 mg, 2.44 mmol, 0.24 ml , 1.5 eq.) and DBU (24.7 mg, 0.16 mmol, 24.4 μl, 0.1 eq.) in DCM (16 ml) were stirred at 25°C for 16 h. The reaction mixture was diluted H2O (10 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1/1). The compound 2-(2-pyridyl)ethyl-2,2,2trichloroethanimidate (300 mg, 1.12 mmol, 69.0% yield) was obtained as a yellow oil.

4-(2-Pyridyl)-2-(trichloromethyl)-4,5-dihydrooxazole.

A mixture of 2-(2-pyridyl)ethyl-2,2,2-trichloroethanimidate (200 mg, 0.74 mmol, 1 eq.) and NIS (504.5 mg, 2.24 mmol, 3 eq.) in DCE ( 5 ml) in a glass vessel (purged with N2, sealed with a PTFE stopper) was heated at 110°C for 3 hours. The mixture was used in the next step without further purification.

2-Amino-2-(2-pyridyl)ethanol.

HCl (12 M, 0.62 mL, 10 eq.) was added to a mixture of 4-(2-pyridyl)-2-(trichloromethyl)-4,5dihydrooxazole (198 mg, 0.74 mmol, 1 eq.) in THF ( 10 ml) and stirred at 25°C for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The compound 2-amino-2-(2-pyridyl)ethanol (100 mg, crude, HCl) was obtained as a brown oil, which was used in the next step without further purification.

N-[2-T hydroxy-1-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), 2-amino-2-(2-pyridyl)ethanol (66.2 mg, 0.37 mmol, 1.2 eq., HCl), DIPEA (122.5 mg, 0.94 mmol, 0.16 ml, 3 eq.) and HATU (180.3 mg, 0.47 mmol, 1.5 eq. ) in DCM (2 ml) was stirred at 25°C for 2 hours. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 28%-58%, 8.5 min). The compound N-[2hydroxy-1-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (80 mg, 0.18 mmol, 57.4% yield) was obtained as brown solid matter.

- 180 046394 No.[(^)-2-Hydroxy-1-(2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 162) and Y-[('1K) -2-hydroxy-1-('2-pyridyl)ethyl|-5-[4-('trifluoromethyl)phenyl|naphthalene-2carboxamide (compound 163).

The racemic compound Y-[2-hydroxy-1-('2-pyridyl)ethyl|-5-[4-('trifluoromethyl)phenyl|naphthalene2-carboxamide (80 mg, 0.18 mmol, 1 equiv.) was purified by the prep method .-SFC (column: DAICEL CHIRALPAK AD(250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH3H2O IPA]; B%: 35%-35%, min). Compound 163 (12.2 mg, 27.8 µmol, 15.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.857 min, mass calc. for C ₂₅ H ₁₉ F ₃ N ₂ O ₂ 436.43 m/z, 437.0 [M+H]+ was obtained. ^1H NMR (400 MHz, CDCl3) δ 4.07 - 4.17 (m, 1H) 4.16 - 4.24 (m, 1H) 5.41 - 5.49 (m, 1H) 7.30 - 7.38 (m, 1H) 7.51 (dd, J=7.13, 1.00 Hz, 1H) 7.56 7.63 (m, 4H) 7.75 - 7.91 (m, 1H) 7.75 - 7.85 (m, 2H) 7.76 -7.82 (m, 1H) 7.86 (s, 1H) 7.88 - 7.93 (m, 1H) 8.02 (d, J=8.13 Hz, 1H) 8.16 (br d, J=6.88 Hz, 1H) 8.49 (s, 1H) 8.59 (br d, J=4.63 Hz, 1H). Compound 162 (14.2 mg, 32.2 µmol, 17.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.857 min, mass calc. for C25H19F3N2O2 436.43 m/z, 437.0[M+H]+ was obtained. ¹ H NMR (400 MHz, CDCl3) δ 4.04 - 4.14 (m, 1H) 4.16 - 4.24 (m, 1H) 5.41 - 5.46 (m, 1H) 7.32 ( dd, J=6.57, 5.07 Hz, 1H) 7.49 - 7.58 (m, 2H) 7.58 - 7.65 (m, 4 H) 7.75 - 7.83 (m, 3H) 7.88 (s, 2H) 8.01 (d, J=7.88 Hz, 1H) 8.07 (br d, J=7.38 Hz, 1H) 8.47 (s, 1H) 8 .58 (d, J=4.25 Hz, 1H).

Example 143: ^)-Na(3-hydroxy-1-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 164) and ^)-Na(3- Hydroxy-1-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 165)

(E)-2-Methyl-N(pyridin-2-ylmethylene)propane-2-sulfinamide.

To a solution of compound 143-1 (3 g, 28.01 mmol, 1 eq.) and compound 143-1a (4.07 g, 33.61 mmol, 1.2 eq.) in DCM (56 ml) at 20° CuSO ₄ (8.94 g, 56.02 mmol, 8.60 mL, 2 eq.) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (100 ml) and then extracted with EA (100 mlx3). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 143-2 (4.32 g, 20.54 mmol, 73. 3% yield) as a yellow oil, which was used immediately in the next step. LCMS (ESI): RT=0.640 min, mass, calc. for C ₁₀ H ₁₄ N ₂ O _s 210.08, m/z obtained 210.9 [M+H]+.

Ethyl 3-(1,1-dimethylethylsulfinamido)-3-(pyridin-2-yl)propanoate.

LDA (2 M, 4.76 mL, 2 eq.) and the resulting mixture was stirred at -78°C for 0.5 h. And then a solution of compound 143-2 (1 g, 4.76 mmol, 1 eq.) in THF (5 ml) was added to the above mixture at -78°C. The reaction mixture was stirred at -78°C for another 0.5 hours. The reaction mixture was quenched with a saturated solution of NH ₄ Cl (20 ml) and then extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, gradient 0~20% ethyl acetate/petroleum ether eluent approximately 30 mL/min) to give compound 143-3 (1.2 g, 3.98 mmol , 83.6% yield) as a yellow solid. LCMS (ESI): RT=0.708 min, mass, calc. for C ₁₄ H ₂₂ N ₂ O ₃ S 298.14, m/z obtained 298.9 [M+H] ⁺ .

Ethyl 3-amino-3-(pyridin-2-yl)propanoate.

To a solution of compound 143-3 (300 mg, 1.01 mmol, 1 eq.) in MeOH (2 ml) at 20°C was added HCl/MeOH (4 M, 1.26 ml, 5 eq.). The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound 143-4 (195 mg, 1.00 mmol, 99.9% yield) as a yellow solid, which used in the next step.

3-Amino-3-(pyridin-2-yl)propan-1-ol.

LAH (76.2 mg, 2.01 mmol, 2 equiv) was added to a solution of compound 143-4 (195 mg, 1.00 mmol, 1 eq.) in THF (3 mL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 h. The reaction mixture was quenched with water (0.08 ml), then 2 N NaOH (0.1 ml), and then water (0.24 ml), and then diluted with EA (20 ml). The resulting mixture was dried over anhydrous Na ₂ SO ₄ and filtered to remove solids. The filtrate was concentrated under reduced pressure to give compound 143-5 (150 mg, 0.99 mmol, 98.2% yield) as a yellow oil, which was used in the next step.

N(3-Hydroxy-1-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 143-5a (150 mg, 0.47 mmol, 1 eq.), compound 143-5 (144.4 mg, 0.95 mmol, 2 eq.) and HATU (234.4 mg, 0.62 mmol, 1.3 eq.) TEA (144.0 mg, 1.42 mmol, 0.20 mL, 3 eq.) was added to DMF (2 ml) at 20°C. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep HPLC (column: Waters Xbridge BEH C18 100x25 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 35%-75%, 9.5 min) to obtain compound 143-6 (130 mg, 0.29 mmol, 60.9% yield) as a colorless oil.

^)-N(3-Hydroxy-1-(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphtamide (compound 164) and ^)-N(3-hydroxy-1 -(pyridin-2-yl)propyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamcd (compound 165).

A sample of compound 143-6 (80 mg, 0.18 mmol, 1 eq.) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 μm); mobile phase: [0.1% NH3H2O ETOH]; V% : 55%-55%, min) to obtain compound 165 (31.7 mg, 70.5 µmol, 39.7% yield) as a white solid and compound 164 (30.8 mg, 68.4 µmol, 38 .5% yield) as a white solid. Compound 165 LCMS (ESI): RT=0.796 min, mass, calc. for C ₂₆ H ₂₁ F ₃ N ₂ O ₂ 450.16, m/z obtained 450.9 [M+H]+; ^1H NMR (400 MHz, CD3OD) δ 8.58 - 8.48 (m, 2H), 8.08 (d, J=8.1 Hz, 1H), 7.93 - 7.79 (m, 5H ), 7.71 - 7.64 (m, 3H), 7.55 (dd, J=7.4, 16.8 Hz, 2H), 7.32 (dd, J=5.4, 7.0 Hz, 1H), 5.42 (dd, J=5.9, 8.4 Hz, 1H), 3.76 - 3.63 (m, 2H), 2.28 2.16 (m, 2H). Compound 164 LCMS (ESI): RT=0.799 min, mass, calc. for C ₂₆ H ₂₁ F ₃ N ₂ O ₂ 450.16, m/z obtained 451.0 [M+H]+; 1H NMR (400 MHz, CD3OD) δ 8.57 - 8.51 (m, 2H), 8.08 (d, J=8.3 Hz, 1H), 7.93 - 7.79 (m, 5H) , 7.71 - 7.63 (m, 3H), 7.60 -7.51 (m, 2H), 7.33 (ddd, J=1.0, 5.0, 7.5 Hz, 1H) , 5.42 (dd, J=5.9, 8.4 Hz, 1H), 3.76 - 3.63 (m, 2H), 2.30-2.13 (m, 2H).

Example 144: N[(^)-3-hydroxy-1-methylpropyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 166) and Y-|(1K)-3-hydroxy-1-methylpropyl |-5-|4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 167)

No.(3-Hydroxy-1-methylpropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamcd.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (90 mg, 0.28 mmol, 1 eq.), 3-aminobutan-1-ol (30.4 mg, 0.34 mmol, 1.2 eq.), HaTu (162.3 mg, 0.42 mmol, 1.5 eq.) and DIPEA (110.3 mg, 0.85 mmol, 0.14 mL, 3 eq.) in DCM (5 mL) stirred at 25°C for 2 hours. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1/1). Compound N(3-hydroxy-1-methylpropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (100 mg, 0.25 mmol, 90.7% yield) was obtained as a white solid.

No.[(^)-3-Hydroxy-1-methylpropyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 166) and No.[(^)-3-hydroxy-1-methylpropyl]- 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 167).

Racemic compound N(3-hydroxy-1-methylpropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (90 mg, 0.23 mmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; V%: 35%-35%, min). Compound 167 (12.0 mg, 30.7 µmol, 13.2% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.923 min, mass calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.39 m/z obtained 388.0 [M+H]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21 (d, J=6.63 Hz, 3 H) 1.62 - 1.82 (m, 2H) 3.45 - 3.54 (m, 2H) 4.14 - 4.24 (m, 1H) 4.47 (t, J=5 .07 Hz, 1H) 7.59 (d,

- 182 046394

J=6.50 Hz, 1H) 7.66 - 7.77 (m, 3H) 7.81 (d, J=8.88 Hz, 1H) 7.88 -7.97 (m, 3H) 8, 12 (d, J=8.25 Hz, 1H) 8.43 (d, J=8.13 Hz, 1H) 8.54 (d, J=1.25 Hz, 1H). Compound 166 (15.4 mg, 39.8 µmol, 17.14% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.927 min, mass calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.39 m/z, 338.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.20 (d, J=6.63 Hz, 3H) 1.62 - 1.82 (m, 2H) 3.49 (brt, J=6 .25 Hz, 2H) 4.14 - 4.23 (m, 1H) 4.49 (br s, 1H) 7.58 (d, J=7.00 Hz, 1H) 7.65 - 7.76 ( m, 3H) 7.80 (d, J=8.88 Hz, 1H) 7.88 - 7.95 (m, 3H) 8.12 (d, J=8.13 Hz, 1H) 8.43 ( d, J=8.13 Hz, 1H) 8.54 (d, J=1.00 Hz, 1H).

Example 145: ^)-N(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 168) and ^)-M4-aminobutan-2-yl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide (compound 169)

tert-Butyl(4-hydroxybutan-2-yl)carbamate.

Boc ₂ O ( 881 mg, 4.04 mmol, 1.2 eq.). The reaction mixture was stirred at 25°C for 2 hours. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 - 1:1) to obtain tert-butyl(4-hydroxybutan-2-yl)carbamate (530 mg, 83% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.42 (br s, 1H), 3.91 (br s, 1H), 3.64 (dd, J=2.9, 7.9 Hz, 2H), 1 .88 - 1.76 (m, 1H), 1.46 (s, 9H), 1.38 - 1.27 (m, 1H), 1.20 (d, J=6.5 Hz, 3H).

tert-Butyl(4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate.

To a solution of tert-butyl-(3-hydroxy-1-methylpropyl)carbamate (430 mg, 2.27 mmol, 1 eq.), isoindoline-1,3-dione (367 mg, 2.50 mmol, 1.1 eq. .) and PPh ₃ (715 mg, 2.73 mmol, 1.2 eq.) in THF (5 ml) was added dropwise DEAD (474 mg, 2.73 mmol, 1.2 eq.) at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 ml) and the resulting mixture was extracted with EA (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 - 2:1) to give tert-butyl (4-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate (700 mg , 78% yield) as a white solid.

2-(3-Aminobutyl)isoindoline-1,3-dione.

A solution of tert-butyl-No[3-(1,3-dioxoisoindolin-2-yl)-1-methylpropyl]carbamate (120 mg, 0.37 mmol, 1 eq.) in 4 M HCl/dioxane (3 ml) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give 2-(3-aminobutyl)isoindoline-1,3-dione (85 mg, crude, HCl) as a white solid.

N(4-(1,3-Dioxoisoindolin-2-yl)butan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), 2-(3-aminobutyl)isoindoline-1,3-dione (80.5 mg, 0.31 mmol, 1 equiv., HCl) and DIPEA (122.5 mg, 0.94 mmol, 3 equiv.) in DCM (3 ml) was added HATU (144.2 mg, 0.38 mmol, 1 ,2 eq.). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 ml) and the resulting mixture was extracted with EA (50 mlx3). Combined organic layers

- 183 046394 dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 - 2:1) to give A-(4-(1,3-dioxoisoindolin-2-yl)bu'gan-2-yl)-5- (4-('trif'gorme'gyl)phenyl)-2-naf'hamide (150 mg, 90% yield) as a white solid.

A-(4-Aminobutan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

NH2NH2-H2O (126.0 mg, 2.52 mmol, 10 eq.) was added to a solution of A-[3-(1,3-dioxoisoindolin-2yl)-1-methylpropyl]-5-[4-(trifluoromethyl)phenyl ]naphthalene-2-carboxamide (130 mg, 0.25 mmol, 1 eq.) in EtOH (8 ml). The reaction mixture was stirred at 25°C for 5 hours. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%-50%, 8.5 min) to obtain N -(4aminobutan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (75 mg, 70% yield, HCl) as a white solid. LCMS (ESI): RT=0.839 min, mass calc. for C ₂₂ H ₂₁ F ₃ N ₂ O 368.16 m/z, 387.1 [M+H]+ was obtained.

^)-A-(4-Aminobutan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 168) and (R)-N-(4aminobutan-2-yl)-5- (4-(trifluoromethyl)phenyl)-2-naphthamide (compound 169).

Na(3-Amino-1-methylpropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (75 mg, 0.17 mmol, 1 equiv, HCl) was separated by SFC (column: Daicel ChiralPak IG (250x0 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; V%: 20%-20%, min). Pure fractions were collected and volatiles were removed in vacuo. The residue was resuspended in water (10 ml) and ACN (1 ml), and then the resulting mixture was lyophilized to dryness, completely removing the remaining solvent to give compound 169 (R)-N(4-aminobutan-2-yl)-5-(4 -(trifluoromethyl)phenyl)-2-naphthamide (22.04 mg, 57 µmol, 32% yield) as a light yellow solid and compound 168 (R)-A-(4-aminobutan-2-yl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide (21.54 mg, 55 µmol, 31% yield) as a light yellow solid. Compound 169 LCMS (ESI): RT=0.845 min, mass calc. for C ₂₂ H ₂₁ F ₃ N ₂ O 368.16 m/z, obtained 387.0 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.52 (m, 2H), 8.13 (d, J=8.0 Hz, 1H), 7.92 (br d, J=8.0 Hz, 3H), 7.81 (d, J=8.8 Hz, 1H ), 7.77 - 7.66 (m, 3H), 7.59 (d, J=6.3 Hz, 1H), 4.25 - 4.12 (m, 1H), 2.61 (t, J=6.8 Hz, 2H), 1.72 - 1.53 (m, 2H), 1.20 (d, J=6.8 Hz, 3H). Compound 168 LCMS (ESI): RT=0.836 min, mass calc. for C22H21F3N2O 368.16 m/z, obtained 387.1 [M+H]+, ¹ H NMR (400 MHz, DMSC-d6) δ 8.62 8.51 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.96 - 7.88 (m, 3H), 7.81 (d, J=9.0 Hz, 1H), 7.77 - 7.66 (m, 3H ), 7.62 7.56 (m, 1H), 4.31 - 4.10 (m, 1H), 2.63 (t, J=6.9 Hz, 2H), 1.73 - 1.55 (m , 2H), 1.21 (d, J=6.5 Hz, 3H).

Example 146: A-((2-(fluoromethyl)pyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 170)

tert-Butyl((2-(fluoromethyl)pyrimidin-4-yl)methyl)carbamate.

A-ethyl-A- (trifluorosulfanyl)ethanamine (26.9 mg, 0.16 mmol, 2 eq.) at 40°C. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-TLC (petroleum ether:ethyl acetate=1:1) to obtain the title compound as a white solid. The compound tert-butyl-M-[[2-(fluoromethyl)pyrimidin-4-yl]methyl]carbamate (8 mg, 33 µmol, 39.6% yield) was obtained as a white solid.

(2-(Fluoromethyl)pyrimidin-4-yl)methanamine.

A solution of tert-butyl-M-[[2-(fluoromethyl)pyrimidin-4-yl]methyl]carbamate (8 mg, 33 µmol, 1 eq.) in 4 M HCl/dioxane (1 ml) was stirred at 25°C in for 2 hours. The reaction mixture was concentrated under reduced pressure. [2-(fluoromethyl)pyrimidin-4-yl]methanamine (5.8 mg, crude, HCl) was obtained as a yellow solid.

N((2-(Fluoromethyl)pyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (10 mg, 31 µmol, 1 equiv.) and DIPEA (12.2 mg, 94 µmol, 3 equiv.) in DCM (1 ml) HATU (14.4 mg, 38 µmol, 1.2 eq) was added. The reaction mixture was stirred at 25°C after 15 minutes. [2-(fluoromethyl)pyrimidin-4yl]methanamine (5.6 mg, 31 µmol, 1 eq, HCl) was then added and the reaction mixture was stirred at 25°C for 45 min. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 ml) and the resulting mixture was extracted with DCM (20 mlx3). The combined organic layers were dried over

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Na ₂ SO ₄ was filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 8.5 min) to obtain the above compound as a light yellow solid. Compound N[[2-(fluoromethyl)pyrimidin-4-yl]methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (1.3 mg, 3.1 μmol, 9.7% yield) was prepared in as a white solid. LCMS (ESI): RT=0.935 min, mass calc. for C ₂₄ H ₁₇ F ₄ N ₃ O 439.13 m/z, obtained 440.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.77 (d, J=5.3 Hz , 1H), 8.57 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.92 - 7.87 ( m, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.73 - 7.66 (m, 3H), 7.59 (d, J=6.5 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 5.60 - 5.46 (m, 2H), 4.76 (s, 2H).

Example 147: N((2-((isoxazol-3-yloxy)methyl)pyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 171)

tert-Butyl((2-((isoxazol-3-yloxy)methyl)pyrimidin-4-yl)methyl)carbamate DEAD (26.2 mg, 0.15 mmol, 1.2 eq.) was added dropwise to the tert solution -butyl-N-[[2-(hydroxymethyl)pyrimidin-4yl]methyl]carbamate (30.0 mg, 0.12 mmol, 1 eq.), isoxazol-3-ol (12.8 mg, 0.15 mmol , 1.2 eq.) and PPh ₃ (39.4 mg, 0.15 mmol, 1.2 eq.) in THF (1 ml) at 0°C under N2 atmosphere. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 2 hours. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-TLC (ethyl acetate) to give the title compound as a light yellow solid. The compound tert-butyl-N-[[2-(isoxazol-3yloxymethyl)pyrimidin-4-yl]methyl]carbamate (15 mg, 41.6 µmol, 33.2% yield) was obtained as a light yellow solid.

(2-((Isoxazol-3-yloxy)methyl)pyrimidin-4-yl)methanamine.

A mixture of tert-butyl-N-[[2-(isoxazol-3-yloxymethyl)pyrimidin-4-yl]methyl]carbamate (15.0 mg, 49 µmol, 1 eq.) in 4 M HCl/dioxane (1 ml) stirred at 15°C for 2 hours. The reaction mixture was concentrated under reduced pressure. [2-(isoxazol-3-yloxymethyl)pyrimidin-4yl]methanamine (10 mg, 41 µmol, 84.1% yield, HCl) was obtained as a yellow solid.

N((2-((Isoxazol-3-yloxy)methyl)pyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (12.0 mg, 38 µmol, 1 eq.), [2-(isoxazol-3-yloxymethyl)pyrimidin-4-yl]methanamine ( 10.0 mg, 41 µmol, 1.1 equiv., HCl) and DIPEA (14.7 mg, 0.11 mmol, 3 equiv.) in DCM (1 ml) was added µmol, 1.2 eq.). 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 extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100x25 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 40%-70%, 9. 5 min) to obtain the title compound (2.5 mg, 5 µmol, 13.1% yield). LCMS (ESI): RT=0.951 min, mass calc. for C ₂₇ H ₁₉ F ₃ N ₄ O ₃ 540.14 m/z, obtained 505.1 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 8.11 (d, J=1.5 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.88 - 7.83 (m, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.68 - 7.60 (m, 3H) , 7.59 - 7.51 (m, 2H), 7.36 - 7.31 (m, 1H), 7.33 (d, J=5.3 Hz, 1H), 6.12 (d, J =1.5 Hz, 1H), 5.56 (s, 2H), 4.85 (d, J=5.0 Hz, 2H).

Example 148: N((2-((2,6-difluorophenoxy)methyl)pyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide (compound 172)

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tert-Butyl((2-chloropyrimidin-4-yl)methyl)carbamate.

A solution of 2-chloropyrimidine-4-carbonitrile (1 g, 7.17 mmol, 1 eq.), Boc ₂ O (3.13 g, 14.33 mmol, 3.29 ml, 2 eq.) and Pd/C ( 200 mg, 10%) in EtOH (60 ml) was stirred at 25°C for 4 hours under H ₂ (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to obtain the title compound as a light yellow solid. The compound tert-butyl-K-[(2-chloropyrimidin-4-yl)methyl]carbamate (630 mg, 2.15 mmol, 29.9% yield) was obtained as a light yellow solid.

tert-Butyl((2-vinylpyrimidin-4-yl)methyl)carbamate.

To a solution of tert-butyl-K-[(2-chloropyrimidin-4-yl)methyl]carbamate (700 mg, 2.87 mmol, 1 eq.), potassium trifluoro(vinyl)borate (461.7 mg, 3.45 mmol, 1.2 eq.) and Na ₂ CO ₃ (608.9 mg, 5.75 mmol, 2 eq.) in dioxane (10 ml) and H2O (2 ml) was added Pd(dppf)Cl ₂ (105, 0 mg, 0.14 mmol, 0.05 eq.) in N2 atmosphere. The suspension was degassed under vacuum and purged with N2 several times. The mixture was stirred at 90°C for 5 hours under N2 atmosphere. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to obtain the title compound as a light yellow solid. The compound tert-butyl-K-[(2vinylpyrimidin-4-yl)methyl]carbamate (530 mg, 2.25 mmol, 78.4% yield) was obtained as a light yellow solid.

tert-Butyl((2-(hydroxymethyl)pyrimidin-4-yl)methyl)carbamate.

tert-Butyl-K-[(2-vinylpyrimidin-4-yl)methyl]carbamate (530 mg, 2.25 mmol, 1 eq.) was dissolved in DCM (10 ml) and cooled to -78°C. Ozone was bubbled through the solution for 15 minutes and the reaction mixture was allowed to warm to 25°C while N ₂ was purged. NaBH4 (681.7 mg, 18.02 mmol, 8 eq.) in MeOH (4 ml) was added and the reaction was allowed to stir 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 2:3) to obtain the title compound. The compound tert-butyl-K-[[2-(hydroxymethyl)pyrimidin-4-yl]methyl]carbamate (75 mg, 0.31 mmol, 13.9% yield) was obtained as a white solid.

tert-Butyl((2-((2,6-difluorophenoxy)methyl)pyrimidin-4-yl)methyl)carbamate DEAD (26.2 mg, 0.15 mmol, 27.3 μL, 1.2 eq.) was added to the solution.

tert-Butyl-K-[[2-(hydroxymethyl)pyrimidin-4-yl]methyl]carbamate (30 mg, 0.12 mmol, 1 eq.), 2,6difluorophenol (16.3 mg, 0.12 mmol, 1 eq.) and PPh ₃ (39.4 mg, 0.15 mmol, 1.2 eq.) in THF (1 ml) dropwise at 0°C under N2 atmosphere. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 2 hours. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-TLC (petroleum ether:ethyl acetate=2:1) to obtain the title compound as a white solid. The compound tert-butyl-K-[[2-[(2,6-difluorophenoxy)methyl]pyrimidin-4yl]methyl]carbamate (40 mg, 88.8 μmol, 70.8% yield) was obtained as a white solid.

(2-((2,6-Difluorophenoxy)methyl)pyrimidin-4-yl)methanamine.

A mixture of tert-butyl-K-[[2-[(2,6-DCfluorophenoxy)methyl]pyrimidin-4-yl]methyl]carbamate (40 mg, 0.11 mmol, 1 eq.) in 4 M HCl/dioxane ( 2 ml) was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The compound [2-[(2,6-difluorophenoxy)methyl]pyrimidin-4yl]methanamine (32 mg, crude, HCl) was obtained as a yellow solid.

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A((2-((2,6-Difluorophenoxy)methyl)pyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of Amethi.l-2-[5-[4-(tri(|)tormeti.l)pheni.l|-2-naphthshftanamine (20 mg, 60.7 µmol, 1 eq.) and KOAc (11.9 mg, 0.12 mmol, 2 eq.) carbonitride was added to MeOH (0.5 ml). To a solution of 5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (30 mg, 94.8 µmol, 1 eq.), [2-[(2,6difluorophenoxy)methyl]pyrimidin-4-yl]methanamine ( HATU (43 .2 mg, 0.11 mmol, 1.2 eq.). 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 extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge VEN C18 100x25 mmx5 μm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ASA |; V%: 56%-86%, 9. 5 min) to obtain the title compound (9.9 mg, 17.7 µmol, 18.7% yield). LCMS (ESI): RT=1.021 min, mass calc. for C ₃ oH ₂ oF ₅ N ₃ O ₂ 549.49 m/z, 550.1 [M+H]+ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 8.74 (d, J=5.1 Hz, 1H), 8.48 (s, 1H), 8.02 (d, J=8.3 Hz, 1H) , 7.93 - 7.85 (m, 2H), 7.79 (d, J=8.0 Hz, 2H), 7.70 (br t, J=4.5 Hz, 1H), 7.66 - 7.60 (m, 3H), 7.53 (d, J=7.0 Hz, 1H), 7.32 (d, J=5.0 Hz, 1H), 6.95 - 6.78 ( m, 3H), 5.44 (s, 2H), 4.85 (d, J=4.9 Hz, 2H).

Example 149: A[(^)-1-(3H-benzimidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 173) and A[(^)-1-( 3H-benzimidazol-4-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 174)

O

(NZ)-N-(3H-Benzimidazol-4-ylmethylene)-2-methylpropane-2-sulfinamide.

A mixture of 3H-benzimidazole-4-carbaldehyde (50 mg, 0.34 mmol, 1 eq.), Ti(roo-PrO) ₄ (194.4 mg, 0.68 mmol, 0.20 ml, 2 eq.) and 2-methylpropane-2-sulfinamide (41.4 mg, 0.34 mmol, 1 eq.) in DCM (2 ml) was stirred at 25°C for 16 hours. The reaction mixture was diluted with H ₂ O (5 ml) and the mixture extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 0/1, EA:MeOH=1:1). The compound (NZ)-N-(3Hbenzimidazol-4-ylmethylene)-2-methylpropan-2-sulfinamide (60 mg, 0.24 mmol, 70.3% yield) was obtained as a yellow oil.

A[1-(3H-Benzimidazol-4-yl)ethyl]-2-methylpropane-2-sulfinamide.

MeMgBr (3 M, 0.24 ml, 3 equiv.) at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with NH ₄ Cl (2 ml), H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , EA:MeOH=1/0 - 1/1). Compound A[1-(3H-benzimidazol-4-yl)ethyl]-2-methylpropane2-sulfinamide (60 mg, 0.22 mmol, 93.9% yield) was obtained as a yellow oil.

Intermediate 4: 1-(3H-benzimidazol-4-yl)ethanamine.

A mixture of N-[1-(3H-benzimidazol-4-yl)ethyl]-2-methylpropane-2-sulfinamide (60 mg, 0.22 mmol, 1 eq.) in HCl/dioxane (4 M, 3.69 ml , 65.32 eq.) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The compound 1-(3Hbenzimidazol-4-yl)ethanamine (50 mg, crude, HCl) was obtained as a yellow oil.

N-[1-(3H-Benzimidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (64.0 mg, 0.20 mmol, 1 eq.), DIPEA (104.6 mg, 0.80 mmol, 0.14 ml, 4 eq.), 1-(3H-benzimidazol-4-yl)ethanamine (40 mg, 0.20 mmol, 1 eq., HCl) and HATU (115.4 mg, 0.30 mmol, 1.5 eq.) in DCM (2 ml) was stirred at 25°C for 16 hours. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge VEH C18

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150x25 mmx5 microns; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ASN]; In%: 55%85%, 8.8 min). The compound N-[1-(3H-benzimidαzol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthaline-2carboxamide (30 mg, 64.6 µmol, 31.9% yield) was obtained as white solid matter.

N-[(1R)-1-(3H-Benzimidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 173) and N-[(1S)-1- (3H-beshimidαzol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthaline-2carboxamide (compound 174).

The racemic compound N-[1-(3H-benzimidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (30 mg, 65.2 μmol, 1 eq.) was purified by SFC (column : DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 µm); mobile phase: [Neu-ETOH]; B%: 40%-40%, min). Compound 174 (17.1 mg, 36.9 µmol, 56.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.886 min, mass calc. for C ₂₇ H ₂₀ F ₃ N ₃ O 459.46 m/z, 460.1 [M+H]+ was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.59 (d, J=6.88 Hz, 3H) 5.61 - 5.80 (m, 1H) 7.09 - 7.24 (m , 2H) 7.42 (br s, 1H) 7.56 (dd, J=7.07, 1.06 Hz, 1H) 7.64 - 7.74 (m, 3H) 7.79 (d, J =8.88 Hz, 1H) 7.86 - 7.96 (m, 3H) 8.13 (d, J=8.25 Hz, 1H) 8.23 (s, 1H) 8.61 (d, J =1.50 Hz, 1H) 9.28 (br s, 1H) 12.53 (br s, 1H) 12.40 - 12.64 (m, 1H). Compound 173 (13.6 mg, 29.7 µmol, 45.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.893 min, mass calc. for C ₂₇ H ₂₀ F ₃ N ₃ O 459.46 m/z, 460.1 [M+H]+ was obtained. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.59 (d, J=7.00 Hz, 3H) 5.71 (br s, 1H) 7.09 - 7.16 (m, 1H) 7 .15 - 7.22 (m, 1H) 7.43 (br d, J=8.25 Hz, 1H) 7.57 (dd, J=7.13, 1.13 Hz, 1H) 7.64 7 .74 (m, 3H) 7.79 (d, J=9.01 Hz, 1H) 7.85 - 7.97 (m, 3H) 8.13 (d, J=8.13 Hz, 1H) 8 .23 (s, 1H) 8.62 (d, J=1.50 Hz, 1H) 9.32 (br s, 1H) 12.50 (br s, 1H).

Example 150: N-[(1R)-1-(benzothiophen-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 175) and N[(^)-1-(benzothiophene -7-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 176)

N[1-(Benzothiophen-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 150-1 (80 mg, 0.25 mmol, 1 eq.) in DCM (2 mL) was added DIEA (130.8 mg, 1.01 mmol, 0.18 mL, 4 eq.) and HATU ( 192.4 mg, 0.51 mmol, 2 eq.). The mixture was stirred at 20°C for 0.5 h. Compound 150-1a (54.1 mg, 0.25 mmol, 1 eq., HCl) was added to the mixture. The mixture was stirred at 20°C for 2 hours. The mixture was diluted with H2O (15 ml), extracted with EA (30 mlx3). The combined organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was checked by HPLC and purified by pre-HPLC (column: Waters Xbridge VEN C18 150x25 mmx5 μm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 70%-100 %, 9.5 min) to obtain compound 150-2 (65 mg, 0.14 mmol, 54.0% yield) as a white solid.

N[(^)-1-(Benzothiophen-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 175) and N[(^)-1-(benzothiophene-7 -yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 176).

Compound 150-2 (60 mg, 0.13 mmol, 1 eq.) was purified by SFC.

The residue was purified by SFC (column: DAICEL CHIRALPAK AD (250 mmx50 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; V%: 35%-35%, min) to obtain compound 175 (15.5 mg, 32.6 µmol, 25.9% yield) as a light yellow solid (RT=2.873 min) and compound 176 (17.6 mg, 37.1 µmol, 29.4% yield) as a light yellow solid. (RT=3.280 min). Compound 175 LCMS (ESI): RT=1.081 min, mass, calc. for C ₂₈ H ₂₀ F ₃ NOS 475.52, m/z obtained 476.1 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.90 - 7.72 (m, 5H), 7, 66 - 7.55 (m, 3H), 7.54 7.36 (m, 5H), 6.66 (br d, J=7.1 Hz, 1H), 5.69 (t, J=7, 0 Hz, 1H), 1.83 (d, J=6.9 Hz, 3H). Compound 176 LCMS (ESI): RT=1.076 min, mass, calc. for C ₂₈ H ₂₀ F ₃ NOS 475.52, m/z obtained 476.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.91 - 7.71 (m, 5H), 7.67 - 7.55 (m, 3H), 7.54 - 7.37 (m, 5H), 6.65 (br d, J=7.4 Hz, 1H), 5.69 (t, J=7, 0 Hz, 1H), 1.83 (d, J=6.9 Hz, 3H).

Example 151: N[(^)-1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 177) and N[(^) -1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 178)

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N[1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (33.6 mg, 0.10 mmol, 1 eq.), 8(1-aminoethyl)-1H-quinolin-2-one (20 mg , 0.10 mmol, 1 eq.), DIPEA (41.2 mg, 0.31 mmol, 55.5 μl, 3 eq.) and HATU (48.4 mg, 0.12 mmol, 1.2 eq. ) in DCM (2 ml) was stirred at 25°C for 2 hours. The reaction mixture was diluted with H ₂ O (5 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 150x25 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 54%-84%, 9. 5 minutes). The compound ^[BAoxo-III-quinolinA-ylAtyl^-ASTrifluoromethnDphenyl^phthaleneA-carboxamide (5.1 mg, 10.3 µmol, 9.7% yield) was obtained as a white solid.

N[(III)-1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4-(trifluoromethyl)phenyl] naphthalene-2-carboxamide (compound 177) and N[(^)- 1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 178).

The racemic compound N[1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (12 mg, 24.67 µmol, 1 equiv.) was purified SFC method (column: DAICEL CHIRALPAK AS-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 30%-30%, min). Compound 178 (4.1 mg, 8.0 µmol, 32.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.972 min, mass calc. for C ₂₉ H ₂₁ F ₃ N ₂ O ₂ 486.48 m/z obtained 487.1p[M+H] ⁺ , 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.80 (d, J=7.03 Hz, 3H) 5.69 - 5.76 (m, 1H) 6.62 (d, J=9.54 Hz, 1H) 7.03 (br s, 1H) 7.13 - 7.17 (m, 1H) 7.37 - 7.41 (m, 1H) 7.43 - 7.49 (m, 4 H) 7.60 (d, J=7.28 Hz, 1H) 7.67 (d, J= 9.54 Hz, 3H) 7.72 (s, 2 H) 7.80 (br d, J=8.03 Hz, 1H) 8.39 (s, 1H) 11.16 (br s, 1H). Compound 177 (3.2 mg, 6.4 µmol, 26.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.971 min, mass calc. for C ₂₉ H ₂₁ F ₃ N ₂ O ₂ 486.48 m/z obtained 487.1 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.88 (d, J=7.03 Hz, 2H) 1.85 - 1.91 (m, 1H) 5.73 - 5.82 (m, 1H) 6.70 (d, J=9.54 Hz, 1H) 7.21 - 7.25 (m, 1H) 7.43 - 7.47 (m, 1H) 7.49 (s, 1H) 7.48 - 7.50 (m, 1H) 7.53 (br d, J=8.28 Hz , 3H) 7.67 - 7.79 (m, 2H) 7.67 - 7.76 (m, 1H) 7.69 - 7.76 (m, 1H) 7.76 - 7.76 (m, 1H) 7.76 - 7.79 (m, 1H) 7.80 - 7.87 (m, 2H) 8.47 (s, 1H) 11.35 (brs, 1H).

Example 152: N((2-cyanopyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 179)

tert-Butyl((2-chloropyrimidin-4-yl)methyl)carbamate.

A solution of 2-chloropyrimidine-4-carbonitrile (1.00 g, 7.17 mmol, 1 eq.), Boc ₂ O (2.97 g, 13.62 mmol, 3.13 ml, 1.9 eq.) and Pd/C (300 mg, 10%) in EtOH (20 ml) was stirred at 25°C for 4 hours under H ₂ (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 - 3:1) to give tert-butyl ((2-chloropyrimidin-4-yl)methyl)carbamate (230 mg, 12.2% yield) in as a light yellow solid. LCMS (ESI): RT=0.766 min, mass calc. for C ₁₀ H ₁₄ ClN ₃ O ₂ 243.08 m/z, 244.0 [M+H]+ was obtained.

tert-Butyl((2-cyanopyrimidin-4-yl)methyl)carbamate.

DAbCo (317.6 mg, 2. 83 mmol, 3 eq.) and NaCN (50 mg, 1.02 mmol, 1.08 eq.). 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 extracted with EA (20 ml x 3).

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The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 - 3:1) to give tert-butyl(2-cyanopyrimidin-4-yl)methyl)carbamate (105 mg, 47.4% yield) as orange solid.

4-(Aminomethyl)pyrimidine-2-carbonitrile.

A mixture of tert-butyl-M-[(2-cyanopyrimidin-4-yl)methyl]carbamate (20 mg, 85.3 µmol, 1 eq.) in HCl/dioxane (1 ml) was stirred at 25°C for 2 hours The reaction mixture was concentrated under reduced pressure to give 4-(aminomethyl)pyrimidine-2-carbonitrile (14 mg, crude, HCl) as a red solid.

N((2-Cyanopyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (30 mg, 94.8 µmol, 1 eq.), 4-(aminomethyl)pyrimidine-2-carbonitrile (14.0 mg, 0. 10 mmol, 1.1 equiv., HCl) and HATU (43.2 mg, 0.11 mmol, 1.2 equiv.) in DCM (1 ml) was added DIPEA (36.7 mg, 0.28 mmol, 3 eq.). 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 extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 150x25 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 55%-85%, 9. 5 min) to give N-((2cyanopyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (8.3 mg, 20.0% yield) as a white solid. LCMS (ESI): RT=0.974 min, mass calc. for C ₂₄ Hi ₅ F ₃ N ₄ O 432.12 m/z, obtained 433.0 [M+H]+, ¹ H NMR (400 MHz, CDClj) δ 8.82 (d, J=5.0 Hz , 1H), 8.47 (d, J=1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.96 - 7.90 (m, 1H), 7 .89 - 7.84 (m, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.68 - 7.60 (m, 4H), 7.55 (d, J=6 .5 Hz, 1H), 7.38 - 7.31 (m, 1H), 4.88 (d, J=5.5 Hz, 2H).

Example 153: N((2-chloropyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 180)

ABOUT

(2-Chloropyrimidin-4-yl)methanamine.

A solution of tert-butyl-N-[(2-chloropyrimidin-4-yl)methyl]carbamate (30 mg, 0.12 mmol, 1 eq.) in HCl/dioxane (1 ml) was stirred at 25°C for 1 hour The reaction mixture was concentrated under reduced pressure to give (2-chloropyrimidin-4-yl)methanamine (25 mg, crude, HCl) as a white solid.

N((2-Chloropyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

Solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (30 mg, 94.8 µmol, 1 eq.), (2chloropyrimidin-4-yl)methanamine (20.4 mg, 0.11 mmol, 1.2 eq., HCl) and HATU (43.2 mg, 0.11 mmol, 1.2 eq.) in DCM (1 ml) was added DIPEA (36.7 mg, 0.28 mmol, 49.5 μl , 3 eq.). 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 extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep HPLC (column: Xtimate C18 10 μ 250 mmx50 mm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 65%-95%, 7.8 min) to obtain the title compound (18.1 mg, 43.2% yield) as a white solid. LCMS (ESI): RT=1.003 min, mass calc. for C ₂₃ H ₁₅ ClF ₃ N ₃ O 441.09 m/z, 442.0 [M+H] ⁺ was obtained. ¹ H NMR (400 MHz, CDCE) δ 8.62 (d, J=5.1 Hz, 1H), 8.47 (d, J=1.6 Hz, 1H), 8.02 (d, J= 8.1 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.88 - 7.84 (m, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.67 - 7.60 (m, 3H), 7.54 (dd, J=7.1, 1.1 Hz, 1H), 7.39 - 7.32 (m, 2H), 4.82 ( d, J=5.4 Hz, 2H).

Example 154: N-[(E)-5-isoxazol-3-yloxypent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 181)

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tert-Butyl-U-[(E)-5-isoxazol-3-yloxypent-3-enyl|carbamate.

To a solution of compound 154-1 (70 mg, 0.34 mmol, 1 eq.), compound 154-1a (32.5 mg, 0.38 mmol, 1.1 eq.) and PPh ₃ (118.5 mg, 0.45 mmol, 1.3 eq.) in THF (1 ml) was added DIAD (91.4 mg, 0.45 mmol, 87 μl, 1.3 eq.) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated. The crude product was triturated with EA/PE (1:2, 1 ml) and filtered to give compound 154-2 (50 mg, crude) as a colorless oil, which was used immediately in the next step.

(E)-5-Isoxazol-3-yloxypent-3-en-1-amine.

A solution of compound 154-2 (50 mg, 0.18 mmol, 1 eq.) in HCl/dioxane (0.5 ml) was stirred at 20°C for 1 hour. The reaction was concentrated to give compound 154-3 (40 mg, crude, HCl) as a yellow oil, which was used immediately in the next step.

U-[(E)-5-Isoxazol-3-yloxypent-3-enyl|-5-[4-(trifluoromethyl)phenyl|naphthalene-2-carboxamide.

To a solution of compound 154-3a (61.8 mg, 0.19 mmol, 1 eq.), HATU (111.4 mg, 0.29 mmol, 1.5 eq.) and compound 154-3 (40 mg, 0 .19 mmol, 1 equiv., HCl) to DCM (2 ml) was added DIEA (101.0 mg, 0.78 mmol, 0.13 ml, 4 equiv.). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with EA (15 ml) and washed with H ₂ O (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 100x19 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-AC^; V%: 55%-85%, 7.8 min) to obtain the title compound (6.5 mg, 13.82 µmol, 7.07% yield) as a white solid. LCMS (ESI): RT=0.936 min, mass calc. for C ₂₆ H ₂₁ F ₃ N ₂ O ₃ , 466.15 m/z, 467.1 [M+H]+ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.91 - 7.83 (m, 1H), 7, 79 (d, J=7.8 Hz, 3H), 7.69 (d, J=2.5 Hz, 1H), 7.65 - 7.59 (m, 3H), 7.51 (d, J =6.0 Hz, 1H), 6.44 (br s, 1H), 5.86 - 5.77 (m, 1H), 5.73 (d, J=2.5 Hz, 1H), 5, 68 - 5.56 (m, 1H), 4.49 (d, J=6.0 Hz, 2H), 3.62 (q, J=6.5 Hz, 2H), 2.45 (q, J =6.9 Hz, 2H).

Example 155: N-[(1R)-1 -(1H-indazol-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 182) and N[(^)- 1-(1H-indazol-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 183)

1H-Indazol-7-ylmethanol.

1H-Indazole-7-carboxylic acid (1 g, 6.17 mmol, 1 eq.) was added to BH3-THF (1 M, 18.50 ml, 3 eq.) at 0°C. The mixture was then stirred at 80°C for 2 hours. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (20 ml x 3).

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The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. No cleaning was carried out. The compound 1H-indazol-7ylmethanol (900 mg, crude) was obtained as a white solid, which was used in the next step without further purification.

1H-Indazole-7-carbaldehyde.

A mixture of N-indazol-7-ylmethanol (800 mg, 5.40 mmol, 1 eq.) and MnO ₂ (2.35 g, 27.00 mmol, 5 eq.) in THF (2 ml) was stirred at 25°C for 2 hours. The resulting product was dissolved in EA and filtered to remove insoluble substances. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 5:1). The compound 1H-indazole-7carbaldehyde (180 mg, 1.23 mmol, 22.81% yield) was obtained as a white solid.

^2)-H-(III-Indazol-7-ylmethylene)-2-methylpropan-2-sulfinamide.

A mixture of N-indazole-7-carbaldehyde (100 mg, 0.68 mmol, 1 eq.), 2-methylpropane-2-sulfinamide (82.9 mg, 0.68 mmol, 1 eq.) and Ti(OEt) ₄ (312.1 mg, 1.37 mmol, 0.28 mL, 2 eq.) in DCM (1 mL) was stirred at 25°C for 16 h. The reaction mixture was diluted with H2O (5 mL) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 3:1). The compound N2)-N-(1H-indazol-7-ylmethylene)2-methylpropan-2-sulfinamide (150 mg, 0.60 mmol, 87.9% yield) was obtained as a yellow solid.

N-[1 -(1H-Indazol-7-yl)ethyl]-2-methylpropane-2-sulfinamide.

MeMgBr (3 M, 0.40 ml, 3 eq.) was added dropwise to a mixture of (N)-H-(N-indazol-7-ylmethylene)-2methylpropan-2-sulfinamide (100 mg, 0.40 mmol, 1 eq.) in THF (2 ml) at 0°C. The mixture was then stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (2 ml), NaOH (2M, 2 ml), H2O (10 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. No cleaning was carried out. The compound N-[1-(1H-indazol-7-yl)ethyl]-2-methylpropane-2-sulfinamide (100 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification.

1-(1H-Indazol-7-yl)ethanamine.

A mixture of Na[1-(1H-indazol-7-yl)ethyl]-2-methylpropane-2-sulfinamide (100 mg, 0.37 mmol, 1 eq.) in HCl/MeOH (4 M, 2 ml, 21, 23 equiv.) was stirred at 25°C for 2 hours. The reaction mixture was diluted with NaOH (4 M 10 ml), H ₂ O (10 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The compound 1-(1H-indazol-7-yl)ethanamine (60 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification.

N[1-(1H-Indazol-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (117.7 mg, 0.37 mmol, 1 eq.), 1(III-indazol-7-yl)ethanamine (60.0 mg, 0.37 mmol, 1 eq.), DIPEA (144.3 mg, 1.12 mmol, 0.19 ml, 3 eq.) and HATU (212.2 mg, 0.55 mmol, 1.5 eq.) in DCM (2 ml) was stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 65%-95%, 7.8 min) . The compound N[1-(1H-indazol-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (70 mg, 0.15 mmol, 40.9% yield) was obtained as white solid.

No.[(^)-1-(1H-Indazol-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 182) and No.[(^)-1-(1H -indazol-7-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 183).

The racemic compound (70 mg, 0.15 mmol, 1 eq.) was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mmx30 mm, 5 μm); mobile phase: [0.1% NH3H2O MEOH]; V%: 45%-45%, min). Compound 182 (22.3 mg, 46.7 µmol, 30.6% yield) was obtained as a white solid. LCMS (ESI): RT=1.017 min, mass calc. for C ₂₇ H ₂₀ F ₃ N ₃ O 459.46 m/z obtained 460.0 [M+H]+, ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.79 (br s, 1H), 8, 37 (d, J=1.5 Hz, 1H), 8.09 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.85 - 7.71 (m, 5H ), 7.62 - 7.55 (m, 3H), 7.50 (dd, J=1.3, 7.0 Hz, 1H), 7.42 (d, J=7.0 Hz, 1H) , 7.17 (t, J=7.7 Hz, 1H), 6.57 (br d, J=9.3 Hz, 1H), 6.03 (br d, J=2.3 Hz, 1H) , 1.92 (d, J=7.0 Hz, 3H), 1.59 (br s, 2H) Compound 183 (20.2 mg, 41.4 µmol, 27.1% yield) was obtained as a white solid substances. LCMS (ESI): RT=1.015 min, mass calc. for C ₂₇ H ₂₀ F ₃ N ₃ O 459.46 m/z obtained 460.0 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) δ 11.77 (br s, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.85 - 7.71 (m, 5H) , 7.63 - 7.55 (m, 3H), 7.50 (dd, J=1.3, 7.0 Hz, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 6.56 (br d, J=9.8 Hz, 1H), 6.08 - 5.98 (m, 1H), 1.92 ( d, J=7.0 Hz, 3H).

Example 156: 3-((5-(4-(trifluoromethyl)phenyl)-2-naphtamido)methyl)-1,2,4-thiadiazole-5-carboxamide

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Ethyl 3-(bromomethyl)-1,2,4-thiadiazole-5-carboxylate.

Ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (6.33 g, 1 equiv.), synthesized according to WO2008023157, NBS (14.14 g, 2 equiv.), benzoyl peroxide (5.77 g , 0.6 equiv.) and CCl ₄ (130 ml) were heated to 90°C for 5 hours. Once complete, the mixture was cooled to room temperature, diluted with EtOAc and washed with us. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC, gradient 0 - 30% EtOAc in Hex to obtain the desired product (7.72 g, 83%). LCMS [M+H]+=251.

Ethyl 3-(azidomethyl)-1,2,4-thiadiazole-5-carboxylate.

Ethyl 3-(bromomethyl)-1,2,4-thiadiazole-5-carboxylate (1.3 g, 1 equiv.), NaN ₃ (0.7 g, 3 equiv.) and DMSO (5 ml) were stirred at kt for 3 hours. Once complete, the mixture was diluted with EtOAc and washed with us. aq. NH4Cl, H2O and saline solution. The organic layer was dried with Na2SO4, concentrated and purified by FCC, gradient 0 - 100% DCM in Hex to obtain the desired product (0.49 g, 44%). LCMS [M+H]+= 214.

-(Azidomethyl)-1,2,4-thiadiazole-5-carboxamide.

Ethyl 3-(azidomethyl)-1,2,4-thiadiazole-5-carboxylate (0.47 g, 1 equiv.), Et ₃ N (0.6 ml), NH3 in EtOH (1.65 ml, 2M ) and EtOH (5 ml) were heated to 80°C for 18 hours in a sealed vessel. Once complete, the mixture was diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and used immediately in the next step without further purification. LCMS [M+H]+=185.

-(Aminomethyl)-1,2,4-thiadiazole-5-carboxamide.

3-(Azidomethyl)-1,2,4-thiadiazole-5-carboxamide (213 mg, 1 equiv.), Pd(OH) ₂ (25 mg) and MeOH (10 ml) were carefully purged with H ₂ . The reaction mixture was stirred under positive pressure H ₂ at 50°C for 5 hours. The reaction was cooled to room temperature, filtered through celite and concentrated five times the desired product, which was used without further purification. LCMS [M+H]+=159.

3-((5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)methyl)-1,2,4-thiadiazole-5-carboxamide.

3-(Aminomethyl)-1,2,4-thiadiazole-5-carboxamide (22 mg, 4 equiv.), 5-(4-(trifluoromethyl)phenyl)-2naphthoyl chloride (10 mg, 1 equiv.), Et ₃ N (0.04 ml, 8 equiv.) and THF (1 ml) were stirred at RT for 2 hours. The mixture was concentrated and purified by FCC, gradient 0 - 60% EtOAc in DCM to obtain the desired product (8 mg, 55%). LCMS [M+H]+=457.

Example 157: N(pyrimidin-4-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 185)

N(Pyrimidin-4-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (30 mg, 94.8 µmol, 1 eq.), HATU (46.8 mg, 0.12 mmol, 1.3 eq.) and DIPEA (36.7 mg, 0.28 mmol, 49.5 µl, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then pyrimidin-4-ylmethanamine (11.3 mg, 0 .10 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10

- 193 046394 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 46%-76%, 9 min). The title compound (7.5 mg, 17.9 µmol, 18.8% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.926 min, mass calc. for C ₂₃ H ₁₆ F ₃ N ₃ O 407.39 m/z, 408.0 [M+H]+ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 9.15 (s, 1H), 8.66 (d, J=5.1 Hz, 1H), 8.41 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.83 (s, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.59 - 7.55 (m, 2H), 7, 55 - 7.51 (m, 2H), 7.45 (d, J=6.9 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H), 4.77 (d, J =4.9 Hz, 2H).

Example 158: N((2-cyanopyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 186)

N(Pyridin-4-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (200 mg, 0.63 mmol, 1 eq.), HATU (360.6 mg, 0.94 mmol, 1.5 eq.) and DIPEA (245.1 mg, 1.90 mmol, 0.33 mL, 3 eq.) in DCM (3 mL) was stirred at 20°C for 1 hour. Then 4-pyridylmethanamine (68.3 mg, 0.63 mmol, 63.9 µl, 1 eq.) was added to the mixture and the mixture was stirred at 20°C for an additional 1 hour. The reaction mixture was diluted with H2O (20 ml) and extracted with EA (20 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). The compound N-(4pyridylmethyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (256 mg, 0.62 mmol, 99.6% yield) was obtained as a white solid.

4-((5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)methyl)pyridine-1-oxide.

m-CPBA (79, 6 mg, 0.36 mmol, 80%, 1.5 eq.). The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , ethyl acetate: methanol = 1/0 - 5:1). Compound N[(1-oxidopyridin-1-yl-4-yl)methyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (74 mg, 0.17 mmol, 71.2% yield) was prepared in as a white solid.

N((2-cyanopyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of N-[(1-oxidopyridin-1-ium-4-yl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (74 mg, 0.17 mmol, 1 eq.) in DCM ( 2 ml) TMSCN (19.1 mg, 0.19 mmol, 24.1 µl, 1.1 eq.) and N-dimethylcarbamoyl chloride (18.8 mg, 0.17 mmol, 16.1 µl, 1 eq.) were added. ). The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C ₁₈ 150x25 mmx5 µm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; V%: 50%-80%, 8.5 min). The title compound (6.0 mg, 13.9 µmol, 7.9% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.985 min, mass calc. for C ₂₅ H ₁₆ F ₃ N ₃ O 431.41 m/z, 432.0 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.55 (d, J=5.1 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 7.98 (d, J=8 ,3 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.80 - 7.76 (m, 2H), 7.74 (d, J=8.0 Hz, 2H), 7 .60 - 7.58 (m, 2H), 7.58 - 7.54 (m, 2H), 7.48 (dd, J=1.1, 7.0 Hz, 1H), 4.61 (s , 2H).

Example 159: N((6-((2,6-difluorophenoxy)methyl)pyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 187)

- 194 046394

6-(Bromomethyl)picolinonitrile.

To a solution of 6-methylpyridin-2-carbonitrile (1 g, 8.46 mmol, 1 eq.) in CCl ₄ (15 ml) was added NBS (1.51 g, 8.46 mmol, 1 eq.) and AIBN (139 .0 mg, 0.84 mmol, 0.1 eq.). The mixture was stirred at 80°C for 16 hours. H ₂ O (30 ml) was added to the reaction mixture and extracted with EA (30 ml x 3 ). The combined organic layers were washed with brine (30 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (40 g SepaFlash® Silica Flash column, EA/PE: 0~10%) to give two major zones to give 6-(bromomethyl)pyridine-2-carbonitrile (979 mg, crude) as yellow solid matter.

6-((2,6-Difluorophenoxy)methyl)picolinonitrile.

To a solution of 2,6-difluorophenol (200 mg, 1.54 mmol, 1 eq.) in DMF (5 ml) was added Cs ₂ CO ₃ (1.0 g, 3.0 mmol, 2 eq.) at 25°C . The mixture was stirred at 25°C for 0.5 h. Then, 6-(bromomethyl)pyridine-2carbonitrile (644.4 mg, 1.5 mmol, 1 eq.) was added to the reaction. The mixture was stirred at 25°C for 2 hours. H2O (20 ml) was added to the mixture and extracted with EA (15 mlx3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (20 g SepaFlash® Silica Flash column, EA/PE: 0~10%) to give 6-[(2,6difluorophenoxy)methyl]pyridine-2-carbonitrile (500 mg, 2.0 mmol, 87.1% yield) as a white solid.

(6-((2,6-Difluorophenoxy)methyl)pyridin-2-yl)methanamine.

A mixture of 6-[(2,6-difluorophenoxy)methyl]pyridine-2-carbonitrile (500 mg, 2.03 mmol, 1 eq.) and NiCl _{2.6 H 2 O} (1.45 g, 6.09 mmol, 3 equiv.) in MeOH (10 ml) was added NaBH ₄ (384.1 mg, 10.15 mmol, 5 equiv.) at 0°C. After addition, the mixture was stirred at 25°C for 3 hours. The filtrate was poured into H2O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20 g SepaFlash® Silica Flash column, EA/PE: 0~30%). The compound [6-[(2,6-difluorophenoxy)methyl]-2pyridyl]methanamine (355 mg, 1.42 mmol, 69.8% yield) was obtained as a yellow solid.

N((6-((2,6-Difluorophenoxy)methyl)pyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.) and HATU (90.1 mg, 0.23 mmol, 1.5 eq.) DIPEA (61.3 mg, 0.47 mmol, 82.6 μL, 3 eq.) was added to DCM (2 mL). After addition, the mixture was stirred at 25°C for 0.5 h and then [6-[(2,6difluorophenoxy)methyl]-2-pyridyl]methanamine (59.3 mg, 0.14 mmol, 0.9 eq) was added .). The resulting mixture was stirred at 25°C for 1.5 hours. The mixture was added with H2O (20 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 68%-98%, 7.8 min) . The title compound (36.2 mg, 66.0 µmol, 20.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.943 min, mass calc. For C ₃ iH ₂ iF ₅ N ₂ O ₂ 548.50 m/z, 549.1 [M+H]+ was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (t, J=5.9 Hz, 1H), 8.65 (d, J=1.3 Hz, 1H), 8.14 (d , J=8.3 Hz, 1H), 8.00 (dd, J=1.8, 8.8 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.89 - 7.81 (m, 2H), 7.77 - 7.68 (m, 3H), 7.64 - 7.58 (m, 1H), 7.48 (d, J=7.5 Hz, 1H ), 7.35 (d, J=7.8 Hz, 1H), 7.21 - 7.08 (m, 3H), 5.23 (s, 2H), 4.61 (d, J=6, 0 Hz, 2H).

Example 160: N[3-hydroxy-1-(2-pyridyl)propyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 188)

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Ethyl^)-3-amino-3-(2-pyridyl)prop-2-enoate.

A mixture of pyridine-2-carbonitrile (1 g, 9.61 mmol, 925.93 µl, 1 eq.), potassium 3-ethoxy-3-oxopropanoate (2.45 g, 14.41 mmol, 1.5 eq.) , ZnCl ₂ (654.5 mg, 4.80 mmol, 0.22 ml, 0.5 eq.), DIPEA (1.49 g, 11.53 mmol, 2.01 ml, 1.2 eq.) c toluene (20 ml) was stirred at 120°C for 24 hours under N2 atmosphere. The reaction mixture was diluted with NH4Cl (20 ml). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). Ethyl^)-3-amino-3-(2-pyridyl)prop-2enoate compound (1 g, 5.10 mmol, 53.0% yield) was obtained as a yellow solid.

-Amino-3-(2-pyridyl)propan-1-ol.

To a solution of ethyl^)-3-amino-3-(2-pyridyl)prop-2-enoate (150 mg, 0.78 mmol, 1 eq.) in THF (1 ml) was added LiAlH4 (148.08 mg, 3 .90 mmol, 5 equiv.) at 0°C. The mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with H2O (0.5 ml), NaOH (2 M, 0.25 ml), filtered and concentrated under reduced pressure to obtain a residue. The compound 3-amino-3-(2-pyridyl)propan-1-ol (40 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification.

N[3-Hydroxy-1-(2-pyridyl)propyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (83.1 mg, 0.26 mmol, 1 eq.), 3-amino-3-(2-pyridyl)propan-1-ol (40 mg , 0.26 mmol, 1 eq.), HATU (149.9 mg, 0.39 mmol, 1.5 eq.) and DIPEA (135.8 mg, 1.05 mmol, 0.18 ml, 4 eq. ) in DCM (1 ml) was stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with saline (10 mlx2), dried with _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 23%-53%, 11.5 min). The title compound (1.5 mg, 3.0 µmol, 1.1% yield, HCl) was obtained as a yellow oil. LCMS (ESI): RT=0.860, mass calc. for C ₂₆ H ₂₁ F ₃ N ₂ O ₂ 450.45 m/z, 451.1 [M+H]+ was obtained. ¹ H NMR (400 MHz, CD3OD) δ ppm 2.25 - 2.47 (m, 2H) 3.74 (dt, J=11.10, 5.39 Hz, 1H) 3.82 - 3.89 ( m, 1H) 5.51 - 5.56 (m, 1H) 7.62 (dd, J=7.07, 1.19 Hz, 1H) 7.68

7.74 (m, 3H) 7.87 (d, J=8.00 Hz, 2H) 7.89 - 7.93 (m, 2H) 7.99 - 8.03 (m, 1H) 8.12 (d, J=8.13 Hz, 1H) 8.18 (br d, J=8.26 Hz, 1H) 8.58 - 8.65 (m, 2H) 8.80 (d, J=5, 75 Hz, 1H).

Example 161: N-[(E)-5-(2,6-difluorophenoxy)pent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthaline-2carboxamide (compound 189)

tert-Butyl-X-(3-hydroxypropyl)carbamate.

To a solution of compound 161-1 (5 g, 66.5 mmol, 5.1 mL, 1 eq.) in DCM (50 mL) was added dropwise a solution of Boc ₂ O (15.9 g, 73.2 mmol, 16. 8 mL, 1.1 eq.) in DCM (30 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was washed with us. NaHCO ₃ (15 ml) and saline (2x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. Compound 161-2 (10 g, 57 mmol, 85.7% yield) was used immediately in the next step as a colorless oil, which was confirmed

- 196 046394 by 1H NMR method. 1H NMR (400 MHz, CDCl ₃ ) δ 4.78 (br s, 1H), 3.66 (t, J=5.6 Hz, 2H), 3.29 (t, J=6.1 Hz, 2H ), 2.74 (br s, 1H), 1.71-1.60 (m, 2H), 1.45 (s, 9H).

tert-Butyl-N-(3-oxopropyl)carbamate.

To a suspension of compound 161-2 (1 g, 5.7 mmol, 0.98 ml, 1 eq.), TVAS (158.6 mg, 0.57 mmol, 0.15 ml, 0.1 eq.), NCS (1.14 g, 8.56 mmol, 1.5 eq.) and TEMPO (89.7 mg, 0.57 mmol, 0.1 eq.) in CHCl ₃ (20 ml) was added a solution of NaHCO ₃ (840 mg , 10 mmol, 0.38 ml, 1.75 eq.) and K2CO3 (138 mg, 0.9 mmol, 1.75e-1 eq.) in H2O (20 ml). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:10) to give compound 161-3 (1 g, crude) as a colorless oil, which was confirmed by 1H NMR. 1H NMR (400 MHz, CDCl ₃ ) δ 9.82 (s, 1H), 4.94 (br d, J=9.6 Hz, 1H), 3.43 (br d, J=5.0 Hz, 2H), 2.75 - 2.71 (m, 2H), 1.44 (br s, 9H). methyl(E)-5-(tert-butoxycarbonylamino)pent-2-enoate

To a solution of compound 161-3 (1 g, 5.77 mmol, 1 eq.) and compound 161-3a (1.58 g, 8.66 mmol, 1.25 mL, 1.5 eq.) in MeCN (10 ml) LiOH-H ₂ O (363.4 mg, 8.66 mmol, 1.5 eq.) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction was concentrated. The residue was diluted with EA (30 ml) and washed with H2O (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:5) to give compound 161-4 (0.3 g, 1.31 mmol, 22.7% yield) as a colorless oil.

tert-Butyl-N-[(E)-5-hydroxypent-3-enyl]carbamate.

To a solution of compound 161-4 (0.1 g, 0.43 mmol, 1 eq.) in DCM (1 mL) was added DIBALH (1 M, 1.0 mL, 2.5 eq.) at 0°C. The reaction mixture was heated to 25°C for 3 hours. The reaction mixture was diluted with DCM (10 ml) and washed with H2O (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:3-1:1) to obtain compound 161-5 (55 mg, 0.27 mmol, 62.6% yield) as a colorless oil, which was confirmed by the method 1H NMR. 1H NMR (400 MHz, CDCl ₃ ) δ 5.80 - 5.57 (m, 2H), 4.56 (br s, 1H), 4.16 - 4.11 (m, 2H), 3.20 ( br d, J=6.0 Hz, 2H), 2.25 (q, J=6.5 Hz, 2H), 1.53 (br s, 1H), 1.45 (s, 9H).

tert-butyl-N-[(E)-5-(2,6-difluorophenoxy)pent-3-enyl]carbamate

To a solution of compound 161-5 (70 mg, 0.34 mmol, 1 eq.), compound 161-5a (49.7 mg, 0.38 mmol, 1.1 eq.) and PPh ₃ (118.5 mg, 0.45 mmol, 1.3 eq.) in THF (1 ml) was added DIAD (91.4 mg, 0.45 mmol, 87 μl, 1.3 eq.) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated. The residue was triturated with EA/PE (1:2, 1 ml) and filtered to give compound 161-6 (150 mg, crude) as a yellow oil, which was used immediately in the next step.

(E)-5-(2,6-difluorophenoxy)pent-3-ene-1-amine

A solution of compound 161-6 (150 mg, 0.47 mmol, 1 eq.) in HCl/dioxane (1 ml) was stirred at 20°C for 1 hour. The reaction was concentrated to give compound 161-7 (100 mg, 92. 1 µmol, 19.2% yield, HCl) as a yellow oil, which was used immediately in the next step.

N-[(E)-5-(2,6-Difluorophenoxy)pent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 161-7a (29.1 mg, 92.1 µmol, 1 eq.), HATU (52.54 mg, 0.13 mmol, 1.5 eq.) and compound 7 (100 mg, 92 µmol, 1 equiv., HCl) in DCM (2 ml) was added DIEA (47.62 mg, 0.36 mmol, 64 μl, 4 equiv.). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with EA (15 ml) and washed with H2O (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 100x19 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 70%-100%, 7.8 min) to obtain the title compound (4.2 mg, 8 µmol, 8.7% yield) as a white solid. LCMS (ESI): RT=1.082 min, mass calc. for C ₂₉ H ₂₂ F ₅ NO ₂ , 511.16 m/z, 512.1 [M+H]+ was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.90 - 7.85 (m, 1H), 7 .81 - 7.73 (m, 3H), 7.65 - 7.57 (m, 3H), 7.51 (d, J=6.3 Hz, 1H), 6.95 - 6.78 (m , 3H), 6.30 (br s, 1H), 5.95 - 5.77 (m, 2H), 4.63 (d, J=5.3 Hz, 2H), 3.58 (q, J =6.4 Hz, 2H), 2.45 (q, J=6.4 Hz, 2H).

Example 162: N((6-fluoropyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 190)

2-((6-Fluoropyridin-2-yl)methyl)isoindoline-1,3-dione.

A mixture of (6-fluoro-2-pyridyl)methanol (200 mg, 1.57 mmol, 1 eq.), isoindoline-1,3-dione (277.7 mg, 1.89 mmol, 1.2 eq.), DIAD (636 mg, 3.15 mmol, 0.61 ml, 2 eq.), PPh ₃ (825 mg, 3.15 mmol, 2 eq.) in THF (3

- 197 046394 ml) was degassed and purged with N2 3 times, and then the mixture was stirred at 25°C for 1 hour under an _N2 atmosphere. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). The compound 2-[(6-fluoro-2-pyridyl)methyl]isoindoline-1,3-dione (300 mg, 1.17 mmol, 74.4% yield) was obtained as a white solid.

(6-Fluoropyridin-2-yl)methanamine.

Hydrazine hydrate (117 mg, 2 .34 mmol, 0.11 ml, 2 eq.). The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. No cleaning was carried out. The compound (6-fluoro-2-pyridyl)methanamine (100 mg, 0.79 mmol, 67.7% yield) was obtained as a yellow oil.

N((6-Fluoropyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (75 mg, 0.23 mmol, 1 eq.), HATU (135 mg, 0.35 mmol, 1.5 eq.) and DIPEA ( 92 mg, 0.71 mmol, 0.12 ml, 3 eq.) in DCM (2 ml) was stirred at 20°C for 1 hour. Then (6-fluoro-2-pyridyl)methanamine (30 mg, 0. 23 mmol, 1 eq.) was added to the mixture and the mixture was stirred at 20°C for another 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C ₁₈ 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 50% 80%, 11.5 min). The title compound (18 mg, 39.5 µmol, 16.6% yield, HCl) was obtained as a white solid. LCMS (ESI): RT=0.997 min, mass calc. for C ₂₄ Hi ₆ F ₄ N ₂ O 424.39 m/z, 425.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CDCI3) δ 8.48 (s, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.92 - 7.89 (m, 2H), 7, 88 7.82 (m, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.67 - 7.62 (m, 3H), 7.55 - 7.52 (m, 1H ), 7.39 (br s, 1H), 7.33 - 7.29 (m, 1H), 6.90 (dd, J=2.5, 8.1 Hz, 1H), 4.82 (d , J=5.1 Hz, 2H).

Example 163: N((6-cyanopyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 191)

N(Pyridin-2-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (200 mg, 0.63 mmol, 1 eq.), HATU (360.6 mg, 0.94 mmol, 1.5 eq.) and DIPEA (245.1 mg, 1.90 mmol, 0.3 mL, 3 eq.) in DCM (3 mL) was stirred at 25°C for 1 hour. Then 2-pyridylmethanamine (75.2 mg, 0.69 mmol, 70.9 µl, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). The compound N-(2pyridylmethyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (200 mg, 0.49 mmol, 77.8% yield) was obtained as a white solid.

2-((5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)methyl)pyridine 1-oxide.

A mixture of N(2-pyridylmethyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (100 mg, 0.24 mmol, 1 eq.) and m-CPBA (74.9 mg, 0.36 mmol , 85%, 1.5 eq.) in DCM (2 ml) was stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate: methanol=1/0 - 5:1). Compound N[(1-oxidopyridin-1-yl-2-yl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (90 mg, 0.21 mmol, 86.5% yield) was obtained as white solid.

N((6-Cyanopyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

N-[(1-oxidopyridin-1-ium-2-yl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide mixture (90 mg, 0.21 mmol, 1 eq.), NN β-dimethylcarbamoyl chloride (22.9 mg, 0.21 mmol, 19 μl, 1 eq.) and TMSCN (23.2 mg, 0.23 mmol, 29 μl, 1.1 eq.) in DCM (2 ml) were stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0

- 198 046394

- 1:1). The title compound (5.6 mg, 12.7 µmol, 5.9% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.992 min, mass calc. for C ₂₅ Hi ₆ F3N3O 431.41 m/z obtained 432.0 [M+H]+, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (d, J=1.8 Hz, 1H) , 8.10 (d, J=8.3 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.97 - 7.93 (m, 1H), 7.92 - 7.88 (m, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.79 (d, J=7.5 Hz, 1H), 7.74 (d, J=8.0 Hz , 1H), 7.73 - 7.67 (m, 3H), 7.60 (dd, J=1.3, 7.0 Hz, 1H), 4.80 (s, 2H).

Example 164: N(3-((isoxazol-3-yloxy)methyl)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 192)

To a solution of [3-[[[5-[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]methyl]phenyl]methyl-4methylbenzenesulfonate (50 mg, 84.7 µmol, 1 eq.) in DMF (1 ml) Cs ₂ CO ₃ (55.2 mg, 0.16 mmol, 2 eq.) was added at 25°C. The mixture was stirred at 25°C for 0.5 h. Isoxazole-3ol (7.21 mg, 84.7 μmol, 1 eq.) was then added to the reaction. The mixture was stirred at 25°C for 2 hours. The mixture was added with H2O (10 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 11.5 min). The title compound (3.1 mg, 5.9 µmol, 7.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.980 min, mass calc. for C ₂₉ H ₂₁ F ₃ N ₂ O ₃ 502.48 m/z obtained 503.1 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 8.25 ( s, 1H), 7.97 (br d, J=8.3 Hz, 1H), 7.84 - 7.71 (m, 4H), 7.62 - 7.53 (m, 3H), 7, 46 (br d, J=7.1 Hz, 1H), 7.41 (s, 1H), 7.33 - 7.23 (m, 3H), 6.02 (s, 1H), 5.16 ( s, 2H), 4.56 (s, 2H).

Example 165: N((1,2,4-thiadiazol-3-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 193)

3-(Azidomethyl)-1,2,4-thiadiazol-5-amine.

3-(Chloromethyl)-1,2,4-thiadiazol-5-amine (500 mg, 3.34 mmol, 1 equiv.), synthesized according to WO2014072930, NaN ₃ (434 mg, 6.68 mmol, 2 equiv.) and DMSO (6 ml) was heated to 70°C. The reaction mixture was stirred at 70°C for 5 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with H2O, brine, dried over Na ₂ SO ₄ , concentrated and used immediately in the next step without further purification (500 mg, 3.2 mmol, 96%). LCMS [M+H]+=157.

-(Azidomethyl)-1,2,4-thiadiazole.

3-(Azidomethyl)-1,2,4-thiadiazol-5-amine (500 mg, 3.2 mmol, 1 equiv.), tBuONO (3.8 ml, 32 mmol, 10 equiv.) and DMF (6 ml ) was heated to 70°C for 8 hours. The mixture was concentrated and purified by FCC, gradient 0 - 40% EtOAc in Hex to give the desired product, a pale yellow oil (220 mg, 1.56 mmol, 49%). LCMS [M+H]+=142.

(1,2,4-Thiadiazol-3-yl)methanamine.

3-(Azidomethyl)-1,2,4-thiadiazole (220 mg, 1.56 mmol, 1 equiv.), Pd(OH) ₂ (25 mg) and MeOH (3 ml) were carefully purged with H2. The reaction mixture was stirred under positive pressure H2 at 50°C for 20 hours. The reaction was cooled to room temperature, filtered through celite and concentrated fivefold

- 199 046394 required product, which was used without further purification. LCMS [M+H]+=116.

N((1,2,4-Thiadiazol-3-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

(1,2,4-Thiadiazol-3-yl)methanamine (14 mg, 0.126 mmol, 2 equiv.), 5-(4-(trifluoromethyl)phenyl)-2naphthoyl chloride (21 mg, 0.0629 mmol, 1 equiv. ), Et ₃ N (0.02 ml, 0.126 mmol, 2 equiv.) and THF (1 ml) were stirred at RT for 2 hours. The mixture was concentrated and purified by FCC, gradient 0 - 30% THF in DCM to obtain the desired product (2.7 mg, 10%). LCMS [M+H]+=414.

Example 166: N(3-((2,6-difluorophenoxy)methyl)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 194)

(3 -(Aminomethyl)phenyl)methanol.

To a solution of 3-formylbenzonitrile (1 g, 7.63 mmol, 1 eq.) in THF (30 ml) was added LiAlH ₄ (578.8 mg, 15.25 mmol, 2 eq.) at 0°C dropwise in an atmosphere nitrogen. After complete addition, the reaction mixture was heated to reflux for 16 hours at 70°C. Treated by adding water (1 ml), 4 M NaOH solution (1 ml) and again water (3 ml), anhydrous Na ₂ SO ₄ (10 g). The precipitate was filtered off and washed with EA (30 ml). The mixture was added with H2O (10 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (40 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (12 g SepaFlash® Silica Flash column, MeOH/EA: 0~20%). The compound (3-(aminomethyl)phenyl)methanol (593 mg, 3.24 mmol, 42.5% yield) was obtained as a yellow oil.

N(3-(Hydroxymethyl)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (150 mg, 0.47 mmol, 1 eq.) and HATU (216.4 mg, 0.56 mmol, 1.2 eq.) DIPEA (245.1 mg, 1.90 mmol, 0.33 mL, 4 eq.) was added to DCM (5 mL). After addition, the mixture was stirred at 25°C for 0.5 h and then [3(aminomethyl)phenyl]methanol (95.4 mg, 0.52 mmol, 1.1 eq.) was added. The resulting mixture was stirred at 25°C for 1.5 hours. The mixture was added with H2O (10 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel (12 g SepaFlash® Silica Flash column, EA/PE: 0-50%). The compound N-[[3(hydroxymethyl)phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (293 mg, 0.60 mmol, 95.2% yield) was obtained as a white solid .

3-((((5-(4-(Trifluoromethyl)phenyl)naphthalene-2-yl)methyl)amino)methyl)benzyl-4-methylbenzenesulfonate.

TEA ( 87.8 mg, 0.86 mmol, 0.12 ml, 2 eq.) and DMAP (26.5 mg, 0.21 mmol, 0.5 eq.). After addition, the mixture was stirred at 25°C for 0.5 h and then 4-methylbenzenesulfonyl chloride (124.1 mg, 0.65 mmol, 1.5 eq.) was added. The mixture was stirred at 25°C for 2.5 hours. The mixture was added with H2O (10 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel (12 g SepaFlash® Silica Flash column, EA/PE: 0~50%). Compound 3-((((5-(4-(trifluoromethyl)phenyl)naphthalene-2-yl)methyl)amino)methyl)benzyl-4-methylbenzenesulfonate (101.2 mg, 0.15 mmol, 35.5% yield ) was obtained as a colorless oil.

N(3-((2,6-Difluorophenoxy)methyl)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 2,6-difluorophenol (11.0 mg, 84.8 µmol, 1 eq.) in DMF (1 ml) was added Cs ₂ CO ₃ (55.2 mg, 0.16 mmol, 2 eq.) at 25 °C. The mixture was stirred at 25°C for 0.5 hours. Then [3-[[[5-[4(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]methyl]phenyl]methyl-4-methylbenzenesulfonate (50.0 mg, 84.8 µmol, 1 eq.) was added to the reaction. The mixture was stirred at 25°C for 2 hours. H ₂ O (10 ml) was added to the mixture and extracted with EA (15 mlx3). The combined organic layers were washed with salt

- 200 046394 solution (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 70%-100%, 7.8 min) . The title compound (12.2 mg, 21.7 µmol, 25.6% yield) was obtained as a white solid. LCMS (ESI): RT=1.101 min, mass calc. for C ₃₂ H ₂₂ F ₅ NO ₂ 547.51 m/z obtained 548.1 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ 9.34 - 9.23 (m, 1H) , 8.61 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.98 (br d, J=8.8 Hz, 1H), 7.92 (br d, J=7.9 Hz, 2H), 7.83 (d, J=8.9 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.60 (d, J=7.0 Hz, 1H), 7.44 (s, 1H), 7.39 - 7.28 (m, 3H), 7.09 (br d, J=9.1 Hz, 3H), 5.14 (s, 2H), 4.55 (br d, J=5.6 Hz, 2H).

Example 167: ^)-M-(1-(1-methyl-1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 195) and ^)-N -(1-(1-methyl-1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 196)

1-Methyl-1H-imidazole-4-carbaldehyde.

To a solution of N-imidazole-4-carbaldehyde (5 g, 52.04 mmol, 1 eq.) in THF (30 mL) was added NaH (2.50 g, 62.44 mmol, 60%, 1.2 eq.) at -78°C, and then the suspension was brought to 25°C and stirred at 25°C for 30 minutes. The reaction mixture was cooled to -78°C and MeI (10.06 g, 70.88 mmol, 4.41 ml, 1.36 eq.) was added dropwise at -78°C. The mixture was gradually heated to 25°C and stirred at 25°C for 16 hours. The reaction mixture was quenched with MeOH (40 ml) and then the suspension was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=1:0-10:1) to obtain the title compound as a yellow solid. The 1methylimidazole-4-carbaldehyde compound (900 mg, 8.17 mmol, 15.71% yield) was obtained as a yellow solid.

2-Methyl-M-((1-methyl-1H-imidazol-4-yl)methylene)propan-2-sulfinamide.

To a solution of 1-methylimidazole-4-carbaldehyde (700 mg, 6.36 mmol, 1 eq.) and 2-methylpropane-2sulfinamide (924.5 mg, 7.63 mmol, 1.2 eq.) in THF (10 ml ) Ti(i-PrO) ₄ (3.61 g, 12.71 mmol, 3.75 ml, 2 eq.) was added at 0°C. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 16 hours. The reaction mixture was poured into water (20 ml) and then the suspension was filtered and washed with EA (50 ml). The filtrate was separated and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH=1:0 - 20:1) to obtain the title compound as a colorless oil. Compound (M2)-2-methyl-N-[(1-methylimidazol-4yl)methylene]propane-2-sulfinamide (1.2 g, 5.63 mmol, 88.5% yield) was obtained as a colorless oil.

2-Methyl-M-(1-(1-methyl-1H-imidazol-4-yl)ethyl)propane-2-sulfinamide.

To a solution of (M2)-2-methyl-N-[(1-methylimidazol-4-yl)methylene]propan-2-sulfinamide (100 mg, 0.46 mmol, 1 eq.) in DCM (2 ml) was added MeMgBr (3 M, 0.31 ml, 2 eq.) at -70°C. The reaction mixture was allowed to warm to 25°C and stirred at 25°C for 2 hours. The suspension was poured into MeOH (10 ml) and then the suspension was concentrated under reduced pressure. The mixture was diluted with EA (30 ml) and filtered, and then the filtrate was concentrated under reduced pressure to give the title compound as a light yellow oil. The compound 2-methyl-M-[1-(1-methylimidazol-4-yl)ethyl]propane2-sulfinamide (150 mg, crude) was obtained as a light yellow oil.

-(1-Methyl-1 H-imidazol-4-yl)ethanamine.

A solution of 2-methyl-M-[1-(1-methylimidazol-4-yl)ethyl]propan-2-sulfinamide (150 mg, 0.65 mmol, 1 eq.) in HCl/MeOH (2 ml) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to obtain the title compound as a yellow solid. The compound 1-(1-methylimidazol-4-yl)ethanamine (120 mg, crude, HCl) was obtained as a yellow solid.

N(1-(1-Methyl-1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), 1-(1-methylimidazol-4-yl)ethanamine (51.1 mg, 0.31 mmol, 1 equiv., HCl) and DIPEA (122.5 mg, 0.94 mmol, 0.16 ml, 3 equiv.) in DCM (3 ml) was added HATU (180.3 mg, 0.47 mmol, 1.5 eq.). The reaction mixture is

- 201 046394 were 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 extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05%HCl)-ACN]; B%: 28%-58%, 8.5 min to obtain the title compound in as a white solid. Compound No. [1-(1-methylimidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (45 mg, 96.8 µmol, 30.6% yield, HCl) was obtained as a white solid.

^)-H-(1-(1-Methyl-1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 195) and ^)-H-(1 -(1-methyl-1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 196).

The racemic compound N[1-(1-methylimidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (45 mg, 97.8 μmol, 1 equiv, HCl) was separated by SFC ( column: DAICEL CHIRALPAK AD 250 mmx30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O MEON]; V%: 55%-55%, min) to give compound 195 (10.1 mg, 23.4 µmol, 47.9% yield) as a light yellow solid. LCMS (ESI): RT=0.864 min, mass calc. for C ₂₄ H ₂₀ F ₃ N ₃ O 423.43 m/z obtained 424.1 [M+H]+, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J=8, 3 Hz, 1H), 8.61 (d, J=1.3 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.97 (dd, J=1.8, 8.9 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.9 Hz, 1H), 7.74 (d, J=8, 0 Hz, 2H), 7.70 (t, J=7.6 Hz, 1H), 7.59 (d, J=7.0 Hz, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 5.17 (quin., J=7.2 Hz, 1H), 3.61 (s, 3H), 1.49 (d, J=6.9 Hz, 3H). Compound 196 (6.7 mg, 15.5 µmol, 31.7% yield) as a light yellow solid. LCMS (ESI): RT=0.869 min, mass calc. for C ₂₄ H ₂₀ F ₃ N ₃ O 423.43 m/z obtained 424.0 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J=8.1 Hz , 1H), 8.61 (s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.97 (br d, J=8.9 Hz, 1H), 7.92 ( d, J=8.1 Hz, 2H), 7.80 (d, J=8.9 Hz, 1H), 7.74 (br d, J=8.0 Hz, 2H), 7.69 (t , J=7.7 Hz, 1H), 7.59 (d, J=7.0 Hz, 1H), 7.51 (s, 1H), 7.00 (s, 1H), 5.17 (quin ., J=7.1 Hz, 1H), 3.61 (s, 3H), 1.49 (d, J=6.9 Hz, 3H).

Example 168: N(1-hydroxy-3-(pyridin-2-yl)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 197)

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (84.3 mg, 0.26 mmol, 1.2 eq.), 2-amino-3-(2-pyridyl)propan-1-ol ( 50 mg, 0.22 mmol, 1 eq., 2 HCl), HATU (101.3 mg, 0.26 mmol, 1.2 eq.) and DIPEA (86.1 mg, 0.66 mmol, 0.11 ml, 3 eq.) in DCM (1 ml) was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (5 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 47%-77%, 8 min). The title compound (6.2 mg, 13.6 µmol, 6.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.825 min,: mass calc. for C ₂₆ H ₂₁ F ₃ N ₂ O ₂ 450.45 m/z, obtained 451.1 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) δ 8.49 (br d, J=4, 5 Hz, 1H), 8.30 (s, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.75 - 7, 68 (m, 3H), 7.61 (t, J=7.7 Hz, 1H), 7.56 - 7.49 (m, 3H), 7.42 (d, J=7.0 Hz, 1H ), 7.24 (d, J=7.9 Hz, 1H), 7.17-7.11 (m, 1H), 4.46 (br d, J=5.8 Hz, 1H), 3, 82 - 3.68 (m, 2H), 3.33 - 3.24 (m, 1H), 3.21 -3.13 (m, 1H).

Example 169: N[(E)-6-isoxazol-3-yloxyhex-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 198)

- 202 046394

tert-ButylA-[(E)-6-isoxazol-3-yl oxyhex-4-enyl]carbamate.

To a solution of compound 169-1 (0.1 g, 0.46 mmol, 1 eq.), compound 169-1a (39.5 mg, 0.46 mmol, 1 eq.) and PPh ₃ (146.2 mg, 0.55 mmol, 1.2 eq.) in THF (1 ml) was added DIAD (112.7 mg, 0.55 mmol, 0.1 ml, 1.2 eq.) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with H ₂ O (3 ml) and extracted with EA (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:3-1:0) to give compound 169-2 (20 mg, 49.5 µmol, 10.6% yield) and used immediately in the next step.

(E)-6-Isoxazol-3-yloxyhex-4-en-1-amine.

A solution of compound 169-2 (20 mg, 49.5 µmol, 1 eq.) in HCl/dioxane (0.5 ml, 4 M) was stirred at 20°C for 1 hour. The reaction was concentrated to give compound 169-3 ( 20 mg, crude, HCl), which was used immediately in the next step as a colorless oil.

N-[(E)-6-Isoxazol-3-yloxyhex-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 169-3a (28 mg, 88.5 µmol, 1 equiv.), compound 169-3 (19.3 mg, 88.5 µmol, 1 equiv., HCl) and HATU (50.4 mg, 0 .13 mmol, 1.5 eq.) DIEA (45.7 mg, 0.35 mmol, 61.6 μl, 4 eq.) was added to DCM (1 mL). The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with DCM (10 ml) and washed with H2O (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 56%-56%, 12 min) to give of the title compound (2.1 mg, 4.3 µmol, 4.9% yield) as a white solid. LCMS (ESI): RT=0.948 min, mass calc. for C ₂₇ H ₂₃ F ₃ N ₂ O ₃ 480.17, m/z obtained 481.1 [M+H]+, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7 .99 (d, J=8.1 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.83 - 7.75 (m, 4H), 7.67 - 7.58 (m , 3H), 7.51 (d, J=7.1 Hz, 1H), 6.43 - 6.34 (m, 1H), 5.86 - 5.75 (m, 2H), 5.63 - 5.48 (m, 1H), 4.47 (d, J=6.3 Hz, 2H), 3.53 (q, J=6.7 Hz, 2H), 2.21 (q, J=7 .2 Hz, 2H), 1.79 (quin., J=7.3 Hz, 2H).

Example 170: ^)-A(1-(1-acetylazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 199) and ^)-A(1-(1 -acetylazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 200)

N-(1-(1-Acetylazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of A[1-(azetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (200 mg, 0.50 mmol, 1 equiv.) and DIPEA (324.3 mg, 2.51 mmol, 0.43 ml, 5 eq.) in DCM (5 ml) was added dropwise acetyl chloride (59.1 mg, 0.75 mmol, 53.7 μl, 1.5 eq.) at 0 °C in N2 atmosphere. After addition, the mixture was stirred at 25°C for 2 hours. The residue was poured into H ₂ O (30 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (12 g SepaFlash® Silica Flash column, EA/MeOH: 0~10%). Compound N-[1-(1-acetylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (135 mg, 0.29 mmol, 58.0% yield) was obtained as yellow solid matter.

^)-A(1-(1-Acetylazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 199) and ^)-N1-(1-acetylazetidin-3- yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 200)

- 203 046394

Racemic N-[1-(1-acetylazetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (95 mg, 0.21 mmol, 1 eq.) was purified by SFC (column : DAICEL CHIRALPAK AS-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 35%-35%, min). The compound was purified by SFC (column: DAICEL CHIRALPAK AS-H (250 mmx30 mm, 5 µm); mobile phase: [0.1% NH ₃ H2O ETOH]; B%: 35%-35%, min). Compound 200 (23.4 mg, 52.6 µmol, 24.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.820 min, mass calc. for C ₂₅ H ₂₃ F ₃ N ₂ O ₂ 440.46 m/z obtained 441.1 [M+H]+, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 - 8.49 (m , 2H), 8.12 (d, J=8.0 Hz, 1H), 7.92 (d, J=8.3 Hz, 3H), 7.81 (d, J=8.8 Hz, 1H ), 7.77 - 7.66 (m, 3H), 7.59 (d, J=7.0 Hz, 1H), 4.39 - 4.26 (m, 1H), 4.21 4.08 (m, 1H), 3.97 - 3.78 (m, 2H), 3.71 - 3.55 (m, 1H), 2.78 - 2.68 (m, 1H), 1.72 (d , J=3.5 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H). Compound 199 (25.8 mg, 58.5 µmol, 27.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.802 min, mass calc. for C ₂₅ H ₂₃ F ₃ N ₂ O ₂ 440.46 m/z obtained 441.1 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ 8.59 - 8.48 (m, 2H), 8.12 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.5 Hz, 3H), 7.81 (d, J=8.8 Hz, 1H) , 7.76 - 7.66 (m, 3H), 7.58 (d, J=7.0 Hz, 1H), 4.38 - 4.25 (m, 1H), 4.20 - 4.08 (m, 1H), 3.96 - 3.78 (m, 2H), 3.70 - 3.56 (m, 1H), 2.78 -2.68 (m, 1H), 1.72 (d , J=3.5 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H).

Example 171: 3-(1-(5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)ethyl)-1,2,4-thiadiazole-5-carboxamide (compound 201)

5-(1-Chloroethyl)-1,3,4-oxathiazol-2-one.

2-Chloropropanamide (1.07 g, 10 mmol, 1 equiv.), chlorocarbonylsulfenyl chloride (4.2 ml, 50 mmol, 5 equiv.) and toluene (25 ml) were heated to 60°C for 5 days. The mixture was concentrated and purified by FCC, gradient 0 - 15% EtOAc in hexanes, to give 5-(1-chloroethyl)-1,3,4-oxathiazol-2-one (1.29 g, 8.1 mmol, 80% ). LCMS [M+H]+=166.

Ethyl 3-(1-chloroethyl)-1,2,4-thiadiazole-5-carboxylate.

5-(1-Chloroethyl)-1,3,4-oxathiazol-2-one (828 mg, 5 mmol, 1 equiv.), ethyl cyanoformate (2.4 ml, 25 mmol, 5 equiv.) and chlorobenzene (12 ml ) heated at 135°C for 4 days. The mixture was cooled, concentrated and purified by FCC gradient O - 15% EtOAc in hexane to give ethyl 3-(1chloroethyl)-1,2,4-thiadiazole-5-carboxylate, a yellow oil (380 mg, 35%). LCMS [M+H]+=221.

Ethyl 3-(1-azidoethyl)-1,2,4-thiadiazole-5-carboxylate.

Ethyl 3-(1-chloroethyl)-1,2,4-thiadiazole-5-carboxylate (220 mg, 1 mmol, 1 equiv.), NaN ₃ (130 mg, 2 mmol, 2 equiv.) and DMSO (1 ml) was stirred at 60°C until the acid was consumed, as determined by LCMS, 4 hours. The reaction mixture was diluted with EtOAc and washed with us. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and used in the next step without further purification. LCMS [M+H]+=228.

Ethyl 3-(1-aminoethyl)-1,2,4-thiadiazole-5-carboxylate.

Ethyl 3-(1-azidoethyl)-1,2,4-thiadiazole-5-carboxylate (113 mg, 0.5 mmol, 1 equiv.), PPh ₃ (197 mg, 0.75 mmol, 1.5 equiv. .) and THF (1 ml) were stirred at room temperature for 2 hours. H2O was added to the reaction mixture and the reaction mixture was stirred for an additional 1 hour. The mixture was extracted with EtOAc, dried with Na ₂ SO ₄ and passed through a silica gel plug with EtOAc to obtain the desired product, which was used without further purification. LCMS [M+H]+=202.

3-(1-(5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)ethyl)-1,2,4-thiadiazole-5-carboxylic acid.

- 204 046394

5-(4-(Trifluoromethyl)phenyl)-2-naphthoic acid (40 mg, 0.12 mmol, 1 equiv.), 1 drop DMF and DCM (3 ml) were cooled to 0°C. (COCl) ₂ (16 µl, 0.19 mmol, 1.5 equiv.) was added dropwise and stirred for 1 h. The mixture was concentrated and redissolved in 1 ml DCM and added to the mixture of ethyl-3-(1aminoethyl)-1, 2,4-thiadiazole-5-carboxylate (35 mg, 0.17 mmol, 1.4 equiv.), Et ₃ N (49 μl, 0.24 mmol, 2 equiv.) and THF (1 ml) at room temperature. t. The reaction was stirred for 18 hours until the acid chloride was consumed, as determined by LCMS. The mixture was diluted with EtOAc, carefully neutralized with 1 N HCl (aq) and separated. The organic layer was washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC, gradient 0 - 20% MeOH in DCM, to give 3-(1-(5-(4(trifluoromethyl)phenyl)-2-naphtamido)ethyl)-1,2,4-thiadiazole-5-carboxylic acid acid (30 mg, 50%). LCMS [M+H]+=472.

3-(1-(5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)ethyl)-1,2,4-thiadiazole-5-carboxamide.

3-(1-(5-(4-(Trifluoromethyl)phenyl)-2-naphtamido)ethyl)-1,2,4-thiadiazole-5-carboxylic acid (30 mg, 1 equiv.), NH4Cl (10 mg, 3 equiv.), HATU (50 mg, 2 equiv.) and DMF were stirred at RT. DIEA (66 µL, 6 equiv.) was carefully added and the mixture was stirred at RT until acid was consumed as determined by LCMS. , 3 hours. The mixture was purified immediately by pre-HPLC to obtain the desired product (3 mg, 10%). LCMS [M+N] ⁺ =471.

Example 172: N-[(E)-6-amino-6-oxo-hex-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 202) o o

To a solution of compound 227 (7 mg, 17.1 µmol, 1 eq.) in acetone (0.5 ml) was added Na ₂ CO ₃ (18.1 mg, 0.17 mmol, 10 eq.) and H ₂ O ₂ (826.0 mg, 7.29 mmol, 0.7 ml, 30% solution) at 0°C. The mixture was then stirred at 20°C for 48 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 45%-75%, 7.8 min ) to obtain the title compound (2.3 mg, 5.3 µmol, 18.4% yield). LCMS (ESI): RT=0.906 min, mass calc. for C ₂₄ H ₂ iF ₃ N ₂ O ₂ , 426.16 m/z, 427.0 [M+H] ⁺ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 8.00 (br d, J=8.5 Hz, 1H), 7.87 (br d, J=8.8 Hz, 1H), 7.78 (br d, J=8.0 Hz, 3H), 7.65 - 7.59 (m, 3H), 7.51 (br d, J=7.0 Hz, 1H), 7.00 - 6.85 (m, 1H), 6.36 (br s, 1H), 5.94 (br d, J=15.6 Hz, 1H), 5.65 - 5.08 (m, 2H), 3.57 (q, J=6.7 Hz, 2H), 2.36 (q, J=7.3 Hz, 2H), 1.94 - 1.81 (m, 2H).

Example 173: ^)-Na(1-(azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 203) and ^)-Na(1-(azetidine-3 -yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 204)

Benzyl-3-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate.

- 205 046394

To a mixture of 1-benzyloxycarbonyl azetidin-3-carboxylic acid (5 g, 21.26 mmol, 1 eq.), HATU (12.12 g, 31.88 mmol, 1.5 eq.) in DCM (50 ml) was added DIPEA (8.24 g, 63.77 mmol, 11.11 ml, 3 eq.) at 25°C. After addition, the mixture was stirred at 25°C for 1 hour and then Nmethoxymethanamine (3.11 g, 31.88 mmol, 1.5 eq., HCl) was added. The resulting mixture was stirred at 25°C for 2 hours. The residue was poured into H2O (100 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (50 mlx3). The combined organic phase was washed with brine (120 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (80 g SepaFlash® Silica Flash column, EA/PE: 0~40%). The benzyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate compound (5.2 g, 18.68 mmol, 87.9% yield) was obtained as a yellow oil.

Benzyl-3-acetylazetidine-1-carboxylate.

To a solution of benzyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (4.5 g, 16.17 mmol, 1 eq.) in THF (80 ml) was added dropwise MeMgBr (3 M, 8.08 ml, 1.5 eq.) at 0°C in an N2 atmosphere. After addition, the mixture was stirred at 25°C for 3 hours. The residue was poured into NH ₄ Cl (130 ml) at 0°C and stirred for 5 minutes. The aqueous phase was extracted with EA (60 mlx3). The combined organic phase was washed with brine (120 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (80 g SepaFlash® Silica Flash column, EA/PE: 0~40%). The compound benzyl-3-acetylazetidin-1-carboxylate (2.8 g, 12.00 mmol, 74.2% yield) was obtained as a colorless oil.

Benzyl 3-(1-((2,4-dimethoxybenzyl)amino)ethyl)azetidine-1-carboxylate.

To a solution of benzyl 3-acetylazetidin-1-carboxylate (2.3 g, 9.86 mmol, 1 equiv.) and (2,4dimethoxyphenyl)methanamine (1.98 g, 11.83 mmol, 1.78 ml, 1 .2 eq.) in MeOH (25 ml) was added HOAc (2.96 g, 49.30 mmol, 2.82 ml, 5 eq.) and stirred at 25°C for 1 h, and then NaBH(OAc) was added ) ₃ (3.13 g, 14.79 mmol, 1.5 eq.). The resulting mixture was stirred at 25°C for 15 hours. Ice water (30 ml) was then added and the mixture was neutralized to a pH of 9~10 aq. NaOH (2 M). The aqueous phase was extracted with EA (30 mlx3). The combined organic phase was washed with brine (60 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (40 g SepaFlash® Silica Flash column, EA/PE: 0~80%). The compound benzyl 3-[1-[(2,4-dimethoxyphenyl)methylamino]ethyl]azetidine-1-carboxylate (1.3 g, 3.21 mmol, 32.5% yield) was obtained as a yellow oil.

Benzyl-3 -(1-(N(2,4-dimethoxybenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphtamido)ethyl)azetidine-1carboxylate.

To a mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (1.09 g, 3.43 mmol, 1.2 eq.), HATU (1.63 g, 4.29 mmol, 1. 5 eq.) in DCM (20 ml) was added DIPEA (1.11 g, 8.58 mmol, 1.50 ml, 3 eq.) at 25°C. After addition, the mixture was stirred at 25°C for 1 hour and then benzyl 3-[1[(2,4-dimethoxyphenyl)methylamino]ethyl]azetidine-1-carboxylate (1.1 g, 2.86 mmol, 1 eq.) (in DCM (5 ml)). The resulting mixture was stirred at 25°C for 15 hours. The residue was poured into H ₂ O (80 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (40 mlx3). The combined organic phase was washed with brine (100 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (40 g SepaFlash® Silica Flash column, EA/PE: 0~30%). Compound benzyl-3-[1-[(2,4-dimethoxyphenyl)methyl-[5-[4(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]ethyl]azetidine-1-carboxylate (1.4 g, 1 .91 mmol, 66.6% yield) was obtained as a colorless oil.

N-(1 -(Azetidin-3 -yl)ethyl)-N-(2,4-dimethoxybenzyl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of benzyl 3-[1-[(2,4-dimethoxyphenyl)methyl-[5-[4-(trifluoromethyl)phenyl]naphthalene-2carbonyl]amino]ethyl]azetidine-1-carboxylate (1.2 g, 1 .76 mmol, 1 equiv.) in MeOH (30 ml) was added Pd/C (200 mg, 10%) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under 15 psi H ₂ at 25°C for 2 hours. The reaction mixture was filtered and the cake was washed with MeOH (10 ml x 2). The filtrate was concentrated in vacuo to give the product. The crude product was used in the next step without additional purification. Compound N[1-(azetidin-3-yl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (945 mg, crude) obtained as a colorless oil.

N-(1 -(Azetidin-3 -yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of N-[1 -(azetidin-3-yl)ethyl]-N-[(2,4-dimethoxyphenyl)methyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (140 mg, 0. 25 mmol, 1 eq.) to DCM (1 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 158.77 eq.). The mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and the cake was washed with MeOH (10 mlx2). The filtrate was concentrated in vacuo to obtain the product. The crude product was purified by pre-HPLC (column: Xtimate C18 150x25mmx5µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 25%-55%, 7.8 min). Compound N[1-(azetidin-3yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (88 mg, 0.22 mmol, 86.5% yield) was obtained as a white solid.

- 206 046394 (K_)-No(1-(Azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 203) and (S)-N-(1(azetidine -3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 204).

The racemic compound ^[1-(azetidin-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (85 mg, 0.21 mmol, 1 equiv) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 µm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; V%: 50%-50%, min). Compound 204 (19.3 mg, 48.4 µmol, 22.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.744 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O 398.42 m/z obtained 399.1 [M+H]+, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 - 8.62 (m, 2H), 8.15 (d, J=8.1 Hz, 1H), 8.02 - 7.88 (m, 3H), 7.82 (d, J=8.9 Hz, 1H), 7, 78 - 7.67 (m, 3H), 7.60 (d, J=6.9 Hz, 1H), 4.42 - 4.30 (m, 1H), 4.01 - 3.87 (m, 3H), 3.84 - 3.72 (m, 1H), 3.05 (sextet, J=8.2 Hz, 1H), 1.14 (d, J=6.6 Hz, 3H). Compound 203 (23.6 mg, 59.2 µmol, 27.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.744 min, mass calc. for C ₂₃ H ₂₁ F ₃ N ₂ O 398.42 m/z obtained 399.1 [M+H] ⁺ , ¹ H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.06 ( d, J=8.3 Hz, 1H), 7.88 - 7.80 (m, 5H), 7.72 - 7.63 (m, 4H), 7.56 (d, J=7.0 Hz , 1H), 4.50 - 4.37 (m, 1H), 3.72 - 3.52 (m, 4H), 2.97 (sextet, J=8.0 Hz, 1H), 1.20 ( d, J=6.6 Hz, 3H).

Example 174: ^)-Na(1-(2-chlorophenyl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 205) and (K_)-Na(1-(2-chlorophenyl) ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 206)

N(1-(2-Chlorophenyl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), 1-(2chlorophenyl)ethanamine (59.0 mg, 0.37 mmol, 1, 2 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (163.4 mg, 1.26 mmol, 0.22 mL, 4 eq.) in DCM (5 mL ) was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 5:1). Compound N[1-(2-chlorophenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (106 mg, 0.22 mmol, 72.3% yield) was obtained as a white solid.

^)-N(1-(2-Chlorophenyl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 205) and (R)-N-(1(2-chlorophenyl)ethyl)- 5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 206).

Racemic compound N[1-(2-chlorophenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (90 mg, 0.19 mmol, 1 eq.) was purified by SFC (column: DAICEL CHIRALPAK AS- H (250 mmx30 mm, 5 µm); mobile phase: [Neu-ETOH]; B%: 35%-35%, min). Compound 205 (40 mg, 87.2 µmol, 44.0% yield) was obtained as a white solid. LCMS (ESI): RT=1.089 min, mass calc. for C ₂ 6H19ClF ₃ NO 453.88 m/z, obtained 454.0 [M+H] ⁺ , ¹ H NMR (400 MHz, CD3Cl) δ 8.38 (s, 1H), 7.98 (d, J =8.3 Hz, 1H), 7.88 - 7.76 (m, 4H), 7.64 - 7.57 (m, 3H), 7.53 - 7.39 (m, 3H), 7, 28 (d, J=1.5 Hz, 1H), 7.25 7.21 (m, 1H), 7.32 - 7.21 (m, 1H), 6.80 (br d, J=7, 5 Hz, 1H), 5.65 (t, J=7.2 Hz, 1H), 1.68 (d, J=7.0 Hz, 3H). Compound 206 (30 mg, 65.4 µmol, 33.0% yield) was obtained as a white solid. LCMS (ESI): RT=1.082 min, mass calc. for C ₂₆ H ₁₉ ClF ₃ NO 453.88 m/z, obtained 454.0 [M+H] ⁺ , ¹ H NMR (400 MHz, CD3Cl) δ 8.39 (d, J=1.1 Hz, 1H ), 7.97 (d, J=8.3 Hz, 1H), 7.88 - 7.77 (m, 3H), 7.64 - 7.58 (m, 3H), 7.50 (dd, J=1.1, 7.1 Hz, 1H), 7.45 (dd, J=1.8, 7.5 Hz, 1H), 7.40 (dd, J=1.5, 7.6 Hz , 1h), 7.30 - 7.27 (m, 1h), 7.25 (dd, J=1.9, 3.3 Hz, 1H), 7.24 - 7.20 (m, 1H), 6.84 (br d, J=7.5 Hz, 1H), 5.65 (quin., J=7.1 Hz, 1H), 1.67 (d, J=6.9 Hz, 3H).

Example 175: N-[(E)-6-(2,6-difluorophenoxy)hex-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthaline-2carboxamide (compound 207)

- 207 046394

1ret-Butyl-K-(4-oxobutyl)carbamate.

To a solution of compound 175-1 (2 g, 10.8 mmol, 1.83 mL, 1 eq.) in THF (30 mL) was added DIBAL-H (1 M, 11.43 mL, 1.06 eq.) at -78°C. The reaction mixture was stirred at -78°C for 2 hours. The reaction was quenched. potassium sodium tartrate (30 ml), filtered and extracted with EA (3x50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 175-2 (2 g, crude) as a colorless oil, which was used immediately in the next step.

Methyl(E)-6-(tert-butoxycarbonylamino)hex-2-enoate.

NaH (640.8 mg, 16.0 mmol, 60%, 1.5 equiv.) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. Compound 175-2 (2 g, 10.6 mmol, 1 eq.) in THF (10 ml) was added to the solution at 0°C and the reaction mixture was stirred at 25°C for 16 hours. The reaction was extinguished by us. NH ₄ Cl (10 ml) and extracted with DCM (3x30 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:5) to give compound 175-3 (1.2 g, 4.93 mmol, 46.2% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.95 (td, J=6.8, 15.7 Hz, 1H), 5.90 5.78 (m, 1H), 4.55 (br s, 1H), 3.15 (br d, J=5.5 Hz, 2H), 2.29 -2.20 (m, 2H), 1.82 (quin., J=7.1 Hz, 1H), 1.71 1.64 (m, 2H), 1.44 (s, 9H).

Cret-Butyl-N-[(E)-6-hydrokCyrekC-4-enyl]kαrbamate.

To a solution of compound 175-3 (0.2 g, 0.82 mmol, 1 eq.) in DCM (4 ml) was added DIBAL-H (1 M, 1.73 ml, 2.1 eq.) at -78° WITH. The reaction mixture was stirred at -78°C for 2 hours. The reaction was quenched. sodium potassium tartrate (20 ml) and filtered. The filtrate was extracted with DCM (2x30 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 175-4 (150 mg, 0.69 mmol, 84.8% yield) as a colorless oil, which was used immediately in the next step. 1H NMR (400 MHz, CDClj) δ 5.68 - 5.54 (m, 2H), 4.61 - 4.38 (m, 1H), 4.10 - 3.96 (m, 2H), 3, 71 -3.47 (m, 1H), 3.07 (br s, 2H), 2.10 - 1.98 (m, 2H), 1.53 (br s, 2H), 1.37 (s, 9H).

Cret-Butyl-N-[(E)-6-(2,6-difluorophenokCi)hekC-4-enyl]carbamate.

To a solution of compound 175-4 (50 mg, 0.23 mmol, 1 eq.), compound 175-4a (30.2 mg, 0.23 mmol, 1 eq.) and PPh ₃ (79.1 mg, 0. 3 mmol, 1.3 eq.) in THF (0.5 mL) was added DIAD (61.0 mg, 0.3 mmol, 58 μl, 1.3 eq.) at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with EA (10 ml) and washed with H2O (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:10-1:3) to give compound 175-5 (25 mg, 52.7 µmol, 22.7% yield) as a colorless oil.

(E)-6-(2,6-DifluorophenokCu)hekC-4-en-1-amine.

To a solution of compound 175-5 (25 mg, 52.6 µmol, 1 equiv) in MeOH (0.5 ml) was added HCl/MeOH (4 M, 26 µl, 2 equiv). The reaction mixture was stirred at 25°C for 1 hour. The reaction was concentrated to give compound 175-6 (21 mg, 49.3 μmol, 93.7% yield, HCl) as a colorless oil, which was used immediately in the next step.

N-[(E)-6-(2,6-DifluorophenokCu)hekC-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 175-6a (15.6 mg, 49.3 µmol, 1 eq.), HATU (28.1 mg, 74.0 µmol, 1.5 eq.) and DIEA (25.5 mg, 0. 19 mmol, 34 μl, 4 eq.) in DCM (1 ml) was added compound 175-6 (21 mg, 49.3 μmol, 1 eq., HCl). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with DCM (20 ml) and washed with H2O (2x10 ml). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 73%-93%, 9.5 min ) to obtain the title compound (8.0 mg, 15.1 µmol, 30.6% yield) as a white solid. LCMS (ESI): RT=1.097 min, mass calc. for C ₃₀ H ₂₄ F ₅ NO ₂ 525.17, m/z obtained 526.1 [M+H]+, 1H NMR (400 MHz, CDClj) δ 8.37 (s, 1H), 7.99 (d , J=8.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.82 - 7.74 (m, 3H), 7.64 - 7.57 (m, 3H), 7.51 (d, J=7.0 Hz, 1H), 6.99 -6.82 (m, 3H), 6.28 (brs, 1H), 5.87 - 5.75 (m , 2H), 4.61 (d, J=5.3 Hz, 2H), 3.56 3.46 (m, 2H), 2.27 - 2.14 (m, 2H), 1.84 - 1 .74 (m, 2H).

Example 176: N(3-(2-methoxyethoxy)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 208) n O O

EDCI (2.0 eq.) H ₂ N

HOBt.NH ₄ (1.2 eq.)

DCM, k. t„ 3 h O.

F

- 208 046394

Methyl 3-(2-methoxyethoxy)benzoate.

A mixture of methyl 3-hydroxybenzoate (1 g, 6.57 mmol, 1 eq.), 1-bromo-2-methoxyethane (1.83 g, 13.15 mmol, 1.23 ml, 2 eq.) and K ₂ CO ₃ (1.82 g, 13.15 mmol, 2 eq.) in acetone (10 ml) was stirred at 60°C for 16 hours. The reaction mixture was diluted with H2O (70 ml) and extracted with DCM (20 ml x 3). The combined organic layers were washed with brine (40 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 10:1). The compound methyl 3-(2-methoxyethoxy)benzoate (1.2 g, 5.71 mmol, 86.8% yield) was obtained as a colorless oil.

3-(2-Methoxyethoxy)benzoic acid.

To a solution of NaOH (1.14 g, 28.54 mmol, 5 eq.) in H2O (5 mL) was added methyl 3-(2methoxyethoxy)benzoate (1.2 g, 5.71 mmol, 1 eq.). The mixture in THF (10 ml) was stirred at 50°C for 5 hours. The reaction was cooled to 25°C and the pH was adjusted to 1 with 4 M HCl. The reaction mixture was diluted with H2O (70 ml) and extracted with DCM (20 mlx3) . The combined organic layers were washed with brine (40 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 -1:1). The compound 3-(2-methoxyethoxy)benzoic acid (850 mg, 4.33 mmol, 75.9% yield) was obtained as a white solid.

3-(2-Methoxyethoxy)benzamide.

A mixture of 3-(2-methoxyethoxy)benzoic acid (480 mg, 2.45 mmol, 1 eq.) EDCI (937.9 mg, 4.89 mmol, 0.73 mL, 2 eq.) in DCM (5 mL) stirred at 20°C for 1 hour. Ammonium 1-oxidobenzotriazole (446.6 mg, 2.94 mmol, 1.2 eq.) was then added to the mixture and the mixture was stirred at 20°C for another 2 hours. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , ethyl acetate:methanol=1/0 - 5:1). The compound 3-(2-methoxyethoxy)benzamide (234 mg, 1.20 mmol, 49.0% yield) was obtained as a white solid.

(3-(2-Methoxyethoxy)phenyl)methanamine.

A mixture of 3-(2-methoxyethoxy)benzamide (134 mg, 0.68 mmol, 1 eq.) and BH ₃ -Me ₂ S (10 M, 0.20 ml, 3 eq.) in THF (2 ml) was stirred at 70°C for 12 hours. The reaction mixture was quenched by adding 4 M HCl 40 ml at 0°C. The reaction was cooled to 25°C and the pH was adjusted to 11 with 4 M NaOH. The reaction mixture was then diluted (10 ml) and extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. [3-(2-methoxyethoxy)phenyl]methanamine (123 mg, crude) was obtained as a colorless oil.

N(3-(2-Methoxyethoxy)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (52.3 mg, 0.16 mmol, 1 eq.), HATU (94.4 mg, 0.24 mmol, 1.5 eq. ) and DIPEA (64.1 mg, 0.49 mmol, 86.5 µl, 3 eq.) in DCM (2 ml) were stirred at 25°C for 1 hour. Then [3-(2-methoxyethoxy)phenyl] methanamine (30 mg, 0.16 mmol, 1.0 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C ₁₈ 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 55%-85%, 8.5 min). The title compound (16.1 mg, 33.4 µmol, 20.2% yield) was obtained as a white solid. LCMS (ESI): RT=1.033 min, mass calc. for C ₂₈ H ₂₄ F ₃ NO ₃ 479.49 m/z, 480.1 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.80 - 7.76 (m, 1H), 7.75 -7.71 (m, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.55 - 7.49 (m, 3H), 7.42 (d, J=6.9 Hz, 1H), 7.24 - 7.16 (m, 1H), 6.89 (br s, 2H), 6.81 - 6.76 (m, 1H), 6.57 (br s, 1H) , 4.59 (d, J=5.4 Hz, 2H), 4.08 - 3.97 (m, 2H), 3.70 - 3.62 (m, 2H), 3.36 (s, 3H ).

Example 177: (E)-5-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]pent-2-enoic acid (compound 209)

NaOH (28.0 mg, 0.7 mmol, 3 eq.). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated. The pH of the residue was adjusted to 3-4 using 2 N aq. HCl and

- 209 046394 extracted with EA (2x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by pre-TLC (EA, UV) to give the title compound (20 mg, 47.9 µmol, 20.4% yield) as a yellow solid. LCMS (ESI): RT=0.919 min, mass calc. for C ₂₃ H ₁₈ F ₃ NO ₃ , 413.12 m/z, 414.1 [M+H]+ was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.18 (br s, 1H), 8.79 (br t, J=5.6 Hz, 1H), 8.54 (s, 1H), 8 ,12 (d, J=8.3 Hz, 1H), 7.92 (br d, J=8.3 Hz, 3H), 7.81 (d, J=8.8 Hz, 1H), 7, 74 (d, J=8.0 Hz, 2H), 7.69 (t, J=7.7 Hz, 1H), 7.59 (d, J=6.5 Hz, 1H), 6.92 - 6.77 (m, 1H), 5.85 (d, J=15.6 Hz, 1H), 3.46 (q, J=6.1 Hz, 2H), 2.54 - 2.52 (m , 2H).

Example 178: N((2-methoxypyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 210)

4-(Bromomethyl)-2-fluoropyridine.

A mixture of 2-fluoro-4-methylpyridine (2 g, 18.00 mmol, 1 eq.), NBS (3.52 g, 19.80 mmol, 1.1 eq.) and AIBN (295.5 mg, 1 eq. 80 mmol, 0.1 eq.) in CCl ₄ (20 ml) was stirred at 80°C for 48 hours. The reaction mixture was diluted with H=O (60 ml) and extracted with DCM (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 10:1). The compound 4-(bromomethyl)-2-fluoropyridine (1.9 g, 10.00 mmol, 55.5% yield) was obtained as a yellow oil and used in the next step without further purification.

(2-Fluoropyridin-4-yl)methanamine.

A mixture of 4-(bromomethyl)-2-fluoropyridine (862 mg, 4.54 mmol, 1 eq.) and NH3-H2O (11.36 g, 90.73 mmol, 12.48 ml, 28% solution, 20 eq. ) was stirred at 0°C for 5 hours. The compound (2-fluoro-4pyridyl)methanamine (527 mg, 4.18 mmol, 92.1% yield) was obtained as a yellow oil and used in the next step without further purification.

tert-Butyl((2-fluoropyridin-4-yl)methyl)carbamate.

A mixture of (2-fluoro-4-pyridyl)methanamine (527 mg, 4.18 mmol, 1 eq.), TEA (1.27 g, 12.53 mmol, 1.74 ml, 3 eq.) and Boc ₂ O (1.82 g, 8.36 mmol, 1.92 mL, 2 eq.) in DCM (5 mL) was stirred at 0°C for 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EA (10 mL x 3 ). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/0 - 10:1). The tert-butyl-M-[(2-fluoro-4-pyridyl)methyl]carbamate compound (20 mg, 88.4 µmol, 2.1% yield) was obtained as a yellow oil.

(2-Methoxypyridin-4-yl)methanamine.

A mixture of tert-butyl-M-[(2-fluoro-4-pyridyl)methyl]carbamate (20 mg, 88.4 µmol, 1 eq.) in MeOH/HCl (4 M, 0.44 ml, 20 eq.) stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The compound (2-methoxy-4-pyridyl)methanamine (12 mg, 68.7 µmol, 77.7% yield, HCl) was obtained as a yellow oil.

N((2-Methoxypyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (10.8 mg, 34.3 µmol, 1 eq.), HATU (19.6 mg, 51.5 µmol, 1.5 eq. ) and DIPEA (13.3 mg, 0.10 mmol, 17.9 µl, 3 eq.) in DCM (1 ml) were stirred at 25°C for 1 hour. Then (2-methoxy-4- pyridyl)methanamine (6 mg, 34.3 µmol, 1 eq., HCl) and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 45%-75%, 11.5 min). The title compound (5.2 mg, 10.8 µmol, 31.6% yield, HCl) was obtained as a white solid. LCMS (ESI): RT=0.953 min, mass calc. for C ₂₅ H ₁₉ F ₃ N ₂ O ₂ 436.43 m/z obtained 437.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 8.19 - 8.06 (m, 2H), 7.97 - 7.88 (m, 2H), 7.86 (br d, J=8.0 Hz, 2H), 7.74 - 7.66 (m, 3H ), 7.60 (d, J=7.0 Hz, 1H), 7.16 (d, J=5.6 Hz, 1H), 7.06 (s, 1H), 4.71 (s, 2H ), 4.01 (s, 3H).

Example 179: N((2-fluoropyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 211)

- 210 046394

2-((2-Fluoropyridin-4-yl)methyl)isoindoline-1,3-dione.

DIAD (318.1 mg, 1.57 mmol, 0.30 mL, 2 eq.) was added dropwise to a solution of isoindoline-1,3-dione (138.8 mg, 0.94 mmol, 1.2 eq.) , (2-fluoro-4-pyridyl)methanol (100 mg, 0.78 mmol, 1 eq.) and PPh ₃ (412.6 mg, 1.57 mmol, 2 eq.) in THF (2 ml) at 0 °C in N ₂ atmosphere. The resulting solution was stirred for 12 hours at 20°C. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 10:1). The compound 2-[(2-fluoro-4-pyridyl)methyl]isoindoline-1,3-dione (200 mg, 0.75 mmol, 96.2% yield) was obtained as a white solid.

(2-Fluoropyridin-4-yl)methanamine.

A mixture of 2-[(2-fluoro-4-pyridyl)methyl]isoindoline-1,3-dione (140 mg, 0.54 mmol, 1 eq.) and hydrazine hydrate (54.7 mg, 1.09 mmol, 53 .1 µl, 2 eq.) in THF (2 ml) was stirred at 20°C for 1 hour. The reaction mixture was diluted with H2O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The compound (2-fluoro-4-pyridyl)methanamine (68 mg, 0.53 mmol, 98.6% yield) was obtained as a white solid.

N((2-Fluoropyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (142.0 mg, 0.44 mmol, 1 eq.), HATU (256.2 mg, 0.67 mmol, 1.5 eq. ) and DIPEA (116.1 mg, 0.89 mmol, 0.15 ml, 2 eq.) in DCM (3 ml) were stirred at 20°C for 1 hour. Then (2-fluoro-4-pyridyl)methanamine (68 mg, 0.53 mmol, 1.2 eq.) was added to the mixture and the mixture was stirred at 20°C for an additional 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 45%-75%, 11.5 min). The title compound (3.5 mg, 7.5 µmol, 1.6% yield, HCl) was obtained as a white solid. LCMS (ESI): RT=0.988 min, mass calc. for C ₂₄ H ₁₆ F ₄ N ₂ O 424.39 m/z obtained 425.1 [M+H]+, 1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.13 ( d, J=5.0 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.85 7.81 (m, 1H), 7.78 - 7.74 (m, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.59 - 7.52 (m, 3H), 7.49 - 7.45 (m, 1H), 7.13 (br d, J=5.0 Hz, 1H), 6.87 (s, 1H), 6.71 (br s, 1H), 4.70 (d, J=6.0 Hz, 2H).

Example 180: N(1-methoxy-2-methylpropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 212)

180-1 180-2

Ν-(1-Γ hydroxy-2-methylpropan-2-yl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 180-1 (45 mg, 0.14 mmol, 1 eq.) and HATU (81.2 mg, 0.21 mmol, 1.5 eq.) in DMF (1 ml) at 30°C was added 180-1a (15.2 mg, 0.17 mmol, 16 μl, 1.2 eq.) and TEA (43.2 mg, 0.43 mmol, 59 μl, 3 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by flash silica gel chromatography (ISCO®; 12 g

- 211 046394

SepaFlash® Silica Flash column, gradient 0~40% ethyl acetate/petroleum ether eluent approximately 20 mL/min) to give compound 180-2 (260 mg, 1.79 mmol, 46.9% yield) as a white solid. LCMS (ESI): RT=0.977 min, mass, calc. for C22H20F3NO2 387.14, m/z obtained 388.0 [M+H]+;

N(1-Methoxy-2-methylpropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 180-2 (18 mg, 46 µmol, 1 eq.) and iodomethane (329.8 mg, 2.32 mmol, 0.14 ml, 50 eq.) in THF (1 ml) was added at 0°C NaH (14.9 mg, 0.37 mmol, 60%, 8 eq.). The mixture was stirred at 20°C for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The reaction mixture was combined with ES10388-115-P1. The reaction mixture was diluted with water (10 ml) and extracted with EA (10 mlx3). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC: (column: Xtimate C18 150x25 mmx5 µm; mobile phase : [water (0.05% HCl)-ACN]; B%: 55%-85%, 8.5 min) to give the title compound (10 mg, 24 µmol, 52.5% yield) as a white solid. . LCMS (ESI): RT=1.012 min, mass, calc. for C23H22F3NO2 401.16, m/z obtained 402.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J=1.6 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.79 - 7.75 (m, 3H), 7.62 - 7.58 (m, 3H), 7.49 (dd, J=1.2, 7.1 Hz, 1H ), 6.51 (s, 1H), 3.50 (s, 2H), 3.45 (s, 3H), 1.53 (s, 6H).

Example 181: ^)-N-(1-(4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 213) and ^)-N-(1- (4-aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 214)

N(1-(4-Aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of Na[1-(4-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (200 mg, 0.40 mmol, 1 equiv.) in dioxane (2 ml) NH^-^O (2.73 g, 23.37 mmol, 3 ml, 30% solution, 58.34 eq.) and CU2O (57.3 mg, 0.40 mmol, 40.9 μl, 1 eq.). The mixture was stirred at 120°C for 16 hours in a stoppered tube. The mixture was added with H ₂ O (10 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (30 ml), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 50%-80%, 7.8 min). Na[1-(4-amino-2-pyridyl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (82 mg, 0.18 mmol, 47.0% yield) was obtained as a white solid substances

^)-N-(1-(4-Aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 213) and ^)-N-(1-(4- aminopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 214).

Racemic compound N[1-(4-amino-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (82 mg, 0.18 mmol, 1 eq.) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 µm); mobile phase: [0.1% NH3H2O ETOH]; V%: 40%-40%, min). Compound 214 (32.4 mg, 74.4 µmol, 39.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.791 min, mass calc. for C25H20F3N3O 435.44 m/z obtained 436.0 [M+H]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (br d, J=7.4 Hz, 1H), 8, 66 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.02 - 7.88 (m, 4H), 7.82 (d, J=8.9 Hz, 1H ), 7.77 - 7.67 (m, 3H), 7.59 (d, J=7.1 Hz, 1H), 6.52 (s, 1H), 6.34 (br d, J=5 .5 Hz, 1H), 6.00 (br s, 2H), 5.10 - 4.98 (m, 1H), 1.49 (br d, J=6.8 Hz, 3H). Compound 213 (30.7 mg, 70.5 µmol, 37.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.793 min, mass calc. for C ₂₅ H ₂₀ F ₃ N ₃ O 435.44 m/z obtained 436.1 [M+H]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (br d, J=7, 9 Hz, 1H), 8.67 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.04 7.89 (m, 4H), 7.82 (d, J =9.0 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.60 (d, J=7.3 Hz, 1H), 6.53 (s, 1H), 6.35 (br d, J=5.3 Hz, 1H), 5.98 (s, 2H), 5.11 - 5.00 (m, 1H), 1.49 (br d, J=6.9 Hz, 3H).

Example 182: N(3-cyanobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 215)

- 212 046394

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.) and HATU (72.1 mg, 0.18 mmol, 1.2 eq.) DIPEA (81.7 mg, 0.63 mmol, 0.11 mL, 4 eq.) was added to DCM (2 mL). After addition, the mixture was stirred at 25°C for 0.5 h and then 3(aminomethyl)benzonitrile (31.3 mg, 0.23 mmol, 1.5 eq.) was added. The resulting mixture was stirred at 25°C for 1.5 hours. H2O (20 ml) was added to the reaction mixture and extracted with EA (15 mlx3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 60%-90%, 7.8 min) . The title compound (41.7 mg, 96.8 µmol, 61.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.911 min, mass calc. for C ₂₆ Hi ₇ F ₃ N ₂ O 430.42 m/z obtained 431.4 [M+H]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (t, J=5.9 Hz, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.98 (dd, J=1.8, 8 .8 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.86 - 7.78 (m, 2H), 7.77 - 7.68 (m, 5H), 7 .63 - 7.54 (m, 2H), 4.59 (d, J=6.0 Hz, 2H).

Example 183: N[(2)-4-cyanobut-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 216)

To a mixture of LHMDS (1 M, 1.0 mL, 1.5 eq.) in THF (3 mL) was added compound 183-1a (143.1 mg, 0.81 mmol, 0.13 mL, 1.2 eq. ) at 0°C and stirred for 30 min. Then compound 183-1 (250 mg, 0.67 mmol, 1 eq.) in THF (3 ml) was added to the mixture and stirred for 2 hours at 25°C. The reaction mixture was quenched with saturated aq. NH ₄ Cl (4 ml), extracted with EA (5 mlx3). The combined organic phase was washed with H2O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography. The product was then purified by SFC (column: Phenomenex-Amylose-1 (250 mmx30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; B%: 35%-35%, min). Compound 217 was obtained (68.81 mg, 0.17 mmol, 25.9% yield). Compound 216 was obtained (27.0 mg, 67 µmol, 10.0% yield). Compound 216 LCMS (ESI): RT=0.858 min, mass calc. for C ₂₃ H ₁₇ F ₃ N ₂ O, 394.13 m/z, 394.9 [M+H]+ was obtained. 1H NMR (400

MHz, CDCl ₃ ) δ 8.39 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.94 - 7.86 (m, 1H) , 7.78 (d, J=8.5 Hz, 3H), 7.68 - 7.59 (m, 3H), 7.52 (dd, J=1.3, 7.0 Hz, 1H), 6.65 (td, J=7.7, 11.0 Hz, 1H), 6.43 (br t, J=5.5 Hz, 1H), 5.46 (d, J=10.8 Hz, 1H), 3.75 (q, J=6.4 Hz, 2H), 2.90 - 2.75 (m, 2H).

Example 184: N-[(E)-4-cyanobut-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 217)

Ooo

- 213 046394 No. (3-Hydroxypropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 184-1 (400 mg, 1.26 mmol, 1 eq.) in DMF (6 mL) was added HATU (721.3 mg, 1.90 mmol, 1.5 eq.), compound 184-1a ( 142.5 mg, 1.90 mmol, 0.15 ml, 1.5 eq.) and TEA (255.9 mg, 2.53 mmol, 0.35 ml, 2 eq.). The mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with H2O (20 ml) and extracted with EA (20 mlx3). The combined organic phase was washed with H2O (10 ml) and brine (10 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used immediately in the next step. Compound 184-2 (430 mg, 0.97 mmol, 76.5% yield) was confirmed to be obtained as a white solid by LCMS.

N(3-Oxopropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 184-2 (380 mg, 1.02 mmol, 1 eq.) in DCM (5 ml) was added DMSO (2.5 ml), DIEA (526.1 mg, 4.07 mmol, 0.71 ml , 4 eq.) and SOa-Py (647.9 mg, 4.07 mmol, 4 eq.). The mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was diluted with H ₂ O (20 ml), extracted with EA (15 mlx3). The combined organic phase was washed with H ₂ O (5 ml) and brine (10 ml x 3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. It was confirmed by NMR that compound 184-3 (300 mg, 0.81 mmol, 79.3% yield) was obtained as a white solid. 1H NMR (400 MHz, CDCI3) δ 9.90 (s, 1H), 8.34 (d, J=1.5 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.82 - 7.74 (m, 3H), 7.65 7.58 (m, 3H), 7.51 (dd, J=1.1, 7.2 Hz, 1H), 6.85 (br s, 1H), 3.83 (q, J=6.0 Hz, 2H), 2.98 - 2.88 (m, 2H).

N[(E)-4-Cyanobut-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a mixture of LHMDS (1 M, 1.0 mL, 1.5 eq.) in THF (3 mL) was added compound 184-3a (143.1 mg, 0.81 mmol, 0.13 mL, 1.2 eq. ) at 0°C and stirred for 30 min. Then compound 184-3 (250 mg, 0.67 mmol, 1 eq.) in THF (3 ml) was added to the mixture and stirred for 2 hours at 25°C. The reaction mixture was quenched with saturated aq. NH ₄ Cl (4 ml), extracted with EA (5 mlx3). The combined organic phase was washed with H ₂ O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography. The product was then purified by SFC (column: Phenomenex-Amylose-1 (250 mmx30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; B%: 35%-35%, min). Compound 217 was obtained (68.81 mg, 0.17 mmol, 25.9% yield). Compound 216 was obtained (27.0 mg, 67 µmol, 10.0% yield). Compound 217 LCMS (ESI): RT=0.858 min, mass calc. for C23H17F3N2O, 394.13 m/z, 394.9 [M+H]+ was obtained. 1H NMR (400 MHz, CDCI3) δ 8.36 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.88 (d, J=9 ,0 Hz, 1H), 7.83 - 7.73 (m, 3H), 7.69 - 7.58 (m, 3H), 7.52 (dd, J=1.0, 7.0 Hz, 1H), 6.77 (td, J=7.2, 16.3 Hz, 1H), 6.46 (br t, J=5.5 Hz, 1H), 5.47 (td, J=1, 3, 16.4 Hz, 1H), 3.67 (q, J=6.5 Hz, 2H), 2.65 (dq, J=1.4, 6.8 Hz, 2H).

Example 185: (R)-N-[1-(2-Amino-3-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 218) and R)-N-(1- (2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 219) o

1-(2-Amino-3-pyridyl)ethanone oxime.

To a solution of compound 185-1 (0.3 g, 2.2 mmol, 1 eq.) in Py (6 ml) was added NH^OH-HCl (229.6 mg, 3.3 mmol, 1.5 eq.) . The reaction was heated at 80°C for 2 hours. The reaction was concentrated. The residue was purified by silica gel column chromatography (EA:PE=1:1) to give compound 1852 (150 mg, 0.99 mmol, 45% yield) as a white solid. 1H NMR (400 MHz, CDCI3) δ 13.23 (br s, 1H), 8.00 (dd, J=1.5, 5.0 Hz, 1H), 7.72 (dd, J=1.8 , 7.8 Hz, 1H), 6.80 (br s, 2H), 6.72 (dd, J=5.1, 7.7 Hz, 1H), 2.38 (s, 3H).

3-(1-Aminoethyl)pyridin-2-amine.

To a mixture of compound 185-2 (0.15 g, 0.99 mmol, 1 eq.) and Zn (259.5 mg, 3.97 mmol, 4 eq.) HCl (3 mL) was slowly added with vigorous stirring. The mixture was heated at 90°C for 16 hours.

- 214 046394 pH of the reaction mixture was adjusted to 9-10 using 2 N aq. NaOH and extracted with EA (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give compound 185-3 (100 mg, crude), which was used immediately in the next step as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.76 (d, J=4.6 Hz, 1H), 7.58 (br s, 2H), 7.33 (br d, J=7.3 Hz, 1H), 6.53 - 6.44 (m, 1H), 6.01 (s, 2H), 4.00 - 3.90 (m, 1H), 1.22 (d, J=6, 4 Hz, 3H).

N[1-(2-Amino-3-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 185-3a (0.15 g, 0.47 mmol, 1 eq.), HATU (216.4 mg, 0.56 mmol, 1.2 eq.) and compound 185-3 (78 mg, 0 .56 mmol, 1.2 eq.) to DMF (4 mL) was added TEA (143.9 mg, 1.42 mmol, 0.19 mL, 3 eq.). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with EA (30 ml) and washed with brine (2x 10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 51%-81%, 9.2 min ) to give compound 185-4 (50 mg, 0.11 mmol, 23% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=1.5 Hz, 1H), 8.04 (dd, J=1.5, 5.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.88 - 7.84 (m, 1H), 7.80 - 7.73 (m, 3H), 7.64 - 7.57 (m, 3H ), 7.56 - 7.50 (m, 2H), 6.68 (dd, J=5.0, 7.5 Hz, 1H), 6.35 (br d, J=9.0 Hz, 1H ), 5.55 - 5.44 (m, 1H), 5.29 (s, 2H), 1.72 (d, J=6.8 Hz, 3H).

(K.)-N-[1-(2-Amino-3-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 218) and N)-N-(1- (2-aminopyridin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 219).

Compound 185-4 (40 mg, 91 µmol, 1 eq.) was separated by SFC (column: YMC CHIRAL Amylose-C (250 mm x 30 mm, 10 µm; mobile phase: [0.1% NH3H2O ETOH]; V%: 40 %-40%, min) to obtain compound 219 (5.5 mg, 12 µmol, 13.7% yield) as a white solid and compound 218 (7.3 mg, 16 µmol, 18.1% yield) in as a white solid. Compound 218 LCMS (ESI): RT=0.869 min, mass calculated for C ₂₅ H ₂₀ F ₃ N ₃ O 435.16 m/z obtained 436.1 [M+H]+, 1H NMR ( 400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.02 - 7.92 (m, 2H), 7.90 - 7.84 (m, 1H), 7.78 (br d, J =8.3 Hz, 3H), 7.67 -7.56 (m, 4H), 7.52 (br d, J=7.0 Hz, 1H), 6.68 (br t, J=6, 0 Hz, 1H), 6.53 (br s, 1H), 5.69 (br s, 2H), 5.54 - 5.43 (m, 1H), 1.73 (br d, J=6, 6 Hz, 3H) Compound 219 LCMS (ESI): RT=0.870 min, mass calculated for C ₂₅ H ₂₀ F ₃ N ₃ O 435.16 m/z obtained 436.0 [M+H]+, 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.02 - 7.92 (m, 2H), 7.90 - 7.84 (m, 1H), 7.78 (br d, J =8.3 Hz, 3H), 7.67 -7.56 (m, 4H), 7.52 (br d, J=7.0 Hz, 1H), 6.68 (br t, J=6, 0 Hz, 1H), 6.53 (br s, 1H), 5.69 (br s, 2H), 5.54 - 5.43 (m, 1H), 1.73 (br d, J=6, 6 Hz, 3H).

Example 186: N((1,2,4-thiadiazol-5-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 220)

^Wed 3 10% (1,2,4-T iadiazol-5 -yl)methanol.

Ethyl 1,2,4-thiadiazole-5-carboxylate (prepared based on the procedure in WO2015130957) (183 mg, 1.2 mmol, 1 equiv.) was dissolved in MeOH (13 ml). NaBH ₄ (81 mg, 2 mmol, 1.7 equiv.) was added carefully and stirred at RT for 1 hour. Once complete, the reaction mixture was quenched with 3 ml H ₂ O at 0°C. The mixture was concentrated and redissolved in a mixture of EtOAc and H2O. The aqueous layer was washed with EtOAc, the combined organic layers were dried with Na ₂ SO ₄ and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=117.

(1,2,4-T iadiazol-5-yl)methylmethanesulfonate.

(1,2,4-Thiadiazol-5-yl)methanol (139 mg, 1 equiv.) was dissolved in DCM (3.5 ml) and MsCl (112 μl, 1.2 equiv.) was added at 0°C. Et ₃ N (251 µl, 1.5 equiv.) was added slowly and the mixture was allowed to warm to rt and stirred for an additional 1 hour. Once complete, the mixture was diluted with DCM and washed with H2O, brine, dried with Na2SO4 and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=195.

- 215 046394

2-((1,2,4-Thiadiazol-5-yl)methyl)isoindoline-1,3-dione.

(1,2,4-Thiadiazol-5-yl)methylmethanesulfonate (300 mg, 1.5 mmol, 1 equiv.), Potassium 1,3-dioxoisoindoline-2ide (344 mg, 1.9 mmol, 1.2 equiv. ) and DMF (3 ml) were stirred at RT for 1 hour. The mixture was diluted with EtOAc, washed with. NH ₄ Cl, H ₂ O, saline, dried with Na ₂ SO ₄ and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=246.

(1,2,4-Thiadiazol-5-yl)methanamine.

2-((1,2,4-Thiadiazol-5-yl)methyl)isoindoline-1,3-dione (370 mg, 1.5 mmol, 1 equiv.) and EtOH (3.3 ml) were stirred at room temperature. t. H2NNH2 (138 µl, 2.7 mmol, 1.8 equiv) was added and the mixture was stirred at 80°C for 30 min. Once complete, the mixture was diluted with DCM and washed with H2O, brine, dried with Na2SO4 and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=116.

N((1,2,4-Thiadiazol-5-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

(1,2,4-Thiadiazol-5-yl)methanamine (70 mg, 0.6 mmol, 1 equiv.), 5-(4-(trifluoromethyl)phenyl)-2naphthoic acid (212 mg, 0.7 mmol, 1.2 equiv.), HATU (347 mg, 0.9 mmol, 1.5 equiv.), DIEA (0.53 ml, 3 mmol, 5 equiv.) and DMF (1 ml) were stirred at room temperature. for 1 hour. Once complete, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product, a colorless solid (26 mg, 10%). LCMS [M+H]+=414. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 4.97 (d, J=5.50 Hz, 2 H) 7.62 - 7.65 (m, 1H) 7.72 - 7.78 ( m, 3H) 7.87 (d, J=9.\7 Hz, 1H) 7.93 (d, J=8.07 Hz, 2H) 7.99 (dd, J=8.80, 1.83 Hz, 1H) 8.17 (d, J=8.07 Hz, 1H) 8.64 - 8.67 (m, 1H) 8.85 (s, 1H) 9.78 (t, J=5.50 Hz, 1H).

Example 187: N((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 221) o

O

^C|=3 9% (3-Methyl-1,2,4-thiadiazol-5-yl)methanol.

Ethyl 3-methyl-1,2,4-thiadiazole-5-carboxylate (prepared based on the procedure in WO2008023157) (199 mg, 1.2 mmol, 1 equiv.) was dissolved in MeOH (13 ml). NaBH ₄ (75 mg, 2 mmol, 1.7 equiv.) was carefully added and stirred at RT for 1 hour. Once complete, the reaction mixture was quenched with 3 ml H2O at 0°C. The mixture was concentrated and redissolved in a mixture of EtOAc and H2O. The aqueous layer was washed with EtOAc, the combined organic layers were dried with Na ₂ SO ₄ and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=131.

(3-Methyl-1,2,4-thiadiazol-5-yl)methylmethanesulfonate.

(3-Methyl-1,2,4-thiadiazol-5-yl)methanol (199 mg, 1 equiv.) was dissolved in DCM (5 ml) and MsCl (143 μl, 1.2 equiv.) was added at 0°C . Et ₃ N (320 µl, 1.5 equiv.) was added slowly and the mixture was allowed to warm to rt and stirred for an additional 1 hour. Once complete, the mixture was diluted with DCM and washed with H2O, brine, dried with Na2SO4 and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=209.

2-((3-Methyl-1,2,4-thiadiazol-5-yl)methyl)isoindoline-1,3-dione.

(3-Methyl-1,2,4-thiadiazol-5-yl)methylmethanesulfonate (100 mg, 0.5 mmol, 1 equiv.), Potassium 1,3dioxoisoindolin-2-ide (107 mg, 0.6 mmol, 1 .2 equiv.) and DMF (1.5 ml) were stirred at RT for 1 hour. The mixture was diluted with EtOAc, washed with. NH4Cl, H2O, saline, dried with Na2SO4 and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=260.

(3-Methyl-1,2,4-thiadiazol-5-yl)methanamine.

2-((3-Methyl-1,2,4-thiadiazol-5-yl)methyl)isoindoline-1,3-dione (100 mg, 0.38 mmol, 1 equiv.) and EtOH (0.8 ml) stirred at room temperature. H2NNH2 (34 µl, 0.69 mmol, 1.8 equiv.) was added and the mixture was stirred

- 216 046394 at 80°C for 30 minutes. Once complete, the mixture was diluted with DCM and washed with H ₂ O, brine, dried with Na ₂ SO ₄ and concentrated. The crude material was used in the next step without further purification. LCMS [M+H]+=130.

N((3-Methyl-1,2,4-thiadiazol-5-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

(3-Methyl-1,2,4-thiadiazol-5-yl)methanamine (70 mg, 0.54 mmol, 1 equiv.), 5-(4-(trifluoromethyl)phenyl)2-naphthoic acid (187 mg, 0.65 mmol, 1.2 equiv.), HATU (309 mg, 0.81 mmol, 1.5 equiv.), DIEA (0.3 ml, 1.6 mmol, 3 equiv.) and DMF (1 ml ) was stirred at room temperature for 1 hour. After completion, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product, a colorless solid (20 mg, 9%). LCMS [M+H]+=428. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 2.59 (s, 3H) 4.91 (d, J=5.87 Hz, 2 H) 7.64 (dd, J=6.97, 1.10 Hz, 1H) 7.72 - 7.78 (m, 3H) 7.87 (d, J=8.80 Hz, 1H) 7.94 (d, J=8.07 Hz, 2 H) 7.99 (dd, J=9.17, 1.83 Hz, 1H) 8.17 (d, J=8.44 Hz, 1H) 8.65 (d, J=1.47 Hz, 1H) 9 .74 (t, J=5.87 Hz, 1H).

No.[(E)-5-amino-5-oxopent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2Example

188:

carboxamide (compound 222)

To a solution of compound 217 (20 mg, 50 µmol, 1 eq.) in acetone (1 ml) was added Na ₂ CO ₃ (26.8 mg, 0.25 mmol, 5 eq.) and H ₂ O ₂ (1.18 g, 10.41 mmol, 1 ml, 30% solution, 205 eq.) at 0°C. The mixture was then stirred at 25°C for 16 hours. The reaction mixture was quenched with H2O (5 ml) and extracted with EA (15 mlx3). The combined organic phase was washed with H ₂ O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by prep HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 49%-49%, 8.5 min) . The title compound (4.5 mg, 11 μmol, 21.5% yield) was confirmed to be obtained as a white solid by LCMS and NMR. LCMS (ESI): RT=0.785 min, mass calc. for C ₂₃ H ₁₉ F ₃ N ₂ O ₂ , 412.14 m/z, 413.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CDCl3) δ 8.35 (d, J=1.3 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.82 - 7.74 (m, 3H), 7.65 - 7.58 (m, 3H), 7.52 (d, J=7.0 Hz, 1H), 6.98 - 6.86 (m, 1H), 6.51 - 6.42 (m, 1H), 5.97 (d, J=15.6 Hz, 1H), 5.69 - 5.15 ( m, 2H), 3.69 (q, J=6.4 Hz, 2H), 2.71 - 2.52 (m, 2H).

Example naftamide

189: ^)-N-(1-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2(compound

223)

^)-M-(1-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4u (trifluoromethyl)phenyl)-2-naphthamide (compound 224)

N(1-(4-(Dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of Na[1-(4-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (200 mg, 0.40 mmol, 1 equiv.) in dioxane (2 ml) Me ₂ NH (2.67 g, 59.22 mmol, 3 ml, 147.8 eq.) and Cu ₂ O (57.3 mg, 0.40 mmol, 40.9 µl, 1 eq.) were added. . The mixture was stirred at 120°C for 16 hours in a stoppered tube. The mixture was added with H2O (10 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (30 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash method

- 217 046394 silica gel chromatography (4g SepaFlash® Silica Flash column, EA/PE: 0~100%). The compound N-[1-[4(dimethylamino)-2-pyridyl]ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (136 mg, 0.29 mmol, 72.5% yield) was obtained in the form of a yellow oil.

^)-M-(1-(4-(Dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 223) and ^)-M-(1- (4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 224).

Racemic compound N[1-[4-(dimethylamino)-2-pyridyl]ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (95 mg, 0.20 mmol, 1 eq.) was purified by SFC (column: DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 40%-40%, min). Compound 223 (33.6 mg, 72.4 µmol, 35.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.807 min, mass calc. for C ₂₇ H ₂₄ F ₃ N ₃ O 463.49 m/z, obtained 464.2 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J=7, 8 Hz, 1H), 8.61 (d, J=1.5 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 8.07 (d, J=6.0 Hz , 1H), 7.98 - 7.87 (m, 3H), 7.81 (d, J=8.8 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.58 ( dd, J=1.1, 7.2 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H), 6.49 (dd, J=2.6, 5.9 Hz, 1H ), 5.13 (quin., J=7.2 Hz, 1H), 2.93 (s, 6H), 1.49 (d, J=7.0 Hz, 3H). Compound 224 (30.3 mg, 65.3 µmol, 31.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.812 min, mass calc. for C ₂₇ H ₂₄ F ₃ N ₃ O 463.49 m/z, obtained 464.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=7.8 Hz, 1H), 8.62 (d, J=1.5 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.08 (d, J=5.8 Hz, 1H), 7.99 -7.89 (m, 3H), 7.82 (d, J=8.8 Hz, 1H), 7.77 - 7.65 (m, 3H), 7.59 (dd , J=1.0, 7.0 Hz, 1H), 6.69 (d, J=2.5 Hz, 1H), 6.50 (dd, J=2.6, 5.9 Hz, 1H) , 5.18 - 5.11 (m, 1H), 2.94 (s, 6H), 1.50 (d, J=7.0 Hz, 3H).

Example 190: N(1-(4-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 225)

N(1-(4-Bromopyridin-2-yl)ethyl)-M-(2,4-dimethoxybenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (1 g, 3.16 mmol, 1 eq.) and HATU (1.80 g, 4.74 mmol, 1.5 eq.) DIPEA (1.63 g, 12.65 mmol, 2.20 mL, 4 eq.) was added to DCM (20 mL). After addition, the mixture was stirred at 25°C for 0.5 h and then 1-(4-bromo-2pyridyl)-M-[(2,4-dimethoxyphenyl)methyl]ethanamine (1.48 g, 3.16 mmol, 1 eq.). The resulting mixture was stirred at 25°C for 1.5 hours. Then H2O (30 ml) was added to the mixture and extracted with EA (40 mlx3). The combined organic layers were washed with brine (50 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (40 g SepaFlash® Silica Flash column, EA/PE: 0~40%) to obtain N[1-(4-bromo-2-pyridyl)ethyl]-N[(2.4 -dimethoxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (1.96 g, 2.99 mmol, 94.4% yield) as a yellow oil.

N(1-(4-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of N[1-(4-bromo-2-pyridyl)ethyl]-M-[(2,4-dimethoxyphenyl)methyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (1.96 g , 3.02 mmol, 1 eq.) TFA (38.50 g, 337.65 mmol, 25.00 mL, 111.89 eq.) was added to DCM (8 mL). The mixture was stirred at 25°C for 16 hours. The pH of the mixture was neutralized to 9~10 using aq. NaOH (4 M). The aqueous phase was extracted with EA (30 mlx3). The combined organic phase was washed with brine (50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to leave a residue. The residue was purified by silica gel flash chromatography (20g SepaFlash® Silica Flash column, EA/PE: 0~60%) to give N[1-(4-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl )phenyl]naphthalene-2-carboxamide (1.19 g, 2.36 mmol, 78.18% yield) as a yellow solid. Compound N[1-(4-bromo-2-pyridyl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (60 mg, 0.11 mmol, 1 eq.) was repurified by flash chromatography on silica gel (12 g SepaFlash® Silica Flash column, EA/PE: 0-50%). The title compound (55 mg, 0.11 mmol, 92.5% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.912 min, mass calc. for C ₂₅ H ₁₈ BrF ₃ N ₂ O 499.32 m/z, obtained 501.0 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=7.8 Hz, 1H), 8.66 (d, J=1.5 Hz, 1H), 8.44 (d, J=5.3 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.98 (dd, J=1.8, 9.0 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.78 - 7.67 (m, 4H), 7.64 - 7.53 (m, 2H), 5.24 (quin., J=7.2 Hz, 1H), 1, 55 (d, J=7.0 Hz, 3H).

Example 191: N-[(E)-5-methylsulfonylpent-4-enyl]-5-[4-(trifluormethyl)phenyl]naphthaline-2carboxamide (compound 226)

- 218 046394

ABOUT

N(4-Hydroxybutyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 191-1 (300 mg, 0.95 mmol, 1 eq.) in DMF (5 ml) was added HATU (541.0 mg, 1.42 mmol, 1.5 eq.), compound 191-1a ( 126.8 mg, 1.42 mmol, 0.13 ml, 1.5 eq.) and TEA (191.9 mg, 1.90 mmol, 0.26 ml, 2 eq.). The mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with H ₂ O (20 ml) and extracted with EA (20 mlx3). The combined organic phase was washed with H2O (10 ml) and brine (10 mlx3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was used immediately in the next step. Compound 191-2 (360 mg, 0.75 mmol, 79.3% yield) was confirmed to be obtained as a white solid by LCMS.

N(4-Oxobutyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 191-2 (310 mg, 0.80 mmol, 1 eq.) in DCM (5 ml) and DMSO (2.5 ml) was added DIEA (413.6 mg, 3.20 mmol, 0.56 ml , 4 eq.) and SO ₃ -Py (509.4 mg, 3.20 mmol, 4 eq.) at 0°C. The mixture was then stirred at 0°C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was diluted with H2O (20 ml), extracted with EA (15 mlx3). The combined organic phase was washed with H2O (5 ml) and brine (10 ml x 3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. It was confirmed by NMR that compound 191-3 (230 mg, 0.42 mmol, 52.2% yield) was obtained as a white solid. ^1H NMR (400 MHz, CDCU) δ 9.86 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H) , 7.90 - 7.86 (m, 1H), 7.78 (d, J=8.0 Hz, 3H), 7.63 - 7.60 (m, 3H), 7.52 - 7.49 (m, 1H), 6.67 (br s, 1H), 3.57 (q, J=6.5 Hz, 2H), 2.68 (t, J=6.5 Hz, 2H), 2, 03 (q, J=6.7 Hz, 2H).

N-[(E)-5-Methylsulfonylpent-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 191-3a (44.8 mg, 0.19 mmol, 1.5 eq.) in THF (1 ml) was added tert-BuOK (21.8 mg, 0.19 mmol, 1.5 eq.) at 0°C. Then compound 191-3 (50 mg, 0.13 mmol, 1 eq.) in THF (1 ml) was added to the mixture and stirred at 0°C for 1 hour. The reaction mixture was quenched with H ₂ O (5 ml), extracted EA (15 mlx3). The combined organic phase was washed with H ₂ O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 63%-63%, 8 min). The title compound (15.8 mg, 34 µmol, 26.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.878 min, mass calc. for C ₂₄ H ₂₂ F ₃ NO ₃ S, 461.13 m/z, 462.0 [M+H]+ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 8.41 - 8.32 (m, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.93 - 7.85 (m, 1H ), 7.78 (d, J=7.8 Hz, 3H), 7.67 - 7.58 (m, 3H), 7.52 (dd, J=1.0, 7.0 Hz, 1H) , 7.05 - 6.95 (m, 1H), 6.48 (d, J=15.3 Hz, 1H), 6.40 (br t, J=5.5 Hz, 1H), 3.58 (q, J=6.6 Hz, 2H), 2.94 (s, 3H), 2.43 (q, J=6.9 Hz, 2H), 1.90 (quin., J=7.2 Hz, 2H).

Example 192: N[(E)-5-cyanopent-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 227) o o

N - [(E)-5 -Cyanopent-4-enyl]-5 - [4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 192-1a (34.4 mg, 0.19 mmol, 31 μL, 1.5 eq.) in THF (1 mL) was added LHMDS (1 M, 0.19 mL, 1.5 eq.) at 0°C and stirred at 0°C for 30 min. Then compound 192-1 (50 mg, 0.13 mmol, 1 eq.) in THF (1 ml) was added to the mixture and stirred at 25°C for 2 hours. The reaction mixture was quenched with NH ₄ Cl (5 ml), extracted EA (15 mlx3). The combined organic phase was washed with H ₂ O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated

- 219 046394 dug in a vacuum.

The crude product was purified by flash silica gel chromatography. The crude product was purified by chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 20%-20%, min) . The title compound (14.9 mg, 36 µmol, 27.8% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.875 min, mass calc. for C ₂₄ H ₁₉ F ₃ N ₂ O, 408.14 m/z, 409.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.99 (br d, J=8.1 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.79 (br d, J=6.5 Hz, 3H), 7.68 - 7.58 (m, 3H), 7.52 (d, J=7.0 Hz, 1H), 6.91 6 .67 (m, 1H), 6.38 (br s, 1H), 5.44 (br d, J=16.5 Hz, 1H), 3.57 (q, J=6.4 Hz, 2H) , 2.38 (q, J=7.2 Hz, 2H), 1.90 1.83 (m, 2H).

Example 193: N[^)-5-cyanopent-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 228)

N[^)-5-Cyanopent-4-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 193-1a (34.4 mg, 0.19 mmol, 31 μL, 1.5 eq.) in THF (1 mL) was added LHMDS (1 M, 0.19 mL, 1.5 eq.) at 0°C and stirred at 0°C for 30 min. Then compound 193-1 (50 mg, 0.13 mmol, 1 eq.) in THF (1 ml) was added to the mixture and stirred at 25°C for 2 hours. The reaction mixture was quenched with NH ₄ Cl (5 ml), extracted EA (15 mlx3). The combined organic phase was washed with H2O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography. The crude product was purified by chiral SFC (column: DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 20%-20%, min) . The title compound (7.20 mg, 17 µmol, 13.3% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.875 min, mass calc. for C ₂₄ H ₁₉ F ₃ N ₂ O, 408.14 m/z, 409.0 [M+H]+ was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.42 - 8.42 (m, 1H), 8.41 (s, 1H), 8.00 (br d, J=8.1 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.84 - 7.76 (m, 3H), 7.61 (br d, J=7.8 Hz, 3H), 7.51 (br d, J=6.9 Hz, 1H), 6.67 - 6.50 (m, 2H), 5.43 (br d, J=10.8 Hz, 1H), 3.58 (q, J=6, 2 Hz, 2H), 2.59 (q, J=7.3 Hz, 2H), 1.95 - 1.88 (m, 2H).

Example 194: N(pyridin-4-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 229)

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.), HATU (72.1 mg, 0.18 mmol, 1.2 eq.) and DIPEA (61.3 mg, 0.47 mmol, 82 μl, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then 4-pyridylmethanamine (18.8 mg, 0.17 mmol, 17 µl, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 5:1). The title compound (21.0 mg, 51.2 µmol, 32.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.842 min, mass calc. for C ₂₄ H ₁₇ F ₃ N ₂ O 406.40 m/z obtained 407.0 [M+H]+, ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.58 - 8.49 (m, 3H) , 8.10 (d, J=8.3 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.97 - 7.83 (m, 3H), 7.73 - 7.66 (m, 3H), 7.60 (dd, J=0.9, 7.1 Hz, 1H), 7.47 (d, J=6.0 Hz, 2H), 4.71 (s, 2H) .

Example 195: Methyl(E)-5-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]pent-2-enoate (compound 230)

- 220 046394

M(3-Hydroxypropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 195-1 (0.6 g, 1.96 mmol, 1 eq.), HATU (894.4 mg, 2.35 mmol, 1.2 eq.) and compound 195-1a (161.9 mg , 2.16 mmol, 0.16 mL, 1.1 eq.) to DMF (10 mL) was added TEA (297.5 mg, 2.94 mmol, 0.4 mL, 1.5 eq.). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with EA (30 ml) and washed with brine (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. Compound 195-2 (720 mg, 1.93 mmol, 98.3% yield) was used immediately in the next step as a white solid.

M(3-Oxopropyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 195-2 (0.7 g, 1.87 mmol, 1 eq.) in DCM (10 mL) was added DIEA (1.21 g, 9.37 mmol, 1.63 mL, 5 eq.) DMSO (5 mL) followed by SO ₃ -Py (1.49 g, 9.37 mmol, 5 eq.) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with EA (20 ml) and washed with brine (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:1) to give compound 195-3 (0.47 g, 1.27 mmol, 67.5% yield) as a white solid.

Methyl(E)-5-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]pent-2-enoate.

To a solution of compound 195-3a (73.5 mg, 0.4 mmol, 58.3 µl, 1.5 eq.) in THF (3 ml) was added dropwise LiHMDS (1 M, 0.4 ml, 1.5 eq.) at 0°C. After 10 min, compound 195-3 (0.1 g, 0.26 mmol, 1 eq) in THF (1 ml) was added. The reaction was heated to 50°C and stirred at 50°C for 32 hours. The reaction was quenched. NH4Cl (10 ml) and washed with EA (2x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The reaction was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 59%-89%, 7.8 min) to obtain the title compound (3.5 mg, 8.1 µmol, 3% yield) as a white solid. LCMS (ESI): RT=0.984 min, mass calc. for C ₂₄ H ₂₀ F ₃ NO ₃ , 427.14 m/z, 428.1 [M+Na]+ was obtained. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.00 (d, J=7.4 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.82 - 7.73 (m, 3H), 7.66 - 7.58 (m, 3H), 7.52 (d, J=6.9 Hz, 1H), 7.08 -6.93 ( m, 1H), 6.35 (br s, 1H), 5.97 (br d, J=14.9 Hz, 1H), 3.75 (s, 3H), 3.72 - 3.65 (m , 2H), 2.67 - 2.55 (m, 2H).

Example 196: M(5-cyano-5-hydroxy-pentyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 231)

To a solution of compound 196-1 (200 mg, 0.50 mmol, 1 eq.) in DCM (1 ml) was added TMSCN (59.6 mg, 0.60 mmol, 75 μl, 1.2 eq.), diiodozinc ( 15.9 mg, 50 µmol, 0.1 equiv.) and TEA (10.1 mg, 0.1 mmol, 14 µl, 0.2 equiv.) at 0°C. The mixture was then stirred at 25°C for 16 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with EA (20 ml), washed with 1 M HCI (10 ml), H2O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography. The title compound (130 mg, 0.30 mmol, 60.8% yield) was obtained as a white solid. LCMS (ESI): RT=0.879 min, mass calc. for C ₂₄ H ₂₁ F ₃ N ₂ O ₂ , 426.16 m/z, 427.0 [M+H]+ was obtained; 1H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.89 - 7.83 (m, 1H), 7, 80 - 7.72 (m, 3H), 7.64 - 7.56 (m, 3H), 7.50 (d, J=7.0 Hz, 1H), 7.53 - 7.47 (m, 1H), 6.54 (br s, 1H), 4.54 (q, J=6.2 Hz, 1H), 3.94 (d, J=6.4 Hz, 1H), 3.56 (br d, J=6.3 Hz, 2H), 2.05 - 1.88 (m, 2H), 1.80 - 1.71 (m, 2H), 1.69 - 1.60 (m, 2H) .

Example 197: ^)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-X-(1-(pyridin-2-yl)ethyl)quinoline-3carboxamide (compound 232)

- 221 046394

To a solution of compound 197-1 (25.0 mg, 68.4 µmol, 1.0 eq.), compound 197-1a (8.3 mg, 68.4 µmol, 1.0 eq.) and DIPEA (17, 6 mg, 0.13 mmol, 2.0 eq.) in DCM (1 ml) was added HATU (39.0 mg, 0.10 mmol, 1.5 eq.). 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 extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 55%-85%, 7.8 min) to obtain the title compound (8.85 mg, 27.5% yield) as a white solid. LCMS (ESI): RT=0.862 min, mass calc. for C ₂₅ H ₁₉ F ₄ N ₃ O ₂ 469.14, m/z obtained 470.0 [M+H]+; ¹ H NMR (400 MHz, CDCl3) δ 9.20 (d, J=2.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.57 (d, J= 4.5 Hz, 1H), 8.16 (d, J=7.0 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.67 - 7.61 (m, 1H), 7.59 - 7.54 (m, 1H), 7.53 - 7.45 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.28 (d, J= 2.8 Hz, 1H), 7.24 (dd, J=5.3, 7.0 Hz, 1H), 5.43 -5.34 (m, 1H), 4.01 (s, 3H), 1.62(s, 3H).

Example 198: ^)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-M-(1-hydroxypropan-2-yl)-6-methoxyquinoline3-carboxamide (compound 233)

Methyl 8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxyquinoline-3-carboxylate.

To a solution of compound 198-1 (200.0 mg, 0.67 mmol, 1.0 eq.), compound 198-1a (140.4 mg, 0.67 mmol, 1.0 eq.) and Na ₂ CO ₃ (143.1 mg, 1.35 mmol, 2.0 eq.) in dioxane (5 ml) and H2O (1 ml) was added Pd(dppf)Cl ₂ (24.7 mg, 33.7 µmol, 0.05 eq.) in an N2 atmosphere. The reaction mixture was stirred at 90°C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (30 ml) and the resulting mixture was extracted with EA (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 5:1) to give compound 198-2 (180 mg, 70.2 yield) as a white solid.

8-(2-Fluoro-4-(trifluoromethyl)phenyl)-6-methoxyquinoline-3-carboxylic acid.

NaOH (1 M, 0.79 mL, 2.0 eq.). The reaction mixture was stirred at 25°C for 1 hour. The pH of the reaction mixture was adjusted to 5 with HCl (1 M), and then the suspension was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 198-3 (130 mg, 90.0% yield) as a white solid.

^)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-M-(1-hydroxypropan-2-yl)-6-methoxyquinoline-3carboxamide.

To a solution of compound 198-3 (25.0 mg, 68.4 µmol, 1.0 eq.), compound 198-3a (5.1 mg, 68.4 µmol, 1.0 eq.) and DIPEA (17, 6 mg, 0.13 mmol, 2.0 eq.) in DCM (1 ml) was added HATU (39.0 mg, 0.10 mmol, 1.5 eq.). 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 extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 50%-80%, 7.8 min) to obtain the title compound (14.48 mg, 50.0% yield) as a white solid. LCMS (ESI): RT=0.887 min, mass calc. for C ₂₁ H ₁₈ F ₄ N ₂ O ₃ 422.13, m/z obtained 423.0 [M+H] ⁺ ; 1H NMR (400 MHz, CDCl3) δ 9.05 (d, J=2.0 Hz, 1H), 8.54 (d, J=2.3 Hz, 1H), 7.64 - 7.58 (m , 1H), 7.57 -7.53 (m, 1H), 7.51 - 7.45 (m, 2H), 7.21 (d, J=2.8 Hz, 1H), 6.57 ( d, J=7.3 Hz, 1H), 4.42 - 4.30 (m, 1H), 3.98 (s, 3H), 3.88 - 3.78 (m, 1H), 3.72 - 3.64 (m, 1H), 2.68 - 2.60 (m, 1H), 1.34 (d, J=6.8 Hz, 3H).

Example 199: N(3-(3-methoxypropanamido)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 234)

N(3-(3-Methoxypropanamido)benzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of N[(3-aminophenyl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (50 mg, 0.11 mmol, 1 eq.), 3-methoxypropanoic acid (14.8 mg, 0.14 mmol, 13.3 µl, 1.2 eq.), DIPEA (46.1 mg, 0.35 mmol, 62.1 µl, 3 eq.) and HATU (67.8 mg, 0.17 mmol , 1.5 eq.) in DCM (3 ml) was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 50%-90%, 7.8 min) . The title compound (35 mg, 68.4 µmol, 57.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.980 min, mass calc. for C ₂₉ H ₂₅ F ₃ N ₂ O ₃ 506.52 m/z, obtained 507.1 [M+H]+, ¹ H NMR (400 MHz, CD ₃ Cl) δ 8.39 (s, 1H), 8.24 (br s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.77 (d, J=7.8 Hz, 2H), 7.61 (dt, J=3.0, 7.9 Hz, 4H), 7.50 (d, J=5.8 Hz, 1H), 7.43 - 7.38 (m , 1H), 7.34 7.29 (m, 1H), 7.15 (d, J=7.0 Hz, 1H), 6.60 (br d, J=5.3 Hz, 1H), 4 .70 (d, J=5.5 Hz, 2H), 3.73 (t, J=5.6 Hz, 2H), 3.45 (s, 3H), 2.63 (t, J=5, 6 Hz, 2H).

Example 200: N(3-aminobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 235)

N(3-Aminobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of tert-butyl-N-[3-[[[5-[4-(trifluoromethyl)phenyl]naphthalene-2-carbonyl]amino]methyl]phenyl]carbamate (400 mg, 0.76 mmol, 1 eq.) and HCl/dioxane (4 M, 0.19 ml, 1 eq.) in dioxane (3 ml) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The compound N[(3-aminophenyl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (350 mg, crude, HCl) was obtained as a yellow solid. The crude product (30 mg) was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 57%-87%, 7.8 min). The title compound (10 mg, 23.3 µmol, 32.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.888 min, mass calc. for C25H19F3N2O 420.43 m/z, obtained 421.1 [M+H] ⁺ , 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (t, J=5.7 Hz, 1H), 8, 63 (s, 1H), 8.13 (d, J=8.1 Hz, 1H), 8.00 (d, J=9.5 Hz, 1H), 7.93 (d, J=8.1 Hz, 2H), 7.83 (d, J=8.9 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.60 (d, J=6.9 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.58 - 6.41 (m, 3H), 5.05 (s, 2H), 4.41 (d, J=5.9 Hz , 2H)

Example 201: tert-butyl(3-((5-(4-(trifluoromethyl)phenyl)-2-naphtamido)methyl)phenyl)carbamate (compound 236)

tert-Butyl(3-((5-(4-(trifluoromethyl)phenyl)-2-naphtamido)methyl)phenyl)carbamate.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.), DIPEA (61.2 mg, 0.47 mmol, 82.6 µl, 3 eq. .) and HATU (90.1 mg, 0.23 mmol, 1.5 eq.) in DCM (3 ml) were stirred at 25°C for 1 hour. Then tert-butyl-L[3-(aminomethyl)phenyl ]carbamate (42.1 mg, 0.18

- 223046394 mmol, 1.2 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. The reaction mixture was diluted with H ₂ O (10 ml). The mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 70%-100%, 7 min). The title compound (30 mg, 57.0 µmol, 36.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.967 min, mass calc. for C ₃₀ H ₂₇ F ₃ N ₂ O ₃ 520.45 m/z, obtained 463.0 [M+H]+, ¹ H NMR (400 MHz, CD ₃ Cl) δ 8.40 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.89 - 7.76 (m, 4H), 7.64 - 7.59 (m, 3H), 7.51 (d, J= 7.0 Hz, 2H), 7.09 (d, J=7.1 Hz, 1H), 6.59 (br s, 1H), 6.52 (br s, 1H), 4.69 (d, J=5.6 Hz, 2H), 1.52 (s, 9H).

Example 202: N(3-acetamidobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 237)

N(3-Acetamidobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

Mixture of Na[(3-aminophenyl)methyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (50 mg, 0.11 mmol, 1 eq.), TEA (24.0 mg, 0.23 mmol, 33.1 µl, 2 eq.) and Ac ₂ O (18.2 mg, 0.17 mmol, 16.7 µl, 1.5 eq.) in DCM (2 ml) were stirred at 25°C for 1 h. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 65%-95%, 7 min). The title compound (15 mg, 32.1 µmol, 27.0% yield) was obtained as a white solid. LCMS (ESI): RT=0.967 min, mass calc. for C ₂₇ H ₂₁ F ₃ N ₂ O ₂ 462.42 m/z, obtained 463.0 [M+H]+, 1H NMR (400 MHz, CD3Cl) δ 8.40 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.89 7.75 (m, 4H), 7.63 - 7.57 (m, 4H), 7.51 (d, J=6.3 Hz , 1H), 7.44 (br d, J=8.0 Hz, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.15 (br d, J=7.5 Hz , 1H), 6.69 (br s, 1H), 4.69 (d, J=5.8 Hz, 2H), 2.17 (s, 3H), 1.59 (s, 4H).

Example 203: N(5-hydroxypentyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 238)

N(5-Hydroxypentyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 203-1 (60 mg, 85 µmol, 1 eq.) in MeOH (1 ml) was added NaOH (2 M, 0.21 ml, 5 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated in vacuo. The pH of the aqueous phase was adjusted to 6 using 1 M aq. HCl and extracted with EA (15 mlx3). The combined organic phase was washed with H2O (5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by prep HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 50%-80%, 7.8 min) . The title compound (20 mg, 49 µmol, 57.5% yield) was obtained as a white solid. LCMS (ESI): RT=0.825 min, mass calc. for C ₂₃ H ₂₂ F ₃ NO ₂ , 401.16 m/z, 402.0 [M+H]+ was obtained. 1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.98 (br d, J=8.1 Hz, 1H), 7.90 - 7.83 (m, 1H), 7 .78 (br d, J=7.8 Hz, 3H), 7.60 (br d, J=7.6 Hz, 3H), 7.50 (br d, J=6.9 Hz, 1H), 6.42 (br s, 1H), 3.69 (t, J=6.3 Hz, 2H), 3.55 (q, J=6.6 Hz, 2H), 1.79 - 1.65 ( m, 4H), 1.57 - 1.48 (m, 2H).

Example 204: N(pyridin-2-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 239)

- 224 046394

U-(Pyridin-2-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.), HATU (72.1 mg, 0.18 mmol, 1.2 eq.) and DIPEA (61.3 mg, 0.47 mmol, 82 µl, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then 2-pyridylmethanamine (18.8 mg, 0.17 mmol, 17 µl, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (10 mM NH4HCO3) ACN]; B%: 51% - 81%, 8.5 min). The title compound (17.6 mg, 43.4 µmol, 27.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.876 min, mass calc. for C ₂₄ H ₁₇ F ₃ N ₂ O 406.40 m/z, 407.0 [M+H]+ was obtained. ^1H NMR (400 MHz, CD3OD) δ 8.59 - 8.52 (m, 2H), 8.10 (d, J=8.1 Hz, 1H), 7.98 - 7.90 (m, 2H ), 7.86 (d, J=8.0 Hz, 3H), 7.73 - 7.66 (m, 3H), 7.60 (dd, J=1.0, 7.1 Hz, 1H) , 7.51 (d, J=7.9 Hz, 1H), 7.35 (dd, J=5.4, 7.1 Hz, 1H), 4.78 (s, 2H).

Example 205: N(3-methoxybenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 240)

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.), HATU (78.1 mg, 0.20 mmol, 1.3 eq.) and DIPEA (61.3 mg, 0.47 mmol, 82.6 µl, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then (3-methoxyphenyl)methanamine (23.8 mg, 0.17 mmol, 22.2 µl, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 3:1). The title compound (28.5 mg, 64.4 µmol, 40.7% yield) was obtained as a white solid. LCMS (ESI): RT=1.038 min, mass calc. for C ₂₆ H ₂₀ F ₃ NO ₂ 435.44 m/z, 436.0 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J=1.5 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.94 - 7.90 (m , 1H), 7.90 - 7.84 (m, 3H), 7.72 - 7.65 (m, 3H), 7.58 (dd, J=1.3, 7.0 Hz, 1H), 7.27 (t, J=8.2 Hz, 1H), 7.01 - 6.96 (m, 2H), 6.87 - 6.82 (m, 1H), 4.62 (s, 2H) , 3.80 (s, 3H).

Example 206: N-benzyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 241)

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.), HATU (72.1 mg, 0.18 mmol, 1.2 eq.) and DIPEA (61.2 mg, 0.47 mmol, 82 µl, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then phenylmethanamine (18.6 mg, 0.17 mmol, 18 µl , 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by co

- 225 046394 column chromatography (SiO2, petroleum ether/ethyl acetate = 1/0 - 5:1). The title compound (28.8 mg, 70.8 µmol, 44.8% yield) was obtained as a white solid. LCMS (ESI): RT=1.048 min, mass calc. for C ₂₅ H ₁₈ F ₃ NO 405.41 m/z, 406.0 [M+H]+ was obtained. 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J=1.8 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.94 - 7.90 (m , 1H), 7.89 - 7.83 (m, 1H), 7.89 - 7.83 (m, 2H), 7.71 - 7.64 (m, 3H), 7.58 (dd, J =1.3, 7.0 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.38 - 7.33 (m, 2H), 7.30 - 7.25 (m, 1H ), 4.62 (s, 2H).

Example 207: (R)-Na(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamcd (compound 242) and R)-Na(1-( 1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 243)

N-(1 -(1H-Imidazol-2-yl)ethyl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (217.3 mg, 0.68 mmol, 1 eq.), DIPEA (266.3 mg, 2.06 mmol, 0.35 ml, 3 eq.) and HATU (391.8 mg, 1.03 mmol, 1.5 eq.) in DCM (3 ml) were stirred at 25°C for 1 h. Then 1-(1H-imidazol-2-yl )ethanamine (84 mg, 0.75 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 22%-52%, 8.5 min). Compound N[1-(III-imidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (43.5 mg, 0.10 mmol, 15.4% yield) was obtained as white solid.

(I)-Na(1-(1H-Imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamcd (compound 242) and (S)Na(1-(1H-imidazole -2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 243.)

The racemic compound N-[1-(N-imidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (43.5 mg, 0.10 mmol, 1 eq.) was purified by SFC and separated by SFC (column: YMC CHIRAL Amylose-C (250 mmx30 mm, 10 µm; mobile phase: [0.1% NH3H2O ETOH]; V%: 40%-40%, min). Compound 242 (39.8 mg, 97.2 µmol, 91.3% yield) was obtained as a white solid LCMS (ESI): RT=0.850 min, mass calculated for C ₂₃ H ₁₈ F ₃ N ₃ O 409.40 m/z obtained. 410.1 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.45 (d, J=1.8 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H ), 7.85 - 7.80 (m, 1H), 7.77 - 7.71 (m, 3H), 7.60 - 7.54 (m, 3H), 7.47 (dd, J=1 ,0, 7.0 Hz, 1H), 7.01 (s, 2H), 5.34 (q, J=7.0 Hz, 1H), 1.61 (d, J=7.0 Hz, 3H Compound 243 (6.4 _{mg ,} 15.0 µmol, 14.1% yield) was obtained as a white solid by LCMS (ESI): RT=0.850 min, mass calculated for _{C23H18F3N3 .} O 409.40 m/z obtained 410.1 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=1.5 Hz, 1H), 7.97 (d, J =8.3 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.78 - 7.71 (m, 3H), 7.60 7.54 (m, 3H), 7.47 (dd, J=1.1, 7.2 Hz, 1H), 7.00 (s, 2H), 5.33 (q, J=7.0 Hz, 1H), 1.60 (d, J= 7.0 Hz, 3H).

Example 208: ^)-N(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide (compound 244)

A)-N(1-(Pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide.

To a solution of compound 208-1 (50.0 mg, 0.14 mmol, 1.0 eq., HCl), compound 208-1a (20.7 mg, 0.17 mmol, 1.2 eq.) and DIPEA ( 54.8 mg, 0.42 mmol, 3.0 eq.) to DCM (2 mL) was added HATU (80.6 mg, 0.21 mmol, 1.5 eq.). The mixture was diluted with water (5 ml) and the resulting mixture was extracted with DCM (10 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 63%-93%, 7.8 min) to obtain the title compound (35.40 mg, 58.8% yield) as a white solid. LCMS (ESI): RT=0.892 min, mass calc. for C ₂₄ H ₁₈ F ₃ N ₃ O 421.14, m/z obtained 422.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.22 (d, J=8.0 Hz, 1H), 8.72 - 8.64 (m, 1H), 8.33 - 8.23 (m, 3H ), 7.88 - 7.77 (m, 3H), 7.70 (dt, J=1.8, 7.7 Hz, 1H), 7.64 - 7.55 (m, 3H), 7, 38 (d, J=7.8 Hz, 1H), 7.21 - 7.26 (m, 1H), 5.48 - 5.38 (m, 1H), 1.70 (d, J=6, 8 Hz, 3H).

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Example 209: N[(E)-5-hydroxypent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (compound 245)

2-[3-[BLAH(T rifenyl)-phosphanyl]propyl]isoindoline-1,3-dione.

To a solution of compound 209-1 (2 g, 7.46 mmol, 1 eq.) in toluene (30 ml) was added PPh ₃ (1.96 g, 7.46 mmol, 1 eq.). The reaction was heated at 110°C for 16 hours. The reaction mixture was filtered and dried under reduced pressure. Compound 209-2 (3.5 g, 6.60 mmol, 88.46% yield) was used immediately in the next step as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.94 - 7.84 (m, 7H), 7.81 - 7.72 (m, 12H), 3.80 - 3.64 (m, 4H ), 2.00 - 1.88 (m, 2H).

2-[(2)-5-[tert-Butyl(dimethyl)silyl]oxypent-3-enyl]isoindoline-1,3-dione.

To a solution of compound 209-2 (0.3 g, 0.56 mmol, 1 eq.) and compound 209-2a (98.5 mg, 0.56 mmol, 107.75 μl, 1 eq.) in PhMe (10 ml) K ₂ CO ₃ (101.6 mg, 0.73 mmol, 1.3 eq.) and 18-CROWN-6 (14.9 mg, 56.5 μmol, 0.1 eq.) were added. The reaction was heated at 110°C for 16 hours. The reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:5) to give compound 209-3 (130 mg, 0.28 mmol, 49.8% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J=3.1, 4.8 Hz, 2H), 7.70 (dd, J=3.0, 5.0 Hz, 2H), 5 .64 - 5.55 (m, 1H), 5.49 - 5.36 (m, 1H), 4.15 (d, J=6.1 Hz, 2H), 3.73 (t, J=7 ,1 Hz, 2H), 2.45 (q, J=7.1 Hz, 2H), 0.84 (s, 8H), 0.00 (s, 6H) (2)-5-[tert-Butyl (dimethyl)silyl]oxypent-3-en-1-amine.

To a solution of compound 209-3 (120.0 mg, 0.34 mmol, 1 eq.) in EtOH (3 ml) was added NH2NH2-H2O (40.9 mg, 0.69 mmol, 39.7 μl, 85% solution , 2 eq.). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated. Compound 209-4 (50 mg, 0.23 mmol, 66.8% yield) was used immediately in the next step as a colorless oil.

No. [(2)-5-[tert-Butyl(dimethyl)silyl]oxypent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide.

To a solution of compound 209-4a (73.4 mg, 0.23 mmol, 1 eq.), HATU (132.3 mg, 0.34 mmol, 1.5 eq.) and DIEA (90.0 mg, 0. 69 mmol, 0.12 mL, 3 eq.) to DCM (3 mL) was added compound 209-4 (50.0 mg, 0.23 mmol, 1 eq.). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM (20 ml) and washed with H2O (2x5 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:5) to give compound 209-5 (100 mg, 0.18 mmol, 78.0% yield) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.89 - 7.83 (m, 1H), 7, 81 - 7.74 (m, 3H), 7.65 - 7.59 (m, 3H), 7.51 (d, J=7.0 Hz, 1H), 6.45 (br s, 1H), 5.79 - 5.69 (m, 1H), 5.58 - 5.51 (m, 1H), 4.31 - 4.12 (m, 2H), 3.58 (q, J=6.3 Hz, 2H), 2.48 (q, J=7.0 Hz, 2H), 0.89 - 0.82 (m, 9H), 0.03 (s, 6H).

N[(E)-5-Hydroxypent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of compound 209-5 (90.0 mg, 0.17 mmol, 1 eq.) in THF (2 mL) was added TBAF (1 M, 0.43 mL, 2.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. The reaction was concentrated. The crude product was purified by silica gel column chromatography (EA:PE=1:10-1:0) to obtain the title compound (35 mg, 85.8 μmol, 49.0% yield) as a white solid. LCMS (ESI): RT=0.932 min, mass calc. for C ₂₃ H ₂₀ F ₃ NO ₂ , 399.14 m/z, 422.1 [M+Na]+ was obtained. 1H NMR (400 MHz, CDCU) δ 8.41 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.88 - 7.80 (m, 2H), 7.78 (br d, J=8.3 Hz, 2H), 7.64 7.56 (m, 3H), 7.50 (d, J=7.0 Hz, 1H), 6.77 (br s, 1H ), 5.92 - 5.82 (m, 1H), 5.75 - 5.64 (m, 1H), 5.75 - 5.64 (m, 1H), 4.25 (br d, J= 6.6 Hz, 2H), 3.59 (q, J=6.1 Hz, 2H), 2.52 (q, J=6.9 Hz, 2H), 1.64 (br s, 1H).

Example 210: ^)-N(1-Methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide (compound 246)

- 227 046394

(I)-X-('1-Methoxypropan-2-yl)-5-('4-(trifluoromethyl)phenyl)quinoline-2-carboxamide.

To a solution of compound 210-1 (50.0 mg, 0.14 mmol, 1.0 eq., HCl), compound 210-1a (15.1 mg, 0.17 mmol, 1.2 eq.) and DIPEA ( 54.8 mg, 0.42 mmol, 3.0 eq.) to DCM (2 mL) was added HATU (80.6 mg, 0.21 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (5 ml) and the resulting mixture was extracted with DCM (10 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 63%-93%, 7.8 min) to obtain the title compound (36.03 mg, 64.9% yield) as a white solid. LCMS (ESI): RT=1.011 min, mass calc. for C ₂₁ H ₁₉ F ₃ N ₂ O ₂ 388.14, m/z obtained 389.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J=8.3 Hz, 1H), 8.33 - 8.26 (m, 2H), 8.21 (d, J=8, 5 Hz, 1H), 7.87 -7.78 (m, 3H), 7.63 - 7.55 (m, 3H), 4.51 - 4.38 (m, 1H), 3.57 (d , J=4.8 Hz, 2H), 3.45 (s, 3H), 1.39 (d, J=6.8 Hz, 3H).

Example 211: A)-H-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide (compound 247)

A)-H-(1-Hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide.

To a solution of compound 211-1 (50.0 mg, 0.14 mmol, 1.0 eq., HCl), compound 211-1a (12.7 mg, 0.17 mmol, 1.2 eq.) and DIPEA ( 54.8 mg, 0.42 mmol, 3.0 eq.) to DCM (2 mL) was added HATU (80.6 mg, 0.21 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (5 ml) and the resulting mixture was extracted with DCM (10 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 54%-54%, 11 min) to give the title compound (6 .84 mg, 11.4% yield, HCl) as a white solid. LCMS (ESI): RT=0.921 min, mass calc. for C ₂₀ H ₁₇ F ₃ N ₂ O ₂ 374.12, m/z obtained 375.0 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=8.5 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.00 - 7.92 (m, 3H), 7.77 (d, J=8.0 Hz, 2H), 7.73 (dd, J=1.0, 7.3 Hz, 1H), 4.16 - 4.05 (m, 1H), 3.58 - 3.50 (m, 2H) , 1.23 (d, J=6.8 Hz, 3H).

Example 212: Aisopropyl-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide (compound 248)

5-(4-(Trifluoromethyl)phenyl)quinoline.

To a solution of compound 212-1 (500.0 mg, 2.40 mmol, 1.0 eq.), compound 212-1a (456.4 mg, 2.40

- 228 046394 mmol, 1.0 eq.) and Na2CO ₃ (509.4 mg, 4.81 mmol, 2.0 eq.) in dioxane (10 ml) and H2O (2 ml) added Pd(dppf)Cl ₂ (87.9 mg, 0.12 mmol, 0.05 eq.) under N2 atmosphere. The reaction mixture was stirred at 90°C for 16 hours under N2 atmosphere. 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 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 10:1) to give compound 212-2 (600 mg, 91.3% yield) as a light yellow oil.

5-(4-(Trifluoromethyl)phenyl)quinoline-1-oxide.

To a solution of compound 212-2 (500.0 mg, 1.83 mmol, 1.0 eq.) in DCM (10 ml) was added m-CPBA (742.9 mg, 3.66 mmol, 85%, 2.0 eq.). The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with NaOH (30 ml, 1 M) and the resulting mixture was extracted with DCM (50 ml x 2). The combined organic layers were washed with NaOH (25 ml, 1M), brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 212-3 (480 mg, crude) as a white solid .

5-(4-(Trifluoromethyl)phenyl)quinoline-2-carbonitrile.

To a solution of compound 212-3 (480.0 mg, 1.66 mmol, 1.0 eq.) in DCE (6 ml) was added TMSCN (181.0 mg, 1.83 mmol, 1.1 eq.) and compound 212-3a (178.4 mg, 1.66 mmol, 1.0 eq.). 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 extracted with EA (30 mlx3). 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 (petroleum ether:ethyl acetate=1:0 to 10:1) to give compound 212-4 (450 mg, 90.9% yield) as a white solid.

5-(4-(Trifluoromethyl)phenyl)quinoline-2-carboxylic acid.

A mixture of compound 212-4 (450.0 mg, 1.51 mmol, 1.0 eq.) in conc. HCl (5 ml, 12 M) was stirred at 70°C for 16 hours. The reaction mixture was cooled to 25°C and then the suspension was filtered to obtain compound 212-5 (500 mg, crude) as a white solid.

No. Isopropyl-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide.

To a solution of compound 212-5 (50.0 mg, 0.14 mmol, 1.0 eq., HCl), compound 212-5a (10.0 mg, 0.17 mmol, 1.2 eq.) and DIPEA ( 54.8 mg, 0.42 mmol, 3.0 eq.) to DCM (2 mL) was added HATU (80.6 mg, 0.21 mmol, 1.5 eq.). The reaction mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (5 ml) and the resulting mixture was extracted with DCM (10 ml x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 65%-95%, 7.8 min) to obtain the title compound (29.20 mg, 57.6% yield) as a white solid. LCMS (ESI): RT=1.032 min, mass calc. for C ₂₀ Hi ₇ F ₃ N ₂ O 358.13, m/z obtained 359.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J=1.3 Hz, 2H), 8.19 (d, J=8.3 Hz, 1H), 8.12 (d, J =8.0 Hz, 1H), 7.86 -7.77 (m, 3H), 7.63 - 7.55 (m, 3H), 4.43 - 4.28 (m, 1H), 1, 37 (d, J=6.5 Hz, 6H).

Example 213: N(4-chlorobutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 249) and N-(4hydroxybutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide ( connection 255)

Ν-(4-Γ hydroxybutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 255)

To a solution of compound 213-1 (50 mg, 0.16 mmol, 1 eq.), compound 213-1a (18.3 mg, 0.21 mmol, 19 μl, 1.3 eq.) and HATU (90.2 mg, 0.24 mmol, 1.5 eq.) TEA (48.0 mg, 0.47 mmol, 66 μl, 3 eq.) was added to DMF (1 ml) at 30°C. The resulting mixture was stirred at 30°C for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by silica gel flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash column, 0~100% ethyl acetate/petroleum ether eluent gradient approximately 20 mL/min) to give compound 255 (50 mg, 0.13 mmol, 81 .6% yield) as a white solid. LCMS (ESI): RT=0.814 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.14, m/z obtained 388.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.89 - 7.85 ( m, 1H), 7.83 - 7.75 (m, 3H), 7.65 - 7.58 (m, 3H), 7.51 (dd, J=1.3, 7.0 Hz, 1H) , 6.65 (brs, 1H), 3.77 (t, J=5.9 Hz, 2H), 3.59 (q, J=6.7 Hz, 2H), 1.86 - 1.77 ( m, 2H), 1.77 - 1.70 (m, 2H).

N(4-chlorobutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 249)

- 229 046394

To a solution of compound 255 (30 mg, 77.4 µmol, 1 eq.) and PPh ₃ (60.9 mg, 0.23 mmol, 3 eq.) in DCM (2 ml) at 30°C was added 1.1, 1,3,3,3-hexachloropropan-2-one (82.0 mg, 0.31 mmol, 47 μL, 4 eq.) and the mixture was stirred at 30°C for 16 hours. The mixture was concentrated to leave a residue. The residue was purified by silica gel flash chromatography (ISCO®; 4 g SepaFlash® Silica Flash column, 0~50% ethyl acetate/petroleum ether eluent gradient approximately 20 mL/min) to give compound 249 (21.8 mg, 53.7 µmol , 69.4% yield) as a white solid. LCMS (ESI): RT=0.921 min, mass, calc. for C ₂₂ H ₁₉ ClF ₃ NO 405.11, m/z obtained 405.9 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.91 - 7.85 (m, 1H), 7 .78 (d, J=8.4 Hz, 3H), 7.66 - 7.58 (m, 3H), 7.51 (d, J=7.0 Hz, 1H), 6.34 (brs, 1H), 3.67 - 3.55 (m, 4H), 1.97 -1.82 (m, 4H).

Example 214: N(1-(pyridin-2-yl)cyclopropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 250)

N-(1 -(Pyridin-2-yl)cyclopropyl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.) and HATU (72.1 mg, 0.18 mmol, 1.2 eq.) DIPEA (61.3 mg, 0.47 mmol, 82.6 μL, 3 eq.) was added to DCM (2 mL). After addition, the mixture was stirred at 25°C for 0.5 h and then 1-(2pyridyl)cyclopropanamine (127.2 mg, 0.23 mmol, 1.5 eq.) was added. The resulting mixture was stirred at 25°C for 1.5 hours. The reaction mixture was added with H2O (20 ml) and extracted with EA (15 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 60%-90%, 9.5 min). The title compound (26.3 mg, 60.8 µmol, 38.4% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.784 min, mass calc. for C ₂₆ H ₁₉ F ₃ N ₂ O 432.44 m/z obtained 455.1 [M+Na]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8, 67 (d, J=1.5 Hz, 1H), 8.46 (d, J=4.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.00 ( dd, J=1.8, 8.8 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 7, 77 - 7.66 (m, 4H), 7.61 (dd, J=1.0, 7.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.16 (dt, J=1.0, 6.1 Hz, 1H), 1.63 - 1.54 (m, 2H), 1.35-1.28 (m, 2H).

Example 215: ^)-N(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 251) and (R)-N-(1-cyclobutylethyl)-5-(4-( trifluoromethyl)phenyl)-2-naphthamide (compound 252)

N-(1-Cyclobutylethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (122.5 mg, 0.94 mmol, 0.16 mL, 3 eq.) in DCM (2 mL) was stirred at 25°C for 1 hour. Then 1-cyclobutylethanamine (47.1 mg, 0.34 mmol, 1.1 eq., HCl) was added to the mixture and the mixture was stirred at 25°C for another 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 - 5:1). The compound N-(1cyclobutylethyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (99 mg, 0.24 mmol, 78.0% yield) was obtained as a white solid.

^)-N(1-Cyclobutylethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 251) and (R)-N-(1cyclobutylethyl)-5-(4-(trifluoromethyl)phenyl)- 2-naphthamide (compound 252).

Racemic compound N(1-cyclobutylethyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (99 mg, 0.24 mmol, 1 eq.) was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 40%-40%, min). Compound 252 (10.7 mg, 26.8 µmol, 10.7% yield) was obtained as a white solid. LCMS (ESI): RT=1.065 min, mass calc. for C ₂₄ H ₂₂ F ₃ NO 397.43 m/z obtained 398.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.43 (s,

- 230 046394

1H), 8.06 (d, J=8.3 Hz, 1H), 7.90 - 7.78 (m, 4H), 7.73 - 7.61 (m, 3H), 7.56 (d , J=7.0 Hz, 1H), 4.23 - 4.09 (m, 1H), 2.50 (br d, J=6.0 Hz, 1H), 2.19 - 2.01 (m , 2H), 1.99 - 1.77 (m, 4H), 1.17 (d, J=6.5 Hz, 3H). Compound 251 (12.7 mg, 31.8 µmol, 12.8% yield) was obtained as a white solid. LCMS (ESI): RT=1.068 min, mass calc. for C ₂₄ H ₂₂ F ₃ NO 397.43 m/z obtained 398.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.90 - 7.82 (m, 4H), 7.72 - 7.64 (m, 3H), 7.57 (dd, J=1.3, 7, 0 Hz, 1H), 4.23 - 4.13 (m, 1H), 2.58 - 2.45 (m, 1H), 2.16 - 2.02 (m, 2H), 1.97 - 1 .79 (m, 4H), 1.18 (d, J=6.8 Hz, 3H).

Example 216: ^)-N-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 253) and ^)-N -(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 254)

1-Methyl-1H-imidazole-2-carbaldehyde.

To a solution of 1-methylimidazole (3 g, 36.54 mmol, 2.91 mL, 1 eq.) in THF (30 mL) was added n-BuLi (2.5 M, 21.92 mL, 1.5 eq. .) at -78°C in an N2 atmosphere. After stirring for 1 hour, DMF (8.01 g, 109.62 mmol, 8.43 mL, 3 eq.) was added dropwise and the mixture was stirred for an additional 16 hours at 25°C. The reaction mixture was diluted with H2O (10 ml). The mixture was extracted with DCM (20 mlx3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 1:1). The 1-methylimidazole-2-carbaldehyde compound (1 g, 9.08 mmol, 24.8% yield) was obtained as a yellow oil.

(E)-2-Methyl-N-((1-methyl-1H-imidazol-2-yl)methylene)propane-2-sulfinamide.

A mixture of 1-methylimidazole-2-carbaldehyde (1 g, 9.08 mmol, 1 eq.), CuSO ₄ (2.90 g, 18.16 mmol, 2.79 ml, 2 eq.) and 2-methylpropane-2 -sulfinamide (660.4 mg, 5.45 mmol, 0.6 eq.) in DCM (5 ml) was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3 ). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 0:1). The compound (NE)-2-methyl-N-[(1methylimidazol-2-yl)methylene]propan-2-sulfinamide (500 mg, 2.34 mmol, 25.8% yield) was obtained as a yellow oil.

2-Methyl-'Y -(1-(1-methyl-1H-imidazol-2-yl)ethyl)propane-2-sulfinamide.

To a solution of (NH)-2-methyl-N-[(1-methylimidazol-2-yl)methylene]propan-2-sulfinamide (500 mg, 2.34 mmol, 1 eq.) in THF (3 ml) was added drops MeMgBr (3 M, 2.34 ml, 3 eq.). The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , EA/MeOH=1/0 - 5:1). The compound 2-methyl-N-[1-(1-methylimidazol-2-yl)ethyl]propane-2sulfinamide (90 mg, 0.39 mmol, 16.7% yield) was obtained as a white solid.

1-(1-Methyl-1H-imidazol-2-yl)ethanamine.

A mixture of 2-methyl-N-[1-(1-methylimidazol-2-yl)ethyl]propan-2-sulfinamide (90 mg, 0.39 mmol, 1 eq.) and HCl/dioxane (4 M, 98.11 µl, 1 eq.) in MeOH (1 ml) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The compound 1-(1methylimidazol-2-yl)ethanamine (50 mg, crude) was obtained as a yellow solid.

N-(1-(1-Methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

Mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (126.3 mg, 0.39 mmol, 1 eq.), DIPEA (154.8 mg, 1.20 mmol, 0.20 ml, 3 eq.) and HATU (227.8 mg, 0.59 mmol, 1.5 eq.) in DCM (1 ml) per

- 231 046394 was stirred at 25°C for 1 hour. Then 1-(1-methylimidazol-2-yl)ethanamine (50 mg, 0.39 mmol, 1 eq.) was added to the mixture and the mixture was stirred at 25°C for further 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 55%-85%, 7 min). Compound N[1-(1-methylimidazol-2-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (45 mg, 0.10 mmol, 26.6% yield) was obtained as white solid matter.

N)-N-(1-(1-Methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 253) and N)-N-(1 -(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 254).

Compound N[1-(1-methylimidazol-2-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (45 mg, 0.10 mmol, 1 eq.) was separated by SFC (column : DAICEL CHIRALPAK AD-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETON]; V%: 40%-40%, min). Compound 253 (15 mg, 35.4 µmol, 33.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.868 min, mass calc. for C ₂₄ H ₂₀ F ₃ N ₃ O 423.43 m/z obtained 424.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.52 (d, J=1.5 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.92 - 7.82 (m, 4H), 7.70 - 7.64 (m, 3H), 7.57 (dd , J=1.3, 7.0 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 6.94 (d, J=1.3 Hz, 1H), 5.53 (q, J=7.0 Hz, 1H), 3.81 - 3.73 (m, 3H), 1.69 (d, J=7.0 Hz, 3H). Compound 254 (15 mg, 35.4 µmol, 33.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.871 min, mass calc. for C ₂₄ H ₂₀ F ₃ N ₃ O 423.43 m/z obtained 424.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.39 (d, J=1.3 Hz, 1H ), 7.95 (d, J=8.3 Hz, 1H), 7.80 - 7.70 (m, 4H), 7.59 - 7.52 (m, 3H), 7.45 (dd, J=1.1, 7.1 Hz, 1H), 6.93 (d, J=0.9 Hz, 1H), 6.81 (d, J=1.0 Hz, 1H), 5.42 - 5.37 (m, 1H), 3.68 - 3.60 (m, 3H), 3.22 - 3.18 (m, 9H), 1.56 (d, J=7.0 Hz, 3H) .

Example 217: N(3-azidopropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 256)

To a solution of compound 265 (25 mg, 63.8 µmol, 1 eq.) in DMF (1 ml) at 30°C was added NaN ₃ (5.0 mg, 76.6 µmol, 1.2 eq.). The resulting mixture was stirred at 60°C for 6 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue (containing some DMF). The residue was purified by prep-HPLC (column: Waters Xbridge 150x50 10u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 59%-89%, 10 min) to obtain compound 256 (15.8 mg, 39.7 µmol, 62.3% yield) as a white solid. LCMS (ESI): RT=0.898 min, mass, calc. for C ₂₁ H ₁₇ F ₃ N ₄ O 398.14, m/z obtained 399.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=1.8 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 - 7.85 ( m, 1H), 7.78 (d, J=7.5 Hz, 3H), 7.65 - 7.58 (m, 3H), 7.52 (dd, J=1.1, 7.2 Hz , 1H), 6.55 (brs, 1H), 3.64 (q, J=6.5 Hz, 2H), 3.51 (t, J=6.5 Hz, 2H), 1.98 (quin ., J=6.5 Hz, 2H).

Example 218: N(1-(hydroxymethyl)cyclopropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 257)

To a solution of compound 218-1 (25 mg, 79 µmol, 1 eq.) and HATU (45.1 mg, 0.12 mmol, 1.5 eq.) in DMF (1 ml) at 30°C was added compound 218- 1a (8.3 mg, 95 µmol, 1.2 eq.) and TEA (24.0 mg, 0.24 mmol, 33 µl, 3 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (column:

- 232 046394

Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-LS'N|; B%: 49%-79%, 9 min) to obtain the title compound (16 mg, 42 µmol, 52.5% yield) as a white solid. LCMS (ESI): RT=0.819 min, mass, calc. for C ₂ 2Hi8F ₃ NO2 385.13, m/z obtained 386.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.87 (d, J= 8.8 Hz, 1H), 7.81 - 7.73 (m, 3H), 7.65 - 7.59 (m, 3H), 7.53 (dd, J=1.1, 7.2 Hz , 1H), 6.81 (s, 1H), 3.94 (t, J=5.1 Hz, 1H), 3.77 (d, J=5.0 Hz, 2H), 1.10 - 1 .06 (m, 2H), 1.05 - 1.01 (m, 2H)

Example 219: ^)-N-(1-amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 258)

Η

Vos. ΧχΝΗ, HCl/Dioxane

W ² --- ⁿ O 80 °C, 4 h

ABOUT

(K)-2-Aminopropanamide.

To a solution of tert-butyl-H-|(1K)-2-amino-1-methyl-2-oxo-ethyl| carbamate (1 g, 5.31 mmol, 1 eq.) in HCl/dioxane (4 M, 15 ml, 11.29 eq.) was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure. Compound (2R)-2-aminopropanamide (412 mg, 3.31 mmol, 62.2% yield, HCl) was obtained as a white solid. The crude product was used in the next step without further purification.

(R)-N-(1-Amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (50 mg, 0.15 mmol, 1 eq.) and HATU (72.1 mg, 0.18 mmol, 1.2 eq.) DIPEA (81.7 mg, 0.63 mmol, 0.11 mL, 4 eq.) was added to DCM (2 mL). After addition, the mixture was stirred at the same temperature (25°C) for 0.5 h and then (2R)-2-aminopropanamide (20.8 mg, 0.16 mmol, 1.06 eq., HCl) was added. The mixture was stirred at 25°C for 1.5 hours. The reaction mixture was added with H2O (20 ml) and extracted with EA (10 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 50%-80%, 7 min). The title compound (36 mg, 93.1 µmol, 58.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.788 min, mass calc. for C ₂₁ H ₁₇ F ₃ N ₂ O ₂ 386.37m/z obtained 409.0 [M+Na]+, ¹ H NMR (400 MHz, DMSO-d6) δ 8.69 - 8.58 (m, 2H ), 8.14 (d, J=8.3 Hz, 1H), 8.03 - 7.89 (m, 3H), 7.82 (d, J=8.8 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.60 (dd, J=1.0, 7.0 Hz, 1H), 7.44 (s, 1H), 7.04 (s, 1H), 4, 49 (quin., J=7.2 Hz, 1H), 1.39 (d, J=7.3 Hz, 3H).

Example 220: ^)-N-(1-amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 259)

HCl / Dioxane °C, 4 h

^)-2-Aminopropanamide.

To a solution of tert-butyl-N-[(^)-2-amino-1-methyl-2-oxo-ethyl]carbamate (1 g, 5.31 mmol, 1 eq.) in HCl/dioxane (4 M, 15 ml, 11.29 eq.) was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure. Compound (2S)-2-aminopropanamide (400 mg, 3.21 mmol, 60.44%

- 233 046394 yield, HCl) was obtained as a white solid. The crude product was used in the next step without further purification.

^)-N(1-Amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.) and HATU (144.2 mg, 0.37 mmol, 1.2 eq.) DIEA (163.4 mg, 1.26 mmol, 0.22 mL, 4 eq.) was added to DCM (3 mL). After addition, the mixture was stirred at 25°C for 0.5 h and then (2S)-2aminopropanamide (43.3 mg, 0.34 mmol, 1.1 eq., HCl) was added. The resulting mixture was stirred at 25°C for 1.5 hours. The reaction mixture was added with H2O (50 ml) and extracted with EA (30 ml x 3). The combined organic layers were washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 50%-80%, 7 min). The title compound (80 mg, 0.20 mmol, 65.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.789 min, mass calc. for C ₂ iHi ₇ F ₃ N ₂ O ₂ 386.37 m/z obtained 409.0 [M+Na]+, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.59 (m , 2H), 8.13 (d, J=8.0 Hz, 1H), 8.00 -7.89 (m, 3H), 7.81 (d, J=9.0 Hz, 1H), 7 .77 - 7.67 (m, 3H), 7.60 (d, J=6.3 Hz, 1H), 7.43 (br s, 1H), 7.03 (s, 1H), 4.49 (quin., J=7.2 Hz, 1H), 1.38 (d, J=7.0 Hz, 3H).

Example 221: N[2-hydroxy-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 260)

Methyl 8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxylate.

To a mixture of compound 221-1 (100 mg, 0.38 mmol, 1 eq.) and compound 221-1a (107.1 mg, 0.56 mmol, 1.5 eq.) in dioxane (3 ml) and H2O ( 0.5 ml) Na ₂ CO ₃ (79.7 mg, 0.75 mmol, 2 eq.) and Pd(dppf)Cl ₂ (27.5 mg, 37.6 µmol, 0.1 eq.) were added. The mixture was degassed and purged with N2 3 times. The mixture was stirred at 80°C for 3 hours. The desired compound was detected by LCMS. The mixture was cooled to 25°C, diluted with water (10 ml) and extracted with EtOAc (20 mlx3). The combined organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/petroleum ether=0% - 20%) to give methyl compound 221-2 (110 mg, 0.32 mmol, 84.8% yield) as a white solid. LCMS (ESI): RT=0.912 min, mass calc. for C ₁₈ H ₁₂ F ₃ NO ₂ 331.08, m/z obtained 331.9 [M+H]+.

8-[4-(Trifluoromethyl)phenyl]quinoline-3-carboxylic acid.

To a mixture of compound 221-2 (100 mg, 0.30 mmol, 1 eq.) in MeOH (4 ml) and H2O (1 ml) was added LiOH-H ₂ O (126.7 mg, 3.02 mmol, 10 eq. .). The mixture was stirred at 50°C for 1 hour. The mixture was cooled to 25°C and concentrated. The residue was diluted with water (15 ml), the pH was adjusted to 5~6 using HCl (1 M), extracted with EtOAc (20 mlx3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give 221-3 (100 mg, crude) as a white solid. LCMS (ESI): RT=0.819 min, mass calc. for C ₁₇ H ₁₀ F ₃ NO ₂ 317.07, m/z obtained 317.9 [M+H]+.

Ν-[2-Γ hydroxy-1 -(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

DIEA (81.5 mg, 0.63 mmol, 0.11 ml, 4 eq.). The mixture was stirred at 25°C for 0.5 h. Compound 221-3a (39.9 mg, 0.19 mmol, 1.2 eq., 2 HCl salt) was added to the mixture. The mixture was stirred at 25°C for 2 hours. The desired compound was detected by LCMS. The mixture was concentrated. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 45%-75%, 7.8 min ) to obtain the title compound (39.6 mg, 90.7 µmol, 57.5% yield) as a white solid. LCMS (ESI): RT=0.723 min, mass calc. for C ₂₄ H ₁₈ F ₃ N ₃ O ₂ 437.14, m/z obtained 438.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 9.38 (d, J=2.4 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.56 (d, J= 4.0 Hz, 1H), 8.20 (br d, J=6.8 Hz, 1H), 7.99 - 7.97 (m,

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1H), 7.82 - 7.70 (m, 7H), 7.51 (d, J=8.4 Hz, 1H), 7.31 - 7.28 (m, 1H), 5.43 - 5 .39 (m, 1H), 4.19 - 4.15 (m, 1H), 4.09 - 4.05 (m, 1H).

Example 222: N-(2-33 odoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 261)

N(2-Chloroethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 222-1 (50 mg, 0.16 mmol, 1 eq.), compound 222-1a (22.0 mg, 0.19 mmol, 1.2 eq., HCl) and HATU (78.1 mg , 0.21 mmol, 1.3 eq.) TEA (48.0 mg, 0.47 mmol, 66 μl, 3 eq.) was added to DMF (1 ml) at 30°C. The resulting mixture was stirred at 30°C for 16 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, gradient 0~50% ethyl acetate/petroleum ether eluent approximately 30 ml/min) and prep-TLC (PE:EA=3:1, UV) to give compound 222-2 (40 mg, 89.6 µmol, 56.7% yield) as a white solid. LCMS (ESI): RT=0.886 min, mass, calc. for C ₂₀ H ₁₅ ClF ₃ NO 377.08, m/z obtained 377.9 [M+H]+.

N(2-Azidoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

NaN ₃ (8.3 mg, 0.13 mmol, 1.2 eq.) was added to a solution of compound 222-2 (40 mg, 0.11 mmol, 1 eq.) in DMF (1 ml) at 30°C. The resulting mixture was stirred at 60°C for 3 hours. The reaction mixture was quenched with water (10 ml) and extracted with EA (10 mlx3). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue (containing some DMF). The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 63%-93%, 9.5 min ) to obtain the title compound (6.5 mg, 17.0 µmol, 16.0% yield) as a white solid. LCMS (ESI): RT=0.875 min, mass, calc. for C ₂₀ H ₁₅ F ₃ N ₄ O 384.12, m/z obtained 385.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J=1.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.91 - 7.87 (m, 1H), 7.82 - 7.76 (m, 3H), 7.66 - 7.60 (m, 3H), 7.52 (dd, J=1.1, 7.2 Hz, 1H ), 6.60 (brs, 1H), 3.72 (q, J=5.7 Hz, 2H), 3.67 - 3.60 (m, 2H).

Example 223: N(2-(pyridin-2-yl)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 262)

To a solution of compound 223-1 (25 mg, 79 µmol, 1 eq.) and HATU (45.1 mg, 0.12 mmol, 1.5 eq.) in DMF (1 ml) at 30°C was added compound 223- 1a (12.9 mg, 95 µmol, 1.2 eq.) and TEA (24.00 mg, 0.24 mmol, 33 µl, 3 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; V%: 68%-78%, 8.5 min) to obtain the title compound (20 mg, 46 µmol, 58.2% yield) as a white solid. LCmS (ESI): RT=0.789 min, mass, calc. for C ₂₆ H ₂ iF ₃ N ₂ O 434.16 m/z, 435.0 [M+H]+ was obtained; 1H NMR (400 MHz, CDCl ₃ ) δ 9.10 (s, 1H), 8.59 (td, J=0.8, 4.1 Hz, 1H), 8.52 (d, J=1.5 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97 - 7.88 (m, 2H), 7.81 - 7.77 (m, 3H), 7.65 - 7.60 (m, 3H), 7.53 - 7.49 (m, 2H), 1.94 (s, 6H)

Example 224: N(1-hydroxy-2-methylpropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 263)

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Compound 224-1a ( 224-1a ( 6.8 mg, 76 µmol, 7 µl, 1.2 eq.) and TEA (19.2 mg, 0.19 mmol, 26 µl, 3 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, vol. /vol)-ACN]; V%: 55%-85%, 7.8 min) to obtain the title compound (20 mg, 52 μmol, 81.6% yield) as a white solid. LCMS (ESI): RT=0.866 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO ₂ 387.14, m/z obtained 388.0 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J=1.4 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.87 (d, J =8.9 Hz, 1H), 7.80 - 7.74 (m, 3H), 7.63 - 7.59 (m, 3H), 7.54 - 7.51 (m, 1H), 6, 34 (brs, 1H), 4.62 (t, J=6.2 Hz, 1H), 3.76 (d, J=6.1 Hz, 2H), 1.48 (s, 6H)

Example 225: N(tert-butyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 264)

To a solution of compound 225-1 (25 mg, 79 µmol, 1 eq.) and HATU (45.1 mg, 0.12 mmol, 1.5 eq.) in DMF (1 ml) at 30°C was added compound 225- 1a (6.9 mg, 95 µmol, 10 µl, 1.2 eq.) and TEA (24.0 mg, 0.24 mmol, 33 µl, 3 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 μm; mobile phase: [water (0.05% ammonium hydroxide, v/v)ACN]; V%: 70%-100%, 7 min) to obtain the title compound (22 mg, 59 μmol, 74.9% yield) as a white solid. LCMS (ESI): RT=0.939 min, mass, calc. for C ₂₂ H ₂₀ F ₃ NO 371.15, m/z obtained 372.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J=1.1 Hz, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.87 7.84 (m , 1H), 7.80 - 7.74 (m, 3H), 7.63 - 7.58 (m, 3H), 7.49 (d, J=7.0 Hz, 1H), 6.11 ( brs, 1H), 1.54 (s, 9H)

Example 226: N(3-chloropropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 265)

To a solution of compound 226-1 (25 mg, 79 µmol, 1 eq.) and HATU (45.1 mg, 0.12 mmol, 1.5 eq.) in DMF (1 ml) at 30°C was added compound 226- 1a (12.3 mg, 95 µmol, 10 µl, 1.2 eq.) and TEA (24.00 mg, 0.24 mmol, 33 µl, 3 eq.). The mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, vol. /vol)-ACN]; V%: 65%-95%, 7 min) to obtain the title compound (20 mg, 51 μmol, 64.6% yield) as a white solid. LCMS (ESI): RT=0.900 min, mass, calc. for C ₂₁ H ₁₇ ClF ₃ NO 391.10, m/z obtained 392.0 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=1.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.91 - 7.84 ( m, 1H), 7.82 - 7.74 (m, 3H), 7.65 - 7.58 (m, 3H), 7.52 (dd, J=1.0, 7.0 Hz, 1H) , 6.54 (brs, 1H), 4.93 - 4.89 (m, 1H), 3.75 - 3.66 (m, 4H), 2.19 (quin., J=6.5 Hz, 2H)

Example 227: ^)-N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide (compound 266)

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^)-5-Chloro-M(1-(pyridin-2-yl)ethyl)quinoxaline-2-carboxamide.

5-Chloroquinoxaline-2-carboxylic acid (70 mg, 0.33 mmol, 1 equiv.), ^)-1-(pyridin-2-yl)ethan-1amine (49 mg, 0.4 mmol, 1.2 equiv. .) and HATU (255 mg, 0.67 mmol, 2 equiv.) were dissolved in DMF (0.5 ml) at room temperature. DIEA (0.23 ml, 1.34 mmol, 4 equiv.) was added slowly and the mixture was stirred at RT until the acid was consumed as determined by LCMS, 3 hours. Once complete, the reaction mixture was diluted with H ₂ O and stirred briefly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product as a brown solid, 80 mg, 67%, LCMS [M+H]+=313.

^)-M(1-(Pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide.

^)-5-chloro-M(1-(pyridin-2-yl)ethyl)quinoxaline-2-carboxamide (80 mg, 0.26 mmol, 1 equiv.), (4(trifluoromethyl)phenyl)boronic acid (58 mg, 0.31 mmol, 1.2 equiv.), Pd(PPh ₃ ) ₄ (3 mg, 0.026 mmol, 0.1 equiv.) and 4:1 dioxane/4 n K ₂ CO ₃ (aq) ( 1 ml:0.25 ml) purged thoroughly with N2 for 10 min. The reaction mixture was sealed in a vessel under microwave irradiation and irradiated at 100°C for 30 min. The mixture was cooled to room temperature, diluted with EtOAc, washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC with a gradient of 0-25% THF in DCM to give the title compound as a yellow solid (100 mg, 93%). LCMS [M+H]+=423. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.64 (d, J=6.97 Hz, 3H) 5.39 (quin., J=7.13 Hz, 1H) 7.48 - 7 .63 (m, 1H) 7.79 (d, J=7.98 Hz, 1H) 7.83 - 7.92 (m, 4H) 8.02 - 8.15 (m, 3H) 8.31 (dd, J=7.15, 2.66 Hz, 1H) 8.70 (dd, J=5.23, 0.73 Hz, 1H) 9.43 (s, 1H) 9.58 (d, J =7.70 Hz, 1H).

Example 228: ^)-M(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide (compound 267)

^)-5-Chloro-M(1-hydroxypropan-2-yl)quinoxaline-2-carboxamide.

5-Chloroquinoxaline-2-carboxylic acid (70 mg, 0.33 mmol, 1 equiv.), ^)-2-aminopropan-1-ol (30 mg, 0.4 mmol, 1.2 equiv.) and HATU ( 255 mg, 0.67 mmol, 2 equiv.) was dissolved in DMF (0.5 ml) at RT. DIEA (0.23 ml, 1.34 mmol, 4 equiv.) was added slowly and the mixture was stirred at RT. until the acid was consumed as determined by LCMS, 3 hours. Once complete, the reaction mixture was diluted with H ₂ O and stirred briefly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product as a brown solid, 80 mg, 90%, LCMS [M+H]+=266.

^)-M(1-Hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide.

^)-5-Chloro-M(1-hydroxypropan-2-yl)quinoxalin-2-carboxamide (80 mg, 0.3 mmol, 1 equiv.), (4(trifluoromethyl)phenyl)boronic acid (68 mg, 0 .36 mmol, 1.2 equiv.), Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol, 0.1 equiv.) and 4:1 dioxane/4 n K ₂ CO ₃ (aq) (1 ml:0.25 ml) purged thoroughly with N2 for 10 min. The reaction mixture was sealed in a vessel under microwave irradiation and irradiated at 100°C for 35 min. The mixture was cooled to room temperature, diluted with EtOAc, washed with H ₂ O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC with a gradient of 0-25% THF in DCM to give the title compound as a yellow solid (73 mg, 65%). LCMS [M+H]+=376.

Example 229: Misopropyl-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide (compound 268)

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5-Chloroquinoxaline-2-carboxylic acid.

5-Chloroquinoxaline-2-carbonitrile (500 mg, 2.6 mmol, 1 equiv.), 4 N NaOH (aq) (6 ml) and H2O (6 ml) were heated to 100°C in a sealed vessel. The mixture was stirred at 100°C for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc and the organic layer was separated. The aqueous layer was acidified with 2N HCl and extracted with EtOAc. The organic layer was dried with NasSO4 and concentrated to give the desired product, a colorless solid, 366 mg, 67%. LCMS [M+H]+=209.

6-Chloro-Ni-isopropylquinoxaline-2-carboxamide.

5-Chloroquinoxaline-2-carboxylic acid (70 mg, 0.33 mmol, 1 equiv.), propan-2-amine (24 mg, 0.4 mmol, 1.2 equiv.) and HATU (255 mg, 0. 67 mmol, 2 equiv.) was dissolved in DMF (0.5 ml) at RT. DIEA (0.23 ml, 1.34 mmol, 4 equiv.) was added slowly and the mixture was stirred at RT until the acid was consumed. , as determined by LCMS, 3 hours. Once complete, the reaction mixture was diluted with H2O and stirred briefly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a brown solid, 27 mg, 33%, LCMS [M+H]+=250.

No. Isopropyl-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide.

5-Chloro-Nisopropylquinoxaline-2-carboxamide (27 mg, 0.11 mmol, 1 equiv.), (4(trifluoromethyl)phenyl)boronic acid (25 mg, 0.13 mmol, 1.2 equiv.), Pd (PPh ₃ ) ₄ (12 mg, 0.01 mmol, 0.1 equiv.) and 4:1 dioxane/4 N K ₂ CO ₃ (aq) (0.8 ml:0.2 ml) were thoroughly purged with N2 within 10 min. The reaction mixture was sealed in a vessel under microwave irradiation and irradiated at 90°C for 30 min. The mixture was cooled to room temperature, diluted with EtOAc, washed with H ₂ O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC with a gradient of 0-25% THF in DCM to give the title compound as a brown solid (10 mg, 26%). LCMS [M+H]+=360.

Example 230: ^)-N(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 269) and ^)-N(1-(oxetan-3 -yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 270)

N-(1 -(Oxetan-3 -yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (122.5 mg, 0.94 mmol, 0.16 mL, 3 eq.) in DCM (2 mL) was stirred at 25°C for 1 hour. Then 1-(oxetan-3-yl) was added to the mixture. ethanamine (35.1 mg, 0.34 mmol, 1.1 eq.) and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 - 5:1). The compound N-[1(oxetan-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (126 mg, 0.29 mmol, 91.7% yield) was obtained as a colorless oil .

^)^-(1-(Oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 269) and (R)-N-(1(oxetan-3-yl )ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 270)

The racemic compound N[1-(oxetan-3-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (99 mg, 0.24 mmol, 1 eq.) was purified by SFC (column: REGIS ( s,s) WHELK-O1 (250

- 238 046394 mmx30 mm, 5 microns); mobile phase: [0.1% NH3H2O ETOH]; V%: 45%-45%, min). Compound 269 (13.7 mg, 33.7 µmol, 13.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.956 min, mass calc. for C ₂₃ H ₂₀ F ₃ NO ₂ 399.41 m/z obtained 400.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.96 (d , J=8.1 Hz, 1H), 7.78 - 7.71 (m, 4H), 7.60 - 7.52 (m, 3H), 7.46 (dd, J=1.1, 7 ,1 Hz, 1H), 4.74 - 4.66 (m, 2H), 4.53 (t, J=6.3 Hz, 1H), 4.51 - 4.45 (m, 1H), 4 .43 (t, J=6.3 Hz, 1H), 3.17 - 3.07 (m, 1H), 1.12 (d, J=6.6 Hz, 3H). Compound 270 (18.5 mg, 45.5 µmol, 18.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.959 min, mass calc. for C ₂₃ H ₂₀ F ₃ NO ₂ 399.41 m/z obtained 400.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.96 (d , J=8.3 Hz, 1H), 7.78 - 7.70 (m, 4H), 7.61 - 7.53 (m, 3H), 7.47 (d, J=7.0 Hz, 1H), 4.73 - 4.67 (m, 2H), 4.54 (t, J=6.1 Hz, 1H), 4.50 - 4.46 (m, 1H), 4.43 (t , J=6.3 Hz, 1H), 3.17 3.08 (m, 1H), 1.13 (d, J=6.8 Hz, 3H).

Example 231: ^)-N-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide (compound 271)

-Chloroquinoxaline-2-carbonitrile.

2,5-Dichloroquinoxaline (1 g, 5 mmol, 1 equiv.), Zn(CN) ₂ (294 mg, 2.5 mmol, 0.5 equiv.), Pd(PPh ₃ ) ₄ (578 mg, 0.5 equiv.), 5 mmol, 0.1 equiv.) and DMF (10 ml, 0.5 M) were thoroughly purged with N2 for 10 min. The reaction mixture was heated at 120°C for 18 hours. The mixture was carefully added to 60 ml of rapidly stirring water and the resulting solid was filtered and dried to obtain 5chloroquinoxaline-2-carbonitrile (850 mg, 90% yield) as a colorless solid. LCMS [M+H]+=190.

5-(4-(Trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid.

5-Chloroquinoxaline-2-carbonitrile (100 mg, 0.53 mmol, 1 equiv.), (4(trifluoromethyl)phenyl)boronic acid (120 mg, 0.63 mmol, 1.2 equiv.), K ₃ PO ₄ (281 mg, 1.33 mmol, 2.5 equiv.), Pd(PPh ₃ ) ₄ (61 mg, 0.05 mmol, 0.1 equiv.) and 4:1 dioxane/H ₂ O (2 ml: 0.5 ml, 0.2 M) was thoroughly purged with N2 for 10 min. The reaction mixture was sealed in a vessel under microwave irradiation and irradiated at 120°C for 70 minutes. The mixture was cooled to room temperature, diluted with EtOAc, carefully neutralized with 1 N HCl (aq) and separated. The organic layer was washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC with a gradient of 0 - 10% MeOH in DCM to give 5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid (25 mg, 0.08 mmol, 15% yield). LCMS [M+H]+=319.

^)-H-(1-Methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide.

5-(4-(Trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid (1 equiv.), ^)-1-methoxypropan-2amine (1.2 equiv.) and HATU (1.2 equiv.) were dissolved in DMF ( 0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. Once complete, the reaction mixture was diluted with H2O and stirred quickly within 20 min. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 6 mg, 55%, LCMS [M+H]+=390. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.26 - 1.32 (m, 3H) 3.43 - 3.47 (m, 3H) 3.51 - 3.56 (m, 2H) 4 .30 - 4.36 (m, 1H) 8.00 8.07 (m, 3H) 8.37 (dd, J=8.35, 1.50 Hz, 1H) 8.52 (dd, J=7 .29, 1.46 Hz, 1H) 8.63 (d, J=8.12 Hz, 2H) 9.79 (s, 1H) 10.02 (d, J=7.65 Hz, 1H).

Example 232: R)-N-(pent-3-yn-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 272) and (R)N(pent-3-yn- 2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 273)

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No. Ethylidene-2-methylpropane-2-sulfinamide.

To a mixture of 2-methylpropane-2-sulfinamide (5 g, 41.25 mmol, 1 eq.) in DCM (50 mL) was added acetaldehyde (9.09 g, 206.27 mmol, 11.58 mL, 5 eq.) and MgSO ₄ (24.83 g, 206.27 mmol, 5 eq.). The mixture was stirred for 12 hours at 25°C. The mixture was filtered and the filter cake was washed with EA (20 mlx3). The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 - 50:1). Naethylidene-2-methylpropane-2-sulfinamide compound (5 g, 33.96 mmol, 82.3% yield) was obtained as a light yellow oil.

2-Methyl-N(pent-3-yn-2-yl)propan-2-sulfinamide.

To a mixture of Na-ethylidene-2-methylpropane-2-sulfinamide (1 g, 6.79 mmol, 1 eq.) in THF (5 ml) was added brom(prop-1-ynyl)magnesium (0.5 M, 16.30 ml, 1.2 eq.). The mixture was stirred for 2 hours at -78°C. The mixture was quenched with EA (30 ml) and the mixture was extracted with EA (20 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was used in the next step without further purification. The compound 2-methylNa(1-methylbut-2-ynyl)propane-2-sulfinamide (1.5 g, crude) was obtained as a yellow oil.

Pent-3-in-2-amine.

To a mixture of 2-methyl-N-(1-methylbut-2-ynyl)propane-2-sulfinamide (1 g, 5.34 mmol, 1 eq.) in MeOH (3 ml) was added HCl/EtOAc (4 M, 19 .10 ml, 14.31 eq.). The mixture was stirred for 1 hour at 25°C. The mixture was concentrated in vacuo. The residue was used in the next step without further purification. Pent-3-yn-2-amine compound (1 g, crude) was obtained as a yellow oil.

No.(Pent-3-yn-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

DIPEA (122.5 mg, 0.94 mmol, 0.16 ml, 3 equiv.) and HATU (240.4 mg, 0.63 mmol, 2 equiv.). The mixture was stirred for 1 hour at 25°C. Pent-3-yn-2-amine (78.8 mg, 0.94 mmol, 3 eq.) was added to the mixture. The mixture was stirred for 1 hour at 25°C. The mixture was quenched with H ₂ O (30 ml) and the mixture was filtered and the filter cake was washed with EA (20 ml x 3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 56%-86%, 8.5 min). Compound N(1-methylbut-2-ynyl)-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (16 mg, 41.9 µmol, 13.2% yield) was obtained as a white solid.

^)-N(Pent-3-in-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 272) and ^)-N(pent-3in-2-yl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 273).

Na(1-methylbut-2-ynyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (16 mg, 41.9 μmol, 1 eq.) was purified by SFC. The racemic compound was purified by pre-SFC method (column: DAICEL CHIRALPAK AS-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; V%: 20%-20%, min). Compound 273 (3.1 mg, 8.2 mmol) was obtained as a white solid. LCMS (ESI): RT=0.918 min, mass calc. for C ₂₃ Hi ₈ F ₃ NO 381.39 m/z obtained 382.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.09 (d, J =8.3 Hz, 1H), 7.91 - 7.84 (m, 4H), 7.72 - 7.65 (m, 3H), 7.58 (dd, J=1.1, 7.1 Hz, 1H), 4.99 4.91 (m, 1H), 1.84 (d, J=2.3 Hz, 3H), 1.50 (d, J=6.9 Hz, 3H). Compound 272 (2.7 mg, 7.2 μmol) was obtained as a white solid. LCMS (ESI): RT=0.910 min, mass calc. for C ₂₃ H ₁₈ F ₃ NO 381.39 m/z obtained 382.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.09 (d, J =8.3 Hz, 1H), 7.91 - 7.83 (m, 4H), 7.74 - 7.65 (m, 3H), 7.59 (d, J=6.8 Hz, 1H) , 4.98 - 4.93 (m, 1H), 1.84 (d, J=2.3 Hz, 3H), 1.50 (d, J=6.9 Hz, 3H).

Example 233: R)-N(but-3-yn-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 274) and (R)N(but-3-yn-2 -yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 275)

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N-(But-3-yn-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (122.5 mg, 0.94 mmol, 0.16 mL, 3 eq.) in DCM (2 mL) was stirred at 25°C for 1 hour. But-3-yn-2-amine (36, 7 mg, 0.34 mmol, 1.1 eq., HCl) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 - 5:1). The compound X-(1-methylprop-2ynyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (97 mg, 0.26 mmol, 83.2% yield) was obtained as a white solid.

^)-H-(But-3-in-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 274) and ^)-H-(but-3-in2-yl) -5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 275).

A(1-Methylprop-2-ynyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (97 mg, 0.26 mmol, 1 eq.) was purified by SFC. The racemic compound was separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm x 30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 30%-30%, min). Compound 274 (18.6 mg, 50.6 µmol, 19.1% yield) was obtained as a white solid. LCMS (ESI): RT=1.009 min, mass calc. for C ₂₂ H ₁₆ F ₃ NO 367.36 m/z obtained 368.0 [M+H]+, ¹ H NMR (400 MHz, DMSO-de) δ 9.08 (d, J=8.0 Hz, 1H), 8.60 (d, J=1.3 Hz, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.97 -7.89 (m, 3H), 7, 82 (d, J=9.0 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.61 (d, J=6.3 Hz, 1H), 4.92 (dt, J =2.3, 7.4 Hz, 1H), 3.23 (d, J=2.3 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H). Compound 275 (25.5 mg, 69.4 µmol, 26.2% yield) was obtained as a white solid LCMS (ESI): RT=1.006 min, mass calc. for C22H16F3NO 367.36 m/z obtained 368.0 [M+H]+, ¹ H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=7.8 Hz, 1H), 8.60 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.97 - 7.91 (m, 3H), 7.82 (d, J=8.8 Hz, 1H) , 7.77 - 7.68 (m, 3H), 7.63 - 7.59 (m, 1H), 4.96 - 4.88 (m, 1H), 3.23 (d, J=2, 3 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H).

Example 234: ^)-H-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 276) and ^)-H-(1- (1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 277)

A(1-(1H-Imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (122.5 mg, 0.94 mmol, 0.16 mL, 3 eq.) in DCM (2 mL) was stirred at 25°C for 1 hour. Then 1-(III-imidazol-4-yl)ethanamine (64.0 mg, 0.34 mmol, 1.1 eq., 2 HCl) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H ₂ O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 27%-57%, 8.5 min). Compound A[1-(III-imidazol-4-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (56 mg, 0.13 mmol, 43.2% yield) was obtained as yellow solid matter.

^)-H-(1-(1H-Imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 276) and (R)A(1-(1H-imidazole -4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 277).

The compound N-[1-(1H-imidazol-4-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (56 mg, 0.13 mmol, 1 eq.) was purified by SFC . The racemic compound was separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mmx30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; V%: 30%-30%, min). Compound 276 (24 mg, 58.0 µmol, 42.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.847 min, mass calc. for C ₂₃ H ₁₈ F ₃ N ₃ O 409.40 m/z obtained 410.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.09 ( br d, J=8.3 Hz, 1H), 7.98 - 7.80 (m, 4H), 7.77 - 7.63 (m, 4H), 7.59 (br d, J=7, 1 Hz, 1H), 5.63 (br d, J=7.1 Hz, 1H), 4.41 - 4.34 (m, 3H), 1.75 (d, J=7.1 Hz, 3H ). Compound 277 (10 mg, 24.1 µmol, 17.6% yield) was obtained as a white solid. LCMS (ESI): RT=0.846 min, mass calc. for C ₂₃ H ₁₈ F ₃ N ₃ O 409.40 m/z obtained 410.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ

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8.50 (s, 1H), 8.05 (br d, J=8.0 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.83 (br d, J=9, 0 Hz, 3H), 7.71 - 7.59 (m, 4H), 7.59 7.50 (m, 1H), 7.07 (s, 1H), 5.39 (q, J=6, 8 Hz, 1H), 1.64 (d, J=7.0 Hz, 3H).

Example 235: ^)-N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 278) and ^)-N -(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 279)

N(1-(2-Methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and N-(1-(1-methyl-1Htetrazol-5-yl )ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of Na[1-(2H-tetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (0.3 g, 0.72 mmol, 1 eq.) in DMF (3 ml) CH3I (207.0 mg, 1.46 mmol, 90.8 µl, 2 eq.) and K2CO3 (302.3 mg, 2.19 mmol, 3 eq.) were added. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to

H2O (10 ml). The mixture was extracted with ethyl acetate (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 48%-78%, 8.5 min). Compound N[1-(1-methyltetrazol-5-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (15 mg, 35.2 μmol, 4.8% yield) was obtained as white solid matter. Compound N[1-(2-methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide (21 mg, 49.3 μmol, 6.7% yield) was obtained as a white solid substances.

^)-N-(1-(2-Methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound

278) and ^)-N-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 279).

Na[1-(2-Methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (21 mg, 49.3 μmol, 1 eq.) was purified by SFC. The residue was purified by prep-SFC (DAICEL CHIRALPAK ADH (250 mm x 30 mm, 5 µm), 0.1% NH3H2O ETOH, 40%, 40%). Compound 278 (2.7 mg, 6.5 µmol, 13.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.851 min, mass calc. for C22H18F3N5O 425.41 m/z obtained 426.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.09 (br d, J=8.3 Hz, 1H), 7.98 - 7.80 (m, 4H), 7.77 - 7.63 (m, 4H), 7.59 (br d, J=7.1 Hz, 1H), 5.63 ( br d, J=7.1 Hz, 1H), 4.41 - 4.34 (m, 3H), 1.75 (d, J=7.1 Hz, 3H). Compound 279 (2.8 mg, 6.6 µmol, 13.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.852 min, mass calc. for C22H18F3N5O 425.41 m/z obtained 426.0 [M+H]+, 1H NMR (400 MHz, CD3OD) δ 8.53 (d, J=1.3 Hz, 1H), 8.10 - 8, 04 (m, 1H), 7.93 - 7.81 (m, 4H), 7.71 - 7.64 (m, 3H), 7.59 - 7.54 (m, 1H), 5.61 (q, J=7.1 Hz, 1H), 4.38 - 4.32 (m, 3H), 1.77 - 1.70 (m, 3H).

Example 236: ^)-N-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 280) and ^)-N -(1-(1-methyl-III-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 281)

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Y-(1-(2-Methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide and Y-(1-(1-methyl-1Htetrazol-5 - yl)ethyl)-5 -(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of Na[1-(2H-tetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (0.3 g, 0.72 mmol, 1 eq.) in DMF (3 ml) CH ₃ I (207.0 mg, 1.46 mmol, 90.8 µl, 2 eq.) and K ₂ CO ₃ (302.3 mg, 2.19 mmol, 3 eq.) were added. The mixture was stirred at 25°C for 3 hours. The reaction solution was added to

H2O (10 ml). The mixture was extracted with ethyl acetate (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 48%-78%, 8.5 min).

The compound N-[1-(1-methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (15 mg, 35.2 μmol, 4.8% yield) was prepared in as a white solid. The compound N-[1-(2methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (21 mg, 49.3 µmol, 6.7% yield) was obtained as white solid matter.

^)-M-(1-(1-Methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound

280) and ^)-M-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 281).

Na[1-(1-Methyltetrazol-5-yl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (15 mg, 35.2 μmol, 1 eq.) was purified by SFC. The residue was purified by prep-SFC (DAICEL CHIRALPAK ADH (250 mm x 30 mm, 5 µm), 0.1% NH ₃ H ₂ O ETOH, 40%, 40%). Compound 280 (2.9 mg, 6.8 µmol, 19.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.839 min, mass calc. for C ₂₂ H ₁₈ F ₃ N ₅ O 425.41 m/z obtained 426.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 7.96 ( d, J=8.3 Hz, 1H), 7.79 - 7.70 (m, 4H), 7.57 (br d, J=7.1 Hz, 3H), 7.47 (d, J= 7.0 Hz, 1H), 5.54 (d, J=7.0 Hz, 1H), 4.50 (s, 2H), 4.09 (s, 3H), 1.69 (d, J= 7.0 Hz, 3H). Compound 281 (2.9 mg, 6.8 µmol, 19.3% yield) was obtained as a white solid. LCMS (ESI): RT=0.839 min, mass calc. for C ₂₂ H ₁₈ F ₃ N ₅ O 425.41 m/z obtained 426.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 8.09 ( d, J=8.1 Hz, 1H), 7.92 - 7.83 (m, 4H), 7.72 - 7.66 (m, 3H), 7.60 (d, J=6.9 Hz , 1H), 5.66 (d, J=7.0 Hz, 1H), 4.21 (s, 3H), 1.81 (d, J=7.0 Hz, 3H).

Example 237: ^)-M-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 282) and ^)-M-(1-(pyrazine -2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 283)

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (122.5 mg, 0.94 mmol, 0.16 ml, 3 eq.) b DCM (2 ml) was stirred at 25°C for 1 hour. Then 1-pyrazin-2-ylethanamine (42.8 mg , 0.34 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v) - ACN]; V%: 50%-80%, 7.8 min) . The racemic compound (14 mg, 32.5 µmol, 10.3% yield) was obtained as a white solid. The racemic compound was separated by the SFC method (column:

REGIS (s,s) WHELK-01 (250 mmx30 mm, 5 µm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; In%: 50%-50%,

- 243 046394 min). Compound 282 (4.7 mg, 11.0 µmol, 33.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.964 min, mass calc. for C ₂₄ H ₁₈ F ₃ N ₃ O 421.41 m/z obtained 422.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.74 (d, J=1.3 Hz, 1H), 8.62 (dd, J=1.5, 2.5 Hz, 1H), 8.54 (d, J=1.5 Hz, 1H), 8.51 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.88 - 7.82 (m, 3H), 7.72 - 7.64 (m, 3H), 7.58 (dd, J=1.3, 7.0 Hz, 1H), 5.41 (q, J=7.0 Hz, 1H), 1.69 ( d, J=7.0 Hz, 3H). Compound 283 (6.4 mg, 15.0 µmol, 45.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.970 min, mass calc. for C24H18F3N3O 421.41 m/z obtained 422.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.72 (d, J=1.4 Hz, 1H), 8.61 (dd , J=1.6, 2.4 Hz, 1H), 8.52 (dd, J=1.9, 12.1 Hz, 2H), 8.08 (d, J=8.3 Hz, 1H) , 7.93 - 7.81 (m, 4H), 7.71 - 7.64 (m, 3H), 7.57 (dd, J=1.1, 7.0 Hz, 1H), 5.40 (q, J=7.0 Hz, 1H), 1.68(d, J=7.1 Hz, 3H).

Example 238: ^)A(1-(2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 284) and ^)A(1-(2H-tetrazole) -5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 285)

tert-Butyl(1-amino-1-oxopropan-2-yl)carbamate.

To a mixture of 2-(tert-butoxycarbonylamino)propanoic acid (2.5 g, 13.21 mmol, 1 eq.) in DMF (10 ml) was added EDCI (3.80 g, 19.82 mmol, 1.5 eq. ) and ammonium 1-oxidobenzotriazole (3.02 g, 19.82 mmol, 1.5 eq.). The mixture was stirred for 12 hours at 25°C. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was used in the next step without further purification. The compound tert-butyl-N(2-amino-1-methyl-2-oxoethyl)carbamate (2.5 g, crude) was obtained as a white solid.

tert-Butyl(1-cyanoethyl)carbamate.

Pyridine (2.52 g, 31.88 mmol, 2.57 ml, 3 eq.) and TFAA (4.46 g, 21.25 mmol, 2.96 ml, 2 eq.). The mixture was stirred for 2 hours at 0°C. The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was used in the next step without further purification. The compound tert-butyl-N(1-cyanoethyl)carbamate (1.8 g, crude) was obtained as a white solid.

tert-Butyl(1 -(2H-tetrazol-5-yl)ethyl)carbamate.

To a solution of tert-butyl A(1-cyanoethyl)carbamate (1.8 g, 10.58 mmol, 1 eq.) in DMF (20 ml) was added NaN ₃ (3.19 g, 49.07 mmol, 4.64 eq. .) and NH4Cl (1.70 g, 31.73 mmol, 1.11 ml, 3 eq.). The mixture was stirred at 120°C for 12 hours. The reaction solution was added to H2O (20 ml). The pH of the aqueous phase was adjusted to 5 and extracted with ethyl acetate (50 mlx3). The combined organic phase was washed with brine (30 mlx5), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was used in the next step without purification. The compound tert-butyl-N[1-(III-tetrazol-5yl)ethyl]carbamate (1.2 g, crude) was obtained as a yellow oil.

1-(2H-Tetrazol-5-yl)ethanamine.

To a mixture of tert-butyl-N[1-(III-tetrazol-5-yl)ethyl]carbamate (0.2 g, 0.93 mmol, 1 eq.) was added HCl/EtOAc (4 M, 3.36 ml, 14.31 eq.). The mixture was stirred for 3 hours at 25°C. The mixture was quenched with H2O (30 ml) and the pH of the mixture was adjusted to 8 with NaOH (4 M). The mixture was extracted with EA (10 mlx3). The combined organic phase was washed with brine (10 mlx3), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was used in the next step without further purification. The compound 1-(1H-tetrazol-5-yl)ethanamine (0.087 g, crude) was obtained as a yellow oil.

^)-N(1-(2H-Tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 284) and (R)-N(1-(2H-tetrazole -5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 285).

HATU (240.4 mg, 0.63 mmol, 2 eq.) and Et ₃ N (95.9 mg, 0.94 mmol, 0.13 ml, 3 eq.). The mixture was stirred for 0.5 h at 25°C. 1-(III-tetrazol-5-yl)ethanamine (71.5 mg, 0.63 mmol, 2 eq.) was added to the mixture. The mixture was stirred for 2.5 hours at 25°C. The mixture was quenched with H2O (30 ml) and the mixture

- 244 046394 was filtered and the filter cake was washed with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)ACN]; B%: 43%-73%, 8.5 min). The racemic compound U-|1-(2H-tetrazol-5-yl)ethyl|-5-|4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (70 mg, 0.17 mmol, 53.8% yield) was prepared in as a white solid. The racemic compound was separated by the prep-SFC method (DAICEL CHIRALPAK IG (250 mm x 50 mm, 10 µm), 0.1% NH ₃ H ₂ O ETOH, 30%, 30%). Compound 284 (13.8 mg, 33.6 µmol, 23.1% yield) was obtained as a white solid. LCMS (ESI): RT=0.805 min, mass calc. for C ₂₁ H ₁₆ F ₃ N ₅ O 411.38 m/z obtained 434.0 [M+Na]+, Ή NMR (400 MHz, CD ₃ OD) δ 8.50 (d, J=1.0 Hz , 1H), 8.05 (d, J=8.3 Hz, 1H), 7.92 - 7.80 (m, 4H), 7.70 - 7.62 (m, 3H), 7.57 - 7.53 (m, 1H), 7.47 (dd, J=7.4, 8.4 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 6.50 (d , J=8.5 Hz, 1H), 5.18 (q, J=6.9 Hz, 1H), 4.58 (br s, 1H), 3.09 (s, 6H), 1.59 ( d, J=7.0 Hz, 3H). Compound 285 (14.0 mg, 34.1 µmol, 23.4% yield) was obtained as a white solid. LCMS (ESI): RT=0.808 min, mass calc. for C ₂₁ H ₁₆ F ₃ N ₅ O 411.38 m/z obtained 434.0 [M+Na]+, ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (d, J=1.3 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.92 - 7.81 (m, 4H), 7.71 - 7.63 (m, 3H), 7.56 (dd, J=1.1, 7.2 Hz, 1H), 7.47 (dd, J=7.4, 8.4 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 6.51 (d, J=8.5 Hz, 1H), 5.18 (q, J=6.8 Hz, 1H), 3.10 (s, 6H), 1.59 (d, J=7.0 Hz, 3H).

Example 239: ^)-No(1-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 286) and ^)-No(1-( 6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide (compound 287)

A mixture of N[1-(6-bromo-2-pyridyl)ethyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (200 mg, 0.40 mmol, 1 eq.), N-methylmethanamine ( 65.3 mg, 0.80 mmol, 73.4 µl, 2 eq., HCl), Cu ₂ O (57.3 mg, 0.40 mmol, 40.9 µl, 1 eq.), DIPEA (258, 8 mg, 2.00 mmol, 348.8 µl, 5 eq.) in dioxane (2 ml) was loaded into a stoppered reaction tube. The reaction temperature was raised to 70°C and the reaction mixture was stirred at 70°C for 16 hours. The residue was poured into H ₂ O (20 ml) and stirred for 5 minutes. The aqueous phase was extracted with EA (10 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (12 g SepaFlash® Silica Flash column, EA/PE: 0~70%) to obtain 103 mg of racemic product. And then the racemic product was separated by chiral SFC method (column: DAICEL CHIRALPAK AD (250 mmx30 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 30%-30%, min). Compound 286 (21.6 mg, 45.2 µmol, 11.2% yield) was obtained as a white solid. LCMS (ESI): RT=0.788 min, mass calc. for C ₂₇ H ₂₄ F ₃ N ₃ O 463.49 m/z obtained 464.1 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.51 (d, J=1.3 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.92 - 7.81 (m, 4H), 7.71 - 7.63 (m, 3H), 7.56 (dd , J=1.1, 7.2 Hz, 1H), 7.47 (dd, J=7.4, 8.4 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H) , 6.51 (d, J=8.5 Hz, 1H), 5.18 (q, J=6.8 Hz, 1H), 3.10 (s, 6H), 1.59 (d, J= 7.0 Hz, 3H). Compound 287 (21.3 mg, 43.6 µmol, 10.9% yield) was obtained as a white solid. LCMS (ESI): RT=0.803 min, mass calc. for C ₂₇ H ₂₄ F ₃ N ₃ O 463.49 m/z obtained 464.2 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.50 (d, J=1.0 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.92 - 7.80 (m, 4H), 7.70 - 7.62 (m, 3H), 7.57 - 7 .53 (m, 1H), 7.47 (dd, J=7.4, 8.4 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 6.50 (d, J=8.5 Hz, 1H), 5.18 (q, J=6.9 Hz, 1H), 4.58 (br s, 1H), 3.09 (s, 6H), 1.59 (d , J=7.0 Hz, 3H).

Example 240: N(3-phenyloxetan-3-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 288)

- 245 046394

2-Methyl-K-(oxetane-3-ylidene)propane-2-sulfinamide.

Ti( OEt) ₄ (23.7 g, 104.1 mmol, 21.58 ml, 1.5 eq.). The mixture was stirred at 30°C for 16 hours. 100 ml of water was added to the mixture. A yellow solid precipitated. The mixture was diluted with EtOAc (80 ml) and filtered. The filter cake was washed with EtOAc (100 mlx2). The combined organic layer was concentrated. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/petroleum ether=0% - 15%) to give compound 240-2 (2.5 g, 14.27 mmol, 20.6% yield) as a yellow liquid.

2-Methyl-K-(3-phenyloxetan-3-yl)propane-2-sulfinamide.

To a solution of compound 240-2a (1.08 g, 6.85 mmol, 0.72 mL, 1.5 eq.) in THF (5 mL) was added n-BuLi (2.5 M, 1.83 mL, 1 eq.) at -78°C. The mixture was stirred at -78°C for 1 hour. Compound 2 (800 mg, 4.56 mmol, 1 eq.) in THF (1 ml) was added. The mixture was stirred at -78°C for 1 hour. The mixture was quenched with NH ₄ Cl (10 ml). The mixture was extracted with EA (20 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash chromatography (ISCO®; 10 g SepaFlash® Silica Flash column, 0~70% ethyl acetate/petroleum ether eluent gradient approximately 18 mL/min) to give compound 240-3 (400 mg, 1.58 mmol , 34.6% yield) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ) δ 7.47 - 7.30 (m, 5H), 5.21 (d, J=6.9 Hz, 1H), 5.09 - 5.05 (m, 2H ), 5.04 5.00 (m, 1H), 4.15 - 4.11 (m, 1H), 1.21 (s, 9H).

3-Phenyloxetane-3-amine.

To a solution of compound 240-3 (100 mg, 0.39 mmol, 1 eq.) in MeOH (1 mL) was added HCl/MeOH (4 M, 0.99 mL, 10 eq.) at 0°C. The mixture was stirred at 0°C for 10 minutes. Us. NaHCO ₃ was added to the mixture until pH=6-7. The mixture was concentrated. The residue was dissolved in EA/MeOH (v/v=10/1). The mixture was filtered. The filtrate was concentrated to give compound 240-4 (50.0 mg, 0.34 mmol, 84.9% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.56 - 7.51 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.35 - 7.30 (m, 1H) , 5.01 (d, J=6.5 Hz, 2H), 4.80 (d, J=6.5 Hz, 2H).

K-(3-Phenyloxetan-3-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a solution of compound 240-5 (50.0 mg, 0.16 mmol, 1 eq.), HATU (90.2 mg, 0.24 mmol, 1.5 eq.) and compound 240-4 (23.6 mg , 0.16 mmol, 1 equiv.) DIEA (40.9 mg, 0.32 mmol, 55 μl, 2 equiv.) was added to DCM (1 ml). The mixture was stirred at 25°C for 2 hours. The mixture was diluted with H2O (5 ml). The mixture was extracted with EA (10 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 5u; mobile phase: [water (0.05% ammonium hydroxide, v/v)-ACN]; V%: 65%-95%, 7.8 min) to obtain the title compound (16.2 mg, 36.3 µmol, 23.0% yield) as a white solid. LCMS (ESI): RT=0.903 min, mass, calc. for C27H20F3NO2 447.14, m/z obtained 448.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.93 - 7.83 (m, 2H), 7.79 (d, J=8.1 Hz, 2H), 7.68 - 7.59 (m, 5H), 7.54 (d, J=7.1 Hz, 1H), 7.42 (t, J= 7.7 Hz, 2H), 7.36 - 7.30 (m, 1H), 7.06 (br s, 1H), 5.22 (d, J=6.8 Hz, 2H), 5.09 (d, J=6.8 Hz, 2H).

Example 241: ^)-K-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 289) and ^)-K-(1-cyclopropylethyl)-5-(4-( trifluoromethyl)phenyl)-2-naphthamide (compound 290)

- 246 046394

^)-M-(1-Cyclopropylethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 289) and (R)-N-(1cyclopropylethyl)-5-(4-(trifluoromethyl)phenyl) -2-naphthamide (compound 290).

A mixture of 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (100 mg, 0.31 mmol, 1 eq.), HATU (180.3 mg, 0.47 mmol, 1.5 eq.) and DIPEA (122.5 mg, 0.94 mmol, 0.16 ml, 3 eq.) in DCM (2 ml) was stirred at 25°C for 1 hour. Then 1-cyclopropylethanamine (29.6 mg, 0.34 mmol, 1.1 eq.) was added to the mixture and the mixture was stirred at 25°C for an additional 1 hour. The reaction mixture was diluted with H2O (10 ml) and the mixture was extracted with EA (10 ml x 3). The combined organic phase was washed with brine (10 mlx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC (column: Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 61%-91%, 8.5 min). The racemic compound K-(1-cyclopropylethyl)-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (65 mg, 0.16 mmol, 53% yield) was obtained as a white solid. The racemic compound was separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mmx30 mm, 5 µm); mobile phase: [0.1% NH3H2O ETOH]; B%: 25%-25%, min). Compound 289 (20 mg, 51.6 µmol, 30.4% yield) was obtained as a white solid. LCMS (ESI): RT=1.038 min, mass calc. for C ₂₃ H ₂₀ F ₃ NO 383.41 m/z obtained 384.0 [M+H]+, ¹ H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.04 (br t , J=7.4 Hz, 1H), 7.90 - 7.76 (m, 4H), 7.70 - 7.59 (m, 3H), 7.56 - 7.48 (m, 1H), 3.63 - 3.48 (m, 1H), 1.35 (d, J=6.6 Hz, 3H), 1.12 - 1.02 (m, 1H), 0.62 -0.46 ( m, 2H), 0.45 - 0.24 (m, 2H). Compound 290 (30 mg, 77.4 µmol, 45.6% yield) was obtained as a white solid. LCMS (ESI): RT=1.036 min, mass calc. for C ₂₃ H ₂₀ F ₃ NO 383.41 m/z obtained 384.0 [M+H] ⁺ , 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.04 (br t, J=7.4 Hz, 1H), 7.90 - 7.76 (m, 4H), 7.70 - 7.59 (m, 3H), 7.56 - 7.48 (m, 1H), 3 .63 -3.48 (m, 1H), 1.35 (d, J=6.6 Hz, 3H), 1.12 - 1.02 (m, 1H), 0.62 - 0.46 (m , 2H), 0.45 - 0.24 (m, 2H).

General method for preparing compound 291 - compound 297:

Methyl 2-(3-bromo-5-methoxybenzyl)-4,4-diethoxybutanoate.

NaH 60% in mineral oil (1.03 g, 25.7 mmol, 2.7 equiv.) was carefully added to 1-bromo-3(bromomethyl)-5-methoxybenzene (2.66 g, 9.5 mmol, 1 equiv.) in 20 ml DMF and stirred at room temperature for 1 hour. Dimethyl 2-(2,2-diethoxyethyl) malonate (3.5 g, 14.3 mmol, 1.5 equiv.) in 12 ml DMF was added dropwise and stirred at room temperature for 4 hours. LiCl (445 mg, 10.5 mmol, 1.1 equiv.) was added carefully and the mixture was heated to 160°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with Et ₂ O and washed us. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated

- 247 046394 was collected and purified by FCC, gradient 0 - 15% EtOAc in hexanes to give methyl 2-(3-bromo-5methoxybenzyl)-4,4-diethoxybutanoate (2.037 g, 5.2 mmol, 55% yield) in the form of a yellow oil. LCMS [M+H]+=389.

Methyl-5-bromo-7-methoxy-2-naphthoate.

Methyl 2-(3-bromo-5-methoxybenzyl)-4,4-diethoxybutanoate (390 mg, 1 mmol, 1 equiv.) in MeOH (0.5 ml) was carefully added to DDQ (230 mg, 1.01 mmol , 1.01 equiv.) in 2 ml of 80% H ₂ SO ₄ (aq.) at 0°C. The mixture was stirred at 0°C for 1 hour and slowly warmed to rt over 1 hour. The solid was filtered, redissolved in EtOAc and the organic layer was washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC, gradient 0 - 20% EtOAc in hexanes, to give methyl 5-bromo-7-methoxy-2-naphthoate (200 mg, 0.68 mmol, 68% yield), colorless solid. LCMS [M+H]+=295.

Methyl 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoate.

5-Bromo-7-methoxy-2-naphthoate (800 mg, 2.7 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (618 mg, 3.2 mmol, 1.2 equiv.) , Pd(PPh ₃ ) ₄ (61 mg, 0.05 mmol, 0.1 equiv.) and 4:1 dioxane/2 M K ₂ CO ₃ (aq) (10.8 ml:2.7 ml, 0 ,2 M) were thoroughly purged with N2 for 10 min. The mixture was heated to 90°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC, gradient 0 - 20% EtOAc in hexanes to give methyl 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoate (884 mg, 2.5 mmol, 91% yield), colorless solid. LCMS [M+N] ⁺ =361.

-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid.

Methyl 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoate (724 mg, 2 mmol, 1 equiv.) was stirred in 24 ml of a 1:1:1 mixture of THF:MeOH:2 N NaOH (aq .) at room temperature for 2 hours. The mixture was concentrated and the residue was dissolved in DCM and acidified with 2 N HCl (aq). The organic layer was dried with Na ₂ SO ₄ and concentrated to give 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (690 mg, 2 mmol, 100% yield), a colorless solid. LCMS [M+H]+=347.

Example 242: N(2-hydroxy-1-(pyridin-2-yl)ethyl)-7-methoxy-5-(4-(trifluoromethyl)phenyl)-2naphthamide (compound 291)

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), 2-amino-2-(pyridin-2yl)ethan-1-ol dihydrochloride (1.2 equiv.) and HATU (1.2 equiv) was dissolved in DMF (0.2 M) at RT. DIEA (4 equiv) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. After completion, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 23 mg, 86%, LCMS [M+H]+=467.

Example 243: ^)-7-methoxy-N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 292)

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), ^)-1-(pyridin-2-yl)ethan1-amine (1.2 equiv.) and HATU ( 1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. Once complete, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 19 mg, 75%, LCMS [M+H]+=451.

Example 244: ^)-7-methoxy-N-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 293)

- 248 046394

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), (P)-1-(pyridin-2-yl)ethan1-amine (1.2 equiv.) and HATU (1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. After completion, the reaction mixture was diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 21 mg, 81%, LCMS [M+H]+=451.

Example 245: ^)-7-methoxy-H-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 294)

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), ^)-1-methoxypropan-2amine hydrochloride (1.2 equiv.) and HATU (1.2 equiv.) dissolved in DMF (0.2M) at RT. DIEA (3 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. Once complete, the reaction mixture was diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 18 mg, 75%, LCMS [M+H]+=418.

Example 246: ^)-7-Methoxy-H-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 295)

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), ^)-1-methoxypropan-2amine hydrochloride (1.2 equiv.) and HATU (1.2 equiv.) dissolved in DMF (0.2M) at RT. DIEA (3 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. Once complete, the reaction mixture was diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 23 mg, 94%, LCMS [M+H]+=418.

Example 247: ^)-H-(1-hydroxypropan-2-yl)-7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthamcd (compound 296)

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), ^)-2-aminopropan-1-ol (1.2 equiv.) and HATU (1.2 equiv. ) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. Once complete, the reaction mixture diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 19 mg, 82%, LCMS [M+H]+=404.

- 249 046394

Example 248: N)-N-(1-hydroxypropan-2-yl)-7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 297)

7-Methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), (K)-2-aminopropan-1-ol (1.2 equiv.) and HATU (1.2 equiv. .) dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2.5 h. Once complete, the reaction mixture diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid, 15 mg, 65%, LCMS [M+H]+=404.

Example 249: N-isopropyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline-9carboxamide (compound 298)

7-Bromo-H-(4-methoxybenzyl)-4-(4-(trifluoromethyl)phenyl)isoquinoline-1-amine.

7-Bromo-1-chloro-4-(4-(trifluoromethyl)phenyl)isoquinoline (60 mg, 1 equiv.) and (4methoxyphenyl)methanamine (0.06 ml, 3 equiv.) were heated to 140°C for 1 h. the reaction was cooled to room temperature and passed through a plug of silica gel with 25% EtOAc in Hex and concentrated to obtain the desired product, which was used immediately in the next step without further purification. LCMS [M+H]+=487.

7-Bromo-4-(4-(trifluoromethyl)phenyl)isoquinoline-1-amine.

7-Bromo-N-(4-methoxybenzyl)-4-(4-(trifluoromethyl)phenyl)isoquinoline-1-amine (1 equiv) and TFA (0.5 ml) were heated to 72°C for 1 hour. The reaction mixture was concentrated, diluted with DCM, neutralized with NaHCO ₃ , dried with Na ₂ SO ₄ , concentrated and used directly in the next step without further purification. LCMS [M+H]+=367.

9-Bromo-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline.

7-Bromo-4-(4-(trifluoromethyl)phenyl)isoquinoline-1-amine (1 equiv), DMF-DMA (0.1 ml) and DMF (1 ml) were heated at 130°C for 6 h. The reaction was cooled and concentrated. The residue was resuspended in MeOH (1 ml) and pyridine (0.1 ml) and hydroxylamine-O-sulfonic acid (29 mg, 1.01 equiv.) were added at room temperature. The reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC gradient 0 - 30% EtOAc in hexane to obtain the desired product (19 mg, 31%). LCMS [M+H]+=392.

Methyl 6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline-9-carboxylate.

Pd( dppf) ₂ Cl ₂ (0.05 equiv.) and Et ₃ N (2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the reaction mixture was concentrated and immediately purified by FCC (5 - 40% EtOAc in Hex) to obtain the desired product. (12 mg, 67%). LCMS [M+H]+=372.

6-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline-9-carboxylic acid.

Methyl 6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline-9-carboxylate (12 mg, 1 equiv.) was suspended in MeOH/THF (1:1, 0 .05 M) and treated with 2 N NaOH (0.1 M) for 4 hours. Reaction

- 250 046394 the mixture was filtered and acidified to pH 2 and the resulting solid was filtered to obtain a colorless solid (11 mg). LCMS [M+H]+=358.

No. Isopropyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline-9-carboxamide.

6-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1-a]isoquinoline-9-carboxylic acid (1 equiv.), propan-2-amine (1.2 equiv.) and HATU (1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2 h. Once complete, the reaction mixture was diluted with H2O and stirred quickly for 20 min. The resulting solid was filtered, washed with H2O and dried to obtain the desired amide product as a colorless solid. LCMS [M+H]+=399.

Example 250: N-isopropyl-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline-9-carboxamide (compound 299)

7-Bromo-H-(2,2-dimethoxyethyl)-4-(4-(trifluoromethyl)phenyl)isoquinoline-1-amine.

7-Bromo-1-chloro-4-(4-(trifluoromethyl)phenyl)isoquinoline (70 mg, 1 equiv.), 2,2-dimethoxyethane-1-amine (3 equiv.) xylenes (3 ml) were heated at 135 °C for 24 hours. The reaction mixture was cooled to room temperature and used immediately. LCMS [M+H]+=455.

9-Bromo-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline.

7-Bromo-H-(2,2-dimethoxyethyl)-4-(4-(trifluoromethyl)phenyl)isoquinoline-1-amine in xylenes (from the previous step) and AcOH (0.1 ml) were irradiated in a microwave vessel at 140 °C for 30 min. Once complete, the mixture was cooled, concentrated and immediately purified by FCC (0 - 10% MeOH in DCM) to obtain the desired product. LCMS [M+H] ⁺ =391.

Methyl 6-(4-(trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline-9-carboxylate.

Pd(dppf) ₂ Cl ₂ (0.05 equiv.) and Et ₃ N (2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the resulting solid was filtered and washed with a minimal amount of MeOH to obtain a red solid, which was used immediately in the next step without further purification (25 mg, 38%). LCMS [M+H]+=371.

6-(4-(Trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline-9-carboxylic acid.

Methyl 6-(4-(trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline-9-carboxylate (25 mg, 1 equiv.) was suspended in MeOH/THF (1:1, 0.05 M) and treated 2 N NaOH (0.1 M) for 2 hours. The reaction mixture was filtered, acidified to pH 2 and the resulting solid was filtered to give a pale yellow solid (22 mg, 91%). LCMS [M+H]+=357.

No. Isopropyl-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline-9-carboxamide.

6-(4-(Trifluoromethyl)phenyl)imidazo[2,1-a]isoquinoline-9-carboxylic acid (22 mg, 1 equiv.), propan-2-amine (1.2 equiv.) and HATU (1, 2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until the acid was consumed as determined by LCMS, 2 h. Once the reaction was complete the mixture was diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product as a colorless solid (24 mg, 94%). LCMS [M+H]+=398.

Example 251: N-isopropyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline-8-carboxamide (compound 300)

- 251 046394

7-Bromo-N-(4-methoxybenzyl)-4-(4-(trifluoromethyl)phenyl)quinoline-2-amine.

7-Bromo-2-chloro-4-(4-(trifluoromethyl)phenyl)quinoline (96 mg, 1 equiv.) and (4-methoxyphenyl)methanamine (0.1 ml, 3 equiv.) were heated to 140°C in for 1 hour. The reaction was cooled to room temperature and passed through a plug of silica gel with 25% EtOAc in Hex and concentrated to give the desired product, which was used immediately in the next step without further purification. LCMS [M+H]+=487.

7-Bromo-4-(4-(trifluoromethyl)phenyl)quinoline-2-amine.

7-Bromo-N-(4-methoxybenzyl)-4-(4-(trifluoromethyl)phenyl)quinoline-2-amine (1 equiv) and TFA (0.3 ml) were heated to 72°C for 1 hour. the reaction mixture was concentrated, diluted with DCM, neutralized with NaHCO ₃ , dried with Na ₂ SO ₄ , concentrated and used immediately in the next step without further purification. LCMS [M+H]+=367.

8-Bromo-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline.

7-Bromo-4-(4-(trifluoromethyl)phenyl)quinoline-2-amine (92 mg, 0.25 mmol, 1 equiv.), DMF-DMA (0.1 ml) and DMF (1 ml) were heated at 130°C for 6 hours. The reaction was cooled and concentrated. The residue was resuspended in MeOH (1 ml) and pyridine (0.1 ml) and hydroxylamine-O-sulfonic acid (29 mg, 1.01 equiv.) was added at RT. The reaction mixture was stirred at RT for 2 hours. The mixture was diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC, gradient 0 - 30% EtOAc in hexane to obtain the desired product (50 mg, 51%). LCMS [M+H]+=392.

Methyl 5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline-8-carboxylate.

To a mixture of 8-bromo-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline (50 mg, 1 equiv.) in MeOH (0.1 M) was added Pd(dppf ) ₂ Cl ₂ (7 mg, 0.05 equiv.) and Et ₃ N (0.04 ml, 2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to RT, the reaction mixture was concentrated and immediately purified by FCC (5 - 40% EtOAc in Hex) to obtain the desired product. (24 mg, 50%). LCMS [M+H]+=372.

5-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline-8-carboxylic acid.

Methyl 5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline-8-carboxylate (24 mg, 1 equiv.), suspended in MeOH/THF (1:1, 0.05 M) and treated with 2 N NaOH (0.1 M) for 4 hours. The reaction mixture was filtered and acidified to pH 2 and the resulting solid was filtered to give a colorless solid (20 mg, 88%). LCMS [M+H]+=358.

No. Isopropyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline-8-carboxamide.

5-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[1,5-a]quinoline-8-carboxylic acid (1 equiv.), propan-2-amine (1.2 equiv.) and HATU (1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2 h. When completed, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product as a colorless solid (11 mg, 98%). LCMS [M+H]+=399.

Example 252: Nmethyl-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-sulfonamide (compound 301)

- 252 046394

9-(Benzylthio)-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline.

To a mixture of 9-bromo-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline (1 equiv.), Xantphos (5 mol.%), Pd2(dba) ₃ (2.5 mol. %) under N2 atmosphere, dioxane (0.1 M) and DIEA (2.0 equiv) were added and then heated to 80°C for 10 min before adding BnSH (1.2 equiv). Heating was continued for 1 hour before cooling to room temperature. The mixture was concentrated and purified by FCC (25% EtOAc in Hex) to give 9-(benzylthio)-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1- a]isoquinoline. LCMS [M+H]+=437.

NMethyl-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-sulfonamide.

9-(Benzylthio)-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline (1 equiv.) was dissolved in MeCN (0.05 M) and cooled to 0°C and treated with HOAc (1 .5 ml/mmol) and water (1 ml/mmol), and then 1,3dichloro-5,5-dimethylimidazolidine-2,4-dione (2.0 equiv.). After 2 hours, the reaction mixture was diluted with EtOAc (20 ml) and washed with water, brine, dried and concentrated to give a yellow solid, used immediately in the next step. A solution of 6-(4(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-sulfonyl chloride (1 equiv.) in DCM (0.2 M) was added to a mixture of MeNH ₂ HCl salt (110 mg) and Et ₃ N (0.4 ml) in THF (2 ml). The resulting suspension was stirred at room temperature for 2 hours, diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC to obtain the desired product. LCMS [M+H] ⁺ =4O8. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 2.62 (s, 3H) 7.84 (br d, J=7.83 Hz, 2H) 7.89 - 8.07 (m, 3H) 8.25 (br dd, J=8.61, 1.96 Hz, 1H) 9.00 - 9.12 (m, 1H) 9.13 - 9.35 (m, 1H).

Example 253: N-isopropyl-5-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]quinoline-8-carboxamide (compound 302)

7-Bromo-N(2,2-dimethoxyethyl)-4-(4-(trifluoromethyl)phenyl)quinoline-2-amine.

7-Bromo-2-chloro-4-(4-(trifluoromethyl)phenyl)quinoline (386 mg, 1 mmol, 1 equiv.), 2,2-dimethoxyethane1-amine (0.33 ml, 3 mmol, 3 equiv. ), 4 A MS (100 mg) and diglyme (3 ml) were heated at 135°C for 24 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered and concentrated. The residue was purified by FCC (0-40% EtOAc in Hex) to obtain the desired product. (185 mg, 41%). LCMS [M+H]+=455.

2-((7-Bromo-4-(4-(trifluoromethyl)phenyl)quinolin-2-yl)amino)acetaldehyde.

7-Bromo-N(2,2-dimethoxyethyl)-4-(4-(trifluoromethyl)phenyl)quinoline-2-amine (176 mg, 0.4 mmol, 1 equiv.), 6 N HCl (1 ml) and dioxane (4 ml) was heated to 110°C for 1 hour. After consumption of the initial

- 253 046394 substances as observed by LCMS, the mixture was cooled to room temperature, diluted with DCM, neutralized us. aq. NaHCO ₃ and extracted with DCM. The combined organic fractions were dried with Na ₂ SO ₄ , concentrated and used immediately in the next step without further purification. LCMS [M+H]+=409.

8-Bromo-5-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]quinoline.

2-((7-Bromo-4-(4-(trifluoromethyl)phenyl)quinolin-2-yl)amino)acetaldehyde (from the previous step), AcOH (0.3 ml) and xylenes (3 ml) were sealed in a vessel under microwave irradiation and irradiated at 140°C for 30 min. After cooling to room temperature, the residue was concentrated and immediately purified by FCC (0 - 75% EtOAc in Hex) to give the desired product. (25 mg, 16%). LCMS [M+H]+=391.

Methyl 5-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]quinoline-8-carboxylate To a mixture of 8-bromo-5-(4(trifluoromethyl)phenyl)imidazo[1,2-a]quinoline (25 mg, 1 equiv.) Pd(dppf) ₂ Cl ₂ (3 mg, 0.05 equiv.) and Et ₃ N (0.02 ml, 2 equiv.) were added to MeOH (0.1 M). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the reaction mixture was concentrated and immediately purified by FCC (5 - 40% EtOAc in Hex) to obtain the desired product. (17 mg, 73%). LCMS [M+H] ⁺ =371.

5-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]quinoline-8-carboxylic acid.

Methyl 5-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]quinoline-8-carboxylate (17 mg, 1 equiv.) was suspended in MeOH/THF (1:1, 0.05 M) and treated 2 N NaOH (0.1 M) for 2 hours. The reaction mixture was filtered and acidified to pH 2 and the resulting solid was filtered to give a colorless solid (11 mg, 67%). LCMS [M+H]+=357.

No. Isopropyl-5-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]quinoline-8-carboxamide.

5-(4-(Trifluoromethyl)phenyl)imidazo[1,2-a]quinoline-8-carboxylic acid (1 equiv.), propan-2-amine (1.2 equiv.) and HATU (1.2 equiv.) ) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until the acid was consumed as determined by LCMS, 2 h. Once complete, the reaction mixture was diluted with H2O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to obtain the desired amide product as a colorless solid (11 mg, 93%). LCMS [M+H]+=398.

Example 254: Nmethyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-sulfonamide (compound 303)

9-(Benzylthio)-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline.

To a mixture of 9-bromo-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline (1 equiv.), Xantphos (5 mol.%), Pd ₂ (dba) ₃ (2.5 mol %) under N2, dioxane (0.1 M) and DIEA (2.0 equiv) were added and then heated to 80°C for 10 min before adding BnSH (1.2 equiv). ). Heating was continued for 1 hour before cooling to rt. The mixture was concentrated and purified by FCC (25% EtOAc in Hex) to give 9-(benzylthio)-6-(4-(trifluoromethyl)phenyl)-[1.2.4] triazolo[3,4-a]isoquinoline. LCMS [M+H]+=436.

No. Methyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-sulfonamide.

9-(Benzylthio)-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline (1 equiv.) was dissolved in MeCN (0.05 M), cooled to 0° C and treated with HOAc (1.5 ml/mmol) and water (1 ml/mmol), followed by 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.0 equiv). After 2 hours, the reaction mixture was diluted with EtOAc (20 ml) and washed with water, brine, dried and concentrated to give a yellow solid, used immediately in the next step. A solution of 6-(4-(trifluoromethyl)phenyl)[1.2.4]triazolo[3,4-a]isoquinoline-9-sulfonyl chloride (1 equiv.) in DCM (0.2 M) was added to a mixture of MeNH2 HCl salt (110 mg) and Et3N (0.4 ml) in THF (2 ml). The resulting suspension was stirred at room temperature for 2 hours, diluted with EtOAc and washed. aq. NH4Cl, H2O and saline solution. The organic layer was dried with Na2SO4, concentrated and purified by FCC to obtain the desired product.

LCMS [M+H]+=407. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.14 (d, J=8.61 Hz, 3H) 7.74 - 7.87 (m, 3H) 7.95 (br d, J= 8.61 Hz, 1H) 8.00 - 8.13 (m, 1H) 8.51 - 8.63 (m, 1H) 8.94 - 9.06 (m, 1H) 9.24 - 9.42 (m, 1H).

- 254 046394

Example 255: N-isopropyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9carboxamide (compound 304)

9-Bromo-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline.

7-Bromo-1-chloro-4-(4-(trifluoromethyl)phenyl)isoquinoline (200 mg, 1 equiv.), H2NNH2-H2O (0.13 ml, 5 equiv.) and EtOH (6 ml) were heated to 90 °C for 16 hours. Once complete, the mixture was added to H2O and the resulting solid was filtered, washed with H2O and dried. The solid and HC(OEt) ₃ (10 ml) were heated to 130°C for 1 hour. The reaction mixture was cooled, added to H2O, filtered and washed with Et ₂ O to obtain the desired product (107 mg, 54%). LCMS [M+H]+=391.

Methyl 6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-carboxylate.

Pd( dppf) ₂ Cl ₂ (0.05 equiv.) and Et ₃ N (2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the resulting solid was filtered and washed with a minimal amount of MeOH to obtain a red solid, which was used immediately in the next step without further purification. LCMS [M+H]+=372.

6-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-carboxylic acid.

Methyl 6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-carboxylate (1 equiv) was suspended in MeOH/THF (1:1, 0.05 M ) and treated with 2N NaOH (0.1 M) for 2 hours. The reaction mixture was filtered and acidified to pH 2 and the resulting solid was filtered to give a pale yellow solid (35 mg, 38%). LCMS [M+H]+=358.

No. Isopropyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-carboxamide.

6-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[3,4-a]isoquinoline-9-carboxylic acid (1 equiv.), propan-2-amine (1.2 equiv.) and HATU (1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2 h. Once complete, the reaction mixture was diluted with H2O and stirred quickly for 20 min. The resulting solid was filtered, washed with H2O and dried to obtain the desired amide product as a colorless solid (6 mg). LCMS [M+H]+=399.

Example 256: N-isopropyl-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-carboxamide (compound 305)

- 255 046394

7-Bromo-4-(4-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one.

7-Bromo-4-iodisoquinolin-1(2H)-one (2 g, 1 equiv.), Cs ₂ CO ₃ (1.1 equiv.), (4(trifluoromethyl)phenyl)boronic acid (1.1 equiv. ), dioxane (200 ml) and H2O (60 ml) were combined and thoroughly purged with N2 for 10 min at room temperature. Pd(PPh ₃ ) ₄ (0.1 equiv.) was added and the mixture was heated at 100°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC, 0-60% EtOAc in hexane to give the desired product (1.6 g, 76%). LCMS [M+H]+=368.

7-Bromo-1-chloro-4-(4-(trifluoromethyl)phenyl)isoquinoline.

7-Bromo-4-(4-(trifluoromethyl)phenyl)isoquinolin-1(2H)-one (1.6 g, 1 equiv.) and POCl ₃ (10 ml) were heated to 105°C for 2 hours. The mixture was carefully added to ice-cold H2O and the resulting solid was carefully neutralized with NaHCO ₃ to obtain the desired product (420 mg, 25%). LCMS [M+H]+=386.

9-Bromo-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline.

7-Bromo-1-chloro-4-(4-(trifluoromethyl)phenyl)isoquinoline (200 mg, 1 equiv.), NaN ₃ (34 mg, 1 equiv.) and DMF (1.5 ml) were heated to 120° C for 18 hours. The mixture was added to H2O, filtered and washed with H2O to obtain the desired product as a brown solid (189 mg, 93%). LCMS [M+H]+=392.

Methyl 6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-carboxylate.

Pd(dppf) ₂ Cl ₂ (0 .05 equiv.) and Et ₃ N (2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the resulting solid was filtered and washed with a minimal amount of MeOH to obtain a red solid, which was immediately used in the next step without further purification. LCMS [M+H]+=373.

6-(4-(Trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-carboxylic acid.

Methyl 6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-carboxylate (1 equiv.), suspended in MeOH/THF (1:1, 0.05 M) and treated with 2 N NaOH (0.1 M) for 2 hours. The reaction mixture was filtered and acidified to pH 2 and the resulting solid was filtered to give a pale yellow solid (51 mg, 56%). LCMS [M+H]+=359.

No. Isopropyl-6-(4-(trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-carboxamide.

6-(4-(Trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline-9-carboxylic acid (1 equiv.), propan-2amine (1.2 equiv.) and HATU (1.2 equiv.) were dissolved in DMF (0.2M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2 h. Once complete, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product as a colorless solid (23 mg, 47%). LCMS [M+H]+=400. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.22 (br d, J=5.09 Hz, 6 H) 4.08 - 4.26 (m, 1H) 6.99 - 7.21 (m, 1H) 7.74 - 7.92 (m, 2H) 7.99 (br d, J=7.04 Hz, 1H) 8.06 (br d, J=6.26 Hz, 1H) 8 .17 - 8.39 (m, 1H) 8.86 (br dd, J=6.07, 0.98 Hz, 1H) 9.27 (br s, 1H).

Example 257: N-isopropyl-1-methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-7carboxamide (compound 306)

- 256 046394

7-Bromo-1-methyl-4-(4-(trifluoromethyl)phenyl)quinolin-2(1H)-one.

7-Bromo-4-(4-(trifluoromethyl)phenyl)quinolin-2(III)-one (185 mg, 0.5 mmol) in DMF (3 ml) at RT was treated with NaH (30 mg, 60% , 1.5 eq.) for 15 min before adding MeI (0.076 ml, 2.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was diluted with water (3 ml) and filtered to obtain a white solid (200 mg, 100%). LCMS [M+H]+=382.

Methyl 1-methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-7-carboxylate.

Pd(dppf) ₂ Cl ₂ ( 0.05 equiv.) and Et ₃ N (2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the resulting solid was filtered and washed with a minimal amount of MeOH to obtain a red solid. LCMS [M+H]+=362.

1-Methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-7-carboxylic acid.

Methyl 1-methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-7-carboxylate (1 equiv.), suspended in MeOH/THF (1:1, 0.05 M ) and treated with 2 HNaOH (0.1 M) for 1 hour. The reaction mixture was filtered, acidified to pH 2 and the resulting solid was filtered to obtain a pale yellow solid. LCMS [M+H]+=348.

No. Isopropyl-1-methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-7-carboxamide.

1-Methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroquinoline-7-carboxylic acid (1 equiv.), propan-2-amine (1.2 equiv.) and HATU ( 1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2 h. When completed, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product as a colorless solid. LCMS [M+H]+=389. ¹ H NMR (400 MHz,

DMSO-d6) δ ppm 1.02 - 1.29 (m, 6 N) 3.75 (br s, 3 H) 4.02 - 4.20 (m, 1H) 6.52 - 6.76 (m, 1H) 7.27 - 7.54 (m, 1H) 7.54 - 7.80 (m, 3H) 7.82 - 7.98 (m, 3H) 8.44 - 8.56 (m, 1H) .

Example 258: N-isopropyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-carboxamide (compound 307)

Methyl 5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-carboxylate.

To a mixture of 8-bromo-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline (1 equiv.) in MeOH (0.1 M) was added Pd(dppf) ₂ Cl ₂ (0.05 equiv.) and Et ₃ N (2 equiv.). CO (gas) was bubbled for 1 h at 70°C. After cooling to room temperature, the resulting solid was filtered and washed with a minimal amount of MeOH to give a red solid (85 mg, 88%). LCMS [M+H]+=372.

5-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-carboxylic acid.

- 257 046394

Methyl 5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-carboxylate (1 equiv) was suspended in MeOH/THF (1:1, 0.05 M ) and treated with 2N NaOH (0.1 M) for 2 hours. The reaction mixture was filtered, acidified to pH 2 and the resulting solid was filtered to give a pale yellow solid (45 mg, 55%). LCMS [M+H]+=358.

No. Isopropyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-carboxamide.

5-(4-(Trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-carboxylic acid (1 equiv.), propan-2-amine (1.2 equiv.) and HATU (1.2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT. until acid was consumed as determined by LCMS, 2 hours. Once complete, the reaction mixture was diluted with H2O and stirred briefly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product as a colorless solid (10 mg, 57%). LCMS [M+H]+=399. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.11 - 1.30 (m, 6 H) 4.06 - 4.22 (m, 1H) 7.70 (br d, J=7.43 Hz, 1H) 7.75 - 7.87 (m, 2H) 7.95 (br d, J=7.04 Hz, 3H) 8.38 - 8.57 (m, 1H) 8.92 (br s , 1H) 10.06 (brs, 1H).

Example 259: N-isopropyl-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-carboxamide (compound 308)

N(3-Bromophenyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propanamide.

Methyl-3-oxo-3-(4-(trifluoromethyl)phenyl), synthesized according to J. Org. Chem. 2018, 83, 303313, (12.3 g, 50 mmol, 1 equiv.) and 3-bromoaniline (8.6 g, 1 equiv.) were mixed and heated to 145°C for 1 hour, then cooled to room temperature. t. Add DCM/hexane (10/10 ml) and filter to obtain a solid and then wash with a minimum amount of DCM to obtain the desired product (6.2 g, 32%). LCMS [M+H]+=387.

7-Bromo-4-(4-(trifluoromethyl)phenyl)quinolin-2(1H)-one.

Na(3-Bromophenyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propanamide (3 g, 7.8 mmol) was added to PPA (20 ml) at 50°C, heated to 100°C for 2 hours and then mixed with ice water. The resulting solid was filtered, dried and recrystallized with EtOH to give a white solid (2 g, 70%). LCMS [M+H]+=369.

7-Bromo-2-chloro-4-(4-(trifluoromethyl)phenyl)quinoline.

7-Bromo-4-(4-(trifluoromethyl)phenyl)quinolin-2-ol (2 g, 5.4 mmol) was suspended in POCl ₃ (15 ml) and heated to 100°C for 2 hours. The solvent was removed and extinguished with ice water. The resulting mixture was neutralized with ammonium hydroxide and extracted with DCM. The organics were washed with water, dried and concentrated to give a yellow solid (1.5 g, 72%). LCMS [M+H]+=387.

8-Bromo-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline.

A mixture of 7-Bromo-2-chloro-4-(4-(trifluoromethyl)phenyl)quinolone (386 mg, 1 equiv.), NaN ₃ (65 mg, 1 equiv.) and DMF (2 ml) was heated to 120°C for 3 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was recrystallized in EtOAc to give a white crystal (200 mg, 51%). LCMS [M+H]+=393.

5-(4-(Trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-carboxylic acid.

8-Bromo-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline (61 mg, 0.16 mmol) in THF (5 ml) at 78°C under N2 was treated dropwise with n- BuLi (2.5 M, 0.068 ml, 1.1 equiv.). After 30 min CO2 bar

- 258 046394 chatted for 15 minutes. The reaction mixture was warmed to room temperature and quenched with water (2 ml), concentrated, extracted with ether and neutralized to give a white solid as 5-(4(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8- carboxylic acid (20 mg, 35%). LCMS [M+H]+=359.

No. Isopropyl-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-carboxamide.

5-(4-(Trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-carboxylic acid (1 equiv.), propan-2amine (1.2 equiv.) and HATU (1.2 equiv.) were dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until acid was consumed as determined by LCMS, 2 h. Once complete, the reaction mixture was diluted with H2O and quickly stirred for 20 minutes. The resulting solid was filtered, washed with H2O and dried to obtain the desired amide product as a colorless solid. LCMS [M+H]+=400.

Example 260: Nmethyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-sulfonamide (compound 309)

7-Bromo-2-hydrazinyl-4-(4-(trifluoromethyl)phenyl)quinoline.

7-Bromo-2-chloro-4-(4-(trifluoromethyl)phenyl)quinoline (386 mg, 1.0 mmol) in EtOH (1 ml) was treated with hydrazine monohydrate (500 mg, 10 equiv.) and heated to 80° From all night. After cooling to room temperature, the reaction mixture was diluted with water, filtered, washed with H2O and dried to give a white solid (360 mg, 90%). LCMS [M+H]+=382.

8-Bromo-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline.

7-Bromo-2-hydrazinyl-4-(4-(trifluoromethyl)phenyl)quinoline (360 mg, 1 equiv.) was dissolved in HC(OEt) ₃ (10 ml) and heated to 130°C for 1 hour. Cool to room temperature. The resulting solid was filtered and dried (300 mg, 85%). LCMS [M+H]+=393.

8-(Benzylthio)-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline.

To a mixture of 8-bromo-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinolone (60 mg, 0.15 mmol), Xantphos (4.4 mg, 5% ), Pd2(dba)3 (3.4 mg, 2.5 mol.%) under N2 atmosphere, dioxane (2 ml) and DIEA (0.053 ml, 2.0 equiv.) were added, and then heated to 80°C in for 10 min before adding BnSH (0.019 ml, 1.2 equiv.). Heating was continued for 1 hour before cooling to rt. The mixture was concentrated and purified by FCC (25% EtOAc in Hex) to give a yellow solid as 8-(benzylthio)-5(4-(trifluoromethyl)phenyl)-[1.2 .4]triazolo[4,3-a]quinolone (38 mg, 58%). LCMS [M+H]+=436.

No. Methyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinoline-8-sulfonamide.

8-(Benzylthio)-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3-a]quinolone (38 mg, 1 equiv.) was dissolved in MeCN (3 ml), cooled to 0 °C and treated with HOAc (0.032 mL) and water (0.021 mL), followed by 1,3dichloro-5,5-dimethylimidazolidine-2,4-dione (35 mg, 2.0 equiv.). After 2 hours, the reaction mixture was diluted with EtOAc (20 ml) and washed with water, brine, dried and concentrated to give a yellow solid, used immediately in the next step. A solution of 5-(4(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-sulfonyl chloride (38 mg, 0.092 mmol) in DCM (0.5 ml) was added to a mixture of MeNH ₂ HCl salt (110 mg) and Et ₃ N (0.4 ml) in THF (2 ml). The resulting suspension was stirred at room temperature for 2 hours, diluted with EtOAc and washed. aq. NH4Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC gradient 0 - 75% EtOAc in hexane to give a white solid (26 mg, 71%). LCMS [M+N]+=407. ^1H NMR (400 MHz, DMSO-d6) δ ppm 3.34 (s, 3H) 7.72 - 7.99 (m, 7H) 8.91 (br s, 1H) 10.26 (br s, 1H ).

Example 261: Nmethyl-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-sulfonamide (compound 310)

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8-(Benzylthio)-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline.

To a mixture of 8-bromo-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline (60 mg, 0.15 mmol), Xantphos (4.4 mg, 5%), Pd ₂ (dba ) ₃ (3.4 mg, 2.5%) under N2, dioxane (2 ml) and DIEA (0.053 ml, 2.0 eq.) were added and then heated to 80°C for 10 min before adding BnSH ( 0.019 ml, 1.2 eq.). Heating was continued for 1 hour before cooling to room temperature. The mixture was purified by FCC (25% EtOAc in Hex) to give 8-(benzylthio)-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a] quinoline (47 mg, 72%) as a yellow solid. LCMS [M+H]+=436.

N-Methyl-5 -(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-sulfonamide.

8-(Benzylthio)-5-(4-(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline (47 mg, 1 equiv.) was dissolved in MeCN (6 ml), cooled to 0°C and treated with HOAc ( 0.039 ml), water (0.026 ml), and then 1,3-dichloro5,5-dimethylimidazolidine-2,4-dione (43 mg, 2.0 equiv.). After 2 hours, the reaction mixture was diluted with EtOAc (20 ml) and washed with water, brine, dried and concentrated to give a yellow solid (41 mg), used immediately in the next step. A solution of 5-(4(trifluoromethyl)phenyl)tetrazolo[1,5-a]quinoline-8-sulfonyl chloride (41 mg, 0.10 mmol) in DCM (0.5 ml) was added to a mixture of MeNH ₂ HCl salt (118 mg ) and Et ₃ N (0.3 ml) in THF (2 ml). The resulting suspension was stirred at room temperature for 2 hours, diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC gradient 0 - 75% EtOAc in hexane to give a white solid (16 mg, 41%). LCMS [M+N]+=408. ^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.34 (s, 3H) 7.84 (br d, J=7.04 Hz, 2H) 7.93 - 8.14 (m, 4H) 8.21 - 8.44 (m, 1H) 9.01 (brs, 1H).

Example 262: (E)-N-(4-(methylsulfonyl)but-3-en-1-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 311)

5-(4-(Trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), (E)-4-(methylsulfonyl)but-3-en-1amine (1.2 equiv.) (synthesized according to JACS, 2010 , 732, 12853-12855) and HATU (1.2 equiv.) were dissolved in DMF (0.2 M) at room temperature. DIEA (2 equiv.) was added slowly and the mixture was stirred at room temperature until the acid was consumed, as determined by LCMS, 2 hours. Once complete, the reaction mixture was diluted with H ₂ O and stirred briefly for 20 minutes. The resulting solid was filtered, washed with H ₂ O and dried to obtain the desired amide product, a brown solid. LCMS [M+H]+=448.

Example 263: (E)-N-(3-(methylsulfonyl)allyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 312)

5-(4-(Trifluoromethyl)phenyl)-2-naphthoic acid (1 equiv.), (E)-3-(methylsulfonyl)prop-2-en-1 amine (1.2 equiv.) and HATU (1, 2 equiv.) was dissolved in DMF (0.2 M) at RT. DIEA (2 equiv.) was added slowly and the mixture was stirred at RT until the acid was consumed, as determined by the method

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LCMS, 2 hours. Once complete, the reaction mixture was diluted with H ₂ O and stirred quickly for 20 minutes. The resulting solid was filtered, washed with H2O and dried to give the desired amide product, a brown solid. LCMS [M+H]+=434.

Example 264: N-[(1R)-3-(dimethylamino)-1-methylpropyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide (compound 313)

N-[(1R)-3-(Dimethylamino)-1-methylpropyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide.

To a solution of N-[(1R)-3-amino-1-methylpropyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide (50 mg, 0.12 mmol, 1 equiv.) and formaldehyde (210 .0 mg, 2.59 mmol, 20 eq.) in MeOH (2 ml) was added Pd/C (50 mg, 10%) under N2 atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30 mmx3 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%60%, 6.5 min) to obtain No[ (^)-3-(dimethylamino)-1-methylpropyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide (7.38 mg, 12.5% yield, HCl) as a white solid. LCMS (ESI): RT=0.872 min, mass calc. for C ₂₄ H ₂₅ F ₃ N ₂ O 414.19 m/z, obtained 415.3 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSC-d6) δ 10.48 (br s, 1H), 8.70 - 8.59 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.98 (dd, J=1.6, 8.9 Hz, 1H), 7 .93 (d, J=8.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.60 (d, J=6.3 Hz, 1H), 4.14 4.10 (m, 1H), 4.15 - 4.08 (m, 2H), 3.18 - 3.02 (m, 2H), 2, 75 (t, J=4.6 Hz, 6H), 2.06 - 1.88 (m, 2H), 1.26 (d, J=6.5 Hz, 3H).

Example 265: N[(^)-1-[1-(2-fluoroethyl)azetidin-3-yl]ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 314)

Benzyl-3-[(1S)-1-aminoethyl] azetidine-1-carboxylate.

To a solution of compound 265-1 (3.8 g, 11.23 mmol, 1 eq.) in MeOH (30 mL) was added HCl/MeOH (4 M, 5 mL, 1.8 eq.). The mixture was stirred at 25°C for 2 hours. Using TLC (DCM/MeOH=10/1, UV 254, I ₂ ) it was observed that the starting material was completely consumed and one new zone was formed. Using LCMS, it was observed that the starting material was completely consumed and ~95% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH and HCl/MeOH to give compound 265-2 (2.61 g, crude) as a colorless solid. The crude product was used in the next step without further purification.

Benzyl 3-[(1 S)-1-[(2,4-dimethoxyphenyl)methylamino]ethyl] azetidine-1-carboxylate.

HOAc ( 1.73 g, 28.89 mmol, 1.65 ml, 3 eq.), stirred at 25°C in those

- 261 046394 for 2 hours and then NaBH(OAc) ₃ (4.08 g, 19.26 mmol, 2 eq.) was added. The resulting mixture was stirred at 25°C for 2 hours. Using TLC (EA/PE=1/1, UV 254) it was observed that the starting material was completely consumed and one new zone was formed. Using LCMS, it was observed that the starting material was completely consumed and ~63% of the desired compound was detected. Ice water (30 ml) was then added and the pH of the mixture was neutralized to 9~10 aq. NaOH (2 M). The aqueous phase was extracted with EA (40 mlx3). The combined organic phase was washed with brine (60 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (20 g SepaFlash® Silica Flash column, EA/PE: 0~50%) to give compound 265-3 (2.8 g, 7.28 mmol, 75.6% yield) in in the form of yellow oil.

Benzyl 3-[(III)-1-[(2,4-dimethoxyphenyl)methyl-[8-[4-(trifluoromethyl)phenyl]quinoline-3carbonyl] amino] ethyl] azetidine-1-carboxylate.

A mixture of compound 265-3a (2.0 g, 6.30 mmol, 1 eq.), HATU (3.60 g, 9.46 mmol, 1.5 eq.) in DMF (20 ml) was added DIPEA (2, 44 g, 18.91 mmol, 3.3 ml, 3 eq.) at 25°C. After addition, the mixture was stirred at 25°C for 1 hour, and then compound 265-3 (2.67 g, 6.93 mmol, 1.1 eq.) in DMF (5 ml) was added. The resulting mixture was stirred at 25°C for 2 hours. Using TLC (DCM/MeOH=20/1, UV 254) it was observed that the starting material was completely consumed and one new zone was formed. Using LCMS, it was observed that the starting material was completely consumed and ~55% of the desired compound was detected. The reaction mixture was diluted with H2O (50 ml) and stirred for 5 min. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (20 g SepaFlash® Silica Flash column, EA/PE: 0~40%) to give compound 265-4 (2.6 g, 3.12 mmol, 49.5% yield) in in the form of yellow oil. This was checked using the LCMS method.

N[(III)-1-(Azetidin-3-yl)ethyl]-N[(2,4-dimethoxyphenyl)methyl]-8-[4-(trifluoromethyl)phenyl]quinoline3-carboxamide.

To a solution of compound 265-4 (2.5 g, 3.66 mmol, 1 eq.) in MeOH (35 ml) was added Pd/C (500 mg, 10%) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25°C for 2 hours. It was observed by LCMS that the starting material was completely consumed and ~80% of the desired compound was detected. The reaction mixture was filtered and the cake was washed with MeOH (10 mlx2). The filtrate was concentrated in vacuo to give compound 265-5 (1.95 g, crude) as a yellow oil. The crude product was used in the next step without further purification.

N[(2,4-Dimethoxyphenyl)methyl]-N-[(III)-1-[1-(2-fluoroethyl)azetidin-3-yl]ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3 -carboxamide.

To a solution of compound 265-5 (200 mg, 0.36 mmol, 1 eq.) in MeCN (2 ml) was added K2CO3 (125.7 mg, 0.91 mmol, 2.5 eq.) and compound 265-5a ( 69.3 mg, 0.55 mmol, 1.5 eq.). The mixture was stirred at 70°C for 16 hours. Using LCMS, it was observed that the starting material was completely consumed and ~91% of the desired compound was detected. The reaction mixture was diluted with H2O (30 ml) and stirred for 5 min. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 ml), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 265-6 (188 mg, crude) as a yellow solid. The crude product was used in the next step without further purification.

N-[(1S)-1-[1-(2-Fluoroethyl)azetidin-3-yl]ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 314).

To a solution of compound 265-6 (165 mg, 0.28 mmol, 1 eq.) in DCM (0.4 mL) was added TFA (3.1 g, 27.0 mmol, 2 mL, 97.5 eq.). The mixture was stirred at 25°C for 16 hours. Using LCMS, it was observed that the starting material was completely consumed and ~77% of the desired compound was detected. Using HPLC, it was observed that the starting material was completely consumed and ~85% of the desired compound was detected. K ₂ CO ₃ (solid) was added to quench the reaction and the pH was adjusted to 9-10. The reaction mixture was filtered and the cake was washed with MeOH (10 mlx2). The filtrate was concentrated in vacuo to obtain the product. The crude product was purified by pre-HPLC (column: Waters Xbridge 150x25 mmx5 µm; mobile phase: [water (0.05% NH ₃ H ₂ O)-ACN]; B%: 45%-75%, 9.5 min ) to obtain the title compound (26.3 mg, 59.0 µmol, 21.3% yield) as a white solid. LCMS (ESI): RT=0.759 min, mass calc. for C ₂₄ H ₂₃ F ₄ N ₃ O 445.18, m/z obtained 446.1 [M+H]+; ^1H NMR (400 MHz, CDCl3) δ 9.38 (d, J=2.3 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.16 (d, J= 5.8 Hz, 1H), 7.98 (dd, J=1.4, 8.2 Hz, 1H), 7.85 - 7.80 (m, 3H), 7.79 - 7.74 (m , 2H), 7.72 - 7.66 (m, 1H), 4.55 (t, J=4.8 Hz, 1H), 4.43 (t, J=4.8 Hz, 1H), 4 .37 - 4.28 (m, 1H), 3.47 - 3.39 (m, 3H), 3.25 (dd, J=3.3, 6.5 Hz, 1H), 2.88 - 2 .81 (m, 1H), 2.80 - 2.73 (m, 1H), 2.58 - 2.50 (m, 1H), 1.32 (d, J=6.5 Hz, 3H).

Example 266: N[(III)-1-[1-(2-hydroxyethyl)azetidin-3-yl]ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline3-carboxamide (compound 315)

- 262 046394

X-[(2,4-Dimethoxyphenyl)methyl|-X-[(^)-1-[1-(2-hydroxyethyl)azetidin-3-yl|ethyl|-8-[4(trifluoromethyl)phenyl]quinoline- 3-carboxamide.

To a solution of compound 266-1 (200 mg, 0.36 mmol, 1 eq.) in DMF (2 ml) was added K ₂ CO ₃ (125.7 mg, 0.91 mmol, 2.5 eq.) and 2- bromoethanol (54.6 mg, 0.44 mmol, 31.0 µl, 1.2 eq.). The mixture was stirred at 25°C for 16 hours. It was observed by LCMS that the starting material was completely consumed and ~75% of the desired compound was detected. The reaction mixture was diluted with H2O (30 ml) and stirred for 5 min. The aqueous phase was extracted with EA (15 mlx3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 266-2 (176 mg, crude) as a yellow solid. The crude product was used in the next step without further purification.

X-[(^)-1-[1-(2-Hydroxyethyl)azetidin-3-yl|ethyl|-8-[4-(trifluoromethyl)phenyl|quinoline-3carboxamide (compound 315).

To a solution of compound 266-2 (150 mg, 0.25 mmol, 1 eq.) in DCM (0.4 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 106.9 eq. ). The mixture was stirred at 25°C for 16 hours. Using LCMS, it was observed that the starting material was completely consumed and ~63% of the desired compound was detected. K ₂ CO ₃ (solid) was added to quench the reaction and the pH was adjusted to 9-10. The reaction mixture was filtered and the cake was washed with MeOH (10 mlx2). The filtrate was concentrated in vacuo to obtain the product. The crude product was purified by pre-HPLC (column: Waters Xbridge

150x25 mmx5 microns; mobile phase: [water (0.05% NH ₃ H ₂ O)-ACN|; B%: 50%-50%, 9.5 min) to obtain the title compound (20.6 mg, 46.5 mmol, 18.4% yield) as a white solid. LCMS (ESI): RT=0.740 min, mass calc. for C ₂₄ H ₂₄ F ₃ N ₃ O ₂ 443.18, m/z obtained 444.1 [M+H|+; C NMR (400 MHz, CDCl ₃ ) δ 9.32 (d, J=2.4 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H), 7.99 (dd, J= 1.4, 8.1 Hz, 1H), 7.84 - 7.79 (m, 3H), 7.79 7.74 (m, 2H), 7.70 (dd, J=7.3, 8 ,1 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 4.37 (m, 1H), 3.59 (t, J=5.3 Hz, 2H), 3, 44 3.37 (m, 2H), 3.35 - 3.30 (m, 1H), 3.19 - 3.13 (m, 1H), 2.65 (dd, J=4.7, 5, 8 Hz, 2H), 2.61 - 2.52 (m, 1H), 1.29 (d, J=6.5 Hz, 3H).

Example 267: N-[(1R)-3-(ethylamino)-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide (compound 316)

N-[(1R)-3-[(2,4-DimeΊΌxyphenyl)methylethylamino]-1-methylpropyl]-8-[4-(ΊrifΌrmethyl)phenyl]quinoline3-carboxamide.

To a solution of compound 267-1 (50 mg, 93.0 µmol, 1 equiv.) in MeOH (3 ml) was added acetaldehyde (20.4 mg, 0.46 mmol, 26.1 µl, 5 equiv.) and Pd C (25 mg, 10%). The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was used in the next step without further purification. Compound 267-2 (50 mg, crude) was obtained as a white solid. LCMS (ESI): RT=0.925 min, mass calc. for C ₃₂ H ₃₄ F ₃ N ₃ O ₃ 565.26 m/z, 566.4 [M+H|+] was obtained.

N-[(1R)-3-(Ethylamino)-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (compound 316).

To a solution of compound 267-2 (50 mg, 88.4 µmol, 1 eq.) in DCE (1.5 ml) was added DIPEA (22.8 mg, 0.17 mmol, 30.7 µl, 2.0 eq. ) and 1-chloroethyl chloroformate (18.9 mg, 0.13 mmol, 1.5 eq.) at 0°C. The mixture was then stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by pre-TLC (SiO2, DCM: MeOH=10:1) to obtain the desired product (30 mg). The product (30 mg) was purified by pre-HPLC (column: 3_Phenomenex Luna C18 75x30 mmx3 μm; mobile phase: [water (0.05% HCl)-ACN|; B%: 25%-55%, 6.5 min ) (2.0 mg, 4.5 µmol, 5.1% yield, HCl). LCMS (ESI): RT=0.843 min, mass calc. for C ₂₃ H ₂₄ F ₃ N ₃ O 415.19 m/z, 416.3 [M+H|+] was obtained. Ή NMR (400 MHz, CD3OD) δ 9.29 (d, J=2.3 Hz, 1H), 9.10 (d, J=2.3 Hz, 1H), 8.23 (dd, J=1 ,3, 8.3 Hz, 1H), 8.00 (dd, J=1.4, 7.3 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.84 (s, 4H), 4.41 - 4.20 (m,

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1H), 3.16 - 3.02 (m, 4H), 2.11 - 1.89 (m, 2H), 1.41 (d, J=6.6 Hz, 3H), 1.35 (t , J=7.3 Hz, 3H).

Example 268: (R)-N-(1-(1-(2,2-difluoroethyl)azetidin-3-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline 3-carboxamide (compound 317)

^)-H-(1-(1-(2,2-Difluoroethyl)azetidin-3-yl)ethyl)-H-(2,4-dimethoxybenzyl)-8-(4(trifluoromethyl)phenyl)quinoline-3- carboxamide

To a solution of compound 268-1 (50 mg, 91.0 µmol, 1 eq.) and K ₂ CO ₃ (37.7 mg, 0.27 mmol, 3 eq.) in ACN (1 ml) at 30°C was added compound 268-1a (39.6 mg, 0.27 mmol, 3 eq.) and the resulting mixture was stirred at 80°C for 30 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 268-2 (55 mg, 89.6 µmol, 98.5% yield) as a colorless oil , which was used at the next stage.

^)-H-(1-(1-(2,2-Difluoroethyl)azetidin-3-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide (compound 317).

A solution of compound 268-2 (55 mg, 89.6 μmol, 1 eq.) in TFA (1 ml) was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was made basic with NH3-H2O (1 ml) and then concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150x25 mmx5 μm; mobile phase: [water (0.05% NH3H2O+10 mM NH ₄ HCO ₃ )-ACN]; B%: 47%-77%, 9. 5 min) to obtain the desired compound (13.1 mg, 28.4 µmol, 31.7% yield) as a white solid. LCMS (ESI): RT=0.777 min, mass, calc. for C ₂₄ H ₂₂ F ₅ N ₃ O 463.17, m/z obtained 464.2 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (d, J=2.3 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H), 8.61 (d , J=8.3 Hz, 1H), 8.18 (dd, J=1.3, 8.3 Hz, 1H), 7.93 (dd, J=1.3, 7.2 Hz, 1H) , 7.87 (q, J=8.4 Hz, 4H), 7.82 - 7.77 (m, 1H), 6.10 - 5.73 (m, 1H), 4.36 - 4.19 (m, 1H), 3.35 - 3.33 (m, 2H), 3.08 (t, J=6.8 Hz, 1H), 3.00 (t, J=6.9 Hz, 1H) , 2.77 (dt, J=4.2, 16.2 Hz, 2H), 2.63 - 2.55 (m, 1H), 1.11 (d, J=6.6 Hz, 3H).

Example 269: ^)-H-(1-(1-(2-fluoroethyl)azetidin-3-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide (compound 318)

^)-Benzyl-3-(1-((2,4-dimethoxybenzyl)amino)ethyl)azetidine-1-carboxylate.

To a solution of compound 269-1a (500 mg, 3.01 mmol, 1 eq.) and compound 269-1 (775.5 mg, 3.31 mmol, 1.1 eq.) in DCM (10 ml) at 30° HOAc (180.7 mg, 3.01 mmol, 0.17 mL, 1 eq.) was added and the mixture was stirred at 30°C for 1 hour. Then NaBH(OAc) ₃ (1.28 g, 6.02 mmol, 2 eq.) was added to the above mixture at 30°C and the resulting mixture was stirred at 30°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with saturated Na ₂ CO ₃ solution (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 269-2 (1.10 g, 2.86 mmol, 95.1% yield) as colorless oil, which was used in the next step.

^)-Benzyl-3-(1-(H-(2,4-dimethoxybenzyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamido)ethyl)azetidine-1-carboxylate.

To a solution of compound 269-2a (650 mg, 2.05 mmol, 1 eq.), compound 269-2 (1.04 g, 2.25 mmol, 1.1

- 264 046394 eq.) and HATU (1.01 g, 2.66 mmol, 1.3 eq.) in DMF (10 ml) at 30°C was added TEA (621.9 mg, 6.15 mmol, 0. 86 ml, 3 eq.) and the resulting mixture was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography (ISCO®; 20 g SepaFlash® Silica Flash column, 0~50% ethyl acetate/petroleum ether eluent gradient approximately 35 mL/min) to give compound 269-3 (1.1 g, 1. 51 mmol, 73.8% yield) as a white solid. LCMS (ESI): RT=1.024 min, mass, calc. for Cr,9H3 ₆ F3N3O5 683.26, m/z obtained 684.2 [M+H]+.

(R)-N-(1-(Azetidin-3-yl)ethyl)-N(2,4-dimethoxybenzyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3 carboxamide.

Pd/C (171.2 mg, 0.16 mmol, 10%, 0 .1 eq.) and the resulting mixture was stirred at 30°C for 6 hours. The reaction mixture was filtered to remove Pd/C and the filtrate was concentrated under reduced pressure to give compound 269-4 (850 mg, 1.48 mmol, 92.3 % yield) as a white solid. LCMS (ESI): RT=0.811 min, mass, calc. for C3|H3 ₀ F3N3O3 549.22, m/z obtained 550.1 [M+ACN+H]+.

^)-No(2,4-Dimethoxybenzyl)-No(1-(1-(2-fluoroethyl)azetidin-3-yl)ethyl)-8-(4(trifluoromethyl)phenyl)quinoline-3-carboxamide.

To a solution of compound 269-4 (40 mg, 72.8 µmol, 1 eq.) and K ₂ CO ₃ (50.3 mg, 0.36 mmol, 5 eq.) in ACN (1 ml) at 30°C was added compound 269-4a (27.7 mg, 0.22 mmol, 3 eq.) and the resulting mixture was stirred at 80°C for 30 hours. The reaction mixture was diluted with water (20 ml) and extracted with EA (20 mlx3). The combined organic layers were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 269-5 (40 mg, 67.2 µmol, 92.3% yield) as a colorless oil .

WX2798: (R)-N-(1-(1-(2-fluoroethyl)azetidin-3-yl)ethyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3 carboxamide.

A solution of compound 269-5 (40 mg, 67.2 μmol, 1 eq.) in TFA (1 ml) was stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove TFA. The residue was made basic with NH3-H2O (1 ml) and then concentrated under reduced pressure to give a residue. The residue was purified by pre-HPLC (column: Waters Xbridge 150x25 mmx5 µm; mobile phase: [water (0.05% NH ₃ H ₂ O)-ACN]; B%: 49%-69%, 9.5 min) to obtain the title compound (8.3 mg, 18.5 µmol, 27.5% yield) as a yellow solid. LCMS (ESI): RT=0.752 min, mass, calc. for C ₂₄ H ₂₃ F ₄ N ₃ O 445.18, m/z obtained 446.1 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (d, J=2.3 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H), 8.60 (d , J=8.3 Hz, 1H), 8.23 -8.14 (m, 1H), 7.93 (dd, J=1.3, 7.0 Hz, 1H), 7.91 - 7, 83 (m, 4H), 7.82 - 7.77 (m, 1H), 4.42 (t, J=4.9 Hz, 1H), 4.33 - 4.29 (m, 1H), 4 ,29 - 4.20 (m, 1H), 3.31 (s, 2H), 3.00 (t, J=6.7 Hz, 1H), 2.91 (t, J=6.7 Hz, 1H), 2.67 (t, J=4.8 Hz, 1H), 2.61 - 2.54 (m, 2H), 1.12 (d, J=6.5 Hz, 3H).

Example 270: N-[(1R)-3-(Dimethylamino)-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide (compound 319)

N-[(1R)-3-(1,3-Dioxoisoindolin-2-yl)-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3 carboxamide.

To a solution of 2-[(3R)-3-aminobutyl]isoindoline-1,3-dione (500 mg, 1.96 mmol, 1 equiv., HCl) and 8-[4(trifluoromethyl)phenyl]quinoline-3-carboxylic acid acid (622.7 mg, 1.96 mmol, 1 eq.) in DCM (5 ml) was added HATU (895.6 mg, 2.36 mmol, 1.2 eq.) and DIPEA (761.1 mg, 5 .89 mmol, 3 eq.). The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (10 ml) and the resulting mixture was extracted with EA (20 ml x 3).

The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness at

- 265 046394 low pressure. The residue was purified by silica gel flash chromatography (ISCO®; 12 g SepaFlash® Silica Flash column, gradient 0~90% petroleum ether/ethyl acetate ether eluent approximately 30 ml/min) to give H-[(1K)-3-(1 ,3-dioxoisoindolin-2-yl)-1-methylpropyl|-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide (767 mg, 1.48 mmol, 75.50% yield), which was obtained as white solid matter.

N-[(1R)-3-Amino-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of N[(G)-3-(1,3-dioxoisoindolin-2-yl)-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline3-carboxamide (650 mg, 1.26 mmol, 1 eq.) in EtOH (7 ml) was added NH2NH2-H2O (739.7 mg, 12.56 mmol, 85%, 10 eq.), and then the reaction mixture was stirred at 25°C for 16 hours. The reaction suspension was filtered and the organic layer was concentrated under reduced pressure. The residue was diluted with water (30 ml) and the resulting mixture was extracted with DCM (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give N[(^)-3-amino-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide ( 403 mg, 72.8% yield), which was obtained as a light yellow solid

N-[(1R)-3 -(Dimethylamino)-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide.

To a solution of N-[(1R)-3-amino-1-methylpropyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide (50 mg, 0.12 mmol, 1 equiv.) and formaldehyde (209 .4 mg, 2.58 mmol, 20 eq.) in MeOH (2 ml) was added Pd/C (50 mg, 10%) under N2 atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75x30 mmx3 µm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%45%, 6.5 min) to obtain No[ (^)-3-(dimethylamino)-1-methylpropyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide (10.12 mg, 22.17 µmol, 17.18% yield, HCl) as white solid. LCMS (ESI): RT=0.756 min, mass calc. for C ₂ 3H ₂₄ F ₃ N ₃ O 415.19 m/z, obtained 416.3 [M+H]+, '11 NMR (400 MHz, DMSO-d6) δ 10.64 (br s, 1H), 9.31 (d, J=2.3 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.90 (d, J=8.3 Hz, 1H), 8, 21 - 8.16 (m, 1H), 7.95 (dd, J=1.3, 7.0 Hz, 1H), 7.91 - 7.85 (m, 4H), 7.84 - 7, 79 (m, 1H), 4.23 - 4.08 (m, 1H), 3.19 - 3.05 (m, 2H), 2.74 (t, J=4.3 Hz, 6H), 2 ,10 - 1.86 (m, 2H), 1.27 (d, J=6.5 Hz, 3H).

Example 271: (R)-N-(1-(1-cyclopropylazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide (compound 320)

(R)-N-(1-(1-Cyclopropylazetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide.

To a mixture of compound 271-1 (60.0 mg, 0.15 mmol, 1.0 eq.) and compound 271-1a (19.4 mg, 0.23 mmol, 1.5 eq.) in DCM (5 ml ) Ου(ΘΑο)2 (54.7 mg, 0.30 mmol, 2.0 eq.) and DIPEA (38.9 mg, 0.30 mmol, 52 μl, 2.0 eq.) were added in one portion at 30 °C. The suspension was degassed in vacuum and purged with O ₂ several times. The mixture was stirred under O ₂ atmosphere (15 psi) at 30°C for 40 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by pre-HPLC: (column: Welch Xtimate C18 150x25 mmx5 µm; mobile phase: [water (0.05% NH3H2O)ACN]; V%: 57%-87%, 9.5 min) to obtain the desired compound (6.85 mg, 16 µmol, 10.3% yield) as a yellow solid. LCMS (ESI): RT=0.878 min, mass, calc. for C ₂₆ H ₂₅ F ₃ N ₂ O 438.19, m/z obtained 439.3 [M+H]+; '11 NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.43 (brd, J=7.8 Hz, 1H), 8.12 (brd, J=8.5 Hz , 1H), 7.92 (brd, J=8.0 Hz, 3H), 7.80 (brd, J=8.6 Hz, 1H), 7.74 (brd, J=7.6 Hz, 2H ), 7.70 - 7.66 (m, 1H), 7.59 (brd, J=6.8 Hz, 1H), 4.24 (brd, J=6.8 Hz, 1H), 3.29 (brs, 3H), 3.09 - 2.95 (m, 2H), 1.83 (brs, 1H), 1.10 (brd, J=6.4 Hz, 3H), 0.35-0, 17 (m, 4H).

Example 272: 8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxyquinoline-3-carboxylic acid (compound 321)

- 266 046394

To a solution of the compound methyl 8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxyquinoline-3carboxylate (30.0 mg, 79.0 µmol, 1.0 eq.) in THF (0.6 ml) and MeOH (0.2 ml) NaOH (1M, 0.16 ml, 2.0 eq.) was added. The reaction mixture was stirred at 25°C for 1 hour. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was determined. The pH of the reaction mixture was adjusted to 5 with HCl (1 M), and then the suspension was extracted with EA (20 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give the title compound (14.48 mg, 49.6% yield) as a white solid. LCMS (ESI): RT=0.931 min, mass calc. for C18H11F4NO3 365.07, m/z obtained 366.0 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.94 (s, 1H), 7.82 (d, J=9.5 Hz, 1H), 7.79 - 7.70 (m, 3H), 7.62 (d, J=2.1 Hz, 1H), 3.97 (s, 3H).

Example 273: 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (compound 322)

Step 1: Methyl 2-(3-bromo-5-methoxybenzyl)-4,4-diethoxybutanoate

NaH 60% in mineral oil (1.03 g, 25.7 mmol, 2.7 equiv.) was carefully added to 1-bromo-3(bromomethyl)-5-methoxybenzene (2.66 g, 9.5 mmol, 1 equiv.) in 20 ml DMF and stirred at room temperature for 1 hour. Dimethyl 2-(2,2-diethoxyethyl) malonate (3.5 g, 14.3 mmol, 1.5 equiv.) in 12 ml DMF was added dropwise and stirred at RT until complete consumption of the starting material was observed by LCMS, 4 h. LiCl (445 mg, 10.5 mmol, 1.1 equiv.) was carefully added and the mixture was heated to 160 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with Et ₂ O and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC, gradient 0 - 15% EtOAc in hexanes to give methyl 2-(3-bromo-5-methoxybenzyl)-4,4diethoxybutanoate (2.037 g, 5.2 mmol , 55% yield) as a yellow oil. LCMS calculated: 389 ([M+H] ⁺ ), m/z obtained: 389.

Step 2: Methyl 5-bromo-7-methoxy-2-naphthoate

Methyl 2-(3-bromo-5-methoxybenzyl)-4,4-diethoxybutanoate (390 mg, 1 mmol, 1 equiv.) in MeOH (0.5 ml) was carefully added to DDQ (230 mg, 1.01 mmol , 1.01 equiv.) in 2 ml of 80% H2SO4 (aq) at 0°C. The mixture was stirred at 0°C for 1 hour and slowly warmed to rt over 1 hour. The solid was filtered, redissolved in EtOAc and the organic layer was washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC, gradient 0 - 20% EtOAc in hexanes, to give methyl 5-bromo-7-methoxy-2-naphthoate (200 mg, 0.68 mmol, 68% yield), colorless solid. LCMS calculated: 295 ([M+H] ⁺ ), m/z obtained: 295.

Step 3: Methyl 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoate

5-Bromo-7-methoxy-2-naphthoate (800 mg, 2.7 mmol, 1 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (618 mg, 3.2 mmol, 1.2 equiv.) , Pd(PPh ₃ ) ₄ (61 mg, 0.05 mmol, 0.1 equiv.) and 4:1 dioxane/2 M K2CO3 (aq) (10.8 ml: 2.7 ml, 0.2 M ) thoroughly purged with N2 for 10 min. The mixture was heated to 90°C for 3 hours, while complete consumption of the starting material was observed using LCMS. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed. aq. NH ₄ Cl, H ₂ O and saline solution. The organic layer was dried with Na ₂ SO ₄ , concentrated and purified by FCC, gradient 0 - 20%

- 267 046394

EtOAc in hexane to give methyl 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoate (884 mg, 2.5 mmol, 91% yield), colorless solid. LCMS calculated: 361 ([M+H]+), m/z received: 361.

Step 4: 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid

Methyl 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoate (724 mg, 2 mmol, 1 equiv.) was stirred in 24 ml of a 1:1:1 mixture of THF:MeOH:2 N NaOH (aq .) at room temperature for 2 hours. The mixture was concentrated, the residue was dissolved in DCM and acidified with 2 N HCl (aq). The organic layer was dried with Na ₂ SO ₄ and concentrated to give 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (690 mg, 2 mmol, 100% yield), a colorless solid. LCMS calculated: 347 ([M+H]+), m/z received: 347.

Example 274: 6-cyclopropoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid (compound 323)

To a solution of compound 274-1 (30 mg, 93 µmol, 1.0 eq.), compound 274-1a (21.2 mg, 0.11 mmol, 1.2 eq.) and Na ₂ CO ₃ (29.6 mg, 0.28 mmol, 3.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (3.4 mg, 4.6 μmol, 0.05 eq. ) in an N2 atmosphere. The reaction mixture was stirred at 90°C for 16 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. The pH of the reaction mixture was adjusted to 6 with HCl (1 M), and then the suspension was extracted with EA (10 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (14.63 mg, 37% yield, HCl) as a white solid. LCMS (ESI): RT=1.002 min, mass calc. for C ₂₀ H ₁₄ F ₃ NO ₃ 373.09, m/z obtained 373.9 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J=2.3 Hz, 1H), 8.97 (d, J=2.3 Hz, 1H), 7.93 (d, J=2.8 Hz, 1H), 7.90 - 7.82 (m, 4H), 7.60 (d, J=2.8 Hz, 1H), 4.10 - 4.03 (m, 1H ), 0.96 - 0.89 (m, 2H), 0.82 - 0.76 (m, 2H).

Example 275: 6-(trifluoromethoxy)-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxylic acid (compound 324)

Step 1: [2-amino-3-bromo-5-(trifluoromethoxy)phenyl]methanol

To a mixture of compound 275-1 (400 mg, 1.3 mmol, 1.0 eq.) in THF (1 ml) was added BH3-THF (1 M, 6.7 ml, 5.0 eq.) at 0°C in an N ₂ atmosphere. The mixture was stirred at 70°C for 4 hours. The desired product was observed by LCMS. Using TLC (PE: EA=1:1, UV), the new zones formed were observed. The mixture was quenched with MeOH (3 ml) at 0°C. The mixture was diluted with H2O (5 ml) and extracted with EA (10 ml x 3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel. Compound 275-2 (380 mg, 1.33 mmol, 99.64% yield) was obtained as a white solid. LCMS (ESI): RT=0.741 min, mass, calc. for C ₈ H ₇ BrF ₃ NO ₂ 284.96, m/z obtained 285.8 [M+H]+; 1H NMR (400 MHz, CDCl ₃ ) δ 7.33 - 7.32 (m, 1H), 6.96 (s, 1H), 4.68 - 4.65 (m, 2H).

Step 2: 2-amino-3-bromo-5-(trifluoromethoxy)benzaldehyde

To a mixture of compound 275-2 (470 mg, 1.6 mmol, 1.0 eq.) in DCM (5 ml) was added MnO ₂ (1.4 g, 16.4

- 268 046394 mmol, 10.0 eq.). The mixture was stirred at 25°C for 3 hours. The desired product was observed by LCMS. Using TLC (PE: EA=3:1, UV), the new zones formed were observed. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain a residue. Compound 275-3 (442 mg, 1.5 mmol, 89% yield) was obtained as a yellow solid. LCMS (ESI): RT=0.813 min, mass, calc. for C ₈ H ₅ BrF ₃ NO ₂ 282.95, m/z obtained 283.7

Step 3: Methyl 8-bromo-6-(trifluoromethoxy)quinoline-3-carboxylate

To a mixture of compound 275-3 (440 mg, 1.5 mmol, 1.0 eq.) and compound 275-3a (156.3 mg, 1.9 mmol, 1.2 eq.) in EtOH (5 ml) was added L-proline (89.2 mg, 0.774 mmol, 0.5 eq.). The mixture was stirred at 80°C for 16 hours. The desired product was observed by LCMS. Using TLC (PE: EA=5:1, UV) the new zone formed was observed. The mixture was diluted with H2O (10 ml) and extracted with EA (20 mlx3). The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography on silica gel. Compound 275-4 (445 mg, 1.3 mmol, 82% yield) was obtained as a white solid. LCMS (ESI): RT=0.847 min, mass, calc. for Ci ₂ H ₇ BrF ₃ NO ₃ 348.96, m/z obtained 351.7 [M+H]+; ^1H NMR (400 MHz, CDCl ₃ ) δ 9.57 - 9.56 (m, 1H), 8.87 - 8.86 (m, 1H), 8.06 - 8.05 (m, 1H), 7.77(s, 1H), 4.05(s, 3H).

Step 4: 6-(trifluoromethoxy)-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxylic acid

To a mixture of compound 275-4 (50 mg, 0.143 mmol, 1.0 eq.), compound 275-4a (32.5 mg, 0.171 mmol, 1.2 eq.), H ₂ O (0.5 ml) and Na ₂ CO ₃ (45.4 mg, 0.428 mmol, 3.0 eq.) in dioxane (2 ml) was added with Pd(dppf)Cl ₂ (5.2 mg, 7.1 μmol, 0.05 eq.). The mixture was degassed and purged with N2 3 times. The mixture was stirred at 90°C for 16 hours under N2 atmosphere. The desired product was observed using LCMS. The pH value of the mixture was adjusted to 6 us. citric acid. The mixture was diluted with H2O (10 ml) and extracted with EA (20 mlx3).

The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by pre-HPLC. The title compound was obtained (17.86 mg, 44.51 µmol, 31.16% yield). LCMS (ESI): RT=0.896 min, mass, calc. for C ₁₈ H9F ₆ NO ₃ 401.5, m/z obtained 401.8 [M+H]+; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.52 - 9.51 (m, 1H), 8.97 - 8.96 (m, 1H), 7.84 - 7.79 (m, 5H), 7.74(s, 1H).

Example 276: 6-methoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid (compound 325)

Step 1: Methyl 6-methoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylate

To a solution of methyl 8-bromo-6-methoxyquinoline-3-carboxylate (300 mg, 1.01 mmol, 1 eq.), [4(trifluoromethyl)phenyl]boronic acid (230.9 mg, 1.22 mmol, 1 ,2 eq.) and Na ₂ CO ₃ (214.7 mg, 2.03 mmol, 2 eq.) in dioxane (5 ml) and H2O (1 ml) was added Pd(dppf)Cl ₂ (37.0 mg, 50 µmol, 0.05 eq.). The reaction mixture was stirred at 90°C for 3 hours. Using LC-MS, complete consumption of the starting material was observed and one main peak with the required MS was determined. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , 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)phenyl)quinoline-3-carboxylate (350 mg, 95.6% yield) as a white solid.

Step 2: 6-methoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid

NaOH was added to a solution of methyl 6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxylate (350 mg, 0.96 mmol, 1 eq.) in THF (6 mL) and MeOH (2 mL). (1 M, 1.94 ml, 2 eq.). The reaction mixture was stirred at 25°C for 1 hour. Using TLC (petroleum ether:ethyl acetate=2:1, UV), it was observed that the starting material was consumed. The reaction mixture was concentrated under reduced pressure, and then the residue was diluted with water (10 ml). The pH of the mixture was adjusted to 5 with HCl (1 M) and then the suspension was filtered to give 6-methoxy-8-(4(trifluoromethyl)phenyl)quinoline-3-carboxylic acid (306.07 mg, 89% yield) in as a white solid. LCmS (ESI): RT=0.942 min, mass calc. for C ₁₈ H ₁₂ F ₃ NO ₃ 347.08 m/z, 348.0 [M+H]+ was obtained; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (d, J=2.3 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 7.91 - 7 .81 (m, 4H), 7.71 (d, J=2.9 Hz, 1H), 7.60 (d, J=2.9 Hz, 1H), 3.97 (s, 3H).

Example 277: 5,6-dichloro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid (compound 326)

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To a solution of compound 277-1 (20 mg, 52 µmol, 1.0 eq.), compound 277-1a (9.9 mg, 52 µmol, 1.0 eq.) and Na ₂ CO ₃ (11 mg, 0.0 eq.) 10 mmol, 2 eq.) in dioxane (1.5 ml) and H ₂ O (0.3 ml) Pd(dppf)Cl ₂ (1.9 mg, 2.6 μmol, 0.05 eq.) was added. The reaction mixture was stirred at 80°C for 16 hours under N ₂ atmosphere. Using LC-MS, complete consumption of the starting material was observed and one major peak with the required MS was identified. The pH of the reaction mixture was adjusted to 5 with HCl (1 M). The mixture was diluted with water (5 ml) and the resulting mixture was extracted with EA (20 ml x 3 ). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (3.56 mg, 16% yield) as a white solid. LCMS (ESI): RT=1.031 min, mass calc. for C ₁₇ H ₈ C ₁₂ F ₃ NO ₂ 384.99, m/z obtained 385.9 [M+H]+; ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.37 (s, 1H), 9.13 (s, 1H), 8.23 (s, 1H), 7.93 - 7.86 (m, 4H).

Example 278: 6-ethoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid (compound 327)

Step 1: 2-amino-3-bromo-5-methoxybenzoic acid

A solution of compound 278-1 (10.0 g, 59.8 mmol, 1.0 eq.) in DMF (200 ml) was added with NBS (10.7 g, 59.8 mmol, 1.0 eq.) at 0° WITH. The reaction mixture was stirred at 25°C for 16 hours. Using LCMS, complete consumption of the starting material was observed and one major peak with the required MS was determined. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and the suspension was filtered to give compound 278-2 (8.7 g, crude) as a dark purple solid. ¹ H NMR (400 MHz, DMSO-d6) δ 7.39 - 7.36 (m, 1H), 7.34 (d, J=3.0 Hz, 1H), 3.69 (s, 3H).

Step 2: (2-amino-3-bromo-5-methoxyphenyl)methanol

To a solution of compound 278-2 (1.0 g, 4.1 mmol, 1.0 eq.) in THF (2 mL) was added BH ₃ -THF (1 M, 12.2 mL, 3.0 eq.) at 0°C. The reaction mixture was stirred at 70°C for 16 hours. Using TLC (petroleum ether:ethyl acetate=2:1), it was observed that the starting material was consumed and one main zone was formed. The reaction was then cooled to 0°C and the reaction was quenched with MeOH (10 ml). The suspension was concentrated under reduced pressure. The mixture was diluted with water (30 ml) and the resulting mixture was extracted with EA (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give compound 278-3 (700 mg, 74% yield) as a brown solid.

Step 3: 2-amino-3-bromo-5-methoxybenzaldehyde

To a solution of compound 278-3 (2.2 g, 9.5 mmol, 1 eq.) in DCM (40 mL) was added MnO ₂ (8.2 g, 95 mmol, 10 eq.). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 278-4 (1.7 g, 78% yield) as a yellow solid.

Step 4: Methyl 8-bromo-6-methoxyquinoline-3-carboxylate

To a solution of compound 278-4 (5.3 g, 23 mmol, 1.0 equiv.) and compound 278-4a (2.3 g, 28 mmol, 2.30

- 270 046394 ml, 1.2 eq.) L-proline (1.33 g, 11.5 mmol, 0.5 eq.) was added to EtOH (60 ml). The reaction mixture was stirred at 80°C for 16 hours. The reaction was cooled to 25°C and then water (30 ml) was added. The suspension was stirred vigorously for 20 minutes and filtered to obtain a cake. The solid was collected and concentrated under high vacuum to give 278-5 (5.5 g, 80% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.38 (d, J=1.8 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 7.85 (d, J =2.6 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H).

Step 5: 8-bromo-6-hydroxyquinoline-3-carboxylic acid

Compound 278-5 (500 mg, 1.69 mmol, 1.0 eq.) was transferred into a tube under microwave irradiation in HBr/AcOH (4 ml). The stoppered tube was heated at 120°C for 1 hour under microwave irradiation. The reaction mixture was poured into ice water (15 g). The resulting mixture was extracted with EA (30 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 278-6 (450 mg, 76% yield) as a yellow solid.

Step 6: Methyl 8-bromo-6-hydroxyquinoline-3-carboxylate

A mixture of compound 278-6 (450 mg, 1.68 mmol, 1.0 eq.) in HCl/MeOH (10 ml) was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted for us. NaHCO ₃ (30 ml) and the resulting mixture was extracted with EA (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give compound 278-7 (320 mg, 67% yield) as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 9.16 (d, J=2.0 Hz, 1H), 8.88 (d, J=2.0 Hz , 1H), 7.84 (d, J=2.5 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 3.95 (s, 3H).

Step 7: Methyl 8-bromo-6-hydroxyquinoline-3-carboxylate

To a solution of compound 278-7 (50 mg, 0.18 mol, 1 eq.) and K ₂ CO ₃ (37 mg, 0.27 mol, 1.5 eq.) in DMF (1 ml) was added EtI (33 mg , 0.21 mol, 17 µl, 1.2 eq.). The reaction mixture was stirred at 60°C for 2 hours. 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 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 278-8 (50 mg, crude) as a white solid.

Step 8: 6-ethoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid

To a solution of compound 278-8 (50 mg, 0.16 mmol, 1.0 eq.), compound 278-8a (37 mg, 0.19 mmol, 1.2 eq.) and Na ₂ CO ₃ (34 mg, 0.32 mmol, 2.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (5.9 mg, 8.1 µmol, 0.05 eq.). The reaction mixture was stirred at 90°C for 16 hours. 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 x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (26.61 mg, 41.5% yield, HCl) as a gray solid. LCMS (ESI): RT=0.863 min, mass calc. for C ₁₉ H ₁₄ F ₃ NO ₃ 361.09, m/z obtained 361.9 [M+H]+; 1H NMR (500 MHz, DMSO-de) δ 9.12 (d, J=2.0 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 7.91 - 7.82 (m, 4H), 7.70 (d, J=2.8 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 4.28 - 4.22 (m, 2H) , 1.44 (t, J=6.9 Hz, 3H).

Example 279: 5,6-difluoro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid (compound 328)

Step 1: A(2-bromo-4,5-difluorophenyl)-2-(hydroxyimino)acetamide

To a solution of compound 279-1 (1.0 g, 4.8 mmol, 1.0 eq.) in H ₂ O (21 ml) was added conc. HCl (0.16 ml), Na ₂ SO ₄ (6.83 g, 48.1 mmol, 10 eq.), chloral hydrate (1.19 g, 7.21 mmol, 1.5 eq.) and hydroxylamine hydrochloride ( 1.2 g, 17.3 mmol, 3.6 eq.). The reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was extracted with EA (50 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give compound 279-2 (700 mg, 52% yield) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.88 (s, 1H), 8.45 (dd, J=7.9, 12.4 Hz, 1H), 8.18 (s, 1H), 7, 61

- 271 046394 (s, 1H), 7.43 (dd, J=7.9, 9.2 Hz, 1H).

Step 2: 7-bromo-4,5-difluoroindoline-2,3-dione

Compound 279-2 (700 mg, 2.51 mmol, 1.0 eq.) was added portionwise to 90% aqueous H ₂ SO ₄ (7 ml) at 70°C. The mixture was stirred at 90°C for 4 hours. The mixture was diluted with water (30 ml) and the resulting mixture was extracted with EA (50 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give compound 279-3 (220 mg, 33% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₀ ) δ 11.52 (s, 1H), 8.11 (dd, J=7.5, 10.6 Hz, 1H).

Step 3: 2-amino-3-bromo-5,6-difluorobenzoic acid

A solution of compound 279-3 (220 mg, 0.840 mmol, 1.0 eq.), NaCl (108 mg, 1.85 mmol, 2.2 eq.) and NaOH (80 mg, 2.0 mmol, 2.4 eq. .) in H2O (10 ml) was stirred at 25°C for 0.5 h. H ₂ O ₂ (0.5 ml, 5.20 mmol, 30% solution, 6.2 eq.) was slowly added, and then aqueous NaOH solution (80 mg NaOH in 10 ml H2O). The reaction mixture was stirred at 25°C for 3 hours. The pH of the suspension was adjusted to 3 with HCl (1 M) and extracted with EA (30 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give compound 279-4 (130 mg, 57% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (dd, J=8.2, 9.9 Hz, 1H).

Step 4: (2-amino-3-bromo-5,6-difluorophenyl)methanol

To a solution of compound 279-4 (100 mg, 0.39 mmol, 1.0 eq.) in THF (3 ml) was added BH3-THF (1 M, 0.40 μl, 1.0 eq.) at 25°C . The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to 0°C and then MeOH (5 ml) was added. The mixture was stirred for 10 minutes and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 279-5 (50 mg, 53% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 - 7.16 (m, 1H), 4.74 (d, J=2.1 Hz, 2H).

Step 5: 2-amino-3-bromo-5,6-difluorobenzaldehyde

A mixture of compound 279-5 (50 mg, 0.21 mmol, 1.0 eq.) and MnO ₂ (183 mg, 2.10 mmol, 10.0 eq.) in DCM (1 ml) was stirred at 25°C in for 2 hours. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure to give compound 279-6 (35 mg, 70% yield) as a yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 10.19 (s, 1H), 7.47 (dd, J=8.3, 9.3 Hz, 1H), 6.64 (br s, 2H)

Step 6: Methyl 8-bromo-5,6-difluoroquinoline-3-carboxylate

A mixture of compound 279-6 (35 mg, 0.15 mmol, 1.0 eq.), compound 279-6a (15 mg, 0.18 mmol, 1.2 eq.) and L-proline (8.5 mg, 74 µmol, 0.5 eq.) in EtOH (2 ml) was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 279-7 (32 mg, 71% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.56 (d, J=1.8 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H), 8.09 (dd, J =7.8, 9.8 Hz, 1H), 4.07 (s, 3H).

Step 7: 5,6-difluoro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid

To a solution of compound 279-7 (30 mg, 99 µmol, 1.0 eq.), compound 279-7a (19 mg, 99 µmol, 1.0 eq.) and Na ₂ CO ₃ (21 mg, 0.20 mmol , 2.0 eq.) in dioxane (2 ml) and H2O (0.4 ml) was added Pd(dppf)Cl ₂ (3.6 mg, 5.0 µmol, 0.05 eq.). The reaction mixture was stirred at 90°C for 16 hours. Using LCMS, it was observed that the starting material remained and one peak with the required MS was determined. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH=6 with HCl (1 M) and extracted with EA (20 mlx3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (4.50 mg, 11% yield) as a light yellow solid. LCMS (ESI): RT=0.974 min, mass calc. for C ₁₇ H ₈ F ₅ NO ₂ 353.05, m/z obtained 354.0 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.90 (br s, 1H), 9.33 (d, J=1.8 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 8.22 (dd, J=8.5, 11.3 Hz, 1H), 7.89 (s, 4H).

Example 280: 5-[4-(pentafluorosulfanyl)phenyl]naphthalene-2-carboxylic acid (compound 329)

To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-carboxylic acid (43.94 mg, 0.14 mmol, 1 eq.) and ( 4-bromophenyl)-pentafluorosulfan (50.06 mg, 0.17 mmol, 1.2 eq.) in dioxane (3 ml) was added Pd(dppf)Cl ₂ (5.39 mg, 7.3 μmol, 0.05 eq.), KOAc (43.40 mg, 0.44 mmol, 3 eq.) under N2 atmosphere. The mixture was stirred for 10 hours at 100°C. Completion of the reaction was observed using LCMS.

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The mixture was quenched with H2O (30 ml) and the mixture was extracted with EA (20 mlx3). The combined organic phase was washed with brine (20 mlx3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The compound 5-[4(pentafluorosulfanyl)phenyl]naphthalene-2-carboxylic acid (11.48 mg, 29.1 μmol, 19.7% yield) was obtained as a white solid. LCMS (ESI): RT=0.882 min, mass, calc. for: C ₁₇ HnF ₅ O ₂ S 374.33, m/z obtained 318.1; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.67 - 12.55 (m, 1H), 8.72 (s, 1H), 8.25 (d, J=8.0 Hz, 1H) , 8.09 (d, J=8.5 Hz, 2H), 8.00 (dd, J=1.4, 8.9 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.79 - 7.64 (m, 4H).

Example 281: 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (compound 330)

Step 1: 5-bromonaphthalene-2-carboxylic acid

To a solution of compound 281-1 (2.0 g, 11.6 mmol, 1.0 eq.) in AcOH (10 ml) was added Br ₂ (1.9 g, 11.6 mmol, 1.0 eq.) and I2 (59 mg, 0.23 mmol, 0.02 eq.). The mixture was stirred at 120°C for 0.5 hour. The reaction mixture was cooled to room temperature to obtain a white solid. The mixture was isolated by filtration, washed with acetic acid (40 mlx3) and then with H2O (30 mlx3) to give compound 281-2 (2.5 g, crude) as a white solid. 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (d, J=1.25 Hz, 1H), 8.20 (m, 2H), 8.13 (dd, J=8.78, 1 .76 Hz, 1H), 8.01 (m, 1H), 7.53 (m, 1H).

Step 2: 5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid

To a solution of compound 281-2 (200 mg, 0.80 mmol, 1.0 eq.) compound 281-2a (182 mg, 0.96 mmol, 1.2 eq.) and Na ₂ CO ₃ (253 mg, 2 .39 mmol, 3.0 eq.) in dioxane (3 ml) and H2O (0.6 ml) was added Pd(dppf)Cl ₂ (29 mg, 40 µmol, 0.05 eq.). The mixture was stirred at 90°C for 16 hours. The mixture was diluted with water (15 ml) and the resulting mixture was extracted with EA (40 ml x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by pre-HPLC to give the title compound (11.08 mg, 4.4% yield) as a white solid. 1st NMR (400 MHz, DMSO-de) δ 8.63 (s, 1H), 8.17 (d, J=8.28 Hz, 1H), 8.06 (m, 1H), 8.00 (dd , J=8.78, 1.51 Hz, 1H), 7.92 (d, J=8.28 Hz, 2H), 7.76 (m, 3H), 7.67 (t, J=7, 53 Hz, 1H), 7.58 (d, J=6.78 Hz, 1H).

Example 282: 5-(6-(trifluoromethyl)pyridin-3-yl)-2-naphthoic acid (compound 331)

Step 1: Methyl 5-bromo-2-naphthoate

To a solution of compound 282-1 (1.8 g, 7.17 mmol, 1 eq.) in MeOH (10 mL) was added H ₂ SO ₄ (12 M, 0.3 mL, 0.5 eq.). The mixture was stirred at 80°C for 2 hours. Using TLC (PE/EA=5/1), it was observed that the starting material was completely consumed. The mixture was concentrated. The residue was diluted with H ₂ O (20 ml). The mixture was extracted with EA (30 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give 282-2 (1.8 g, crude) as a white solid.

Step 2: Methyl 5-(6-(trifluoromethyl)pyridin-3-yl)-2-naphthoate

To a solution of compound 282-2 (300.0 mg, 1.13 mmol, 1 eq.), compound 282-2a (324.1 mg, 1.70 mmol, 1.5 eq.) and K ₂ CO ₃ (312 .8 mg, 2.26 mmol, 2 eq.) in dioxane (4 ml) and H2O (1 ml), Pd(dppf)Cl2 (41.4 mg, 56.6 μmol, 0.05 eq.) was added. The mixture was degassed and purged with N2 3 times, then the mixture was stirred at 80°C for 16 hours under an _N2 atmosphere. Using TLC (PE/EA=10/1), a new formed zone was observed. The mixture was diluted with H ₂ O (10 ml). The mixture was extracted with EA (20 _mlx3 ). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to give compound 282-3 (290.0 mg, 0.86 mmol, 75.8% yield) as a white solid.

Step 3: 5-(6-(trifluoromethyl)pyridin-3-yl)-2-naphthoic acid

To a solution of compound 282-3 (290.0 mg, 0.86 mmol, 1 eq.) in MeOH (3 ml) and THF (1.5 ml) was added

- 273 046394

NaOH (350.1 mg, 8.75 mmol, 10 eq.) in H2O (1.5 ml). The mixture was stirred at 20°C for 1 hour. The desired product was observed to be formed by LCMS. Using TLC (PE/EA=10/1), it was determined that the starting material was completely consumed. The mixture was concentrated. 1 N HCl was added to the residue until the pH value was 6-7. The mixture was extracted with EA (15 mlx3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (250.0 mg, 0.79 mmol, 90.0% yield) as a white solid. LCMS (ESI): RT=0.814 min, mass, calc. for C ₁₇ H ₁₀ F ₃ NO ₂ 317.07, m/z obtained 317.9 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J=1.8 Hz, 1H), 8.74 (d, J=1.5 Hz, 1H), 8.32 - 8, 25 (m, 2H), 8.10 (d, J=8.0 Hz, 1H), 8.02 (dd, J=1.8, 8.8 Hz, 1H), 7.83 (d, J =8.8 Hz, 1H), 7.78 7.70 (m, 2H).

Example 283: 5-[5-(trifluoromethyl)-2-thienyl]naphthalene-2-carboxylic acid (compound 332)

Step 1: Methyl 5-[5-(trifluoromethyl)-2-thienyl]naphthalene-2-carboxylate

To a solution of compound 283-1 (100.0 mg, 0.38 mmol, 1 eq.) and compound 283-1a (73.9 mg, 0.38 mmol, 1 eq.) in THF (2 ml) and H2O ( 0.5 ml) added Na ₂ CO ₃ (48.0 mg, 0.45 mmol, 1.2 eq.) and Pd(PPh ₃ ) ₂ Cl ₂ (13.2 mg, 18.9 µmol, 0.05 eq.). The mixture was degassed in vacuo and purged with N2 3 times. The mixture was stirred at 63°C for 4.5 hours. The desired compound was not detected by LCMS. Using TLC (PE/EA=10/1, UV), new formed zones were observed. The mixture was diluted with H2O (10 ml), extracted with EA (20 mlx3). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography to give compound 283-2 (100.0 mg, 0.28 mmol, 74.9% yield) as a white solid.

Step 2: 5-[5-(trifluoromethyl)-2-thienyl]naphthalene-2-carboxylic acid

NaOH ₍ 118, 9 mg, 2.97 mmol, 10 eq.). The mixture was stirred at 20°C for 1 hour. Complete consumption of the starting material was observed using TLC (PE/EA=5/1, UV). The mixture was concentrated. The residue was diluted with H ₂ O (10 ml) and the pH was adjusted to 6 - 7 with 1 N HCl. The mixture was extracted with EA (20 mlx3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (90 mg, crude) as a white solid. LCMS (ESI): RT=2.788 - 2.921 min, mass, calc. for C ₁₆ H ₉ F ₃ O ₂ S 322.03, m/z obtained 321.02 [M-H]-; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (d, J=1.3 Hz, 1H), 8.24 - 8.13 (m, 2H), 8.07 (d, J=8, 0 Hz, 1H), 7.71 (dd, J=1.1, 7.2 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.56 - 7.52 (m, 1H ), 7.24 -7.18 (m, 1H).

Example 284: 5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxylic acid (compound 333)

A mixture of the compound 5-(4-(trifluoromethyl)phenyl)quinoline-2-carbonitrile (30.0 mg, 0.10 mmol, 1.0 eq.) in conc. HCl (1 ml, 12 M) was stirred at 70°C for 16 hours. Complete consumption of the starting material was observed by LC-MS and one major peak was detected with the required MS. The reaction mixture was cooled to 25°C and then the suspension was filtered to obtain a residue as a white solid. The residue was purified by pre-HPLC to give the title compound (11.43 mg, 31.8% yield) as a yellow solid. LCMS (ESI): RT=0.887 min, mass calc. for C ₁₇ H ₁₀ F ₃ NO ₂ 417.26, m/z obtained 418.0 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (d, J=8.8 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.03 - 7.90 (m, 3H), 7.85 - 7.72 (m, 3H).

Example 285: 5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid (compound 334)

- 274 046394

Step 1: 5-chloroquinoxaline-2-carbonitrile

2,5-Dichloroquinoxaline (1 g, 5 mmol, 1 equiv.), Zn(CN)2 (294 mg, 2.5 mmol, 0.5 equiv.), Pd(PPh ₃ ) ₄ (578 mg, 0. 5 mmol, 0.1 equiv.) and DMF (10 ml, 0.5 M) were thoroughly purged with N2 for 10 min. The reaction mixture was heated at 120°C for 18 hours until complete consumption of the starting material, which was observed using LCMS. The mixture was carefully added to 60 ml of rapidly stirred water and the resulting solid was filtered and dried to give 5-chloroquinoxaline-2-carbonitrile (850 mg, 90% yield) as a colorless solid. LCMS calculated: 190 ([M+H]+), m/z received: 190.

Step 2: 5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid

5-Chloroquinoxaline-2-carbonitrile (100 mg, 0.53 mmol, 1 equiv.), (4(trifluoromethyl)phenyl)boronic acid (120 mg, 0.63 mmol, 1.2 equiv.), K3PO4 (281 mg , 1.33 mmol, 2.5 equiv.), Pd(PPh ₃ ) ₄ (61 mg, 0.05 mmol, 0.1 equiv.) and 4:1 dioxane/H ₂ O (2 ml: 0.5 ml, 0.2 M) were thoroughly purged with N2 for 10 min. The reaction mixture was sealed in a vessel under microwave irradiation and irradiated at 120°C for 70 minutes. The mixture was cooled to room temperature, diluted with EtOAc, carefully neutralized with 1 N HCl (aq) and separated. The organic layer was washed with H2O, brine, dried with Na ₂ SO ₄ and concentrated. The residue was purified by FCC, gradient 0 - 10% MeOH in DCM, to give 5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid (25 mg, 0.08 mmol, 15% yield). LCMS calculated: 319 ([M+H]+), m/z received: 319.

Example 286: 1-hydroxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (compound 335)

To a solution of methyl 1-hydroxy-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylate (30 mg, 86.6 µmol, 1 eq.) in THF (1 ml) and H2O (0.2 ml) NaOH (6.9 mg, 0.17 mmol, 2 eq.) was added. The mixture was stirred at 60°C for 1 hour. Using LCMS, it was observed that the starting material was consumed. Using TLC (PE:EA=5:1), consumption of the starting material was observed and one new zone was detected. HCl (1 M, 3 ml) was added to the solution to pH 5. The mixture was extracted with ethyl acetate (5 ml x 3). The combined organic layers were washed with brine (8 mlx2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by pre-HPLC. The compound 1-hydroxy-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid (14.1 mg, 42.2 μmol, 48.8% yield) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.33 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.71 ( dd, J=8.4, 15.7 Hz, 3H), 7.53 - 7.40 (m, 2H), 6.87 (d, J=8.8 Hz, 1H).

Example 287: 4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylic acid (compound 336)

To a solution of methyl 4-(4-(trifluoromethyl)phenyl)isoquinoline-7-carboxylate (80 mg, 0.24 mmol, 1 equiv.) in MeOH (2 ml), THF (2 ml) and H2O (2 ml) NaOH (28.9 mg, 0.72 mmol, 3 eq.) was added. The reaction mixture was stirred at 25°C for 2 hours. MeOH and THF were removed. The pH value of the aqueous layer was adjusted

- 275 046394 up to 5-6 with 1 N aq. HCl and extracted with EA (2x15 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was triturated with MeOH (15 ml), filtered and dried under reduced pressure to obtain the indicated compound LCMS (ESI): RT=0.710 min, mass calc. for C ₁₇ H ₁₀ F ₃ NO ₂ 317.07, m/z obtained 317.9 [M+H]+, 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.43 (s, 1H), 9, 60 (s, 1H), 8.92 (s, 1H), 8.62 (s, 1H), 8.26 (dd, J=8.82, 1.56 Hz, 1H), 7.96 (d , J=8.13 Hz, 2H), 7.91 (d, J=8.76 Hz, 1H), 7.83 (d, J=8.00 Hz, 2H).

Example 288: 2-methyl-1-oxo-4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylic acid (compound 337)

To a solution of methyl 2-methyl-1-oxo-4-(4-(trifluoromethyl)phenyl)-1,2-dihydroisoquinoline-7 carboxylate (20 mg, 55.3 µmol, 1 equiv.) in MeOH (1.5 ml), THF (1.5 ml) and H2O (2 ml) NaOH (6.6 mg, 0.16 mmol, 3 eq.) was added. The reaction mixture was stirred at 25°C for 1.5 hours. Using LCMS, it was observed that 88% of the desired product was detected. MeOH and THF were removed from the reaction mixture. The pH of the residue was adjusted to 5 with 1 N aq. HCl and extracted with EA (2x10 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The indicated compound was obtained. LCMS (ESI): RT=0.908 min, mass, calc. for C ₁₈ H ₁₂ F ₃ NO ₃ 347.08, m/z obtained 348.4 [M+1]+. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 9.12 - 9.28 (m, 1H), 8.19 (d, J=8.38 Hz, 1H), 7.69 (d, J=8 .13 Hz, 2H), 747 (d, J=8.00 Hz, 3H), 7.12 (s, 1H), 3.62 (s, 3H).

II. Biological assessment.

Example A1. YAP reporter assay.

HEK293T cells stably transfected with the 8XTBD luciferase reporter and pRLTK in 384-well plates were treated with test compounds starting at 3 μM (final concentration in the assay plate), 1:3 dilution and 10 points in quadruplicate. After 24-hour incubation with compounds at 37°C and 5% CO2, cells were lysed and 8XTBD-driven firefly luciferase activity and TK-driven control Renilla luciferase activity were measured using the Promega Dual luciferase reporter assay system.

Reagents: Reagents used for this study: DMEM: Invitrogen #11960077, Dual-Glo Luciferase Assay System: Promega-E2980, Puromycin Dihydrochloride: Invitrogen-A1113803, 384well plate: PerkinElmer-6007480, L-Glutamine: Invitrogen-25030164, hygromycin B : Invitrogen10687010 and penicillin-streptomycin: Merk-TMS-AB2-C

Wednesdays. The media used for this assay were as follows: culture medium: DMEM + 1 μg/ml puromycin + 200 μg/ml hygromycin (with 10% FBS + 1 mM L-glutamine) and assay medium: DMEM (with 10% FBS + 1 mM L-glutamine + 1x P/S).

Cell seeding: Suitable medium was heated to 37°C in a water bath: culture medium, assay medium, 1× D-PBS, 0.05% trypsin-EDTA. After removing all media, cells were trypsinized, then washed with 1× sterile D-PBS followed by 2 ml of 0.05% trypsin-EDTA. The cells were then incubated at room temperature for one minute. Then 10 ml/75 cm ² of assay medium was added to each flask. The cells were then carefully resuspended in the medium using a 10 mL pipette until the clumps disappeared completely. The cells were then transferred to 50 ml centrifuge tubes and centrifuged at 800 rpm for 5 min. The medium was removed and the cells were resuspended in assay medium. An aliquot of cells was used to calculate cell density (cells/mL). Then the cell suspension was diluted with analytical medium to a concentration of 6x10 ⁴ cells/ml. Then, 50 μl of the cell suspension was placed on a 384-well plate (PerkinElmer-6007480), 3x103 cells/well, and the cells were incubated in an incubator at 37°C, 5% CO ₂ .

Compound Treatment: During the day (plate incubation for 3-4 hours), test compounds were added using Echo, starting at 3 µM (final concentration in the assay plate), 1:3 dilution, 10 points, in quadruplicate. The plate was placed in a 5% CO2 incubator at 37°C for 24 hours.

Detection. Dual-Glo Luciferase Reagent was prepared by transferring the contents of one vial of Dual-Glo Luciferase Buffer into one vial of Dual-Glo Luciferase Substrate to create Dual-Glo Luciferase Reagent. Mixing was carried out by turning over until the substrate was completely dissolved. After mixing, the reagent was poured into 15 ml test tubes. In the afternoon (24 hours after compound treatment), DMEM+ medium in 384-well plates was aspirated with

- 276 046394 using a device for washing microplates.

Measurement of firefly luciferase activity: 20 μl of Dual-Glo luciferase reagent was added to 384-well plates. The plates were protected from light so as not to interfere with the analysis. The plates were shaken for 1 min, and then the plates were centrifuged at 1000 rpm for 30 s. After waiting for at least 10 min, firefly luminescence was measured using Envision.

Measurement of renilla luciferase activity: 20 μl of Stop-Glo reagent was added to 384-well plates. The plates were shaken for 1 min and then centrifuged at 1000 rpm for 30 s. After waiting for at least 10 min, renilla luminescence was measured using Envision.

The compound's IC50 and maximum inhibition of firefly luciferase and renilla luciferase activities were reported separately. IC50 activity of firefly luciferase is shown in Table. 4 below.

Table 4

No. connections Name Firefly Luciferase IC50 (µM) 1 M-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 2 K-(methylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 3 M-methyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide A

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4 T4-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide A 5 X-ethyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide A 6 X-isopropyl-5-(4-(trifluoromethyl)phenyl)naphthalene-2sulfonamide IN 7 X-isopropyl-4-[4-(trifluoromethyl)phenyl]quinoline-7carboxamide IN 8 8-bromo-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 9 methyl 1-[4-(trifluoromethyl)phenyl]isoquinoline-6-carboxylate IN 10 methyl 1-chloro-4-[4-(trifluoromethyl)phenyl] isoquinoline-7 carboxylate WITH AND T4-isopropyl-1-[4-(trifluoromethyl)phenyl]isoquinoline-6carboxamide A 12 tert-butyl(7-(isopropylcarbamoyl)-4-(4- (trifluoromethyl)phenyl)naphthalene-1-yl)carbamate IN 13 8-chloro-M-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 14 methyl-1-oxo-4-[4-(trifluoromethyl)phenyl]-2H-isoquinoline-7 carboxylate A 15 methyl 2-methyl-1-oxo-4-[4-(trifluoromethyl)phenyl]isoquinoline 7-carboxylate IN 16 8-amino-M-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 17 8-acetamido-M-isopropyl-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 18 T4-isopropyl-8-methylsulfanyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 19 T4-isopropyl-8-methyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide A 20 8-ethynyl-N-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide A 21 8-ethyl-M-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide A

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22 8-cyclopropyl-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 23 X-isopropyl-8-(methylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 24 methyl 4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylate A 25 X-isopropyl-4-[4-(trifluoromethyl)phenyl]isoquinoline-7carboxamide IN 26 X-isopropyl-2-methyl-1-oxo-4-(4-(trifluoromethyl)phenyl)-1,2d ihydroisoquinoline-7-carboxamide A 27 X-isopropyl-8-methylsulfinyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 28 X-isopropyl-8-methylsulfonyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide WITH 29 X-sulfamoyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN thirty X-isopropyl-8-(X-methylacetamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 31 8-amino-7-bromo-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 32 7-bromo-X-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide A 33 8-amino-7-chloro-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 34 X-isopropyl-8-(X-methylmethylsulfonamido)-5-(4(trifluoromethyl)phenyl)-2-naphthamide WITH 35 X-isopropyl-5-[4-(trifluoromethyl)phenyl] benzo[e][1.2.3]benzoxadiazole-8-carboxamide IN 36 7-chloro-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 37 X-isopropyl-8-methoxy-5-[4-(trifluoromethyl)phenyl]naphthalene2-carboxamide A 38 7-ethynyl-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 39 X-isopropyl-7-methoxy-5-[4-(trifluoromethyl)phenyl]naphthalene- A

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2-carboxamide 40 X-(2-(2-(2-acetamidoethoxy)ethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 41 X-isopropyl-7-methyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 42 X-isopropyl-7-(methylthio)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 43 7-cyclopropyl-X-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 44 7-amino-T4-isopropyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2 carboxamide A 45 X-isopropyl-7-methylsulfinyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 46 X-isopropyl-7-methylsulfonyl-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 47 7-ethyl-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 48 7-acetamido-X-isopropyl-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 49 tert-butyl(2-(2-(2-(5-(4-(trifluoromethyl)phenyl)-2naphtamido)ethoxy)ethoxy)ethyl)carbamate IN 50 X-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 51 X-isopropyl-7-(X-methylacetamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 52 X-isopropyl-7-(methylsulfonamido)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 53 X-isopropyl-7-(X-methylmethylsulfonamido)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 54 X-(2,2,2-trifluoroethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 55 M-cyclopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 56 X-(1,3-dihydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A

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57 X-(2-(2-methoxyethoxy)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 58 X-(2-methoxyethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 59 (8)-X-(1-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 60 (C)-X-(1-aminopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 62 X-(1,3-difluoropropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 63 2-amino-X-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2- <1]thiazole-8-carboxamide A 64 (8)-X-(1-(dimethylamino)propan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide WITH 65 (K)-X-(1-(dimethylamino)propan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide WITH 66 (S)-N-( 1 -(pyrrolidin-1 -yl)propan-2-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide IN 67 (R)-N-( 1 -(pyrrolidin-1 -yl)propan-2-yl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide V 68 X-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2-(1]thiazol-8carboxamide A 70 (B)-18G-(1-morpholinopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide WITH 71 X-isopropyl-5-(4-(trifluoromethyl)phenyl)naphtho[1,2-(1]oxazole8-carboxamide A 72 5,6-difluoro-L-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline3-carboxamide A 73 5,6-difluoro-L-(methylsulfonyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide IN 76 T\G-(4-oxo-2,8,11-trioxa-5-azatridecan-13-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN

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77 18G-(5-oxo-2,9,12-trioxa-6-azatetradecan-14-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 78 H-(ethylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 80 6-ethoxy-A-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxamide A 81 6-ethoxy-A-(methylsulfonyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide IN 84 (8)-H-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 85 (K)-H-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 86 H-(2-hydroxyethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 87 H-isopropyl-8-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 88 8-iodo-K-isopropyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 89 (8)-H-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 90 (8)-H-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 91 (K)-H-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 92 H-(1-(methylamino)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 93 (K)-H-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 94 5,6-dichloro-A-isopropyl-8-(4-(trifluoromethyl)phenyl)quinoline3-carboxamide A 95 7-amino-8-hydroxy-18G-isopropyl-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 96 5,6-dichloro-A-(methylsulfonyl)-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxamide IN

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97 A-isopropyl-6-methoxy-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxamide A 98 7V-[(1R)-2-hydroxy-1-methylethyl]-6-methoxy-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide A 99 (7?)-A-(1-hydroxypropan-2-yl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide A 100 (7?)-A-(1-methoxypropan-2-yl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide IN 101 (7?)-A-(1-(pyridin-2-yl)ethyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide IN 102 (S)-N-(l -methoxypropan-2-yl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide A 103 (5)-A-(1-(pyridin-2-yl)ethyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide A 104 A-isopropyl-6-(trifluoromethoxy)-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide A 105 A-[2-hydroxy-1-(2-pyridyl)ethyl]-6-methoxy-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide A 106 6-methoxy-A-[(17?)-1-(2-pyridyl)ethyl]-8-[4- (trifluoromethyl)phenyl]quinoline-3-carboxamide IN 107 6-methoxy-A-[(17?)-2-methoxy-1-methylethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide A 108 6-methoxy-A-[(15)-1-(2-pyridyl)ethyl]-8-[4- (trifluoromethyl)phenyl]quinoline-3-carboxamide A 109 6-methoxy-A-[(15)-2-methoxy-1-methylethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide A 110 T4-(2-hydroxy-1-(pyridin-2-yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 111 U-(prop-2-yn-1-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 112 T4-(but-3-in-1-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A FROM T4-(cyanomethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A

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114 X-(2-cyanoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 115 X,X-(disulfandiylbis(ethane-2,1-diyl))bis(5-(4(trifluoromethyl)phenyl)-2-naphthamide) WITH 116 6-cyclopropoxy-7U-isopropyl-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide A 121 N-(l-phenylcyclopropyl)-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 122 6-cyclopropoxy-7U-(methylsulfonyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide IN 123 A-(methylsulfonyl)-6-(trifluoromethoxy)-8-(4(trifluoromethyl)phenyl)quinoline-3-carboxamide WITH 124 X-(2-(methylamino)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 125 X-(2-(X-methylcyanamido)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 126 X-(3-(methylamino)propyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 127 X-(3-(X-methylcyanamido)propyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide V 128 (8)-X-(1-(6-aminopyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide V 129 (K)-X-(1-(6-aminopyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide A 130 A-[(18)-1-(azetidin-3-yl)-2-hydroxy-ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide WITH 133 (K)-A-(1-(1-(2-hydroxyethyl)azetidin-3-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide V 137 (R)-N-( 1 -(1 -(2,2-difluoroethyl)azetidin-3 -yl)ethyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide V 140 N-[(1S)-1-[1 -(2-hydroxyethyl)azetide in-3-yl]ethyl]-5 - [4(trifluoromethyl)phenyl]naphthalene-2-carboxamide V

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141 (K)-A-(1-(3-hydroxyazetidin-3-yl)ethyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide WITH 143 #-((15)-1-(1-isopropylase etidin-3-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide WITH 144 (/?)-LC1 -(1-(2-fluoroethyl (azetide in-3-yl (ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 148 7V-[(17?)-1-(1-ethylase etidin-3-yl)ethyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide V 149 #-[( 1S)-1 -(1 -ethyl azetidin-3 -yl)ethyl] -5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide V 150 7V-[(17?)-1-(1-ethylase etidin-3-yl)ethyl]-8-[4- (trifluoromethyl)phenyl]quinoline-3-carboxamide With 153 N-[(1R)-1-(1-methyl azetide in-3-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide V 155 (S)-7V-( 1 -(3-hydroxyazetidin-3-yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide V 156 7V-[(17?)-1-(1-methylase etidin-3-yl)ethyl]-8-[4- (trifluoromethyl)phenyl]quinoline-3-carboxamide V 158 A-[(17?)-1-(azetidin-3-yl)ethyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide V 160 N-(1,5-dihydroxypentan-3-yl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide With 161 N-(1,5-dihydroxypentan-3-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide V 162 N-[(18)-2-hydroxy-1-(2-pyridyl)ethyl]-5 -[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide With 163 N- [(1 R)-2-hydroxy-1 -(2-pyr idyl)ethyl] -5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 164 (S)-N-(3 -hydroxy-1 -(pyridin-2-yl)propyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide A 165 (R)-N-(3 -hydroxy-1 -(pyridin-2-yl)propyl)-5-(4- WITH

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(trifluoromethyl)phenyl)-2-naphthamide 166 N-[(1S)-3-hydroxy-1-methylpropyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 167 N-[(1R)-3-hydroxy-1-methylpropyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 168 (U)-LC4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 169 (7?)-7U-(4-aminobutan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 170 A-((2-(fluoromethyl)pyrimidin-4-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 171 A-((2-((isoxazol-3-yloxy)methyl)pyrimidin-4-yl)methyl)-5(4-(trifluoromethyl)phenyl)-2-naphthamide IN 172 L>G-((2-((2,6-difluorophenoxy)methyl)pyrimidin-4-yl)methyl)-5(4-(trifluoromethyl)phenyl)-2-naphthamide WITH 173 N- [(1R)-1 -(3N-benzimide azol-4-yl)ethyl] -5 -[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 174 N-[(1S)-1 -(3N-benzimidazol-4-yl)ethyl] -5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 176 A-[(77?)-1-(benzothiophen-7-yl)ethyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 177 N- [(1R)-1 -(2-oxo-1 N-quinolin-8-yl)ethyl] -5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 178 N-[(l 8)-1-(2-oxo-1H-quinolin-8-yl)ethyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide WITH 179 A-((2-cyanopyrimidin-4-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 180 A-((2-chloropyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 181 A-((2-chloropyrimidin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide A

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182 N- [(1R)-1-(1 H-indazol-7-yl)ethyl] -5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 183 N-[(l 8)-1-(1H-indazol-7-yl)ethyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide WITH 184 3-((5-(4-(trifluoromethyl)phenyl)-2-naphtamido)methyl)-1,2,4thiadiazol-5-carboxamide A 185 X-(pyrimidin-4-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 186 18G-((2-cyanopyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide A 187 T\G-((6-((2,6-difluorophenoxy)methyl)pyridin-2-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 188 X-[3-hydroxy-1-(2-pyridyl)propyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 190 X-((6-fluoropyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 191 18G-((6-cyanopyridin-2-yl)methyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 192 18G-(3-((isoxazol-3-yloxy)methyl)benzyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 193 4-((1,2,4-thiadiazol-3-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 195 (8)-4-(1-(1-methyl-1H-imidazol-4-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide A 196 (R)-N-( 1 -(1 -methyl-1 H-imide azol-4-yl)ethyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide IN 197 M-(1-hydroxy-3-(pyridin-2-yl)propan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 198 4-[(E)-6-isoxazol-3-yloxyhex-4-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 199 (R)-N-(l-(l-acetylase etidin-3-yl)ethyl)-5-(4- IN

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(trifluoromethyl)phenyl)-2-naphthamide 200 (S)-N-( 1 -(1 -acetylazetidin-3 -yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 201 3 -(1 -(5 -(4-(trifluoromethyl)phenyl)-2-naphtamido)ethyl)-1,2,4thiadiazol-5-carboxamide A 202 A-[(E)-6-amino-6-oxohex-4-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 203 (R)-N-(l -(azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 204 (8)-M-(1-(azetidin-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide IN 206 (R)-N-(l -(2-chlorophenyl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 208 18G-(3-(2-methoxyethoxy)benzyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 209 (E)-5-[[5-[4-(trifluoromethyl)phenyl]naphthalene-2carbonyl]amino]pent-2-enoic acid WITH 210 18G-((2-methoxypyridin-4-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 211 18G-((2-fluoropyridin-4-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 212 N-(1-methoxy-2-methylpropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 213 (B)-M-(1-(4-aminopyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide IN 214 (8)-M-(1-(4-aminopyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide WITH 215 18G-(3-cyanobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 216 A-[(2)-4-cyanobut-3-enyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 217 7U-[(E)-4-cyanobut-3-enyl]-5-[4- A

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(trifluoromethyl)phenyl]naphthalene-2-carboxamide 218 (I)-L-[1-(2-amino-3-pyridyl)ethyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 220 A-((1,2,4-thiadiazol-5-yl)methyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 221 A-((3-methyl-1,2,4-thiadiazol-5-yl)methyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 222 N-[(E)-5-amino-5-oxopent-3-enyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide A 223 (R)-N-(l -(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide IN 224 (S)-N-(l-(4-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide WITH 225 M-(1-(4-bromopyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide A 227 N-[(E)-5-cyanopent-4-enyl]-5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 228 A-[(2)-5-cyanopent-4-enyl]-5-[4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide A 229 M-(pyridin-4-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 230 methyl(E)-5 - [[ 5 -[4-(trifluoromethyl)phenyl] naphthalene-2 carbonyl] amino] pent-2-enoate IN 231 N-(5-cyano-5-hydroxypentyl)-5 - [4- (trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 232 (A)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxy-A-(1- (pyridin-2-yl)ethyl)quinoline-3-carboxamide A 233 (7?)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-A-(1-hydroxypropan2-yl)-6-methoxyquinoline-3-carboxamide A 234 N-(3 -(3-methoxypropanamido)benzyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide A

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235 M-(3-aminobenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 236 tert-butyl(3-((5-(4-(trifluoromethyl)phenyl)-2-naphtamido)methyl)phenyl)carbamate IN 237 M-(3-acetamidobenzyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 238 M-(5-hydroxypentyl)-5-[4-(trifluoromethyl)phenyl]naphthalene-2carboxamide IN 239 M-(pyridin-2-ylmethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 240 M-(3-methoxybenzyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 241 M-benzyl-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 242 (K)^-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 243 (8)^-(1-(1H-imidazol-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 244 (5)-A-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide A 245 M-[(E)-5-hydroxypent-3-enyl]-5-[4-(trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 246 (5)-A-(1-methoxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide IN 247 (7?)-A-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxamide IN 248 A-isopropyl-5-(4-(trifluoromethyl)phenyl)quinoline-2carboxamide V 249 A-(4-chlorobutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 250 M-(1-(pyridin-2-yl)cyclopropyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide V 251 (8)-Na-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide V 252 (8)^-(1-cyclobutylethyl)-5-(4-(trifluoromethyl)phenyl)-2- V

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naftamide 253 (8)-A-(1-(1-methyl-1H-imidazol-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide WITH 254 (R)-N-( 1 -(1 -methyl-1 H-imide azol-2-yl)ethyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide IN 255 7U-(4-hydroxybutyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 256 A-(3-azidopropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 257 7U-(1-(hydroxymethyl)cyclopropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 258 (B)-M-(1-amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 259 (S)-N-(1-amino-1-oxopropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 260 M-[2-hydroxy-1-(2-pyridyl)ethyl]-8-[4-(trifluoromethyl)phenyl]quinoline-3-carboxamide A 261 A-(2-azidoethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 262 A-(2-(pyridin-2-yl)propan-2-yl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 263 N-(1-hydroxy-2-methylpropan-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 264 A-(tert-butyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 265 7U-(3-chloropropyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 266 (5)-A-(1-(pyridin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide V 267 (7?)-7U-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxamide V 268 7U-Isopropyl-5-(4-(trifluoromethyl)phenyl)quinoxaline-2carboxamide V 269 (S)-N-(l -(oxetan-3 -yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 270 (B)-14-(1-(oxetan-3-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2- IN

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naftamide 272 (8)-18G-(pent-3-yn-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 273 (C)-1U-(pent-3-yn-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 274 (8)-M-(but-3-in-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 275 (C)-18G-(but-3-in-2-yl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 276 (8)-M-C1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 277 (K)^-(1-(1H-imidazol-4-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)2-naphthamide IN 278 (8)-M-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide IN 279 (K)^-(1-(2-methyl-2H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide A 280 (8)^-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide WITH 281 (K)^-(1-(1-methyl-1H-tetrazol-5-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2-naphthamide V 282 (8)^-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide V 283 (K)^-(1-(pyrazin-2-yl)ethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 286 (R)-N-(l -(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide A 287 (8)-18G-(1-(6-(dimethylamino)pyridin-2-yl)ethyl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide IN 288 18G-(3-phenyloxetan-3-yl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 289 (8)^-(1-cyclopropylethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A 290 (R)-N-(l -cyclopropylethyl)-5-(4-(trifluoromethyl)phenyl)-2naphthamide A

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291 ?/-(2-hydroxy-1 -(pyr idin-2-yl)ethyl)-7-methoxy-5 -(4(trifluoromethyl)phenyl)-2-naphthamide A 292 A) ^- 7-methoxy-b>G-(1 -(pyridin-2-yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 293 (7?)-7-methoxy-M-(1 -(pyr id in-2-yl)ethyl)-5 -(4(trifluoromethyl)phenyl)-2-naphthamide A 294 (5)-7-methoxy-X-(1-methoxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 295 (7?)-7-mctokch-N-(1-methoxypropan-2-yl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 296 (S)-N-(1-hydroxypropan-2-yl)-7-methoxy-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 297 (R)-N-(1-hydroxypropan-2-yl)-7-methoxy-5-(4(trifluoromethyl)phenyl)-2-naphthamide A 298 7U-isopropyl-6-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[5,1a]isoquinoline-9-carboxamide IN 299 7U-isopropyl-6-(4-(trifluoromethyl)phenyl)imidazo[2,1 a]isoquinoline-9-carboxamide IN 300 L'-isopropyl-5 -(4-(trifluoromethyl)phenyl)-[1.2,4]triazolo[1,5a]quinoline-8-carboxamide IN 306 TV-isopropyl-1-methyl-2-oxo-4-(4-(trifluoromethyl)phenyl)-1,2d ihydroquinoline-7-carboxamide V 307 7U-isopropyl-5-(4-(trifluoromethyl)phenyl)-[1.2.4]triazolo[4,3a]quinoline-8-carboxamide V 311 (£)-A-(4-(methylsulfonyl)but-3-en-1-yl)-5-(4- (trifluoromethyl)phenyl)-2-naphthamide A 313 7U-[(17?)-3-(dimethylamino)-1-methylpropyl]-5-[4(trifluoromethyl)phenyl]naphthalene-2-carboxamide IN 316 TV-[( 17?)-3 -(ethylamino)-1-methylpropyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide V 317 (7?)-7U-(1-(1-(2,2-difluoroethyl)azetidin-3-yl)ethyl)-8-(4- V

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(trifluoromethyl)phenyl)quinoline-3-carboxamide 318 (7?)-A-(1-(1-(2-fluoroethyl)azetidin-3-yl)ethyl)-8-(4- (trifluoromethyl)phenyl)quinoline-3-carboxamide IN 319 A-[(17?)-3-(dimethylamino)-1-methylpropyl]-8-[4(trifluoromethyl)phenyl]quinoline-3-carboxamide IN 320 (R)-7V-(1-(1-cyclopropyl azetide in-3-yl)ethyl)-5-(4(trifluoromethyl)phenyl)-2-naphthamide IN 321 8-(2-fluoro-4-(trifluoromethyl)phenyl)-6-methoxyquinoline-3carboxylic acid A 322 7-methoxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid A 323 6-cyclopropoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3carboxylic acid A 324 6-(trifluoromethoxy)-8-[4-(trifluoromethyl)phenyl]quinoline-3carboxylic acid A 325 6-methoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid A 326 5,6-dichloro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid A 327 6-ethoxy-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid A 328 5,6-difluoro-8-(4-(trifluoromethyl)phenyl)quinoline-3-carboxylic acid A 329 5-[4-(pentafluorosulfanyl)phenyl]naphthalene-2-carboxylic acid A 330 5 - [4-(trifluoromethyl)phenyl]naphthalene-2-carboxylic acid A 331 5-(6-(trifluoromethyl)pyridin-3-yl)-2-naphthoic acid IN 332 5-[5-(trifluoromethyl)-2-thienyl]naphthalene-2-carboxylic acid A 333 5-(4-(trifluoromethyl)phenyl)quinoline-2-carboxylic acid IN 334 5-(4-(trifluoromethyl)phenyl)quinoxaline-2-carboxylic acid IN 335 1-hydroxy-5-(4-(trifluoromethyl)phenyl)-2-naphthoic acid A 336 4-[4-(trifluoromethyl)phenyl]isoquinoline-7-carboxylic acid IN 337 2-methyl-1-oxo-4-(4-(trifluoromethyl)phenyl)-1,2dihydroisoquinoline-7-carboxylic acid IN

Note: IC50 biochemical assay data are indicated within the following ranges:

A: <0.100 µM;

B: >0.100 µM to <1.000 µM;

C: > 1,000 µM to < 3,000 µM;

D: > 3,000 µM.

Example A2. Tumor suppression assay.

The procedures described herein for tumor suppression assays are those described in PCT/US2013/043752 (WO 2013/188138). Procedures in mice are performed in accordance with the guidelines of the validated animal protocol and methods. After cells have grown to 90% confluence, the cells are harvested by trypsinization, washed with phosphate-buffered saline (PBS), and resuspended in PBS supplemented with 50% Matrigel (BD Biosciences). For

- 294 046394 injections prepare the appropriate number of cells, for example 200 µl per injection site. Immunocompromised mice are given dorsolateral subcutaneous injections. Any of the compounds described herein are suitably formulated and then administered at a suitable dose. Control mice received vehicle only. The average diameter of the tumor is recorded (two perpendicular axes of the tumor are measured). Data are expressed in tumor volume, estimated as ([width]2xlength/2). A paired two-tailed Student's t test was used to determine statistical significance.

Example A3. Cell proliferation assay.

Cancer cell lines are seeded in 384-well plates 24 hours before drug exposure. After incubation for various periods of time with test compounds, starting at 3 μM (final concentration in the assay plate), 1:3 dilution and 10 points in duplicate, the number of viable cells and proliferative cells was determined using the CellTiter-Luminescent Cell Viability Assay Kit. Glo® (Promega) and HCS Click-iT EdU Assay Kit (Invitrogen) according to manufacturers' protocols. IC ₅₀ values and maximum % inhibition of test compounds are calculated using dose-response curves.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of the present invention and within the scope of the appended claims.

Claims (15)

1. A compound of formula (IVa) or (IVb) or a pharmaceutically acceptable salt thereof: Formula (IVb); where each R ^X independently represents hydrogen, halogen, -OR ³ ; each R ² represents F; each R ³ independently represents hydrogen, C 1 -C ₆ alkyl, optionally substituted with halogen, unsubstituted C ₃ -C ₁₀ cycloalkyl; Where R ⁵ is -CF ₃ or -SF5; and n is 0 or 1. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) is characterized by the structure of formula (IVa): - 295 046394 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IV) is characterized by the structure of formula (IVb): R ^x R ^x O R ⁵ Formula (IVb). 4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: each R ^X independently represents hydrogen or -OR ³ . 5. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: each R ^X independently represents hydrogen, -OCH3, -OCH2CH3 or -OCF3. 6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, where: R ⁵ represents -CF ₃ . 7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where: n represents 0. 8. Compound of formula (Ia) or a pharmaceutically acceptable salt thereof: R ⁵ Formula (1a) wherein each R ^X independently represents hydrogen, halogen, -OH, -NH2, -CH3, -CH2CH3, cyclopropyl, -CF3 or -OCH3; R ¹ represents substituted or unsubstituted ^-^alkyl, and if Ci-Cbalkyl is substituted, then it is substituted with 1 or 2 substituents, each independently selected from -OH, -NH ₂ , azetidinyl, pyridyl and aminopyridyl; R ⁵ represents -CF ₃ ; and n represents 0. 9. A compound according to claim 8 or a pharmaceutically acceptable salt thereof where: - 296 046394 each R ^X is independently hydrogen, halogen, or -OCH3. 10. A compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein: each R ^X represents hydrogen. 11. A compound according to any one of claims 8-10 or a pharmaceutically acceptable salt thereof, where: R ¹ represents Cl-C ₆ alkyl substituted with 6-aminopyridin-2-yl or 2-aminopyridin-3yl. 12. A compound according to any one of claims 8-10 or a pharmaceutically acceptable salt thereof, where: R ¹ represents C1- _C6 alkyl substituted with pyridinyl. 13. A compound characterized by one of the following structures: - 297 046394 - 298 or a pharmaceutically acceptable salt of any of the preceding compounds. 14. A compound characterized by one of the following structures: or a pharmaceutically acceptable salt of any of the preceding compounds. 15. A pharmaceutical composition containing a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.