Substituted indole dimer compounds

Abstract

A compound of formula (I), an N-oxide, or a salt thereof, wherein G, G, L, R 1a , R 1b , R4, R5, n, m, x, and y are as defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions containing such compounds. These compounds are useful for treating inflammation and autoimmune diseases. TIFF2022505827000067.tif26150

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 749,924, filed October 24, 2018, the entire contents of which are incorporated herein by reference.

[0002] Description of the Invention The present invention relates generally to substituted indole dimeric compounds useful as inhibitors of signaling through Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9), or combinations thereof. Provided herein are substituted indole dimeric compounds, compositions comprising such compounds, and methods of their use. The present invention further relates to pharmaceutical compositions containing at least one compound according to the invention that are useful in the treatment of conditions associated with TLR modulation, such as inflammation and autoimmune diseases, as well as methods of inhibiting the activity of TLRs in a mammal. [Background technology]

[0003] 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 microorganisms, including bacteria, fungi, parasites, and viruses (reviewed in Kawai, T. et al., Nature Immunol., 11: 373-384 (2010)). Ligands bind to the receptors, except for TLR3, and induce dimerization and recruitment of adapter molecules to a conserved cytoplasmic motif in the receptor called the Toll / IL-1 receptor (TIR) ​​domain. All TLRs recruit the adapter molecule MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, JE et al., Nature Rev. Immunol., 10: 89-102 (2010)).

[0004] Toll-like receptors (TLRs) are a series of evolutionarily conserved transmembrane innate immune receptors involved in the first line of defense. As pattern recognition receptors, TLRs protect against foreign molecules activated by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) derived from damaged tissues. A total of 13 TLR family members, of which 10 in humans, have been identified, spanning either the cell surface or endosomal compartments. TLR7-9 is one of a set that is located in endosomes and responds to single-stranded RNA (TLR7 and TLR8) or unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs (TLR9).

[0005] Activation of TLR7 / 8 / 9 can initiate various inflammatory responses (cytokine production, B cell activation and IgG production, type I interferon response). In the case of autoimmune disorders, abnormal persistent activation of TLR7 / 8 / 9 leads to exacerbation of the pathology. Overexpression of TLR7 in mice was shown to exacerbate autoimmune disease, whereas knockout of TLR7 mice was found to be protective against disease in lupus-prone MRL / lpr mice. Dual knockout of TLR7 and 9 showed further enhanced protection.

[0006] Since many conditions may benefit from treatments involving modulation of cytokines, IFN production and B cell activation, it is readily apparent that novel compounds capable of modulating TLR7 and / or TLR8 and / or TLR9, and methods employing these compounds, may provide substantial therapeutic benefit to a wide variety of patients.

[0007] The present invention relates to a series of novel substituted indole dimeric compounds that have been 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 for their druggability. Summary of the Invention

[0008] The present invention provides compounds of formula (I) or stereoisomers, tautomers, pharma- ceutically acceptable salts, solvates or prodrugs thereof, which are useful as inhibitors of signaling through Toll-like receptors 7, 8, or 9, and are useful in the treatment of proliferative, allergic, autoimmune and inflammatory diseases.

[0009] The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the invention or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0010] The present invention also provides a method of inhibiting Toll-like receptors 7, 8, or 9, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharma-ceutically acceptable salt, solvate, or prodrug thereof.

[0011] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate or prodrug thereof.

[0012] The present invention also provides a method for treating a disease or disorder associated with Toll-like receptor 7, 8, or 9 activity, comprising administering to a mammal in need thereof at least one compound of formula (I) or salts, solvates, and prodrugs thereof. The present invention also provides processes and intermediates for making the compounds of formula (I), or salts, solvates, and prodrugs thereof. The present invention also provides at least one compound of formula (I), or salts, solvates, and prodrugs thereof, for use in therapy.

[0013] The present invention also provides the use of at least one compound of formula (I), or salts, solvates and prodrugs thereof, for the manufacture of a medicament for the treatment or prevention of Toll-like receptor 7, 8 or 9 associated conditions, such as allergic diseases, autoimmune diseases, inflammatory diseases and proliferative diseases.

[0014] The compounds of formula (I) and compositions comprising the compounds of formula (I) may be used to treat, prevent, or cure a variety of conditions associated with Toll-like receptors 7, 8, or 9. Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases, and proliferative diseases.

[0015] These and other features of the invention will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The first aspect of the present invention relates to a compound of formula (I): [ka] [In formula: L is -(CH2) q -or- L1-NR x C(O)-(CH2) t -C(O)NR x -L2-; L1 and L2 are independently -(CH2) 1-3 - and; q is an integer ranging from 10 to 30; t is an integer ranging from 2 to 24; G1 and G2 are independently (i) [ka] Is it; (ii) [ka] Is it; (iii) [ka] Is it; (iv) [ka] [ka] [ka] or a 9-membered heterocyclic ring selected from (v) [ka] is a 10-membered heterocyclic ring selected from: R 1a and R 1b are independently H, Cl, -CN, C 1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxy-fluoroalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 Cycloalkyl), -C(O)O(C 1-3 alkyl), or tetrahydropyranyl; R2 is independently halo, -CN, -OH, -NO2, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 Alkyl), C 1-3Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 alkyl), -O(CH2) 1-2 O.C.(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(CH2) 0-2 C(O)NR y R y , -C(O)NR x (C 1-5 Hydroxyalkyl), -C(O)NR x (C 2-6 Alkoxyalkyl), -C(O)NR x (C 3-6 Cycloalkyl), -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 Hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 Cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x CH2(C 3-6 Cycloalkyl), -(CH2) 0-2 S(O)2(C 1-3 alkyl), -(CH2) 0-2 (C 3-6 Cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl); R 2a is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl; R 2b are each independently H, halo, -CN, -NR x R x , C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 alkyl), -(CH2) 0-3 C(O)NR x R x , -(CH2) 1-3 (C 3-6 Cycloalkyl), -C(O)O(C 1-3 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CR x R x , or -CR x =CH(C 3-6 cycloalkyl); R 2c is R 2a or R 2b and; R 2d is R 2a or R 2b where R 2c and R 2d One of them is R 2a and R 2c and R 2d The other of R 2b and; R4 is independently F, -OH, or C 1-2alkyl, or -OCH; or two R4 bonded to the same carbon atom form =O; or when m or n is at least 2, each of the two R4 can be bonded to different carbon atoms adjacent to the nitrogen atom of the piperidinyl ring to form a -CH2CH2- bridge; R5 is independently F, Cl, -CN, C 1-3 Alkyl, C 1-2 fluoroalkyl, or -OCH3; R x are each independently H or -CH3; R y each independently represents H or C 1-6 is alkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is, independently at each occurrence, 0, 1, 2, 3, or 4; x is 0, 1, or 2; and y is 0, 1, or 2] The present invention provides at least one compound, N-oxide, or salt thereof, of the formula:

[0017] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are independently: [ka] and;L,R 1a , R 1b , R4, R5, m, n, x, and y are defined in the first or second aspect, or a salt thereof. One embodiment is a compound of Formula (I), an N-oxide, or a salt thereof, wherein G1 and G2 are independently: [ka] and L, R 1a , R 1b, R2, R4, R5, m, n, x, and y are defined in the first aspect,

[0018] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are independently: [ka] and L, R 1a , R 1b , R 2a , R 2b , R 2c , R 2d , R4, R5, m, n, x, and y are defined as in the first aspect, or a salt thereof. 2a C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 Cycloalkyl, -CHC(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl; R 2b each independently represents H, F, Cl, -CN, -NR x R x , C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 0-2 O(C 1-2 alkyl), -(CH2) 0-2 C(O)NR x R x , -(CH2) 1-3 (cyclopropyl), -C(O)O(C 1-2 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CH2, or -CH=CH(C 3-6 cycloalkyl). 2ais -CH3; R 2b Also included are compounds where each is independently H, Cl, or -CH3.

[0019] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] [ka] [ka] and L, R are 9-membered heterocyclic rings selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0020] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 10-membered heterocyclic rings selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0021] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having one nitrogen heteroatom selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0022] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having two nitrogen heteroatoms selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0023] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having two nitrogen heteroatoms and substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0024] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] [ka] and L, R are 9-membered heterocyclic rings having 3 nitrogen heteroatoms and substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0025] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having 3 nitrogen heteroatoms and substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0026] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having 4 nitrogen heteroatoms selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0027] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] L, R are 9-membered heterocyclic rings having 4 nitrogen heteroatoms and substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0028] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and R is a 9-membered heterocyclic ring having 1 or 2 oxygen heteroatoms, optionally substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0029] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and R is a 9-membered heterocyclic ring having 1 or 2 nitrogen heteroatoms and 1 oxygen heteroatom, optionally substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0030] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having 1 or 2 nitrogen heteroatoms and 1 sulfur heteroatom selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0031] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 9-membered heterocyclic rings having two nitrogen heteroatoms and one oxygen heteroatom, substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0032] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 10-membered heterocyclic rings having one nitrogen heteroatom selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0033] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and L, R are 10-membered heterocyclic rings having two nitrogen heteroatoms selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0034] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each independently: [ka] and R is a 10-membered heterocyclic ring having 1 or 2 nitrogen heteroatoms and 1 oxygen heteroatom, optionally substituted with =O, selected from 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof.

[0035] One embodiment is a compound of Formula (I), an N-oxide, or a salt thereof, wherein G1 and G2 are each independently: (i) [ka] Is it; (ii) [ka] Is it; (iii) [ka] Is it; (iv) [ka] and;L,R 1a , R 1b , R 2a , R 2b The present invention provides a compound, N-oxide, or salt thereof, wherein R, R, R, R, m, n, p, x, and y are defined as in the first aspect. 1a and R 1b are each independently -CHCH or -CH(CH); R are each independently -CH or -OCH; R 2a are each -CH3; R 2b R4 is, each independently, F, -CH3, or -OCH3; and R5 is, each independently, F, Cl, -CN, -CH3, -CF3, or -OCH3.

[0036] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each [ka] and;L,R 1a , R 1b , R2, R4, R5, m, n, p, x, and y are defined as in the first aspect, or a salt thereof. This embodiment includes compounds where each R2 is independently -CH3 or -OCH3. This embodiment also includes compounds where each R2 is -OCH3.

[0037] One embodiment is a compound of formula (I) or a salt thereof, wherein G1 and G2 are each [ka] and;L,R 1a , R 1b , R4, R5, m, n, x, and y are defined as in the first aspect, or a salt thereof. 1a and R 1b are independently H, Cl, -CN, C 1-4 Alkyl, or C 1-2 Fluoroalkyl. 1a and R 1b Also included are compounds where is independently -CH2CH3 or -CH(CH3)2.

[0038] One embodiment is a compound, N-oxide, or salt thereof of formula (I), where: L is -(CH2) q -or- L1-NR x C(O)-(CH2) t -C(O)NR x -L2-; q is an integer ranging from 8 to 26; t is an integer ranging from 2 to 16; G1, G2, L1, L2, R 1a , R 1b , R 1b , R 2a , R 2b , R 2c , R 2d , R4, R5, R x The present invention provides a compound, N-oxide, or salt thereof, wherein m, n, x, p, and y are defined in the first aspect. Within this embodiment are compounds where q is an integer in the range of 10 to 24; and t is an integer in the range of 2 to 16. Within this embodiment are compounds where 1 is an integer in the range of 16 to 20, and t is an integer in the range of 2 to 12. Additionally, within this embodiment are compounds where q is 16, 17, or 18; and t is an integer in the range of 2 to 12.

[0039] One embodiment is a compound, N-oxide, or salt thereof of formula (I), where: L is -(CH2) q -; q is an integer ranging from 8 to 26; G1, G2, R1a , R 1b , R 1b , R 2a , R 2b , R 2c , R 2d The present invention provides a compound or a salt thereof, wherein R4, R5, m, n, x, and y are defined as in the first aspect. Within this embodiment, compounds are provided wherein q is an integer in the range of 10 to 24. Also included are compounds wherein q is an integer in the range of 16 to 20. Additionally, within this embodiment, compounds are provided wherein q is 16, 17, or 18.

[0040] One embodiment is a compound, N-oxide, or salt thereof of formula (I), where: L is -L-NR x C(O)-(CH2) t -C(O)NR x -L2-; t is an integer ranging from 2 to 16; G1, G2, L1, L2, R 1a , R 1b , R 2a , R 2b , R 2c , R 2d , R4, R5, R x The present invention provides a compound or a salt thereof, wherein m, n, p, x, and y are defined as in the first aspect. Within this embodiment are compounds where t is an integer ranging from 2 to 16. Within this embodiment are compounds where t is an integer ranging from 2 to 12. Additionally, within this embodiment are compounds where t is an integer ranging from 2 to 12; and L1 and L2 are each -(CH2)2-.

[0041] One embodiment is a compound, N-oxide, or salt thereof of formula (I), wherein: R 1a and R 1b are independently H, Cl, -CN, C 1-4 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxy-fluoroalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 Cycloalkyl), -C(O)O(C 1-3alkyl), or tetrahydropyranyl; R2 is independently halo, -CN, -OH, -NO2, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 Alkyl), C 1-3 Fluoroalkoxy, C 2-4 Alkoxyalkoxy, -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -C(O)NR y R y , -NR y R y , -NR x C(O)(C 1-3 alkyl), -NR x (CH2-cyclopropyl), C 3-6 R4 is independently selected from the group consisting of F, -OH, -C(O)(thiazolyl), -cycloalkyl, -methylpiperidinyl, -methylpiperazinyl, -amino-oxadiazolyl, -imidazolyl, -triazolyl, and -C(O)(thiazolyl); 1-2 alkyl, or -OCH3; or two R4 attached to the same carbon atom form =O; R5 is each independently F, Cl, -CN, C 1-2 Alkyl, C 1-2 fluoroalkyl, or -OCH3; and G1, G2, L, R 2a , R 2b , R 2c , R 2d , R x , R y The present invention provides a compound, N-oxide, or salt thereof, wherein m, n, p, x, and y are defined in the first aspect. This embodiment includes compounds where m is 0, 1, or 2; n is 0, 1, or 2; p is 0, 1, or 2; x is 0 or 1; and y is 0 or 1.

[0042] One embodiment is a compound, N-oxide, or salt thereof of formula (I), wherein: R1a and R 1b are independently H, Cl, -CN, C 1-4 Alkyl, or C 1-2 R2 is, independently at each occurrence, F, Cl, -CN, -OH, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -O(C 1-4 Alkyl), C 1-2 Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 alkyl), -O(CH2) 1-2 O.C.(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -C(O)NR y R y , -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 Hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 Cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x (CH2-cyclopropyl), C 3-6 cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl); R5 is F, Cl, -CN, C 1-2 alkyl, or -OCH; m is 0; n is 0; and G1, G2, L, R 2b , R 2c , R 2d , R4, R x , Ry The present invention provides a compound, N-oxide, or salt thereof, wherein x, x, and y are defined in the first aspect.

[0043] One embodiment is a compound, N-oxide, or salt thereof of formula (I), wherein m is 0, 1, or 2; n is 0, 1, or 2; and G1, G2, L, R 1b , R 2a , R 2b , R 2c , R 2d , R4, R5, R x , R y The present invention provides a compound, N-oxide, or salt thereof, wherein x, x, and y are defined in the first aspect.

[0044] One embodiment is a compound of formula (I), an N-oxide, or a salt thereof, wherein: G1 and G2 are each [ka] ;R 1a and R 1b R2 is each -OCH3; L is -(CH2) 18 -or- L1-NR x C(O)-(CH2) t -C(O)NR x The present invention provides a compound, N-oxide, or salt thereof, wherein G1 and G2 are each -L2-; L1 and L2 are each -(CH2)2-; t is an integer ranging from 2 to 12; m is 0; n is 0; p is each 1; x is 0; and y is 0. This embodiment also provides a compound, N-oxide, or salt thereof, wherein G1 and G2 are each [ka] Compounds are included in the present invention,

[0045] One embodiment is a compound of formula (I) or a salt thereof, wherein the compound is: N1,N13-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tridecanediamide (1); N1,N14-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tetradecanediamide (2); N1,N12-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)dodecanediamide (3); N1,N11-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)undecanediamide (4); N1,N9-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)nonanediamide (5); N1,N8-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)octanediamide (6); N1,N10-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)decanediamide (7); N1,N7-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)heptanediamide (8); N1,N6-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)adipamide (9); N1,N12-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)dodecanediamide (10); N1,N4-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)succinamide (11); or 1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane (12) or a salt thereof.

[0046] The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. The invention encompasses all combinations of the aspects and / or embodiments of the invention described herein. It is understood that any and all embodiments of the present invention can be combined with any other embodiment to describe further embodiments. It is also understood that each individual element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe further embodiments.

[0047] definition The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It should be understood that certain features of the present invention that are described in the context of separate embodiments for clarity of description may also be combined to form a single embodiment. Conversely, various features of the present invention that are described in the context of a single embodiment for brevity of description may also be combined to form subcombinations thereof. The embodiments described herein as typical or preferred examples are intended to be illustrative and not limiting of the invention.

[0048] Unless otherwise specified 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 term "compound" refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I), as well as two or more compounds of formula (I).

[0049] Unless otherwise specified, any heteroatom with unsatisfied valences is intended to have sufficient hydrogen atoms to satisfy the valences. The definitions set forth herein supersede any definitions set forth in any patent, patent application, and / or patent application publication, which are incorporated herein by reference.

[0050] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification, either individually or as part of a larger group (except where they are limited in specific instances). Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds.

[0051] According to the convention in the field, the symbols: [ka] is used in structural formulas herein to indicate the bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0052] 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 "amino" refers to the group -NH2. The term "oxo" refers to the group =O.

[0053] The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 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 t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in a subscript after the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" means straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0054] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0055] The term "cyanoalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CHCN, -CHCHCN, and -C 1-4 Examples include cyanoalkyl. The term "aminoalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and -C 1-4 Aminoalkyl is an example.

[0056] The term "hydroxyalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and -CH 1-4 Hydroxyalkyl is an example. 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 -CHFCHOH, -CHCHFC(CH)OH, and -CHFCH(CH)OH. 1-4 Hydroxy-fluoroalkyl is an example.

[0057] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing 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 a number appears in a subscript after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms.

[0058] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, such as a methoxy group (-OCH). 1-3 "Alkoxy" means an alkoxy group having 1 to 3 carbon atoms. The term "alkoxyalkyl," as used herein, refers to an alkoxy group attached through its oxygen atom to an alkyl group attached to the parent molecular moiety, such as a methoxymethyl group (-CH2OCH3). 2-4 "Alkoxyalkyl" refers to an alkoxyalkyl group having 2 to 4 carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0059] The term "pharmacologically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, and are commensurate with a reasonable benefit / risk ratio. The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. A freeze-drying procedure may be used to obtain the compound of formula (I) as an amorphous solid.

[0060] It should further be recognized that solvates (e.g., hydrates) of the compounds of formula (I) are also within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. "Solvates" consist of both solution-phase and separable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0061] Various forms of prodrugs are well known in the art and are described in the following references: a)The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Chapter 31, (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier 1985); c) A Textbook of Drug Design and Development, edited by P. Krogsgaard-Larson and H. Bundgaard, Chapter 5, pp. 113-191, (Harwood Academic Publishers, 1991); and d)Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH 2003) It is described in.

[0062] The manufacture of prodrugs is well known in the art and is described, for example, in King, FD (ed.), Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, CG (ed.), The Practice of Medicinal Chemistry, Academic Press, San Diego, CA (1999); Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587, (2018).

[0063] Furthermore, after the compound of formula (I) is prepared, it can be isolated and purified to obtain a composition containing 99% or more by weight of the compound of formula (I) ("substantially pure"), which can then be used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also contemplated as part of the present invention.

[0064] "Stable compound" and "stable structure" are intended to refer to 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 embodies stable compounds.

[0065] A "therapeutically effective amount" is intended to encompass an amount of a compound of the present invention alone, or in combination with a compound as claimed, or in combination with other active ingredients, effective to act as an inhibitor against TLR7 / 8 / 9 or to treat or prevent autoimmune and / or inflammatory conditions, such as SLE, IBD, multiple sclerosis (MS), Sjogren's syndrome, and rheumatoid arthritis.

[0066] "Treating" or "treatment", as used herein, extends to the treatment of a condition in a mammal, particularly a human, and includes (a) preventing the onset of the condition in a mammal, particularly where such mammal is susceptible to, but has not yet been diagnosed as having, the condition; (b) inhibiting the condition, i.e., arresting its onset; and / or (c) alleviating the condition, i.e., causing regression of the condition.

[0067] The compounds of the present invention are intended to include all isotopes of atoms present in the 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 are 13 C and 14C. Isotopically labeled compounds of the invention can generally be prepared by common techniques known to those of skill in the art, or by methods analogous to those described herein, substituting appropriately isotopically labeled reagents for unlabeled reagents otherwise used. For example, methyl (-CH3) also encompasses deuterated methyl groups, such as -CD3.

[0068] usefulness The human immune system has evolved to defend the body against microbes, viruses and parasites that can cause infection, disease or death. Complex regulatory mechanisms ensure that the various cellular components of the immune system target foreign substances or organisms while not causing permanent or significant damage to the individual. Although the initiating events are not fully understood at present, in autoimmune pathologies, the immune system directs its inflammatory response to target organs in the affected individual. Various autoimmune diseases are typically characterized by the predominant or initial target organ or tissue affected by the disease, such as the joints 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 intestine in the case of inflammatory bowel disease.

[0069] The compounds of the present invention inhibit signaling through Toll-like receptors 7, 8, or 9 (TLR7, TLR8, TLR9) or combinations thereof. Thus, the compounds of formula (I) have utility in treating conditions involving 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 regulated as a result of intracellular signaling.

[0070] As used herein, the term "treat" or "treatment" includes the treatment of a condition in a mammal, particularly a human, and includes (a) preventing or delaying the onset of the condition in such a mammal, particularly when the mammal is susceptible to the condition but has not yet been diagnosed as suffering from the condition; (b) inhibiting the condition, i.e., arresting its progression; and / or (c) achieving a complete or partial alleviation of the symptoms or condition, and / or palliating, ameliorating, reducing or curing the disease or disorder and / or its symptoms.

[0071] In view of its activity as a selective inhibitor of TLR7, TLR8 or TLR9, the compounds of formula (I) are also useful in treating TLR7, TLR8 or TLR9 family receptor associated diseases, respectively, but are 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; autoinflammatory diseases including cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndromes (TRAPS), familial Mediterranean fever (FMF), adult-onset Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis. These compounds are useful in treating metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disorders, osteoarthritis, osteoporosis, multiple myeloma-related bone disorder; proliferative disorders such as acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as solid tumors, angiogenic disorders including ocular neovascularization and infantile hemangiomas; infectious diseases such as sepsis, septic shock and bacillary dysentery; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, cerebral ischemia, or neurodegenerative diseases caused by traumatic injury, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and neoplastic and viral diseases such as HIV infection, and CMV retinitis, AIDS.

[0072] More specifically, specific conditions or diseases that may be treated with the compounds of the present invention include, but are not limited to, 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, and the like. inflammation, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, infectious onset Fever and myalgia, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, heartburn, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, neurodegenerative diseases caused by cerebral ischemia or traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization and infantile hemangiomas; acute hepatitis infection (hepatitis A, hepatitis B, hepatitis and hepatitis C), HIV infection and CMV retinitis, viral diseases including AIDS, ARC or malignant tumors and herpes; stroke, myocardial ischemia, ischemia in apoptotic 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 synthase-2, and pemphigus vulgaris. This embodiment includes a method of treatment where the condition is selected from 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-reperfusion injury caused by stroke, and cardiac ischemia-reperfusion injury caused by myocardial infarction. Another method of treatment is one in which the condition is multiple myeloma.

[0073] In one embodiment, the compounds of formula (I) are useful for the treatment of cancer, including Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B-cell lymphoma, primary CNS lymphoma.

[0074] In addition, the TLR7, TLR8, or TLR9 inhibitors of the present invention inhibit the expression of inducible pro-inflammatory proteins, such as prostaglandin endoperoxidase synthase-2 (PGHS-2) (also called cyclooxygenase-2 (COX-2)), IL-1, IL-6, IL-18, chemokines, etc. Thus, further TLR7 / 8 / 9-associated symptoms include edema, analgesia, fever, and pain, such as neuromuscular pain, headache, cancer-induced pain, dental pain, and arthritis pain. The compounds of the present invention may also be used to treat veterinary viral infections, such as lentivirus infections (including, but not limited to, equine infectious anemia virus infections); or retrovirus infections (including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus infections).

[0075] Thus, the present invention provides a method of treating such conditions, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a salt thereof. A "therapeutically effective 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 an autoimmune disease or chronic inflammatory disease.

[0076] Methods of treating TLR7, TLR8, or TLR9 associated conditions may include administering a compound of formula (I) alone or in combination with each other and / or other suitable therapeutic agents useful in treating such conditions. Thus, a "therapeutically effective amount" is also intended to include the amount of a combination of compounds that is claimed to be effective in inhibiting TLR7, TLR8, or TLR9 and / or treating a disease associated with TLR7, TLR8, or TLR9.

[0077] Examples 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); nonsteroidal anti-inflammatory drugs (NSAIDs) 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®); antimalarials such as hydroxychloroquine; cytotoxic agents such as azathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or RAPAMUNE®) or derivatives thereof.

[0078] The other therapeutic agents described above, when utilized in combination with the compounds of the present invention, may be used, for example, in amounts as indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of skill in the art. In the methods of the present invention, such other therapeutic agents may be administered prior to, simultaneously with, or after administration of the compounds of the present invention. 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.

[0079] The compositions of the invention may contain other therapeutic agents as described above and may be formulated according to methods such as techniques well known in the art of pharmaceutical formulation, for example, by utilizing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.) of a type appropriate for the desired mode of administration. Accordingly, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharma- ceutically acceptable carrier.

[0080] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors well within the scope of the skilled artisan's concerns. These include, but are not limited to, the type and characteristics of the active agent being formulated; the subject to which the composition containing the active agent is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid forms. Such carriers can include many different components and additives in addition to the active agent, and such additional components are included in the formulation for a variety of reasons well known to those skilled in the art, such as stabilization of the active agent, binders, etc. Descriptions of suitable pharmacopoeia acceptable carriers and the factors involved in their selection can be found in many readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 17th Edition (1985), the contents of which are incorporated herein by reference.

[0081] The compounds of formula (I) may be administered by any means appropriate to the condition to be treated, which may vary depending on the need for site-specific treatment or the amount of compound of formula (I) delivered.

[0082] Also included within the scope of the present invention is a series of pharmaceutical compositions comprising a compound of formula (I) and one or more non-toxic pharma- ceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "carrier" materials), and optionally other active ingredients. The compound of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such route, in a dose effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, transmucosally, or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, in the form of dosage unit formulations containing conventional pharma- cetically acceptable carriers, adjuvants, and vehicles. For example, the pharmaceutical carrier may contain a mixture of mannitol or lactose with microcrystalline cellulose. The mixture may contain additional ingredients such as lubricants, disintegrants such as magnesium stearate, crospovidone, and the like. The carrier mixture may be filled into gelatin capsules or compressed into tablets. For example, the pharmaceutical composition may be administered as an oral dosage form or as an injection.

[0083] 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 prepared in the form of a dosage unit containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The daily dose suitable for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.

[0084] Any pharmaceutical composition of the present invention can be delivered orally, for example, via any acceptable and applicable oral formulation.Typical oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs.The pharmaceutical composition intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration.In order to provide a pharma-ceutically acceptable formulation, the pharmaceutical composition of the present invention can contain at least one agent selected from sweeteners, flavoring agents, coloring agents, analgesics, antioxidants and preservatives.

[0085] Tablets can be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharma- ceutically acceptable excipient suitable for tablet preparation. Typical excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, sodium croscarmellose, corn starch, and alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. In addition, tablets can be either uncoated or coated by known techniques to either mask the unpleasant taste of unpleasant-tasting drugs, delay disintegration, and delay the absorption of active ingredients in the digestive tract, thereby prolonging the action of the active ingredients. Typical water-soluble taste-masking substances include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0086] Hard gelatin capsules may be prepared, for example, 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 be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier, such as, for example, polyethylene glycol; at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.

[0087] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) with at least one excipient suitable for preparing aqueous suspensions.Typical excipients suitable for preparing aqueous suspensions include, but are not limited to, suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides, such as lecithin; condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols, such as heptadecaethylene-oxycetanol; condensation products of ethylene oxides and partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain, by way of example only, at least one preservative, such as 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).

[0088] Oily suspensions can be prepared by suspending at least one compound of formula (I) in any of the following: vegetable oils, such as peanut oil; olive oil; sesame oil; and coconut oil; or mineral oils, such as liquid paraffin.Oily suspensions can also contain at least one thickening agent, such as beeswax; hard paraffin; and cetyl alcohol.To provide acceptable oily suspensions, at least one sweetener and / or at least one flavoring agent, as described above, can be added to the oily suspension.Oily suspensions can further contain at least one preservative, including, but not limited to, antioxidants, such as butylated hydroxyanisole and alpha-tocopherol.

[0089] Dispersible powder or granule can be prepared, for example, by mixing at least one compound represented by formula (I) with at least one dispersing agent and / or wetting agent; with at least one suspending agent; and / or with at least one preservative.Suitable dispersing agents, wetting agents and suspending agents are as described above.Exemplary preservatives include, but are not limited to, antioxidants, for example, ascorbic acid.In addition, dispersible powder or granule can also contain at least one excipient, including, but are not limited to, sweeteners; flavoring agents; and coloring agents.

[0090] The emulsion of at least one compound of formula (I) may be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of formula (I) may be composed of known ingredients in a known manner. The oil phase may be provided, for example, by vegetable oils, such as, for example, olive oil and peanut oil; mineral oils, for example, liquid paraffin; and mixtures thereof. The oil phase may contain only an emulsifier, but may also contain a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Suitable emulsifiers include, for example, but are not limited to, naturally occurring phosphatides, such as soy lecithin; esters or partial esters derived from fatty acids, such as sorbitan monooleate, and hexitol anhydrides; and condensation products of partial esters, such as polyoxyethylene sorbitan monooleate, and ethylene oxide. It is preferred to include a hydrophilic emulsifier together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to incorporate both an oil and a fat. The emulsifier, with or without stabilizers, forms the so-called emulsifying wax, which, together with fats and oils, forms the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations. The emulsion may also contain sweeteners, flavorings, preservatives and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or together with waxes, or other materials well known in the art.

[0091] The compound of formula (I) can also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly, via any medicamentously acceptable and suitable injectable form.Typical injectable forms include, but are not limited to, for example, sterile aqueous solutions, including acceptable vehicles and solvents such as water, Ringer's solution and sodium chloride isotonic solution; sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0092] Preparations for parenteral administration may be in 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 carriers or diluents mentioned for use in preparations 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, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum and / or various buffers. Other adjuvants and methods of administration are well known in the pharmaceutical field. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose or water, or with cyclodextrins (i.e. Captisol), cosolvent solubilizers (i.e. propylene glycol) or micellar solubilizers (i.e. Tween 80).

[0093] Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used therein include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are found to be useful in injectable preparations.

[0094] Sterile injectable oil-in-water microemulsions can be prepared, for example, by 1) dissolving at least one compound of formula (I) in an oil phase, such as a mixture of soybean oil and lecithin; 2) combining the oil phase containing the compound of formula (I) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

[0095] Sterile aqueous or oily suspensions can be prepared according to methods known in the art. For example, sterile aqueous or aqueous suspensions can be prepared using non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol; sterile oily suspensions can be prepared using sterile, non-toxic acceptable solvents or suspending media, such as sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as oleic acid.

[0096] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween, polyethoxylated castor oil such as CREMOPHOR® surfactants (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, polyvinylpyrrolidone, cellulosic materials, 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-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to facilitate delivery of the compounds in the formulations described herein.

[0097] The pharma- ceutical active compounds of the present invention can be processed according to conventional operations in the field of pharmacy to produce medicaments for administration to patients, including humans and other mammals. The pharmaceutical compositions may be subjected to common pharmaceutical practices, such as sterilization, and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like. Tablets and pills may further be prepared with enteric coatings. Such compositions may also contain adjuvants, such as wetting agents, sweeteners, flavoring agents, and fragrances.

[0098] The amount of compound and dosing regimen administered to treat a condition with the compounds and / or compositions of the present invention will depend on a variety of factors, including the age, weight, sex, medical condition, type of disease, severity of disease, route and frequency of administration, and the particular compound utilized. Thus, dosing regimens may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001-100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight, most preferably between about 0.005-10 mg / kg body weight, may be appropriate. The daily dose may be administered in one to four doses per day. Other dosing regimens include cycles of administration once a week and once every two days.

[0099] For carrying out treatment, the active compound of the present invention is usually combined with one or more adjuvants suitable for the suggested administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can contain release control agent, as can be provided by dispersing the active compound in hydroxypropylmethylcellulose.

[0100] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and, optionally, further agents selected from any pharma- ceutically acceptable carrier, adjuvant, and vehicle. Alternatively, the compositions of the present invention comprise a compound of formula (I) or a prodrug thereof as described herein, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0101] The present invention also encompasses an article of manufacture. As used herein, an article of manufacture includes, but is not limited to, a kit and a package. An article of manufacture of the present invention includes (a) a first container; (b) a pharmaceutical composition contained in the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharma- ceutically acceptable salt form thereof; and (c) a package insert indicating that the pharmaceutical composition can be used to treat an inflammatory disorder and / or an autoimmune disease (as described above). In another embodiment, the package insert describes that the pharmaceutical composition can be used in combination with a second therapeutic agent (as described above) to treat an inflammatory disorder and / or an autoimmune disease. The article of manufacture can further include (d) a second container, wherein components (a) and (b) are contained in the second container, and component (c) is placed inside or outside the second container. Being contained in the first and second containers means that each container holds its items within its boundaries.

[0102] The first container is a container used to hold a pharmaceutical composition. This container may be for manufacturing, storage, shipping, and / or individual / bulk sale. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., tubes for cream formulations), or any other container used to manufacture, hold, store, or distribute pharmaceutical products.

[0103] The second container is a container 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, bins, bags (e.g., paper or plastic bags), sachets, and sacks. The package insert can be physically attached to the outside of the first container via tape, adhesive, staples, or another adhesive method, or can be placed inside the second container without any physical means of attachment to the first container. Alternatively, the package insert can be placed outside the second container. When placed outside the second container, the package insert is preferably physically attached via tape, adhesive, staples, or another adhesive method. Alternatively, the package insert can be adjacent to or in contact with the outside of the second container without being physically attached.

[0104] The package insert is a label, tag, marker, etc., that describes information about the pharmaceutical composition contained in the first container. The information described will usually be determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is sold. In one embodiment, the package insert specifically describes the indication for which the pharmaceutical composition is approved. The package insert may be made of any material that allows a person to read the 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 is formed (e.g., printed or coated).

[0105] Manufacturing method The compounds of the present invention can be prepared in many ways well known to those 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 with variations thereon as recognized by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All references cited herein are incorporated herein by reference.

[0106] The compounds of the present invention can be prepared using the reactions and methods described in this section. The reactions are carried out in solvents suitable for the reagents and materials employed, and the reactions are suitable for transformation. It should also be understood that in the following description of the synthetic methods, all reaction conditions proposed, including the choice of solvent, reaction environment, reaction temperature, duration of the experiment, and work-up procedures, are selected to be standard conditions for the reaction, which would be readily recognized by one skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups on the various parts of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on the substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods will then need to be used. This will sometimes require judgment to modify the order of synthetic steps or to select one particular process scheme over another to obtain the desired compound of the present invention. It should also be understood that another major factor in planning a synthetic route in this field is the correct selection of the protecting groups used to protect the functional groups present in the compounds described in the present invention. An authoritative manual teaching many of these modifications to one of skill in the art is Greene and Wuts (Protective Groups in Organic Synthesis, 3rd ed., Wiley and Sons, 1999).

[0107] Working Example The preparation of the compounds of formula (I), and intermediates used in the preparation of the compounds of formula (I), may be prepared using the procedures set forth in the following examples, and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not intended to be limiting, but rather to illustrate how the compounds of formula (I) may be prepared. The starting materials and reagents used in these examples, if not prepared by the procedures described herein, are generally either commercially available, reported in the chemical literature, or can be prepared using procedures described in the chemical literature.

[0108] Abbreviation [Table 1] [Table 2]

[0109] Analytical and preparative HPLC conditions: QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, 1.7μm particles; Mobile phase A: 5:95 acetonitrile:water + 10mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water + 10mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 min, then hold at 100% B for 0.75 min; Flow: 1.0mL / min; Detection: UV (220nm)

[0110] QC-ACN-TFA-XB: Column: Waters Acquity UPLC BEH C18, 2.1x50mm, 1.7μm particles; Mobile phase A: 5:95 acetonitrile:water + 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water + 0.1% trifluoroacetic acid; Temperature: 50°C; Gradient: 0-100% B over 3 min, then hold at 100% B for 0.75 min; Flow: 1.0mL / min; Detection: UV (220nm)

[0111] (TS): Column: Waters Acquity UPLC BEH C18 (2.1x50mm), 1.7 micron; Solvent A = 100% water + 0.05% TFA; Solvent B = 100% acetonitrile + 0.05% TFA; Gradient = 2-98% B over 1 min, then hold at 98% B for 0.5 min; Flow rate: 0.8 mL / min; Detection: UV (254 nm)

[0112] Example 1 N1,N13-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tridecanediamide [ka]

[0113] Intermediate 1A: 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-amine [ka] To a 20 mL scintillation vial was added tert-butyl 4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidine-1-carboxylate (200 mg, 0.408 mmol), DCM (3 mL), and TFA (3 mL). The reaction was stirred at room temperature for 30 min, at which point LCMS indicated Boc deprotection was complete. The vial was concentrated under a stream of N2 and triturated several times with ether, at which point a solid formed. The product was dissolved in DMF (5 mL) and DIEA (0.214 mL, 1.225 mmol) was added, followed by tert-butyl (2-oxoethyl)carbamate (195 mg, 1.225 mmol). After 30 min, sodium triacetoxyborohydride (260 mg, 1.225 mmol) was added. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified on silica gel (DCM / MeOH 0-15%) to give tert-butyl (2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)carbamate, which was immediately treated with TFA / DCM for 30 min. LCMS shows removal of the Boc group. The solvent was removed under vacuum. The material was diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated to give 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-amine (72 mg, 0.166 mmol, 40.7% yield). LCMS retention time 0.6 min [TS]; MS (E + ) m / z: 433.3 (M+H)

[0114] Example 1: To a mixture of tridecanedioic acid (6.78 mg, 0.028 mmol) and DIEA (0.015 mL, 0.083 mmol) in DMF (2 mL), HATU (21.10 mg, 0.055 mmol) was added. After 30 minutes, 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-amine (24 mg, 0.055 mmol) was added. The reaction mixture was stirred for 1 hour. The reaction mixture was filtered and purified by HPLC to give N1,N13-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tridecanediamide (12.4 mg, 0.011 mmol, 40.8% yield). LCMS retention time 0.77 min [TS]; MS(E + ) m / z: 1073.8 (M+H); 1 H NMR (500MHz, DMSO-d6)δ 11.25(s,2H), 8.61-8.55(m,2H), 8.53-8.49(m,2H), 8.22-8.12(m,2H), 7.62-7.55 (m,2H), 7.37(d,J=8.2Hz,2H), 7.16(s,2H), 7.04(brd,J=8.5Hz,2H), 4.11-4.04(m, 6H), 3.66(brd,J=11.0Hz,2H), 3.23-3.09(m,6H), 2.98-2.78(m,2H), 2.54-2.48(m, 9H), 2.21-1.90(m,12H), 1.57-1.48(m,4H), 1.48-1.42(m,12H), 1.34-1.17(m,15H)

[0115] The following examples were prepared following the general procedures described in the examples above. [ka]

[0116] Table 1 [Table 3]

[0117] Example 12 1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane [ka] To a mixture of 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (21.73 mg, 0.056 mmol) and potassium carbonate (15.42 mg, 0.112 mmol) in DMF (2 mL), 1,18-dibromooctadecane (11.5 mg, 0.028 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, heated to 70° C., and stirred overnight. The reaction mixture was cooled, filtered and purified by HPLC to give 1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane (8 mg, 7.62 μmol, 27.3% yield). LCMS retention time 2.65 min [QC-ACN-AA-XB]; MS(E + ) m / z: 1030.07 (M+H); 1 H NMR (500MHz, DMSO-d6) δ 11.24(s,2H), 8.53(s,2H), 8.50(s,2H), 7.58(s,2H), 7.37(d,J=8.5Hz,2H ), 7.13(s,2H), 7.04(brd,J=8.2Hz,2H), 4.06(s,6H), 3.32(dt,J=14.0, 7. 0Hz,2H), 3.06(brd,J=7.0Hz,6H), 2.92(brs,2H), 2.52-2.49(m,6H), 2.14 -1.88(m,7H), 1.68(brs,4H), 1.45(brd,J=7.0Hz,11H), 1.38-1.17(m,30H)

[0118] Comparative Example Compound C1 1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane-1,18-dione [ka] To a mixture of octadecanedioic acid (8.88 mg, 0.028 mmol) and DIEA (0.015 mL, 0.085 mmol) in DMF (2 mL) was added HATU (21.48 mg, 0.056 mmol). After 30 min, 6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (22 mg, 0.056 mmol) was added. The reaction mixture was stirred for 2 hours, then filtered and purified by HPLC to give 1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane-1,18-dione (10.6 mg, 10.02 μmol, 35.5% yield). LCMS retention time 3.02 min [QC-ACN-AA-XB]; MS(E + ) m / z: 1057.94 (M+H); 1 H NMR (500MHz, DMSO-d6)δ 11.15(s,2H), 8.56(s,2H), 8.51(s,2H), 7.57(s,2H), 7.32(d,J=8.2Hz,2H), 7.15(s,2H), 7.03(brd,J=8.5Hz,2H), 4.59(brd,J=11.9Hz,2H), 4.08(s,6H), 3.12(brt,J=11.9Hz,2H), 2.85(brt,J=12.2Hz,2H), 2.61(brt,J=11.6Hz,2H), 2.46-2.18(m,5H), 1.85(brt,J=15.3H z,4H), 1.70-1.57(m,2H), 1.56-1.48(m,6H), 1.46(brd,J=7.0Hz,12H), 1.36-1.20(m,27H)

[0119] The following compounds were prepared following the general procedures described for the compounds above. [ka]

[0120] Table 2 [Table 4]

[0121] Comparative Example Compound C4 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-amine [ka] The preparation of comparative compound C4 is described in Intermediate 1A.

[0122] Comparative Example Compound C5 N-(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)acetamide [ka] To a mixture of 2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethan-1-amine·2TFA (20 mg, 0.030 mmol) and TEA (0.013 mL, 0.091 mmol) in DCM (1 mL) was added acetic anhydride (2.86 μL, 0.030 mmol). The reaction mixture was stirred for 1 h, then the solvent was removed in vacuo and the crude material was purified by HPLC to give N-(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)acetamide (12.6 mg, 0.026 mmol, 87% yield). LCMS retention time 1.16 min [QC-ACN-AA-XB]; MS(E + ) m / z: 475.1 (M+H); 1 H NMR (500MHz, DMSO-d6)δ 11.14(s,1H), 8.56(s,1H), 8.52(s,1H), 7.81(brs,1H), 7.58(s,1H), 7.33(d ,J=8.2Hz,1H), 7.16(s,1H), 7.05(brd,J=8.9Hz,1H), 4.09(s,3H), 3.27-3.1 7(m,1H), 3.03(brd,J=10.7Hz,1H), 2.65-2.56(m,2H), 2.48-2.36(m,2H), 2. 14(brt,J=8.2Hz,2H), 1.92(s,3H), 1.87-1.69(m,6H), 1.47(d,J=7.0Hz,6H)

[0123] Biological assays The pharmacological properties of the compounds of the invention can be confirmed in a number of biological assays. The following representative biological assays have been carried out with the compounds of the invention.

[0124] TLR7 / 8 / 9 Inhibitory Receptor Assay HEK-Blue® cells (Invivogen) overexpressing human TLR7, TLR8 or TLR9 receptors, using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of an IFN-β minimal promoter fusion with five NF-κB and AP-1-binding sites, were used to screen inhibitors of these receptors. Briefly, cells were seeded in Greiner 384-well plates (15,000 cells / well for TLR7, 20,000 cells / well for TLR8, and 25,000 cells / well for TLR9) and then treated with test compounds in DMSO to give final dose response concentrations ranging from 0.05 nM to 50 μM. After 30 minutes of pretreatment with compounds at room temperature, the cells are then stimulated with TLR7 ligand (gardiquimod at 7.5 μM final concentration), TLR8 ligand (R848 at 15.9 μM final concentration), or TLR9 ligand (ODN2006 at 5 nM final concentration) to activate NF-κB and AP-1, thereby inducing the production of SEAP. After 22 hours of incubation at 37° C. and 5% CO2, SEAP levels are measured by adding HEK-Blue® detection reagent (Invivogen), cell culture medium, which allows the detection of SEAP, according to the manufacturer's specifications. % inhibition is measured as the % reduction in HEK-Blue signal present in wells treated with agonist and DMSO alone compared to wells treated with known inhibitors.

[0125] Table 2 TLR7 / 8 / 9 Receptor Assay Data [Table 5]

Claims

1. Formula (I): [Formula 1] [In the formula: L is -(CH ２ ) １８ - or -L １ -NR ｘ C(O)-(CH ２ ) ｔ -C(O)NR ｘ -L ２ - and L １ and L ２ are each -(CH ２ ) ２ - and t is an integer ranging from 2 to 12; G １ and G ２ are, respectively, [Case 2] and R １ａ and R １ｂ are each -CH(CH ３ ) ２ and R ２ Each independently represents -OCH ３ and R ４ are each independently F, —OH, C １－２ Alkyl, or -OCH ３ or two R ４ form =O; or when m or n is at least 2, two R ４ are each bonded to a different carbon atom adjacent to the nitrogen atom in the piperidinyl ring and are each —CH ２ CH ２ - capable of forming crosslinks; R ５ are each independently F, Cl, -CN, C １－３ Alkyl, C １－２ Fluoroalkyl, or -OCH ３ and R ｘare each independently H or -CH ３ and m is 0; n is 0; p is 1 at each occurrence; x is 0; and y is 0. A compound represented by the formula:

2. The compound is: N1,N13-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tridecanediamide (1); N1,N14-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tetradecanediamide (2); N1,N12-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)dodecanediamide (3); N1,N11-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)undecanediamide (4); N1,N9-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)nonanediamide (5); N1,N8-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)octanediamide (6); N1,N10-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)decanediamide (7); N1,N7-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)heptanediamide (8); N1,N6-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)adipamide (9); N1,N12-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)dodecanediamide (10); N1,N4-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)succinamide (11); or 1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane (12) or a salt thereof.

3. 3. A pharmaceutical composition comprising a compound according to claim 1 or 2, or a salt thereof, and a pharma- ceutically acceptable carrier.

4. 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, for use in therapy.

5. A pharmaceutical composition according to claim 3 for use in therapy.

6. The pharmaceutical composition according to claim 5 for treating an autoimmune disease or a chronic inflammatory disease.

7. 7. The pharmaceutical composition of claim 6, wherein the autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjogren's syndrome.

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