COMPOUNDS AND METHODS

The present invention relates to no vel retinoid-related orphan receptor gamma (RORy) modulators and their use in the treatment of diseases mediated by RORy.

Background of the Invention Retinoid-related orphan receptors (RORs) are transcription factors which belong to the steroid hormone nuclear receptor superfamily (Jetten & Joo (2006) Adv. Dev. Biol. 16:313-355). The ROR. family consists of three members, ROR. alpha (RORa), ROR beta (RORp), and ROR gamma (RORy), each encoded by a separate gene (RORA, RORB, and RORC, respectively). RORs contain four principal domains shared by the majorit '- of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain, and a ligand binding domain. Each ROR gene generates several isoforms which differ only in their N-terminal A/B domain. Two isoforms of RORy have been identified: RORyl and RORyt (also known as RORy2). RORy is a term used to describe both RORyl and/or RORyt.

While RORyl is expressed in a variety of tissues including thymus, muscle, kidney and li v er, RORyt is exclusi v ely expressed in the cells of the immune system. RORyt has been identified as a key regulator of Thl 7 cell differentiation. Thl 7 cells are a subset of T helper cells which produce IL- 17 and other proinflammatory cytokines. Thl 7 cells have been shown to have key functions in several mouse autoimmune disease models including experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). In addition, Thl 7 cells or their products have been shown to be associated with the pathology of a variety of human inflammatory and autoimmune disorders including multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma (Jetten (2009) Nucl. Recept. Signal. 7:e003; Manel et ai. (2008) Nat. Immunol 9:641 -649). The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Thl 7 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Steinman (2008) J. Exp. Med. 205: 1517- 1522; Leung et ai. (2010) Cell. Mol. Immunol. 7: 182- 189). There is evidence that Thl 7 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Korn et ai. (2009) Aram. Rev. Immunol. 27:485-517).

RORyt plays a critical role in the pathogenic responses of Thl 7 cells (Ivanov et al. (2006) Cell 126: 1 121 -1 13 ). RORyt deficient mice produce few Thl 7 cells, in addition, RORyt deficiency resulted in amelioration of EAE. Further support for the role of RORyt in the pathogenesis of autoimmune or inflammatory diseases can be found in the following references: Jetteii & .Too (2006) Adv. Dev. Biol. 16:313-355; Meier et al. (2007) Immunity 26:643-654; Aloisi & Pujol-Borrell (2006) Nat. Rev. Immunol. 6:205-217; Jager et al. (2009) J. Immunol. 183 :7169- 7177; Serafmi et al. (2004) Brain Pathol. l 4: 164- 174; Magliozzi et al. (2007) Brain 130: 1089- 1 104 Barnes (2008) Nat. Rev. Immunol. 8: 1 83- 192.

in light of the role RORy plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORy activity, which can be used in the treatment of diseases mediated by RORy.

Summary of the Invention

The invention is directed to novel RORy modulators and their use in the treatment of diseases mediated by RORy. Specifically, the invention is directed to compounds according to Formula I):

wherein:

m is 0, 1 , or 2;

n is 0, 1 , 2, or 3;

X ¹ , X , X ³ , X ⁴ , and X ⁵ are each independently selected from N, N ^f -0 ^" , CH, and CR ⁵ , wherein 0-3 of X ^! , X ² , X ³ , X ⁴ , and X ⁵ are N or ⁺ -0 ^" and 1 -3 ofX ¹ , X ² , X ³ , X ⁴ , and X ^s are CR ⁵ ; one of Y ¹ and Y ^{^} is O or NR^ and the other is a bond;

or X ¹ is CR ⁵ , Y ¹ is NR ⁸ , Y ² is a bond, and R ⁵ and R ⁸ taken together with the atoms to which they are attached form a five to seven membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (C;-C ₄ )alkyl;

Cy is (CrCs)cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one, two, or three times, independently, by (C, -C6)alkyl,

(Ci -Cejhaioaikyl, (C ₃ -C6)eycloalkyl, halogen, oxo, cyano, hydroxy!, by droxyiC; -Ch lky!,

(d-Cgjalkoxy, -((Co-C ₃ )alkyl)NHC0 ₂ R ⁷ , -· ( ^' tr( . !alkyl ( -C ^' _: laikyl iC ) R .

^■ i( C,r ( ; !u!ky! )M K i ())R . ··! · ( _; ,-C : Ki iky!

-((C ₀ -C3)alkyl)CONR ⁷ R , -((Co-C ₃ )alkyl)C(0)R ⁷ , (Ci-C4)alkoxy(Ci-C ₆ )alkyl, amino(C C ₆ )aikyl, ((Ci-C4)aJkyl)((Ci-C ₄ )alkyl)amino(Ci-C6)alkyl, (Ci-C ₄ )alkylamino(Ci-C6)aJkyl, amino, (Ci-C4)alky!amino, ((G, -C4)alkyl)((Ci -C ₄ )a]kyl)amino, and, heteroaryl, ary{(Ci-C6)alkyl, heteroaryl(Ci~C ₆ )alkyl, or heterocycloalkyl;

Z is O, S, S0 ₂ , C <). NR ⁶ , or a bond;

A ¹ , Α ^Δ , A A", and A ⁵ are each independently selected from N, N^-O ^" , CH, and CR'°, wherein 0-3 of A', A ² , A ^" ', A ⁴ , and A ⁵ are N or N ^'* -0 ^" and 0-3 of A ¹ , A ² , A*, A ⁴ , and A* are CR ¹⁰ ;

R ¹ is {( ^' :-( ja!kyi. (C ₃ -C ₆ )haloalkyi, (C ₃ -C ₈ )c cloalky1, (C ₃ -C ₆ )a]koxy,

(C ₁ -C ₆ )alkoxy(Ci-C ₂ )alkyL aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaiyl(Ci-C6)alkyl, or heterocycloalkyl, each of which is optionally substituted one, two, or three times, independently, by

R ⁵ ;

R ² is hydrogen, (Ci -Cejalkyi, or (C-. -C^haloajkyl;

or R ^! and R ² taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one, two, or three times, independently, by R ⁵ ;

R ³ and R ^ia are each independently hydrogen, hydroxy!, (Ci -Ce -kyi, (Ci-C6)haloalkyl, halogen, (Q-Cejaikoxy, amino, or ((Ci-C4)alkyl)((Ci-C4)alkyl)ammo;

each R ⁴ is independently selected from hydrogen, halogen, (Q -G alkyl, (C i-Cyhaloalkyl, -CO ₂ R ⁷ , -CONR ⁷ R ⁸ , -OR ⁹ , and - R ^S R ⁹ , wherein said (C ₁ -C ₆ )alkyl or i ( ^• C, )haloaik i is optionally substituted by hydroxy! . -OR ⁹ , -( ^" O R -CONR ⁷ R ⁸ , or -NR R ⁹ ;

each R ⁴ is independently selected from hydrogen, halogen, hydroxy!, amino, and

(CrC ₆ )alkyl;

or R ⁴ and R ⁴ taken together with the carbon atom to which they are attached form a thi'ee to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci-C )alkyl, (Ci -C4)ha!oa!kyl,

(C ₃ -C ₆ )cycloalkyl, -C0 ₂ R ⁷ , -CONR ⁷ R ⁸ , hydroxy!, hydroxy(C,-C ₆ )alkyl, (C C ₄ )alkoxy,

(Ci-C4)alkoxy(Ci - C6)aikyl, amino, (Ct-C ₄ )aIkylamino, ((Ci -C ₄ )alkyI)((Ci-C4)alkyl)aniino, -NHCO2R ⁷ , -N((C _! -C4)alkyl)C0 ₂ R ⁷ , -NHC(0)R ⁷ , or -N((Ci -C ₄ )alkyl)C(0)R ⁷ ;

each R ^' ' is independently selected from (G-Cejalkyl, (C|-C _£l )haloalky!, (C ₃ -C6)cycloalkyl, halogen, cyano, hydroxy!, hydroxy(Ci -Ce^lkyl, (C Cyalkoxy, (C[-C ₄ )alkoxy(Ci-C6)alkyl, amino, (CrC ₄ )alkylamino, ((Ci-C ₄ )alkyl)((Ci-C ₄ )alkyl)amino, aryl, heteroaryl, aryl(Ci -Ce alkyl, heteroaryl(Ci-C6)alkyl, and heterocycloalkyl;

R ⁶ is hydrogen, (C;-C ₆ )alkyL (Ci-C ₆ )ha1oa1kyl, (C ₃ -C ₆ )cycloalky1, hydroxy(Ci-C ₆ )alkyl, (C ₁ -C ₄ )alkoxy(Ci-C ₆ )alkyl _> -((C ₀ -C ₃ )alkyl)CO ₂ R ⁷ , -((Co-C ₃ )alkyl)CO R ⁷ R ⁸ , aryl, heteroaryl, aryl(Ci-C ₆ )alkyl, heteroaryl(C; -C ₆ )alkyl, or heterocycloalkyl; R ^? is hydrogen, (Q -C^jalkyJ, (Ci-C6)haloaUkyl, (C;,-C ₆ )cycloalky1,

(Ci-C ₄ )alkoxy(Ci-C ₆ )alkyl, ary!, heteroary], aryl(C-i -C ₆ )alkyI, beteroaryI(Ci-C ₆ )alkyl, or heterocycloalkyl;

R ⁸ is hydrogen, (Cj-Cyalkyl, or (Ci -Cejhaloalkyl;

or R' and ⁸ taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional eteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (C-i-Q)alkyl, (CrC^haloalkyl, (C C ₆ )cycloalkyl, -C0 ₂ H, -C0 ₂ (C _r C ₄ )alkyL hydroxyl, hydroxy(C C ₆ )alkyl, (C _r C ₄ )alkoxy, (Ci-C ₄ )alkoxy(C] -Cejalkyl, amino, (Ci-C ₄ )alkylamino, or ((Ci-C ₄ )alkyl)((Ci-C ₄ )alkyl)amino;

R ⁹ is -C(0)R ⁷ , -C0 ₂ R ⁷ , -C(0)NR ⁷ R ⁸ , (C ^• C. i iky! (C ¾haloalkyl, (Cs- cycloalkyl, aiyl, heteroaryl, aryl(CrC ₆ )alkyi, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl, wherein said (CrCe kyl, (Ci -C ₆ )haloalkyl, (C;,-C6)cycloalkyl, aryl, heteroaryl, aiyl(C;-C6)alkyl,

heteroaryi(Ci - C6)alkyi, or heterocycloalkyl is optionally substituted by -C0 ₂ R ^' ', -CONH ₂ ,

-CONH(Ci-C ₄ )alkyJ, -CON((C-i-C ₄ )a]kyl)((Ci-C ₄ )alkyl), hydroxyl, (Ci-C ₄ )alkoxy, amino,

(Ci-C ₄ )alkylamino, ((Ci-C ₄ )alkyl)((Ci-C ₄ )alkyl)amino, -NHC0 ₂ R ⁷ , -N((Ci-C ₄ )alkyl)C0 ₂ R ⁷ , -NHC(0)R ⁷ , or -N((Ci-C ₄ )alkyl)C(0)R ⁷ ;

or R ^s and R"" taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (C-i-C ₄ )alkyl, (Ci-C ₄ )haloalkyl, iCrCs)cycloalkyl, -CO ₂ H, -C0 ₂ (C ₁ -C ₄ )alkyl _> -CO R'R ⁸ , hydroxy!, hydroxy(C C ₆ )alkyl,

·; ( ·( ^' : S iko . (Ci-C ₄ )alkoxy(Ci -Cejaikyl, amino, (Ci-C ₄ )alkylamino,

((Ci-C ₄ )alkyl)((Ci -C ₄ )alkyl)amino, - N l ·:( ^" ( ⁾ R -N((Ci -C ₄ )alkyl)C0 ₂ R ⁷ , -NHC(0)R ⁷ , or

-N((Ci-C ₄ )alkyl)C(0)R ⁷ ; and

R ¹⁰ is (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (CrC ₆ )cycloalkyl, halogen, cyano, hydroxyl, hyciroxy(Cr-C ₆ )aikyl, (C _r -C ₆ )alkoxy, (C · ( i !a lkoAVi i -C saikyi . -((C ₀ -C ₃ )alkyl)CO ₂ R ⁷ ,

-((Co-C ₃ )alk d)CONR ⁷ R ⁸ , amino(Ci -C ₆ )alkyl, t i C - C ^ i ik ! )(( ( ^' ••( )a!k ! ;nn .ino( i ^' - ( ^" _il )aiky!. (Ci-C ₄ )alkylamino(CrC ₆ )al]iyl, amino, (Ci-C ₄ )alkylammo, ((CrC ₄ )al3 yl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl;

or a salt thereof, particularly, a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, this invention provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of diseases mediated by RORy. ^' The invention further provides for the use of a compound of of Formula (I) or a pharmaceutically acceptable salt thereof as an active therapeutic substance in the treatment of a disease mediated by RORy.

In another aspect, the invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect the invention provides the use of a compound of Formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases mediated by RORy.

Examples of such diseases for which compounds of Formula (I) may be used include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, uveitis, dry eye, glomerulonephritis, Crohn's disease and asthma, especially psoriasis

In yet another aspect, the invention is directed to methods of treating such diseases for example by administering to a patient (e.g. hitman) in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention

As used herein, the term "alkyl" represents a saturated, straight, or branched hy drocarbon moiety. The term "(Ci -Ce alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyf, i-butyl, pentyl, and hexyl. C ₀ alkyl means that no alkyl group is present in the moiety. Thus, -((C ₀ )alkyl)CONH ₂ is equivalent to -CONH ₂ .

When the term "alkyl" is used in combination with other substituent groups, such as

"haloalkyl", "hydroxyalkyl", "alkoxyaikyl", "arylalkyf ', or "heteroarylalkyl", the term "alkyl" is intended to encompass a divalent straight or branehed-chain hydrocarbon radical. For example, "arylalkyi" is intended to mean the radical -alkylarvl, wherem the alkyl moiety thereof is a divalent straight or branehed-chain carbon radical and the aryl moiety thereof is as defined herein, and is represented by, for example, the bonding arrangement present in a benzyl group (-Ci-T-phenyl); "halofCi -Chalky!" is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branehed-chain carbon radical, and is represented by, for example, a trifluoromethyl group (-CF ₃ ).

As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring. The term "(Cj-Cglcycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight ring carbon atoms. Exemplary "(C3-Cg)cycloalkyl" groups useful in the present invention include cyclopropyi, cyelobutyi, cyclopenryl, cyciohexyl, cyciolieptyl, and cyclooctyl. "Alkoxy" means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom. The term "(Ci-C ₄ )alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least i and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(C[-C ₄ )alkoxy" groups useful in the present invention include, but are not limited to, metboxy, ethoxy, «-propoxy, isopropoxy, n-butoxy, s-butoxy, and i-butoxy.

"Aryl" represents a group or moiety comprising an aromatic, monovalent monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms, to which may be fused one or more cycloalkyl rings.

Generally, in the compounds of this invention, aryl is phenyl.

Heterocyclic groups may be heteroaryl or heterocycloalkyl groups.

"Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including I to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryls useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, iriazolyl, ietrazolyl, thiazolyi, oxazolyl, isoxazoiyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyf, isobenzofuryl, 2,3-dibydrobenzofuryl, 1,3-benzodioxolyl,

dihydrobenzodioxinyl, benzothienyl, mdolizinyl, indolyl, isoindolyl, dihydroindolyl,

benziniidazolyl, dihydrobenziniidazolyl, benzoxazoivL dihydrobenzoxazolyl, benzthiazoivl, benzoisotlisazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyi, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoqumolinyl, quinoxalinyl, cinnolinyl, ph halazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.

Generally, the heteroaryl groups present in the compounds of this invention are

5-membered and/or 6-memehred monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroa.ryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, iriazolyl, ietrazolyl, thiazolyi, oxazolyl, isoxazoiyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl,

"Heterocycloalkyl" represents a group or moiety comprising a non-aromatic, monovalent monocyclic or bicyclic radical, which is saturated or partially unsaturated, containing 3 to 10 ring atoms, which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, illustrative examples of heterocycloalkyls useful in the present invention include, but are not limited to, azetidmyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazmyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- oxathiofanyl, 1 ,3-oxathianyf , 1 ,3-dithianyl, hexahydro- 1 H- 1 ,4-diazep nyl, azabicylo[3.2.1 joctyl, azabicylo[3.3.1 jnonyl, azabicylo[4.3.()]nonyl, oxabicylo[2.2.1]heptyl and 1 ,5,9-triazacyclododecyl.

Generally, in the compounds of this invention, heteroeycloalkyl groups are 5-7 membered heterocycloalkyi groups, such as pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,3-dioxolanyl, piperidinyl, piperazmyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, and hexahydro- 1H- 1 ,4-diazepinyl .

"Oxo" represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C=0).

The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo suhstituents.

"Hydroxy" or "hydroxyl" is intended to mean the radical -OH.

"RORy" refers to all isoforms encoded by the RORC gene which include RORyl and

RORyt.

"RORy modulator" refers to a chemical compound that inhibits, either directly or indirectly, the activity of RORy. RORy modulators include antagonists and inverse agonists of RORy.

"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

As used herein, the term "compound(s) of the invention" means a compound of Formula (I) (as defined above) in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a pharmaceutically acceptable salt thereof! and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates)), and mixtures of various forms.

As used herein, the term "optionally substituted" indicates that a group, such as alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heieroarvl, may be unsubstituted, or the group may be substituted with one or more subststuent(s) as defined. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.

The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. The alternati ve definitions for the various groups and substituent groups of Formula (1) provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions.

Suitably, m is 0, 1 , or 2. In a specific embodiment of this invention, m is 1.

Suitably, n is 0, 1 , 2, or 3. In another embodiment of this invention, n is 1 or 2.

Suitably, X ¹ , X ^z , X ³ , X ⁴ , and X ⁵ are each independently selected from N, N ^÷ -0 ^" (i.e. N- oxide), CH, and CR ⁵ , wherein 0-3 of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are N or N ⁺ -0 ^" and 0-3 of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are CR ³ . In another embodiment of this in v ention, X ¹ , X , X ³ , X ^* , and X ⁵ are each independently selected from , ^r -Q ^~ , CH, and CR ^"5 , wherein 0-2 of X ¹ , X ² , X', X ⁴ , and X ^J are N or hT-O ^" and 0-3 of X ¹ , X ^z , X X ⁴ , and X ⁵ are CR ⁵ . In another embodiment of this invention, X ^! and X ⁵ are each independently selected from N, N' -O ^" , CH, and CR ⁵ , and X ² , X ^J , and X ^* are each independently selected from CH and CR ^' \ In another embodiment of this invention, X ¹ and X ³ are each independently selected from , N ⁺ -0 ^~ , CH, and CR\ and X ^" , X', and X ⁴ are each

independently selected from CH and CR ³ , wherein at least one of X ¹ and X ⁵ is N or NT-CT and 0-3 of X ¹ , X ^z , X', X ^" , and X ⁵ are CR ⁵ . In another embodiment of this invention, X ¹ and X ³ are each independently seiecied from N, N ^f -Q ^" , and a carbon atom substituted by hydrogen, halogen, cya.no, (C;-C4)alkyl, (Ci-C4)haloalkyl, (Ci-C ₄ )alkoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)amino (i.e. N, N ^÷ -0 ^~ , CH, and CR ⁵ , wherein R ³ is halogen, cyano, (Ci-C4)alkoxy, or ((Ci-C4)alkyl)((C] -C4)alkyl)amino), and X X ³ , and X ⁴ are each independently a carbon atom substituted by hydrogen, halogen, cyano, (Ci-C ₄ )alkyl, (Ci or ((Ci-C4)alkyl)((Ci -C4)alkyi)amino (i.e. CH or CR ³ , wherein R ^J is halogen, cyano, (Ci-G aJkyl,

(Ci-C ₄ )haloalkyl, (C-i -C ₄ )alkoxy, or ((Ci-C4)alkyl)((C _! -C ₄ )alky1)amino), wherein at least one of X ¹ and X ³ is N or N ⁺ -0 ^~ and 2-4 of X ¹ , X ^" \ X ³ , X ⁴ , and X ³ are a carbon atom substituted by hydrogen (i.e. CH). In another embodiment of this invention, X is N or IST-O ^' , and X ¹ , X X ^' and X ⁵ are each independently a carbon atom substituted by hydrogen, halogen, cyano, (Ci-C ₄ )aikyl,

(Ci-C4)ha1oa1kyl, (Ci-C4)alkoxy, or ((CrC4)alkyl)((Ci-C4)alkyl)amino, wherein 2-4 of X ¹ , X X ⁴ , and X ⁵ are a carbon atom substituted by hydrogen. In another embodiment of this invention, X ¹ , X", X ³ , X ⁴ , and X ⁵ are each independently selected from CH and CR ^J , wherein 0-3 of X ¹ , X ^" , X', X ⁴ , and X ³ are CR ⁵ . In another embodiment of this invention, X ¹ , X ^" , X ³ , X", and X ^' are each independently a carbon atom substituted by hydrogen, halogen, cyano, (Q -Chalky 1,

(C _; -C ₄ )haiQaikyl, (C C ₄ )alkoxy, or ((Ci-C-4)alkyl)((Ci-C ₄ )alkyj.)ammo, wherein 2-5 of X ¹ , X ² , X ³ , X ⁴ , and X ⁵ are a carbon atom substituted by hvdrogen. In another embodiment of this invention, X ¹ is a carbon atom substituted by halogen, (Ci -C ₄ )alkyl, (CrQ)haloalkyl, cyano, (Ci-C ₄ )alkoxy, or ((Ci-C4)alkyl)((C[-C4)alkyl)amino, and X", X ³ , X ⁴ , and X ⁵ are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C ₄ )alkyl, (C _t -C ₄ )haloalkyl, cyano, (Ci-C ₄ )alkoxy, or ((Ci-C4)aJkyl){(Ci-C4)alkyl)amino, wherein 2-4 of X ² , X ³ , X ⁴ , and X ⁵ are a carbon atom substituted by hydrogen.

Suitably, one of Y ¹ and Y ^{^} is O or NR ⁶ and the other is a bond. In another embodiment of this invention, one of Y ^: and Y' is O, NH, or N((Cj - C4)alkyi) and the other is a bond. In a specific embodiment of this invention, Y ^l is NH or NCH ₃ and Y is a bond, in another specific embodiment of this invention, Y ¹ is NH and Y ^" is a bond. In another specific embodiment of this invention, Y ¹ is a bond and Y~ is NH.

In another embodiment of this invention, X ¹ is CR ³ , Y ^: is NR ⁸ , Y is a bond, and R ⁵ and R ⁸ taken together with the atoms to which they are attached form a five to seven membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl. In another embodiment of this invention, X ¹ is CR ⁵ , Y' is NR ⁸ , Y ^' is a bond, and R ^" and R ⁸ taken together represent -CH?-, -CH ₂ CH ₂ -, or

-CH ₂ CH ₂ CH ₂ -.

Suitably, Cy is (Cs-Qjcycloalkyl, lieterocycloafkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted one, two, or three times, independently, by (Ci-Celaikyl, (Ci-C6)haloalkyl, halogen, oxo, cyano, hydroxyl,

hydroxy(Ci-C ₆ )a{kyl, (Ci-C ₆ )alkoxy,

-((Co-C ₃ )a1kyl)N((Ci-C4)alkyl)C0 ₂ R ⁷ , -((Cfl-C ₃ )alkyl)NHC(0)R ⁷ ,

-((Cfl-C ₃ )alkyl)N((Ci-C ₄ )alkyO

^■■ ((Co-C3)alkyi)C(0)R ⁷ , (Ci-C ₄ )alkoxy(C _! -C ₆ )alk>i uminoi C -C^aik i.

((Ci-C4)alkyl)((Ci -C4)alkyJ)amino(Ci-C,s)alkyl, amino,

(Cj-C ₄ )aikylammo, ((Ci-C4)aikyl)((Ci-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci-C ₆ )alkyl, heteroaryl(Ci-C6)alkyi, or heterocycloalkyl. In another embodiment of this invention, Cy is heterocycloalkyl, phenyi, or 5- or 6 -membered heteroary l, each of which is optionally substituted one or two times, independently, by (Ci-CejalkyJ, (C-.-CVibaloalkyl, halogen, cyano, (Ci-C ₄ )alkoxy, ((Ci-C4.)alkyl)amino ((Ci-C4.)alkyr)((Ci-C4)alkyl)amino, -((C ₀ -C¾)alkyl)CO2R', or -((Co-C ₃ )alkyl)COTslR'R ⁸ . In another embodiment of this invention, Cy is (C ₃ -C ₆ )cycloalkyl, azetidinyl, pyrrolidiiiyl, pyrazolidinyi, pyrazolinyf, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl piperidinyl, piperazinyl, morpholinyl,

thiomorpholinyl, tetrahydropyranyl, dihydropyranyl, dioxanyl, oxathianyl, phenyl furanyl, thienyl, pyrroly], imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, i othiazolyl, pyridiny], pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, each of which is optionally substituted one, two, or three times, independently, by (Ci-CeJalkyl, (Ci -Ce haloalkyi, (C;,-C ₆ )eycloallvyl, halogen, oxo, cyano, hydroxy 1, hydroxy(Ci-C6)alkyl,

(Cr-C ₆ )aikoxy, - u i , _: -C )a!ky i ;X U( X) .R . (Co-C3)aikyi)N((C _r -C ₄ )allvyl)C0 ₂ R ⁷ ,

-((< C ₃ )a1kyl)NHC(0)R ⁷ , ·1 ϊ ^" Γί · _: Ηύ1νν! )\ ί ί ί · ^•• ( ^" _: )aiky!)( ^" K)}R . -{ ((VC alkyhCO -R .

-((Co-C ₃ )a]l<yi)CONR ⁷ R ⁸ , -((Co-C ₃ )alkyl)C(0)R ⁷ , (Ci-C ₄ )a1koxy(Ci-C ₆ )alky1, amino(Ci-C ₆ )aikyl, ((Ci-C4)alkyl)((Ci -C4)alkyl)amino(Ci-C6)alkyl, (Ci -C4)alkylammo(Ci-C6)alkyl, amino,

(Cj-C4)alkylamino, ((Ci-C4)alkyl)((Ci-C ₄ )alkyl)amino, aryl, heteroaryl, aryl(Ci -Cejalkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl. In another embodiment of this invention, Cy is piperidinyl, piperazinyl, phenyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substiiuted one, two, or three times, independently, by (Ci-C6)alkyl, (Ci -CeJhaloalkyl, (C _. r-Celeycloallvyl, halogen, oxo, cyano, hydroxy 1, hydroxy(Ci-C6)alkyl,

(CrC ₆ )alkoxy,••(i ( ^' i _r ( ^' : )a!K l ;\ i ICO R . -« ^' :r C : saiky 1 )N( ( ^" -( ^' : ) ? ikynC ⁾ - .

-((Co-C ₃ )a1kyl)NHC(0)R ⁷ , -((C9-C ₃ )alky])N((r ^. _i -C4)alkyr)C(0)R ⁷ , -((Co-C ₃ )alkyl)C0 ₂ R ⁷ ,

-((Co-C ₃ )alkyl)CONR ⁷ R ⁸ , -((C ₀ -C ₃ )alkyl)C(O)R ⁷ , (Ci-C ₄ )alkoxy(Cx-C ₆ )alkyl, ammQ(Ci-C6)alkyL ((Ci-C4)alkyl)((Ci -C4)alkyl)amino(CrC ₆ )alkyl, (C] -C4)alkyIamino(Ci-C6)alkyl, amino,

(Ci-C ₄ )alky1amino, ((Ci-C4)alkyl)((Ci-C4)alkyl)ammo, aryl, heteroaryl, aryl(C] -C6)alkyl, heteroaryl(C-i-C6)alkyi, or heterocycloalkyl. In another embodiment of this invention, Cy is piperidinyl, piperazinyl, phenyl pyridinyl, pyridazinyl, pyraziny l, or pyrimidinyl, each of which is optionally substituted one or two times, independently, by (C, -Cejaikyl, (Ci-Cyhaloalkyi, halogen, cyano, (C, -C ₄ )alkoxy, (Ci-C4)a{kyl)((Ci-C ₄ )alkyl)amino, -((Co-C ₃ )alky{)C02H,

-((Co-C ₃ )a1kyl)C02(Ci-C6)alkyL or -((Co-C ₃ )alkyl)CONH(CrC ₆ )a1kyl. In another embodiment of this invention, Cy is phenyl, which is optionally substituted one, two, or three times, independently, by (Ci -Ce alkyl, (Ci-C6)haloalkyl, (C ₃ -C6)cycloalkyl, halogen, oxo, cyano, hydroxy!,

hydroxy(Ci-C ₆ )alkyi, i C -G aikoxy. -((C ₀ -C ₃ )alkyl)NHCO ₂ R ⁷ ,

-( >( \ )alky! >\ ^{( (} C -C _; ;a!k> i ^' O R . -((C ₀ -C ₃ )alkyl) HC(O)R ⁷ ,

-((C ₀ -C ₃ )alkyl)N((C ₁ -C ₄ )alkyl)C(O)R ⁷ , -((C ₀ -C ₃ )alkyl)CO ₂ R ⁷ , -((C ₀ -C ₃ )alkyl)CONR ⁷ R ⁸ ,

-((C ₀ -C ₃ )alkyl)C(O)R ⁷ , (Ci-C4)alkoxy(Ci-C ₆ )alkyL amino(C C ₆ )alkyi,

((Ci-C4)ajkyl)C(Ci-C4)alkyl)ammo(C-i-C6)a]kyl, (Ci-C4)alkylammo(Ci-C6)aJkyl, amino,

(Ci-C4)alkylamino, ((Ci-C ₄ )alky1)((CrC4)a1kyl)amino, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heterocycloalkyl. In another embodiment of this invention, Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (C]-C )alkyl, fC _r C ₄ )haloalkyl, cyano, (C _r C ₄ )alkoxy, -((Co-C ₃ )alkyl)C0 ₂ R ⁷ , or -((C ₀ -C ₃ )alkyl)CONR ⁷ R ^s or ((Ci-C4)alkyl)((Ci -C ₄ )alkyl)amino. In another embodiment of this invention, Cy is phenyl, which is optionally substituted one or two times, independently, by halogen, (Ci-C ₄ )alkyl,

(Cj~C ₄ )haloalkyl, cyano, (Ci-C ₄ )alkoxy, or ((C-i-C ₄ )alliyI)((Ci-C4)aIkyl)aminQ. In a specific embodiment of this invention, Cy is phenyl.

Suitably, Z is O, S, S0 ₂ , C=0, R ⁶ , or a bond. In another embodiment of this invention, Z is O, NR°, or a bond. In another embodiment of this invention, Z is O, NH,

-N(CrC ₄ )alkyl, -Nii i/,ri Yia!k ! K X> -R . -N((C ₀ -C ₃ )aikyl)CONR ⁷ R ⁸ or a bond. In another embodiment of this invention, Z is a bond, O, or NH. In another embodiment of this invention, Z is O or NH. In a specific embodiment of this invention, Z is O.

Suitably, A ¹ , A ² , A', A ⁴ , and A ³ are each independently selected from N, N ^: -O ^" , CH, and CR. ¹⁰ , wherein 0-3 of A ¹ , A ^"' , A', A ⁴ , and A ⁵ are N or TsT-O ^" and 0-3 of A ¹ , A", A ³ , A ⁴ , and A ⁵ are C R ^l!) , In another embodiment of this invention, A ¹ , A , A ³ , A ⁴ , and A ^' ' are each independently selected from N, N'-O ^" , and a carbon atom substituted by hydrogen, halogen, cyano, (Q -Chalky 1, (CrC ₄ )haloaikyl, hydroxyl, (Q -C ₄ )alkoxy, or ((Ci-C ₄ )aikyl)((Cj -C ₄ )aIkyl)amino, wherein 1 -2 of A ¹ , A ² , A ³ , A ⁴ , and A ⁵ are N or N ⁺ -0 ^~ and 1 -4 of A ¹ , A ^7" , A ³ , A ⁴ , and A ⁵ are a carbon atom substituted by hydrogen, in another embodiment of this invention, A ² and A ⁴ are each

independently selected from N, N ^{1 "} -0 ^" , and a carbon atom substituted by hydrogen, halogen, cyano, (Cj-C ₄ )alkyl, hydroxy!, (Ci-C ₄ )alkoxy, or ((Ci-C ₄ )alkyl)((Ci-C ₄ )alkyi)amino, and A ¹ , A ³ , and A ⁵ are each independently a carbon atom substituted by hydrogen, halogen, (Ci -C )alky], hydroxy!, (Ci-C,i)alkoxy, or ((Ci-C )alkyl)((Ci-C ₄ )alkyl)amino, wherein at least one of ¹ and A* is N or N ⁺ - O ^" . In another embodiment of this invention, A" and A ⁴ are each independently selected from N, ΝΓ-Ο ^' , CH, and C(i C, -C )alkyl), and A ¹ , A', and A ³ are each independently selected from CH and C((Ci -C ₄ )alky{), wherein at least one of A ^7" and A ⁴ is N or N ⁺ -0 ^" .

Suitably, R ¹ is (C ₃ -C ₆ )alkyi, (C3-C ₆ )haloalkyl, (CrC ₈ )cycloalkyl, (C ₃ -C ₆ )alkoxy,

(Ci-C6)alkoxy(C [-C ₂ )alkyl, aryl, heteroaryl, aryl(C[-C6)alkyl, heteroaryl(C] -C6)alkyl, or

heterocycloalkyl, each of which is optionally subsiituted one, two, or three times, independently, by R ^' \ In another embodiment of this invention, R ^l is (C ₃ -C6)alkyl, (C ₃ -Cg)cycloalkyi,

(Ci -Cg)alkoxy(Ci-C ₂ )aikyl ₅ aryl, or heteroaryl, each of which is optionally substituted one, two, or three times, independently, by R ⁵ . In another embodiment of this invention, R ¹ is (C ₃ -C ₆ )alkyl, (C ₃ -C ₆ )eycloalkyl, (Ci - C ₆ )alkoxy(Ci-C ₂ )alkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazoiyl, tetrazolyl, thiazolyi, oxazolyl, isoxazolyi, oxadiazolyl, thiadiazoiyl, isothiazolyi, pyridiny], pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl, % ^r herein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridmvl, pyridazinyl, pyrazinyl, pyrimidinyi, or triazinyl is optionally substituted one or two times, independently, by halogen, (C _r C ₄ )alkyl, cyano, (Ci-C4)alkoxy, or ((C [-Chalk l)((Ci-C4)alkyl)amino (i.e. wherein R ⁵ is halogen, (CrCi)alkyl, (C j -C4)haloalkyl, cyano, (Ci~C ₄ )alkoxy, or ((CrC ₄ )alkyi)((Ci-C4)alkyl)amino). in another embodiment of this invention, R ¹ is (C3~C ₆ )alkyl, (C3-C ₆ )cycfoalkyl, phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyi, or triazinyl, wherein said phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, ihiazolvl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyi, or triazinyl is optionally substituted one or two times, independently, by halogen, (Q -Chalky 1, (Ci-C4)alkoxy, or ((CrC ₄ )alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R ¹ is (C Cei lkyi. In another embodiment of this invention, R ^l is (C -Cejalkyl. In another embodiment of this invention, R ¹ is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (d~C ₄ )alkyl, (Ci-C4)haloalkyf, cyano, (C ₃ -C ₄ )alkoxy, or ((Ci-C4)alkyl)((Ci-C ₄ )alkyl)amino. In another embodiment of this invention, R' is phenyl or pyridinyl, each of which is optionally substituted one or two times, independently, by halogen, (Ci-C ₄ )alkyl, (Ci-C ₄ )alkoxy, or ((Ci-C ₄ )alkyl)((Ci-C4)alkyl)amino. In another embodiment of this invention, R ¹ is phenyl optionally substituted one or two times, independently, by halogen, (Ci-C4)alkyl, (Ci -C ₄ )haloalkyl, cyano, (Ci-C4)alkoxy, or ((C[-C ₄ )aikyl)((Ci-C4)alkyl)amino. In a specific embodiment of this inv ention, R ¹ is phenyl or pyridinyl. In another specific embodiment of this invention, R ¹ is phenyl.

Suitably, R is hydrogen, (Ci-Cyalkyf, or (Ci-Cr hafoafkyl. In another embodiment of this invention, hydrogen or (C[-C ₄ )alkyl. In another embodiment of this invention, R is hydrogen or methyl. In a specific embodiment of this invention, R" is hydrogen.

In another embodiment of this invention, R ^l and R- taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one, two, or three times, independently, by R\ In another embodiment of this invention, R' and R ^" taken together represent -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

Suitably, R ³ and R' ^a are each independently hydrogen, hydroxyl, (Ci-C ₆ )alkyl,

(Ci-Cg)haloalkyl, halogen, (Ci-Ce)alkoxy, amino, or

((Ci-C4)alkyl)((Ci-C4)alkyl)arnino. In another embodiment of this invention, R ^' and R ³ " are each independently hydrogen or methyl. In a specific embodiment of this invention, R ⁵ and R ^,a are each independently hydrogen. Suitably, each R ^' is independently selected from hydrogen, halogen, (Q -Cejaikyl,

(C _r C ₆ )haloalkyl, -C0 ₂ R ⁷ , -CONR ⁷ R ⁸ , -OR ⁹ , and ~NR ⁸ R ⁹ , wherein said (Q-Qjalkyl or

(C _r C ₆ )haloalkyl is optionally substituted by hydroxy!, -OR ⁹ , -C0 ₂ R ⁷ , -C0NR ⁷ R ⁸ , or -NR ⁸ R ⁹ . In another embodiment of this invention, each R ⁴ is independently selected from hydrogen,

(C;-C ₄ )alkyL ( -C )haloalkyl, -OR ⁹ , and -NR ⁸ R ^y , wherein said (Ci-C ₄ )alkyl or (CrC ₄ )haioa{kyl is optionally substituted by hydroxy!, -OR ⁹ , -C0 ₂ R', -CONR'R ⁸ , or -NR ⁸ R ^y . In another embodiment of this invention, each R ⁴ is independently selected from hydrogen, halogen, (CrC ₄ )alkyl,

(C i -Cl alkylamino, ((Ci -C ₄ )alkyl)((Ci -C ₄ )alkyl)amino, (Ci-C ₄ )a.lkoxy(Ci-C4)alkylamino,

-NHC0 ₂ (CrC ₄ )alkyl, i ( -Oaikox v . hydiOxy(C ₂ -C ₄ )alkoxy, (CrC ₄ )alkoxy(C ₂ -C ₄ )alkoxy, amino(C2-C ₄ )alkoxy, -0((Ci -C ₄ )alkyl)C0 ₂ R ⁷ , -0( (( ^' -C : )alkyi )CO\ H. ·.

-0((C _r C ₄ )alkyl)CONH(Ci-C ₄ )alky1, -0((C ₁ -C ₄ )alkyl)CON((Ci-C ₄ )alkyl)((C ₁ -C ₄ )alkyl), and C0 ₂ R ⁷ . In another embodiment of this invention, each R ^* is independently selected from hydrogen, halogen, (Ci -C ₄ )alkyl, (Ci -C ₄ )alkylaniino, ((Ci-C ₄ )alkyl)((Ci -C ₄ )alkyl)amino,

(Ci-C ₄ )alkoxy(Ci-C ₄ )alkylamino, (Ci-C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy,

(Ci-C )alkoxy(C ₂ -C ₄ )alkoxy, amino(C ₂ -C ₄ )alkoxy, -0((Ci-C ₃ )alkyl)C0 ₂ H,

·( ⁾ (( (· -< : ! ilkx ! }< O i C - aik l. -0((Ci-C ₃ )alkyl)CONH(C _r C ₄ )alkyl, and -0((C] -C:,)alk> ^r l)CON((Ci-C ₄ )alkyl)((CrC ₄ )alkyl). In another embodiment of this invention, each R" is independently selected from hydrogen, (Ci-C ₄ )alkyl, (Ci-C ₄ )alkoxy,

hydroxy(C ₂ -C ₄ )alkoxy, (Ci-C )alkoxy(C ₂ -C ₄ )alkoxy, amino(C ₂ -C ₄ )alkoxy, -0((Ci-C3)alkyl)C0 ₂ H, -0((Ci-C ₃ )alkyl)C0 ₂ (Ci-C ₄ )alkyL -0((Ci-C ₃ )alkyl)CONH ₂ , -0((Ci-C ₃ )alk l)CONH(Ci -C ₄ )alkyl, and -0((Ci-C3)alkyl)CON((Ci -C ₄ )alkyl)((Ci -C ₄ )alkyl). In another embodiment of this invention, each R ⁴ is independently selected from (Ci-C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy,

(Ci-C )alkoxy(C ₂ -C ₄ )alkoxy, amino(C ₂ -C ₄ )alkoxy, -0((Ci-C ₃ )alkyl)C0 ₂ H,

·( ⁾ (( (· -< : ! ilkx ! }< O i C•C . ialky i. -0((C _r C ₃ )alkyl)CONH ₂ , -0((Ci-C ₃ )alkyl)CONH(C _r C ₄ )alkyl, and -0((Ci -C:,)alkyl)CON((Ci-C ₄ )alkyl)((CrC ₄ )alkyl). In another embodiment of this invention, each R" is independently selected from (Cj-C ₄ )alkoxy, -0((Ci-C ₃ )a{kyl)C0 ₂ H,

-0((Ci-C ₃ )alkyl)C0 ₂ (Ci-C ₄ )alkyl, -0((C C ₃ )alkyl)CONH ₂ , -0((C ₁ -C ₃ )alkyI)CONH(C ₁ -C ₄ )alkyl, and -0((C [-C3)alkyl)CON((Ci-C ₄ )alkyl)((C] -C ₄ )alkyl). In another embodiment of this invention, each R ⁴ is independently selected from (Ci-C ₄ )alkyl and (Q -C ₄ )alkoxy. In a specific embodiment of this invention, each R ⁴ is hydrogen.

Suitably, each R ^4a is independently selected from hydrogen, halogen, hydroxyl, amino, and (Ci -Cg)alkyl. In another embodiment of this invention, each R ^4a is independently selected from hydrogen, halogen, and (Ci-C ₄ )alkyl. In another embodiment of this invention, each R is independently selected from is hydrogen, fluorine, and methyl. In another embodiment of this invention, each R ^"a is independently selected from is hydrogen and methyl. In a specific embodiment of this invention, each R ^4a is hydrogen. In a specific embodiment of this invention, each R" ^a is methyl.

In another embodiment of this invention, R ⁴ and R ^4a taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano,

(C,-C ₄ )alkyl, (C C ₄ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, ~C0 ₂ R ⁷ , -CONR ⁷ R ^s , hydroxy!,

hydroxy(Ci-C ₆ )aikyl, (CrC ₄ )alkoxy, (Ci-C ₄ )alkoxy(Ci-C ₆ )alkyl, amino, (Ci-C ₄ )alkylamino, ((Ci-C ₄ )alkyl)((Ci-C ₄ )alkyl)amino, -NHC0 ₂ R ⁷ , -N((C _r C )arkyl)C0 ₂ R ⁷ , -NHC(0)R ⁷ , or

-N((Ci-C4)alkyl)C(0)R ^/ . In another embodiment of this invention, R ⁴ and R ^a taken together represent -CH ₂ CH ₂ ~, -CH ₂ CH ₂ CH ₂ ~, -CH ₂ CH ₂ CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -.

One articular embodiment of the invention is a compound of Formula (la):

wherein: n is 1 or 2;

X ¹ , X ^7" , X ³ , and X ⁴ are each independently selected from N, N ⁺ -0 ^" , CH, and CR ⁵ , wherein 0-2 of X ¹ , X ² , X ³ , and X ⁴ are N or N ⁺ ~(T and 0-2 X ¹ , X ² , X ³ , and X ⁴ are CR ⁵ ;

Y ¹ is NH or NCI¾ and Y ² is a bond;

K ¹ , K ^" , K ³ , and K ⁴ are each independently selected from N, N ^"h -Q ^" , CH, and CR'°, wherein 0-2 of K ¹ , . K ³ , and K ⁴ are N or N ⁺ -0 ^" and 0-2 of K ^l , K ² , K ³ , and K ⁴ are CR ¹⁰ ;

Z is O, NR ⁶ , or a bond;

A ¹ , A ² , A ³ , A ⁴ , and A ⁵ are each independently selected from N, N ^' -O ^" , CH, and CR ¹⁰ , wherein 0-3 of A ¹ , A ² , A ⁵ , A ⁴ , and A ⁵ are N or \ ·() and 0-3 of A ¹ , A ² , A ³ , A ⁴ , and A ⁵ are CR ¹⁰ ;

R. ^; is (CVCejalkyl, C3-C6)h ioaikyi, (C3-Cg)cycloalkyi, (C ₃ -C6)aikoxy,

(Ci-C6)alkoxy(C|-C ₂ )alkyl, aiyl, heteroaryl, aryl(d-C6)alkyI, heteroar d(Ci-C6)alkyl, or heterocycloalkyi, each of which is optionally substituted one, two, or three times, independently, by

R ⁵ ;

R ² is hydrogen, (C- _; -C6)aikyl, or (Ci -C6)haloalkyl; or R ^l and R taken together with the carbon atom to which they are attached form a three to eight membered ring, optionally containing a heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted one, two, or three times, independently, by R ⁵ ;

R ^" and R ^Ja are each independently hydrogen, hydroxy!, (Ci-C/ alkyl, (Ci-C4)haloalkyl, halogen, (C; -C ₄ )alkoxy, amino, (Ci-C4)alkylamino, or ((Ci-C4)alkyl){{Ci~C4)alkyl)amino;

each R ⁴ is independently selected from hydrogen, halogen, (Ci -C^lalkyl, (Ci-C4)haloaikyl, -OR ⁹ , and -NR^R ⁹ , wherein said (Ci -C ₄ )alkyl or (C _r C ₄ )haloalkyl is optionally substituted by hydroxy!, -OR ⁹ , -CO -R . · ( ON R R\ or -NR ⁸ R ⁹ :

each R ^4a is independently selected from hydrogen, halogen, hydroxy!, amino, and

(Ci-C ₄ )alkyl;

each R ⁵ is independent!y selected from (d-C6)alkyl, (d-Cejhaloalkyl, (d-Q,)cye!oalkyl, halogen, cyano, hydroxy!, hydroxy(d -C6)alkyL (d -Cyalkoxy, (C[-C4)alkoxy(Ci-C6)alkyl, amino, (Cj-C4)alkylamino, ((d-C4)alkyl)((d-C4)alkyl)amino, aryl, heteroaryl, aryl(Ci -Q alkyl, heteroaryl(Ci-C6)alkyl, and heteroeycioaikyl;

R ⁶ is hydrogen, (d~Gs)alkyl, (Ci-C ₆ )ha!oa!ky1, (d-C ₆ )cycloalkyl, hydroxy(0|-Q _« )alky{,

(Ci-C4)alkoxy(C _] -C ₆ )alkyl _> -((C ₀ -C ₃ )alkyl)CO2R ⁷ , -((Co-C ₃ )alkyl)CO R ⁷ R ⁸ , aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, or heteroeycioaikyl;

R' is hydrogen, (d-Q-)alkyi, (Ci -C jha!oa!kyl, (d-Cejeyc!oalkyi,

(Ci-C4)alkoxy(C|-C6)alkyl, aryl, heteroaryl, aryl(C-i-C6)alkyi, heteroary!(d~d)alkyl, or heteroeycioaikyl;

R* is hydrogen, (d -Q alkyi, or (Ci-C6)haioalkyl;

or R ⁷ and R ^s taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by (Ci-C4)alkyl, (Ci-C4)haloalkyl, (CrC ₆ )cycloalkyl, -C ^' O -i i. · ( ( ) ( ^' ··( ^' . )aik> i. hydroxy!, hydroxy(C C ₆ )aikyl, i i - . yM. o\y . (C C ₄ )aJkoxy(Ci-C ) lkyJ, amino, (Ci-C4)a{ky!amino, or ((Ci-C4)a]kyl)((Ci-C4)alkyl)ammo;

R ⁹ is -C(0)R ⁷ , -C0 ₂ R ⁷ , -C(0)NR ⁷ R ⁸ , (C C ₆ )alkyl, (C _r C ₆ )haloalkyL (C ₃ -C ₆ )cycloalkyl, aryl, heteroaryl, aryl(d-Qi)alkyl, heteroaryl(d -Q alkyl, or heteroeycioaikyl, wherein said ·; ( ·( ^' ., ;·;!! kyi . (Ci -C ₆ )haloalkyL (C ₃ -C ₆ )eycloalkyl, aryl, heteroaryl,

heteroaryl(Ci-C6)alkyl, or heteroeycioaikyl is optionally substituted by -CO ₂ R ^' ', -CONH ₂ , -CO H(C C ₄ )alkyl, -CON((Ci-C ₄ )alkyl)((Ci-C ₄ )alkyl), hydroxy!, (Ci-C ₄ )alkoxy, amino, (C ₁ -C ₄ )alkylamino, ((d-C ₄ )alkyl)((d-C ₄ )alkyl)ammo, - N i !CO R . -N((C _r C4)alkyi)C0 ₂ R ⁷ , ^• \ i iC ( ⁾ ! . or -N((Q -C ₄ )alkyl)C(0)R ⁷ ;

or R ^s and R ⁹ taken together with the nitrogen atom to which they are attached form a four to eight membered ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, which ring is optionally substituted by cyano, (Ci -C )aikyl, (Ci-C ₄ )b.aloajkyl, (C ₃ -C ₆ )cycloalkyl, ~C0 ₂ H, -C0 ₂ (CrC ₄ )aikyl, -CONR ⁷ R ⁸ , hydroxy!, hydroxy(C C ₆ )alkyl,

(Ci-C ₄ )alkoxy, (C ₁ -C ₄ )alkoxy(Ci-C6)alkyl, amino, (Ci -C aikylamino,

((Ci-C4)alkyl)((Ci -C ₄ )alkyl)amino, -NHCO2R ⁷ , -N((Ci-C4)alkyl)C0 ₂ R ⁷ , -NHC(0)R ⁷ , or

-N((C C ₄ )a!k ])C(O)R ⁷ ; and

R ¹⁰ is (Ci-C ₆ )alkyl, (C-i -C ₆ )haloalkyl, (C ₃ -C ₆ )cycloalkyl, halogen, cyano, hydroxyl, hydroxy(C C ₆ )alkyl, (C C ₆ )alkoxy, (C ₁ -C ₄ )alkoxy(C _r C ₆ )alkyl, -((C _(r C ₃ )alkyl)C0 ₂ R ⁷ ,

-((Co-C ₃ )alkyl)CONR ⁷ R ⁸ , amino(C C ₆ )alkyi, i (C ^• C . i lk l )i ( ( -C. )alk ! 5» mi no( C · ί V. s l i. (Ci-C4)alkylamino(Ci -C6)alkyi, amino, (Ci-C4)alkylamino, ((Q -C4)alkyl)((Ci-C4)alkyl)amino, aryi, heteroaiyl, aryl(Ci-C6)alkyl, heteroaryl(Ci-Ce)alkyl, or heterocycloalkyl;

or a pharmaceutically acceptable salt thereof.

Another particular embodiment of the invention is a compound of Formula (la) wherein: m is 1 ;

n is 1 or 2;

X ¹ , X ² , X ^" , and X ^" are each independently a carbon atom substituted by hydrogen, halogen, cyano, (C;-C ₄ )alkyL (C] -C ₄ )haloalkyi, (C;-C ₄ )alkoxy, or ((Ci -C ₄ )alkyl)((Ci-C ₄ )alkyl)ammo, wherein 2-4 of X ^' , X , X ^'' , and X ⁴ are a carbon atom substituted by hydrogen;

Y ^l is NH or NCH ₃ and is a bond;

K ¹ , K ⁴ , K ³ , and K ⁴ are each independently a carbon atom substituted by hydrogen, halogen, (Ci-C ₄ )alkyl, (Ci -C ₄ )alkoxy, or ((C, -C ₄ )alkyl)((Ci -C ₄ )alkyl)amino, wherein 2-4 of K ¹ , K ² , K ³ , and K ⁴ are a carbon atom substituted by hydrogen;

Z. is O, NH, -N(Ci-C ₄ )alkyl, -N((Co-C ₃ )alkyl)C0 ₂ R ⁷ , -N((Co-C ₃ )alkyl)CONR ⁷ R ⁸ , or a bond;

A ² and A ⁴ are each independently selected from N, ΙΝΓ-Ο ^" , CH, and C((C )alkyl), and A ¹ , A\ and A ⁵ are each independently selected from CH and C((Ci-C ₄ )alkyl), wherein at least one of A ² and A ⁴ is N or N ^" -0 ^' ;

R ^l is (C ₃ -C6)alkyl, (C ₃ -C,s)lialoalkyl, (C ₃ -Cs)cycioalkyl, (C ₃ -C6)alkoxy,

(Ci-C6)alkoxy(Ci-C2)alkyl, aryi, heteroaryl, aryl(C-i-C6)alkyi, heteroar d(Ci-C ₆ )alkyl, or heterocycloalkyl, each of which is optionally substituted one, two, or three times, independently, by

R ⁵ ;

R ^" is hydrogen;

R ³ and R' ^a are each independently hydrogen or methyl;

each R ⁴ is independently selected from hydrogen, (Ci-C ₄ )alkyl, (C _r C ₄ )alkoxy, hydroxy(C ₂ -C ₄ )alkoxy, (C _r C ₄ )aikylamino, ((Ci-C ₄ )alkyl)((C[-C )alkyl)amino,

(Ci-C ₄ )a{koxy(Ci-C ₄ )alky{amino, (Ci-C ₄ )alkoxy(C2-C ₄ )alkoxy, amino(C2-C ₄ )alkoxy,

-Οί ί ( -C ^' : )aiky! ^' () ! i. -0((Ci-C ₃ )alkyl)C0 ₂ (Ci-C ₄ )alkyl, -(){(( ^' -C .hi!ky! K i>\ ! ^• Οί ί ί ^' - ^• C : )aiky!)C Ni l ^" -C, Hiikyi. and -0((C ₁ -C ₃ )alkyl)CON((Ci-C4)alkyl)((C ₁ -C ₄ )alkyl); each R ^4a is independently selected from hydrogen, hydroxy!, amino, and (Ci -C ₄ )alky3; each ί ' is independently selected from (Ci-C ₆ )alkyl, (C _r C ₆ )haloalkyl, (C3-C ₆ )cycloalkyi, halogen, cyano, hydroxy!, hydroxy(Ci -Ce^lkyl, (C Cyalkoxy, (C[-C4)alkoxy(Ci-C6)alkyl, amino, (C; -C4)alky]amino, ((Ci-C4)alkyl)((Ci-C4)alkyl)ammo, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaiyl(Ci-C ₆ )alkyf, and heterocycloalkyl;

R ⁷ is hydrogen, (C;-C ₆ )alkyl, (Ci -Ce haloalkyi, (C3-C ₆ )cycloalkyl,

(C;-C4) ikoxy(C _r C6)aikyL aryl, heteroaryl, aryi(Ci -C ₆ )alkyL heteroaryI(C[-C ₆ )alkyl, or heterocycloalkyl; and

R ⁸ is hydrogen, (Ci -Cejalkyl, or (CrCejhaloaikyl;

or a pharmaceutically acceptable salt thereof.

Another particular embodiment of the invention is a compound of Formula (la) wherein: m is 1 ;

n is 1 or 2;

X ¹ , Χ', X ³ , and X ⁴ are each independently a carbon atom substituted by hydrogen, halogen cyano, (Ci-C4)alkyl, (C;-C ₄ )aikoxy, or ((Ci-C4)alkyl)((Ci-C4)alkyl)ammo, wherein 2-4 of X ^' , X , X ^'' , and X ⁴ are a carbon atom substituted by hydrogen;

Y ¹ is MH and Y ² is a bond;

K ¹ , K , K', and K ⁴ are each independently a carbon atom substituted by hydrogen, halogen (Ci-C ₄ )alkyl, (Q -C ₄ )alkoxy, or ((C[-C ₄ )alkyl)((Ci -C ₄ )alkyl)amino, wherein 2-4 of K ¹ , K ² , K ³ , and K ⁴ are a carbon atom substituted by hydrogen;

Z is O, NH, -N(Ci-C ₄ )alkyl, or a bond;

A ² and A ⁴ are each independently selected from N, ΙΝΓ-Ο ^" , CH, and C((C )alkyl), and A ¹ , A\ and A ⁵ are each independently selected from CH and C((Ci-C4)alkyl), wherein at least one of A ² and A ⁴ is N or N ^" -0 ^' ;

R ^l is phenyl optionally substituted one or two times, independently, by halogen,

(Ci-C4)alkyl, (Ci-C4)haloalkyl, cyano, (Ci-C4)alkoxy, or ((Ci-C )alkyl)((Ci-C4)aJkyl)aminQ;

R ² is hydrogen;

R ³ and R ^id are each independently hydrogen or methyl;

each R ⁴ is independently selected from hydrogen, (Ci-C ₄ )alkylamino, ((Ci-C4)alkyl)((Ci-C4)alkyl)amino, and (Ci-C ₄ )alkoxy; and

each R ^4a is independently selected from hydrogen, hydroxyl, amino, and (Ci-C4)alkyl; or a pharmaceutically acceptable salt thereof.

Specific compounds of this invention include:

N-((2-chioro-4-methylphenyl)(ph^ N-((4-chloro-3-methylphenyl)(phenyl)methyl)-2-(4-((2-methyjp yridin-3- yi)methoxy)phei yl)acetamide;

N^((2,4-dimethylphenyl)(pyridin-2-yl)melhyl)-2-(4-((2-met hylpyridm-3- yl)methoxy)phenyl)acetamide;

A ^r -((4-chloro-2-methyjphenyl)(phenyj methyl)-2-(4-((2,4-dimethylpyTidin-3- yl)methoxy)phenyi)acetamide;

N-((2-chloro-4-methylphenyl)(phenyl)methyl)-2-(4-(pyrimid in-5-ylmethoxy)phenyl)ac 2-(4-(ben2yloxy)phenyl)-N-((4-chlorophenyl)(phenyl)inethyl)a ceta.mide;

N~(l-(4-chloro-2-methylphenyl)-3-methylbutyi)-2-(4-((2-me thylpyrid ^" in-3- yi)methoxy)phenyl)acetamide;

N-((2,4-dimethy3phenyl)(pheny3)metliy3)-2-^

A-((2,4-dichloro-5-fluorophenyl)(phenyl)methyl)-2-(4-((2-met hylpyridin-3- yl)methoxy)phenyi)acetaniide;

A ^r -((2,4-(iime†hylpheny])(phenyl)methyl)-2-(4-(((2-met y]pyridm-3- yl)methyl)amino)phenyi)acetamide;

N-((4-chloro-2-methylphenyl)(l -methyl- lH-pyTazol-4-yl)methyl)-2-(4-((2-methylpyridin-3- yi)methoxy)phenyl)aceiainide;

2-(2,4-dimethylphenyl)-A'-(4-((2-iT!ethylpyTidin-3-yl)m

A ^r -((4-chioro-2-Tnethylphenyl)(phenyl)methyl)-2-(4-((2-m ethylpyridin-3-yl)oxy)^

A-((2,4-dimethylphenyl)(phenyl)methyl)-2-(3-methyl-4-((2- niethylpyridin-3- yl)methoxy)phenyi)acetaniide;

N-((4-chloro-2-methyJphenyl)(phen^

yl)methyl)amino)piperidin- 1 -yl)acetamide;

N-((2,4-dimethylphenyl)(phenyl)me1hyl)-2-(4-methyl-4-(((2 -methylpyTidin-3- yi)methyl)amino)p ^" iperidin~ 1 -yl)acetamide;

N-((2,4-dimet y]phenyl)(pheny])methyl)-2-(4-(2- ydroxy-2-(2-met y]pyridm

yi)ethoxy)phenyi)acetamide;

A-((2-chloro-4-methylphenyl)(phenyl)methyl)-2-(4-(pyridin -3-ylmethoxy)phenyl)acetami N-((2,4-d ^" imethylphenyl)(phenyl)methyl)-2-(4-(pyridin-3-yimethox y)pheity^ acetaniide; A ^r -C(4-chloro-2-met y]phenyl)(phenyj)methyl)-2-(4-(pyridm-3-ylmethoxy)ph^ acetamide; 2-(4-((2-methylpyridm-3-yl)methox

N-(l-(4-chlorophenyl)-4-methylpentyl)-2-(4-((2-methylpyridin -3-yl)methoxy)phenyl)acetamW N~((3,5-dimethylpyridin-2-yl)(phenyl)-methyl)~2-(4-((2~methy lpyridin-3- yi)methoxy)phenyl)acetamide;

A ^r -((3,4-dimethy3phenyl)(pheny3)methyl)-2-(4-((2-Tnethyl pyridin-3-yi)methoxy)ph N-((2,4-dimethy]phenyl)( hen^

A ^r -((2,4-dimethy3phenyl)(pheny3)methyl)-2-(4-((6-Tnethyl pyridin-3-yi)methoxy)phe A-((4-chloro-2-methylphenyl)(phenyl)-me1hyl)-2-(4-((2-methyl pyridi ^" n-3- yl)methoxy)phenyl)acetamide;

A'-((4~cliloiO-2-metiiyiphenyl)(phenyi)-metliyl)~2-(4-((

yl)methoxy)phenyi)acetamide;

N-((2,4-(McUorophenyi)(phenyl)methyl)-2-(4-(^^

N-((2,4-dimeihy3phenyl)(plieiiy3)methyi)-2 -(4-(pyridm

N-((2,4-dimeihyiphenyl)(plienyi)m^

N-((2,4-dimethylphenyl)(p3ienyl)met y3)-2-(4-Cl-hydroxy-2-(2-methylpyridi yi)ethyl)phenyl)acetamide;

N-( l-(3,5-dimethylpyridin-2-yl)-4-met^

yl)ethyl)phenyl)acet amide;

2-(4-(l-(2-amino-2-oxoethoxy)-2-(2-methylpyridin-3-yl)eth yl)p3ienyl)-N-((2,4- dimethylphenyi)(phenyl)me hyr)acetamide;

N-((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(4-(2-(4,6-dih ydroxypyTimidm-5- yi)ethoxy)phenyi)acetaniide;

N-((4~cbloro-2-met3iylpiienyl)(pbenyl)raethyl)-2-{4-(2-(4 -ch

yi)ethoxy)phenyi)acetamide;

N-((4-c oro-2-methylphenyl)(phen^

N-((4-chloro-2-methylphenyl)(phenyl)methyi)-2-(2-(((2-methyl pyridin-3-yl)methy

4-yl)acetamide;

N-((4-chloro-2-methylpheny3)(phenyl)methyi)-2-(3-methyl-4-(( 2-methylpyridin-3- yl)methoxy)phenyl)acetamide;

N-(l-(4-chlorophenyl)-2-meihyipropyl)-2-( ^^

2-(4-((2-met3iy3pyridm-3-yl)me†hoxy^

N-((2,4-dimethyiphenyl)(thiazoi-5-yl)methyi)-2-(4-((2-methy3 pyTidin-3- yl)methoxy)phenyl)acetamide;

N-((5-methylpyridm-2-yl)^ enyl)methyl)-2-(4-((2-methylpyridin-3-yl)

N-(l-(2,4-dimetbylplienyi)-4~raethylpet)ty3)~2-(4-(

yl)ethyl)phenyl)acetamide;

N-(l-(3,5-dimethylpyridin-2-yl)-4-methylpeniyl)-2-(4-((2- methylpyridin-3- yi)methoxy)phenyl)aceiainide;

2~(j -(4-(2~(((2,4-dimet3iylphenyl)(pheny3)metliyl)amino)

3-y3)ethoxy)acetic acid; N-((4-hydroxy-2-methyiphenyl)(phenyl)memy

yi)methoxy)phei yl)acetamide;

2-(4-((4-chlorobenzyl)oxy)phenyl)-N-((4-chlorophenyl)(phe nyl)methyl)acetamide;

or a pharmaceutically acceptable salt thereof.

The meaning of any functional group or substituent thereon at any one occurrence in Formula (I), or any sub formula thereof, is independent of its meaning, or any other functional group's or substituent's meaning, at any other occurrence, unless stated otherwise.

The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent such as an alkyl group. Where the

stereochemistry of a chiral center present in Formula (I), or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (T) containing one or more chiral center may be used as racemic mixtures, enantiomericaliy enriched mixtures, or as enantiomericaliy pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula (I) which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1 ) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired

stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

"Enantiomericaliy enriched" refers to products whose enantiomeric excess is greater than zero. For example, enantiomericaliy enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.

"Enantiomeric excess" or "ee" is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).

"Enantiomerically pure" means products whose enantiomeric excess is 99% ee or greater. When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as

"polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof.

Polymorphs have the same chemical composition but differ in packing, geometrical aiTangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in erystailizing/recrystaiiizing the compound.

For solvates of the compounds of Formula (I), or salts thereof, that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

Because of their potential use in medicine, the salts of the compounds of Formula (1) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of Formula (I).

Salts of the compounds of Formula (I) containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galaeturonic acid, alpha- hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfat.es, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, capiylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacaies, fumarates, maleates, butyne- 1 ,4-dioates, hexyne- 1,6- dictates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates,

phenylpropionat.es, phenyfbutrates, citrates, lactates, γ-hydroxybutyrates, glycoiates, tartrates mandelates, and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates and naphthaleiie-2-suffonat.es.

Salts of the compounds of Formula (I) containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts arid ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, pieoline, dicyclohexylamine, N,A ^r -dibenzyletbylenediamine, 2- hydroxyethylamine, fos-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine,

dibenzylpiperidine, dehydroabietylamine, NJ -Wsdehy (koabietylamine, glucamine, N- methylglucamine, coliidine, quinine, quinoiine, and basic amino acid such as lysine and arginine.

Other non-pharmaceutically acceptable salts, e.g. trifluoroacetate, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non-sioichiometric forms of the salts of the compounds of Formula (I).

If a compound of Formula (I) containing a basic amine or other basic functional group is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable meihod known to the art, including treatmeni of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pK _a than the free base form of the compound. Similarly, if a compound of Formula (I) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic

9 acid, suitably an inorganic or organic acid having a lower pK _a than the free acid form of the compound.

The invention also includes various deuterated forms of the compounds of Formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I). Commercially available deuterated starting materials may be employed in the preparation of deuterated forms of the compounds of Formula (I), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. lithium aluminum deuteride or sodium borodeuteride). Methods of Use

Modulators of RORy can be useful in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases and cancer. Such inflammatory or autoimmune diseases include multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, graft-versus-host disease (GVHD), Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I diabetes, neuromyelitis optica, myasthenia gravis, uveitis, Behcets disease, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, allergic contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ankylosing spondylitis, Hashimoto Thyroiditis, dry eye and glomerulonephritis, myocarditis, especially psoriasis Such cancers include multiple myeloma and lytic bone disease associated with multiple myeloma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, bladder carcinoma, gastric cancer, hepatocellular carcinoma, melanoma, medulloblastoma and colon cancer. Accordingly, in another aspect the invention is directed to methods of treating such diseases using a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.

In a further aspect, the invention is directed to a compound of Formula (I) or a

pharmaceutically acceptable salt thereof for use in therapy. In particular, for use in the treatment of diseases mediated by RORy, particularly autoimmune or inflammatory diseases and cancer, such as those disclosed above.

In a further aspect, the invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases mediated by RORy, particularly autoimmune or inflammator '' diseases and cancer, such as those disclosed above. As used herein, "treatment" in reference to a condition means: (1 ) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological man festat ons of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.

As indicated above, "treatment" of a condition includes prevention of the condition. The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a. drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

An "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the bioiogieai or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, "patient" refers to a human or a mammal, especially a human.

The compounds of the invention may be administered by any suitable route of

administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.

The compounds of the invention may be administered once or according to a closing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 1 mg to 1000 nig.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of Formula (Γ), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenierally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention . All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention.

Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate

functionalities when such functionalities are present within compounds of the invention.

Preferred "pro-moieties" for compounds of the invention include: ester, carbonate ester, hemi- ester, phosphate ester, nitro ester, sulfate ester, sulfoxide, amide, carbamate, azo-, phosphatide, glycoside, ether, acetal, and ketal derivatives of the compounds of Formula (I).

Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.

The inv ention further includes the use of compounds of the invention as an active therapeutic substance, in particular in the treatment of diseases mediated by RQRy. In another embodiment, the invention relates to the use of compounds of the invention in the preparation of a medicament for the treatment of diseases mediated by RORy.

Examples of such diseases include autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, Sjorgen's syndrome, optic neuritis, chronic obstructive pulmonary disease, asthma, type I. diabetes, neuromyelitis optica, Myasthenia Gravis, uveitis, Guillain-Barre syndrome, psoriatic arthritis, Graves' disease, allergic contact dermatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, ankylosing spondylitis, Hashimoto Thyroiditis, Dry Eye, glomerulonephritis, myocarditis and cancer diseases including multiple myeloma and lytic bone disease associated with multiple myeloma, acute myelogenous leukemia (AML), head and neck squamous cell carcinoma, bladder carcinoma, gastric cancer, hepatocellular carcinoma, melanoma, medulloblastoma and colon cancer.

The in v ent ion includes the use of compounds of the invention for the preparation of a composition for treating or ameliorating diseases mediated by RORy in a subject in need thereof, wherein the composition comprises a mixture of one or more of the compounds of the invention and an optional pharmaceutically acceptable excipient.

The compounds of the invention may be used alone or in combination with one or more other therapeutic agents. Accordingly the present invention provides a combination comprising a compound of Formula (!) or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents. Such combinations may be presented individually (wherein each active is in separate composition) or the actives are presented in a combined composition.

This invention provides a combination of a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, and one or more therapeutic agents for the treatment of an inflammatory disease and/or an autoimmune disease, for example, a TNF-a inhibitor; a non- selective COX-l/COX-2 inhibitor; a selective COX-2 inhibitor, such as celecoxib; agents including methotrexate, leflunomide, sulfasalazine, azathioprine, penicillamine, bucill amine, actarit, mizoribine, fobenzarit, hydroxychloroquine, d-penicillamine, aurothiomalate, auranofin, parenteral and/or oral gold, cyclophosphamide, a BAFF/ APRIL inhibitor, CTLA-4-Ig, or a mimetic of CTLA-4-Ig; 5-lipoxygenase (5-LO) inhibitor, or a 5 -lipoxygenase activating protein (FLAP) antagonist; a leukotriene modifier, including a leukotriene receptor antagonist, such as niontelukast, zafirlukast, pranlukast; a phosphodiesterase type TV (PDE-TV) inhibitor, such as cilomilast (ariflo) or roflumilast; an antihistamine HI receptor antagonist; anticholinergic agents such as muscarinic antagonists (ipratropium bromide and tiotropium bromide), as well as selective muscarinic M3 antagonists; β-adrenoceptor agonists such as salmeteroi, formoterol, arformoterol, terbutaline, metaproterenol, albuterol and the like; a DP receptor antagonist, such as S-5751 and laropiprant; TP receptor antagonists such as seratrodast; neurokinin antagonists ( 1 N 2); VLA-4 antagonists; a corticosteroid, such as triamcinolone acetonide, budesonide, beclomethasone, fluticasone and mometasone; insulin-like growth factor type I (IGF-1 ) mimetic; kinase inhibitors including Janus Kinase inhibitors (e.g., JAK 1 and/or JAK2 and/or JAK 3 and/or TYK2), p38 MAPK, Syk or IKK2; rituximab; selective co-stimulation modulator such as abatacept; IL-l inhibitor anakinra, IL- 6 inhibitor tocilizumab, and IL12/1L-23 inhibitor ustekimumab; anti-IL17 antibody, anti-iL17R antibody, anti-IL21 antibody, or anti-IL22 antibody, SlPl agonists including fingolimod; interferon beta 1; naializumab: a mTOR inhibitor such as raparnycin, cyelosporine, tacrolimus: non-steroidal antiinflammatory agent (NSAID), including alminoprofen, benoxaprofen, bucloxic acid, earprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen, indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenciofenac, fenclozic acid, fentiazac, furofenae, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidonietaein, and zomepirac, flufenaniic acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, diflunisal and flufenisal, isoxicam, piroxicam, sudoxicam, tenoxican, acetyl salicylic acid, apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone; fumaric acid derivative, BG-12; chemokine or chemokine receptor inhibitor, such as a CCR- 1, CCR-2, CCR-3 and CCR-9 antagonist.

This invention further provides a combination of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents for the treatment of multiple myeloma, for example, Bortezomib-dexamethasone, Boriezomib-dexarneihasone- cyclophosphami.de, Bortezomib-dexamethasone-ienalidomide, Lenalidomide-dexamethasone, Melphalan-prednisone-thalidomide, Melphalan-prednisone-bortezomib, Melphalan-prednisone- lenalidomide, Lenalidomide- dexamethasone- clarithromycin and any of the above combinations plus agents used to treat bone disease in multiple myeloma including bisphosponates, RANK-L inhibitors such as Denusomab and anabolic bone building drugs such as parathyroid hormone (PTH).

This invention also provides a combination of a compound of Formula (I), or a

pharmaceutically acceptable salt thereof, and one or more therapeutic agents for ihe treatment of colon and/or rectal cancer, for example FOLFOX® (Jeucovorin [folinic acid], 5-Fluoruracil, and oxaliplatin), FOLFIRI® (leucovorin, 5-Fluoruracil, and irinotecan), CapeOX® (capecitabine and oxali latin), any of the above combinations plus either bevacizurnab or cetuximab (but not both), 5- Fiuoruracil and leucovorin, with or without bevacizurnab, Capecitabine, with or without bevacizurnab, FOLFOXIRI® (leucovorin, 5-Fluoruracii, oxaliplatin, and irinotecan), Irinotecan, with or without cetuximab, Cetuximab alone, and Panitumumab alone. Compositions

The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipient(s).

The pharmaceutical compositions of the invention may he prepared and packaged in hulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form. For oral application, for example, one or more tablets or capsules may be administered. A dose of the pharmaceutical composition contains at feast a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula I or a salt, particularly a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention .

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional therapeutically active compounds.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the inv ention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.

The compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, eiixers, suspensions, solutions, emulsions, sachets, and cachets: (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifters, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on ho w much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are a v aiiabie to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company ), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g.

microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycoiaie, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

Compound Preparation

The compounds of Formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the kno wledge of a skilled organic chemist. The reaction sequences provided in these Schemes are applicable for producing compounds of the invention having a variety of different X'-X ³ , R, R ¹ , R\ R ^3a , R ⁴ , R ^4a , K ^x -K ⁴ , and A ^l -A ⁵ groups, as defined above, employing appropriate precursors. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different subsiituen!s using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). in some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

Sch me I

Conditions: a) R'MgBr or R'Li, THF, aBH ₄ , MeOH; b) N¾OH ^« HCI, pyridine; c) Zn, EtOH, NH ₄ OH, NH ₄ OAc.

Conditions: a) K ₂ C0 ₃ or Cs ₂ C0 ₃ o aH, DMF or acetone or CH ₃ CN; b) NaOH, MeOH, H ₂ 0; c) (II), EDC, HOBt, DMAP or Et ₃ N or DIPEA, DMF or THF or CH ₂ C1 ₂ ; or (Π), HATU, NMM, DMF or CH ₂ C ^" i ₂ .

Scheme 3

Conditions: a ) Cul, Cs ₂ C(¾, (CH ₃ ) ₂ NCH ₂ C0 ₂ H, 1,4-dioxane; b) LiOH, THF, Η,Ο; c) (II), EDC, HOBi, DMAP or Ets or DIPEA, DMF or THF or CH ₂ C1 ₂ ; or (II), HATU, NMM, DMF or CH ₂ C1 ₂ .

or

Conditions: a) (II), EDC, HOBl, Et ₅ N or DIPEA, DMF or THF or C¾C1 ₂ ; or (II), HATU, NMM, DMF or CH ₂ C1 ₂ ; b) K ₂ C0 ₃ or Cs ₂ C0 ₃ or NaH, DMF or acetone or CH ₃ CN (X - CI or Br); or PPh ₃ , DIAD, THF (X ^■ OH).

Conditions: a) κ-BuL ^' R'CHO, THF, -78 °C-0 °C; b) SOCl ₂ , CH ₂ C1 ₂ , 0 °C-rt; c) NaCN, K _: C0 ₃ , DMF, 60 °C: d) NaOH, ΕΐΟΗ, H ₂ 0, reflux; e) H ₂ S0 ₄ , AcOH, H ₂ 0, reflux; f) (ill), EDC, HOB;, ΕΙ.,Ν or DIPEA, DMF or THF or <¾<¾ or (ΠΪ), HATU, NMM, CH ₂ C1 ₂ ; g) K ₂ C0 ₃ or Cs,C0 ₃ or NaH, DMF or acetone or CHjCN.

Z is O or NR ^! X is CI or Br

Conditions: a) K ₂ C0 ₃ or C¾C0 ₃ or NaH, KI, DMF or acetone or CH ₃ CN; b) LiOH, THF, H ₂ 0; c) (II), EDC. HOBt, DMAP or Et ₃ or DTPEA, DMF or THF or CH ₂ C1 ₂ ; or (II), HATU, MM, DMF or U K I ,

Examples

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

Compounds names were generated using the software program CheniBioDraw Ultra

VI 2.0 available from CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge, MA 02140 USA (http:// www.cambridgesQft.com).

Abbreviations

AcOH acetic acid

ATBN azobi si sobutyronitril e

Λ Ί ; aluminum trichloride

aq. aqueous

Ar argon gas

Br ₂ bromine

CBi-4 carbon tetrabromide

CC1 ₄ carbon tetrachloride

en α dichloromethane CH ₃ CN aeetonitrile

CH ₃ I methyl iodide

(CH ₂ 0) _n paraformaldehyde

CI s SO .i I methanesulfonic acid

corse. concentrated

Cs ₂ C0 ₃ cesium carbonate

CuBr copper(l) bromide

CuCN copper(I) cyanide

Cul copper(l) iodide

(COCi) ₂ oxalyl chloride

DTPEA N,N-diisopropylethy3arrime

DMAP 4~(dimethy1amino)pyridine

DME 1 ,2-dimethoxy ethane

DMF N,N- dimefhy lformamide

DMSO dim ethylsulfoxide

EtOAc ethyl acetate

EDC A ^r -(3-dimethylammopropyl)-N-ethylcarbodiimide hydrochloride

Et ₃ N triethylamine

Et ₂ 0 diethyl ether

EtOH ethanol

FeS ⁽ ¾ iron(II) sulfate

h hour(s)

H hydrogen gas

HATU 0-(7-azabenzotriazol- 1 -y\)~N,N,N ',Ν ^" '-tetramethyluronium hexafluoropliosphate

HBr hydrobromic acid

HCi hydrochloric acid

H ₂ 0 water

HNO3 nitric acid

HOBt hydroxybenzotriazole

HPLC high-performance liquid chromatography

H2SO4 suifm'ic acid

iodine

/-PrMgCl isopropylmagnesium chloride

K2CO3 potassium carbonate

K ₃ Fe(C ) ₆ potassium ferrieyanide

KQi-Bu potassium ieri-butoxide

K3PO4 potassium phosphate tribasic

LCMS liquid chromatography mass spectrometry

LiAllrL lithium aluminum hydride

LiOH lithium hydroxide

m-CPBA me/a-chloroperbenzoic acid

MeMgBr methyl magnesium bromide

MeOH methanol

Mg magnesium

MgCl ₂ magnesium chloride

mm minute(s)

Mn0 ₂ manganese dioxide

N ₂ nitrogen gas

NaBH ₄ sodium borohydride

NaCN sodium cyanide

Na ₂ C0 ₃ sodium carbonate

NaH sodium hydride

NaHC0 ₃ sodium bicarbonate Xai iSO : sodium bisulfite

aNi sodium azide

NaOH sodium hydroxide

Na ₂ S0 ₄ sodium sulfate

«-BuLi «-butyllithium

NH ₄ CI ammonium chloride

NMM N~methylmorpholme

PCC pyridinium chloroehromate

Pd/C palladium on carbon

Pd(dppf)Cl ₂ [l -bis(diphenylphosphino)ferrocene]dichloropalladittm(II)

Pd(PPli tetrakis(tripheny 3phosphine)pal3 adi um(0)

PhSO - nitrobenzene

POCl _. , phosphoryl chloride

PPh ₃ triphenyiphosphme

/>-Ts<)H para-toluene sulfonic acid

R _f retention factor

Tt room temperature

Rt retention time

SOCi;, thionyi chloride

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

^® T3P 2,4,6-tripropyl- 3 ,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide

Zn zinc powder

LCMS Conditions

LCMS-P1 : Column: Waters Sunfire C 18, 3.5 μ,ηι, 50 x 4.6 mm; Temperature: 50 °C: Mobile Phase: A: water (0.05% TFA) B: acetonitrile (0.05% TFA); Gradient: 5% B for 0.2 min, increase to 95% B within 1.2 min, 95% B for 1.6 min, return to 5% B within 0.01 min.; Flow Rate: i 8 n l . min: Detection: PDA 190-400 m

LCMS-G7: Column: XBridge CI 8, 3.6 μχα, 50 x 4.6 mm; Temperature: 50 °C;

Mobile Phase: A: water (0.1% formic acid) B: methanol; Gradient: 10% B for 0.1 min, increase to 95% B within 2,5 min, 95% B for 2.5 min, return io 10% B within 0.1 min, 10% B for 2 min.; Flow Rate: 1 .0 mL/min; Detection: PDA 190-400 nm

LCMS-G9: Column: XBridge CI 8, 3.6 μτη, 50 x 4.6 mm; Temperature: 50 °C;

Mobile Phase: A: water (0.1% ammonium acetate) B: methanol; Gradient: 10% B for 0.2 min, increase to 95% B within 5 min, 95% B for 2 min, return to 10% B within 0.1 min, 10% B for 2 min.; Flow Rate: 0.8 mL/min; Detection: PDA 190-400 nm

LCMS-G 12: Column: Sunfire C I 8, 5 μτη, 50 x 4.6 mm; Temperature: 50 °C; Mobile Phase: A: water (0.1% formic acid) B: methanol; Gradient: 30% B for 0.1 min, increase to 90% B within 4 min, 99% B for 4 min, return to 30% B within 0.1 min, 10% B for 2. min.: Flow Rate: 0.8 mL/min; Detection: PDA. 190-400 nm LCMS-G30: Column: Eclipse XDB CI 8, 5 um, 250 x 4.6 mm; Temperature: 50 °C; Mobile Phase: A: water (0.05% TFA) B: acetonitrile (0.05% TFA); Gradient: 30% B for 0.2 min, increase to 95% B within 15 min, 95% B for 5 min, return to 30% B within 3 min 30% B for 5 min.; Flow Rate: 0.8 mL/min; Detection: PDA 190-400 nm

LCMS-X: Column: Eclipse XDB CI 8, 5 μιη, 150 x 4.6 mm; Temperature: 50 °C;

Mobile Phase: A: water (0.1% formic acid) B: acetonitrile (0.1% formic acid); Gradient: 10% B for 0.1 min, increase to 90% B within 5 min, 100% within 2 min. 100% B for 4 min, return to 10% B within 0.01 min, 10% B for 1 min.; Flow Rate: 1.0 mL/min; Detection: PDA 190-400 nm

LCMS-T1 : Column: Eclipse XDB C18, 5 μηι, 150 x 4.6 mm; Temperature: 50 °C; Mobile Phase: water (0.05% TFA) B: acetonitrile (0.05% TFA); Gradient: 5% B for 0.1 min, increase to 95% B within 7 min, 100% within 2 min, return to 5% B within 0.1 min, 5% B for 3 min.; Flow Rate: 1.0 mL/min; Detection: PDA 190-400 nm

Example 1

N-((2-chioro-4-memylphenyl xy)phenyl)acet amide

(a) (2-chloro-4-methylphenyl)phenylmethanamine

To a solution of 2-chloro-4-methylbenzonitrile (0.50 g, 3.31 mmol) in anhydrous THF (7 mL) at 0 °C was added 1 M solution of phenyl magnesium bromide in THF (4.96 mL, 4.96 mmol) over 10 minutes and the resulting mixture was warmed to rt. The reaction mixture was stirred at rt for 30 minutes followed by heating to 60 "C and stirred at the same temperature for 2 h. After completion of the imine formation, the reaction mixture was cooled to 0 °C and methanol (10 mL) was added very slowly followed by sodium borohydri.de (0.188 g, 4.96 mmol). The resulting mixture was warmed to rt and stirred overnight After completion of the reaction, solvent was removed under vacuum and water (20 mL) was added into the reaction mixture and extracted with ethyl acetate (2 35 mL). The combined organic layers were dried over NaaSC and

concentrated. The product was purified by silica gel column chromatography (10% ethyl acetate/Hexanes) to provide title compound (0.16 g, 21 %). ¹ IT X. ^' vi R (400 MITz, DMSO~d ₆ ) δ ppm 7.59-7.61 (d, 1 i n. 7.24-7.32 (m, 4 H), 7.15-7.19 (q, 3 H), 5.37 (s, 1 H), 2.31-2.34 (t, 1 H), 2.26 (s, 3 H). (b) methyl 2-(4-(pyridm-3-ylmethoxy)pheny3)acetate

3-Pieoiyl chloride hydrochloride (0.2 g, 1.20 mmol) was dissolved in 5N aq. NaOH (5mL); stirred for 5 minutes and then extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and used crude in the next step. To a solution of methyl 2-(4-hydroxyphenyl)acetate (0.20 g, 1.20 mmol) in anhydrous acetone (10 ml.) at rt was added K ₂ C0 ₃ (0.500 g, 3.6 mmol) followed by 3-picolyl chloride and the resulting mixture was heated to reflux overnight. After completion of the reaction, sol vent was evaporated under vacuum and water ( 10 mL) was added to the residue and extracted with ethyl acetate (2. X 25 mL). The combined organic layers were washed with brine (25 mL), dried over a ₂ S0 _4; and evaporated to obtain title compound (0.250 g, 80.73%) as a fight yellow oil which was used in the next step without furiher purification. ¾ NMR (400 MHz, DM80-d ₆ ) δ ppm 8.66 (d, 1 H), 8.53-8.55 (dd, 1 H), 7.85-7.87 (d, 1 H), 7.41 -7.44 (dd, 1 H), 7.18-7.20 (d, 2 H), 6.97-6.99 (d, 2 H), 5.14 (s, 2 U s . 3.60 (s, 5 H).

(c) 2-(4-(pyridin-3-ylmethoxy)phenyl)acetic acid

To a solution of methy l 2-(4-(pyridm-3-ylmethoxy)phenyl)a.cetate (0.250 g, 0.97 mmol) in methanol (5 mL) at 25 °C was added 2N aqueous solution of NaOH (5 ml.) and the resulting mixture was stirred at rt for 1 h. After completion of the reaction, the solvent was evaporated in vacuum and water (1 0 mL) was added into the residue. The aqueous layer was extracted with ethyl acetate (2 X 10 mL) to remove the impurities and the organic layers were discarded. The aqueous layer was then made acidic using 5 N aq. HCi and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with brine (2.0 mL) and dried over NajSQ*, and evaporated in vacuum to obtain title compound (70 mg, 55%) which was used in the next step.

(d) N-((2-chloro-4-methylphenyl)iph^

To a solution of 2-(4-(pyridm-3-yj.methoxy)phenyl)acetic acid (0.070 g, 0.28 mmol) in DMF (5 mL) at 25 °C was added HOBt (0.054 g, 0.35 mmol), EDC (0.068 g, 0.35 mmol), and DMAP (0.070 g, 0.57 mmol) and the resulting mixture was stirred at rt for 10 minutes. (2-chloro-4- methylphenyl)(phenyl)methanamine (0.074 g, 0.31 mmol) in DMF (1 mL) was added slowly and the stirring at rt was continued overnight. After comple tion of the reaction, water ( 10 mL) was added into the reaction mixture slowly in an ice bath and the solid obtained was filtered off and washed with water (1 0 mL) followed by hexanes (10 mL) and dried under vacuum to obtain title compound (85 mg, 65%). LCMS-X1 : 457.6 [M+Hf; R _t - 5.82 mi . ^ι' Ά NMR (400 MHz, DMSO-de) δ pm 8.94-8.96 (d, 1 H), 8.65-8.66 (d, 1 i n. 8.53-8.55 (dd, 1 H), 7.84-7.86 (d, 1 H), 7.40-7.43 (dd, 1 H), 7.23-7.33 (m, 5 H), 7.13-7.20 (m, 5 H), 6.94-6.96 (d, 2 H), 6.33-6.35 (d, 1 H), 5.12 (s, 2 H), 3.45 (s, 2 H), 2.28 (s, 3 H).

Example 2

N-((4-chloro-3-memyJphenyl)(phen^

y3)methoxy)phenyl)acetami

(a) (2-methylpyridin-3-yl)methanol

To the suspension of LiAIH ₄ (2.62. g, 68.8mmol) in THF (50 mL) was added the solution of methyl 2-methylnicotinate (5.2 g, 34.4 mmol) in THF (10 mL) slowly at 0 °C. After the addition, the resulting mixture was stirred at rt overnight. Water (2.62 mL), 2 M aq. NaOH (5.2 mL), and 1¾0 (7.86 mL) were added successively. Then the reaction mixture was stirred at ri for 30 min and the solid precipitated was removed by filtration. The filtrate was concentrated under reduced pressure and the title compound was used in the next step without further purification. LCMS- Pl : 124, i \) H I .

(b) 3-(chioromethyl)-2-metbylpyridine

To the solution of (2-methylpyridin-3-yl)methanol (2.4 g, 19.5mmo3) in dichloromethane (20 mL) was added SOCl ₂ (3.1 g, 24mmol) dropwise at 0 °C. After stirring at rt for 2 h, the soivent was evaporated in vacuum and the crude title compound was used directly in the next step without further purification. LCMS-P1 : 142, | vi · 1 ! | .

(c) ethyl 2-(4-((2-methylpyTidin-3-yl)methoxy)phenyi)acetate

To the solution of 3-(chioromethyi)-2-mefhyipyTidine (2.8 g, 19.5 mmol) and ethyl 2-(4- hydroxyphenyl)acetate (1.8g, 10 mmol) in MeC (10 mL) was added K ₂ C0 ₃ (3.45 g, 25mmoi), and then the mixture was heated to reflux overnight. The reaction mixture was evaporated in vacuum; water was added, then extracted with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ S0 ₄ , After removal of soivent, the residue was purified by column chromatography to afford the title compound as a light-yellow solid (1 .41g, 49%) LCMS-Pl : 286, [M+H] ⁺ . (d) 2-(4-((2-methylpyridin-3-yl)methoxy)phenyi)acetic acid hydrochloride

To the suspension of ethyl 2-(4-((2-methylpyridin-3-yl)methoxy)phenyl)acetate ( 1 g, 3.5 mmol) in THF/Water (10 mL, 1 : 1) was added NaOH (280 mg, 7 mmol). After stirring at rt for 30min, the reaction mixture was concentrated under vacuum to remove the excess THF. To the residue aq. HCi (2M) was added slowly until the precipitate appeared. Then the precipitate was collected by filtration to give the title compound as a white solid (742 mg, 82%). LCMS-P1 : 258 i vi - ! i i .

(e) (4-chloro-3-methylphenyl)(phenyl)m.eth.anamine

This compound was prepared from 4-chloro-3-methylbenzonitrile and phenylmagnesium bromide essentially as example 1 (a) and the crude title compound was used directly for the next step. LCMS-P 1 : 215.0 [M-N1¾] ' ^' ; J¾ - 1.261 min.

(f) A ^L ((4-ch3oro-3-methyiphenyl)(phenyi)memyl)-2-(4-((2-meth ylpyridin-3- y l)me thoxy)pheny 1) ace tamide

To a solution of 2-(4-((2~methylpyridin-3-yi)methoxy)phenyl)acetic acid hydrochloride (50 mg, 0.17 mmol) in dichloromeihane (12 mL) was added (4-chloro-3- methy3phenyl)(pheny3)methanamine (54 g, 0.2 mmol), EDC (38mg, 0.20 mmol), HOBt (27mg, 0.20 mmol), and DIEA (66 mg, 0.51 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water (30 mL) and extracted by dichloromeihane (30 mL* 3). The combined organic solvents were washed with 1% HCI aqueous solution, and dried over a ₂ S0 ₄ . After removal of solvent, the crude compound was purified by column chromatography on silica gel (EtOAc: petroleum ether = 1 : 4) to provide title compound (18mg, Yield: 20.7%). LCMS-P 1 : 471 i i ί ; ; R _t = 2.24 min. Ή NMR (400 MHz, MeOH-cU) δ ppm 8.38 (d, J = 1.6 Hz , 1H), 8.37 (d, J = 1.6 Hz 1H), 7.27- 7.34 (m, 8H), 7.19 (m, 1H), 7.10 (m, 3H), 6.83-6.88 (m, 2H), 6.1 1 (s, 1H), 5.1 0 (s, 2H). 3.53 (m, 2H). 2.60 (s, 31 1 :·. 2.30 (s, 3H).

Example 3

N~((2,4-dimethylphenyl)(pyridin-2~yl)methyl)-2-(4-((2~methyl pyridin-3- yl)methoxy)pheny3)acetam.id

To the solution of (2,4-diTnethylpheny3)(pyridm-2-yl)methai amine hydrochloride (60mg, 0.23mmol) in DMF (3mL) was added 2-(4-((2-methylpyridin-3-yl)methoxy)phenyl)acetic acid (75mg, 0.29mmol), EDC (56mg, 0.29mmol), HOBt (39mg, 0.29mmol), then DIPEA (68mg, 0.53mmol). The resulting mixture was heated at 45 °C overnight, the mixture was poured into water, extracted with EtOAc (5mL X 2), and the combined organic layer were washed with brine, dried with Na ₂ S0 ₄ . and evaporated in vacuum. The residue was purified by preparatory HPLC using 10- 100% water/aceionitrile with 0.1% TFA to afford ihe title compound as a white solid (7 mg, 6%). MS: 452 | M H | . Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.82 (d, J - 8.4 Hz, 1H), 8.49 (d, J= 4.0 Hz, 1H), 8.39 (dd, J = 1 .6 Hz, 4.8 Hz, 1H), 7.77-7.74 (m, 2H), 7.31-7.18 (m, 5H), 6.96- 6.90 (m, 5H), 6.21 i d. J = 8.0 Hz, 1 H), 5.08 (s, 21 1 ). 3.47 (s, 2H), 2.50 (s, 3ίί), 2.23 (s, M l ). 2.21 (s, 3H).

Example 4

N-((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(4-((2,4-di methylpyridin-3- y l)me thoxy)pheny 1) ace tamide

(a) (2,4-dimethylpyridin-3-yl)methano3

To a solution of ethyl 2,4-dimethylnicotinate ( 1.0 g, 5.57 mmol) in dry tetrahydrofuran (10 mL), lithium aluminum hydride (1.0 M solution in THF, 8.36 mL, 8.36 mmoi) was added at 0°C during 30 minutes and stirred at rt for 1.5h. After 1 .5 h, excess of LiAlH ₄ as decomposed with crushed ice and the residue was extracted with ethyl acetate (300 mL). The combined organic layers were dried over NaiSC and concentrated and the product was purified by silica gel column chromatography (2.5% MeOH: dichloromeihane) to provide the title compound (0.650 g, 84.9%). 1 ! N (400 MHz, DMSO-d ₆ ) δ ppm 8.16-8.18 (d, 1 H), 7.01 -7.02 (d, 1 H), 4.89-4.92, (t, 1 H), 4.50-4.51 (d, 2 H), 2.50 (s, 3 H), 2.34 (s, 3 H).

(b) 3-(c oroniethyl)-2,4-dimethylpyridine

To a suspension of (2,4-dimethylpyridin-3-yl)methanol (0.300 g, 2.1 8 mmol) in dichloromeihane (2.0 mL) was added thiony] chloride (0.4 mL, 5.48 mmol) at 0 °C and the reaction was stirred at 0 °C for 30 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to provide the title compound (0.340 g, 88.2.3%). The crude title compound was used in the next step without further purification.

(c) methyl 2-(4-((2,4-dimethylpyridin-3-yl)methoxy)phenyl)acetate

To a solution of methyl 2-(4-hydroxyphenyi)aeetate (0.300 g, 1.80 mmol) in DMF (2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 0.086 g, 2, 16 mmol) at 0 °C and the reaction mixture was stirred for 20 min. 3-(chloromemyl)-2,4-dimemylpyridme (0.282 g, 1.80 mmol) was added and the reaction mixture was warmed to 55 "C where it was stirred for 4 h. The reaction mixture was then cooled to room temp and stirred overnight. The reaction mixture was poured into crashed ice and extracted with dichlororaetliane (2.50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (14% EtOAc/Hexane) to provide the title compound (0.128 g, 25%). (d) 2-(4-((2,4-dimethylpyrid n-3-y])methoxy)phenyl)acetic acid

This compound was synthesized from methyl 2-(4-((2,4-dimethylpyridm-3- yl)methoxy)phenyl)acetate essentially as described in example 2 (d). The crude title compound obtained was carried forward to the next step. (e) (4-chloro-2-methylphenyl)(phenyl)methanamine

This compound was synthesized from 4-chloro-2~methylbenzonitrile and

phenylmagnesium bromide essentially as described in example 1 (a). (0.16 g, 20.83 %). ^l H NMR (400 MHz, DMSO-de) δ ppm 7.59-7.61 (d, 1 H), 7.24-7.32 (m, 4 H), 7.15-7.19 (q, 3 H), 5.37 (s, i H), 2.31 -2.34 (t, 1 I D. 2.26 (s, 3 H).

(f) N-((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(4-((2,4-dimet hy1pyridin-3- yl)methoxy)pheny3)acetamide

This compound was synthesized from 2-(4-((2,4-dimethylpyridin-3- yl)metlioxy)phenyl)acetic acid and (4-chloro-2~methylphenyi)(phenyl)methananiine essentially as example 1 (d) and was purified using EtOAc: Hexanes (72%) as the mobile phase to provide the title compound (0.025 g, 13.96 %). LCMS-X1 : 485.5 [M+H] ⁺ ; R _t - 5.53 min. ΐί NMR (400 MHz, DMSOd ₆ ) δ ppm 8.36-8.38 (d, I i n. 6.99-7.31 (m, 13 H), 6.48-6.50 (d, 1 H), 6.22-6.24 (d, i H),5.02 (s, 2 H), 3.64 (s, 2 H i. 2.62 (s, 3 H), 2.36 (s, 3 I D. 2.33 (s, 3H). Example S A^(2.-chloro-4-methylplieny

(a.) Pyriniidin-5-ylineihanol

To a solution of pyrimidine-5-carbaldehyde (0.300 g, 2.77 mmol) in methanol (6 mL), sodium borohydride (0.158g, 4.16 mmol) was added at 0 °C over 10 minutes and the reaction mixture was stirred at the same temperature for 30 min. After completion of the reaction, the solvent was removed under vacuum. The residue obtained was poured into water (30 mL), extracted with ethyl acetate ( 150 mL), The organic layer was dried over sodium sulfate and concentrated to provide the title compound (0.160 g, 52.4%), ¹ H NMR (400 MHz, DMSQ-d ₆ ) δ ppm 9.18-9.20 (s, 1 H), 8.74 (s, 2 H),5.49-5.67 (b, 1 H), 4.60 (s, 2 H).

(b) 5 -(chioromethyl)pyrimidine

This compound was synthesized from pyrimidm-5-yimethanol essentially as described example 2 (b). The crude title compound was obtained and carried forward in the next step.

(c) methyl 2-(4-(pyrimidin-5-yImethoxy)phenyl)acetate

This compound was synthesized from methyl 2-(4-hydroxyphenyl)acetate and 5- (cliloromethyljpyrimidrne essentially as described in example 4 (c). (0.150 g, 41 ,55%). Ή NMR (400 MHz, DMSO-dg) δ ppm 9.18 (s, 1 H), 8.91 (s, 2 H), 7.19-7.21 (d, 2 H), 6.99-7.01 (d, 2 H), 5.17 (s, 2 H), 3.6 i i s. 2 H), 3.60(s, 3 H).

(d) 2-(4-(pyrimidin-5-ylmethoxy)phenyi)acet c acid hydrochloride

To a solution of methyl 2-(4-(pyrimidin-5-ylmethoxy)phenyl)acetate (0.145 g, 0.56 mmol) in 4 N aq. NaOH (5 mL) was stirred at rt for 30 min. Then reaction mixture was acidified with HC1 (6N) during which white solid precipitates out. The precipitate was washed with water , triturated with hexanes (20 mL), and dried under vacuum to provide the title compound (0.065 g, 47%). ¾ NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.17 (s, 1 H), 8.91 (s, 2 H), 7.18-7.20 (d, 2 H), 6.98- 7.00 (d, 2 I I I. 5.17 (s, 2 H), 3.50 (s, 2 H).

(e) N-((2-chloro-4-methylphenyl)(phenyl)^ The compound was synthesized from 2-(4-(pyrimidin-5-ylmethoxy)phenyl)acetic acid hydrochloride and (2-ch]oro-4-methyfphenyl)(phenyf)methanamine essentially as example 1 (d) and purified as follows: the reaction mixture was cooled to 0 °C and water (10 rnL) was added during which solid precipitates out. The solid obtained was filtered and washed with water and hexanes (20 rnL) and then triturated with diethyl ether (30 mL) to provide the title compound (0.045 g, 40%). LCMS-X1 : 458.6 | \i i l l : R. - 6.40 min. H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.17 (s, 1 H), 8.95-8.97 (d, 1 H), 8.90 fs, 2H), 7.13-7.34 (m, 10 H), 6.96-6.98 (d, 2 H), 6.33- 6.35 (d, 1 H), 5.16 (s, 2 ! H.3.46 (s, 2 H), 2.28 (s, 3 H).

Example 6

2-(4-(benzyloxy)phenyl)-N-

(a) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetam ide

To a solution of (4-c orophenyl)(phenyl)niemanamine (3.0 g, 1 1 ,8 mmol) in DMF (15.0 mL) was added DMAP (2.62 g, 21 .4 mmol), EDC (2.72 g, 14.1 mmol), HOBt (2.17 g, 14.1 mmol) followed by 2-(4-hydroxyphenyl)acetic acid ( 1 .63 g, 10.7 mmol) and the reaction mixture was stirred at it for 1 h. After completion of the reaction, the reaction mixture was concentrated, diluted with EtOAc (50 mL), washed with water (25 mL) and brine (25 mL). After drying (NaaSO^! and conceniration of the combined organic lay ers, the product was purified by silica gel column chromatography (40% EtO Ac/He ane) to provide the title compound (4.5 g, 65.2%). MS (EST+) 352.0 [M + H]. ^l H NMR (400 MHz, DMSO-d ₆ ) 8 ppm 9.25 (s, 1 H), 8.94-8.96, (d, I H), 3.37-3.39 (d, 2 H), 7.28-7.34 (m,3 H), 7.24-7.26 (m 3 H),7.04-7.06 (d, 2 H), 6.65-6.67 (d, 2 H), 6.07-6.09 (d, 1 H), 4.08 (s, 2 H).

(b) 2-(4-(benzyioxy)phenyl)-A ^L ((4-chk)roplienyf)(phenyl)methyi)acetamide

To a solution of N-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetam ide (0.150 g, 0.426 mmol) in DMF (2.0 mL) was added 60% sodium hydride (0.020 g, 0.51 mmol) at 0°C and the reaction was stirred for 20 min. After 20 minutes, benzyl bromide (0.088 g, 0.51 1 mmol) was added and the reaction was stirred for 1 h. After completion of the reaction, the reaction mixture was dumped into crushed ice, extracted with ethyl acetate (100 mL). After drying (N ₂ S0 ₄ ) and concentration of the combined organic layers, the product was purified by silica gel column chromatography (14% EtOAc/Hexane) to provide the title compound (0.095 g, 50.53%). LCMS-X1 : 442.2 [M+H] ⁺ ; R. - 5.37 min. H NMR (400 MHz, CDC1 ₃ ) δ ppm 8.99-9.01 (d, 1 H), 7.42-7.44 (d, 2 H), 7.37-7.40 (m, 4 H), 7.30-7.34 (m, 3 H), 7.24-7.28 (m, 5 H), 7.16-7.19 id, 2 H), 6.91 -6.94 (d, 2 H), 6.07-6.09 i d. 1 H), 5.09 (s, 2 H), 3.55 (s, 2 H).

Example 7

N-(l -(4-chloro-2-methylphenyl)-3-methylbutyl)-2-(4-((2-methylpyr idin-3- yl)me thoxy)pheny 1) ace tamide

(a) 1 -(4-chforo-2-methylphenyl)-3-methylbutan- 1 -amine

To a solution of 4 -eh!oro-2- methyl benzonitrile (0.5 g, 3.29 mmol) in dry THF (5 mL) at rt was added isoburylmagnesium bromide (1 .2 M solution in Et ₂ 0, 6.8 mL, 8.24 mmol) dropwise and the reaction mixture was heated to 70 °C for 5 h. After completion of the inline formation the reaction mixture was quenched with saturated aq. H ₄ C1 solution and the product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was dissolved in dry MeOH ( 10 mL) cooled to 0 °C and sodium borohydride was added (146 nig, 3.95 mmol). The reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched with brine and the solvent was removed under reduced pressure. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (neutral alumina, eluent 2-5% MeOH in€Ή ₂ ί¾) to afford the title compound (130 mg, 17%) as a yellow viscous liquid. (b) N-(l -(4-chioro-2-memylphenyl)-3-memylburyi)-2-(4-h^

To a stirred solution of 4-hydroxyphenyl acetic acid ( 100 mg, 0.66 mmol) i dry DMF (5 mL) were added HATU (299 mg, 0.78 mmol) followed by l -(4-chloro-2-methylphenyl)~3- memylbutan- 1 -amine ( 130 mg, 10.66 mmol) in dry DMF (2 mL) and MM (0.2 mL, 1.97 mmol) at 0 °C, The reaction mixture was slowly warmed to rt and stirred for a further 4 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was purified by column chromatography (silica 60- 120 mesh, eluent 30-40% EtOAc in petroleum ether) to afford the title compound(100 mg, 44%), ^] H NMR (400 MHz, MeOH-d ₄ ) δ ppm 7.21 - 7.18 (m, i l l ). 7.14 (m, 11 1 ). 7.08 - 7.06 i d. ./ 8.5 Hz, 2H), 6.72 - 6.69 (d, ,/ 8.5 Hz, 2H), 5.17 - 5.1 1 (m, IH), 3.41 - 3.40 (d, ./ 4.3 Hz, 11 1 ). 2.35 (s, 3H), 1.69 - 1.61 (m, 3H), 0.94 - 0.93 (m, 6H)

(c) A ^r -(l -(4-chloro-2-methylphenyl)-3-methylbutyl)-2-(4-((2-rnethyIpy ridin-3- y l)me thoxy)pheny 1) ace tamide

To a stirred solution of V-( l -(4-chloro--2 -methylphenyl)--3 -methylbutyl)-2-(4- hydroxypheixyi)aceiamide (100 mg, 0.29 mmol) in dry MeCN ( 10 mL) was added CS ₃ CO ₃ ( 188 mg, 0.57 mmol) followed by 3-(chloromethyl)-2-methylpyridme (60 mg, 0.43 mmol) in a sealed tube and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was purified by column chromatography (silica 60- 120 mesh, eluesit 20% EtOAc in CH2CI2) followed by preparative TLC on silica gel (eluent 20% EtOAc in (¾(¾) to afford the title compound (35 mg, 27%). LCMS-G30: 452.3 [M+H] +; R, = 16.07 min. ^X H NMR (400 MHz, CDCI ₃ ) δ ppm 8.50 - 8.48 (dd, J= 4.9 Hz, 1.6 Hz, 1H), 7.75 ^■■ 7.73 (dd, J = 7.7 Hz, 1.4 Hz, 1H), 7.20 - 7.17 (m, 3H), 7.13 - 7.09 (m, 2H), 6.99 - 6.96 (d, J = 8.5 Hz, 2H), 6.93 - 6.91 (d, J = 8.3 Hz, IH), 5.52 - 5.50 (d, J = 8.0 Hz, I H), 5.21 - 5.15 (m, IH), 5.06 (s, 2H), 3.51 - 3.50 (d, J = 4.3 Hz, 2H), 2.61 (s, 3H), 2.37 (s, 3H), 1.51 - 1.42 ·: m. 3H), 0.93 - 0.88 (m, 61 h.

Example 8

N-((2,4-dimethylpheny3)(p thoxy

(a) 1 -(2-meihyipyridin-3-yl)eihanone

To a solution of freshly distilled acetyl acetone (40.0 g, 0.399 mol) in dry toluene (400 ml.) were added freshly distilled acrolein (35.6 g, 0.599 mol) followed by ammonium acetate (52.0 g, 0.799 mol). The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was filtered through a celite bed and washed with MeOH. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (silica gel 60- 120 mesh, eluent 50-70% EtOAc in petroleum ether) to afford the title compound (8.5 g, 16%). Ή NMR (300 MHz, CDC1 ₃ ) δ ppm 8.62 - 8.60 (d, ./ 4.8 Hz, I H), 7.99 - 7.96 (d, ,/ 7.9 Hz, IH), 7.25 - 7.23 (m, 1 H), 2.76 (s, i U. 2.61 (d, J = 1.1 Hz, 3H)

(b) 2-(2-methy3pyridin-3-yl)- 1 -moiphol

A mixture of l -(2-methylpyridin-3-yl)ethanone (8.5 g, 0.062 mol), morpholine (5.4 g, 0.062 mol) and sulfur (2.0 g, 0.062 mol) were added and the reaction mixture was refiuxed at 120 °C for 8 h. The reaction mixture was poured into ice-water and the product was extracted with CH ₂ CI ₂ . The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 70-80% EtOAc in petroleum ether) to afford the title compound (3.8 g, 26%) as brown solid. ^; H NMR (300 MHz, CDC1 ₃ ) δ ppm 8.42 - 8.40 (d, J 4.8 Hz, 1H), 7.51 - 7.48 (d, J = 7.5 Hz, IH), 7.15 - 7.1 1 (dd, J= 7.7 Hz, 4.8 Hz, 1H), 4.41 - 4.38 (m, 11 1 ). 4.21 (s, 2H), 3.82 - 3.79 (m, 21 1 ). 3.53 (m, 4H), 2.50 (s, 3H)

(c) methyl 2-(2-methylpyridin-3-yl)aceta

To a solution of 2-(2-methylpyridin-3-yl)- 1 -morpholinoetharjethione (1.5 g, 6.35 mmol) in

MeOH (3 mL) was added conc.H ₂ .SO ₄ (3 mL) at 0 °C. The reaction mixture was allowed to warm to rt and then heated to 100 °C for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in water. The pH of the aqueous layer was adjusted to 8 using saturated Na ₂ C0 ₃ solution. The product was extracted with CH2CI2. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60- 120 mesh, eluent 60% EtOAc in petroleum ether) to afford the title compound (400 nig, 38%). ¾ NMR (300 MHz, CDC1 ₃ ) 6 ppm 8.43 - 8.41 (dd, J- 4.8 Hz, 1.5 Hz, I H), 7.51 - 7.48 (m, I H), 7.13 - 7.09 (dd, .7- 7.7 Hz, 4.8 Hz, IH), 3.71 (s, 3H), 3.65 (s, 2H), 2.55 (s, 3H) (d) 2-(2-methylpyridm-3-yl)ethano]

To a solution of methyl 2-(2-methylpyridin-3-yi)acetate (400 mg, 2.4 mmol) in dry THF (5 mL) was added LiAlH ₄ (1.93 ml.,, 3.87 mmol, 2M in THF) drop wise at 0 °C, The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched carefully with water. The reaction mixture was diluted with EtOAc and filtered through a celite bed. The organic layer was dried over anhydrous Na ₂ S0 ₄ and concentrated under vacuum to give the title compound (250 mg, 75%) which was used as such for the next step. ^! H NMR (400 MHz, CDCi ₃ ) 8 ppm 8.37 - 8.36 (dd, J = 4.7 Hz, 1 .2 Hz, IH), 7.50 - 7.48 (d, J= 7.7 Hz, 1H), 7.1 1 - 7.08 (dd, J = 7.5 Hz, 4.8 Hz, I H), 3.90 - 3.87 ( J= 6.8 Hz, 2H), 2.92 - 2.89 (t, J= 6.7 Hz, 2H), 2.57 (s, 3H)

(e) N-((2,4-ditnethylphenyl)(phenyl)methyl)-2-(4-hydiOxyphenyl)a cetamide

To a stirred solution of 4-hydroxyphenyj. acetic acid (100 mg, 0.66 mmol) in dry DMF (5 mL) were added HATU (300 mg, 0.78 mmol) followed by (2,4- dimethylphenyl)(phenyl)methanamine (138 mg, 0.66 mmol) and NMM (0.3 mL, 2.63 mmol) at 0 °C. The reaction mixture was slowly warmed to rt and stirred for 3 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with 10% N HC0 ₃ solution, water, and brine, successively. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude product was purified by washing with diethyl ether to give the title compound (205 mg, 91%) as off-white solid. Ή NMR (400 MHz, CDC1 ₃ ) δ ppm 9.20 (s, IH), 8.78 - 8.76 (d, J = 8.3 Hz, I H), 7.32 - 7.28 (m, 2H), 7.25 - 7.23 (m, IH), 7.16 - 7.14 (m, 2H), 7.05 - 7.03 (d, J = 8.5 Hz, IH), 6.96 - 6.95 (m, 3H), 6.66 - 6.64 (d, J = 8.5 Hz, 2H), 6.18 - 6.16 (d, J = 8.5 Hz, IH), 3.33 (s, 2Ή), 2.23 (s, 3H), 2, 14 (s, 3H) (f) N-((2,4-drmethylphenyl)(pheiiyl)methyl)-2-(4-(2-(2-methylpyr idin-3- yl)ethoxy)phenyl)acetamide

A solution of diisopropyl azodicarboxylate (90 mg, 0.433 mmol) in dry TFIF (2 mL) was added drop-wise to a solution of N-((2,4-dimethylphenyl)(phenyl)methyi)-2-(4- hydroxyphenyl)acetamide (100 mg, 0.29 mmol), 2-(2-methylpyridin-3-y])etbanol (40 mg, 0.29 mmol) and triphenylphosphine (1 14 mg, 0,43 mmol) in dry THF (6 ml.) at rt. The reaction mixture was further stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 40-50% EtOAc in petroleum ether) followed by preparative HPLC using 10-100% water/acetonitrile with 0.1% TFA to give the title compound (15 mg, 1 1%). LCMS-G7: 465,5 [M+H] ⁺ ; R, = 6, 10 rain. ^l H NMR. (400 MHz, CDClj) δ ppm 8.41 - 8.40 (d, J = 3.8 Hz, 1H), 7.54 - 7.52 (d, J = 7.6 Hz, IH), 7.26 - 7.26 (m, 3H), 7.19 - 7.17 (d, J= 8.5 Hz, 2H), 7.12 - 7.09 (m, I H), 7.07 - 7.05 ( in. 2H), 6.98 (s, I H), 6.93 - 6.91 (m, IH), 6.87 - 6.85 (d, J- 8.5 Hz, 2H), 6.77 - 6.76 i d. 7.6 Hz, IH), 6.37 - 6.35 (d, ,/ 8.2 Hz, IH), 5.91 - 5.89 (d, J= 8.2 Hz, IH), 4.19 - 4.16 (t, J = 6.7 Hz, 2H), 3.58 (s, 2H), 3.13 - 3.10 (t J = 6.7 Hz, 2H), 2.62 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H).

Example 9

N-((2,4-dichloro-5-fluorophenyl)(phe^

yl)methoxy)phenyl)acetamide

(a) (2,4-dichloTO-5-fluorophenyl)(pheny3)methanamine

This compound was synthesized from 2,4-dichloro-5-fluoro benzonitrile and

phenylmagnesium bromide essentially as described in example 1 (a). Ή NMR (400 MHz, CDCls) δ ppm 7.52 - 7.49 (d, J = 10.0 Hz, 1 H), 7.40 - 7.25 (ra, 6H), 5.56 (s, IH).

(b) N-((2,4-dichloro-5-fluorophenyl)(phenyl)me1hyl)-2-(4-hydroxy phenyl)acetamide

This compound was synthesized from (2,4-dichloro-5-fluoi phenyl)(phenyi)methanamine and 2-(4-hydroxyphenyl)acetic acid essentially as example 7 (b) and was purified by column chromatography (silica 60- 120 mesh, eluent 30-40% EtOAc in petroleum ether) to give the title compound (300 mg, 57%) as a white solid. ^l H NMR (400 MHz, MeOH-cL) δ ppm 7.58 - 7.56 (d, ./ = 6.7 Hz, IH), 7.36 ^■ 7.27 (m, 3H), 7.18 - 7.1 1 (m, 5H), 6.74 ^■■ 6.72 i d. ./ 8.5 Hz, 2H), 6.38 - 6.36 (m, IH), 3.48 (d, J = 1 .8 Hz, 2H).

(c) A ^r -((2,4-dichloro-5-fluorophenyl)(phenyl)methyl)-2-(4-(( 2-methylpyridin-3- yl)methoxy)phenyl)acetamide

This compound was synthesized from N-((2,4-d ^" ichloiO-5-fluo ^" rophenyl)(phenyl)methyl)-2- (4-hydroxyphenyl)acetamide and 3-(chloromethyl)-2-methylpyridine essentially as example 7(c) and was purified by column chromatography (silica 60- 120 mesh, elue t 5- 10% MeOH in CH2CI2) followed by preparative TLC on silica gel (eluent 20% EtOAc in CH2CI2) to afford the title compound (40 mg, 16%). LCMS-G7: 508.0 [M+ HV : R _t = 3.97 ιηϊηΉ NMR (400 MHz, MeOH-d ₄ ) δ ppm 8.38 - 8.37 (dd, /= 5.0 Hz, 1.5 Hz, IH), 7.89 - 7.87 (dd, J= 7.7 Hz, 1.4 Hz, I H), 7.59 - 7.57 id, J = 6.8 Hz, 1 H), 7.37 - 7.29 (m, 4H), 7.27 - 7.25 (d, J= 8.8 Hz, 2H), 7.18 - 7.16 2H), 7.13 - 7.11 (d, J= 10.0 Hz, 1H), 7.00 - 6.98 (d, J= 8.8 Hz, 2H), 6.38 (s, 1H), 5.13 (s, 2H), 3.55 - 3.54 (d, J 2.8 Hz, 2H), 2.58 (s, 31 ! }.

Example 10

N-((2,4-dimethylpheny])(p

y3)methyl)amino)phenyl)acetamide

(a) N-((2,4-dime1hylphenyl de

To a stirred solution of 2-(4-nitrophenyl)acetic acid (362 mg, 2 mmol) in 12 mL of dieliloromethane were added HOBi (540 mg, 4 mmol), EDC (768 mg, 4 mmol), DIPEA ( 1 g, 8 mmol) and (2,4-dimethylphenyl)(phenyl)meihanamine (506 mg, 2.4 mmol). The resulting mixture was stirred at it overnight. Dichloromethane (10 mL) was added to the mixture and the mixture was washed with diluted HQ (10 ml, X 3), brine (10 mL X 3), and the organic layer was dried over NajSC . After removal of solvent, the residue was recrystallized from ethyl acetate to give the title product (600 mg, yield: 80 %) as a white solid. LCMS-P1 :397 [M+Naf ; ¾ : 1 .75 min.

(b) 2-(4-aminophenyl)-N-((2,4- etamide

To a solution of N-((2,4-dimethylphenyl)(phenyl)methyl)-2-(4-nitrophenyl)acet amide (600 mg, 1.6 mmol) in saturated aq. NH ₄ C1 (15 mL) were added Zn dust (520mg, 8mmol) and DMF (10 mL) under nitrogen. The reaction mixture was stirred at 50 °C for 12 h. A fter completion of the reaction, Zinc was separated by filtration and water (100 mL) was added to the reaction mixture. The mixture was extracted with dichlo omethane (3 X 100 mL). The combined organic layers were dried over Na ₂ S0 ₄ . Removal of solvent gave the title compound (530 mg, yield: 96%) as a yellow solid. LCMS-P1 : 345 [M+H] ⁺ ; ¾ : 1.43 min.

(c) A ^r -((2,4-dimethyiphenyl)(phenyi)methyl)-2-(4-(((2-methyl pyridm-3- y l)me thy 1) amino)phenyl)acetamide

To a solution of 2-(4-aminophenyl)-N-((2,4-diniethylphenyl)(phenyl)methyl)ace tamide (58 mg, 0, 169 rnmol) in MeCN (10 mL ) was added 3-(chloromethyl)-2-methylpyridine (27 mg, 0.152 mmol) and K2CO ₃ (63 mg, 0.457 mmol). The mixture was stirred at 65 °C for 12 h. After completion of the reaction, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL X 3). The combined organic layers were washed with brine ( 15 mL X 3) and dried over Na ₂ S0 ₄ . The solvent was evaporated to give a residue which was reciystallized from 10% ethyl acetate in petroleum ether to give the title compound as a white solid (35mg, 51.3%). LCMS-P 1 : 450 [M+Hf ; R _t - 1.97 min. Ή NMR (400 MHz, Me(3H-d ₄ ) δ ppm 8.28 ^■ 4.8 Hz, l l h. 7.73(d, J = 7.6 Hz, 1 H), 7.74-6.55(m, 12H), 6.55 (d, ./ 8.8Hz, 1 H), 6.26 (s, 1H), 4.33 (s, 2H), 3.43 (s, 2H), 2.53(s, 3H), 2.16 (s, 3H), 2.15 (s, 3H).

Example 11

A-((4-chloro-2-methylphenyl)(l -methyl- lH-pyrazol-4-yl)methyl)-2-(4-((2-methylpyridin-3- yl)methoxy)phenyl)acetamide

(a) ethyl 2-(4-((2-methylpyridin-3-yl)methoxy)phenyf)acetate

This compound was synthesized from ethyl 2-(4-hydroxyphenyl)acetate and 3-

(chloromethyl)-2-methylpyridine hydrochloride essentially as described in example 2 (c). ( T .41g, 49%). MS: 286, ; Μ · Η | .

(b) 2-(4-((2-methylpyridin-3-yl)methoxy)phenyl)acetic acid hydrochloride

To the suspension of ethyl 2-(4-((2-methylpyridin-3-yl)methoxy)phenyl)acetate ( lg,

3.5mmol) in THF/ Water (! OniL, 1 : 1) was added NaOH (280 mg, 7 mmol). After Stirling at rt for 30 min, the reaction mixture was evaporated in vacuum to remove the excess THF. HCl (2M) was added slowly to the residue until the precipitate appeared. Then the precipitate was collected to give the title compound as a white solid (742mg, 82%). MS: 258 [M+H] ⁺ .

(c) (4-chloro-2-methylphenyl)(l -methyl- 1 H-pyrazol-4-yl)methanamme

To a stirred solution of 4-bromo-l -methyl- IH-pyrazole ( g, 6.2 mmol) in 20 mL of THF was added dropwise w-BuLi (2.72 mL, 6.8 mmol, 2.5 N in hexanes) at -78 °C under nitrogen.

After stirring at that temperature for 30 min, 4-chloro-2-methylbenzonitrile (1.026g, 6.8 mmol) was added. The reaction mixture was slowly warmed to rt. Methanol (10 mL) was added followed by addition of aBH ₄ (472 mg, 12.4 mmol). After stirring at rt overnight, the mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (15 mL) and dried over Na ₂ SC> ₄ . After removal of solvent, the crude product was purified by silica gel column chromatography (CrLCli/MeOH = 30/1) to give the title compound as colorless oil (150 mg, yield: 10%). LCMS-P1 : 236.0 [M+H] ⁺ , rt - 1.129 min. (d) N-((4-ch3oro-2-methylpbenyl)(l -methyl- lH-p_ Tazof-4-yi)methyf)-2-(4-((2-methylpyridin-3- y l)me thoxy)pheny 1) ace tamide

This compound was synthesized from (4-chloro-2-methylphenyl)( 1 -methyl- lH-pyrazol-4- yl)methanamine and 2-(4-((2-methylpyridm-3-yl)methoxy)phenyl)acetic acid hydrochloride essentially as described in example 3. LCMS-P1 : 475.0 [M+Hf; R _t = 1. 303 min. Ή NMR (400 MHz, CDC1 ₃ ) δ ppm 8.84 (d, .1 7.6 Hz, i l l ). 8.61 i d. 5.2 Hz, 1H), 8.21 (d, ./ 6.8 Hz, i l l ).

7.63 (t, J= 6.0 Hz, 1H), 7.35-7.18 (m, 7H), 6.99 (d, J= 8.8 Hz, 2H), 6.03 (d, J= 8.0 Hz, 1H), 5.20

(s, 2H), 3.75 (s, 3H), 2.64 (s, 3H), 2.21 (s, 3H).

Example 12

2-(2,4-dimethylphenyl)-N-( -((2-methylpyridin-3-yl)methoxy)beiizyi)-2-phenyla.cetamide

(a) 2-( ^' 2,4-diinethylphenyl)-2-plienyfacetic acid

The solution of mandelic acid (10.0 g, 65.7 mmol) in m-xylene (56.79 mL, 460 mmol) was heated to 60-70 °C followed by the addition of SnC (1 1.5 mL, 98.6 mmol) over 2 h. The reaction mixture was cooled to rt and then stirred for 6 h at rt. The completion of the reaction was monitored by TLC on silica gel using Hexanes: EtOAc (1 : 1) as mobile phase. After completion of the reaction, ice-water (100 mL) was added, and the reaction mixture was extracted with diethyl ether (3 x 250 mL). The combined ether layers were discarded. The remaining reaction mixture was extracted with 8% aqueous Na ₂ C0 ₃ (10 x 50 mL) and the combined aqueous layer was then acidified using 6 N HQ (20 mL) and the solid obtained was filtered and dried. The crude solid product was purified using silica gei column chromatography using 20% EtOAc: Hexanes to obtain title compound (6.25 g, 39.63 %) as a solid. Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.6 (s, 1 H), 7.21 -7.33 (m, 6 H), 7.09-7.12 (m, 1 H), 6.97-7.06 (m, 3 H), 5.12 (s, 1 H), 2.23 (s, 3 H), 2, 17-2, 18 (d, 4 H). (b) 2-(2,4-dimethylphenyl)-N-(4-hydroxybenzyl)-2-phenyj.acetanii de.

To a solution of 2-(2,4-dimethyipbenyl)-2-pheny3acetic acid (0.25 g, 1 ,04 mmol) in anhydrous DMF (10 mL) at 25 °C was added EDC (0.237 g, 1.24 mmol) and the reaction was stirred for 30 min at rt under argon atmosphere followed by addition of HOBt (0.19 g, 1.24 mmol), 4-dimethylamino pyridine (0.19 g, 1.56 mmol) and 4-(aminomethyl)phenol (0, 154 g, 1 ,24 mmol), and the reaction mixture was stirred overnight under argon atmosphere. After completion of the reaction, the reaction mixture was cooled and water ( 10 mL) was added drop wise during which solid precipitated out. The solid precipitate was collected by filtration, washed with hexanes (2 x 10 mL), and dried under vacuum to provide title compound (0.065 g, 18.10 %) ^l H NMR (400 MHz, DMSO-de) δ ppm 9.29 (s, 1 H), 8.55-8.58 (t, 1 H), 7.26-7.30 (t, 2 H), 7.16-7.20 (m, 4 H), 7.00-7.02 (d, 2 H), 6.93-6.95 (d, 2 H), 6.65-6.68 id, 2 H), 5.07 (s, 1 H), 4.1 1 -4.22 (m, 2 H), 2.22 (s, 3 H), 2.15 (s, 3 H).

(c) 2-(2,4-dimethylphenyl)-A 4~((2-me

To the solution of 2-(2,4-dimethylphenyl)-N-(4-hydroxybenzyl)-2-phenylacetamide (52mg, 0. 15 mmol) and 3-(chloromethyl)-2~methylpyridine hydrochloride (32. mg, 0.18 mmol) in DMF (5 mL) was added K2CO ₃ (62 mg, 0,45 mmol). The resulting mixture was stirred at rt for 48 h.

Then the mixture was poured into water and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine and dried over Na ₂ S0 ₄ . A fter removal of solvent, the residue was purified by preparatory TLC on silica gel to afford the title compound (20 nig, 30%) as a white solid. MS: 4 l j .YM l | : H NMR (400 MHz, DMSOd ₆ ) δ ppm 8.63 (t, ,/ 5.6 Hz, l i s }. 8.40 (dd. ./ 1.2 Hz, 5.2 Hz, 1H), 7.77-7.75 fm, 1H), 7.30-6.93 (m, 13H), 5.10 (s, 2H), 5.08 (s, 1H), 4.28-4.18 (m, 2H), 2.22 (s, 3H), 2.15 (s, 3H).

Example 13

N~((4-chioro-2-methylp

fa) ethyl 2-(4-((2-methylpyridin-3-yl)oxy)phenyl)acetate

To a solution of ethyl 2~(4-hydroxyphenyl)acetate ( 1.36 g, 7.55 mmoi) in 6 mL of 1 ,4- dioxane were added 3-bromo-2-methyipyridine (1.0 g, 5.8 mmol), Cul (330 sng, 1.74 mmol), CS2CO ₃ (5.67 g, 17.4 mmol) and N^V-dimethylglycine (180 mg, 1.74 mmol) under nitrogen. The resulting mixture was sealed and heated in a microwave (120 °C for 60 mill). After cooling to rt, water (30 mL) was added and the reaction mixture was extracted with EtOAc (30 mL X 3). The combined organic layers were washed with brine (30 mLx3), and dried over After removal of solvent, the residue was purified by silica gel column chromatography (petroleum ether/EtOAc=5/l ) to obtain title compound (600 mg, yield: 38%) as a yellow oil. LCMS-P1 : 272 i \) ! i ; ; R : 1.293 mm.

(b) 2-(4-((2-metb.ylpyridin-3-yl)oxy)phenyl)acetic acid

To a solution of ethyl 2-(4-((2-methy3pyridm-3-yl)oxy)phenyl)acetate (300 mg, 1.1 mmol) in THF (8 mL) and water (2 mL) was added LiOH (465 mg, 1 1 mmol). The mixture was stirred at rt overnight. Then water (10 mL) was added to the mixture. AcOH was used to adjust the aqueous phase to pH=3-4. Then the mixture was extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine (15 mL X 3) and dried over Na ₂ Si)4. _T he solvent was evaporated to give the title compound (210 mg, 78%) as a white solid. The title compound was used in the next step without any further purification. LCMS-P1 : 244 [M+H] ^" ; R _t : 1.082 mm. (c) N-((4-cWoro-2-methylphenyl)(phenyl)methyl)-2-(4-((2-methylpy ridin-3- yl)oxy)phenyl)acetamide

This compound was synthesized from 2-(4-((2-methylpyridin-3-yl)oxy)phenyl)acetic acid and (4-chloro-2-methylphenyl)(phenyl)methanamine essentially as example 3 (42 mg, yield: 1 1%). LCMS-P1 : 457 [M+H] ^" ; R _t : 1 .518 min. ^! H NMR (500 MHz, DMSO~d ₆ ,) δ ppm 8.97 (d, J = 8.0 Hz, lH), 8.26 (t, J = 1.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.28-7.23 (m, 7H), 7.18 (d, J = 7.5 Hz, 2H), 7.1 1 i d. J = 8.0 Hz, I I I ;. 6.90 (d, ./ 8.5 Hz, 2H), 6.19 i d. 8.0 Hz, l ! . 3.51 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H). Example 14

A ^r -((2,4-d methy3phenyl)(pheny3)methyl)-2-(3-methy3-4-((2-methyIpyTidin -3- yl)methoxy)phenyl)acetami

(a) N-((2,4-dimethylphenyl)(phe

This compound was synthesized from (2,4-dimethylphenyl)(phenyl)methanamine and 2-(4- methoxy-3-methy{phenyl)acetic acid essentially as example 3 which was used in the next step without any further purification. LCMS-P 3 : 374 [M+H] ⁺ ; R _t : 1.805 min.

(b) N-((2,4~dimethylphenyl)(ph nyl)acetami

To a solution of N-((4-chloro-2~methylphenyi)(phenyl)methyl)-2 ^■ (4~methoxy-3 - raethylphenyl)acetamide (200 mg, 0. 5 mmoi) in 10 mL CH2CI2 was added boron tribromide (215 mg, 0,8 mmol) under nitrogen at -78 °C. The mixture was allowed to warm to it slowly and stirred overnight. The solvent was evaporated to give the title compound (162 mg, 85%) as a yellow solid. The title compound was used in the next step without further purification. LCMS- Pl : 360 ! Vi - ! ! i : R _t : 1.696 min.

(c) N-((2 ₅ 4-dimethyiphenyl)(phenyi)m

y l)me thoxy)pheny 1) ace tamide

To a stirred solution of A-((2,4-dimethylphenyi)(phenyl)methyl)-2-(4~hydroxy-3- methylphenyl)acetamide (162 mg, 0.45 mmol) in CH ₃ CN (20 mL) was added 3-(c loromethyl)-2- methylpyridine (89 mg, 0.54 mmol), and K CO. (186 mg, 1.35 mmol). The resulting mixture was stirred at 50 °C overnight. After cooling to rt, the solid was separated by filtration. The filtrate was concentrated and the title compound was purified by preparatory TLC on silica gel (petroleum ether/EtOAc=3/2) to obtain title compound (86 mg, yield: 41%) as a white solid. LCMS-P1 : 465 I Π ; ; R _t : 1 .602 min. ^! H NMR (400 MHz, DMSO~d ₆ ) δ ppm 8.83 (d, J= 8.4 Hz, 1H), 8.40-8.38 (m, 1 H), 7.79-7.77 (m, 1H), 7.32-7.22 (m, 4H), 7.15 (d, J= 7.2 Hz, 2H), 7.04-6.95 (m, 6H), 6.17 (d, ,/ 8.0 Hz, 1H), 5.09 (s, 2H), 3.40 (s, 2H), 2.49 (s, 3H), 2.22 (s, 3H), 2.14 fs, 3H), 2.13 (s, 3H).

Example IS

N-((4-chloro-2-methylphenyi)(phenyl^

yl)methyl)amino)piperid ^" in- -yl)acetamide

(a) methyl 2-(4-((teri-butoxycarbonyl)ammo)piperidin- 1 -yl)acetate

To the solution of iert-butyl piperidin-4-ylcarbamaie (1 g, 5 mmol) in DMF ( 10 mL) were added methyl-2-brornoacetate (842 mg, 5.5 mmol) and K3CO3 (1.38 g, 10 mmol)and stirred at rt for 30 min. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, and dried over Na ₂ S0 ₄ . After removal of solvent, the title compound (1.3g, 96%) was used in the next step without further purification. LCMS-P 1 : 273, [m+H] ¹ .

(b) ) methyl 2-(4-aminopiperidin-l-yl)acetate hydrochloride To the solution of methyl 2-(4-((tert-butoxycarbonyl)ammo)piperidin- 1 -yl)acetate (2.72 mg, Immol) in MeOH (5 mL) was added 1 M HCi in Et ₂ 0 (4 mL, 4 mmol). Then the mixture was stirred at rt for 3 h. The reaction mixture was evaporated in vacuum. The title compound (239 mg, 98%) was used in the next step without further purification. MS: 173 [M+H] ⁺ ;

(c) methyl 2-(4-(((2-methylpyridm-3-yf)methy])amino)piperidin- 1 -y3)acetate

To the mixture of methyl 2-(4-aminopiperidin- 1 -yl)acetate hydrochloride (190 mg, 0.78 mmol) and 3-(chloromethyl)-2-meihyipyridine hydrochloride (151 mg, 0.85 mmoi) in DMF (3 mL) was added K ₂ CO ₃ (428 mg, 3.1 mmol) and potassium iodide (64.3 mg, 0.38 mmol), then the mixture was heated at 60 °C overnight under argon protection. The reaction mixture was cooled to rt and poured into water (10 mL), and extracted with EtOAc. The combined organic layers were washed with brine, and dried over NaiSC . The organic solvents were removed under vacuum, and the residue was purified by silica gel column chromatography (0 - 100% ethyl acetate/hexanes) to give the title compound as a colorless oil (1 OOmg, 46.3%) MS: 278 [M+H] ⁺ ;

(d) 2-(4-(((2-methylpyridin-3-yl)methyl)amino)piperidin- 1 -yl)aeetic acid

To the suspension of methyl 2-(4-(((2-methylpyridin-3-yl)methyl)amino)piperidin- l- yl)acetate (100 mg, 0.36mmol) in THF/Water (4 mL, 1 : 1 ) was added LiOH (30 mg, 0.72 mmol) and the resulting mixture was stirred at rt for 30 min. The reaction mixture was neutralized by HCI (1M). All the solvent was removed under reduced pressure and the title compound was used directly to the next step without further purification. MS: 264 [M+H] ^' ;

(e) A ^r -((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(4-(((2-m ethylpyridin-3- yl)methyl)amino)piperidin- 1 -yi)acetamide

To the solution of 2-(4-(((2-methylpyridin-3-yl)methyl)amino)piperidin- l-yl)acetic acid

(crude product) in DMF (3 mL) were added (4-chloro-2-methylphenyl)(phenyl)m.ethanamine hydrochloride (1 16 mg, 0.43 mmol), EDC (83 mg, 0.43 mmol), HOBt (58 mg, 0.43 mmol), and DIPEA (93 mg, 0.72 mmol). The resulting mixture was heated at 45 °C overnight. After cooling to rt, the mixture was extracted with EiOAc (15 mL X 2). The combined organic layers were washed with brine and dried over Is^SC After removal of solvent, the residue was purified by preparatory HPLC using 10-100% water/acetonitrile with 0.1% TFA to afford the title compound as a white solid 31 mg, 18%. MS: 477 [M+Hf; Ίί NMR (400 MHz, DM8Q-d ₆ ) 8 ppm 8.46 (d, J = 8.4 Hz, 1H), 8.27 (dd, J= 4Hz, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.34-7.14 (m, 9H), 6.23 (d, J= 8.8 Hz, 1H), 3.67 (s, 2H), 2.99 (s, 2H), 2,77-2,74 (m, 2H), 2.46 (s, 3H), 2.23 (s, 3H), 2.09 ( J = 7.2 Hz, 21 1 ). 1.81 (d, J= 12Hz, 2H), 1.32-1.23 (m, 2H). Example 16

A-((2,4-dimethylphenyl)(phenyl)methyl)-2-(4-methyl-4-(((2-me thylpyridin-3- yl)methyl)atnino)piperidin- -yl)acet amide

(a) 1 -tert-butyl 4-met yl piperidine-l,4-dicarboxylate

To the suspension of 1 -(i ri-butoxycarbonyl)piperidine-4-carboxylic acid (4.58 g, 20 mmol) and K ₂ CO ₃ (5.26 g, 40 mmol) in DMF (20 mL) was added iodomethane (4.26 g, 30 mmol) slowly. Then the resulting mixture was stirred ai rt overnight under argon. The solid was removed by filtration. The resulting filtrate was extracted with EtOAc. The combined organic solvents were washed with brine and dried with Na ₂ S0 . After removal of solvent, the crude title compound (4.7g, 98%) was used in the next step without further purification. MS: 244.0 , i vi - l i i .

(b) 1 -tert-butyl 4-methyl 4-methylpiperidme- 1 ,4-dicarboxylate

To the solution of 1 -tert-butyl 4-methyl piperidine- 1 ,4-dicarboxylate (607 mg,2.5m mol) in THF (5 mL) was added 2 M lithium diisopropylamine (1.5 mL, 3 mmol) dropwise at -78 °C under argon protection. After stirring at -78 °C for 1 hour, iodomethane (426 mg, 3 mmol) was added. The resulting mixture was allowed to warm up to rt slowly, and stirred at rt overnight. The reaction mixture was quenched with NH ₄ CI (sat.), . extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na ₂ S0 ₄ . After removal of solvent, the residue was purified by gel silica column chromatography with petroleum etber:EtOAc=5: l to afford the title compound as a colorless oil (274mg, 43%). MS: 258.0 [M+H] ⁺ ;

(c) l -(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid

To the suspension of 1 -tert-butyl 4-methyl 4-methylpiperidine- 1 ,4-dicarboxylate (274 mg, 1.07 mmol) in water/THF (4 mL, 1: 1) was added LiOH ^: Ii ₂ 0 (89 mg, 2.13 mmol), and then the mixture was stirred at 45 °C overnight. The reaction mixture was cooled to rt and the pH was adjusted to 5-6 by using 2. N HC1. Then the mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ S0 ₄ . A fter removal of solvent, the crude title compound (145 mg, 56%) was used in the next step without further purification. MS: 244.0 [M+Hf;

(d) teri-butyl 4-(((benzy loxy)carbonyl)amino)-4-methylpiperidine- 1 -carboxylate

To the solution of l-(iert-butoxycarbony{)-4-methylpiperidine-4-carboxylic acid (1 1mg,

0.58 mmol) in toluene (3 niL) was added triethylamine (88 rag, 0.87 mmoi), diphenyl

phosphorazidate (313 mg, 0.81 mmol), and phenylmethanol (313 mg, 12.9 mmol). The mixture was stirred at rt for 1 hour, and then heated to 80 °C under argon protection overnight. After cooling to rt, the solvent was removed under reduced pressure, the residue was purified by gel silica column chromatography with petroleum ether: EtOAc=5: l to afford the title compound as colorless oil 90mg, 44.5%. MS: 349.0 [M+H] ⁺ ;

(e) benzyl (4-methylpiperidin-4-yl)carbamate

To a solution of teri-butyl 4-(((benzy]oxy)carbonyl)amino)-4-methylpiperidine-l- carboxylate (1.1 g, 3.7 mmol) in l,4-dioxane(2mL) was added HCl/l,4-dioxane(8 ixiL, AN, 32 mmol), the resulting mixture was heated to 50 °C overnight. After cooling to rt, the solvent was removed under reduced pressure. To the residue was added EtOAc and acetone. The precipitate was collected by filtration to give the title compound as a white solid (550 mg, 70%). MS:249 [M+H] ⁺ ;

( f) ethyl 2-(4-(((¾e ^" nzyloxy)carbonyl)amino)-4-meihyipiperidin- 1 -yl)acetate

To the solution of benzyl (4-methylpiperidin-4-yl)carbamate (124 mg, 0.5 mmol) in DMF (3 ml.) was added ethyl 2-bromoacetate (100 mg, 0.6 mmol) and K2CO ₃ (138 mg, 1 mmol). Then the mixture was heated to 60 °C for 3 h. After cooling to rt, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ S0 ₄ . After removal of solvent, the residue was purified by gel silica column

chromatography with petroleum ether: EtOAc ^~ l : l to afford the title compound as colorless oil 100 mg, 60%. MS: 335 [M+H] ⁺ ; (g) ethyl 2-(4-amino-4-methylpiperidin- 1 -yl)acetate

To the solution of ethyl 2-(4-(((benzyloxy)carbonyr)am no)-4-methylpiperid n-l -y3)acetate (1 10 mg, 0.33 mmol) in EtOAc (5 mL) was added 10% Pd ^' C (1 1 mg), then the mixture was stirred at rt under hydrogen atmosphere overnight . Pd/C was removed by filtration. The organic layer was removed under reduced pressure to give the titled compound as a colorless oil (60 mg, 91%). MS: 201 [M+Hf ; (h) ethyl 2-(4-Tnethyl-4-(((2-Tnethylpyridin-3-yl)methy3)ammo)piperidi n- 1 -yl)acetate

This compound was synthesized from ethyl 2-(4-(((benzyloxy)carbonyl)amino)-4- methylpiperidin- l -yl)aeetate and 3-(chloromethyl)-2-methylpyridine hydrochloride essentially as example 15 (c) (200 mg crude product was obtained), MS: 306 [M+H] ^"

(i) 2-(4-memyl-4-(((2-methylpyridin-3-yl)memyl) acid

This compound was synihesized from ethyl 2~(4-meihyI-4-(((2-meihyIpyridin-3- yl)methyl)amino)piperidin- l-yI)aceta.te essentially as example 15 (d) (300 mg crude product was obtained). MS: 278 [M+H] ⁺ ;

(j) N-((2,4-dimethylphenyl)(phenyl)methyl)-2-(4-methyl-4-(((2-me thylpyri

yl)niemyl)amino)piperidin- 1 -yi)aceiamide

This compound was synthesized from 2-(4-xnethy1-4-(((2-methy1pyridin-3- y3)methyl)amino)piperidin- 1 -yl)acetic acid and (2,4-dimethylpheny l)(phenyl)methanamine essentially as example 15 (e) (20 mg, 7% over three steps). MS: 471 | M I f ] : Ti MR (400 MHz, DMSO-de) δ ppm 8.32-8.27 (m 2H), 7.69 (d, J= 8Hz, IH), 7.32 (t, J= 7.2 Hz, 2H), 7.26- 7.23 (m IH), 7.18-7.14 (m 3H), 7.03-7.6.96 (m, 3H), 6.23 (d, J= 8.8Hz, 1H), 3.58 (s, IH), 3.00 (s, i i ). 2.39-2.30 (m 3), 2.24 (s 3H), 2.39 (s 3H), 1.62-1.47 (m, 5Ή), 1.10 (s,3H).

Example 17

Λ'- ((2 ,4 - dim emy ipheny 3 ) ( e^

y3)ethoxy)pheny3)acetamide

To a cooled (0 °C) solution of l -(2- methyIpyrid ne-3-yl) ethanone (360 mg, 2.67 mmol) in hydrogen bromide-acetic acid solution (33%, 4mL) was added a solution of bromine (45 mg, 2.8 mmol) in dichloromethane ( 1 mL) slowly. The reaction mixture was allowed to rt, and the mixture was stirred at the same temperature for 2 h. The obtained solid was washed with ethyl acetate to give the title compound as a white powder (673 mg, yield: 85.5%). LCMS-P1 : 215.9 i \) 1 1 1 : R 1.02min.

(b) methyl 2-(4-(2-(2-methylpyridin-3-yl)-2-oxoethoxy)phenyl)acetate

A mixture of 2-bromo~ i ~(2-methy{pyridin~3-yl)ethanone hvdrobroniide (295 mg, 1 mmol), methyl 2-(4-hydroxypheny3) acetate (199.2 mg, 1.1 mmol) and potassium carbonate (414 mg, 3mol) in DMF (5 mL), was stirred at 50 °C overnight under argon. The reaction mixture was cooled to rt and filtered. The filtrate was dissolved in water (20 mL) and extracted by methyl tert- butyi ether (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. and concentrated under reduced pressure and purified by column chromatography on silica gel

(petroleum ether/EtOAc-2/ 1) to obtain title compound (141 mg, yield: 47 %). i i NMR (400 MHz, DMSO-de) δ ρτη 8.61 ( dd. ,/ 1.6 Hz, 5.2 Hz, i l l ;. 8.29 (tkl. J 1.6 Hz, 5.7 Hz, 2H), 7.41 (dd, J= 5.7 Hz, 7.6 Hz, 1H), 7.17 (d, J= 8.0 Hz, 2.H), 6.91 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H), 3.60 is, 5H), 2.58 (s, 3H).

(c) 2-(4-(2-(2-methylpyridin-3-yl)-2-oxoethoxy)phenyl)acetic acid

A mixture of methyl 2-(4-(2-(2-metliylpyridin-3 -yl)-2-oxoethoxy)phenyl)acetate (141 mg, 0.472 mmol) and NaOH (94 mg, 2.55 mmol) in THF:H ₂ 0 ( l Q:2mL) was stirred at rt for 1 h. The reaction mixture was extracted by methyl ½r/-butyl ether (3 x 1 0 mL) and the aqueous phase was adjusted pH to 5 with cone. HC1. The aqueous layer was then extracted with ethyl acetate (3 x 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate was and concentrated under reduced pressure to obtain the title compound (90mg, yield: 64 %). LCMS- Pl : 286.0 [M+Hf; R _t - 1.096min. (d) N-((2,4-dimethylphenyl)(phenyty^

oxoethoxy)phenyl)acetamide

A mixture of 2-(4~(2-(2-methylpyridin-3-yl)-2-oxoethoxy)phenyl)acetic acid (60 mg, 0.21 mmol), EDC (80.8 mg, 0.42 mmol), and HOBt (28.6 mg, 0.25 mmol) in dichloromethane (2 mL), was stirred at rt for 0.5 h. Then (2,4-dimethylphenyl)(phenyl)methaiiamine (53 mg, 0.21 mmol) was added. After the addition, the mixture was stirred at rt overnight. The reaction mixture was washed with water (3 x 1 mL), the organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography on silica gel (petroleum ether/EtOAc=l : l) to obtain title compound (45 mg, 45%). ^l H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.82 (d, J 8.4 Hz, i l l ). 8.61 (dd, J= 1.6 Hz, 4.8 Hz, 1H), 8.29 (dd, ./ 1 .6 Hz, 4.8 Hz, 1 H), 7.40 (dd, J = 4.8 Hz, 7.6 Hz, 1H), 7.73-7.24 (m, 3H), 7.17-7.14 (m, 4H), 6.95 (m, 3H), 6.87 (d, J - 8.8 Hz , 2H), 6.17 (d, /= 8.8 Hz , 1H), 5.39 (s, 2H), 3.44 (s, 2H), 2.58 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H).

(e) N-((2,4-dirnethylphenyl)(phenyl)meth^

yl)ethoxy)phenyl)aeetamide

To a 0 °C solution ofN-((2,4-dimethylphenyl)(pheny1)methyl)-2-(4-(2-(2-methylpy ridm-3- yl)~2-oxoethoxy)phenyf)acetamide (35 mg, 0.073 mmol) in MeOH (4 mL) was added NaBH ₄ (5.6 mg, 0.146 mmol). The reaction mixture was stirred at rt for 2h. Then water (2mL) was added to the mixture and concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleu ether/EtOAc=l /l) to obtain title compound as a white solid (1 8 g, yield: 51%). LCMS-P1 : 481 .2 [M+H] ; R. - 1 .93 min. Π NMR (400 MHz, DMSO~d ₆ ) δ ppm 8.81 (d, J= 8.0 Hz, I H), 8.35 (dd, J= 1.6 Hz, 4.8 Hz, IH), 7.85 (dd, J =1.6 Hz, 6 Hz, IH), 7.30 (t, J= 7.2 Hz, 2H), 7.25 (m, 2H), 7.16(s, 2H), 7.14 (s, 2H), 6.97-6.97(m,3H), 6.86 (s, IH), 6.84 (s, I H), 6.17 i d. ./ 8.8 Hz , I H), 5.71 (d, /= 4.8 Hz I H), 5.1 0 (q, J = 4.8 Hz, IH), 3. 99 (d, J = 6.0 Hz, 2H), 3.42 (s, 2H), 2.54 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H).

Following essentially the procedure as described in Example 1 , the compounds in T able 1 were prepared.

Table 1

Following essentially the procedure as described in Example 2, the compounds in T able 2 were prepared.

Table 2

yl)methoxy)phenyl)aceta.mide Following essentially the procedure as described in Example 5, the compounds in T able 3 were prepared.

Table 3

Following essentially the procedure as described in Example 9, the compound n Table 4 was prepared.

Table 4

Example 32

A ^r -((2,4-dimethy3phenyl)(pheny3)methyl)-2-(4-(l-hydroxy- 2-(2-methy3pyridin-3- yl)ethyl)phenyl)acetami

(a) Ethyl 2-(4-((tri

Ethynyltrimethylsilane (2.15g, 21.42mmol) was added drop-wise to a solution of ethyl 2-(4- bromopheny1)acetate (5 g, 19,8 mmol), Cul (385 mg, 1.98 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (1.42g, 1.98mmol) in 120 mL of Et ₃ N at 0 °C under nitrogen atmosphere. The resulting mixture was refluxed overnight and Et ₃ N was removed under reduced pressure to give a crude solid which was purified by silica gel column chromatography (Petroleum ether/E†.OAc=10/l) to obtain title compound (2.6g, yield: 50.5 %). LCMS-A024: 261.7 [M+H] ⁺ ; Rt = 2.26 min.

(b) methyl 2-(4-ethyny3ph

K ₂ C0 ₃ (0.223g, 16 mmol) was added to a stirred solution of ethyl 2-(4- ((irimethylsilyl)ethynyi)phenyl)acetate (2.6 g, 8 mmol) in 30 mL of MeOH at 0 °C. The resulting mixture was stirred at rt for 1 h. Then water (200 mL) was added. The mixture was extracted with CH2CI2 (3 x 300 mL) and dried over Na ₂ S0 ₄ . After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography (Petroleum ether EtOAc=5/l ) to give title compound (1.4 g, 7.5 mmol, yield: 93.8 %). LCMS-A024: 175.1 [M+H] ^"h ; Rt - 1.66 min.

(c) methyl 2-(4-((2-methy1pyridin-3-yl)ethynyl)phenyl)acetate:

86 Methyl 2-(4-ethynylp enyl)acetate (0.9 g, 4.39 mmoi) was added drop-wise to a stirred solution of 3-bromo-2-methylpyrid ne (0.8 g, 4.39 mmoi), Cul (89 mg, 0.44 mmoi), and Pd( PPh _: i;C ^' ! _; (316 mg, 0.44 mmoi) in 50 mL of Et ₃ N 0 °C under nitrogen atmosphere. The resulting mixture was reiluxed overnight. Et ₃ N was removed under reduced pressure to give a crude solid which was purified by silica gel column chromatography (Petroleum ether/EtOAc=5/l) to obtain title compound (0.2 g, yield : 17.2 %). LCMS-A024: 266.0 [M+H] ⁺ ; Rt - 1.31 min.

(d) 2-(4-((2-methylpyridin-3

A solution of Li OH (71mg, IJmmol) in water (2mL) was added to the suspension of methyl 2-(4- ((2-methylpyridin-3-yl)ethynyl)phenyl)acetate (90mg, 0.339mmol) in THF (5mL). After stirring at rt for 4 li, the reaction mixture was evaporated under reduced pressure to remove the excess THF. Then HCi (2M) was added slowly until a precipitate appeared. Then the precipitate was collected to give the titled compound (50mg, yield 58.6%). LCMS-A024: 252.7 | M - i ! |■

(e) 2-(4~(2-(2-methylpyrid ^" i -3-yl)acetyI)phenyl)acetic acid:

H ₂ SO (41 mg, 0.39 mmoi) was added to a solution of 2-(4-((2-methylpyridin-3- yl)ethynyl)phenyl)acetic acid (50 mg, 0.19 mmoi) and HgS0 (59 mg, 0.19 mmoi) in acetone (5 mL) and H ₂ 0 (1 mL) under nitrogen. The mixture was reiluxed overnight. After cooling to rt, H ₂ 0 (20 mL) was added and the mixture was extracted with CF1 ₂ C1 ₂ (3 x 30 mL) and dried over Na ₂ S0 . After removal of the solvent, the crude product was purified by flash chromatography (Petroleum ether./EtOAc=l/l) to give title compound (20 mg, yield: 38 %). LCMS-A024: 270.7 I Π ; : Ri 1.02 min.

(f) A-((2,4-dimethyiphenyl)( henyi)methyl)-2-(4-(2-(2-methylpyridin-3- yl)acetyl)phenyl)acetamide:

This compound was synthesized from 2-(4-(2-(2-methylpyridin-3-yl)acetyl)phenyl)acetic acid and (2;4-dimethylphenyi)(phenyl)methanamine essentially as described in example 2 (f) (20mg, Yield: 64.6%). LCMS-A024: 463.7 , [M+H . Rt=1.38min

(g) N-((2,4-dimethyipbenyl)(phenyi)meth^

y3)etbyl)phenyl)acetarm

NaBH ₄ (5 nig, 0.13 mmol) was added portion-wise to a solution of N-((2,4- dimethylphenyl)(phenyl)methyl)-2-(4-(2-(2-methylpyridin-3-yl )acetyl)phenyl)acetami (20 mg, 0.04 mmol) in MeOH (5 mL) at 0 °C, After the addition was complete, the mixture was allowed to warm up to rt and stirred overnight. The reaction was diluted with water (10 mL) and extracted with &¼(¾ (3 x 10 mL). The combined extracts were dried over a ₂ S0 ₄ and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Petroleum ether/EtOAc=l/l) to obtain title compound ( 10 mg, yield: 49.8 %). LCMS-A024: 465.7 [M+H ; RT = 1.34 min. ^! H NMR (DMSO~d ₆ , 400MHz): δ 8.85 (d, J = 8.4 Hz, 1 H), 8.40 (dd, .71 = 1.2 Hz , J2= 4.8 Hz, lH), 7.45 (dd, Jl= 1.2 Hz , J2= 7.2 Hz, 1 H), 7.33-6.95 (m, 13H), 6.1 8 [ d. 8.4 Hz, 1H), 5.31 i d. 4.4! iz. iH), 4.72 (t, ./ 2.8 Hz, 1H), 3.5 (s, 2H), 2.85 (t, J = 5.2 Hz, 2H), 2.37 (s, 3H), 2.23 (s, 3H), 2.15 (s, 3H) .

Following essential the same procedure as described in example 32, the compounds in table 5 were prepared.

Table 5

Example 34

2-(4-(l-(2-amino-2-oxoethoxy)-2-(2-methylpyridin-3-yl)ethyl) phenyl)-N-((2,4- dimethylphenyl) phenyl

NaH (3.44 mg, 60% in oil) was added to a solution of N-((2,4- dimethylpheny])(phenyi)methyl)-2-(4-(l-hydroxy-2-(2-methylpy rid

(20 mg, 0.043 mrnol) in TFIF (5 mL) at rt, and the reaction mixture was stirred for 30 min, followed by addition of 2-bromoacetamide (7.1 mg, 0.052 mmol). The mixture was stirred for 48 h, water

(20 mL.) was then added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield a residue which was purified by reverse phase FIPLC using water/acetonitrile wiih 0,05% TFA to obtain title compound (3 mg, 13.6%). LCMS-A024:

522.3[M+H] ⁺ ; R : 1 ,37 min. H NMR (CDC1 ₃ , 400MHz): δ 8.59 (s, IH), 7,79 (d, J = 4.8Hz, IH), 7.39-7.03 (m, 9H), 6.92-6.79 (m, 4H), 6.29 (d, J = 8.0Hz, 1H), 6.03 (d, J = 8.0 Hz, I H), 5.49 (s, 1H), 4.53 (s, 1H), 3.80-3.66 (m, 1 H), 3.55 (s, 2H), 3.21 -3.03 (m, 2H), 2.60 (s, 3H), 2.22 (s, 3H), 2.15 (s, 3H). tmpie J 3

N-((4-chloro-2-methy3phenyl)(jphenyl)methyl)-2-(4-(2-(4,6-di hydroxypyri

yl)ethoxy)phenyl)acetamide

(a) ethyl 2-(4-(2

Potassium carbonate (18, 1 g, 130mmol) and 1 ,2-dibromoetbane (82.6 g, 439 mmol) were added to a stirred solution of ethyl 2-(4-hydroxyphenyi)acetate (13.6 g, 73 mmol) in CH ₃ CN (300 mL). The resulting mixture was stirred at 80 °C overnight. After cooling to rt, the mixture was extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine, dried over a ₂ S0 ₄ , and concentrated under reduced pressure. The obtained crude product was purified by flash chromatography (Petroleum ether/EtOAc = 50/1) to give 16 g of ethyl 2-(4-(2- bromoethoxy)phenyl)acetate (yield 73%). LC-MS (024): 288.9 | M l ! ] ; RT - 1.652 min. MMR (CDC , 400MHz): 7.22 (d, J= 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2 \ l ). 4.29 (t, J = 6Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.64 (t, /= 6.4 Hz, 2H), 1.26 (t, J= 7.2 Hz, 3H).

(b) diethyl 2-(2-(4-(2-ethoxy-2-oxoethyi)pheiioxy)ethyi)malonate:

NaOEt (340mg, 5mmol) was added to a solution of diethyl malonate (800mg, 5mmol) in EtOH (5mL). After the mixture was stirred at rt for 1 h, ethyl 2-(4-(2- bromoethoxy)phenyl)acetate (1.44g, 5mmol) was added. The resulting mixture was heated to reflux for 3 h. After cooling to rt, the solvent was evaporated under reduced pressure, and the residue was extracted with toluene (l OmL x 3). The combined the extracts were concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound as colorless oil (440mg, yield 24%). LC-MS (010): 366.9 [M+Hf; RT - 2.0 min.

(c) ethyl 2-(4-(2-(4,6-dihydroxypjTimidin-5-yl)ethoxy)phenyl)acetate:

Diethyl 2-(2-(4-(2-ethoxy-2-oxoethyl)phenoxy)ethyl)malonate (440 mg, 1 .2 mniol) and formimidamide acetate (1 50mg, 1 .44mmol) were added to a solution of NaOEt (98 mg, 1 .44 mmol) in EtOH (5 mL). The resulting mixture was stirred at rt overnight, then neutralized with cone HC1 at 0 °C, After the organic solvent was concentrated under reduced pressure, the residue was washed with water. The precipitate was collected by filtration and dried under reduced pressure to afford the title compound as a white solid (70mg, yield 18%). LC-MS (024): 31 9.0 | M · Π | : Rt - 1.23 mm.

(d) 2-(4-(2-(4,6-dihydroxypyrimidin-5-yl)ethoxy)phenyl)acetic acid: This compound was synthesized from ethyl 2-(4-(2-(4,6-dihydroxypyrimidin-5-yl)ethoxy)phenyl)acetate essentially as example 15 (d) and was used directly to the next step without further purification. LC-MS (010): 290.9 ; VI l l | ; Rt = 1 .37 min.

(e) A-((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(4-(2-(4,6-dih ydroxypyrimidm-5- yl)ethoxy)phenyl)a.cetamide: This compound was synthesized from 2-(4~(2-(4,6- dihydroxypyrimidm-5-yl)ethoxy)phenyl)acetie acid and (4-chloro-2- methy3phenyl)(pheny3)methanamine hydrochloride essential3y as example 2 (f) (6mg, yield 14%), LC-MS (024): 504.0 j N 1 1 1 j : Rt = 1.50 min. l ! NMR (DMSO-d6, 400MHz): δ 1 1.93 (s, 2H), 8.88 (d, J= 8Hz, IH), 7.97 (s 1H), 7.33 (t, d, J = 8Hz, 2H), 7.22-7.28 (ni 3H), 7.16 (t, J= 8.8Hz, 4H), 7, 10 (d, J = 8.4Hz, I H), 6.86 (d, J=8.8Hz, 1H), 6.17 (d, J= 8Hz, IH), 3.93 ( J = 8Hz, 2H), 3.43 (s, 2H), 2.72(t, J = 8Hz, 2H), 2.18 (s, 3H). Example 36

N~((4-chloro-2-methylpheny3 phenyl)methyl)-2-(4-(2-(4-chloro-6-hydroxypyrimidin-5- yl)ethoxy)phenyl)acetamide

(a) ethyl 2-(4-(2-(4,6-dichloropyrimidin-5-yl)ethoxy)phenyl)acetate:

ethyl 2-(4-(2-(4,6-dihydroxypyrimidin-5-yl)ethoxy)phenyl)acetate (318mg, lmmol) was added to POCij (3mL), and the mixture was heated to reflux for 1 h. The excess POCI ₃ was then evaporated under reduced pressure and the residue was poured into water, neutralized with NaHC(¾ (cone) at 0 °C, then extracted with 0¾(¾. The combined extracts were dried over Na ₂ S€) ₄ , and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to give the title commpound as yellow oil (124mg, yield 35%). LC-MS (024): 355.0 j VI · i 1 1 : Rt - 1.71 min.

(b) 2-(4-(2-(4-c oro-6-hydroxypyrimidin-5-yl)ethoxy)phenyl)acetic acid: This compound was synthesized from ethyl 2-(4-(2-(4,6-dich]oropyrimidin-5-yi)etlioxy)phenyi)acetate essentially as example 15 (d) and was used directly to the next step without further purification. LC-MS (024): 309.0 j M - i i j : Rt = 1.2 min.

(c) N-((4-ehJoro-2-methyiphi;nyl)(phen

y])ethoxy)pheny3)acetamide: This compound was synthesized from 2-(4-(2-(4-cbloro-6- hydroxypyrimidin-5-yl)ethoxy)phenyl)acetic acid and (4-chloro-2- methylphenyl)(phenyl)methanamine hydrochloride essentially as example 2 (t) (8mg, yield 24%). LC-MS (022): 522.0 [ M i l l : Rt - 1.7 min. i i NMR (DMSO-d6, 400Μ Π/): δ 12.87 (s, ! i i :·. 8.96 (d, J = 8Hz, IH), 8.19 (s IH), 7.40 (t, d, J = 7.6 Hz, 21 ! ) 7.29-7.35 (m 3H), 7.21 -7.24 (m, 4H), 7.16 (d, J = 8.4Hz, I H), 6.9 ! ( d. ./ 8.4Hz, I H), 6.24 i d. ./ 8Hz, I H), 4.13 (t, J = 8Hz, 11 1 ). 3.50 (s, 2H), 3.00 (t, J - ---- 12 Hz, 2H), 2.25 (s, 3H).

Example 37

N-((4-chloro-2-methy3phenyl)(phenyl)methyl)-2-(4-(2-(pyrimid in-5-yr)ethoxy)ph

(a) ethyl 2-(4-(

Pd/C (5mg) and triethylamine (30mg, 0.297mmo3) were added to a solution of ethyl 2-(4-(2-(4,6- dichloropyriniidin-5-yl)ethoxy)phenyl)acetate (48mg, 0.135mmol) in EtOH (2mL). The mixture was stirred under hydrogen (1 atm) for 2 h. The Pd/C was removed by filtration through a pad of Celite. Concentration of organic solvent under reduced pressure gave the title compound as a white solid (35mg), which was used directly in the next step without further purification. LC-MS (024): 287.0 i Λ t i 1 1 : R i 1.42 min

(b) 2-(4-(2-(pyrirnidin-5-y{)ethoxy)pheny{)acetic acid: This compound was synthesized from ethyl 2-(4-(2-(pyrimidin-5-yl)ethoxy)phenyl)acetate essentially as example 15 (d) and was used directly to the next step without further purification. LC-MS (024): 259.0 [M+H] ⁺ ; RT = 1.18 min

(c) N-((4-chloro-2-methylphenyl)(phenyl)methyl)~2-(4-(2-(pyrimid in-5- yl)ethoxy)phenyl)acetamide: HATU (41mg, 0.1 Immol) was added to a solution of 2-(4-(2- (pyrimidin-5-yl)ethoxy)phenyl)acetic acid (28mg, 0, 1 lmmol) in DMF (2 mL) and the mixture was stirred at ri for 40min. Then (4-chloro-2-methylphenyl)(phenyl)methanamine hydrochloride (40 mg, 0.09mmol) was added, and the resulting mixture was stirred at rt for 3 h. The reaction mixture was poured into water and extracted with EtOAc (l OmL x 3). The combined extracts were washed with water, and brine, and then dried over Na ₂ SC)4. After removal of solvent under reduced pressure, the residue was used purified by prep-TLC to give the title compound as a white solid (16mg, yield 31%). LC-MS (024): 472.0 [M+H] ⁺ ; RT = 1.7 min. Ή NMR (DMSO-d6, 400MHz): δ 9.12 (s, 1H), 8.95 (d, J = 8Hz, 1 H), 8.84 (s 2H), 7.39 ( d, J = 7.6 Hz, 2H), 7.28-7.34 (m 3H), 7.21 -7.23 (m, 4H), 7.15 (d, J = 8 Hz, i l l s. 6.91 \. 8.8 Hz, 1H), (·.. > .·.( d. ./ 8.4Hz, IE), 4.26 (t, 6.41 I /.. 2H), 3.49 (s, 2H), 3. 1 ! ·! !. ./ 6.4 Hz, 2H), 2.24 (s, 3H).

Example 38

V-((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(2-(((2-methyl pyridm-3-yI)m

-yl)acetamide

(a) 2-Methymicotinaldehyde:

(2-Methyl-pyridin-3-yl)-methanol (1.0 g, 8.13 mmol) was dissolved in dry CHyCli (30 mL) and argon gas was purged for 1 0 min. Dess-Martin periodinane (4.5 g, 10.5 mmol) was added to the reaction mixture at 0 °C, The reaction mixture was allowed to come to rt and further stirred for 2 h.

The reaction mixture was quenched with saturated NaIiC0 ₃ solution. The organic product was extracted with EtOAc, The combined organic extracts were washed with saturated sodium thiosulfate solution, water and brine solution. Solvent was removed under reduced pressure to the crude 2-methylnicotinaldehyde (600 mg, crude) .which was used as such for the next step.

TLC: 100% EtOAc, 0.4. Ή NMR (300 MHz, CDCL) δ 10.33 (s, IH), 8.70 - 8.68 (dd, ./ 4.8 Hz, 1.8 Hz, 1 H), 8.12 - 8.09 (dd, J = 7.7 Hz, 1.8 Hz, IH), 7.36 - 7.32 (dd, J = 7.7 Hz, 4.8 Hz, I I I ). 2.89 (s, 3H)

(b) methyl 2-(2-(((2-m azol-4-yl)acetate:

Methyl-2-amino-4-thiazolacetate (420 mg, 2.5 mmol) was added to a solution of 2- methylnicotinaldehyde (300 mg, 2.5 mmol) in 1 ,2-dichloroethane (5 mL), followed by sodium triacetoxyborohydride (1.0 g, 5.0 mmol) at 0 . The reaction mixture was allowed to come to rt and stirred for 10 h. The reaction mixture was quenched with 10% aqueous NaHCO, solution and extracted with EtOAc. The combined extracts were dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column

chromatography (silica gel 60- 120 mesh, eluent 5- 10% MeOH in CH ₂ CI ₂ ) to afford methyl 2-(2~ (((2-methylpyridin-3-yl)methyl)amino)thiazol-4-yl)acetate (80 mg) along with (2-meihyl-pyridin- 3-yi)-methanol as mixture. TLC: 100% EtOAc, R _t - = 0.3. LC-MS purity >40%

(c) 2-(2-(((2-Methylpyridin-3-yl)raethyl)amino)lhiazo{-4-yl)acet ic acid: This compound was synthesized from methyl 2-(2-(((2-methylpyridin-3-y])methyl)amino)thiazol-4-yl)aceta te essentially as example 15 (d) and was used directly to the next step without turiher purification. TLC: 100% EtOAc, R _f = 0.2. LC-MS purity >42%

(d) N-((4-cUoro-2-methylphenyl)(phenyl)methyl)-2-(2-(((2-methylp yridin-3- yl)methyl)amino)thiazol-4-yl)acetamide: This compound was synthesized from 2-(2-(((2- methylpyridin-3-yl)methyl)ammo)thiazol-4-yl)acetic acid and (4-chloro-2- methylphenyl)(phenyl)niethanamine essentially as example 7 (b) (25 mg, yield 15%). TLC: petroleum ether: EtOAc 3 :7, R _f = 0.3. LC-MS purity >98%, HPLC purity >97%. ^¾ H NMR (400 MHz, MeOD) δ 8.31 (m, I H), 7.73 - 7.71 (d, J = 7.5 Hz, IH), 7.33 - 7.26 (m, 2H), 7.22 - 7.1 1 (m, 61 ! ). 7.07 - 7.05 fm, IH), 6.36 (br s, I H), 6.28 (s, IH), 4.46 (s, 21 1 ;·. 3.51 (s, 2H), 2.51 (s, 3H), 2.22 (s, 3H). Example 39

N-((4-chloro-2-methylplienyi)(phe^^

yl)methoxy)phenyl)acetamide

(a) N-((4-chloro-2-methylpheny3)(phenyl)methyi)-2-(4-methoxy-3- methylphenyliacetamide:

This compound was synthesized from 2-(4-methoxy-3-methylphenyl)acetic acid and (4-chloro-2- methylphenyl)(phenyl)methanamine essentially as described in example 2 (i) and was used in the next step without any further purification. LC-MS: 394 [M H] ^"h ; Rt : 1 ,818 min.

(b) N-((4-ch3.oro-2-methylplieny3)(phenyl)methyl)-2-(4-hydroxy-3 - met3iylphenyl)acetamide:

BBr ₃ (76 mg, 0.31 mmol) was added to a solution of A'-((4-chloro-2-methyj.phenyl)(phenyl)methy]) -2-(4-methoxy-3-methy3phenyl)acetamide (100 mg, 0.25 mmol) in 10 ml. CILC^ under N ₂ atmosphere at -78 °C. The mixture was allowed to warm up to rt overnight. The solvent was evaporated under reduced pressure to get N-((4-chIoro-2-methylphenyl)(phenyl)methyl)-2-(4- 3iydroxy-3-methylphenyl)acetamide (86 mg, yield 89%) as yellow solid, which was used in the next step without any further purification. LC-MS: 380 i \i ! i i : Rt : 1.658 min.

(c) A-((4-chloro-2-methylphenyl)(phenyl)methyl)-2-(3-methyl-4-(( 2-methylpyridin-3- yl)methoxy)phenyl)acetamide: 3-(Chloromethyl)~2-methylpyridine (49 mg, 0,27 mmol) and CO. (91mg, 0.66 mmol) were added to a solution of N-((4-chloro-2- methy3phenyl)(pheny3)met3iyl)-2-(4-hydroxy-3-met3iylp3ieny3) acetamide (86 mg, 0.22 mmol) in 20 mL of CH ₃ CN. The resulting mixture was stirred at 50 °C overnight. After cooling to rt, the solid was filtered off. The organic solvent was removed under reduced pressure and the residue was purified by Pre-TLC (Petroleum ether/EtOAc-3/2) to obtain N-((4-chioro-2- methylphenyl)(pheiiyl)methyi)-2-(3-methyl-4-((2-methylpyridi n-3-

(60 mg, yield: 54%) as white solid. LC-MS: 485 j \1 i f ] : Rt: 1.510 min. ¾ NMR (DMSO-d6, 400MHz): δ 8.91 (d, J = 8.0 Hz, 1 H), 8.41 -8.40 (m, 1H), 7.80-7.78 (m, 1 H), 7.35-6.98 (m, 12H), 6.1 8 (d, J = 8.5 Hz, i 1 1 !. 5.1 1 (s, 21 n. 3.42 (s, 2H), 2.51 (s, 3H), 2.19 (s, M l ). 2.15 (s, 3H).

Example 40

N-(l-(4-c orophenyl)-2-methylpro

(a) i -(4-chlorophenyl)-2-methyipropan- i -amine: i-PrMgBr (2N, 3mL, 6mmol) was added drop- wise to a solution of 4-chlorobenzonitrile (680mg, 5 mmol) in THF (dry, 5 mL) at r.t under argon atmosphere. After ihe addition, the mixture was stirred at rt overnight. Meihanoi (5mL) was then added, followed by aBH ₄ (2.22mg, 6mmoi). After stirring for additional 30 min, the mixture was quenched with water, and then extracted with EtOAc. The combined organic layers were extracted with HC1 ( IN). The pH value of aqueous phase was adjusted the pH to 9-10 with NaOH ( IN), then extracted with EtOAc again. The combined organic layers were washed with brine, and dried over Ma ₂ S04. A fter removal of the solvent, the residue was solidified by using HC1/Et ₂ 0. T he solid was collected by filtration to give the titled compound as a yellow solid (200mg, yield 18%). LC-MS: m/z = 182 , av. l l )

(b) N-(l -(4-chlorophenyl)-2~methylpropyl)-2-(4-((2-inethylpyridin-3- yi)methoxy)phenyl)acetamide: This compound was synthesized from 2-(4-((2-methylpyridin-3- yl)methoxy)pheny3)acetic acid and l -(4-chloiOphenyl)-2-methylpropan- l-amine essentially as example 15 (e) (20 mg, yield 23%). LC-MS: 423 [M+Hf . l ! NMR (DMSO, 4()0MHz): δ 8.41 - 8.39 (m, 2H), 7.77-7.74 (m, 1H), 7.35 ( l, J= 8.0Hz, 2H), 7.28 (d, J= 8.0Hz, 2H), 7.23 (dd, J= 4.8Hz, 8.0Hz, 1H), 7.16 (d, J= 8.0Hz, 2H), 6.95 (d, J = 8.8Hz, 2H), 5.09 (s, 2H), 4.51 (t, J = 8.8Hz, 1H), 3.44-3.34 (m, 21 11 1.95- 1.87 i m. 1H), 0.86 (d, J = 6.81 1/. M l ). 0.69 (s, J - 6.8Hz, 3H). Example 41

2~(4-((2-methy]p_ Tidm-3-

(a) 2-(4-((2-methylpyridin-3-yl)memoxy)ph^^

y1)acetamide: This compound was synthesized from 2-(4-((2-m.ethylpyridm-3- y3)methoxy)phenyl)acetic acid a d 4-(4-chlorophenyl)tetrahydTO-2H-pyran-4-amine essentially as described in example 2 (i) (41 mg, yield: 60%). LC-MS: 451 [M+H] ⁺ ; RT = 1.532 min. Ή MMR (DMSO-d6, 400MHz): δ 8.40-8.38 (m, 1H), 8.25 (s, 1H), 7.77-7.75 (m, 1H), 7.34-7.29 (m, 4H), 7.24-7.18 (m, 3H), 6.97 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H),3.69-3.66 (m, 2H), 3.53 (i, J= 1 1.2 Hz, 2H), 3.41 (s, 2H),2.48 (s, 3H), 2.23 ( ;!. ./ 13.2 Hz, 2H), 1.87-1 .81 (m, 2H).

Example 42

A ^r -((2,4-o^methylphenyj)(thiazol-5-yl)me†hyl)-2-(4-((2 -methylpyridin-3- y3)methoxy)phenyl)acetamide

(a) (2,4-dimethylphenyl)(thiazol-5-yl)methananiine: 2-PrMgCl (3.6 mL, 7.2 mmoi, 2N solution in THF) was added to a stirred solution of 5-bromothiazole (972 mg, 6 mmoi) in THF (20 mL) at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 30 min, 2,4-dimet3iy3benzomtrile (943 mg, 7.2 mmoi) was added. The solution was further stirred for 1 h at 0 °C, then NaBFM (456mg, 12mmol) was added, followed by addition of MeOH (20 mL). The resulting mixture was allowed to stir at rt overnight, and then NH4C1 (sat.) was added. The resulting mixture was extracted with EtOAc, the combined extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column

(petroleum ether/EtOAc = 1/1 to CH ₂ Cl ₂ /MeOii = 50/1) to yield (2,4-dimethylphenyl)(thiazol-5- yljmethanamine (50 mg,yield: 5%). LC-MS (024): m/z = 202.0, [M-NH2]+. Rt - 1.17min, purit 96.5%

(b) A-((2,4-ilimethylpheny3)(tl iazol-5-yl)memyi)-2-(4-((2-memylpyridin-3- yl)methoxy)phenyl)acetamide: This compound was synthesized from 2-(4-((2-methylpyridin-3- yl)methoxy)phenyl)acetic acid and (2,4-dimethylphenyl)(thiazol-5-yl)methanamine essentially as described in example 2 (f) (12mg, Yield: 26.3%). LC-MS: m/z - 458.2 , [M+Hf . Rt=l .89min, purity 95.62%. ^] H NMR (MEOD, 400MHz): δ 8.38(m, IH), 7.88 (tn, I H), 7.76 (m, IH), 7.54 (d, J = 3.6Hz, IH), 7.28 (m, 3H), 6.98 (m, 5H), 6.57fs, IH), 5.12 (s, 2H), 3.56 (s, 3H), 2.58 (s, 3H), 2.28 (m, 3H).

Example 43

A¾5-memyipyridin-2-y

(a) N-((5-methylpyridin-2-yl)(phenyl}methyl)-2-(4-((2-methylpyri din-3- yl)methoxy)phenyl)acetainide: This compound was synthesized from 2-(4-((2-methylpyridin-3- yi)methoxy)phenyl)acetic acid and (5-methylpyridm-2-yl)(phenyl)methanamine essentially as described in example 2 (f) (26mg, Yield: 52.6%). LC-MS: m/z - 438.2, [M+Hf, Rt - 1.87min, purity 91.95%. ^! H NMR (MEOD, 400MHz): δ 8.37 (m, 2H), 7.88 (m, IB), 7.58 (m, IH), 7.21 - 7.3 l (m, 9H), 6.99 (m, 2H), 6.13 (s, IH), 5.50 (s, 2H), 3.56 (s, 2H), 3.58 (s, 2H), 2.58 (m, 3H), 2.34 (s, 3H).

Example 44

A-(l -(2,4-dimethylphenyl)-4-methylpentyl)-2-(4-(l -hydroxy-2-(2-methylpyridin-3- yl)ethyl)phenyl)acetami

(a) N-(^ -(2,4-dimethylphenyl)-4-methylpentyl)-2-(4-(2-(2-methylpyrid m-3- yi)acetyl)phenyl)acetamide: This compound was synthesized from 2-(4-(2-(2-meth.ylpyridin-3- yl)acetyl)phenyl)acetic acid and l -(2,4-dimethylphenyl)-4-methylpentan- l -amine essentially as described in example 2 (f) (48mg, Yield: 32%). LC-MS (AO 12): m/z = 457.2 , [M+Hf. Rt =

1 ,76min

(b) A'-(l -(2,4-dimethylplienyf)-4-methylpentyl)-2-(4-(l -hydroxy-2-(2-methyfpy yl)ethyl)phenyl)acetamide: This compound was synthesized from N-(l -(2,4-dimethylphenyl)-4- methylpentyl)-2-(4-(2-(2-methylpyridin-3-yl)acetyl)phenyl)ac etamide essentially as described in example 5 (a) (5 mg, yield: 1 1 %). LC-MS (A024): 459.3 [M+H] ⁺ ; RT - 1.44 min. ^l H NMR •M l :()[). 40()MHz): δ 8.21 (d. ,/ 4.8Hz, 1.2 Hz, 1 H), 7.49-7.46 (m, 1H), 7.24-7.19 (m, 4l . 7.16- 7.10 (m, 2H), 6.98-6.94 (m, 2H), 5.01 (t, 1 H), 4.87 (t, 1H), 3.48 (d. ,/ 3.2Hz, 2H), 3.07-2.98 (m, 2H), 2.41 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H) ,1.72-1 .69 (m, 2H), 1.56-1.53 (m, 1H), 1.30-1.10 (ni, 2H), 0.87 ( i. 6H).

Example 45

yl)methoxy)pbenyl)acetamide

(a) l-(3,5-dimethylpyridin-2-yl)-4-methylpentan-1 -amine: To a solution of 3,5- dimethylpicolinonitrile (792 mg, 6 mmol) in 20 niL of THF under N ₂ protection at 0°C was dropped isopentylmagnesium bromide which was freshly prepared and used immediately (0.5N in THF, 21.6 ffiL). After the addition, the mixture was allowed to warm up to rt and stirred for 2 h. Then NaBH ₄ (456mg, 12 mmol) was added followed by addition of MeOH (15 niL). After stirring for 3 h, 15mL of H ₄ Cl (sat. 15 ml.) aqueous solution was added to quench the reaction, and the mixture was extracted with EtOAc (20 niL x 4). The combined EtOAc extracts were extracted with IN HC1 (15 mLx3). The pH value of the aqueous phase was adjusted to ~- 1 1, and then EtOAc (20 mL 3) was used to extract the desired amine. The combined EtOAc extracts were dried over a ₂ S0 ₄ . Removal of solvent under reduced pressure yielded cmde l-(3,5-dimethylpyridin-2-yl)-4- methylpentan- 1 -amine (800 mg) as an amber oil, which was used directly with any further purification. LCMSA024: 207.2 (M+H ; Rt - 1.29 min ; Purity=100% (254nm).

(b) A ^L (1 -(3,5-dimethylpyridin-2-y{)-4-nietliylpentyl)-2-(4-(

yl)methoxy)phenyi)acetamide: This compound was synthesized from l-(3,5-dimethylp_yridin-2- yl)-4-methyipentan- 1 -amine and 1 2-(4-((2-methylpyridin-3-yl)methoxy)phenyl)acetic acid essentialiy as described in example 2 (f) (33.6 mg, Yield: 49.2%). LC-MS (024): 46. | M · i l | ; Rt: 1.23 min. ^! H NMR (DMSO, 400MHz): δ 8.59 (br, 1H), 8.31-8.23 (m, 2H), 7.71 -7.68 (m, 2H), 7.15 (d, J= 8.4 Hz, 2H), 6.95 (d, J - 8.4 Hz, 2H), 5.18 (s, 2H), 4.92 (t, J= 7.2 Hz, I H), 3.43 i d. ./ 13.6 Hz, IH), 3.34 i d. ./ 14 Hz, 1H), 2.64 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 1.24 (m, 2H), 1.46- 1.40 (m, IH), 1.19-0.95 (m, 2H), 0.77 (d, J= 6.8 Hz, 3H), 0.76 (d, J= 12 Hz, 3H). Example 46

2- (l -(4-(2-(((2,4-dimethylphenyl)(pheiiy])metliyl)amrao

3- yl)ethoxy)acetic acid

(a) A ^r -((2,4-dimethy3phenyl)(phenyl)methyl)-2-(4-(2-(2-Tne hylpyridin-3- yl)acetyl)phenyl)acetamide: This compound was synthesized from (2,4- dimethylphenyl)(phenyl)meihanamine and 2-(4-(2-(2-methylpyridin-3 -yl)acetyi)phenyl)acetic acid essentially as described in example 2 (f) (490mg, Yield: 35%). LC-MS (A026): mix = 463.2. , [M+H] ⁺ . Rt - 1 .98min

(b) N-((2,4-dimethylphenyl)(phenyl)methyl)-2-(4-( l -hydroxy-2-(2-methylpyridm yl)ethyl)phenyl)acetamide: This compound was synthesized from N-((2,4- diniethylphenyi)(phenyl)methyl)-2-(4-(2-(2-methy{pyTidin~3-y l)

essentially as described in example 5 (a) (500 mg, yield: 90%). LC-MS (AO 12): 465.2 [M+H] ⁺ ; RT 1.60 rnin.

(c) Ethyl 2-(l -(4-(2-(((2,4-dimethylphenyl)(phenyl)methyl)amino)-2-oxoethy l)phenyl)-2- (2-methylpyridm-3-yl)ethoxy)acetate:

Ethyl 2-bromoacetate (1 12mg, 0.67 mmol), CS2CO ₃ (241 mg, 0.74mmol), and KI (T .2mg, 0.0()7mmoi) were added to a solution of N-((2,4-d ^" irnethylphenyl)(phenyl)methyl)-2-(4-(l -hydroxy- 2-(2-niethylpyridin-3 -yl)ethyl)phenyl)a.cetamide (170mg, 0.37mmol) in MeCN (20 mL). After the addition, the mixture was heated at 65 °C overnight. The reaction was diluted with water (30 mL), and extracted with EtOAc (50 mL x 3), dried over Na ₂ SC) ₄ , and concentrated under reduced pressure. The resulting residue was purified by Pre-TLC to obtain ethyl 2-( l -(4-(2-(((2,4- dimethylpheny])(phenyl)methyi)am

yl)ethoxy)acetate (168 mg, yield: 100%). LC-MS (A024): 551 [M+H ; RT - 1.43min.

(d) 2-(l -(4-(2-(((2,4-dimethylphenyl)(phenyl)methyl)amino)-2-oxoethy l)phenyl)-2-(2- memylpyridm-3-yl)ethoxy)acetic acid: This compound was synthesized from ethyl 2-(l -(4-(2- (((2,4-dimethylph6nyl)(ph

y])ethoxy)acetate essentially as described in example 15 (d) (9 mg, yield: 8%). LC-MS (A026): 523.2 [M+H] ⁺ ; R = 1.74min. Ή NMR (DMSO, 400MHz): δ 8.87 (d, J= 8.4 Hz, 1H), 8.67 (d, J - 5.6 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.76 (t 1H), 7.33-7.16 (m, 9H), 7.00-6.98 (m, 3H), 6.18 (d, J = 8.4 Hz, 1H), 5.48 (d, J= 4.8 Hz, 1H), 4.85 (s, 2H), 3.50 (s, 2H), 3.10-3.07 (m, 2H) 2.53 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H).

Example 47

N-((4-hydi xy-2~methylphenyl)(phenyl)methyl)-2-(4~((2-methylpyridin-3- y] )niethoxy)pheny 1) ace

(a) 4-hydroxy-2-methylbenzonitrile:

Decanethiol (261mg, 1.Smmoi) and t-BuOK (T68mg, 1.5 mmol) were added to a solution of 4-methoxy-2-methylbenzonitrile (147mg, 1 mmol) in DMF (5mL). The reaction mixture was stirred at 1 10 °C for 3 h. The mixture was then diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The extracts were washed with brine (10 mL x 3), dried over Ma ₂ S0 ₄ , and concentrated under reduced pressure. The resulting residue was purified by silica gel column with (petroleum ether:EtOAc=l 0: 1 ) to provide 4-hydroxy-2-methylbenzonitrile (70mg, yield:52.6%). LC-MS (01 1): 134.70 [M+H] ^" ; Rt : 1.44 min, Purity: 80% (254 nm).

(b) 4-(amino(phenyl)methyi)-3-methylpheno{: This compound was synthesized from 4-hydroxy-2-raethylbenzonitrile and

phenylmagnesium bromide essentially as described in example 1 (a) ( 150 mg, yield: 28.8%).

LCMSA024: MS: 197 [M-NPT ; Rt = 1.1 1 min.

(c) (4-(benzyloxy)-2-methylphenyl)(phenyl)methanamine: This compound was synthesized from 4~( ^' benzyfoxy)~2-methyfbenzomtrile and phenylmagnesium bromide essentially as described in example 1 (a) (400 mg, yield:37%.). LC-MS (010): 288.7 [M-NH2] ⁺ ; Rt = 1.593 min, purity : 100% 214.

(e) N-((4-hydroxy-2-methylphenyl)(phenyl)meihy

yl)methoxy)pheny])acetamide: This compound was synthesized from 4-(amsno(phenyJ)methyl)~ 3-methylphenol and 2-(4-((2-methylpyridin-3-yl)methoxy)phenyl)acetic acid essentially as described in example 15 (e) (7mg, yield: 8%). LC-MS039: 453.3[M+H] ⁺ ; RT === 1.566 min;

Purity: 100% ( 214nm). Ή NMR (MeOD, 400MHz): δ 8.38 (d, J= 4.0Hz, 1H), 7.88 (d, J = 7.6Hz, 1H), 7.32-7.28 (in, 6H), 7.16 (d, J = 7.2Hz, 2H), 6.99 (d, J= 8.4Hz, 2H), 6.84 (d, J = 8.4Hz, 1 H), 6.63 (4 J- 2.0Hz, 1 H), 6.55 (dd, J = 8.4Hz, 2.4Hz, 1H), 6.25 (s, lH), 5.13 (s, 2H), 3.54 (s, 2H), 2.59 (s, 3H), 2.16 (s, 3H).

Example 48

2-(4-((4-chloroberizyl)oxy)phenyl)-N ^' -((4-chlorophenyl)(phenyl)methyl)acetamide

This compound was synthesized fro N-((4-chloropheny{)(phenyl)methyl)-2-(4- hydrox\^henyf)acetamide and 1 -(bromomethy!)-4-chlorobenzene essentially as described in example 12 (c) (0.025 g, 1.85%) ^l B NMR (400 MHz, DMSO) δ 8.99-9.02 (d, 1 i n. 7.45-7.48 (m, 3 H), 7.37-7.39 (d, 2 H), 7.30-7.34 (m, 2 H), 7.23-7.28 (m, 5 H), 7.16-7.19 (d, 2 H), 6.90-6.93 (d, 2 H), 6.06-6.09 (d, 1 H), 5.07 (s, 2 H), 3.46 (s, 2 H), MS (ESI+) mlz 474.1 (M - H); LCMS purity Biological Date

As stated above, the compounds according to Formula (I) are RORy modulators, and are useful in the treatment of diseases mediated by RORy. The biological activities of the compounds according to Formula 0) can be determined using any suitable assay for determining the activity of a candidate compound as a RORy modulator, as well as tissue and in vivo models.

Dual Fluorescence Energy Transfer (FRET) Assay

This assay is based on the knowledge that nuclear receptors interact with cofactors (transcription factors) in a ligand dependent manner. RORy is a typical nuclear receptor in that it has an AF2 domain in the ligand binding domain (LBD) which interacts with co-activators. The sites of interaction have been mapped to the LXXLL motifs in the co-activator SRC 1(2) sequences. Short peptide sequences containing the LXXLL motif mimic the behavior of full-length co- activator.

The assay measures ligand-mediated interaction of the co-activator peptide with the purified bacterial-expressed RORy ligand binding domain (RORy-LBD) to indirectly assess ligand binding, RORy has a basal level of interaction with the co-activator SRC 1 (2) in the absence of ligand, thus it is possible to find ligands that inhibit or enhance the RORy/SRCl(2) interaction.

Materials

Generation of RORy-LBD bacterial expression piasmid

Human RORy Ligand Binding Domain (RORy-LBD) was expressed in E.coli strain BL21(DE3) as an amino -terminal polyhistidine tagged fusion protein. DNA encoding this recombinant protein was sub-cloned into a modified pET21 expression vector (Novagen). A modified polyhistidine tag (MKKHHHHHHLVPRGS) (SEQ ID No: 1) was fused in frame to residues 263-518 of the human RORy sequence.

Protein Purification

Approximately 50 g E.coli cell pellet was resuspended in 300 mL of lysis buffer (30 mM imidazole pH 7.0 and 150 mM NaCl). Cells were lysed by sonication and cell debris was removed by centrifugation for 30 minutes at 20,000 g at 4 °C. The cleared supernatant was filtered through a 0.45 μΜ cellulose acetate membrane filter. The clarified iysate was loaded onto a column (XK-26) packed with ProBond Nickel Chelating resin (InVitrogen), pre-equiiibrated with 30 mM imidazole pH 7.0 and 150 mM NaCl. After washing to baseline absorbance with the equilibration buffer, the column was developed with a gradient from 30 to 500 mM imidazole pH 7.0. Column fractions containing the RORy-LBD protein were pooled and concentrated to a volume of 5 mL. The concentrated protein was loaded onto a Superdex 200 column pre- equilibrated with 20 mM Tris-Ci pH 7.2 and 200 mM NaCl. T he fractions containing the desired RORy-LBD protein were pooled together.

Protein Biotinylation

Purified RORy-LBD was buffer exchanged by exhaustive dialysis [3 changes of at least 20 volumes (>8000x)] against PBS [100 mM NaPhosphate, pH 8 and 150 mM aCll The concentration of RORy-LBD was approximately 30 μΜ in PBS. Five-fold molar excess of NHS- LC-Biotin (Pierce) was added in a minimal volume of PBS. This solution was incubated with occasional gentle mixing for 60 minutes at ambient rt. The modified RORy-LBD was dialyzed against 2 buffer changes - TBS pH 8.0 containing 5 mM DTT, 2 mM EDTA and 2% sucrose - each at least 20 times of the volume. The modified protein was distributed inf o aliquots, frozen on dry ice and stored at -80 °C, The biotinylated RORy-LBD was subjected to mass spectrometric analysis to reveal the extent of modification by the biotinylation reagent, in general,

approximately 95% of the protein had at least a single site of biotinylation and the overall extent of biotinylation followed a normal distribution of multiple sites ranged from one to five.

A biotinylated peptide corresponding to amino acid 676 to 700

(CPS SHS SLTERHKILHRLLQEG SPS) (SEQ ID No: 2) of the co-activator steroid receptor coactivator SRC 1(2) was generated using similar method.

j sa

Preparation of Europium labeled SRC 1(2) peptide: biotinylated SRC 1(2) solution was prepared by adding an appropriate amount of biotinylated SRC 1 (2) from the 100 μΜ stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of Europium labeled Streptavidin was then added to the biotinylated SRC 1(2) solution in a tube to give a final concentration of 10 nM. The tube was inverted gently and incubated for 15 minutes at rt. Twenty-fold excess biotin from the 10 mM stock solution was added and the tube was inverted gently and incubated for 10 minutes at rt.

Preparation of APC labeled RORy-LBD: biotinylated RORy-LBD solution was prepared by adding an appropriate amount of biotinylated RORy-LBD from the stock solution to a buffer containing 10 mM of freshly added DTT from solid to give a final concentration of 40 nM. An appropriate amount of APC labeled Streptavidin was then added to the biotinylated RORy-LBD solution in a tube to give a final concentration of 20 nM. The tube was inverted gently and incubated for 15 minutes at rt. Twenty-fold excess biotin from the 10 mM stock solution was then added and the tube was inverted gently and incubated for 10 minutes at rt.

Equal volumes of the above-described Europium labeled SRC 1 (2) peptide and the APC labeled RORy-LBD were gently mixed together to give 20 nM RORy-LBD, 10 nM APC- Strepavidin, 20 nM SRC 1(2) and 5 nM Europium- Streptavidin. The reaction mixtures were incubated for 5 minutes. Using a Thermo Corabi Multidrop 384 stacker unit, 25 μΕ of the reaction mixtures per well was added to the 384-well assay plates containing 1 jxL of test compound per well in 100% DMSO. The plates were incubated for 1 hour and then read on ViewLux in Lance mode for EU/APC.

Results

All exemplified compounds (Examples 1 -48) were tested in the dual FRET assay described above and were found to have a pIC ₅₀ between 5 and 9.