CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application Serial No. 62/599,101 filed December 15, 2017 which is incorporated herein in its entirety.

DESCRIPTION

The present invention generally relates to substituted indole ether compounds useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Provided herein are substituted indole ether compounds, compositions comprising such compounds, and methods of their use. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention that are useful for the treatment of conditions related to TER modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting the activity of TLRs m a mammal.

Toll/IL-1 receptor family members are important regulators of inflammation and host resistance. The Toll-like receptor family recognizes molecular patterns derived from infectious organisms including bacteria, fungi, parasites, and viruses (reviewed in Kawai,

T. et al., Nature Immunol, 1 1 :373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to a conserved cytoplasmic motif in the receptor termed the Toll/IL-1 receptor (TIR) domain. With the exception of TLR3, all

TLRs recruit the adaptor molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, J.E. et al Nature Rev. Immunol , 10:89-102 (2010)).

Toll-like receptors (TLRs) are a family of evolutionarily conserved,

transmembrane innate immune receptors that participate in the first-line defense. As pattern recognition receptors, the TLRs protect against foreign molecules, activated by pathogen associated molecular patterns (PAMPs), or from damaged tissue, activated by- danger associated molecular patterns (DAMPs). A total of 13 TLR family members have been identified, 10 in human, that span either the cell surface or the endosomal compartment. TLR7/8/9 are among the set that are endosomally located and respond to single-stranded RNA (TLR7and TLR8) or unmethylated single-stranded D A containing cytosine-phosphate-guanine (CpG) motifs (TLR9).

Activation of TLR7/8/9 can initiate a variety of inflammatory' responses (cytokine production, B cell activation and IgG production, Type I interferon response). In the case of autoimmune disorders, the aberrant sustained activation of TLR7/8/9 leads to worsening of disease states. Whereas overexpression of TLR7 in mice has been shown to exacerbate autoimmune disease, knockout of TLR7 in mice was found to be protective against disease in lupus-prone MRL/lpr mice. Dual knockout of TLR7 and 9 showed further enhanced protection.

As numerous conditions may benefit by treatment involving modulation of cytokines, IFN production and B cell activity, it is immediately apparent that new compounds capable of modulating TLR7 and/or TLR8 and/or TLR9 and methods of using these compounds could provide substantial therapeutic benefits to a wide variety of patients.

The present invention relates to a new class of substituted indole ether compounds found to be effective inhibitors of signaling through TLR7/8/9. These compounds are provided to be useful as pharmaceuticals with desirable stability', bioavailability, therapeutic index, and toxicity values that are important to their drugabi!ity.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (I) that are useful as inhibitors of signaling through Toll-like receptor 7, 8, or 9 and are useful for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases, or stereoisomers, N-oxides, tautomers, pharmaceutically acceptable salts, solvates or prodrugs thereof.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for inhibition of Toll-like receptor 7, 8, or 9 comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or

stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof. The present invention also provides a method for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprisin administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method of treating a disease or disorder associated with Toll-like receptor 7, 8, or 9 activity, the method comprising administering to a mammal in need thereof, at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof.

The present invention also provides processes and intermediates for making the compounds of Formula (1) including salts, solvates, and prodrugs thereof.

The present invention also provides at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for use in therapy.

The present invention also provides the use of at least one of the compounds of Formula (I) or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for the treatment of prophylaxis of Toll-like receptor 7, 8, or 9 related conditions, such as allergic disease, autoimmune diseases, inflammatory diseases, and proliferative diseases.

The compound of Formula (1) and compositions comprising the compounds of Formula (I) may be used in treating, preventing, or curing various Toll-like receptor 7, 8, or 9 related conditions. Pharmaceutical compositions comprisin these compounds are useful for treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as allergic disease, autoimmune diseases, inflammatory diseases, and proliferative diseases.

These and other features of the invention will be set forth in expanded form as the disclosure continues.

DETAILED DESCRIPTION

The first aspect of the present invention provides at least one compound of Formula (I):

N-oxide, or a salt thereof, wherein

(iv) a 9-membered heterocyclic ring selected from:

(v) lO-membered heterocyclic ring selected from:

A is -L-Re;

L is a bond, -(CRxR*)i-2-, --(C R . ,) : ( K ,C O! f ) . -(CRxRx)i- ₂ 0- -CRxRxC(O)-, -CR _X R _X C(0)NR _X (CR _X R _X )O-4-, -CR _X R _X NR _X C(())(CR _X R _X )O-4~, or

-CRxRxNRxC (0)(CRxRx)o®-;

Ri is H, Cl, -CN, Ci-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C1-3 hydroxy- fluoroalkyl, -CRv=CH ₂ , C3-6 cycloalky , -CH ₂ (C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), or tetrahydropyranyl;

each R;2 is independently halo, -CN, -OH, -NO?., Ci-4 alkyl, C1-2 fluoroalkyl, C1-2

cyanoalkyl, C1-3 hydroxy alk l, C1-3 aminoa!kyl, -0(CH2)I-20H, -(CH2)o-40(Ci-4 alkyl), C1-3 fluoroalkoxy, -(Cl ! '}; vO{( = 3 alkyl), -0(CH ₂ )I-20C(0)(CI-3 alkyl), -()(( ^' ! i’)i AlCR-,. -C(0)0(Ci 3 alkyl), -{ ! 1 ),, '( ^' (() )\R, R,. -C(0)NR _* (Ci-s hydroxy alkyl), -C(0)NRx(C2-6 alkoxy alkyl), -C(0)NRx(C3-6 cycloalkyl), -NRyRy, -NR, (C 1-3 fluoroalkyl), -NR _y (Ci-4 hydroxyalkyl), -NRxCH2(phenyl),

-NRxS(0)2(C3-6 cycloalkyl), -NRxC(0)(Ci-3 alkyl), -NR _x CH ₂ (C3-« cycloalkyl), (CH ₂ )O-2S(0)2(CI-3 alkyl), -(( l l’k C * cycloalkyl), -(Cl Hu '{phenyl ) morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpipendinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(0)(thiazolyl);

R _2a is C 1—6 alkyl, C1-3 fluoroalkyl, Ci-6 hydroxyalkyl, Ci-3 aminoalkyl, -(CH2)o-40(Ci-3 alkyl), C3-6 cycloalkyl, -(CH2)I-3C(0)NR R _X , -CH2(C3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phen l;

each ib is independently H, halo, -CN, -NRxRx, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C1-3 fluoroalkoxy, -(CH2)o-2.0(C 1-3 alkyl), -(CH ₂ )o-3C(Q)NRxRx, (CH2) 1--3 (C 3 -6 cycloalkyl), -C(0)0(Ci-3 alkyl), ~€(0)NR _x (Ci-3 alkyl),

-CRx=CRxRx, or -CR =CH(C3-6 cycloalkyl);

R2C is R2a or R _2b ;

Rad is Ria or R ₂ .b; provided that one of R ₂ .c and R ₂ .d is R _2a , and the other of R?c and R _{2d i} s R210

each Rs is independently F, Cl, -CN, C1-3 alkyl, C1-2 fluoroalkyl, or -OCH3;

b i s .

-CRXRXC(0)NR _X (CRXRX)I- ₂ CHFCR _X RXOH; or

(ii) azabicyclo|3.2.1 ]octaiiyl, azaspiro[5.5]undecanyl, azetidinyl, C3-6 cycloalkyl, diazahicyclol 2.2.1 Jheptanyl, diazaspiro|3.5 |nonanyl, imidazolyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl, or quinuclidinyl, each substituted with zero to 3 Rea; each Rea is independently F, Cl, -OH, -CN, Ci-6 alkyl, Ci-4 fluoroalkyl, Ci-e hydroxyalkyl, -(CH ₂ )I- ₂ 0(CI-3 alkyl), -NR _X R _X , -(CH ₂ )I-2NRXR _x ,

— ( C Rx ) J— 2 S ( O ) 2 ( C i -- alkyl), -(CRxRx)i-2C<0)0R _y , -(CRxRx)i-2C<0)NRxRx, -C(0)(CR _X R _X )I-2NR _X R _x , -(CR _x R _x )i-2(phenyl), oxetanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, isopropylpiperidinyl, isobut lpiperidinyl, piperaziny!, or -O(piperidinyl);

Rv is H, C i—2 alkyl, or C1-2 fluoroalkyl;

each R _x is independently H or -CHs;

each Rv is independently H or C1-6 alkyl;

n is zero, 1, or 2; and

p is zero, 1 , 2, 3, or 4.

The second aspect of the present invention provides at least one compound of Formula (1), N-oxide, or a salt thereof, wherein:

G is defined in the first aspect;

A is -L-Re;

L is a bond, -(CRxRx)i- ₂ - -(CRxRx)i- ₂ CRx(OH)- -(CRxRx)i- ₂ 0- -CRxRxC(O)- CR _X R _X C(0)NR _X (CR _X R _X )O-4-, -CR _X RXNR _X C(0)(CR _X R _X )O-4-, or

-CRXR _X NRXC(0)(CRXR _X )O-4-;

RI is H, Cl, -CN, Ci— 4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C1-3 hydroxy- fluoroalkyl, -CR _V CH ₂ , C3-6 cycloalkyl, -CH2CC3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), or tetrahydropyranyl;

each R2 is independently halo, -CN, -OH, -NO2, C1--4 alkyl, C1-2 fluoroalkyl, C1-2 cyanoalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, -0(CH2)I-20H, -(CH ₂ )o-40(Ci-4 alkyl), Ci -3 fluoroalkoxy, -(CH2)i- ₄ 0(Ci-3 alkyl), -0(CH2)i-20C(0)(Ci-3 alkyl), -OK S f 2 ) s 'N R RN. -C(0)0(C _] -3 alkyl), -(CH2)o 2C(0)NR _y R _y , -C(0)NR _X (CJ-5 hydroxyalkyl), -C(0)NRx(C2-6 alkoxyalkyl), -C(0)NR _x (C3-6 cycloalkyl), -NR _y R _y , -NR _y (Ci-3 fluoroalkyl), -NR _y (Ci-4 hydroxyalkyl), -NRxCH ₂ (phenyl),

— NRxS (0)2(03— 6 cycloalkyl), -NR _x C(0)(Ci-3 alkyl), -NRxCH ₂ (C3-6 cycloalkyl), -(CH2)o-2S(0) ₂ (Ci-3 alkyl), -(CH2)o-2(C3-6 cycloalkyl), -(CH2)o-2(phenyl), morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(0)(thiazolyl);

R¾ is Ci-e alkyl, C1-3 fluoroalkyl, Cs-e hydroxyalkyl, C1-3 aminoalkyl, -(CH ₂ )o- 0(C]-3 alkyl), C3-6 cycloalkyl, -(CH ₂ )I-3C(0)NRXR _x , -CFbtTh-e cycloalkyl), -CH ₂ (phenyl), tetrah drofuranyl, tetrahydropyranyl, or phenyl;

each R¾ is independently H, halo, -CN, -NRxRx, Ci-e alkyl, C1-3 fluoroalkyl, C1-3

hydroxyalkyl, 0,-3 fluoroalkoxy, -(CH ₂ )o- ₂ 0(Ci-3 alkyl), -(CH ₂ )o-3C(0)NRxRx, (CH ₂ )I-3(C3-6 cycloalkyl), -C(0)0(Ci-3 alkyl), -C(0)NR (CI-3 alkyl),

-CRx=CRxRx, or -CR _x =CH(C3-e cycloalkyl);

R _2.C is R _2a or R ₂ .b;

R _2d is R _2a or R2t _> ; provided that one of R¾ and M is R _2a , and the other of R _2c and R ₂ .d is R _2b ;

each Rs is independently F, Cl, -CN, C1-3 alkyl, Ci- ₂ fluoroalkyl, or -OCH3;

Re is:

(1) -CR _X R _X C(0)NRX(CR _X RX)I-30H, -CR _X R _X C(0)NR _X (CR _X RX)I- ₂ NR _X R _X , or

-CR _X RXC(0)NR _X (CRXR _X )I- ₂ CHFCR _X RXOH; or

(ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl, azetidinyl, C3-6 cyc!oa!kyl, diazabicyclo[2.2. l ]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl,

tetrahydrofuranyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyk piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zero to 3 Re _a ; each Rea is independently F, Cl, -OH, -CN, Ci-e alkyl, C1-4 fluoroalkyl, Ci-e

hydroxyalkyl, -(CH ₂ )I- ₂ 0(CI-3 alkyl), -NRxRx, -(CH ₂ )I- ₂ NRXR _x ,

-(CRXRX)I- ₂ S(0) ₂ (CI-3 alkyl), -(CRxR _* ) _l-2 C(0)NR _x Rx, -C(0)(CRxRx)i- ₂ NRxR _x , oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, isobuty Ipiperidinyl, piperazinyl, or -O(piperidinyl);

Rv is H, Ci- ₂ alkyl, or C1-2 fluoroalkyl;

each Rx is independently H or -CH ₃ ;

each R _y is independently H or Ci-e alkxd;

n is zero, l, or 2; and

p is zero, 1, 2, 3, or 4. One embodiment provides a compound of Formula (I) or a salt thereof wherein G

is: ; and A, Ri, R5, and n are defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a salt thereof

(F¾) _P

G \ /

wherein G is: or ^% — N ; and A, Ri, R ₂ , Rs, n, and p are defined m the first aspect or the second aspect.

One embodiment provides a compound of Formula (I) or a salt thereof wherein G

R:?c, R?.d, R5, Rx, n, and p are defined in the first aspect or the second aspect. Included in this embodiment are compounds in which R?.a is Ci 4 alkyl, C1-2 fluoroalkyl, C1-4 hydroxyalkyi, -(( l l·); dX i l·. C3-6 cycloalkyl, ~Ci I ·ί {ϋ)\H ,R .. -Cl HC ; .·.

cycloalkyl), -CH ₂ (phenyl), tetrahydrofuranyl, or phenyl; and each Ra is independently H, F, Cl, -CN, -NRxllx, Ci-6 alkyl, C1-2 fluoroalkyl, Ci-3 hydroxyalkyi, -(CH ₂ )O- ₂ 0(C J ₂ alkyl), -(CH ₂ )o-2C(0)NRxR _x , -(CH ₂ )i-3(cyclopropyl), -C(0)0(Ci- ₂ alkyl),

-C(0)NRX(CI-3 alkyl), -CRx=CH ₂ , or -CH==CFI(C3-6 cycloalkyl). Also included in this embodiment are compounds in which R¾ is -CFb; and each 11¾ is independently H, Cl, or -CFI3.

One embodiment provides a compound of Formula (I) or a salt thereof wherein G is a 9-membered heterocyclic ring selected from:

and A, Ri, R2, Rs, n, and p are defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (1) or a salt thereof wherein G is a lO-membered heterocyclic ring selected from:

and A, Ri, R ₂ , Rs, n, and p are defined in the first aspect or the second aspect.

One embodiment provides a compound of Formula (I), N-oxide, or a salt thereof

wherein ; (iii)

(Ί ί ( ί(»Cί 1( i i _'( ^' l ! ·( ^' {( 1 1 .K)l 1. ··( i ! ( (0}M KΊ 1 C ! ! %! ! ·. or

-Cf i C{0)M I( 1 1 C l IG( ^' ((Ί i FOI i; or (ii) azabicydo[3.2. Ijoctanyl,

azaspiro[5.5]undecanyl, azetidinyl, cyclohexyl, diazabicyclo[2.2. l]heptanyl,

diazaspiro|3.5]nonanyl, morpholinyl, octaliydrocyclopenta[cjpyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl, or quinudidiny], each substituted with zero to 2 Re _a ; each Re _a is independently F, -OH, -CH3, -CH2CH2CH3, -C(CH ₃ )2, -P RCl 1ί(Ί l·.}'. -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, ···( 1 H1Ί 1{( ^' ί ! .)01 1.

-CH ₂ CH2S(0)2CH3, -CH ₂ C(0)0H, -CH ₂ C(0)N(CH3)2, -C(0)CH ₂ N(CH3)2,

-CH ₂ (phenyl), morpholinyl, oxetanyl, tetrahydropyranyl, piperidinyl,

isopropylpipendinyl, isobutylpiperidinyl, or -O(piperidinyl); n is zero; and p is zero.

One embodiment provides a compound of Formula (I) or a salt thereof wherein R· is H, Cl, -CN, Ci— 4 alkyl, Ci-3 fluoroalkyl, C1-3 hydroxy alkyl, C1-3 hydroxy-fluoroalkyl, C3-6 cycloalkyl, -CH ₂ (C3-6 cycloalkyl), or -C(0)0(Ci-3 alkyl); and G, A, Rs, and n are defined in the first aspect or the second aspect. Included in this embodiment are compounds in which Ri is H, Cl, -CN, C1-4 alkyl, C1-2 fluoroalkyl, C1-2 hydroxyalkyl, or — C(0)0(Ci— 2 alkyl). Also included in this embodiment are compounds in which Ri is -CH2CH3 or ···( Hid U

One embodiment provides a compound of Formula (I) or a salt thereof wherein each R2 is independently F, Cl, Br, -CN, -OH, -NO2, Ci-4 alkyl, C1-2 fluoroalkyl, C1-2 cyanoalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, -OCH2OH, -(CH2)O-20(CI-4 alkyl), C1-2 fluoroalkoxy, -(CH2)I-20(CI-3 alkyl), -0(CH2)i-20C(0)(Ci- ₂ alkyl), -0(CH2)i-2NRxR _x , -C(0)0(Ci_2 alkyl), -C(0)NR _y R _y , -C(0)NRx(Ci-s hydroxyalkyl), -C(0)NRx(C _2-6 alkoxy alkyl), -C(0)NRx(C3-6 cycloalkyl), -NR _y R _y , -NR _y (Ci-3 fluoroalkyl), -NR _y (Ci-4 hydroxyalkyl), -NR _X C(0)(CI-3 alkyl), ~(CH ₂ )o-2S(0)2(C 1-3 alkyl), C3-6 cycloalkyl, phenyl, morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, or triazolyl; and A, G, Ri, Rs, R _x , R _y , n, and p are defined in the first aspect or the second aspect. Included in this embodiment are compounds in which each R2 is independently F, Cl, -CN, -OH, Ci-4 alkyl, C1-2 fluoroalkyl, Ci-2 cyanoalkyl, C1-3 hydroxyalkyl, Ci-3 aminoalkyl, -(CH ₂ )o- _2Q (Ci-4 alkyl), -NRyRy, -( CH ₂ )o- ₂ C (0)NR _V R _y , -C(0)NRx(Ci-4 hydroxyalkyl), -C(0)NRx(C _2-4 alkoxyalkyl), -C(Q)NR _x (C3-6 cycloalkyl), -(CH2)o-2S(0) ₂ (Ci-3 alkyl), -(CH2)O-I(C3-6 cycloalkyl), morpholinyl, -(CH2)o-i(phenyl), or dimethyl pyrazolyl. Also included in this embodiment are compounds in which each R2 is independently -CH3 or -OCH3.

One embodiment provides a compound of Formula (I) or a salt thereof wherein L is a bond, -(CRxRxh-?.-, -CR _* R _* C(0)-, -CRxR _* C(0)NRx(CR _* R _* )o-2-,

-CR _X R _X NR _X C(0)(CR _X R _X )O-2-, or -CRxRxNRxC(0)(CRxR _x )o-2-; and A, G, Ri, Rs, Re, Rx, and n are defined in the first aspect or the second aspect. Included in this embodiment are compounds in which L is a bond, -(CRxR _x )i-2-, -CH ₂ C(0)-, -CH2C(0)NRx(CRxRx)o-2- -CH2NR _X C(0)-, or -CH?.NRxC(0)CH2-. -Also included in this embodiment are compounds in which L is a bond, -CH2-, -CH2CH2-, -CH2C(0)~, -C¾C(0)NH-, One embodiment pro vides a compound of Formula (I) or a salt thereof wherein L is a bond; and A, G, Ri, R. _% Re, and n are defined in the first aspect or the second aspect. Included in this embodiment are compounds in R¾ is azetidinyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zero to 2 Rc, _a ; and each ea is independently F, -OH, -CFfi, -CH2CH2CH3, -C(CH3)2, -CH2CH(CH3)2, -CH2CH2CF3, -CH2CH2CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH ₂ CH(CH3)OH, Ci bi (Oi fibO! !. -CH2CH2OCH3, -M b. -N(CHJ)2, -CH2NH2, -CH2CH2NH2,

-( ^' I bb! I S{() )’( l 1 -P bOOl Ci bp. -(U»C! bMCi fib. oxetanyl,

tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, or --O(piperidinyl).

One embodiment provides a compound of Formula (I) or a salt thereof wherein L is a bond; Re is azetidinyl, cyclohexyl, imidazolyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl, or quinuclidinyl, each substituted with zero to 2 Re _a ; and each Re _{a i} s independently F, -OH, -GI F, -CH2.CH2.CH3, -CfCHsty, -Cl I ·( ^' ! 1{CH ·.) ·. -CH2CH2CF3, CH2CH2CH2CF3, -CH2CH2OH, -CH2CH2CH2OH, -CH ₂ CH(CH3)OH, -CH ₂ C(CH3) ₂ OH, -CH2CH2OCH3, -M l ··· -N(CH ₃ )?., -CH2NH2, -CH2CH2NH2,

-Cl bCl bSiObC! I -C! bCiOjOH. -Cl bCi(»\iCl fib. -C. ^' iOK/H'MCi bb.

-CH ₂ (phenyl), morpholinyl, oxetanyl, tetrahydropyranyl, piperidinyl,

isopropylpipendinyi, isobutylpiperidinyl, or -O(piperidinyi); and G, Ri, Rs, and n are defined in the first aspect or the second aspect.

One embodiment pro vides a compound of Formula (I) or a salt thereof wherein Re is -NRxRx, -CRXRXC(0)NRX(CRXRX)I- ₃ ()H, -CR*RXC(0)NR*(CRXRX)I- ₂ NR _X RX, or -CR _X R _X C(Q)NR _X (CR _X R _X )I-2CHFCR _X R _X OH; and A, G, Ri, Rs, Rx, and n are defined m the first aspect or the second aspect. Included in this embodiment are compounds in which Re is -NRxRx, -C H CiO)M !Ci bi R JtyOi 1. -Cl bC(0)M id fiCI fiC. ^' R ·,H·.0! I.

···( ^' ! I ( ^‘ { () ) N I ti l I ( I fiNRxR or -CH ₂ C(0)NHCH ₂ CHFCR _* Rx0H. Also included in this embodiment are compounds in which Re is -NH(CH ₃ ), -NfQHty,

-CH ₂ C(0)NHCH ₂ C(CH3) ₂ 0H, ( 1 l ( ^' ίO)M l( 1 W i fi( i( i fibOi f

-CH2C(0)NHCH2CH2NH2, or -CH ₂ C(0)NHCH2CHFC(CH3)20H.

One embodiment provides a compound of Formula (I) or a salt thereof wherein R is azabicyclo| 3.2.1 ]octanyl, azaspiro[5.5]undecanyl, azetidinyl, C ₃ -6 cycloalkyl, diazabicyclo[2.2. l ]heptanyl, diazaspiro[3.5]nonanyl, imidazolyl, morphohnyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, phenyl, piperazinyl, piperidinyl, pyrrolidinyl, pyridinyl, or quinuclidinyl, each substituted with zero to 3 Rea; and A, G, L, Ri, Re, Rea, and n are defined in the first aspect or the second aspect. Included in this embodiment are compounds in which Re is azabicydoj 3.2.1 joctanyl,

azaspiro[5.5]undecanyl, azetidinyl, cyclohexyl, diazabicyclo[2.2. ljheptanyl,

diazaspiro[3.5]nonanyl, morpholinyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zero to 2 Re _a ; and each Rea is independently F, -OH, Ci-4 alkyl, Ci-4 fluoroalkyl, Ci-4 hydroxyalkyl,

--{( 1 1 ·)! ·0(Ί 1 :.. -NRxRx, -(CH2)I-2NR R , -(CH2)I-2S(0) ₂ (C I-2 alkyl),

-(CH ₂ )i-2C(O)NRxRx, -C(0)CH2NRXR _X , oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidmyl, piperazinyl, or -O(piperidinyl); and Rx is defined m the first aspect. Additionally, included in this embodiment are compounds in which each Rea is independently F, -OH, -CHs, -CH2CH2CH3, -C ^' iC ^' l fib. -C. ^' i i !{(Ί F.K

-CH2CH2CF3, -CH2CH2 CH2CF3 , -CH2CH2OH, -CH2CH2CH2OH, (Ί 1 ( 1 l(( ^' l 1 ;}()! I. -CH ₂ C(CH3) ₂ 0H, -CH2CH2OCH3, -CH ₂ C(0)0H, -NHZ, -N(CH3>2, -CH2NH2, -CH2CH2NH2, -CH ₂ CH ₂ S(0)2CH3, -CH ₂ C(0)N(CH3>2, -C(0)CH ₂ N(CH3)2, oxetanyl, tetrahydropyranyl, piperidinyl, isopropyl, isobutylpiperidinyl, or -O(piperidinyl).

One embodiment provides a compound of Formula (I) or a salt thereof wherein each R-5 is independently F, Cl, -CN, C1-2 alkyl, C1--2 fluoroalkyl, or -OCH3; and A, G,

Ri, and n are defined in the first aspect or the second aspect. Included in this embodiment are compounds in which each Rs is independently F, Cl, -CN, C1-2 alkyl, or -OCH3; and n is zero or 1. Also included m this embodiment are compounds in which 11 is zero.

One embodiment provides a compound of Formula (I), N-oxide, or a salt thereof, wherein said compound is selected from 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5- (piperidin-4-yloxy)-lH-indole (1); (S)-5-(3-isopropyl-5-(piperidin-3-yloxy)-lH-indol-2- yl)-l ,3-dimethylpyridin-2(l H)-one (8); (S)-6-(3-isopropyl-5-(piperidin-3-yloxy)-lH- indol-2-yl)-8-methyl-[l ,2,4]triazolo[l,5-a]pyridine (9); 6-(3-isopropyl-5-(piperidin-4- yloxy)- lH-indol-2-yl)-8-methyl -[ 1 ,2,4]triazolo[ 1 ,5-a] pyridine (10); 5-(3-isopropyl-5- (piperidin-4-yloxy)-lH-indol-2-yl)-l ,3-dimethylpyridin-2(lH)-one (11); 3-chloro-5-(3- isopropyl-5-(piperidin-4-yloxy)-lH-indol-2-yl)-l,4-dimethylp yridin-2(lH)-one (13); 5- (3-isopropyJ-5-(piperidin-4-yloxy)-lH-indol-2-yJ)-l,3,4-trim ethylpyridin-2(lH)-one (14); 6-(3-isopropyl-5-(piperidin-4-yloxy)-lH-indol-2-yl)-7,8-dime thyl-[l,2,4]triazolo[4,3-a] pyridine (17); 6-(3-isopropyl-5-(piperidin-4-yloxy)-lH-indol-2-yl)-8-methox y-[l,2,4] triazoloj l,5-a]pyridine (20); l-(4-((2-(2,6-dime†hylpyridin-4-yl)-3-isopropyl-lH-indol-5 - yl)oxy)piperidin-l-yl)-2-methylpropan-2-ol (21); l-(4-((3-isopropyl-2-(8-methyl-[l,2,4] triazolo[l,5-a]pyridin-6-yl)-lH-indol-5-yl)oxy)piperidin-l-y l)-2-methylpropan-2-ol (22); 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-((l-methylpiperid in-4-yl)oxy)-lH-indole (29); 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-((l-isopropylpipe ridin-4-yl)oxy)-lH- indole (31); 6-(3-isopropy]-5-((l-methylpiperidin-4-yl)oxy)-lH-indol-2-y] )-8-methyl- [l,2,4]triazolo[l ,5-a]pyridine (32); (S)-5-(3-isopropyl-5-((l-methylpiperidin-3-yl)oxy)- lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (37); (S)-6-(3-isopropyl-5-((l- methylpiperidin-3-yl)oxy)-lH-indol-2-yl)-8-methyl-[l,2,4]tri azolo[l,5-a]pyridine (38); 5- (3-isopropyl-5-((l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl) oxy)-lH-indol-2-yl)-l,3- dimethylpyiidin-2(lH)-one (39); (S)-5-(3-isopropyl-5-((l-(tetrahydro-2H-pyran-4- yl)pi peri din-3 - l)oxy)-lH-indol-2-yl)-l ,3-dimethylpyridin-2(l H)-one (40); 5-(3- isopropy]-5-((l-isopropy]piperidin-4-yl)oxy)-lH-indol-2-y])- l,3,4-trimethylpyridin- 2(lH)-one (45); 3-chloro-5-(3-isopropyl-5-((l-mediylpiperidin-4-yl)oxy)-lH-i ndol-2-yl)- l,4-dimethylpyridin-2(lH)-one (46); 6-(3-isopropyl-5-((l-isopropylpiperidin-4-yl)oxy)- lH-indol-2-yl)-8-methyl-[ L2,4|iriazolo[l,5-a|pyridine (47); 5-(3-isopropyl-5-((l- isopropylpiperidin-4-yl)oxy)-lH-indol-2-yl)-l ,3,4-trimethylpyridin-2(lH)-one (48); 5-(3- isopropyl-5-((l-(oxetan-3~yl)piperidin-4-yl)oxy)-lH-indol-2~ yl)-l,3,4-triinethylpyridin- 2(lH)-one (50); 6-(3-isopropyl-5-((l-methylpiperidin-4-yl) oxy)-lH-indoI-2-yl)-7,8- dimethyl-[l,2,4]triazolo[4,3-a]pyridine (53); 6-(3-isopropyl-5-((l-(oxetan-3-yl)piperidin-

4-yl)oxy)-lH-indol-2-yl)-7,8-dimethyl-[l,2,4]triazolo[4,3 -a]pyridine (56); 6-(3-isopropyS-

5-((l-isopropylpiperidin-4-yl)oxy)-lH-indol-2-yl)-7,8-dim ethyl-[l,2,4]triazolo [4,3- aipyridine (57); 6-(3-isopropyJ-5-((l-propyJpiperidin-4-yl)oxy)-lH-indol-2-yJ )-7,8- dimethyl-[l ,2,4]triazolo[4,3-a]pyridine (63); 4-((3-isopropyl-2-(8-methyl-[l ,2,4]triazolo

[1 ,5-a]pyridin-6-yl)-lH-indol-5-yl)oxy)-N,N-dimethylcyclohexan -l -amine (64); 6-(3~ isopropyl-5-((l-methylpiperidin-4-yl)oxy)-lH-indol-2-yl)-8-m ethoxy-[l ,2,4]triazolo[ l,5- a] pyridine (65); 6-(3-isopropyl-5-((l-isopropylpiperidin-4-yl)oxy)-lH-indol-2 -yl)-8- methoxy-[],2,4]triazolo[L5-a]pyridine (66); 6-(3-isopropyl-5-((l-propylpiperidin-4- yl)oxy)-lH-mdol-2-yl)~8-methoxy-[L2,4]triazolo[l,5-a]pyridin e (67); 6-(3-isopropyl-5- ((l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)-lH-indol-2 -yl)-8-methyJ-[ l,2,4] triazolo[l,5-a]pyridine (68); l-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5- yl)oxy)piperidin-l -yl) propan-2-ol (69); 2-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl- lH-indol-5-yl)oxy)piperidin-l-yl) ethan-l-ol (70); 3-(4-((2-(2,6-dimethylpyridin-4-yl)-3- isopropyl-lH-indoI-5-yl)oxy)piperidin-l-yl)propan-l-ol (72); 2-(2,6-dimethylpyridin-4- yl)-3-isopropyl-5-((l-(2-methoxyethyl)piperidin-4-yl)oxy)-lH -indole (75); 5-(5-((l- isobutylpiperidin-4-yl)oxy)-3-isopropyl-lH-indol-2-yl)-l,3-d imethylpyridin-2(lH)-one (76); 6-(5-((l -isobutylpiperidin-4-yl)oxy)-3-isopropyl-lH-indol-2-yl)-8-me thyl-

[1.2.4]triazolo[l ,5-a]pyridine (77); 5-(3-isopropyl-5-((l-(4,4,4-trifluorobutyl) piperidin-4- yl)oxy)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (78); 2-(4-((2-(2,6- diniethylpyridin~4-yl)-3-isopropyl-lH-indol-5-yl)oxy)piperid m~l-yl)-N,N- dimethylacetamide (79); (S)-2-(3-((2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3- i sopropyl- lH-indol-5-yl)oxy)piperidin- 1 -yl)-N,N-dimethylacetaroide (82); (S)-2-(3-((3- isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-lH -indol-5-yl)oxy)piperidin-l- }d)-N,N-dimethylacetamide (83); 2-(3-((2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 3-isopropyl-lH-indol-5-yl)oxy)piperidin-l -y])-N,N-dimethylacetamide (84); 2-(4-((3- isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-lH -indol-5-yl)oxy)piperidin-l - yl) N, -dimethylacetamide (85); 2-(4-((3-isopropyl-2-(l,4,5-trimethyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)oxy)piperidin-l-yl)-N,N-d imethylacetamide (87); 2- (4-((2-(7,8-dimethyl-[l ,2,4]triazolo [4,3-a]pyridin-6-yl)-3-isopropyl-lH-indol-5-yl)oxy) piperidin-l-yl)-N,N-dimethylacetamide (90); 2-(dinietliylamino)-l-(4-((2-(2,6- dimethylpyndin-4-yi)-3-isopropyi-lH-indol-5-yl)oxy)pipendin- l-yi)eihanone (95); (S)-5- (5-((l-(dimethylglycy] )piperidin-3-yl)oxy)-3-isopropyl-lH-indol-2-yl)-l,3- dimethy!pyridin-2(lH)-one (98); (S)-2-(dimethylamino)-l-(3-((3-isopropyl-2-(8-methyl-

[1.2.4]triazolo[l,5-a]pyridin-6-yl)-lH-indol-5-yl)oxy)pip eridin-l-yl)ethan-l-one (99); 5- (5-((l-(dimethylglycyl)piperidin-4-yl)oxy)-3-isopropyl-lH-in dol-2-yl)-l,3- dimethylpyridin-2(lH)-one (100); 2-(dimethylaniino)-l -(4-((3-isopropyl-2-(8-methyl-

[ 1 ,2,4] triazolo [ 1 ,5 -a]py ridin-6-y 1)- 1 H-indol-5 -y l)oxy )piperidin- 1 -y l)ethan - 1 -one ( 101); 5-

(5-((l-(dimethylgJycyl)piperidin-4-yl)oxy)-3-isopropyl-lH -indol-2-yl)-l,3,4- trirnethylpyridin-2(IH)-one (104); l -(4-((2-(7,8-dimethyl-[l,2,4]triazolo[4,3-a]pyridin-6- yl)-3-isopropyl- 1 H-indol-5-y 1 )oxy)piperidin- 1 -y!)~2-(dimethylamino)ethan~ 1 -one (105); l-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-y l)oxy)piperidin-l-yl)-2- (methylamino)ethanone (109); 2-(4-((2-(l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-3- isopropyl-lH-indol-5-yl)oxy)piperidin-l-yl)-N-methylacetamid e (112); 2-(4-((3- isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-lH -indol-5-yl)oxy)piperidin-l - yl)-N-methylacetamide (114); 2-(4-((3-isopropyl-2-(l,4,5-trimethyl-6-oxo-l,6- dihydropyridin-3-yl)-lH-indol-5-yl)oxy)piperidin-l-yl)-N-met hylacetaniide (115); 2- (3,4-dimethoxyphenyl)-3-ethyl-5-((r-isobutyl-[l,4'-bipiperid in]-4-yl)oxy)-lH-indole (118); (R)-3-isopropyl-2-(2-methylpyridin-4-yl)-5-(pyrrolidin-3-ylo xy)-lH-indole (1 7); 3-ethyl-2-(2-methylpyridin-4-yl)-5-(piperidin-4-yloxy)-lH-in dole (163); 3-isopropyl-2- (2-methy]pyridin-4-yl)-5-(piperidin-4-yloxy)- iH-indole (164); (S)-2-(3,4- dimethoxyphenyl)-3-isopropyl-5-(pyrrolidin-3-yloxy)-lH-indol e (170); 2-(3,4- dimethoxyphenyl)-3-isopropyl-5-(piperidin-4-yloxy)-lH-indole (171); 3-isopropyl-2-(2- methylpyridin-4-yl)-5-(piperidin-3-yloxy)-lH-indole (177); 3-isopropyl-5-((l- methylpiperidin-4-yl)oxy)-2-(2-methylpyridin-4-yl)-lH-indole (179); (S)-3~ethyl-2-(2- methylpyridin-4-yl)-5-(pyrroiidin-3-yloxy)-lH-indole (182); 3-isopropyl-2-(2- methylpyridin-4-yi)-5-((4-(piperidin-4-yloxy)cyclohexyl)oxy) -lH-indo!e (184-185); 3- isopropy]-5-((l-isopropy]piperidin-4-yl)oxy)-2-(2-methylpyri din-4-yl)-lH-indole (186); 3-isopropyl-2-(2-methylpyridin-4-yl)-5-((l-(3,3,3-trifluorop ropyl)piperidin-4-yl)oxy)-lH- indole (187); 3-ethyl-5-((l-isopropylpyiTolidm-3-yl)oxy)-2-(2-methyipyridi n-4-yl)-lH- indo!e (190); (R)-3-isopropyl-2-(2-methylpyridin-4-yl)-5-((l-methylpyrfoli din-3-yl)oxy)- IH-indole (193); 3-isopropyl-5-((l '-isopropyl-[l ,4'-bipiperidin]-4-yl)oxy)-2-(2- methylpyridin-4-yl)-lH-indole (195); 2-(dimethylamino)-l-(4-((3-isopropyl-2-(2- methylpyridin-4-yl)-lH-indoI-5-yl)oxy)piperidin-l-yl)ethan-l -one (196); and 2-(4-((2- (2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-yl)oxy)pip eridin-l-yl)acetic acid (197).

One embodiment provides a compound of Formula (1), N -oxide, or a salt thereof, where said compound is selected from 6-(3-isopropyl-5-(2-(pyrroIidin-l-yl)ethoxy)-lH- indol-2-yl)-8-methy]-[i,2,4]lriazolo [1,5-a] pyridine (2); 6-(5-(2-(4,4-difluoropiperidin-l - yl)ethoxy)-3-isopropyl-lH-mdoS-2-yl)-8-methyl~[l,2,4]triazol o[i,5-a]pyridme (3); 6-(5-

(2-(3-fluoropiperidin-l-yl)ethoxy)-3-isopropyl-lH-indoI-2 -yl)-8-methyl-

[l,2,4]triazolo[l ,5-a]pyridine (4); 4-(2-((3-isopropy]-2-(8-methyl-[l,2,4]triazolo [1,5- a]pyridin-6-yl)-lH-indol-5-yl)oxy)ethyl)morpholine (5); 2-(2,6-dimethylpyridin-4-yl)-3- isopropyl-5-(piperidin-4-ylmethoxy)-lH-indole (6); 5-(3-isopropyl-5-(piperidin-4- ylmethoxy)-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (7); 6-(3-isopropyl-5- (piperidin-4-ylmethoxy)- lH-indol-2-yl)-8-methyl -[ 1,2,4] triazolo[ 1 ,5-a]pyridine ( 12);

5-(3-isopropyl-5-(piperidin-4-yimethoxy)-lH-indol-2-yl)-l ,3,4-trimethylpyridin-2(lH)- one (15); 6-(3-isopropyl-5-(piperidin-4-ylmethoxy)-lH-indol-2-yl)-7,8- dimethyl-

1 1 ,2,4]t zolo[4,3-a jpyridine (16); 6-(5-(azetidin-3-ylmethoxy)-3-isopropyl-lH-indol-2- yl)-8-methyl-[l,2,4]triazolo[l,5-a]pyridine (18); 6-(5-(azetidin-3-ylmethoxy)-3- isopropyl-lH-indol-2-yl)-7,8-dimethyl-[l,2,4]triazolo[4,3-a] pyridine (19); l-(3-(((2-(2,6- dimethylpyndin-4-yi)-3-isopropyi-lH-indol-5-yl)oxy)meihyl)pi peridin-l-yi)-2- methylpropan-2-ol (23); l -(4-(((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5- yl)oxy) methyl)piperidin-l -yl)-2-methylpropan-2-ol (24); 5-(5-((l -(2 -hydroxy -2- methylpropyl)piperidin-4-yl)methoxy)-3-isopropyl-lH-indol-2- yl)-l,3-dimethylpyridin- 2(lH)-one (25); l-(3-(((3-isopropyl-2-(8-methyl-[ l,2,4]triazolo[l,5-a]pyridin-6-yl)-lH- indol-5-yl)oxy)meihyl) azetidin-i -yl)-2-methylpropan-2-ol (26); 1 -(4-(((3-isopropyl-2-(8- methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-lH-indol-5-yl)oxy )methyl)piperidin-l-yl)-2- methylpropan-2-ol (27); l-(3-(((2-(7,8-dimethyl-[ l,2,4]triazolo[4,3-a]pyridin-6-yJ)-3- isopropy]-lH-indol-5-yl)oxy)methyl) azetidin-l-yl)-2-methylpropan-2-ol (28); 2-(2,6- dimethylpyridin-4-yl)-3-isopropyl-5-((l-methylpiperidin-3-yl )methoxy)-lH-indole (30); 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-((l-methylpiperid in-4-yl)methoxy -lH-indole (33); 5-(3-isopropyl-5-((l-methylpiperidin-4-yl)methoxy)-lH-indol- 2-yl)-l,3- dimethylpyridin-2(lH)-one (34); 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-((l - isopropylpiperidin-4-yl)methoxy)-lH-indole (35); 5-(3-isopropyl-5-((l- isopropylpiperidin-4-y l)methoxy)- lH-indol-2-yl)-l ,3-dimethylpyridin-2(lH)-one (36); 6- (3-isopropyl-5-((l-methylpiperidin-4-yl)methoxy)-lH-indol-2- yl)-8-methyl-[l,2,4] triazolo[l,5-a]pyridine (41); 6-(3-isopropyl-5-((l-isopropylpiperidin-4-yl)methoxy)-lH- indol-2-yl)-8-methyl-[l,2,4]triazolo[L5-a]pyridine (42); 6-(3-isopropyl-5-((l-(oxe†an-3- yl)piperidin-4-yl)methoxy)-lH-indoi-2-yl)-8-methyl-[ 1,2,4 jtriazoloj l,5-a]pyridme (43);

6-(3-isopropyl-5-((l-(tetrahydro-2H-pyran-4-y])piperidin- 4-yl)methoxy)-lH-indol-2-yl)-

8-methyl-[l,2,4]triazolo[l,5-a]pyridine (44); 5-(3-isopropyl-5-((l-isopropylpiperidin-4- yl)methoxy)-lH-indol-2-yi)-l,3,4-trimethyipyridin-2(lH)-one (49); 5-(3-isopropyl-5-((l-

(oxetan-3-yl)piperidin-4-yl)melhoxy)-lH-indol-2-yl)- i,3,4-trimelhylpyridin-2( iH)-one

(51); 6-(3-isopropyl-5-((l-(oxetan-3-yl)piperidin-4-yl)methoxy)-lH -indol-2-yl)-7,8- dimethyl-[l,2,4]triazolo[4,3-a]pyridine (52); 6-(3-isopropyl-5-((l-methylpiperidin-4-yl) methoxy)-! H-indol-2-yl)-7,8-dimethyl-[ l,2,4]triazoIo[4,3-a]pyridine (54); 6-(3- isopropyl-5-((l-isopropylpiperidin-4-yl)methoxy)-lH-indol-2- yl)-7,8-dimethyl-[l,2,4] triazolo[4,3-a]pyridine (55); 6-(3-isopropyl-5-((l-isopropylazetidin-3-yl)methoxy)-lH- indol-2-yl)-8-methyl-[l,2,4] triazolo[l,5-a]pyridine (58); 6-(3-isopropyl-5-((l- methylazetidin-3-yl)methoxy)-lH-indol-2-yl)-8-methyl-[ l,2,4[triazolof l,5-a]pyridine

(59); 6-(3-isopropyl-5-((l-(oxetan-3-yl)azetidin-3-yl)methoxy)-lH- indol-2-yl)-8-methyl-

[l,2,4]triazolo[L5-a]pyridine (60); 6-(3-isopropyl-5-((l-methylazetidin-3-yl)methoxy)- lH-indol-2-yi)-7,8-dimethyi-[l,2,4]triazoio[4,3-a]pyridine (61); 6-(3-isopropyl-5-((l- propylpiperidin-4-yl)niethoxy)-lH-indol-2-y])-7,8-dimethyl-[ l,2,4]triazolo[4,3-a] pyridine (62); 2-(4-(((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5- yl)oxy) methyl)piperidin-l-yl)ethan-l-ol (71); 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-((l-(2- methoxy ethy l)piperidin-4-y l)methoxy )- 1 H -indole (73); 5 -(3 -isopropyl -5 -(( 1 -(2- methoxyethyl)piperidin-4-yi)methoxy)-lH-indol-2-yl)-],3-dime diylpyridin-2(lH)-one

(74); 2-(4-(((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5- yl)oxy)methyl) piperidin-l-yl)-N,N-dimethylacetamide (80); 2-(4-(((2-(l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)oxy)methyl)pi peridin-l -yl)-N,N- dimethy!acetamide (81); 2-(4-(((3-isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a]pyridi n-6- yl)-lH-indol-5-yl)oxy)methyl)pipendin-l-yl)-N,N-dimethylacet amide (86); 2-(4-(((3- isopropyl-2-(l ,4,5-tnmethyi-6-oxo-l,6-dihydropyndin-3-yl)-lH-indol-5-yl)ox y)meihyl) piperidin-l -y])-N,N-dimethylacetamide (88); 2-(4-(((2-(7,8-dimethyl-[1 ,2,4]triazolo[4,3- a]pyridin-6-yl)-3-isopropyl-lH-indol-5-yl)oxy) methyl)piperidin-l-yl)-N,N- dimethyiacetamide (89); 6-(3-isopropyl-5-((l-(2-(methylsulfonyl)ethyl)piperidin-4-yl ) methoxy )-lH-indol-2-y])-8-methyl-[ 1,2, 4] triazolo[l,5-a]pyridine (91); 6-(3-isopropyl-5-

(( 1 -(2-(methylsulfonyl)ethyl) azetidin-3-yl)methoxy)-lH-indol-2-yl)-8-methyl~[l ,2,4] triazoloj l,5-a]pyridme (92); 2-(4-((3-isopropyl-2-(8-methoxy-[l,2,4]triazolo[l,5-a] pyridm-6-yl)-lH-mdol-5-yl)oxy)piperidin-l-yi)-N,N-dimethylac etamide (93); 2-(2,6- dimethylpyridin-4-yl)-3-isopropyl-5-(piperidin-3-ylmethoxy)- lH-indole, 2 TFA (94); 2-

(dimethylamino)-l-(4-(((2-(2,6-dimethylpyridin-4-yl)-3-is opropyl-lH-indol-5-yl)oxy) methyl)piperidin-l-yl)ethan-l -one (96); 5-(5-((l-(dimethylglycjd)piperidin-4-yl) methoxy )-3-isopropyl-lH-indol-2-yl)-l,3-dimethylpyridin-2(lH)-one (97); 2-

(dimethylamino)-l-(4-(((3-isopropyl-2-(8-methyl-[l,2,4]tr iazolo[l,5-a]pyridin-6-yl)-lH- indol-5-yl)oxy)methyl)piperidin- 1 -yl)ethan- 1 -one (102); 5-(5-(( 1 -(dimethylgly cyl) piperidin-4-yl)methoxy)-3-isopropyl-lH-indol-2-yl)-l,3,4-tri methyJpyridin-2(lH)-one (103); l-(4-(((2-(7,8-dimethyl-[l ,2,4]triazo]o[4,3-a]pyridin-6-yl)-3-isopropyl-lH-indol-5- yl)oxy)methy!) piperidin-l-yl)-2-(dimethylamino)ethan-l-one (106); 2-(dimethylannno)~ l-(3-(((3-isopropyl-2-(8-methyl-[l,2,4]tiiazoio[L5-a]pyridin -6-yl)-lH-indol-5-yI)oxy) methyl)azetidin-l-yl) ethan-l-one (107); l-(3-(((2-(7,8-dimethyl-[l,2,4]triazoIo[4,3- a]pyridin-6-yl)-3-isopropyl-lH~indol~5-yl)oxy)meihyl)azeiidi n-l~yl)-2-(dimetliylamino) ethan-l-one (108); 2-(4-(((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5- yl)oxy) methy l)piperidin- 1 -y l)-N-methylacetamide ( 110); 2-(4-(((2-(l ,5-dimethy 1-6-oxo- 1,6- dihydropyridin-3-yl)-3-isopropyl-lH-indol-5-yl)oxy)niethyl)p iperidin-l -yl)-N- methylacetamide (1 1 1); 2-(4-(((3-isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a] pyridin-6- yl)-lH-indol-5-yl)oxy)methyl)pipendin-l-yl)-N-methylacetamid e (113); 2-(4-(((3- isopropyl-2-(l ,4,5-trimethyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indol-5-yl) oxy)methyl) piperidin-1 -yl)-N-mediylacetamide (116); (S)-2-((2-(3,4-dimetboxyphenyl)-3-isopropyl- lH-indol-5-yl)oxy)-N-(pyrrolidin-3-ylmethyl)acetamide (117); (S)-2-((2-(3,4- dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)-N-(pyrrolidi n-3-ylmethyl)acetamide (119); (S)-l-(3-aminopiperidin-l -yl)-2-((2-(3,4-dimethoxypheny])-3-isopropy]-lH-indol- 5-yl)oxy)ethan-l-one (120); 2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl) oxy)-N-methyl-N -((1 s,4s)-quinuclidin-3-yl)acetamide (121); 1 -(3-(2-aminoethyl) piperidin-l-yl)-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-i ndol-5-yl)oxy)ethan-l-one (122); 1 -((6R,7S)-7-amino-2-a?.aspiro| 5.5 ] undecan-2-yl)-2-((2-(3,4-dimethoxyphenyl)-3- isopropyl-lH-indol-5-yl)oxy)ethan-l-one (123); 2-((2-(3,4-dimethoxyphenyl)-3- isopropyl-lH-indol-5-yl)oxy)-N-((5S)-8-methyl-8-azabicyclo[3 .2.1]octan-2-yl)acetamide (124); 2-((2-(3,4-dirnethoxyphenyl)-3-isopropyl-lH-indo]-5-yl)oxy)- N-((! s,4s)- quinuclidin-3-yl)acetamide (125); 2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH~mdol~5- yl)oxy)-N-(piperidin-2-ylmethyl)acetamide (126); 2-((2-(3,4-dimethoxyphenyl)-3- isopropyl-lH-indol-5-yl)oxy)-N-methyl-N-(piperidin-3-yl)acet amide (127); N-(3- aminocyclohexyl)-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH- indol-5-yl)oxy) acetamide (128); 2-((2-(3 ,4~dimethoxyphenyl)-3~isopropyl- lH-indol-5-yl)oxy)- 1 - ( piperazin- 1 -y l)ethan- 1 -one ( 129); N-(( 1 R,2R)-2-ammocy clohexy l)-2-((2-(3,4- dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)acetamide (130); N-(4- aniinocyclohexyl)-2-((2-(3,4-dimeihoxyphenyl)-3-isopropyl-lH -indol-5~yl)oxy) acetamide (131); l-((lR,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-((2-(3,4- dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl) oxy)ethan-l-one (132); 2-((2-(3,4- dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)-N-((4-hydrox y-l-methylpiperi din-4- yl)methyl)acetamide (133); (S)-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl) oxy)-N-(pyrrolidin-3-yl)acetamide (134); (R)-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl- lH-indol-5-yl)oxy)-N-(pyrrolidin-3-yl)acetamide (135); 2-((2-(3,4-dimethoxyphenyl)-3- isopropyl-lH-indol-5-yl)oxy)-N-(piperidin-4-yl)acetamide (136); (R)~2-((2-(3,4~ dimethoxyphenyl)-3-isopropyl-lH~indol-5-yl)oxy)-N-(pipendin- 3-yl)acetamide (137); 2- ((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)-l -(4-(piperidin-4-yloxy) piperidin-l-yl)ethan-l-one (138); 2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5- yl)oxy)-N-(l -isopropylpiperidin~4~yl)acetamide (139); 2-((3-isopropyl-2-(2- methylpyridin-4-yl)- lH-indol-5-yl)oxy)- 1 -(2,6-diazaspiro[3.5 ]nonan-6-yl)ethan- 1 -one (140); 2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indoI-5-yl)oxy)- l-(2,7-diazaspiro [3.5]nonan-2-yl)ethan- 1 -one (141); 2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5- yl)oxy)-N-(octahydrocyclopenta[c]pyrrol-4-yl)acetamide (142); l-([2,4'-bipiperidin]-l- yl)-2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indoI-5-yl)o xy)ethan-l-one (143); 2-((3- isopropy]-2-(2-melhyipyridin-4-yl)-lH-indol-5-yi)oxy)-l-(2,8 -diazaspiro[4.5]decan-2- yl)ethan-l-one (144); l-(hexahydropyrrolo[3 _, 4-c]pyrrol-2(lH)-yl)-2-((3-isopropyl-2-(2- methylpyridin-4-yl)-lH-indol-5-yl)oxy)ethan-l-one (145); 2-((3-isopropyi-2-(2- methylpyridin-4-yl)-lH-indol-5-yl)oxy)-N-(2-(piperidin-3-yl) ethyl)acetamide (146); l-(4- (aminomethyl)piperidin-l -yl)-2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5- yl)oxy)ethan-l-one (147); 2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5-yl)oxy)- N-methyl-N-(pipendin-4-yi) acetamide (148); 2-((3-isopropyl-2-(2-methylpyridin-4-yl)- !H-indol-5-yl)oxy)- 1 -(5-methylhexahy dropyrroloj 3,4-clpyrrol-2(l H)-yl)ethan- 1 -one (149); 2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)-N -(2-hydroxy-2- methylpropyl)acetamide (150); N-(2-hydroxy-2-methylpropyl)-2-((3-isopropyl-2-(2- methylpyridin-4-yl)-lH-indol-5-yl)oxy)acetamide (151); (R)-N-(2-fluoro-3-hydroxy-3- methylbutyl)-2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-ind ol-5-yl)oxy)acetamide (152); 2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)-N -(3-hydroxy-3- methylbutyl)acetamide (153); (R)-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5- yl)oxy)-N-(2-f!uoro-3-hydroxy-3-niethylbut>4) acetamide (154); N-(3-hydroxy-3- methylbut d)-2-((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5-yl)ox y)acetamide

(155); 5-(3-isopropyl-5-(piperidin-4-yloxy)-lH-indol-2-yl)-l,3-dime thylpyridin-2(lH)- one ( 156); 2-(3,4-dimethoxyphenyl)-3-isopropyl-5-(2-(piperidin-4-yl)eth oxy)- lH-indole (158); 2-(3,4-dimethoxypheny])-3-isopropyl-5-(piperidin-4-ylmelhoxy )-lH-indole (159);

5 -(( 1 -benzy Ipiperi din-4-y l)methoxy )-2-(3 ,4-dimeth oxy pheny 1)~3 -isopropyl- lH-indol e (160); 3-ethyl-2-(2-methylpyndin-4-yl)-5-(piperidm-4-yimethoxy)-lH- indole (161); 2- (3,4-dimethoxyphenyl)-3-ethy!-5-(piperidin-4-ylmethoxy)-lH-i ndole (162); 5- (benzyloxy)~3~isopropy!~2~(2~methy!pyridin~4~y!)-!H-indoie (165); 3-isopropyl~2-(2- methylpyridin-4-yl)-5-(2-(pyrrolidin-l-yl)ethoxy)-lH-indole (166); 2-((3-isopropyl-2-(2- methylpyridin-4-yl)-lH-indol-5-yl)oxy)-N,N-dimethylethan-l -amine (167); 4-(4-(((3- isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5-yl)oxy)Tnethyl )phenyl)morpho]ine (168); 3-isopropyl-2-(2-methylpyridin-4-yl)-5-(pyridin-3-ylmethoxy) - lH-indole (169); 2-((3- isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5-yl)oxy)-N-meth ylethan-l -amine (172); 4- (2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5-yl)oxy)e thyl)morpholine (173); 3- isopropy4~2~(2-methy!pyridin~4~yl)-5~(pyridin~4~yhnethoxy)~l H-indo!e (174); 4-(2-((3- isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5-yl)oxy)ethyl)m orpholine (175); 5-((lH- imidazol-4-yl)methoxy)-3-isopropyl-2-(2-methylpyridin-4-yl)- lH-indole (176); 5-((lH- imidazol-4-y l)methoxy )-3-isopropyl-2-(2-methylpy ri din-4-y ])- lH-indol e ( 178); 3- isopropyl-2-(2-methylpyridin-4-yl)-5-(piperidin-3-ylmethoxy) -lH-indole (180); 3- isopropyl-5-((l-methylpiperidin-3-yl)methoxy)-2-(2-methylpyr idin-4-yl)-lH-indole (181); 3-ethyl-5-((l-methylpiperidin-4-yl)methoxy)-2-(2-methylpyrid in-4-yl)-lH-indole (183); 3-isopropyl-5-((l-methylpiperidin-4-yl)methoxy)-2-(2-methylp yridin-4-yl)-lH- indole (188); 3-ethyl-5-((l-methylpiperidin-4-yl)oxy)-2-(2-methylpyridin-4 -yl)-lH-indole (189); 3-isopropyl-5-((l-isopropylpiperidin-4-yd)methoxy)-2-(2-meth ylpyridin-4-yd)-lH- indole (191); 3-ethyl-2-(2-methylpyridin-4-yl)-5-(2-(pyrro]idin-l-yl)ethox y)-lH-indole (192); and 3-isopropyl-5-((l-(2-methoxyethyl)pyrrolidin-3-yl)methoxy)-2 -(2- methylpyridin-4-yl)-lH-indole (194).

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The invention encompasses all

combinations of the aspects and/or embodiments of the invention noted herein. It is understood that any and all embodiments of the present invention may he taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also to be understood that each individual element of the

embodiments is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

DEFINITIONS

The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplar} or preferred are intended to be illustrative and not limiting.

Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example,“a” and“an” may refer to either one, or one or more.

As used herein, the phrase“compounds” refers to at least one compound. For example, a compound of Formula (I) includes a compound of Formula (I) and two or more compounds of Formula (I).

Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and/or patent application publication incorporated herein by reference.

Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited m specific instances) either individually or as part of a larger group.

Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

The terms“halo” and“halogen,” as used herein, refer to F, Cl, Br, and I.

The term“cyano” refers to the group -CN

The term“ammo” refers to the group -NH _2.

The term "oxo" refers to the group =0.

The term“alkyl” as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and /-butyl), and pentyl (e.g., n-pentyd, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4- methylpentyi. When numbers appear in a subscript after the symbol“C”, the subscript defines with more specificity the number of carbon atoms that a particular group may contain. For example,“Ci-e alkyl” denotes straight and branched chain alkyl groups with one to six carbon atoms.

The term "fluoroalkyl" as used herein is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "Ci-4 fluoroalkyl" is intended to include Ci, Ci, Ch, and C ₄ alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

The term "cyanoalkyl" includes both branched and straight-chain saturated alky l groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and C1-4 cyanoalkyl.

The term "aminoa!kyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and Ci _-4 aminoalkyl.

The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and Ci- ₄ hydroxyalkyl.

The term "hydroxy -fluoroalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups and one or more fluorine atoms. For example, "hydroxy -fluoroalkyl" includes -CHFCH2OH, -CH ₂ CHFC(CH3)20H, and Ci-4 hydroxy-fluoroalkyl.

The term“cycloalkyl,” as used herein, refers to a group derived from a non- aromatic monocyclic or polycyclic hydrocarbon molecule by removal of one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol“C”, the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group may contain. For example, “C3-C6 cycloalky 1” denotes cycloalkyl groups with three to six carbon atoms.

The term“alkoxy,” as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, for example, methoxy group (-OCH3). For example,“C M alkoxy” denotes alkoxy groups with one to three carbon atoms.

The term“alkoxy alkyl,” as used herein, refers to an alkoxy group attached through its oxygen atom to an alkyl group, which is atached to the parent molecular moiety', for example, methoxy methyl group (-CH2OCH3). For example,“C2-4 alkoxyalkyi” denotes alkoxy alkyl groups with two to four carbon atoms, such as -CH2OCH3, -CH2.CH2.OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

The phrase“pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or 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, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The compounds of Formula (I) can he provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of Formula (I) as amorphous solids.

It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (Ϊ) are also within the scope of the present invention. The term“solvate” means a physical association of a compound of Formula (I) with one or more solvent molecules, whether organic or inorganic. This phy sical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal latice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary' solvates include hydrates, ethanolates, methanol ales, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

Various forms of prodrugs are well known m the art and are described m:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 1 13 - 191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M Mayer, (Wiley-VCH, 2003).

In addition, compounds of Formula (1), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formula (I) (“substantially pure”), which is then used or formulated as described herein. Such“substantially pure” compounds of Formula (1) are also contemplated herein as part of the present invention.

“Stable compound” and“stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention alone or an amount of the combination of compounds claimed or an amount of a compound of the present invention in combination with other active ingredients effective to act as an inhibitor to TLR7/8/9, or effective to treat or prevent autoimmune and/or inflammatory disease states, such as SEE, IBD, multiple sclerosis (MS), and Sjogren's syndrome, and rheumatoid arthritis.

As used herein,“treating” or“treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

The compounds of the present invention are intended to include ail isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T) Isotopes of carbon include ¹³ C and ^!4 C. Isotopically -labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically -labeled reagent m place of the non-labeled reagent otherwise employed. For example, methyl (- CHi) also includes deuterated methyl groups such as -CD3.

UTILITY

The human immune system has evolved to defend the body from micro- organisms, viruses, and parasites that can cause infection, disease or death. Complex regulator} mechanisms ensure that the various cellular components of the immune system target the foreign substances or organisms, while not causing permanent or significant damage to the individual. While the initiating events are not well understood at this time, in autoimmune disease states the immune system directs its inflammatory' response to target organs in the afflicted individual. Different autoimmune diseases are typically characterized by the predominate or initial target organ or tissues affected; such as the joint in the case of rheumatoid arthritis, the thyroid gland in the case of Hashimoto’s thyroiditis, the central nervous system in the case of multiple sclerosis, the pancreas in the case of type I diabetes, and the bowel m the case of inflammatory' bowel disease.

The compounds of the invention inhibit signaling through Toll-like receptor 7, or 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Accordingly, compounds of Formula (I) have utility in treating conditions associated with the inhibition of signaling through one or more of TLR7, TLR8, or TLR9. Such conditions include TLR7, TLR8, or TLR9 receptor associated diseases in which cytokine levels are modulated as a consequence of intracellular signaling.

As used herein, the terms "treating" or "treatment" encompass the treatment of a disease state in a mammal, particularly in a human, and include: (a) preventing or delaying the occurrence of the disease state in a mammal, in particular, when such mammal is predisposed to the disease state but has not yet been diagnosed as having it;

(b) inhibiting the disease state, i.e., arresting its development; and/or (c) achieving a full or partial reduction of the symptoms or disease state, and/or alleviating, ameliorating, lessening, or curing the disease or disorder and/or its symptoms.

In view of their activity as selective inhibitors of TLR7, TLR8, or TLR9, compounds of Formula (1) are useful in treating TLR7, TLR8, or TLR9 family receptor associated diseases, but not limited to, inflammatory diseases such as Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis; auto- inflammatory diseases including Cryopyrin-Associated Periodic Syndromes (CAPS),

TNF Receptor Associated Periodic Syndrome (TRAPS), Familial Mediterranean Fever (FMF), adult onset Still’s disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive hone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myelogenous leukemia, chronic my elogenous leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, and infantile haemangiomas; infectious diseases such as sepsis, septic shock, and Shigellosis;

neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury, oncologic and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma, HIV infection, CMV retinitis, and AIDS.

More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic b-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic

myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia m stroke heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase syndase-2, and pemphigus vulgaris. Included in this embodiment are methods of treatment in which the condition is selected from lupus including lupus nephritis and systemic lupus erythematosus (SLE), Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Also included are methods of treatment in which the condition is selected from ischemia reperfusion injury, including cerebral ischemia reperfusions injury arising from stroke and cardiac ischemia reperfusion injury arising from myocardial infarction. Another method of treatment is one in which the condition is multiple myeloma.

In one embodiment, the compounds of Formula (I) are useful in treating cancer, including Waldenstrom’s Macroglobulmemia (WM), diffuse large B cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B cell lymphoma, and primary CNS lymphoma.

In addition, the TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin

endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2), IL-1,

IL-6, IL-18, chemokines. Accordingly, additional TLR7/8/9 associated conditions include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain. The inventi ve compounds also may be used to treat veterinary viral infections, such as lenti virus infections, including, but not limited to equine infectious anemia virus; or retrovirus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.

The present invention thus provides methods for treating such conditions, comprising administering to a subject m need thereof a therapeutically -effective amount of at least one compound of Formula (I) or a salt thereof. "Therapeutically effecti ve amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to inhibit autoimmune disease or chrome inflammatory disease.

Tire methods of treating TLR7, TLR8, or TLR9 associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions.

Accordingly, "therapeutically effective amount" is also intended to include an amount of the combination of compounds claimed that is effective to inhibit TLR7, TLR8, or TLR9 and/or treat diseases associated with TLR7, TLR8, or TLR9.

Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs (CSAIDs), Interleukin- 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NS AIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®); anti-malarials such as hydroxychloroquine; cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed m combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. in the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventi v e compounds. The present invention also provides pharmaceutical compositions capable of treating TLR7/8/9 receptor-associated conditions, including IL-1 family receptor-mediated diseases as described above.

The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known m the art of pharmaceutical formulation.

Accordingly, the present invention further includes compositions comprising one or more compounds of Formula (1) and a pharmaceutically acceptable carrier.

A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the deliver} _' of biologically active agents to animals, in particular, mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purvie of those of ordinary skill in the art. These include without limitation the type and nature of the active agent being formulated; the subject to which the agent- containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variet of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable

pharmaceutically acceptable earners, and factors involved in their selection, are found in a variety _' of readily available sources such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), which is incorporated herein by reference in its entirety.

Compounds in accordance with Formula (I) can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Formula (I) compound to be delivered.

Also embraced within this invention is a class of pharmaceutical compositions comprising a compound of Formula (I) and one or more non-toxic, pharmaceutically - acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The compounds of Formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, or parenteraliy including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and mtrastemally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as erospovidone. The carrier mixture may be filled into a gelatin capsule or compressed as a tablet. The pharmaceutical composition may be administered as an oral dosage for or an infusion, for example.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may var' widely depending on the condition of the patient and other factors, but, can be determined using routine methods.

Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations. Exemplary oral preparations, include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically palatable preparations, a pharmaceutical composition in accordance with the invention can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents. A tablet can, for example, be prepared by admixing at least one compound of Formula (I) with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microerystal!ine cellulose, sodium crosscarmel!ose, com starch, and algimc acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc. Additionally, a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period. Exemplary water soluble taste masking materials, include, but are not limited to, hydroxy propy!-methylcel!ulose and hydroxypropyi-cellulose. Exemplary' time delay materials, include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

Hard gelatin capsules cars, for example, be prepared by mixing at least one compound of Formula (I) with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.

Soft gelatin capsules can, for example, be prepared by mixing at least one compound of Formula (I) with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

An aqueous suspension can be prepared, for example, by admixing at least one compound of Formula (I) with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary' excipients suitable for the manufacture of an aqueous suspension, include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcell ulose, hydroxypropylmethyl- eellu!ose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyethylene sorbitan monooleate. An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n- propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.

Oily suspensions can, for example, be prepared by suspending at least one compound of Formula (I) in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin.

An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol. In order to provide a palatable oily suspension, at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension. An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti oxidant, such as, for example, butylated hydroxy anisol, and alpha-tocopherol.

Dispersible powders and granules can, for example, be prepared by admixing at least one compound of Formula (I) with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents are as already described above. Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid. In addition, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.

An emulsion of at least one compound of Formula (I) thereof can, for example, be prepared as an oil-in-water emulsion. The oily phase of the emulsions comprising compounds of Formula (I) may be constituted from known ingredients in a known manner. The oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monooleate. Preferably , a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the ivax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium !aury! sulfate, glyceryl distearate alone or with a wax, or other materials w-ell known in the art.

The compounds of Formula (I) can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, w ^? ater, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in water microemulsions; and aqueous or oleaginous suspensions.

Formulations for parenteral administration may be m the form of aqueous or non- aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well and widely- known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

A sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of Formula (I) m an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Formula (1) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.

A sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art. For example, a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1, 3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.

Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems

(SEDDS) such as d-alpha-tocopherol poly ethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as

CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

The amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. A daily dose of about 0.001 to 100 mg/kg body weight, preferably between about 0.0025 and about 50 mg/kg body weight and most preferably between about 0.005 to 10 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.

For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered orally, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Pharmaceutical compositions of this invention comprise at least one compound of Formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternate compositions of this invention comprise a compound of the Formula (1) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (e) a package insert stating that the pharmaceutical composition can be used for the treatment of an inflammatory disorder and/or an autoimmune disease (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent to treat an inflammatory disorder and/or an autoimmune disease. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceutical composition.

This container can be for manufacturing, storing, shipping, and/or indrvidual/buik selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

Tire second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes

(e.g , cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.

Tire package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g. the United States Food and Drug

Administration). In one embodiment, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. For example, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

METHODS OF PREPARATION

The compounds of the present invention ca be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.

The compounds of this invention may be prepared using the reacti ons and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below', it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Third Edition, Wiley and Sons, 1999).

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (1), can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used m these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.

ABBREVIATIONS

Ac acetyl

ACN acetonitrile

AcOH acetic acid

anhyd. anhydrous

aq. aqueous

Bn benzyl

Bu butyl

Boc te?t-butoxy carbonyl

CV Column V olumes DCE dichloroethane

DCM dichloromethane

DMAP dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EtOAc ethyl acetate

Et ethyl

EtOH ethanol

H or He hydrogen

h, hr or hrs hour(s)

HCTU 0-(6-Chlorobenzotriazol- 1 -yl)-N,A ^T ,N .N -tetramethy luronium hexafluorophosphate

hex hexane

i iso

IP A isopropyl alcohol

HOAc acetic acid

HC1 hydrochloric acid

HPLC high pressure liquid chromatography

LC liquid chromatography

M molar

niM milhmolar

Me methyl

MeOH methanol

MHz megahertz

min. minute(s)

mins minute(s)

M ⁴¹ (M+H) ⁺

MS mass spectrometry

n or N normal

NBS n-bromosuccinimide

nm nanometer nM nanomolar

NMP N-methylpyrrohdine

Pd/C palladium on carbon

PdCb.(dppf)2 [Lr-te(dipheiiylphosphino)ferroeene]dichioropailadium(ii)

Pd(PPh3)4 tetrakis(tripheny lphosphine)palladium

Ph phenyl

PPh ₃ triphenylphosphine

Pr propyl

PSI pounds per square inch

PyBOP bromotripyrrolidinophosphonium hexafluorophosphate

Ret Time retention time

sat. saturated

SFC supercritical fluid chromatography

TEA tnethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

Analytical and Preparative HPLC conditions:

QC- ACN-AA-XB : Column: Waters Acquity UPLC BEH Cl 8, 2.1 x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 rnM ammonium acetate;

Mobile Phase B: 95:5 acetomtrile:water with 10 mM ammonium acetate; Temperature:

50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

QC-ACN-TFA-XB: Column: Waters Acquit} UPLC BEH Cl 8, 2.1 x 50 mm, 1.7 pm particles; Mobile Phase A: 5:95 acetomtrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

Method Al : L3 Acquity: Column: (LCMS) UPLC BEH CIS, 2.1 x 50 mm, 1.7 pm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range:

2%~98% B (0 to 1 min) 98%B (to 1.5 min) 98%-2% B (to 1.6 min); Gradient Time: 1.6 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 min; Detection: Detector 1 : UV at 220 nm; Detector 2: MS (ESI ⁺ ).

Method Bl : L2 Aquity(4); Column: (LCMS) IJPLC BEH Cl 8, 2.1 x 50 mm, 1 .7 pm particles; Mobile Phase: (A) water; (B) acetonitrile; Buffer: 0.05% TFA; Gradient Range: 2%-98% B (0 to 1 min) 98%B (to 1.5 mm) 98%-2% B (to 1.5 min); Gradient Time: 1.8 min; Flow Rate: 0.8 mL/min; Analysis Time: 2.2 mm; Detection: Detector 1 : UV at 220 nm; Detector 2: MS (ESI ⁺ ).

(A): Column-Ascentis Express C 18 (50 X 2.1 mm-2.7 pm) Mphase A: 10 mM

M l . ( 001 1 in water: ACN (98:02); Mphase B: 10 mM i . GOOD in water: ACN (02:98), Gradient: 0-100% B over 3 minutes, Flow ^::: 1 mL/min

(D): Kinetex XB-C18 (75 x 3 mm) 2.6 micron; Solvent A: 10 mM ammonium formate in water: acetonitrile (98:02); Mobile Phase B: 10 mM ammonium formate in water:

acetonitrile (02:98); Temperature: 50 °C; Gradient: 0-100% B over 3 minutes; Flow rate:

1.1 mL/min; Detection: UV at 220 nm.

TEMPLATE 1

tert-buty 1 5 -hy droxy -3 -isopropyl- 1 H-in dole- 1 -carboxy late

Intermediate T-1A: 5~bromo-3-isopropyl-lH-indole

A 250 mL round bottom flask was charged with triethylsilane (8.90 g, 77 mmol), trichloroacetic acid (6.25 g, 38.3 mmol) and toluene (50 mL). The solution was heated to 70 °C. A solution of 5-bromo-lH-indoIe (5.0 g, 25.5 mmol) and acetone (2.247 mL, 30.6 mmol) in toluene (30 mL) was added drop wise via an addition funnel. The resulting brown solution was heated at 70 °C for 1.5 h. The solution was cooled to 10 °C. The reaction was quenched with 10% sodium bicarbonate. The reaction mixture was diluted with diethyl ether. The organic layer was separated, dried and concentrated under vacuum to afford crude compound. The crude material was purified using silica gel chromatography eluting with 5% ethyl acetate in hexanes to give 5-bromo-3-isopropyl- IH-indole (5.5 g, 23.10 mmol 95% yield) as an oil. LC retention time 1.42 min [D] MS m/z: 238.2 (M+H). ^! H NMR (400 MHz, DMSO-de) d 1 1.03-10.90 (m, 1H), 7.75-7.64 (m, 1 1 1). 7.33-7.28 (m, 1H), 7.19-7.13 (m, 21 1 ). 3 19-3.04 (m, i l l }. 1.31-1.26 (m, 6H).

Intermediate T-1B: tert-butyl 5-bromo-3-isopropyl-lH-indole-l-carboxylate

To a stirred solution of 5-bromo-3-isopropyl-lH-indole (1.13 g, 4.75 mmol) in THF (9.49 mL) was added DMAP (0.116 g, 0.949 mmol) and triethylamine (0.661 mL, 4.75 mmol). The solution was stirred at room temperature while di-tert-butyl dicarbonate (1.102 mL, 4.75 mmol) was added over 5 minutes. The colorless solution was stirred for 3 hours at room temperature and the solution was concentrated under vacuum to give an off-yellow oily solid. The material was purified by column chromatography (40 g Silica) eluting with a gradient from 100% hexanes to 50% EtO Ac/hexanes. Like fractions were combined and concentrated under vacuum to afford tert-butyl 5-bromo-3-isopropyl-lH- indole- 1 -carboxy late (1.6 g, 4.73 mmol, 100% yield) as a solid. LC retention time 1.47mm [Al] ^l H NMR (400 MHz, DMSG-de) d 7.98 (d, J=8.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 11 1). 7.46 (dd, J 8.8. 2.0 Hz, i l l }. 7.41 (d, J=0.6 Hz, 11 1 }. 3.11 (qd, J 6.9 6.1 Hz, i l l }. 1.62 (s, 91 1 }. 1.27 (d, j 6.8 Hz, 61 1 }

Intermediate T-l C: tert-butyl 3-isopropyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaboro!an-2- y ])- !H-indol e- 1 -carboxy late

To a flask containing tert-butyl 5-bromo-3-isopropyl-lH-indole-l-carboxylate (1.6 g, 4.73 mmol) were added toluene (23.65 mL) and bis(benzomtrile)palladium(ll) chloride (0.045 g, 0.118 mmol). The flask was sealed with a rubber septum, evacuated, and degassed with N ₂ several times. The reaction mixture was stirred at room

temperature for 20 min. Triethy!amine (3.30 mL, 23.65 mmol) (previously degassed) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.030 mL, 7.10 mmol) were added. The vial was heated to 75 °C for 1 hour. The solution was cooled to room temperature, passed through a pad of celite and concentrated under vacuum. The resulting oil was purifi ed by column chromatography (40 g Silica, 100% hexanes to 50% EtQ Ac/hexanes). Like fractions were concentrated under vacuum to give a light gold oil which was purified by column chromatography (25g Silica, 100% hexanes-50% EtOAc/hexanes). Like fractions were combined and concentrated under vacuum to afford tert-butyl 3-isopropyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-l-ca rboxylate (1.2 g, 3.11 mmol, 65.8% yield) as an off-white solid. MS (M ^+l ) rn/z: 386.2, LC retention time 1.32 min [Al] ^! H NMR (400 MHz, CHLOROFORM-d) d 8 12 (d, 1=7.9 Hz, 1H), 8 05 (s, 1 1 1 ). 7.76 (dd, 1=8.3, 1.0 Hz, 1H), 7.31 (s, 1H), 3.25-3.10 (m, i l l). 1.68-1.66 (m, 9H), 1.38 (s, 12H), 1.36 (d, 1=7.0 Hz, 61 1 }. Template 1 : tert-butyl 5-hydroxy-3-isopropyl-lH-indole-l-carboxylate

To a flask containing tert-butyl 3-isopropyi-5-(4,4,5,5-tetramethyl-i,3,2- dioxaborolan-2-yl)-lH-indole-l -carboxylate (1.1 g, 2 85 mmol) were added THE (28.5 mL) and sodium hydroxide (14.27 mL, 14.27 mmol). The flask was cooled to 0 °C.

Hydrogen peroxide (0.583 mL, 5.71 mmol) was added dropwise over 10 minutes.

Stirring w¾s continued for 30 minutes. The solution w¾s acidified to pH 5 with 1 N HC1.

The solution was extracted with EtOAc (3 x 25 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under vacuum to give a clear oil. The clear oil was purified by column chromatography (25 silica, 100% hexanes-50% EtO Ac _/ hexanes), like fractions were combined and concentrated to afford tert-butyl 5- hydroxy-3-isopropyl-lH-indoie-l-carboxylate (577 mg, 2.075 mmol, 72.7% yield) as a white solid. MS (M ⁺¹ ) m/z: 220.1 (MH ert butyl). LC retention time 1.04 min [Al] ¾ NMR (400 MHz, DMSO-ds) d 9.17 (s, 1H), 7.81 (d, 1 8.8 Hz, 1H), 7.26 (s, 1H), 6.91 (d, J 2.3 Hz, 1H), 6.76 (dd, j 8.8. 2.3 Hz, i l l }. 3.06-2.91 (m, i l l). 1.60 (s, 9H), 1.26 (d, 1=6 8 Hz, 6H).

TEMPLATE 2

tert-butyl 5-((l -(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-lH-ind ole-I - carboxyl ate

To a flask containing tert-butyl 5-hydroxy-3-isopropyl-lH-indole-l-carboxylate (577 mg, 2.096 mmol) were added THE (40 mL), tert-butyl 4-hydroxypiperidine-l - carboxylate (590 mg, 2.93 mmol), and triphenylphosphine (769 mg, 2.93 mmol). The flask was cooled to 0 °C and (E)-diazene-l,2-diylbis(piperidin-l-ylmethanone) (740 mg, 2.93 mmol) was added. The flask was flushed with N ₂ and stirred for 1 hour at 0 °C. The flask was warmed to room temperature. The reaction mixture was stirred overnight. LCMS indicated the reaction was incomplete. Tert-butyl 4-hydroxypiperidine-l- carboxylate (590 mg, 2.93 mmol), triphenylphosphine (769 mg, 2.93 mmol), and (E)- diazene-l,2-diylbis(piperidin-l-ylmethanone) (740 mg, 2.93 mmol) were added to the flask. The reaction mixture was heated to 45 °C for 3 hours at which point the reaction was complete. Water (25 mL) was added and the mixture was extracted with EtOAc (3 x 25 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give an off-white foam, which was purified by column chromatography (25g Silica, 100% hexanes-50% EtO Ac/hexanes). Like fractions were combined and concentrated under vacuum to afford tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4- yl)oxy)-3-isopropyi-lH-indole-l-carboxylate (661 mg, 1.427 mmol, 68.1% yield) as a white foam. MS (M ⁺¹ ) m/z: 347.1 (MH ⁺ -2tert butyl). LC retention time 1.30 min [At]. ^! H NMR (400 MHz, CHLOROFORM-d) d 8.00 (br. s., 1H), 7.31 (br. s., 1H), 7.07 (d,

.1 2.3 Hz, 11 1 ). 6.93 (dd, .1=9.0, 2.4 Hz, I I I). 4.48 (it, j 7 1. 3 4 Hz, i l l). 3.78-3 69 (m, 2H), 3 39-3.29 (m, 2H), 3.06 (spt, 1=6.7 Hz, 1H), 2.00-1.88 (m, 2H), 1.84-1.72 (m, 2H), 1.66 (s, 9H), 1.48 (s, 9H), 1.34 (d, j 6.8 Hz, 6H).

TEMPLATE 3

tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-3-yl)methoxy)-3-isoprop yl-lH-indole-l- carboxyl ate

Template 3 was prepared according to the general preparation disclosed in

Template 2 utilizing tert-butyl 3-(hydroxymethyl)piperidine-l-carboxylate (CAS # 4606- 65-9). Isolated tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-3-yl)methoxy)-3- isopropyl-lH-indole-l-carboxylate (90 mg, 0.190 mmol, 52.4% yield). MS (M ^{l i} ) mJr. 473.3. LC retention time 1.33 ntin [AT|.

TEMPLATE 4

tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-3-isoprop yl-lH-indoJe-l - carboxylate

Template 4 was prepared according to the general preparation disclosed in Template 2 utilizing tert-butyl 4-(hy droxy methyl)piperidine- 1 -carboxyl ate (CAS# 123855-51-6). Isolated tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-3- isopropyl-lH-indole-l-carboxylate (681 mg, 1.441 mmol, 52.9% yield). MS (M ⁺ⁱ ) m/z\ 361.1 (MH ⁺ - 2 tert-butyl). LC retention time 1.32 min [Al] . Ή NMR (400 MHz, DMSO-de) 6 7.90 (d, .1 9.0 Hz, 11 1 ). 7.31 (s, 11 1 ). 7.09 (d, .1 2.3 Hz, I I I ). 6.92 (dd, .1 9.0. 2.4 Hz, I I I}. 3.98 (d, .1 I 1 .9 Hz, 21 1). 3.88 (d, .1 6.4 Hz, 2H), 3.13-3.01 (m, i l l). 2.81- 2.66 (m, 2H), 1.99-1.86 (m, 1H), 1.77 (d, J=10.6 Hz, 2.1 1 ). 1.61 (s, 9H), 1.40 (s, 9H), 1.28 (d, j 6.8 Hz, 6H), 1.23-1.09 (m, 2H).

TEMPLATE 5

(S)-tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-3-yl)oxy)-3-isopropyl-l H-indole-l- carboxylate

Template 5 was prepared according to the general preparation disclosed in Template 2 utilizing (R)-tert-butyl 3-hydroxypiperidine-l -carboxylate (CAS# 143900-43- 0). Isolated (S)-tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-3-yl)oxy)-3-isopropyl-l H- indole-l-carboxylate (200 mg, 0.436 mmol, 42.9% yield). MS (M ⁺¹ ) m/z 347.1 (MH ⁺ - 2 tert-butyl). LC retention time 1.30 min [Ai]

TEMPLATE 6

tert-butyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-3-isopropy l-lH-indole-l- carboxylate

Template 6 was prepared according to the general preparation disclosed in

Template 2 utilizing tert-butyl 3-(hy droxy methyl)azetidine- 1 -carboxylate (CAS# 142253- 56-3). Isolated tert-butyl 5-((l-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)-3-isopropy l- IH-indole-l-carboxylate (672 mg, 1.512 mmol, 83% yield). MS (M ⁺¹ ) m/z: 332.8 (MH ⁺ - 2 tert-butyl). LC retention time 1.25 min [ A 1 ] . TEMPLATE 7

tert-butyl 3-isopropyl-5-(2-morpholinoethoxy)-lH-indole-l-carboxylate

Template 7 was prepared according to the general preparation disclosed in Template 2 utilizing 2-morpholinoethanol (CAS# 622-40-2). Isolated tert-butyl 3- isopropyl-5-(2~morpho!inoeihoxy)-lH-indo!e-l~carboxy!ate (31 mg, 0.080 mmol, 27.5% yield). MS (M ^l ) m/z: 388.9. LC retention time 0.86 mm [Al]

TEMPLATE 8

2-((l-(tert-butoxycarbonyl)-2-(3,4-dimethoxyphenyl)-3-isopro pyl-lH-indol-5- yl)oxy)acetic acid

Intermediate T-8A: 5-chloro-3-isopropyl-lH-indole

In a 500 mL round bottom flask were added 5-chloro-lH-indole (5 g, 33.0 mmol), trichloroacetic acid (8.08 g, 49.5 mmol) and triethylsilane (15.80 mL, 99 mmol) in toluene (200 mL). The reaction mixture was heated at 90 °C for 16 h. The reaction mixture was cooled to room temperature and treated with ice water (100 mL) and extracted with diethyl ether (2 X 100 mL). The organic layers were combined and washed with 1.5 M potassium phosphate dibasic solution (2X 100 mL) and saturated aqueous sodium chloride solution (I X 100 mL), dried (NarSOf), filtered and

concentrated. The crude product was dissolved m a small amount of DCM and charged to a pre-packed 1SCO silica gel 120 g column and eluted over a 20 min gradient with 0%- 50% EtOAc in hexanes to afford 5-chloro-3-isopropyl-lH-indole (6 g, 31.0 mmol, 94 % yield). MS (M ⁺¹ ) m'r 194. LC retention time 1.20 min [QC-ACN-TFA-XB] ¹ H NMR (400 MHz, DMSO-de) d 10.94 (hr s, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.35 (d, J= 8.6 Hz, 1H), 7.16 (d, ./ 2. Hz, i l l ). 7.05 (dd, J= 8.6, 2.0 Hz, 1 1 1 ). 3.18-3.05 (m, i l l ). 1.29 (d, ./ 6.H Hz, 6H).

Intermediate T-8B: 2-bromo-5-chloro-3-isopropyl-lH-indole

5-chloro-3-isopropyl-lH-indole (7.79 g, 40.2 mmol) (T-1A) was dissolved in DCE (80 mL). NBS (6.80 g, 38.2 mmol) in DCE (80 mL) was added via dropping funnel over 13 minutes. LCMS analysis displays complete reaction. The reaction was quenched by addition of 10% aqueous sodium sulfite solution (25 mL). The reaction mixture was extracted with DCM. The organic extracts were combined, dried (NaaSOr), filtered and concentrated to afford 2-bromo-5-chloro-3-isopropyl-lH-indole (l0.9g, 100%) as a dark brown oil. MS (M ⁺¹ ) m'r. 272/274. LC retention time 1.08 min [Method Bl] ¾ NMR (400 MHz, CHLOROFORM-d) d 7.93 (br. s„ 1 1 1 ). 7 67-7.60 (m, 1H), 7.22-7.15 (m, 1H),

7.12-7.07 (m, i l l ). 3 20 (quin, .7=7 1 Hz, H I). 1.40 (d, .7=7 0 Hz, 61 1 )

Intermediate T-8C: 5-chioro-2-(3,4-diniethoxyphenyl)-3-isopropyl-lH-mdole

To a mixture containing 2-bromo-5-chloro-3-isopropyl-lH-indole (28 g, 103 mmol), (3,4-dimethoxyphenyl)boronic acid (18.69 g, 103 mmol) and PdCl2(dppf)-DCM adduct (4.20 g, 5.14 mmol) in THF (200 mL) was added 3 M aqueous solution of tripotassium phosphate (103 mL, 308 mmol). The reaction mixture was purged with nitrogen for 5 minutes and heated to 50 °C for 3 hr. The reaction mixture was cooled to ambient temperature and concentrated dryness. The crude material was dissolved in DCM (150 mL) and water (250 mL) was added slowly. The reaction mixture was stirred resulting in the formation of precipitate. The precipitate was filtered and washed with di ethyl ether (150 mL) to afford 5-chloro-2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indole (28g, 81% yield) as light yellow' solid. MS (M ⁺ⁱ ) m/z: 330. LC retention time 2.6 min [A]

Intermediate T-8D: tert-butyl 5-chloro-2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indole- 1-carboxylate

To a solution containing 5~chloro~2-(3,4-dimethoxyphenyl)-3-isopropyl-lH- indole (T-8C) (1.8 g, 5.46 mmol) in THF (20 mL) was added BQC-anhydride (1.521 mL, 6.55 mmol) followed by the addition of TEA (0.761 mL, 5.46 mmol) and DMAP (0.133 g, 1.092 mmol). The reaction mixture was stirred for 4 h and concentrated in vacuo. The residue was re-dissolved in DCM (10 mL), adsorbed to small amount of silica gel (20 g) and purified on ISCO silica column (24 g) using hexanes/EtOAc0%-50% over a 15 min gradient to afford tert-butyl 5-chloro-2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indole-I - carhoxylate (2.2 g, 5.12 mmol, 94 % yield). MS (M ⁺¹ ) m/z\ 430. LC retention time 1.3 min [Bl]

Intermediate T-8E: tert-butyl 2-(3, 4-dimethoxyphenyl)-3-isopropyl-5-(4, 4,5,5- tetramethy 1- 1 ,3,2-di oxaborolan-2-y 1)- 1 H-indol e~ 1 -carboxyl ate

To a mixture of tert-butyl 2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indole-l- carboxylate (2.2 g, 5.56 mmol), bis(benzonitriie)palladiurn(ii) chloride (0 053 g, 0.139 mmol), and S-Phos (0.228 g, 0.556 mmol) in a screw cap vial was added dioxane (25 mL) followed by the addition of TEA (25 mL, 179 mmol) and pinacolborane (1.614 mL, 11.13 mmol). The vial was fitted with a Teflon lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repeated three times. The needle was removed and the vial was heated at 85 °C for 4 h. The reaction mixture was concentrated in vacuo. The crude product was dissolved in a small amount of DCM, adsorbed to 5 g silica, and purified on 80 g 1SCO column silica gel cartridge which was eluted with a 20 min gradient from 0%-50% hexanes/ethylacetate to afford ten-butyl 2-(3,4-dimethoxyphenyl)- 3-isopropy 1 -5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-y 1)- IH-indol e- 1 -carboxyl ate (2.5 g, 4.79 mmol, 86 % yield). MS (M ⁺ⁱ j m/z 522 LC retention time 1.3 min [Bl]

Intermediate T-8F : ten-butyl 2-(3,4-dimethoxyphenyl)-5-hydroxy-3-isopropyl-lH-indole- 1 -carboxyl ate

To a cooled (ice bath) solution containing tert-butyl 2-(3,4-dimethoxyphenyl)-3 isopropyl-5-(4,4,5,5-tetramethyl-I ,3,2-dioxaborolan-2-yl)-1H-indole-l -carboxylate (T-

8E) (2.5 g, 4.8 mmol) in THF (25 mL) was added 1 N aqueous sodium hydroxide (24 mL, 24 mmol) followed by the dropwise addition of hydrogen peroxide (2.5 mL, 24 mmol), 30% in water. The mixture was stirred for an additional 30 min. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with 10% aqueous solution of sodium bisulfite (2X 50 mL) and saturate aqueous NaCl solution (1 X 25 mL). The organic layer was dried (TteSOr), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel 40 g ISCO column winch w¾s eluted over a 15 mm gradient with 0%-100% hexanes/ethylacetate to afford tert-butyl 2-(3,4-dimethoxyphenyl)-5-hydroxy-3-isopropyl-lH-indole-l- carboxylate (1.25 g, 3.04 mmol, 63.4 % yield). MS (M ⁺ⁱ ) mz: 412. LC retention time 1.03 min [Bl ] Ή NMR (400 MHz, CHLOROFORM-d) d 8.14 (d, = 8.9 Hz, i l l }. 7. 18 (d, ./ 2.4 Hz, I I I). 6.95-6.82 (rn, 4H), 3.96 i s. 31 1 ). 3 89 is. 31 1 ). 2 92 (quin, .7=7 1 Hz, 1 1 1). 1 32 (d, =7.1 Hz, 6H), 1.29-1.24 (m, 9H).

Intermediate T-8G: ten-butyl 2-(3,4-dimethoxyphenyl)-5-(2-ethoxy-2-oxoethoxy)-3- i sopropy 1- 1 H-indole- 1 -carboxy late

To a mixture containing tert-butyl 2-(3,4-dimethoxyphenyJ)-5-hydroxy-3- isopropyl-lH-indole-l -carboxylate (T-8F) (1 g, 2.4 mmol) and cesium carbonate (1.9 g, 4.9 mmol) in acetonitrile (20 mL) was added ethyl bromoacetate (0.40 mL, 3.6 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with diethylether (50 mL) and the solids were filtered through a pad of celite The filtrate was concentrated and the crude material was dissolved in a small amount of DCM and charged to an ISCO silica gel 24 g ISCO Column which was eluted over a 10 min gradient with 0%-50% hexanes/ethyl acetate to afford tert-butyl 2-(3,4-dimethoxyphenyl)-5-(2-ethoxy-2- oxoethoxy)-3-isopropyl-lH-indole-l-carboxylate (1.20 g, 2.412 mmol, 99 % yield). MS (M ^{+ 1} ) m/z: 498. LC retention time 1.15 min [Bl |.

Template T-8:

To a solution containing tert-butyl 2~(3,4~dimethoxyphenyl)~5~(2~ethoxy~2~ oxoethoxy)-3-isopropyl-lH-indole-l-carboxylate (L25g, 2.5 mmol), m THF/MeOH (20 mL/5 mL) was added aqueous 1 N NaOH solution (5 mL, 5.0 mmol). The reaction mixture was stirred for 4 h, then concentrated to ~ 10 mL and acidified to pH 6 using 1 N aqueous HC1. The resulting solids were filtered and washed with w¾ter and diethyl ether and dried to afford 2-((l-(tert-butoxycarbonyl)-2-(3,4-dimethoxyphenyl)-3-isopro pyl-l H- indo!-5-y!)oxy)acetic acid (1 g, 99% yield). MS (M ^H ) m/z\ 470. LC retention time 1.01 min [Bl] ¾ NMR (400 MHz, CHLOROFORM-d) d 8.22 (d, J= 9.0 Hz, 1H), 7.28-7.26 (m, 1 1 1). 6.99 (dd, .7=9.1, 2.6 Hz, i l l }. 6.96-6.93 (m, 1 1 1). 6.90-6.86 (m, i l l ). 6.83 (d, .7=1.8 Hz, 1H), 4.78 (s, 2H), 4.02-3.93 (m, 3H), 3 92-3.85 (m, 3H), 3.00-2 89 (m, 1H), 1.35-1.32 (m, 3H), 1.32-1.31 (m, 3H), 1.29-1.26 (m, 8H).

TEMPLATE 9

2-((l-(tert-butoxycarbonyl)-3-isopiOpyl-2-(2-methylpyridin-4 -yl)-lH-indol-5-yl)oxy)

acetic acid

Intermediate T-9A: tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-lH-indole-l- carboxylate

To a solution containing tert-butyl 5-hydroxy-3-isopropyl-lH-indole-l- carboxylate (T-l ) (750 mg, 2.7 mmol) in DCM (20 mL) were added TBDMS-C1 (452 mg, 3.00 mmol) and imidazole (185 mg, 2.72 mmol). The reaction mixture was stirred for 20 h and concentrated, dissolved in ethyiacetate (100 mL), washed with 0.1 M aqueous HC1 solution (100 mL), water (100 mL), and saturated aqueous NaCl solution (50 mL). The organic layer was dried with NaaSCL, filtered and concentrated in vacuo. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel 12 g ISCO column which was eluted over a 15 min gradient with 0%-lQ% hexanes/ethylacetate to afford tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-lH- indol e- 1 -carboxylate (700 mg, 1.797 mmol, 66.0 % yield). MS (M ^H ) m/z: 390. LC retention time 1.51 min [ B 1 ] .

Intermediate T-9B: tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaboroian-2-yi)-lH-indole-l-carboxylate

A solution containing tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-lH- indole- 1 -carboxylate (700 mg, 1.797 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.458 mL, 2.246 mmol) in THF (12 mL) was cooled to -78 °C under a nitrogen atmosphere and treated with LDA (2 M THF) (1.168 mL, 2.336 mmol). The reaction mixture was warmed to -30 °C over 1 h and stirred at this temperature for 1 h. The reaction mixture was treated with saturated aqueous NH4CI solution (10 mi). The ice bath w ^? as removed and the reaction mixture was diluted with ethyl acetate (100 mL) and water (20 mL). The reaction contents were poured into a separatory funnel, the aqueous layer removed, and the organic layer was washed with water (50 mi), and saturated aqueous NaCl solution (20 mL). The organic layer w¾s dried a?.S04, filtered and concentrated in vacuo to give crude material. The crude material was dissolved in a small amount of DCM and charged to an ISCO silica gel (12 g ISCO column) which was eluted over a 10 min gradient with 0%-l0% hexanes/ethylacetate to afford tert-butyl 5- ((tert-butyldimethylsilyl)oxy)-3-isopropyl-2-(4,4,5,5-tetram ethyl-l,3,2-dioxaborolan-2- y])-lH-indole-l-carboxylate (700 mg, 1.358 mmol, 76 % yield) MS (M ^+l ) m/z: 516. LC retention time 1.55 min [B 1 ] .

Intermediate T-9C: tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2-(2- niethy lpyridin-4-yl)-l H-indole- 1 -carboxylate

To a mixture containing tert-huly] 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2- (4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-indole-l-carboxylate (2.2 g, 4.3 mmol), 4-bromo-2-methylpyridine (0.633 mL, 5.3 mmol), and Xphos Pd G2 (0.101 g, 0.13 mmol) in a screw cap vial was added THF (25 mL) followed by the addition of an aqueous solution of potassium phosphate, tribasic (4.5 mL, 13.5 mmol). The vial was fitted with a Teflon lined septum cap. The system was evacuated under vacuum (via a needle from a nitrogen/vacuum manifold line) and backfilled with nitrogen gas. The procedure was repealed three times. The needle was removed and the vial was heated at 75 °C for 18h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous NaCl solution (25 mL). The organic was dried (NazSOr), filtered and concentrated. The crude product was dissolved m a small amount of DCM and charged to an ISCO silica gel 40 g ISCO column which was eluted over a 15 min gradient with 0%-50% hexanes/ethyl acetate to afford tert-butyl 5-((tert~

butyldimethylsiJyl)oxy)-3-isopropyl-2-(2-methylpyridin-4- yJ)-lH-indoJe-l-carboxylate (1.8 g, 3 74 mmol, 88% yield). MS (M ^+] ) m/z: 481. LC retention time 1.12 min [B 1 ] .

Intermediate T-9D: tert-butyl 5-hydroxy-3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indole- 1-carboxyiate

To a solution containing tert-butyl 5-((tert-butyldimethylsilyl)oxy)-3-isopropyl-2- (2-methylpyridin-4-yl)-lH-indole-l-carboxylate (400 mg, 0.83 mmol) in THF (10 mL) was added 1 M TBAF solution in THF, (1.7 mL, 1.7 mmol). The mixture was stirred for 1 h. The reaction mixture was diluted with pH 7 buffer (25 mL) and extracted with ethyl acetate (3 X 40 mL). The organic extracts were combined and washed with water (1 X 30 mL) and saturated aqueous NaCl solution, dried (Na?.S04), filtered and concentrated to afford tert-butyl 5-hydroxy-3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indole-l- carboxylate (300 mg, 0.819 mmol, 98 % yield). MS (M ⁺¹ ) m/z: no parent ion present. LC retention time 1.07 mm [Method Bl] Ή NMR (400 MHz, CHLOROFORM-d) d 8.62- 8.54 (m, I I I ). 8.22 (d, J 9.0 Hz, i l l). 7.27 (d, .7=2.6 Hz, I I I). 7.13 (s, I I I). 7.09-7.05 (m, i l l ). 7 02 (dd, 9. 1. 2.6 Hz, 11 1). 2.96-2.81 (ra, i l l ). 2 65 (s, 31 1 ). 1 34 (s, 3H), 1 33 (s, 3H), 1.29-1.21 (m, 9H).

Intermediate T-9E: tert-butyl 5-(2-ethoxy-2-oxoethoxy)-3-isopropyl-2-(2-methylpyridin- 4— y 1 )— lH-indole- 1 -carboxyl ate

To a solution containing tert-butyl 5-hydroxy -3-isopropyl-2-(2-methylpyridin-4 y])-lH-indole~ l~carboxylate (300 mg, 0.819 mmol) and cesium carbonate (533 mg, 1.637 mmol) in DMF (5 mL) was added ethyl 2-bromoacetate (0.100 mL, 0.901 mmol). The reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with aqueous 1014 LiCI solution (3 X 20 ml.) and saturated aqueous NaCl solution (1 X 10), dried (Na2SC)4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to an ISC0 silica gel (12g ISCO column) which was eluted over a 10 min gradient with Q%-50% hexanes/ethylacetate to afford tert-butyl 5-(2-ethoxy-2-oxoethoxy)-3-isopropyl- 2-(2-methy!pyridin-4-y!)-lH-indo!e~l~earboxylate (350 mg, 0.773 mmol, 94% yield). MS (M ⁺¹ ) m/z\ 453. LC retention time 0.87 mm [B 1 ] .

Template 9: To a solution containing tert-butyl 5-(2-ethoxy-2-oxoethoxy)-3-isopropyl-2-(2- methylpyridin-4-yl)-lH-indole-l -carboxylate (350 mg, 0.773 mmol) in a mixture of THE (5 mL)/methanol (1 mL) was added 1 N aqueous NaOH solution (3.87 ml , 3.87 mmol). The reaction mixture was stirred for 16 h at room temperature and heated at 75 °C for 4h. The reaction mixture was cooled to room temperature and acidified with aqueous 0.5 N HC1 to pH 5. The resulting solids were filtered, rinsed with water, and dried to afford 2- ((3-isopropyl-2-(2-methylpyridin-4-yl)-lH-indol-5-yl)oxy)ace tic acid (250 mg, 0.771 mmol, 100% yield). MS (M ⁺¹ ) m/z. 325. LC retention time 0.59 mm [Bl j. 'H NMR

(400 MHz DMSO-de.) d 11.14 (s, 1H), 8.58-8.54 (m, 1H), 7.44-7.40 (m, 1H), 7.37-7 33 (m, 1H), 7.32-7.28 (m, i l l). 7 17 (d. ./ 2.3 Hz, 11 1 ). 6.84 (dd, J=8.9, 2 4 Hz. I Hi.. 4.67 (s,

2H), 3.46-3.21 (m, 1H), 2.57 (s, 3H), 1.43 (s„ 3H), 1.41 (s„ 3H).

EXAMPLE 1

2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-(piperidin-4-ylox y)-lH-indole

Intermediate 1A: tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-2 - (4,4,5,5-tetramethyl-l,3,2-dioxaboroJan-2-yJ)-lH-indole-l-ca rboxylate

To a previously dried, N?. flushed 40 mL vial with pressure relief septum were added tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-l H-indole-l- carboxylate (661 mg, 1.441 mmol), THE (15 mL), and 2-isopropoxy -4,4,5, 5-tetramethyl- 1,3,2-dioxaborolane (282 mg, 1.513 mmol). The solution was cooled to -20 °C in a NMP/dry ice bath. LDA (2.0 M in THE) (2.162 mL, 4.32 mmol) was added dropwise over 5 minutes. After 1 hour, LCMS indicated the reaction was complete. The reaction was quenched with 1 M KHSC The mixture was warmed to room temperature. The solution was diluted with water (10 mL) and extracted with EtOAc (3 x 20 niL) The combined organics were dried over sodium sulfate, filtered and concentrated under vacuum to give a clear, light oil. The resulting oil was purified by column

chromatography (24 g Silica, 100% hexanes-50%EtO Ac/hexanes), like fractions were combined and concentrated under vacuum to afford tert-butyl 5-((l -(tert-butoxy carbonyl) piperidin-4-yl)oxy)-3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2-yl)-lH- indole-l-carboxylate (755 mg, 1.292 mmol, 90% yield) as a white foam. MS (M ^+] ) m/z: 585.3 LC retention time 1.33 min [A1 J. 'H NMR (400 MHz, DMSO-de) d 7 73 (d, J=9.0 Hz, 1 1 1). 7.17 (d, j 2.4 Hz, 11 1 ). 6 98 (dd, 1=9.0, 2.4 Hz, 1H), 4.57 (dt, 1=7 9, 4.1

Hz, 1H), 3.70-3 60 (m, 2H), 3.25-3.08 (in, 3H), 1.90 (ddd, J=9.7, 6.3, 3.0 Hz, 2H), 1.63 (s, 9H), 1.58-1.48 (m, 21 1 ). 1.41 (s, 9H), 1.33 (s, 12H), 1.31 (d, j 7. 1 Hz, 6H).

Intermediate IB: tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-(2,6- dimethylpyridin-4-yi)-3-isopropyi-lH-indole-l-carboxylate

To a 20 mL vial with pressure relief septum w-ere added tert-butyl 5-((l-(tert- butoxycarbonyl)piperidin-4-yl)oxy)-3-isopropyl-2-(4,4,5,5-te tramethyl-l,3,2- dioxahoroian-2~yl)-IH-indole-l-carboxylate (500 mg, 0.855 mmol), 4-bromo-2,6- dimethylpyridine (191 mg, 1.026 mmol), 2nd generation Xphos pre-catalyst (33.6 mg, 0.043 mmol), and THF (8554 pi). The vial was evacuated and flushed with N ₂ several times. Tripotassium phosphate (855 mΐ, 2,57 mmol) wns added. The vial wns evacuated and flushed with N2 several times. The vial was heated to 65 °C After 2 h, LCMS indicated the reaction was complete. Brine (25 mL) was added and the mixture was extracted with EtOAc (3 x 25 mL of EtOAc). The combined organics were dried over sodium sulfate, filtered, and concentrated under vacuum to give a clear, off-yellow oil. The oil was purified by column chromatography (25 g Silica, 100% hexanes- 100% EtOAc), like fractions were combined, and concentrated under vacuum to afford tert- butyl 5-((l -(tert-butoxycarbonyl)piperidin-4-yl)oxy)-2-(2,6-dimethylpyr idin-4-yl)-3- isopropyl-lH-indole-l-carboxylate, (420 mg, 0.745 mmol, 87% yield) as an off-white foam. MS (M ^+! ) m/z\ 564.3. LC retention time 0.99 min f AI]. ¾ NMR (400 MHz, CHLOROFORM-d) d 8.17 (d, J 9.0 Hz, I I I). 7.23 (d, j 2.3 Hz, 1 H), 7.00-6.95 (m, i l l ). 6.90 (s, 2H), 4.48 (tt, j 7 i . 3.4 Hz, 1H), 3.79-3 69 (m, 2H), 3.35 (ddd, J 13.4.. 7.8, 3 8 Hz, 2H), 2.93-2.81 (m, 1H), 2.57 (s, 6H), 2.00-1.90 (m, 2H), 1.85-1.75 (m, 2H), 1.48 (s, 9H), 1.32 (d, J 7. ! Hz, 61 1 ·. 1.23 is. 9H). Example 1 :

To a 20 mL vial containing tert-butyl 5-((l-(tert-butoxycarbonyl)piperidin-4-yl) oxy)-2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indole-l -carboxylate (400 mg, 0.710 mmol) Ά as added HC1 (2.0 M in dioxane) (2 mL, 4.00 mmol). The reaction mixture was stirred at room temperature for 3 hours at which time LCMS indicated the reaction was complete. The solution was concentrated under a stream of N ₂ and triturated several times with Et ₂ 0 and dried under vacuum to afford 2-(2,6-dimethylpyridin-4-yl)-3- isopropy 1-5 -(piperidin-4-y loxy )- 1 H-indole, 2 HC1 as a yellow solid. MS (M ⁺ⁱ ) rn/z:. 363.9. LC retention time 1.19 mm [QC-ACN-AA-XB] ¾ NMR (400 MHz, DMSO-de) d 1 1.61 (s, i l l ). 7.73 (s, 11 1 ). 7.38 (d, J 8.8 Hz, i l l ). 7.34 (d, J 2. 1 Hz, i l l ). 6.98 (dd, J=8.9, 2.3 Hz, 1H), 4.65 (dt, j 7.0. 3.7 Hz, 1H), 3.24 (br. s., 2H), 3.09 (br. s., 2H), 2.76

(s, 6H), 2.16-2.05 (m, 2H), 1.94-1.81 (m, 2H), 1.46 (d, j 7.0 Hz, 6H) (2 protons were obscured by H ₂ 0 peak).

EXAMPLE 2

6-(3-isopropy]-5-(2-(pyrrolidin-l -yl)ethoxy)-lH-indol-2-yl)-8-methyl-[l ,2,4]triazo]o

[l,5~a]pyridine

Intermediate 2A: tert-butyl 5-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxahoroian-2-y3)-lH-indo3e-l-carboxylate

A solution containing tert-butyl 5-chloro-3-isopropyl-lH-indole-l-carboxylate (1 g, 3.40 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.903 mL, 4.42 mmol) in dry THF (20 mL) under a nitrogen atmosphere was cooled in a dry ice/acetone bath at -78 °C and treated with LDA (2M in THF) (2.55 mL, 5.11 mmol). The mixture was stirred at -78 °C for 30 min, allowed to warm to -30 °C over 1 h, and stirred at -30 °C for 30 min. The reaction mixture was treated with 10% aqueous NHUCl solution (15 mL) and diluted with ethylacetate (100 mL). The organic layer was washed with water and saturated aqueous NaCl, dried (Na?.SQ4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and charged to an ISCO silica gel (24 g ISCO Column) which was eluted over a 15 min gradient with 0%-50% hexanes/ethylacetate to afford tert-butyl 5-chloro-3-isopropyl-2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)- lH-indole-l-carboxylate (1.2 g, 2.86 mmol, 84% yield). MS (M ⁺¹ ) m/z: 364.2 (MH ⁺ - tertbutyl). LC retention time 1.36 min [B bj. ^] H NMR (400 MHz, CHLOROFORM-d) d

.80-7 74 (m, 1H), 7.60-7.57 (m, i l l ). 7.22-7.17 (m, i l l ). 3.24-3.08 (m, i l l). 1.70-1.67

(m, 9H), 1.46-1.44 (m, 12H), 1.43-1.42 (m, 3H), 1.41-1.39 (m, 3H).

Intermediate 2B: tert-butyl 5~chloro~3~isopropyT~2~(8~methyT~[l,2,4]triazolo[] ,5-a] py ridin-6-y 1)- 1 H-indole- 1 -carboxy late

To a 20 mL vial with pressure relief septum were added tert-butyl 5-chloro-3- isopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH -indole-l-carboxylate (1 g, 2.382 mmol), 6-bromo-8-methyl-[l,2,4]triazolo[l,5-a]pyridine (0.556 g, 2.62 mmol), XPhos Pd G2 (0.094 g, 0.1 19 mmol), and TOP (6 mL). The vial was evacuated and flushed with N several times. Tripotassium phosphate (2.382 mL, 7 15 mmol) was added. The vial was evacuated and flushed with N?. several times. The reaction mixture was heated to 65 °C for 3 hours at which time LCMS indicated the reaction was complete. The reaction was diluted with water (25 mL) and extracted with EtOAc (3 x 15 mL). Organics were combined, washed with brine (1 x 10 mL) and dried over sodium sulfate, filtered and concentrated under vacuum to give an oil. A white solid formed on standing. The solid was triturated with Et20. A white solid was filtered off and dried under vacuum to afford tert-butyl 5-chloro-3-isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a] pyridm-6-yi)-lH-mdole-l-carboxylate (743 mg, 1.714 mmol, 71.9% yield). MS (M ^+] ) m/z 424.9. LC retention time 1.19 min [Al ]. Ή NMR (400 MHz, DMSO-de) d 8.97 (d, J=0.5 Hz, I I I). 8.54 (s, 1H), 8.22 (d, .1 8 9 Hz, 11 1 ). 7.85 (d, 1=2.1 Hz, i l l ). 7.53 (s, i l l ). 7.42 (dd, 1=8.9, 2.1 Hz, 1H), 2.87 (qum, 1=7.1 Hz, 1H), 2.59 (s, 3H), 1.29 (br. s., 6H), 1.12 (s, 9H).

Intermediate 2C: tert-butyl 3-isopropyl-2-(8-methyl-[l ,2,4]triazolo[l,5-a]pyridin-6-yl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-l-ca rboxylate

To a 40 mL vial with pressure relief septum were added tert-butyl 5-chloro-3- isopropyl-2-(8-methyl-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl)- 1 H-indole- 1 -carboxylate (743 mg, 1.749 mmol), bis(benzonitrile)palladium(ll) chloride (16.77 mg, 0.044 mmol), 2- dicyclohexylphosphino-2', 6' -dimethoxy biphenyl (71.8 mg, 0.175 mmol), and toluene (3497 mΐ). The vial was evacuated and degassed with N ₂ several times. The vial was stirred at room temperature for 20 min. Triethyiamine (1219 mΐ, 8.74 mmol) (previously degassed) and 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (381 mΐ, 2.62 mmol) were added and the reaction mixture was heated to 80 °C for 4 horns. LCMS indicated the reaction was complete. The solution was passed through a pad of celite, concentrated under vacuum to give a yellow oil. The yellow oil was purified by Isco (40 g Silica, 100% hexanes-50% EtO Ac/hexanes). Like fractions were concentrated under vacuum to afford teri-butyi 3-isopropyl-2-(8-methyl-[ l,2,4]triazolo[l,5-a]pyridin-6-yl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole-l-carboxylate (903 mg, 1.749 mmol, 100% yield). MS (M ⁺¹ ) m/z 516.9. LC retention time 1.20 mm [AG]

Intermediate 2D: tert-butyl 5-hydroxy-3-isopropyl-2-(8-methyl-[l ,2,4]triazolo[l,5-a] py ridin-6-y 1)- 1 H-indole- 1 -carboxy late

To a 200 mL round bottom flask were added tert-butyl 3-isopropyl-2-(8-methyl- [l,2,4]triazolo[l,5-a]pyridin-6-yl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH- indole-1 -carboxy late (0.903 g, 1.749 mmol), THE (17.49 mL) and sodium hydroxide (8.74 mL, 8.74 mmol). The flask was cooled to 0 °C. Hy drogen peroxide (0.357 mL,

3.50 mmol) was added dropwise over 10 minutes and stirring continued for 30 minutes. LCMS indicated the reaction was complete. The solution was acidified to pH 5 with IN HC1. The solution was extracted with EtO Ac (3 x 25 mL), the combined organic were dried over sodium sulfate, filtered and concentrated under vacuum to give a clear oil. The clear oil was purified by Isco (25 silica, 100% hexanes-50% EtO Ac/hexanes), like fractions were combined and concentrated to afford tert-butyl 5-hydroxy-3-isopropyl-2- (8-methyl-j l,2,4]tnazoio| T,5-a]pyridin-6-yl)-lH-indole-l-carboxylate (640 mg, 1.496 mmol, 86% yield). MS (M ⁺ⁱ ) m/z: 406.9. LC retention time 0.92 min [A1 ]. ^l H NMR (400 MHz, DMSO-de) d 9 24 (s, 1H), 8.89 (d, J=0.6 Hz, 1H), 8 51 (s, 1H), 8 01 (d, 1=8.9 Hz, 1H), 7.48 (d, J=l.l Hz, 11 1). 7.11 (d, J 2.3 Hz, i l l). 6.83 (dd, 1=8.9, 2.3 Hz, i l l).

2.81 is pi. J 7. 1 Hz, 1H), 2.58 (s, 3H), 1.32-1.21 (in, 6H), 1.11 (s, 9H). Intermediate 2E: tert-butyl 5-(2-hydroxyethoxy)-3-isopropyl-2-(8-methyl-| 1 ,2,4jtnazolo [ 1 ,5-a]pyridin-6-y 1)- lH-indole- 1 -carboxylate

To a 1 dram vial with pressure relief septum were added tert-bulyl 5-hydroxy-3- isopropy]-2-(8-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-y])-lH -indole-l -carboxylate (300 mg, 0.738 mmol) and potassium carbonate (204 mg, 1.476 mmol) in MeOH (1 mL). Oxirane (2.5 M in THF) (1.476 mL, 3.69 mmol) was added. The vial sealed and heated to 50 °C with stirring for 1 hour. The reaction mixture was filtered, concentrated under vacuum, and the resulting oil was purified by Isco (12g Silica, 10% hexanes-100% EtOAc). Product fractions were combined and concentrated under vacuum to afford tert- butyl 5-(2-hydroxyethoxy)-3-isopropyl-2-(8-methyl-[l,2,4]triazolo[ l,5-a]pyridin-6-yl)- lH-indole-l-carboxylate (135 mg, 0.297 mmol, 40.2% yield) as a white foam. MS (M ^+l ) m/ _å 450.9. LC retention time 0.94 min [Al] Intermediate 2F: tert-butyl 3-isopropyl-2-(8-methyl-[l,2,4]triazolo[ l,5-a|pyridin-6-yl)-5- (2-((methylsulfonyl)oxy)ethoxy)~lH~indole-l -carboxylate

To a 1 dram vial cooled to 0 °C were added tert-butyl 5-(2-hydroxyethoxy)-3- isopropyl-2-(8-methyl-[l ,2,4]triazolo[l ,5-a]pyridin-6-yl)-lH-indole-l -carboxylate (135 mg, 0.300 mmol), DCM (1 mL), and triethylamine (0.042 mL, 0.300 mmol).

Methanesulfonyl chloride (0.035 mL, 0.449 mmol) was added and the reaction mixture was stirred for 1 hour. Reaction mixture was stirred at room temperature overnight. LCMS indicated the reaction was complete. Material was concentrated under vacuum to afford tert-butyl 34sopropyl-2-(8-methyl-[ 1,2,4 jtriazolo[l,5-ajpyridin-6-yT)-5-(2- ((methylsulfonyljoxy (ethoxy )-lH-indole~l~carhoxylate (150 mg, 0.284 mol, 95% yield). MS (M ⁺ⁱ j m/ ^' r. 528.8. LC retention time 0.98 min [At] Example 2:

To a 1 dram vial were added tert-hutyl 3-isopropyS-2-(8-methyl-[i,2,4]1xiazo!o [l,5-ajpyridiii-6-yl)-5-(2-((methylsulfoiiyl)oxy)ethoxy)-lH- iiidole-l-carboxylate (50 mg, 0.095 mmol), DCM (1 mL), and pyrrolidine (20.18 mg, 0.284 mmol). The reaction mixture was stirred at room temperature overnight. LCMS indicated the reaction was complete. The reaction mixture was diluted with water (2 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to give an oil. The oil was treated with 1 : 1 TFA:DCM (2 mL) for 30 minutes. LCMS indicated the reaction was complete. The oil was concentrated under a stream of N ₂ . The crude material was purified via prep HPLC to afford 6-(3-isopropyl-5-(2-(pynOlidin-l-yl)ethoxy)-lH-indol- 2-yl)-8-methyl-[l ,2,4jtriazolo[ l,5-a]pyridine (28.1 mg, 0.068 mmol, 72.2% yield). MS (M ⁺ⁱ ) m/z: 404.3. LC retention time 1 19 min [QC-ACN-AA-XB] 'H NMR (500 MHz, DMSO-de) 6 11.09 (hr. s . 1H), 8.78 (hr s., i l l). 8.52 (s, 1H), 7.59 (s, 1H), 7.28 (d, .1 8 7 Hz, I I I). 7.18 (s, I I I) 6.80 (d, j H 7 Hz, l i t). 4.10 (†, J 5.5 Hz, 2H), 3.28-3.18 (m, I I I}. 2.84 (hr. s., 21 1). 2.62 (s, 3H), 2.58 (br. s., il l ). 1.71 (br. s., 41 1). 1.41 (d, 1=7 0 Hz, 6H).

Tire following examples were prepared according to the general procedure for Example 2.

TABLE 1

The following examples were prepared according to the general procedure for Example 1.

TABLE 2

EXAMPLE 21

l (4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-yl) oxy)piperidin-l-yl)-2- methylpropan-2-ol

To a 1 dram vial containing 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl

(piperidin-4-yloxy)-lH-indole, 2 HCi (30 mg , 0.069 mmol) were added methanol (687 mΐ), potassium carbonate (38.0 mg, 0.275 mmol), and 2,2-dimethyloxirane (14.87 mg, 0.206 mmol). The vial was capped and the reaction mixture was stirred at room temperature. After 2 hours, LCMS indicated the reaction was complete. The solution was passed through a pad of celite that was washed with MeOH. The filtered solution was concentrated under a stream of N ₂ . The resulting oil was dissolved in DMF (2 ml,). The crude material was purified via prep HPLC. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 1 ~(4-((2-(2,6- dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-yl)oxy)piperidi n-l-yl)-2-methylpropan-2- ol (27.6 mg, 0.063 mmol, 92% yield). MS (M ⁺¹ ) m/z: 436.0. LC retention time 1.57 min [QC-ACN-AA-XB] . ^! 1 1 NMR (500 MHz, DMSO-tk) d 11.01 (s, 1H), 7.25 (d, .1 8.8 Hz, 1H), 7.17 (s, 1H), 7.12 (s, 2H), 6.80 (d, 1=8.8 Hz, 1H), 4.24 (br s., 1H), 3.55 (br. s„ i l l ). 3.35-3.25 (m, 1H), 2.83 (br. s., 2H), 2.54 (s, 2H), 2.48 (s, 6H), 2.36 (t, J 9.5 Hz, 2H),

2.21 (s, 21 1 ). 1.64 (d, J=9.2 Hz, 2H), 1.39 (d, J 6.9 Hz, 6H), 1.08 (s, 6H).

The following examples were prepared according to the general procedure for Example 21.

TABLE 3

EXAMPLE 29

2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-((l-methylpiperid in-4-yJ)oxy)-lH-indole

To a 1 dram vial containing 2-(2,6-dimethylpyridm-4-yl)-3-isopropyl~5-

(piperidin-4-yloxy)-lH-indole, 2 HQ (30 mg, 0.069 mmol) were added DMF (687 mΐ), DIEA (24.01 mΐ, 0.137 mmol), and formaldehyde (25.6 mί, 0.344 mmol). The reaction mixture was stirred for 10 minutes. Acetic acid (3 94 mΐ, 0.069 mmol) and sodium triacetoxyborohydride (29.1 mg, 0.137 mmol) were added and the reaction mixture was stirred for 15 minutes, at which time LCMS indicated that the reaction was complete. Hie reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 niL) Organic layer was combined and concentrated under vacuum. The crude material vras purified with prep HPLC. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl- 5-((l-methylpiperidin~4-yl)oxy)~lH-indo]e (13 5 mg, 0.035 mmol, 51.5% yield). MS (M ^{+ 1} ) mJr. 378.4. LC retention time 1.32 min [QC-ACN-AA-XB]. H NMR (500 MHz, DMSO-de) d 11.02 (s, III), 7.26 (d, .1 8.7 Hz, 1H), 7.18 (s, 1H), 7.12 (s, 2H), 6.80 (d,

.1 8.2 Hz, III).4.27 (hr. s, III}.3.35-3.24 (m.111).2.63 (hr. s, 211).2.48 (s, 511).2.18 (s,111).1.89 (s, -111).1.66 (d, 1=89 Hz, 2H), 1.39 (d, 1=69 Hz, 61!)

The following examples were prepared according to the general procedure for Example 29.

TABLE 4

EXAMPLE 69

l-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-y l)oxy)piperidin-l-yl) propan-2-ol

To a vial containing 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-(piperidin-4- yloxy)-lH-indole, 2 HC1 (30 mg, 0.069 mmol) were added N-methyl-2-pyrrolidinone (687 mΐ), DBU (51.8 mΐ, 0.344 mmol), and 2-bromopropan-l-ol (47.8 mg, 0.344 mmol). The vial was capped and the reaction mixture was stirred at room temperature overnight. LCMS indicaled starting material was still present. The reaction mixture was transferred to a 2 dram vial with pressure relief septum and heated to 80 °C for 1 hour. LCMS indicated the reaction w¾s complete. The reaction mixture was diluted w ith brine (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organics were dried under a stream of N ₂ . The solid material was dissolved in 2 ml. of DMF and the crude material was purified via prep HPLC. Fractions containing the product were combined and dried via centrifugal evaporation to afford l-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH- indol-5-yl)oxy)piperidin-l -yl)propan-2-ol (10.1 mg, 0.024 mmol, 34.9% yield). MS (M ⁺¹ ) m/z: 422.0. LC retention time 1.28 m [QC-ACN-AA-XB] ¾ NMR (500 MHz, DMSO-de) 5 11.07-10.97 (m, 1H), 7.29-7.23 (m, 1H), 7.21-7.17 (m, 1H), 7.15-7.12 (m, 2H), 6.84-6.78 (m, 1H), 4.32-4.24 (m, 1H), 3.82-3.71 (m, 1H), 3.37-3.27 (m, 1H), 3.38- 3.26 (m, 1H), 2.82-2 72 (m, 2H), 2.57-2.53 (m, 5H), 2.34-2.25 (m, 3H), 2.24-2.19 (m, i l l }. 1.97-1.88 (m, 71 1). 1.72-1.60 (m, 2H), 1.45-1.36 (m, 6H), 1.10-0.99 (m, 3H).

The following examples w¾re prepared according to the general procedure for Example 69.

TABLE 5

EXAMPLE 79

2-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-y l)oxy)piperidin-l-yl)-N,N- dimethy lacetami de

To a 1 dram vial containing 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5- (piperidin-4-y]oxy)-lH-indole, 2 HC1 (15 mg, 0 034 mmol) were added NMP (1 mL) and DBU (0.021 mL, 0 137 mmol). 2-Chloro-N,N-dimethylacetamide (12 53 mg, 0.103 mmol) was added and the reaction mixture was stirred at room temperature overnight. LCMS indicated the reaction was complete. The crude material was purified via prep

HIM ( Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-y l)oxy) piperidin-l-yl)-N,N-dimethylacetamide (9.2 mg, 0.020 mmol, 58.5% yield). MS (M ⁺¹ ) m/z 449.4 LC retention time 1.50 min [QC-ACN-AA-XB] Ή NMR (500 MHz, DMSO-de) 6 11.02 (s, i l l ). 7.25 (d, 1=8 8 Hz, ! Hl 7.19 (s, 1H), 7.13 (s, 2H), 6.81 (d, 1=8.6 Hz, 1H), 4.27 (br. s., M l). 3.36-3.25 (m, 1H), 3.15 (s, 1H), 3.02 (s, 3H), 2.80 (s, 31 1 ). 2 73 (br. s., 2H), 2.49 (s, 6H), 2.32 (br s., 21 1). 1.90 (s, 3H), 1.65 (d, .! 8 8 Hz, 21 1). 1.40 (d, 1=7 0 Hz, 6H). The following examples were prepared according to the general procedure for

Example 79.

TABLE 6

EXAMPLE 94 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-(piperidin-3-ylme thoxy)-lH-indole, 2 TFA

Example 94 was prepared according to the general procedure for Example 1 using Template T-1C with tert-butyl 3-(hy droxymethyl)piperi dine- l-carboxy late (CAS # 4606- 65-9). Isolated 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-(piperidin-3-ylme thoxy)-lH- indole, 2 TEA (10.1 g. 0.017 mmol, 18.71 % yield). MS (M ⁺¹ ) m/z: 378 1 . LC retention time 1.31 min [QC-ACN-AA-XB] ³ H NMR (500 MHz, DMSO-de) d 1 1.02 (s, M l ). 7.25 id. 1=8.7 Hz, 1H), 7.13 (s, 3H), 6.78 (d, 1=8.5 Hz, 1H), 3.87-3.78 (m, 2H), 3.46 (br. s., i l l ). 3.35-3.27 (m, i l l ). 3.15 (d, 1=10.8 Hz, 1 1 1 ). 2.99-2.91 (m, i l l ). 2.54 (s, 51 1 ). 2.48 (s, 31 1 ). 1.96 (br s., l i t ) 1.86-1.80 ( m. 21 1 ). 1.65 (d, 1=1 1 .9 Hz, 11 1 ). 1.41 (d, 1=7.0

Hz, 6H), 1.30-1.19 (m, 1H).

2-(dimethylamino)-l-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isop ropyl-lH-indol-5- y l)oxy )piperidin- 1 -y l)ethanone

To a 1 dram vial were added 2~(dimethy!amino)acetic acid (21.27 mg, 0.206 mmol), PyBOP (107 mg, 0.206 mmol), and DMF (687 mΐ). The vial was stirred at room temperature for 10 rmnutes. 2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-(piperidin-4- yloxy)-lH-indole, 2 HC1 (30 mg, 0.069 mmol) and DIEA (24.01 mΐ, 0.1 37 mmol) were added. The vial was capped and the reaction mixture was stirred overnight at room temperature. LCMS indicated the reaction was complete. The volume was brought up to 2 mL with DMF and the crude material was purified via prep HPLC. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 2-(dimethylamino)-l-(4-((2-(2,6-dimethylpyridin-4-yl)-3-isop ropyl-lH-indol-5-yl) oxy)piperidin-l-yl)ethanone (24.8 mg, 0.054 mmol, 79% yield). MS (M ⁺¹ ) m/ _å : 449.0. LC retention time 137 min [QC-ACN-AA-XB] Ti NMR (500 MHz, DMSO-de) d 11.04 (s, ill).727 (d, 1=8.8 Hz, ill).7.23 (s, ill).7.13 (s, 211).684 (d, 1=8.6 Hz, ill).453 (br. s., 1H), 3.81 (br. s., 2H), 3.57 (d, .1 12.5 Hz, 1H), 3.43-3.35 (m, 1H), 3.32-3.25 (m, 211), 3.10 (d, 1=6.8 Hz, 2H), 3.00 (br. s., 1H), 2.48 (s, 5H), 2.18 (s, 5H), 1.93 (br. s., 1H),

1.72 (br s., 1H), 1.64 (br. s„ 111).1.53 (d, 1=8.9 Hz, 111).139 (d, 1=69 Hz, 611)

The following examples were prepared according to the general procedures for Examples 94 and 95.

TABLE?

EXAMPLE 109

l (4-((2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-lH-indoJ-5-yl) oxy)piperidin-l-yl)-2-

(methylamino)ethanone

To a 1 dram vial were added 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (26.0 g, 0.137 mmol), PyBOP (71.5 mg, 0.137 mmol), and DMF (458 mΐ). The mixture was stirred at room temperature for 10 minutes. 2-(2,6-dimethylpyridin-4-yl)-3- isopropyl-5-(piperidin-4-yloxy)-lH-indole, 2 HC1 (20 mg, 0.046 mmol) and DIEA (16.01 mΐ, 0.092 mmol) were added. The vial was capped. The reaction mixture was stirred overnight at room temperature. The sample was dissol ved in 10 ml, of water and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (1 x 10 mL) and dried over magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was dissolved in 1 : 1 (DCM:TFA) and stirred for 30 minutes at which time the Boc was removed. The solution was concentrated under vacuum to give a yellow oil. The crude material was purified via prep HPLC. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford l-(4-((2-(2,6- dimethylpyridin-4-yl)-3-isopropyl-lH-indol-5-yl)oxy)piperidi n-l-yl)-2-(methylamino) ethanone (17.8 mg, 0.041 mmol, 89% yield). MS (M ^l ) m/z: 435.4. LC retention time 1.25 min [QC-ACN-AA-XB] 'll NMR (500 MHz, DMSO-de) d 11.05 (s, ill).7.27 (d, .1 8.8 Hz, 1H), 7.23 (s, 1H), 7.13 (s, 2H), 6.84 (d, J 8.6 Hz, 1H), 454 (hr. s, 111).3.82 (hr. s, 1H), 3.63 (br s., 111}..3.38-325 Cm.2H), 2.54 (s, 3H), 2.48 (s, 6H), 2.31 (s, 4H), 1.88 (s, 4H), 1.40 (d, 1=6.9 Hz, 6H).

The following examples were prepared according to the general procedure for Example 109.

TABLE 8

EXAMPLE 117

( _< S')-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl-lH-indol-5 -yl)oxy)-N-(pyrroiidin-3- ylmethyl)acetamide

A mixture containing n-boc-ethylenediamine (8 mg, 0.05 mmol), HCTU (25 mg, 0.06 mmol) and 2-((l-(tert-butoxycarbonyl)-2-(3,4-dimethoxyphenyl)-3-isopro pyl-lH- indol-5-yl)oxy)acetic acid (Template T-8) (15 mg, 0.03 mmol) were suspended in THF (0.5 mL) and treated with TEA (0.022 mL, 0.160 mmol). The reaction mixture was stirred for 8 h and concentrated to dryness. The residue was treated with TFA (50%) in DCM (1 mL) for 30 min to facilitate the removal of the Boc groups. The reaction mixture was re-concentrated to dryness and dissolved m acetonitrile (2 mL), filtered through an Acrodisc, 13 ram, 0.45 micron nylon membrane syringe filter and purified via preparative LC/MS with the following conditions: Column: XBridge Cl 8, 19 x 200 mm, 5-pm particles: Mobile Phase A: 5:95 acetonitrile: water with 0.1% tnfluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1 % trifluoroacetic acid; Gradient: 10-

100% B over 10 minutes, then a 5 -minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford N -(2-aminoethyl)-2-((2-(3,4-dimethoxyphenyl)-3-isopropyl- lH-indol-5- yl)oxy)acetamide, TFA (4.5 mg, 25%). MS (M ⁺ⁱ ) m/z 412.1. LC retention time 1.23 min j QC-ACN-TFA-XB j . ¾ NMR (500 MHz, DMSO-de) d 10.67 (s, 1H), 8.14 (br s, ill).708 (br d, .7=8.7 Hz, ill}.7.04-6.97 (m, 1H), 692-6.80 (m, 311).6.63 (br d, ./ 8.1 Hz, 111)..4.30 (s, 2H), 3.65 (s, 3H), 3.62 (s, 3H), 3.38 (br m, 1H), 3.19-3.07 (m, 211).2.63 (br s, 211).1.20 (br d, ./ 6.8 Hz, 6H).

The following examples were prepared according to the general procedure for Example 117.

TABLE 9

The following examples were prepared according to the general procedures described above.

TABLE 10

BIOLOGICAL ASSAYS

The pharmacological properties of the compounds of this in vention may be confirmed by a number of biological assays. The exemplified biological assays, which follow, have been carried out with compounds of the invention.

TLR7/8/9 Inhibition Reporter Assays

HEK-Blue™-cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9 receptors were used for screening inhibitors of these receptors using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of the IFN-b minimal promoter fused to five NF-kB and AP-1 -binding sites. Briefly, cells are seeded into Greiner 384 well plates (15000 cells per well for TLR7, 20,000 for TLR8 and 25,000 for TLR9) and then treated with test compounds in DMSO to yield a final dose response concentration range of 0.05 nM - 50 mM. After a 30 minute compound pre-treatment at room temperature, the cells are then stimulated with a TLR7 ligand (gardiquimod at a final concentration of 7.5 mM), TLR8 ligand (R848 at a final concentration of 15.9 mM) or TLR9 ligand (GDN2QQ6 at a final concentration of 5 nM) to activate NF-kB and AP-1 which induce the production of SEAP. After a 22 hour incubation at 37 °C, 5% CO2, SEAP levels are determined with the addition of HEK-Blue™ Detection reagent (Invivogen), a cell culture medium that allows for detection of SEAP, according to manufacturer’s specifications. The percent inhibition is determined as the % reduction in the HEK-Blue signal present in wells treated with agonist plus DMSO alone compared to wells treated with a known inhibitor.

TABLE 10

TLR7/8/9 Reporter Assay Data