HK1232797B - Modulators of toll-like receptors for the treatment of hiv - Google Patents

Description

Toll-like receptor modulators for the treatment of HIV

Technical Field

The present application generally relates to compounds and pharmaceutical compositions that selectively modulate toll-like receptors (eg, TLR7) and methods of using these compounds to treat human immunodeficiency virus (HIV) infection.

Background Art

The innate immune system provides the body's first line of defense against invading pathogens. During the innate immune response, invading pathogens are recognized by germline-encoded receptors, whose activation initiates a signaling cascade that induces cytokine expression. Innate immune system receptors have broad specificity, recognizing molecular structures that are highly conserved among different pathogens. One family of these receptors is termed Toll-like receptors (TLRs) due to their homology to receptors first identified and named in Drosophila and found on cells such as macrophages, dendritic cells, and epithelial cells.

There are at least ten distinct TLRs in mammals. For some of these receptors, their ligands and corresponding signaling cascades have been identified. For example, TLR2 is activated by lipoproteins from bacteria (e.g., Escherichia coli), TLR3 is activated by double-stranded RNA, TLR4 is activated by lipopolysaccharides (i.e., LPS or endotoxins) from Gram-negative bacteria (e.g., Salmonella and E. coli O157:H7), TLR5 is activated by flagellin from motile bacteria (e.g., Listeria monocytogenes), TLR7 recognizes and responds to imiquimod, and TLR9 is activated by unmethylated CpG sequences in pathogen DNA. Stimulation of each of these receptors leads to activation of the transcription factor NF-κB and other signaling molecules involved in regulating cytokine gene expression, including those encoding tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and certain chemokines. TLR7 agonists are immunostimulants and induce endogenous interferon-α production in vivo.

There are many diseases, disorders, and symptoms associated with TLRs for which treatment with TLR agonists is considered promising, including but not limited to melanoma, non-small cell lung cancer, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, liver fibrosis, and viral infections.

TLR7 modulating compounds include U.S. Patent Nos. 8,367,670, 8,629,142, and 8,809,527 TLR7 agonist compounds, as indicated by the IFN-α minimum effective concentration (MEC). The activity of the TLR7 agonist GS-9620 has been discussed in Lanford et al., Gastroenterology 2013 June; 144(7): 1508-17; Roethle et al., Journal of Medicinal Chemistry, Vol. 56, No. 18, pp. 7324-7333, discuss the TLR7 agonist activity of compounds in U.S. Patent Nos. 8,367,670, 8,629,142, and 8,809,527, including those of Examples 4, 49, 89, 99, and 105.

U.S. Patent No. 8,507,507 discloses TLR7 agonist compounds including 4-amino-6-(2-methoxyethoxy)-1-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one. U.S. Patent No. 7,968,544 teaches TLR7 agonist compounds including 6-amino-2-butoxy-9-(3-(pyrrolidin-1-ylmethyl)benzyl)-9H-purin-8-ol.

Around the world, more than 30 million people have been infected with HIV. Developed many drugs and combination therapies for the treatment of human HIV infection. Although combined antiretroviral therapy (cART) and highly active antiretroviral therapy (HAART) can reduce HIV virus activation, usually below 50 HIV RNA copies/ml plasma, there is no therapy that can eliminate the cells of HIV infection of inactive replication HIV (commonly referred to as patient's HIV latent reservoir). The strategy of " kicking out and killing " method for the treatment of HIV has been sought, wherein the cells of the latent reservoir " kick out " HIV infected cells to induce transcription of static and replicative HIV provirus, produce transient viremia (viremia) and make activated cells susceptible to " killing " of antiretroviral therapy. The “kick-out” program has tested a variety of agents, including histone deacetylase inhibitors, disulfiram, PD-1 antibodies, and HIV vaccines, as mentioned in the following papers: Prospects for Treatment of Latent HIV, Barton et al., Pharm. & Therap., Vol. 93, No. 1, pp. 46-56; Neutralizing the HIV Reservoir, Marsden et al., Cell, 158, Aug. 28, 2014, pp. 971-972; HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies, Battistini et al., Viruses 2014, 6, 1715-1758; and Quantification of HIV-1 latency reversal inresting CD4+ T cells from patients on suppressive antiretroviral therapy, Cillo et al., PNAS, May 13, 2014, 111, No. 19, pp. 7078-7083.

There remains a need for new agents and therapies that can aid in the activation of latent HIV-infected cells to enhance the activity of antiretroviral therapy and immune responses.

Summary of the Invention

Provided herein are therapeutic methods, regimens, pharmaceutical formulations, and kits useful for treating HIV infection in humans, wherein the therapeutic methods, regimens, pharmaceutical formulations, and kits each comprise the use of a TLR7 modulating compound, including a compound of Formula II or a pharmaceutically acceptable salt thereof:

in:

YZ is –CR ⁴ R ⁵ -, -CR ⁴ R ⁵ -CR ⁴ R ⁵ -, -C(O)CR ⁴ R ⁵ -, -CR ⁴ R ⁵ C(O)-, -NR ⁸ C(O)-, -C(O)NR ⁸ -, -CR ⁴ R ⁵ S(O) ₂ -, or –CR ⁵ =CR ⁵ -;

L ¹ is -NR ⁸ -, -O-, -S-, -N(R ⁸ )C(O)-, -S(O) ₂ -, -S(O)-, -C(O)N(R ⁸ )-, -N(R ⁸ )S(O) ₂ -, -S(O) ₂ N(R ⁸ )-, or a covalent bond;

^R1 is _C1 - _C8 alkyl, _C1 - _C8 substituted alkyl, haloalkyl, C2- _C8 alkenyl, _C2 - _C8 substituted alkenyl, _C2 - _C8 alkynyl, _C2 - _C8 substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, _{carbocyclylalkyl} , substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl;

X ¹ is C ₁ -C ₈ alkylene, C ₁ -C ₈ substituted alkylene, heteroalkylene, substituted heteroalkylene, C ₂ -C 8 alkenylene, C ₂ -C ₈ substituted alkenylene, _C 2 -C ₈ alkynylene, C _{2 -C 8} substituted alkynylene, carbocyclylene, substituted carbocyclylene, heterocyclylene, substituted heterocyclylene, -NR ⁸ -, -O-, -C(O)-, -S(O)-, S(O) ₂ -, or a bond;

D is carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl, wherein the carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl is substituted with one or two -L ² -NR ⁶ R ⁷ ; or

D is heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl, wherein the heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl contains one to four nitrogen atoms;

L ² is each independently C ₁ -C ₈ alkylene, C ₁ -C ₈ substituted alkylene, heteroalkylene, substituted heteroalkylene, or a covalent bond;

R ³ is each independently halogen, cyano, azido, nitro, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, hydroxy, amino, heteroalkyl, substituted heteroalkyl, C ₁ -C ₈ alkoxy, haloalkyl, haloalkoxy, -CHO, -C(O)OR ⁸ , -S(O)R ⁸ , -S(O) ₂ R ⁸ ; -C(O)NR ⁹ R ¹⁰ , -N(R ⁹ )C(O)R ⁸ , carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ substituted alkenyl, C ₂ -C ₈ alkynyl, C ₂ -C ₈ substituted alkynyl, -S(O) ₂ NR ⁹ R ¹⁰ , -N(R ⁹ )S(O) ₂ R ⁸ , -N(R ⁹ )S(O) ₂ OR ¹⁰ , -OS(O) ₂ NR ⁹ R ¹⁰ ;

n is 0, 1, 2, 3, 4 or 5;

^R4 and ^R5 are each independently H, _C1 - _C8 alkyl, _C1 - _C8 substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, cyano, azido, OR8, -C(O)H, -C ₍ O) ^R8 , -S(O) ^R8 , ^-S (O) ^2R8 , -C(O) ^OR8 , or -C(O) ^NR9R10 ; ^or

^R4 and ^R5 together with the carbon atoms to which they are attached form a carbocycle, a substituted carbocycle, a heterocycle or a substituted heterocycle; or

When R ⁴ and R ⁵ are on the same carbon atom, together with the carbon atom to which they are attached, they represent -C(O)- or -C(NR ⁸ )-; or

Two R ⁴ or two R ⁵ on adjacent carbon atoms together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic, substituted carbocyclic, heterocyclic, or substituted heterocyclic ring;

^R6 and ^R7 are each independently H, _C1 - _C8 alkyl, _C1 - _C8 substituted alkyl, _C2 - _C8 alkenyl, _C2 - _C8 substituted alkenyl, _C2 - _C8 alkynyl, _C2 - _C8 substituted alkynyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, -C(O)H, -C(O) ^R8 , -S(O) ^R8 , -S(O ⁾ _2R8 , -C(O)OR ⁸ , or -C(O)NR ⁹ R ¹⁰ , S(O) ₂ NR ⁹ R ¹⁰ ; or

^R6 and ^R7 together with the nitrogen atom to which they are both attached form a substituted or unsubstituted heterocyclic ring which may contain one or more heteroatoms selected from N, O, P or S; or

R ⁷ and L ² together with the nitrogen atom to which they are both attached form a substituted or unsubstituted 3 to 8 membered heterocyclic ring which may contain one or more additional heteroatoms selected from N, O, S or P;

R ^is H, _C1 - _C8 alkyl, _C1 - _C8 substituted alkyl, haloalkyl, C2- _C8 alkenyl, _C2 - _C8 substituted alkenyl, _C2 - _C8 alkynyl, _C2 - _C8 substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, _{carbocyclylalkyl} , substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl; and

^R9 and ^R10 are each independently H, _C1 - _C8 alkyl, _C1 - _C8 substituted alkyl, _C2 - _C8 alkenyl, _C2 - _C8 substituted alkenyl, _C2 - _C8 alkynyl, _C2 - _C8 substituted alkynyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl; or

^R9 and ^R10 together with the nitrogen atom to which they are both attached form a substituted or unsubstituted heterocyclic ring;

wherein each of the substituted alkyl, substituted alkenyl, substituted alkynyl, substituted heteroalkyl, substituted carbocyclyl, substituted carbocyclylalkyl, substituted heterocyclyl, substituted heterocyclylalkyl, substituted aralkyl, substituted heteroaralkyl, substituted carbocyclylheteroalkyl, substituted heterocyclylheteroalkyl, substituted arylheteroalkyl, substituted heteroarylheteroalkyl, substituted alkylene, substituted heteroalkylene, substituted alkenylene, substituted alkynylene, substituted carbocyclylene, or substituted heterocyclylene is independently substituted by one to four groups selected from -halogen, -R, ^-O- , =O, -OR, -SR, -S-, -NR2, -N(+)R3, =NR, -C(halogen _{)3 ,} -CR(halogen) ² _, -CR2(halogen), -CN, -OCN, -SCN, -N=C=O, -NCS, _-NO , _-NO2 , = _{N2 ,} -N _3. -NRC(=O)R, -NRC(=O)OR, -NRC(=O)NRR, -C(=O)NRR, -C(=O)OR, -OC(=O)NRR, -OC(=O)OR, -C(=O)R, -S(=O) ₂ OR, -S(=O) ₂ R, -OS(=O) ₂ OR, -S(=O) ₂ NR, -S(=O)R, -NRS(=O) ₂ R, -NRS(=O) ₂ NRR, -NRS(=O) ₂ OR, -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -P(O)(OR)(O)R, -C(＝O)R, -C(＝S)R, -C(＝O)OR, -C(＝S)OR, -C(＝O)SR, -C(＝S)SR, -C(＝O)NRR, -C(＝S)NRR, -C(＝NR)NRR and -NRC(＝NR)NRR; wherein each R is independently H, alkyl, cycloalkyl, aryl, aralkyl or heterocyclyl.

The compound of formula II and pharmaceutically acceptable salts thereof can be prepared by the methods disclosed in US 2010/014330, US 8,367,670 and US 8,629,142 (Desai et al.), which are incorporated herein by reference in their entireties, or by other methods known in the art.

Without being bound by any theory, the inventors currently believe that the compound of Formula II and the compounds of Examples 119, 120, 121, 123 and 124 are agonists of TLR7 and may also be agonists of other TLRs.

Another aspect of the invention includes a method for treating HIV infection in a human, comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula II.

The present invention includes the various aspects and embodiments and combinations of preferences described herein throughout the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the absolute viral load per animal on each study day in the SIV ⁺ rhesus macaques study.

Figure 2 depicts the change in viral load from baseline (Day 0) on each study day in the SIV ⁺ rhesus macaque study.

Figure 3 depicts the absolute viral load per animal on each study day in the SIV ⁺ rhesus macaque study.

Figure 4 depicts CD8 ⁺ T lymphocyte activation induced by administration of the compound of Example 4 in a SIV ⁺ rhesus monkey study.

Figure 5 depicts NK cell activation induced by administration of the compound of Example 4 in a SIV ⁺ rhesus monkey study.

Figure 6 depicts changes in activated CD4 lymphocytes in SIV ⁺ rhesus monkeys on cART following administration of the compound of Example 4.

Figure 7 depicts ex vivo activation of HIV by the compound of Example 49 in PBMCs from HIV+ patients on cART.

Figure 8 depicts that maximal HIV activation by the compound of Example 49 is dependent on IFNα/β signaling.

FIG. 9 depicts ex vivo activation of HIV by recombinant IFNα.

Figure 10 depicts the correlation of HIV activation indicated by vRNA levels plotted at concentrations of Example 49 that induce peak IP-10 or I-TAC levels.

Figure 11 depicts HIV induction in PBMCs treated with Example 4 or DMSO and subsequent stimulation with a PKC agonist (indole lactam).

FIG. 12 depicts the increased proliferation levels in CD8 cells treated with Example 49.

FIG. 13 depicts the increased proliferation levels in CD8 cells treated with Example 49 and an IDO1 inhibitor.

Figure 14 depicts the enhanced killing of HIV-infected CD4 cells treated with Example 49 and PGT121.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the present invention, examples of which are illustrated in the accompanying structures and formulas. Although the present invention will be described in conjunction with the enumerated claims, it will be understood that the present invention is not intended to limit the invention to those claims. On the contrary, the present invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims.

All documents cited herein are hereby incorporated by reference in their entirety for all instances.

TLR7 modulating compounds (TLR7 modulators) that can be used in the methods, combinations, pharmaceutical compositions, uses and dosing regimens described herein include GSK2245035, imiquimod, resiquimod (R848), R-852 (PF-4878691), ANA773, 5-amino-7-hydroxy-3-((2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)thiazolo[4,5-d]pyrimidin-2(3H)-one (active metabolite of ANA773), AZD8848 (DSP3025), SM-360320, IMO-8400, CL097, CL075 (3M002), Gardiquimod ^™ (1-(4-amino-2-ethylaminomethylimidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol), etoribine, 6-amino-2-(butylamino)-7,9-dihydro-9-[(6-methyl-3-pyridyl)methyl]-8H-purin-8-one (SM-276001), 852A (N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide), 3M-854A and 3M-052, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide -4-yl)-4,4-dimethylpentan-2-one (S-34240), loxoribine, and in US8729088B2, US8728486B2, US8728465B2, US20140142086A1, US20140134132A1, US20110053893A1, WO2013068438A1, US20130109647A1, US20130136776A1, US20130243726A1, US7,968,544, US8,507,50 7. US2010/0256169, US4,643,992, US4,539,205, US5,011,828, US5,041,426, US4,880,784, US2003/0195209, US2003/018 6949, US2003/0176458, US2003/0162806, US2003/0100764, US2003/0065005, US2002/0173655, US5,395,937, US2010/0215 642, US2010/0210598, US2010/0256169, US2009/0324551, US2010/0029585, US20120035193, US20110282061, US20140024664, US20100240623, US2008026924, US20140045837, US20130236492 and US20130018042, the contents of which are incorporated herein by reference in their entirety.

For the uses, methods, dosing regimens, pharmaceutical formulations/compositions, and kits described herein, there are separate embodiments comprising the use of a TLR7 modulating compound of structural formula II, wherein the compound is described in the following separate group:

(a) L ¹ is –NR ⁸ -;

(b) L ¹ is –O-;

(c) L ¹ is –S-;

(d) L ¹ is –S(O)-;

(e) ^L1 is a covalent bond;

(f) L ¹ is -C(O)N(R ⁸ )-;

(g) L ¹ is -N(R ⁸ )S(O) ₂

(h) L ¹ is -S(O) ₂ N(R ⁸ )-.

(i) ^R1 is an alkyl group;

(j) R ¹ is a substituted alkyl group;

(k) R ¹ is heteroalkyl;

(1) R ¹ is a substituted heteroalkyl group;

(m) X ¹ is an alkylene group

(n) X ¹ is a substituted alkylene group;

(o) X ¹ is heteroalkylene;

(p) X ¹ is a substituted heteroalkylene;

(q) X ¹ is a C ₁ -C ₆ alkylene group;

(r) X ¹ is a substituted C ₁ -C ₆ alkylene group;

(s) X ¹ is C ₁ -C ₆ heteroalkylene;

(t) X ¹ is a substituted C ₁ -C ₆ heteroalkylene group;

(u) X ¹ is –CH ₂ -;

(v) D is carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl, wherein the carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl is substituted with one or two -L ² -NR ⁶ R ⁷ ;

(w) D is a heterocyclyl or heteroaryl group, wherein the heterocyclyl or heteroaryl group contains four nitrogen atoms;

(x) D is a 3- to 12-membered carbocyclyl or a 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with -L ² -NR ⁶ R ⁷ ;

(y) D is phenyl, biphenyl or pyridyl, wherein the phenyl, biphenyl or pyridyl is substituted with -L ² -NR ⁶ R ⁷ ;

(z) D is heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl, wherein the heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl contains one to four nitrogen atoms;

(aa) D is heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl, wherein the heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl is optionally substituted pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted 1,2,3,4-tetrahydroquinolinyl;

(bb) D is carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein the carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl is substituted with one or two ^{-L2- NR6R7} , and ^{R6 and R7} are independently H, alkyl, heteroalkyl, or together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclyl;

(cc) D is carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl, wherein the carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl is substituted with one or two ^{-L2- NR6R7} , and ^R6 and ^R7 together with the nitrogen atom to which they are attached form a 4- to 10-membered saturated, partially saturated or unsaturated monocyclic or bicyclic ^ring containing 0 to 3 other heteroatoms selected from N, O or S;

(dd) D is carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl, wherein the carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl is substituted with one or two ^-L2 - ^NR6R7 , and ^R7 together with ^L2 and the N to which they are attached form a substituted or unsubstituted 3- to 8-membered heterocyclic ring which may contain one or more additional heteroatoms selected from N, O, S or P ^;

(ee)YZ- is -CR ⁴ R ⁵ -;

(ff)-YZ-is-CR ⁴ R ⁵ -CR ⁴ R ⁵ -;

(gg)-YZ- is -CR ⁴ R ⁵ -, wherein each R ⁴ or R ⁵ is independently H or C ₁ -C ₆ alkyl;

(hh)-YZ- is –CH ₂ -;

(ii) -YZ- is –(CH ₂ ) ₂ -; and

(jj)-Y-Z- is –C(O)-.

In each of the embodiments listed above in (a) through (jj), it is understood that except for the definitions specifically given, all variables of that embodiment are as defined above for Formula II.

In one embodiment of Formula II, -YZ is ^-CR4R5- or ^{-CR4R5 - CR4R5-} , and D is carbocyclyl, substituted carbocyclyl, heterocyclyl ^, or substituted heterocyclyl, wherein said carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl is substituted with one or two ^{-L2 - NR6R7} . In another aspect of this embodiment, D is 3- to 12-membered carbocyclyl or 3- to 12-membered heterocyclyl, wherein said carbocyclyl or heterocyclyl is substituted ^{with -L2} - ^NR6R7 . In another aspect of this embodiment, D is phenyl, ^biphenyl , or pyridinyl, wherein said phenyl, biphenyl, or pyridinyl is substituted ^{with -L2} - ^NR6R7 .

In another aspect of this embodiment, R ⁶ and R ⁷ are independently H, alkyl, heteroalkyl, or together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclyl. In another aspect of this embodiment, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, form a 4- to 10-membered mono- or bicyclic saturated, partially saturated, or unsaturated ring containing 0 to 3 additional heteroatoms selected from N, O, or S. In another aspect of this embodiment, R ⁷ , together with L ² and the nitrogen to which they are attached, form a substituted or unsubstituted 3- to 8-membered heterocyclic ring, which may contain one or more additional heteroatoms selected from N, O, S, or P. In another aspect of this embodiment, R ⁶ and R ⁷ are each independently H, alkyl, or heteroaryl. In another aspect of this embodiment, R ⁶ and R ^7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- to 6-membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, L ¹ is -NH- or -O-. In another aspect of this embodiment, R ¹ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is -CR ⁴ R ⁵ - or -CR ⁴ R ⁵ -CR ⁴ R ⁵ -, and D is heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl group contains one to four nitrogen atoms. In another aspect of this embodiment, D is optionally substituted pyridyl, optionally substituted piperidyl, optionally substituted piperazinyl, or optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In another aspect of this embodiment, L ¹ is -NH- or -O-. In another aspect of this embodiment, R ¹ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is ^-CR4R5- , wherein ^R4 or ^R5 are independently H or _CH3 and D is carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl, wherein said carbocyclyl, substituted carbocyclyl, heterocyclyl or substituted heterocyclyl is substituted ^with one or two ^-L2 - ^NR6R7 . In another aspect of this embodiment, D is 3- to 12-membered carbocyclyl or 3- to 12-membered heterocyclyl, wherein said carbocyclyl or heterocyclyl is substituted with ^-L2 - ^NR6R7 . In another aspect of this embodiment, D is phenyl, biphenyl or pyridinyl, wherein said phenyl, biphenyl or pyridinyl is substituted ^{with -L2} - ^NR6R7 . In another aspect of this embodiment, ^{R6 and R7} are independently H, alkyl, heteroalkyl, or together with the nitrogen atom to which they are attached ^, form a substituted or unsubstituted heterocyclyl. In another aspect of this embodiment, R ⁶ and R ^7, together with the nitrogen atom to which they are attached, form a 4- to 10-membered mono- or bicyclic saturated, partially saturated, or unsaturated ring containing 0-3 additional heteroatoms selected from N, O, or S. In another aspect of this embodiment, R ⁷ , together with L ² and the N to which they are both attached, form a substituted or unsubstituted 3- to 8-membered heterocyclic ring which may contain one or more heteroatoms selected from N, O, S, or P. In another aspect of this embodiment, R ⁶ and R ⁷ are each independently H, alkyl, or heteroaryl. In another aspect of this embodiment, R ⁶ and R ^7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- to 6-membered heterocyclic ring containing 0-2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, L ¹ is -NH- or -O-. In another aspect of this embodiment, R ¹ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is ^-CR4R5- , wherein ^R4 or ^R5 are each independently H or _CH3 , and D is heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl group contains one ^to four nitrogen atoms. In another aspect of this embodiment, D is optionally substituted pyridyl, optionally substituted piperidyl, optionally substituted piperazinyl, or optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In another aspect of this embodiment, ^L1 is -NH- or -O-. In another aspect of this embodiment, ^R1 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is ^-CR4R5- , wherein ^R4 and ^R5, together with the carbon to which they are attached, are ^-C (O)- and D is carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein the carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl is substituted with ^one or two ^-L2 - ^NR6R7 . In another aspect of this embodiment, D is 3- to 12-membered carbocyclyl or 3- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is substituted with ^-L2 - ^NR6R7 . In another aspect of this embodiment, D is phenyl, biphenyl, or pyridinyl, wherein the phenyl, biphenyl, or pyridinyl is substituted ^{with -L2} - ^NR6R7 . In another aspect of this embodiment, ^R6 and ^R7 are independently H, ^alkyl , heteroalkyl, or, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclyl. In another aspect of this embodiment, ^R and ^R, together with the nitrogen atom to which they are attached, form a 4- to 10-membered mono- or bicyclic saturated, partially saturated, or unsaturated ring containing 0 to 3 additional heteroatoms selected from N, O, or S. In another aspect of this embodiment, ^R, together with ^L and the nitrogen to which they are attached, form a substituted or unsubstituted 3- to 8-membered heterocyclic ring which may contain one or more additional heteroatoms selected from N, O, S, or P. In another aspect of this embodiment, ^R and ^R are independently H, alkyl, or heteroaryl. In another aspect of this embodiment, ^R and ^R, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- to 6-membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, ^L is -NH- or -O-. In another aspect of this embodiment, ^R is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is ^-CR4R5- , wherein ^R4 and ^{R5, together} with the carbon to which they are attached, are -C(O)-, and D is heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl group includes one to four nitrogen atoms. In another aspect of this embodiment, D is optionally substituted pyridyl, optionally substituted piperidyl, optionally substituted piperazinyl, or optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In another aspect of this embodiment, ^L1 is -NH- or -O-. In another aspect of this embodiment, ^R1 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is _-CH2CH2- , and _D is carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl, wherein said carbocyclyl, substituted carbocyclyl, heterocyclyl, or substituted heterocyclyl is substituted with one or two ^-L2 - ^NR6R7 . In another aspect of this embodiment, D is 3- to 12-membered carbocyclyl or 3- to 12-membered heterocyclyl, wherein said carbocyclyl or heterocyclyl is substituted with ^-L2 - ^NR6R7 . In another aspect of this embodiment, D is phenyl, biphenyl, or pyridinyl, wherein said phenyl, biphenyl, or pyridinyl is substituted ^with -L2 ^{- NR6R7} . In another aspect of this embodiment, ^{R6 and R7} are independently H, alkyl, heteroalkyl, or together with the nitrogen atom to which they are attached ^, form a substituted or unsubstituted heterocyclyl. In another aspect of this embodiment, ^R6 and ^R7, together with the nitrogen atom to which they are attached, form a 4- to 10-membered mono- or bicyclic saturated, partially saturated, or saturated ring containing 0 to 3 additional heteroatoms selected from N, O, or S. In another aspect of this embodiment, ^R7 , ^L2 , and the N to which they are both attached, form a substituted or unsubstituted 3- to 8-membered heterocyclic ring that may contain one or more additional heteroatoms selected from N, O, S, or P. In another aspect of this embodiment, ^R6 and ^R7 are independently H, alkyl, or heteroaryl. In another aspect of this embodiment, ^R6 and ^R7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4- to 6-membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, ^L1 is -NH- or -O-. In another aspect of this embodiment, ^R1 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In one embodiment of Formula II, -YZ- is -CH ₂ CH ₂ -, and D is heterocyclyl or heteroaryl, wherein the heterocyclyl or heteroaryl group contains one to four nitrogen atoms. In another aspect of this embodiment, D is optionally substituted pyridyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted 1,2,3,4-tetrahydroisoquinolinyl. In another aspect of this embodiment, L ¹ is -NH- or -O-. In another aspect of this embodiment, R ¹ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl.

In separate embodiments of the uses, methods of treatment, dosing regimens, pharmaceutical formulations, and kits described herein, the TLR7 modulating compound of Formula II is represented by Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

L ¹ is –NH- or –O-;

R ¹ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl;

R ⁴ and R ⁵ are each independently H or C ₁ -C ₆ alkyl, or R ⁴ and R ⁵ together with the carbon atom to which they are attached are -C(O)-;

^X1 is _C1 - _C6 alkylene, _C1 - _C6 heteroalkylene, or _C1 - _C6 substituted heteroalkylene;

D is phenyl, biphenyl or pyridyl, wherein the phenyl, biphenyl or pyridyl is substituted with -L ² -NR ⁶ R ⁷ ;

or

D is pyridyl, piperidinyl, piperazinyl or 1,2,3,4-tetrahydroisoquinolinyl;

n is 0 or 1;

R ³ is halogen, cyano, alkyl, carbocyclyl, carbocyclylalkyl, haloalkyl, -C(O)OR ⁸ , -C(O)NR ⁹ R ¹⁰ or -CHO;

L ² is C ₁ -C ₆ alkylene or a covalent bond;

^R6 and ^R7 are each independently H, alkyl or heteroaryl; or

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O or S.

In one embodiment of Formula Ia, R ⁴ and R ⁵ are each independently H or C ₁ -C ₆ alkyl. In another embodiment of Formula Ia, R ⁴ and R ⁵ are each H. In another embodiment of Formula Ia, R ⁴ and R ⁵ , together with the carbon to which they are attached, are —C(O)—. In another embodiment of Formula Ia, L ¹ is —O—. In another embodiment of Formula Ia, L ¹ is —NH—. In another embodiment of Formula Ia, X ¹ is C ₁ -C ₆ alkylene. In another embodiment of Formula Ia, X ¹ is C ₁ -C ₆ heteroalkylene. In another embodiment of Formula Ia, X ¹ is C ₁ -C ₆ substituted heteroalkylene. In another embodiment of Formula Ia, X ¹ is —CH ₂ —. In another embodiment of Formula Ia, D is phenyl, biphenyl, or pyridinyl, wherein said phenyl, biphenyl, or pyridinyl is substituted with —L ² —NR ⁶ R ⁷ . In another embodiment of Formula Ia, D is pyridinyl, piperidinyl, or piperazinyl. In another embodiment of Formula Ia, ^L is _-CH- . In another embodiment of Formula Ia, ^R and ^R are each independently H, alkyl, or heteroaryl. In another embodiment of Formula Ia, ^R and R, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted ^4-6 membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, or S.

In one embodiment of Formula Ia, R ⁴ and R ⁵ are each independently H or CH ₃ , and D is phenyl, biphenyl, or pyridinyl, wherein the phenyl, biphenyl, or pyridinyl is substituted with —L ² —NR ⁶ R ⁷ . In another aspect of this embodiment, R ⁶ and R ⁷ are each independently H, alkyl, or heteroaryl. In another aspect of this embodiment, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4-6 membered heterocyclic ring comprising 0 to 2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, L ² is —CH ₂ —. In another aspect of this embodiment, X ¹ is —CH ₂ —. In another aspect of this embodiment, L ¹ is —O—. In another aspect of this embodiment, L ¹ is —NH—.

In one embodiment of Formula Ia, R ⁴ and R ⁵ are each independently H or CH ₃ , and D is pyridinyl, piperidinyl, or piperazinyl. In another aspect of this embodiment, X ¹ is —CH ₂ —. In another aspect of this embodiment, X ¹ is C ₁ -C ₆ alkylene. In another aspect of this embodiment, X ¹ is C _{1 -C 6} heteroalkylene. In another aspect of this embodiment, X ¹ is C ₁ -C ₆ substituted heteroalkylene. In another aspect of this embodiment, L ¹ is —O—. In another aspect of this embodiment, L ¹ is —NH—.

In one embodiment of Formula Ia, ^R and R ^, together with the carbon atoms to which they are attached, are -C(O)-, and D is phenyl, biphenyl, or pyridinyl, wherein said phenyl, biphenyl, or pyridinyl is substituted with -L- ^{NR - R} . In another aspect of this embodiment, ^R and ^R are each independently H, alkyl, or heteroaryl. In another aspect of this embodiment, ^R and R ^, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4-6 membered heterocyclic ring comprising 0 to 2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, ^L is _-CH- . In another aspect of this embodiment, ^X is _-CH- . In another aspect of this embodiment, ^L is -O-. In another aspect of this embodiment, ^L is -NH-.

In one embodiment of Formula Ia, ^R and R ^, together with the carbon to which they are attached, are -C(O)-, and D is pyridyl, piperidinyl, piperazinyl, or 1,2,3,4-tetrahydroisoquinolinyl. In another aspect of this embodiment, ^Xi is _-CH2- . In another aspect of this embodiment, ^Xi is _C1 - _C6 alkylene. In another aspect of this embodiment, ^Xi is _C1 - _C6 heteroalkylene. In another aspect of this embodiment, ^Xi is _C1 - _C6 substituted heteroalkylene. In another aspect of this embodiment, ^Li is -O-. In another aspect of this embodiment, ^Li is -NH-.

In separate embodiments of the uses, methods of treatment, dosing regimens, pharmaceutical formulations, and kits described herein, the TLR7 modulating compound of Formula II is represented by Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein

L ¹ is –NH- or –O-;

R ¹ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, carbocyclylalkyl, or substituted carbocyclylalkyl;

^R4 and ^R5 are each independently H or _C1 - _C6 alkyl, or any ^R4 and ^R5 on the same carbon atom when taken together with the carbon atom to which they are attached are -C(O)-;

^X1 is _C1 - _C6 alkylene, _C1 - _C6 heteroalkylene, or _C1 - _C6 substituted heteroalkylene;

D is phenyl, biphenyl or pyridyl, wherein the phenyl, biphenyl or pyridyl is substituted with -L ² -NR ⁶ R ⁷ ;

or

D is pyridyl, piperidinyl, piperazinyl or 1,2,3,4-tetrahydroisoquinolinyl;

n is 0 or 1;

R ³ is halogen, cyano, alkyl, carbocyclyl, carbocyclylalkyl, haloalkyl, -C(O)OR ⁸ , -C(O)NR ⁹ R ¹⁰ or -CHO;

L ² is C ₁ -C ₆ alkylene or a covalent bond;

^R6 and ^R7 are each independently H, alkyl or heteroaryl; or

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O or S.

In one embodiment of Formula IIa, R ⁴ and R ⁵ are each independently H or C ₁ -C ₆ alkyl. In another embodiment of Formula IIa, R ⁴ and R ⁵ are each H. In another embodiment of Formula IIa, L ¹ is –O—. In another embodiment of Formula IIa, L ¹ is –NH—. In another embodiment of Formula IIa, X ¹ is C ₁ -C ₆ alkylene. In another embodiment of Formula IIa, X ¹ is C ₁ -C ₆ heteroalkylene. In another embodiment of Formula IIa, X ¹ is C ₁ -C ₆ substituted heteroalkylene. In another embodiment of Formula IIa, X ¹ is –CH ₂ -. In another embodiment of Formula IIa, D is phenyl, biphenyl, or pyridinyl, wherein the phenyl, biphenyl, or pyridinyl is substituted with –L ² -NR ⁶ R ^7. In another embodiment of Formula IIa, D is pyridinyl, piperidinyl, piperazinyl, or 1,2,3,4-tetrahydroisoquinolinyl. In another embodiment of Formula IIa, L ² is -CH ₂ -. In another embodiment of Formula IIa, R ⁶ and R ⁷ are each independently H, alkyl, or heteroaryl. In another embodiment of Formula IIa, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4-6 membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, or S.

In one embodiment of Formula IIa, ^R4 and ^R5 are each independently H or _CH3 , and D is phenyl, biphenyl, or pyridinyl, wherein the phenyl, biphenyl, or pyridinyl is substituted with ^-L2 - ^NR6R7 . In another aspect of this embodiment, ^R6 and ^R7 are each independently H, alkyl, or heteroaryl. ^In another aspect of this embodiment, ^R6 and ^R7, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 4-6 membered heterocyclic ring comprising 0 to 2 heteroatoms selected from N, O, or S. In another aspect of this embodiment, ^L2 is _-CH2- . In another aspect of this embodiment, ^X1 is _-CH2- . In another aspect of this embodiment, ^L1 is -O-. In another aspect of this embodiment, ^L1 is -NH-.

In one embodiment of Formula IIa, R ⁴ and R ⁵ are each independently H or CH ₃ , and D is pyridyl, piperidinyl, or piperazinyl. In another aspect of this embodiment, X ¹ is —CH ₂ —. In another aspect of this embodiment, X ¹ is C ₁ -C ₆ alkylene. In another aspect of this embodiment, X ¹ is C _{1 -C 6} heteroalkylene. In another aspect of this embodiment, X ¹ is C ₁ -C ₆ substituted heteroalkylene. In another aspect of this embodiment, L ¹ is —O—. In another aspect of this embodiment, L ¹ is —NH—.

The uses, methods of treatment, dosing regimens, pharmaceutical formulations, and kits described herein each comprise further embodiments wherein the TLR7 modulating compound is selected from a compound of formula III, or a pharmaceutically acceptable salt thereof:

in:

The D ring represents a moiety selected from the group consisting of:

wherein, in each case, the pyrrolidin-1-ylmethyl group, the piperidin-1-ylmethyl group or the morpholinomethyl group is bound to the 3-position or the 4-position of the phenyl ring to which it is bound;

L ¹ is -NR ⁸ -, -O-, -S-, -N(R ⁸ )C(O)-, -S(O) ₂ -, -S(O)-, -C(O)N(R ⁸ )-, -N(R ⁸ )S(O) ₂ -, -S(O) ₂ N(R ⁸ )-, or a covalent bond;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted with one substituent selected from the group consisting _{of haloalkyl, OH, -OC1-C6 alkyl} , _-SO2 - _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin _{- 2} -onyl and tetrahydropyranyl; and

^R8 is selected from H, _C1 - _C8 alkyl, substituted _C1 - _C8 alkyl, C1-C8 haloalkyl, _C2 - _C8 alkenyl, substituted _C2 - _C8 alkenyl, _C2 - _C8 alkynyl and substituted _C2 - _C8 alkynyl, wherein the substituted _C1 - _C8 alkyl, substituted _C2 - _C8 alkenyl and substituted _C2 - _{C8 alkynyl} are substituted with 1, 2, ₃ or 4 substituents independently selected from F, Cl, Br, I, CN, OH, -OC1- _C3 alkyl, -SC1 _{- C3} alkyl, -C(O) _{-C1 -C3 alkyl} , _-CO2H and -C(O)-OC1 _{-C3 alkyl} .

The uses, methods, dosing regimens, compositions, and kits described herein each comprise further separate embodiments, wherein the TLR7 modulating compound is independently selected from Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof:

wherein, in each case, the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound, and L ¹ , R ¹ and R ⁸ are each as defined above for formula III.

Also provided herein are further separate embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is -NR ⁸ -, -O-, -S-, -N(R ⁸ )C(O)-, -S(O) ₂ -, -S(O)-, -C(O)N(R ⁸ )-, -N(R ⁸ )S(O) ₂ -, -S(O) ₂ N(R ⁸ )-, or a covalent bond;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted _with one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- _{2 -} onyl, and tetrahydropyranyl; and

R ⁸ is selected from H, C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl, wherein the substituted C ₁ -C ₆ alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, CN, OH, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -C(O)-C ₁ -C ₃ alkyl, -CO ₂ H, and -C(O)-OC ₁ -C ₃ alkyl.

Also provided herein are additional separate embodiments of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is -NR ⁸ -, -O-, -S-, -N(R ⁸ )C(O)-, -S(O) ₂ -, -S(O)-, -C(O)N(R ⁸ )-, -N(R ⁸ )S(O) ₂ -, -S(O) ₂ N(R ⁸ )-, or a covalent bond;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted _with one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- _{2 -} onyl, and tetrahydropyranyl; and

R ⁸ is selected from H, C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl, wherein the substituted C ₁ -C ₆ alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, CN, OH, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -C(O)-C ₁ -C ₃ alkyl, -CO ₂ H, and -C(O)-OC ₁ -C ₃ alkyl.

Also provided herein are further separate embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –NR ⁸ -, -O- or -S-;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted _with one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- _{2 -} onyl, and tetrahydropyranyl; and

R ⁸ is selected from H, C ₁ -C ₆ alkyl or substituted C ₁ -C ₆ alkyl, wherein the substituted C ₁ -C ₆ alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, I, CN, OH, -OC ₁ -C ₃ alkyl, -SC ₁ -C ₃ alkyl, -C(O)-C ₁ -C ₃ alkyl, -CO ₂ H, and -C(O)-OC ₁ -C ₃ alkyl.

Also provided herein are further individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –NR ⁸ -, -O- or -S-;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted _with one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- _{2 -} onyl, and tetrahydropyranyl; and

^R8 is selected from H, _C1 - _C3 alkyl or substituted _C1 - _C3 alkyl, wherein the substituted _C1 - _C3 alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, Br, _I , CN, OH, -OC1- _C3 alkyl, -SC1 _{-C3 alkyl} , -C(O) _-C1 - _C3 alkyl, _-CO2H and -C(O)-OC1 _{-C3 alkyl} .

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –NR ⁸ -, -O- or -S-;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted _with one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- _{2 -} onyl, and tetrahydropyranyl; and

R ⁸ is selected from H and C ₁ -C ₃ alkyl.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –NR ⁸ -;

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl substituted _with one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- _{2 -} onyl, and tetrahydropyranyl; and

R ⁸ is selected from H and C ₁ -C ₃ alkyl.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –S-; and

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl _substituted by one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin _- 2 _- onyl, and tetrahydropyranyl.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –O-; and

^R1 is _C3 - _C6 cycloalkyl, unsubstituted _C1 - _C8 alkyl, or C1-C8 alkyl _substituted by one substituent selected from haloalkyl, OH, -OC1- _{C6 alkyl} , -SO2- _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, phenyl, pyridyl, imidazolyl, furyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin _- 2 _- onyl, and tetrahydropyranyl.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –NR ⁸ -;

R1 ^is unsubstituted _C1 - _C6 alkyl, or _C1 - _C6 alkyl substituted with one substituent selected from fluoroalkyl, OH and -OC1- _{C3 alkyl} ; and

R ⁸ is selected from H and C ₁ -C ₃ alkyl.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –NR ⁸ -;

R1 ^is unsubstituted _C1 - _C6 alkyl, or _C1 - _C6 alkyl substituted with one _-OC1 - _C3 alkyl substituent; and

R ⁸ is selected from H and C ₁ -C ₃ alkyl.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –S-; and

R ¹ is an unsubstituted C ₁ -C ₆ alkyl group, or a C _{1 -C 6} alkyl group substituted with one substituent selected from the group consisting of a fluoroalkyl group, OH, and a -OC ₁ -C ₃ alkyl group.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment: the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound; L ¹ is -S-; and R ¹ is unsubstituted C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl substituted with one -OC ₁ -C ₃ alkyl substituent.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment:

A pyrrolidin-1-ylmethyl group, a piperidin-1-ylmethyl group, or a morpholinomethyl group is bound to the 3-position or 4-position of the benzene ring to which it is bound;

L ¹ is –O-; and

R ¹ is an unsubstituted C ₁ -C ₆ alkyl group, or a C _{1 -C 6} alkyl group substituted with one substituent selected from the group consisting of a fluoroalkyl group, OH, and a -OC ₁ -C ₃ alkyl group.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment: the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound; L ¹ is -O-; and R ¹ is unsubstituted C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl substituted with one -OC ₁ -C ₃ alkyl substituent.

Also provided herein are additional individual embodiments of each of the uses, methods, dosing regimens, compositions, and kits described herein, wherein the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment: the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound; L ¹ is -O-; and R ¹ is unsubstituted C ₁ -C ₆ alkyl. In further other embodiments, the TLR7 modulating compound is independently selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e) or Formula III(f), or a pharmaceutically acceptable salt thereof, wherein in each embodiment: the pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl or morpholinomethyl group is bound to the 3-position or 4-position of the phenyl ring to which it is bound; L ¹ is -O-; and R ¹ is an unsubstituted C ₃ -C ₆ alkyl group.

The uses, methods, dosing regimens, compositions, and kits described herein each include additional separate embodiments, wherein the TLR7 modulating compound is independently selected from Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), or Formula III(f)(2), or a pharmaceutically acceptable salt thereof:

wherein, in various embodiments, R ¹ is C ₃ -C ₆ cycloalkyl, unsubstituted C ₁ -C ₈ alkyl, or C 1 -C 8 alkyl substituted with one substituent selected from the group consisting of haloalkyl, OH, —OC ₁ -C ₆ alkyl, —SO ₂ -C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, phenyl, pyridyl, imidazolyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin- ₂ -onyl, and _{tetrahydropyranyl} .

The uses, methods, dosing regimens, compositions and kits described herein each include further separate embodiments wherein the TLR7 modulating compound is independently selected from a compound of Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2), or a pharmaceutically acceptable salt thereof: wherein R ¹ is unsubstituted C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted with one substituent selected from fluoroalkyl, OH and -OC ₁ -C ₃ alkyl.

The uses, methods, dosing regimens, compositions, and kits described herein each include additional separate embodiments, wherein the TLR7 modulating compound is independently selected from a compound of Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), or Formula III(f)(2), or a pharmaceutically acceptable salt thereof: wherein R ¹ is unsubstituted C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted with one -OC ₁ -C ₃ alkyl substituent.

The uses, methods, dosing regimens, compositions, and kits described herein each include additional separate embodiments, wherein the TLR7 modulating compound is independently selected from a compound of Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), or Formula III(f)(2), or a pharmaceutically acceptable salt thereof: wherein R ¹ is unsubstituted C ₁ -C ₆ alkyl.

The uses, methods, dosing regimens, compositions, and kits described herein each include additional separate embodiments, wherein the TLR7 modulating compound is independently selected from a compound of Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), or Formula III(f)(2), or a pharmaceutically acceptable salt thereof: wherein R ¹ is C ₁ -C ₆ alkyl substituted with one -OC ₁ -C ₃ alkyl substituent.

definition

Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. The absence of a specific term or phrase should not be construed as indefinite or unclear, but rather the terms herein are used with their ordinary meanings. When a trade name is used herein, applicants intend to include both the trade name product and the active pharmaceutical ingredient of the trade name product independently.

The abbreviation "HIV" refers to the human immunodeficiency virus that causes acquired immunodeficiency syndrome "AIDS."

The terms "treat," "treat," and grammatical equivalents thereof, when used in the context of treatment of a disease, means slowing or halting the progression of the disease, or ameliorating at least one symptom of the disease, and more preferably ameliorating more than one symptom of the disease.

As used herein, "compounds of the present invention," "compounds described herein," and "compounds of Formula Ia," "Formula II," or "Formula IIa," as well as references to compounds of other formulae herein, refer to compounds having a specific formula, structure, or chemical name, including alternative forms thereof, such as solvated forms, hydrated forms, esterified forms, or physiologically functional derivatives thereof. Compounds of the present invention also include tautomeric forms thereof, such as the tautomeric "enols" described herein. Similarly, with respect to isolatable intermediates, the phrase "compound of Formula (number)" refers to compounds of that formula and alternative forms thereof.

The term "combination antiretroviral therapy" ("cART") refers to a combination or "cocktail" of antiretroviral drugs used to treat human viral infections, including HIV infection. As used herein, the terms "combination antiretroviral therapy" and "cART" include combinations and regimens commonly referred to as highly active antiretroviral therapy (HAART). HAART and cART combinations and regimens typically include multiple, often three or more drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 agonists, and/or integrase inhibitors.

The terms "chronic set point," "set point of chronic HIV infection," "viral load set point," and "viral set point of chronic HIV infection" refer to the HIV viral load established in a patient's blood following infection or following the introduction of antiretroviral therapy or treatment, including combination antiretroviral therapy or treatment.

The terms "viral load" and "HIV viral load" refer to the detectable HIV level in the blood of an HIV-infected person after HIV infection or after treatment with antiretroviral therapy (e.g., using a cART or HAART regimen). It can be calculated by estimating the amount of virus in the body fluids involved. For example, it can be given as HIV RNA copies/ml of blood or plasma. "Undetectable" HIV viral load includes situations where HIV RNA copies cannot be detected by standard viral load tests. Undetectable HIV viral load as used herein refers to a viral load of less than 50 HIVRNA copies per ml of blood or plasma. The term "viremia" refers to the presence of measurable circulating viruses or viral particles in a virally infected person. The term "transient viremia" refers to a brief, transient, or temporary increase in measurable circulating viruses or viral particles in a virally infected person. Examples of transient HIV viremia include a period during which HIV-1 RNA levels in the blood or plasma of an HIV-infected person have been maintained at a concentration of less than 50 HIV-1 RNA copies per mL for a period of time, which HIV-1 RNA levels transiently, transiently, or temporarily rise to a concentration of greater than 50 copies/mL, such as 50 to 2,000 copies/mL, or a period during which HIV-1 RNA levels in the blood or plasma of an HIV-infected person have been maintained at a concentration of less than 40 HIV-1 RNA copies per mL for a period of time, which HIV-1 RNA levels transiently, transiently, or temporarily rise to a concentration of greater than 40 copies/mL, such as 40 to 2,000 copies/mL. Transient, transient, or temporary viremia can be established at a concentration of greater than 50 copies after repeated testing for an "undetectable" HIV viral load of less than 50 copies/mL for a specified period of time (e.g., one month, three months, six months, nine months, or one year). After repeating the test for an "undetectable" HIV viral load below 50 copies/mL when a specified number or series of test concentrations are less than 50 copies of HIV-1 RNA/mL according to a medical provider, a concentration greater than 50 copies/mL can also be established. In a separate embodiment, the number of continuous test concentrations less than 50 copies can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 25, 26, 27, 28, 29 or 30, and can be used for example to perform daily, weekly, biweekly, monthly, bimonthly, quarterly (every three months), semiannually (twice a year) or annually (once a year) testing.

The terms "viral suppression" and "virological suppression" refer to a response to treatment in which measurable levels of viremia in a human infected with a virus are maintained at or below the desired level for a given human or antiviral treatment or dosing regimen. An example of HIV viral suppression in an HIV-infected human can be the maintenance of a measurable HIV viral load in a human of less than 200 copies of HIV-1 RNA per milliliter of blood or plasma. Other examples of virological suppression are the maintenance of a viral load in a human of less than 100 copies/mL, less than 50 copies/mL, less than 40 copies/mL, less than 30 copies/mL, and less than 20 copies/mL.

The terms "latent HIV reservoir," "HIV latent reservoir," "HIV reservoir," "latent reservoir," and "latent HIV infection" refer to resting CD4+ T lymphocytes or other cells that are infected with HIV but are not actively producing HIV. Cells that are currently inactive and infected with HIV are called "latently infected cells." Antiretroviral therapy (ART) can reduce HIV levels in the blood to undetectable levels, while the HIV latent reservoir continues to survive. When latently infected cells reactivate, the cells begin to produce HIV (HIV replication).

The term "dosing regimen" refers to a systematic schedule for administering a pharmaceutically effective agent to a patient in need thereof (eg, a human in need thereof) to achieve a therapeutic purpose.

The terms "regulation" and "modulator" refer to the effect of an agent exciting (activating or enhancing) or antagonizing (inhibiting or weakening) the function of a biological target. Agonists or enhancers include those modulators that increase TLR3, TLR4, TLR7 or TLR9 receptor activity. In each method, combination, kit, purpose, composition and dosage regimen utilizing or containing a TLR7 modulator or TLR7 modulating compound described herein, there is a separate embodiment in which the TLR7 modulator or TLR7 modulating compound is a TLR7 agonist. TLR7 agonism can be determined by the PBMC assay protocol in U.S. Patent No. US5,064,698. Its contents are incorporated herein by reference, as well as Bioorg.Med.Chem.Lett.16,4559 (2006). Specifically, cryopreserved PBMCs were thawed and seeded in 96-well plates at 750,000 cells/well, with 190 fJ of Liwell cell culture medium per well. The PBMCs were then incubated at 37°C, 5% _CO2 for 1 hour. Afterwards, PBMC were incubated at 37°C, 5% CO2 _for 1 hour. The compound to be tested was then titrated in 8 points, half logarithmic dilutions, into 10f.LL cell 55 culture medium. The plate was incubated at 37°C and 5% _CO2 for 24 hours, then centrifuged at 1200rpm for 10 minutes, and then the supernatant was collected and stored at -80°C. Cytokine secretion was determined using a Luminex analytical instrument with Luminex and Upstate multiplex kits. The IFN-α MEC value of the compound is the lowest concentration at which the compound stimulates IFN-α production at least 3 times higher than the background, as determined using the above-mentioned assay. Compounds providing values (f.lM) within the range of >0.03f.LM or =0.03f.LM are considered to be TLR7 agonist compounds.

The term "HIV antibody" refers to non-neutralizing HIV antibodies and neutralizing HIV antibodies, including broadly neutralizing HIV antibodies. The terms "broadly neutralizing HIV-1 antibodies" and "broadly neutralizing HIV-1 antibodies" (bNAbs) refer to neutralizing antibodies that neutralize multiple HIV-1 strains.

The abbreviations "IL" and "IL-" refer to "interleukin," e.g., interleukin.

The terms "nucleoside-sparing," "nucleotide-sparing," and "nucleic acid-sparing" refer to antiretroviral combinations, dosing regimens, formulations, or therapies that do not utilize nucleoside or nucleotide drug agents, such as nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs).

The term "pharmaceutically acceptable" with respect to a substance as used herein means that the substance is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and is effective for its intended use when used in a pharmaceutical composition.

As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound according to the invention which, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., has a reasonable benefit/risk ratio, is generally water or oil soluble or dispersible, and is effective for its intended use. The term includes, but is not limited to, pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, in SM Birge et al., J. Pharm. Sci., 1977, 66 , pp. 1-19.

As used herein, the term "pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed from inorganic or organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids including but not limited to acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconolactic acid, benzoic ... Sugar acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfuric acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (hydroxyethylsulfonic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.

As used herein, the term "pharmaceutically acceptable base addition salt" means salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable, and which are formed from inorganic bases, including but not limited to ammonia, or hydroxides, carbonates or bicarbonates of ammonia or metal cations such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include but are not limited to primary, secondary and tertiary amines, quaternary ammonium compounds, substituted amines (including naturally occurring substituted amines), cyclic amines and salts of basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, sea salts, ... isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, sea salts, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2- Examples of the present invention include hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

The terms "mL" and "ml" refer to milliliters.

The terms "antiviral agent," "antiretroviral agent," or "antiretroviral compound" refer to compounds or agents used to treat HIV infection in humans.

As used herein, the terms "antiviral agent" and "antiviral substance" refer to agents that effectively inhibit the formation and/or replication of viruses in humans, including but not limited to agents that interfere with host or viral mechanisms necessary for the formation and/or replication of viruses in humans. The terms "antiviral agent" and "antiviral substance" include, for example, HIV integrase catalytic site inhibitors selected from the group consisting of: raltegravir (Merck); elvitegravir (Gilead); soltegravir (GSK; ViiV); GSK1265744 (GSK744) (GSK; ViiV) and dolutegravir; HIV nucleoside reverse transcriptase inhibitors selected from the group consisting of: abacavir (GSK); didanosine (BMS); tenofovir disoproxil fumarate (Gilead); tenofovir alafenamide (TAF); emtricitabine (Gilead); lamivudine (GSK/Shire); stavudine (BMS); zidovudine (GSK); abacavir, efavirenz (Achillion); CMX-157 (Chimerix) and festinavir (Oncolys); HIV non-nucleoside reverse transcriptase inhibitors selected from the group consisting of: nabendazim (BMS); Virapine (BI); efavirenz (BMS); etravirine (J&J); rilpivirine (TMC278, R278474; J&J); fosdivirine (GSK/ViiV); MK-1439 (Merck); and lesvirine (Pfizer/ViiV); HIV protease inhibitors selected from: atazanavir (BMS); darunavir (J&J); indinavir (Merck); and lopinavir (Abbott) ; nelfinavir (Pfizer); saquinavir (Hoffmann-LaRoche); tipranavir (BI); ritonavir (Abbott); and fusamprenavir (GSK/Vertex); HIV entry inhibitors selected from maraviroc (Pfizer); enfuvirtide (Trimeris); and BMS-663068 (BMS); and HIV maturation inhibitors selected from bevirimab (Myriad Genetics). When used in combination with one or more antiviral agents described herein, enhancers (e.g., coenzyme inhibitors or ritonavir) are included in the terms "antiviral agent" and "antiviral agent."

The terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to an amount effective to elicit a desired biological or medical response, including an amount of a compound effective to produce a therapeutic effect on a disease when administered to a subject. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. An effective amount can encompass a range of amounts. A pharmaceutically effective amount includes an amount of an agent that is effective when combined with other agents.

The terms "composition," "pharmaceutical composition," "formulation," and "pharmaceutical formulation" refer to a composition comprising a pharmaceutically effective amount of a pharmaceutically active agent and a pharmaceutically acceptable carrier or excipient.

The terms "kit" and "pharmaceutical kit" refer to a commercially available kit or package comprising one or more pharmaceutical compositions and instructions for use in one or more suitable containers. Such a kit may also be referred to as a "pack" or "pharmaceutical pack."

"Alkyl" is a saturated or unsaturated hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., _C1 - _C20 alkyl), 1 to 10 carbon atoms (i.e., _C1 - _C10 alkyl), or 1 to 6 carbon atoms (i.e., _C1 - _C6 alkyl). Examples of suitable alkyl groups include, but are not limited to:

methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl ( n -Pr, n -propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl ( i -Pr, i -propyl, -CH(CH ₃ ) ₂ ), 1-butyl ( n -Bu, n -butyl, -CH ₂ CH ₂ CH ₂ CH _{3 )} , 2-methyl-1-propyl ( i -Bu, i -butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl ( s -Bu, s -butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl ( t -Bu, t -butyl, -C(CH ₃ ) ₃ ), 1-pentyl ( n -pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl ( -CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) _, 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH _{2 3 ) 3 ) , and octyl ( - ( CH 2 ) 7 CH 3 ) . ​ ​ ​ ​ ​ ​ ​ ​ ​ ​}

"Alkoxy" refers to a group having the formula -Oalkyl, wherein the alkyl group as defined above is attached to the parent molecule through an oxygen atom. The alkyl portion of the alkoxy group can have 1 to 20 carbon atoms (i.e., _C1 - _C20 alkoxy), 1 to 12 carbon atoms (i.e., _C1 - _C12 alkoxy), or 1 to 6 carbon atoms (i.e., _C1 - _C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O- _CH3 or -OMe), ethoxy ( _-OCH2CH3 or -OEt), tert-butoxy (-OC( _CH3 ) ₃ or _-OtBu ), and the like.

"Haloalkyl" is an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl portion of the haloalkyl group can have 1 to 20 carbon atoms (i.e., _C1 - _C20 haloalkyl), 1 to 12 carbon atoms (i.e., _C1 - _C12 haloalkyl), or 1 to 6 carbon atoms (i.e., _C1 - _C6 haloalkyl). In one embodiment, the haloalkyl group has 1 to 3 carbon atoms (i.e., _C1 - _C3 haloalkyl). Examples of suitable haloalkyl groups include, but are not limited to, _-CF3 , _-CHF2 , _-CFH2 , _-CH2CF3 , and _the like.

"Alkenyl" is a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., _C2 - _C20 alkenyl), 2 to 12 carbon atoms (i.e., _C2 - _C12 alkenyl), or 2 to 6 carbon atoms (i.e., _C2 - _C6 alkenyl). Examples of suitable alkenyl groups include, but are _not limited _to , ethylene, vinyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), _{cyclopropenyl} ( _-C5H7 ) _, and 5-hexenyl ( _{-CH2CH2CH2CH2CH} = _CH2 ).

"Alkynyl" is a hydrocarbon containing normal, secondary, tertiary, or cyclic carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., _C2 - _C20 alkynyl), 2 to 12 carbon atoms (i.e., _C2 - _C12 alkyne), or 2 to 6 carbon atoms (i.e., _C2 - _C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl ( _-CH2C≡CH ), and the like.

"Alkylene" refers to a saturated, branched, straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Common alkylene groups include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _{CH3 )} -), 1,2-ethylene ( _-CH2CH2- ), 1,1-propylene (-CH( _{CH2CH3 )} -), 1,2-propylene ( _{-CH2CH ( CH3} )-), 1,3 _{-propylene (-CH2CH2CH2- ) ,} 1,4-butylene ( _{-CH2CH2CH2CH2-} ), _{and the} like.

"Alkenylene" refers to an unsaturated, branched, straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent olefin. For example, an alkenylene radical can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Common alkenylene groups include, but are not limited to, 1,2-vinylene (-CH=CH-).

"Alkynylene" refers to an unsaturated, branched, straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example, an alkynylene radical can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Common alkynylene radicals include, but are not limited to, ethynylene (-C≡C-), propargyl ( _{-CH≡C- )} , _{and 4} -pentynyl (-CH≡CH≡C-).

"Aminoalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by an amino group.

"Acylaminoalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or ^sp3 carbon atom) is replaced by a ^-NRaCORb group, where ^Ra is hydrogen or alkyl and ^Rb is alkyl, substituted alkyl, aryl or substituted aryl, as defined herein, for example, -( _CH2 ) _2- NHC(O) _CH3 , -( _CH2 ) _3- NH-C(O) _-CH3 , and the like.

"Aryl" refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Common aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, and the like.

"Arylene" refers to an aryl group as defined above having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent aryl group. Typical arylene groups include, but are not limited to, phenylene.

"Arylalkyl" refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by an aryl group. Typical aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthophenylethyl-1-yl etc. Aryl groups can comprise 6 to 20 carbon atoms, for example, an alkyl moiety is 1 to 6 carbon atoms, and an aryl moiety is 6 to 14 carbon atoms.

"Arylalkenyl" refers to a non-cyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom, but also an sp2 carbon atom) is replaced by an aryl group. The aryl portion of the arylalkenyl group can include, for example, any aryl group disclosed herein, and the alkenyl portion of the arylalkenyl group can include, for example, any alkenyl group disclosed herein. The arylalkenyl group can contain 6 to 20 carbon atoms, for example, the alkenyl portion is 1 to 6 carbon atoms and the aryl portion is 6 to 14 carbon atoms.

"Arylalkynyl" refers to a non-cyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom, but also an sp atom) is replaced by an aryl group. The aryl portion of the arylalkynyl group can include, for example, any aryl group disclosed herein, and the alkynyl portion of the arylalkynyl group can include, for example, any alkynyl group disclosed herein. The arylalkynyl group can contain 6 to 20 carbon atoms, for example, the alkynyl portion is 1 to 6 carbon atoms, and the aryl portion is 6 to 14 carbon atoms.

"Halogen" refers to F, Cl, Br or I.

As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with at least one halogen. Examples of branched or straight-chain "haloalkyl" used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl groups that are independently substituted with one or more halogens (e.g., fluorine, chlorine, bromine, and iodine). The term "haloalkyl" should be interpreted as including substituents such as perfluoroalkyl groups such as -CF _3. The term "fluoroalkyl" used herein refers to a branched or straight-chain alkyl group having one or more fluorine atoms. Examples include C ₁ -C ₃ fluoroalkyl groups, such as fluoromethyl, 2-fluoroethyl, 3-fluoropropyl, 2-fluoropropyl, difluoromethyl, 2,2-difluoroethyl, 2,2-difluoropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoropropyl.

As used herein, the term "haloalkoxy" refers to a group -OR ^a , wherein ^Ra is a haloalkyl group as defined herein. By way of non-limiting example, haloalkoxy groups include -O(CH ₂ )F, -O(CH)F ₂ , and -OCF ₃ .

The term "substituted" in reference to alkyl, aryl, aralkyl, carbocyclyl, heterocyclyl and other groups used herein, such as "substituted alkyl", "substituted aryl", "substituted aralkyl", "substituted heterocyclyl" and "substituted carbocyclyl", refers to alkyl, alkylene, aryl, aralkyl, heterocyclyl groups in which one or more hydrogen atoms are independently replaced by non-hydrogen substituents. Typical substituents include, but are not limited to, -X, -R, -O-, ＝O, -OR, -SR, -S-, _-NR2 , -N(+) _R3 , ＝NR, _-CX3 , -CRX2, _-CR2X , _-CN , -OCN, -SCN, -N＝C＝O, -NCS, -NO, _-NO2 , ＝ _N2 , _-N3 , -NRC(＝O)R, -NRC(＝O)OR, -NRC(＝O)NRR, -C(＝O)NRR, -C(＝O)OR, -OC(＝O)NRR, -OC(＝O)OR, -C(＝O)R, -S(＝O) _2OR , -S(＝O) _2R , -OS(＝O) _2OR , -S(＝O) _2NR , -S(＝O)R, -NRS(＝O) ₂ R, -NRS(=O) _2NRR , -NRS(=O) _2OR , -OP(=O)(OR) ₂ , -P(=O)(OR) ₂ , -P(O)(OR)(O)R, -C(=O)R, -C(=S)R, -C(=O)OR, -C(=S)OR, -C(=O)SR, -C(=S)SR, -C(=O)NRR, -C(=S)NRR, -C(=NR)NRR, -NRC(=NR)NRR, wherein each X is independently halogen: F, Cl, Br or I; and each R is independently H, alkyl, cycloalkyl, aryl, aralkyl, heterocycle or protecting group or prodrug moiety. Divalent groups can also be similarly substituted.

Those skilled in the art will recognize that when moieties such as "alkyl," "aryl," "heterocyclyl," etc. are substituted with one or more substituents, they may also be referred to as "alkylene," "arylene," "heterocyclyl," etc. moieties (i.e., referring to at least one hydrogen atom of the parent "alkyl," "aryl," "heterocyclyl" moiety having been replaced by the specified substituent). When moieties such as "alkyl," "aryl," "heterocyclyl," etc. are referred to herein as "substituted" or generally indicated as substituted (or optionally substituted, e.g., when the number of substituents ranges from zero to a positive integer), then the terms "alkyl," "aryl," "heterocyclyl," etc. are understood to be interchangeable with "alkylene," "arylene," "heterocyclyl," etc.

"Heteroalkyl" refers to an alkyl group in which one or more carbon atoms have been replaced by a heteroatom, such as O, N, or S. For example, if a carbon atom of an alkyl group attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., _-OCH3 , etc.), an amine (e.g., _-NHCH3 , -N( _CH3 ) ₂ , etc.), or a thioalkyl group (e.g., _-SCH3 ), respectively. If a non-terminal carbon atom of an alkyl group not attached to the parent molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., _-CH2CH2 - _O - _CH3 , etc.), an alkylamine (e.g. _{, -CH2NHCH3} , _-CH2N ( _CH3 ) ₂ , etc.), or a thioalkyl ether (e.g., _-CH2 -S- _CH3 ), respectively. If the terminal carbon atom of an alkyl group is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is a hydroxyalkyl group (e.g., _{-CH2CH2 -} OH), an aminoalkyl group ₍ e.g., _-CH2NH2 ), or an alkylthiol group (e.g., _-CH2CH2 - _SH ), respectively. The heteroalkyl group may have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. _{A C1} - _C6 heteroalkyl group refers to a heteroalkyl group having 1 to 6 carbon atoms.

The term "heterocycle" or "heterocyclic group" as used herein includes, for example, but is not limited to, the heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1996); New York, 1950 to present), particularly Volumes 13, 14, 16, 19 and 28; and J.Am.Chem.Soc. (1960) 82:5566. In a specific embodiment of the present invention, "heterocycle" includes "carbocycle" herein, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, P and S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Heterocycles include aromatic and non-aromatic mono-, di-, and polycyclic rings, whether fused, bridged or spirocyclic. As used herein, the term "heterocycle" includes, but is not limited to, "heteroaryl".

Substituted heterocyclyls include, for example, heterocycles substituted with any substituent disclosed herein, including carbonyl. Non-limiting examples of carbonyl-substituted heterocyclyls are:

Examples of heterocycles include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrophenylthio, tetrahydrophenylthiothiosulfide, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidine 1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthrenyl, thia ... anthranyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, azathiophene pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl and bis-tetrahydrofuranyl:

.

By way of example and not limitation, the carbon-bonded heterocycle is attached at the 2, 3, 4, 5, or 6 position of a pyridine; the 3, 4, 5, or 6 position of a pyridazine; the 2, 4, 5, or 6 position of a pyrimidine; the 2, 3, 5, or 6 position of a pyrazine; the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiophene (thiofuran, thiophene), pyrrole, or tetrahydropyrrole; the 2, 4, or 5 position of an oxazole, imidazole, or thiazole; the 3, 4, or 5 position of an isoxazole, pyrazole, or isothiazole; the 2 or 3 position of an acridine; the 2, 3, or 4 position of an azetidine; the 2, 3, 4, 5, 6, 7, or 8 position of a quinoline; or the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline. More typically, carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen-bonded heterocycles are at the 1-position of acridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole; at the 2-position of isoindole or isoindole; at the 4-position of morpholine; at the 9-position of carbazole or β-carboline. More typically, nitrogen-bonded heterocycles include 1-acridinyl, 1-azetidinyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

"Heterocyclylene" refers to a heterocyclyl radical as defined herein obtained by replacing a carbon atom of a heterocyclyl radical or a hydrogen atom of a heteroatom with an open valence state. Similarly, "heteroarylene" refers to an aromatic heterocyclyl radical.

"Heterocyclylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom) is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkylene moiety). Typical heterocyclylalkyl groups include, but are not limited to, heterocyclyl- _CH2- , 2-(heterocyclyl)eth-1-yl, and the like, where the "heterocyclyl" portion includes any of the heterocyclyl groups described above, including those disclosed in Principles of Modern Heterocyclic Chemistry . Those skilled in the art will appreciate that the heterocyclyl group can be attached to the alkyl portion of the heterocyclylalkyl group via a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. A heterocyclylalkyl group comprises from 2 to 20 carbon atoms, for example, an aralkyl group comprises from 1 to 6 carbon atoms in the alkyl portion and from 1 to 14 carbon atoms in the heterocyclyl moiety. Examples of heterocyclylalkyl include, but are not limited to, 5-membered heterocycles containing sulfur, oxygen and/or nitrogen, such as thiazolylmethyl, 2-thiazolyleth-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, and the like; 6-membered heterocycles containing sulfur, oxygen and/or nitrogen, such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and the like.

"Heterocyclylalkenyl" refers to a non-cyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom, but also an sp2 carbon atom) is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkenyl-moiety). The heterocyclyl portion of a typical heterocyclylalkenyl group includes any of the heterocyclyl groups described herein, including those disclosed in Principles of Modern Heterocyclic Chemistry , and the alkenyl portion of a heterocyclylalkenyl group includes any alkenyl group disclosed herein. It will be understood by those skilled in the art that the heterocyclyl group can be attached to the alkenyl portion of the heterocyclylalkenyl group via a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. A heterocyclylalkenyl group includes from 2 to 20 carbon atoms, for example, the alkenyl portion of the heterocyclylalkenyl group includes from 1 to 6 carbon atoms and the heterocyclyl portion includes from 1 to 14 carbon atoms.

"Heterocyclylalkynyl" refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom (typically a terminal or sp3 carbon atom, but also an sp carbon atom) is replaced by a heterocyclyl group (i.e., a heterocyclyl-alkynyl-moiety). The heterocyclyl portion of the heterocyclylalkynyl group includes any heterocyclyl group described herein, including those disclosed in Principles of Modern Heterocyclic Chemistry , and the alkynyl portion of the heterocyclylalkynyl group includes any alkynyl group disclosed herein. It will be understood by those skilled in the art that the heterocyclyl group can be attached to the alkynyl portion of the heterocyclylalkynyl group via a carbon-carbon bond or a carbon-heteroatom bond, provided that the resulting group is chemically stable. A heterocyclylalkynyl group includes from 2 to 20 carbon atoms, for example, the alkynyl portion of the heterocyclylalkynyl group includes from 1 to 6 carbon atoms and the heterocyclyl portion includes from 1 to 14 carbon atoms.

" Heteroaryl " refers to a monovalent aromatic heterocyclic radical having at least one heteroatom in the ring. The limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulphur and nitrogen. The limiting examples of heteroaryl rings include those listed in the definition of " heterocyclic radical ", including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furyl, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl etc. Heteroaryl also includes a monovalent aromatic heterocyclic radical that comprises an aryl moiety and a heteroaryl. The limiting examples of these heteroaryls are:

"Carbocycle" or "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic ring having from 3 to 7 carbon atoms as a monocycle, from 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have from 3 to 6 ring atoms, and more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7-12 ring atoms, for example, arranged as a bicyclic (4,5), (5,5), (5,6), or (6,6) system or 9 or 10 ring atoms, arranged as a (5,6) or (6,6) system. Carbocycles include aromatic and non-aromatic monocyclic, bicyclic, and polycyclic rings, whether fused, bridged, or spirocyclic. Non-limiting examples of monocyclic carbocycles include cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, or aryl groups such as phenyl, etc. Thus, "carbocycle" as used herein includes, but is not limited to, "aryl," "phenyl," and "biphenyl."

"Carbocyclylene" refers to a carbocyclyl or carbocycle as defined above having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent carbocyclyl. Typical carbocyclylene groups include, but are not limited to, phenylene. Thus, as used herein, "carbocyclylene" includes, but is not limited to, "arylene."

" carbocyclylalkyl " refers to acyclic alkyl group, wherein with one of the hydrogen atom of carbon atom (being generally terminal or sp3 carbon atom) bonding by carbocyclyl group as defined above replacement.Typical carbocyclylalkyl includes but is not limited to aralkyl, for example benzyl, 2-phenyl second-1-base, naphthylmethyl, 2-naphthyl second-1-base, naphthobenzyl, 2-naphthophenyl second-1-base or cycloalkylalkyl (such as cyclopropylmethyl, cyclobutylethyl, cyclohexylmethyl etc.).Aralkyl can comprise 6 to 20 carbon atoms, for example, alkyl moiety is 1 to 6 carbon atom, and aryl moiety is 6 to 14 carbon atoms.Cycloalkylalkyl can comprise 4 to 20 carbon atoms, for example, alkyl moiety is 1 to 6 carbon atom, and cycloalkyl is 3 to 14 carbon atoms.

"Arylheteroalkyl" refers to a heteroalkyl group as defined herein in which a hydrogen atom that may be attached to a carbon atom or a heteroatom has been replaced by an aryl group as defined herein. The aryl group may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group may have the formula -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylenearyl, and the like. In addition, any alkylene moiety in the above formula may be further substituted with any substituent as defined or exemplified herein.

"Heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced by a heteroaryl group, as defined herein. Non-limiting examples of heteroarylalkyl groups include _-CH2 -pyridyl, -CH2-pyrrolyl, _-CH2 -oxazolyl, -CH2-indolyl, _-CH2 -isoindolyl, _-CH2 -purinyl, -CH2-furyl, _-CH2 -thienyl, -CH2-benzofuranyl, _-CH2 -benzothienyl, _{-CH2 -} carbazolyl, _-CH2 -imidazolyl, _-CH2 -thiazolyl, _-CH2 -isoxazolyl, _-CH2 -pyrazolyl, _-CH2 -isothiazolyl, _-CH2 -quinolyl, -CH2-isoquinolyl, _-CH2 -pyridazinyl, _-CH2 -pyrimidinyl, _-CH2 -pyrazinyl, -CH( _{CH3 )} -pyridyl, -CH( _CH3 )-pyrrolyl, -CH( _{CH3 )} -pyrrolyl, -CH( _{CH3 )} -pyrazol ... )-oxazolyl, -CH(CH ₃ )-indolyl, -CH(CH _{3 )-isoindolyl, -CH(CH 3} )-purinyl, -CH(CH ₃ )-furyl, -CH(CH ₃ )-thienyl, -CH(CH ₃ )-benzofuranyl, -CH(CH ₃ )-benzothienyl, -CH(CH ₃ )-carbazolyl, -CH(CH ₃ )-imidazolyl, -CH(CH ₃ )-thiazolyl, -CH(CH ₃ )-isoxazolyl, -CH(CH ₃ )-pyrazolyl, -CH(CH ₃ )-isothiazolyl, -CH(CH ₃ )-quinolyl, -CH(CH _{3 )} -isoquinolyl, -CH(CH ₃ )-pyridazinyl, -CH(CH ₃ )-pyrimidinyl, -CH(CH ₃ )-pyrazinyl, etc.

The term "optionally substituted" when referring to a particular moiety of a compound of the formulae of the invention (eg, optionally substituted aryl) means that the moiety has 0, 1, or more substituents.

As will be appreciated by those skilled in the art, the compounds of the present invention can exist in solvated or hydrated forms. The scope of the present invention includes these forms. Likewise, as will be appreciated by those skilled in the art, the compounds can be esterified. The scope of the present invention includes esters and other physiologically functional derivatives. The scope of the present invention also includes tautomeric forms, i.e., the tautomeric "enols" described herein. Furthermore, the scope of the present invention includes prodrug forms of the compounds described herein.

"Ester" refers to any ester of a compound wherein any -COOH functional group of the molecule is replaced by a -C(O)OR functional group, or wherein any -OH functional group of the molecule is replaced by a -C(O)OR functional group, wherein the R portion of the ester is any carbon-containing group that forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, and substituted derivatives thereof. Esters may also include esters of "tautomeric enols" as described above, as shown below:

.

The term "esters thereof" includes, but is not limited to, pharmaceutically acceptable esters thereof.

As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a drug substance, i.e., an active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and/or metabolic chemical reactions, etc. Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound.

Those skilled in the art will recognize that the substituents and other moieties of the compounds of the general formula herein should be selected so as to provide sufficiently stable compounds to provide pharmaceutically useful compounds that can be formulated into acceptable stable pharmaceutical compositions. Compounds of Formula I or II having such stability are considered to fall within the scope of the present invention.

As will be appreciated by those skilled in the art, the compounds of the present invention may contain one or more chiral centers. The scope of the present invention includes these forms. Likewise, as will be appreciated by those skilled in the art, the compounds are capable of esterification. The scope of the present invention includes esters and other physiologically functional derivatives. The scope of the present invention also includes tautomeric forms, i.e., tautomeric "enols" as described herein. Furthermore, the scope of the present invention includes prodrug forms of the compounds described herein.

The compounds of the formula herein and their pharmaceutically acceptable salts can exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism refers to the ability of a crystalline compound to exist in different crystal structures. Polymorphism can generally occur according to changes in temperature, pressure, or both. Polymorphism can also be caused by changes in the crystallization method. Polymorphs can be distinguished by various physical characterizations known in the art, such as X-ray diffraction patterns, solubility, and melting points. Crystalline polymorphism can be caused by differences in crystal packing (packing polymorphism) or packing differences between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism refers to the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention can exist due to differences in crystal packing (packing pseudopolymorphism) or due to packing differences between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of Formula I-II compounds and pharmaceutically acceptable salts thereof.

The compounds of the formula herein and their pharmaceutically acceptable salts may also exist as amorphous solids. As used herein, an amorphous solid is a solid in which the positions of the atoms in the solid lack long-range order. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, may be used to produce the amorphous forms of the present invention. The present invention includes the use of all amorphous forms of the compounds described herein and their pharmaceutically acceptable salts.

Certain compounds described herein contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. Also within the scope of the present invention are individual isomers of the compounds represented by the formulae of the present invention, as well as any fully or partially balanced mixtures thereof. The present invention also includes mixtures of individual isomers of the compounds represented by the above formulae with isomers in which one or more chiral centers are inverted.

The term "chiral" refers to molecules that have the property of having non-superimposable mirror-image partners, while the term "achiral" refers to molecules whose mirror-image partners are superimposable. The term "stereoisomers" refers to compounds that have identical chemical composition but differ in the arrangement of the atoms or groups in space. "Diastereomers" refer to stereoisomers with two or more chiral centers whose molecules are not mirror images of each other. Diastereomers generally have different physical properties, for example, melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The stereochemical definitions and conventions used herein generally follow the McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, compiled by SP Parker; and Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York, by Eliel, E. and Wilen, S. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to refer to the absolute configuration of the molecule at the chiral center of the molecule. The prefixes d and l, or (+) and (-) are used to indicate that plane polarized light is rotated by the compound, and (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A special stereoisomer is also referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The present invention includes salts or solvates of the compounds described herein, including combinations thereof, such as solvates of salts. The compounds of the present invention may exist in solvated forms (such as hydrates) or unsolvated forms, and the present invention encompasses all such forms.

Generally, but not exclusively, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention.

Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chlorides, bromides, sulfates, phosphates and nitrates; organic acid addition salts such as acetates, lactobionates, propionates, succinates, lactates, glycolates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, p-toluenesulfonates and ascorbates; salts formed with acidic amino acids such as aspartate and glutamate; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; ammonium salts; organic base salts such as trimethylamine salts, triethylamine salts, pyridinium salts, picoline salts, dicyclohexylamine salts and N,N'-dibenzylethylenediamine salts; and salts formed with basic amino acids such as lysine salts and arginine salts. In some cases, the salt may be a hydrate or an ethanol solvate.

Any formula or structure given herein, including compounds of Formula II and specific examples of compounds herein and pharmaceutically acceptable salts thereof, is also intended to represent unlabeled forms of the compound or its salt as well as isotopically labeled forms. Isotopically labeled compounds or their salts have the structure described by the formula given herein, with the difference that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H (deuterium, D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Various isotopically labeled compounds or their salts of the present disclosure, such as those incorporating radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C. Such isotopically labeled compounds or salts thereof are useful in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiotherapy of subjects (e.g., humans).

The present disclosure also includes compounds of Formula I and pharmaceutically acceptable salts thereof, wherein 1 to n hydrogens attached to the carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds can exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of the compounds herein or their pharmaceutically acceptable salts when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12): 524-527(1984). Such compounds are synthesized by methods well known in the art, for example, by using raw materials in which one or more hydrogens have been replaced by deuterium.

Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (e.g., deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements and/or improvement in therapeutic index). ¹⁸ F-labeled compounds may be used for PET or SPECT studies. Isotope-labeled compounds of the present disclosure and their prodrugs may generally be prepared by performing the methods disclosed in the following schemes or examples and preparations using readily available isotope-labeled reagents in place of non-isotope-labeled reagents. It should be understood that, herein, deuterium is considered to be a substituent in the compounds disclosed herein and their pharmaceutically acceptable salts.

The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be a hydrogen with its natural abundance isotopic composition. Thus, in the compounds of the present disclosure or their salts, any atom specifically designated as deuterium (D) is intended to represent deuterium.

Metabolites of the compounds of the present invention

Metabolites of the compounds described herein are also within the scope of the present invention. Such products may be caused, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, the present invention includes compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce its metabolites. Typically, a radiolabeled (e.g., C ¹⁴ or H ³ ) compound of the present invention is prepared, administered parenterally to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg/kg), allowed sufficient time for metabolism (usually about 30 seconds to 30 hours), and its conversion products are isolated from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes retained in the metabolites). Metabolite structures are determined in conventional manner, such as by MS or NMR analysis. Generally, analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. Conversion products, as long as they are not otherwise found in vivo, can be used for diagnostic determination of therapeutic doses of the compounds of the present invention, even if they themselves have no anti-infective activity.

The definitions and substituents of various superordinate and subclass groups of the compounds of the present invention are described and illustrated herein. It will be understood by those skilled in the art that any combination of the above definitions and substituents should not result in an unrealizable substance or compound. An "unrealizable substance or compound" refers to a compound structure that violates relevant scientific principles (e.g., having more than four covalently bonded carbon atoms) or a compound that is too unstable to be isolated and formulated into a pharmaceutically acceptable dosage form.

pharmaceutical preparations

The compounds of the present invention are formulated with conventional carriers and excipients, which are selected according to conventional practice. Tablets will contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and, when intended to be delivered in a form other than oral administration, will generally be isotonic. All formulations optionally contain excipients such as those listed in the Handbook of Pharmaceutical Excipients (1986), which is incorporated herein by reference in its entirety. Excipients include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose), stearic acid, etc. The pH value of the formulation ranges from about 3 to about 11, but is typically about 7 to 10.

Although the active ingredients can be administered alone, it is preferable to formulate them as pharmaceutical formulations. The formulations of the present invention, whether for veterinary or human use, comprise at least one active ingredient together with one or more acceptable carriers and, optionally, other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not physiologically deleterious to the recipient thereof.

Preparations include those suitable for the above-mentioned route of administration. Preparations can be conveniently made into unit dosage forms and can be made into preparations by any method well-known in the pharmaceutical field. Technology and preparations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA.), which is incorporated herein by reference in its entirety. This type of method includes the step of mixing the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, the preparation is prepared as follows: by uniformly and closely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, the product is shaped.

Formulations of the present invention suitable for oral administration may be prepared as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

The pharmaceutical preparation according to the present invention comprises one or more compounds of the present invention and one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. The pharmaceutical preparation containing the active ingredient can be any form suitable for a specified method of administration. When used for oral application, for example, tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions specified for oral application can be prepared according to any method known in the art of preparing pharmaceutical compositions, and such compositions can contain one or more reagents, including sweeteners, flavorings, coloring agents and preservatives, so as to provide a palatable preparation. Tablets containing active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, polyvinylpyrrolidone, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate, used alone or with a wax, can be used.

The effective dose of active ingredient depends at least on the character of the patient's condition being treated, toxicity, whether the compound is used prophylactically (lower dose) or for active disease or illness, delivery method and pharmaceutical preparation, and will be determined by clinician using conventional dose escalation research.Effective dose can be expected to be about 0.0001 to about 10mg/kg body weight/day, usually about 0.001 to about 1mg/kg body weight/day, more typically about 0.01 to about 1mg/kg body weight/day, even more typically about 0.05 to about 0.5mg/kg body weight every day.For example, the daily candidate dose of the adult of about 70kg body weight will be at about 0.05mg to about 100mg, or about 0.1mg to about 25mg, or about 0.4mg to about 6mg in the range of, and can take the form of single dose or multiple dose.

In another embodiment, the present application discloses a pharmaceutical composition comprising a compound of Formula I or II or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

Route of administration

One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), among others. It will be appreciated that the preferred route may vary, for example, depending on the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally.

Combination therapy

In one embodiment, the compounds of the present invention are used in combination with another active therapeutic ingredient or active therapeutic agent.

In one embodiment, one or more TLR7 modulating compounds described herein may be selected for use in combination with other active agents for treating patients suffering from HIV viral infection.

Combinations of compounds are typically selected based on the condition to be treated, cross-reactivity of the ingredients, and the pharmaceutical properties of the combination. For example, when treating infections such as HIV, the compositions of the invention are combined with other active agents such as those described herein.

Suitable active agents or ingredients that can be combined with the TLR7 modulating compounds described herein or salts thereof can include one or more compounds selected from TLR7 agonists selected from ANA-975, SM-360320, and mixtures thereof.

In addition, the compounds of the present invention can be used in combination with other therapeutic agents for the treatment or prevention of AIDS and/or one or more other diseases (e.g., bacterial and/or fungal infections, other viral infections such as hepatitis B or hepatitis C, or cancers such as Kaposi's sarcoma) in human subjects suffering from AIDS. The other therapeutic agents can be co-formulated with one or more salts of the present invention (e.g., co-formulated in a tablet).

Examples of such other therapeutic agents include agents effective in treating or preventing viral, parasitic or bacterial infections or related conditions, or for treating tumors or related conditions, including 3'-azido-3'-deoxythymidine (zidovudine, AZT), 2'-deoxy-3'-thiocytidine (3TC), 2',3'-dideoxy-2',3'-didehydroadenosine (D4A), 2',3'-dideoxy-2',3'-didehydrothymidine (D4 T), carbovir (carbocyclic 2',3'-dideoxy-2',3'-didehydroguanosine), 3'-azido-2',3'-dideoxyuridine, 5-fluorothymidine, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), 2-chlorodeoxyadenosine, 2-deoxycoformycin, 5-fluorouracil, 5-fluorouridine, 5-fluoro-2'-deoxyuridine, 5-trifluoromethyl-2'-deoxyuridine, 6-azauracil, 5-fluoroorotic acid, methotrexate, triacetyluridine, 1-(2'-deoxy-2'-fluoro-1-β-arabinosyl)-5-iodine (FIAC), tetrahydroimidazo(4,5,1-jk)-(1,4)-benzodiazepine-2(1H)-thione (TIBO), 2'-nor-cyclic-GMP, 6-methoxypurine arabinoside (ara-M), 6-methoxypurine arabinoside 2'- O-valerate; cytosine arabinoside (ara-C), 2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI); acyclic nucleosides such as acyclovir, penciclovir, famciclovir, ganciclovir, HPMPC, PMEA, PMEG, PMPA, PMPDAP, FPMPA, HPMPA, HPMPDAP, (2R,5R)-9-tetrahydro-5-(phosphonomethoxy)-2-furyladenine, (2R,5R)-1-tetrahydro-5-(phosphonomethoxy)-2-furylthymidine; other antiviral agents include ribavirin (adenine arabinoside), 2-thio-6-azauracil, tuberculin, aurintricarboxylic acid, 3-deazaneoplanocin ), neomycin, rimantadine, adamantane, and foscarnet sodium (foscarnet trisodium); antibacterial agents, including bactericidal fluoroquinolones (ciprofloxacin, pefloxacin, etc.); aminoglycoside bactericidal antibiotics (streptomycin, gentamicin, amikacin, etc.); β-lactamase inhibitors (cephalosporins, penicillins, etc.); other antibacterial drugs include tetracycline, isoniazid, rifampicin, cefoperazone, clarithromycin, and azithromycin; antiparasitic or antifungal agents include pentamidine amidine (1,5-bis(4'-aminophenoxy)pentane), 9-deazainosine, sulfamethoxazole, sulfadiazine, quinazolinamide, quinine, fluconazole, ketoconazole, itraconazole, amphotericin B, 5-flucytosine, clotrimazole, hexadecylphosphocholine, and nystatin; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole, dilazep, and nitrobenzylthioinosine; immunomodulators such as FK506, cyclopentyl sulfadiazine, and cyclopentyl sulfadiazine; Sporogen A, thymosin α-1; cytokines including TNF and TGF-β; interferons including IFN-α, IFN-β and IFN-γ; interleukins including various interleukins, macrophage/granulocyte colony-stimulating factors (including GM-CSF, G-CSF, M-CSF), cytokine antagonists including anti-TNF antibodies, anti-interleukin antibodies, soluble interleukin receptors, protein kinase C inhibitors, etc.

Suitable active therapeutic agents or active therapeutic ingredients having anti-HIV activity that can be combined with the compounds of the present invention include:

1) HIV protease inhibitors, such as amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir, brenavir, darunavir, TMC-126, mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100;

2) non-nucleoside HIV reverse transcriptase inhibitors, such as caravirine, imivirine, tavidin, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150 and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355BS, VRX840773, UK-453,061, RDEA806, KM023, and MK-1439;

3) nucleoside HIV reverse transcriptase inhibitors, such as zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amidosavir, efavirenz, alovudine, MIV-210, racivir (-FTC), D-d4FC, emtricitabine, phosphinosine (azide), fosalvudine tizumab, fosalvudine tizumab, arithiab (AVX754), amidosavir, KP-1461, abacavir + lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine;

4) Nucleotide HIV reverse transcriptase inhibitors, such as tenofovir, tenofovir disoproxil fumarate + emtricitabine, tenofovir disoproxil fumarate + emtricitabine + efavirenz, as well as adefovir, CMX-157 and TAF;

5) HIV integrase inhibitors, such as curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine phosphorylation inhibitors, derivatives of tyrosine phosphorylation inhibitors, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812 and L-870810, MK-0518 (raltegravir), BMS-707035, MK-2048, BA-011, BMS-538158, GSK364735C, GSK1265744 (GSK744), and dolutegravir;

6) HIV non-catalytic site, or allosteric integrase inhibitors (NCINIs), including, but not limited to, BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), each of which is incorporated herein by reference in its entirety;

7) gp41 inhibitors, such as enfuvirtide, sifuvirtide, FB006M and TRI-1144, SPC3, DES6, Locus gp41, CovX and REP 9;

8) CXCR4 inhibitors, such as AMD-070;

9) Entry inhibitors, such as SP01A and TNX-355; 9) gp120 inhibitors, such as BMS-488043 and BlockAide/CR;

10) G6PD and NADH-oxidase inhibitors, such as immunoglobulins;

11) CCR5 inhibitors, such as alavir, virivirox, INCB9471, PRO-140, INCB15050, PF-232798, CCR5mAb004, and maraviroc;

12) interferons, such as pegylated rIFN-α2b, pegylated rIFN-α2a, rIFN-α2b, IFNα-2bXL, rIFN-α2a, consensus IFNα, infergen, rebif, locteron, AVI-005, PEG-infergen, pegylated IFN-β, oral interferon α, zyme protein, reaferon, intermax α, r-IFN-β, interferon + actimmune, IFN-ω and DUROS, and albuferon;

13) Ribavirin analogs, such as rebetol, copegus, levovirin, VX-497, and taribavirin hydrochloride;

14) NS5a inhibitors, such as BMS-790052, GS-5885, GSK62336805, ACH-2928AZD2836, AZD7295, BMS-790052, BMS-824393, GS-5885, PPI-1301, PPI-461, A-831, and A-689;

15) NS5b polymerase inhibitors, such as IDX-375, NM-283, valocitabine, R1626, PSI-6130 (R1656), HIV-796, BILB1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, sertrabuvir (ANA598), sofosbuvir, and XTL-2125;

16) NS3 protease inhibitors, such as SCH-503034 (SCH-7), VX-950 (telaprevir), ITMN-191, and BILN-2065;

17) α-glucosidase 1 inhibitors, such as MX-3253 (celgosivir) and UT-231B;

18) Hepatoprotective agents, such as IDN-6556, ME 3738, MitoQ, and LB-84451;

19) Non-nucleoside inhibitors of HIV, such as benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives;

20) Other drugs used to treat HIV, such as Zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, baviximab, oglufacil, PYN-17, KPE02003002, CPG-10101, KRN-civacir, GI-5005, ANA-975 (etoribin), XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811

21) Pharmacokinetic enhancers, such as BAS-100 and SPI452;

22) RNase H inhibitors, such as ODN-93 and ODN-112;

23) Other anti-HIV agents, such as VGV-1, PA-457 (bevirimat), Ampligen, HRG214, cytolin, polymun, VGX-410, KD247, AMZ 0026, CYT99007, A-221 HIV, BAY 50-4798, MDX010 (ipilimumab), PBS119, ALG889, and PA-1050040.

Other agents useful in the methods herein include monoclonal antibodies targeting arginase-1, adenosine deaminase, adenosine receptors, IL-4, IL-6 (e.g., siltuximab/Sylvant ^™ ), IL-10, IL-12, IL-18, IL-21, c-Kit, stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), histone methyltransferases (HMTs), glycogen synthase kinase 3 (GSK3), and CD32b, as well as their small molecule inhibitors.

Also useful are farnesyltransferase inhibitors, such as lonafarnib (SCH66336, Sarasar ^™ ), Chaetomellic acid A, FPT inhibitors I, II, and III, FTase inhibitors I (CAS 149759-96-6) and II (CAS 156707-43-6), FTI-276 trifluoroacetate, FTI-277 trifluoroacetate, FTI-2153, GGTI-297, Gingerol, gliotoxin, L-744,832 dihydrochloride, manunomycin A, tipifarnib (R115777, Zarnestra), α-hydroxyfarnesylphosphonic acid, BZA- 5B, manumycin A, hydroxyfarnesylphosphonic acid, butyric acid, 2-[[(2S)-2-[(2S,3S)-2-[[(2R)-2-amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy-1-oxo-3-phenylpropyl]amino]-4-(methylsulfonyl)-1-methylethyl ester, (2S)-(9cl), BMS-214662, BMS-316810, dichloro Benzoprim (2,4-diamino-5-(4-(3,4-dichlorobenzylamino)-3-nitrophenyl)-6-ethylpyrimidine), B-581, B-956 (N-(8(R)-amino-2(S)-benzyl-5(S)-isopropyl-9-sulfanyl-3(Z),6(E)-nonadienoyl)-L-methionine), OSI-754, perillyl alcohol (1-cyclohexene-1-methanol, 4-(1-methylvinyl)-, RPR-114334, Sch-48755, Sch-226374, (7,8-dichloro-5H-dibenzo(b,e)(1,4)diazepin-11-yl)-pyridin-3-ylmethanamine, J-104126, L-639749, L-731734 (pentanamide, 2-(2-((2-amino-3-mercaptopropyl)amino)-3-methylbenzene (2-(2-((2-amino-3-mercaptopropyl)amino)-3-methylpentyl)oxy)-1-oxo-3-phenylpropyl)amino)-4-(methylsulfonyl), 1-methylethyl esters, (2S-(1(R*(R*)),2R*(S*),3R*))-), L-745631(1-piperazinepropanethiol, β-amino-2-(2-methoxyethyl)-4-(1-naphthylcarbonyl)-, (βR,2S)-), N-acetyl-N-naphthylmethyl-2(S)-((1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetyl)amino-3(S)-methylpentylamine, (2α)-2-hydroxy-24,25-dihydroxylanost-8-en-3-one, UCF-1-C (2,4-decadienamide, N-(5-hydroxy-5-(74 (2-hydroxy-5-oxo-1-cyclopenten-l-yl)amino-oxo-1,3,5-heptatrienyl)-2-oxo-7-oxabicyclo (4.1.0) hept-3-en-3-yl)-2,4,6-trimethyl-, (1S-(1α ,3(2E,4E,6S*),5α,5(1E,3E,5E),6α))-), UCF-116-B, ARGLABIN(3H-oxirano[8,8a]azulo[4,5-b]furan-8(4aH)-one and 5,6,6a,7,9a,9b-hexahydro-1,4a-dimethyl-7-methylene-,(3aR,4aS,6aS,9aS,9bR)-).

Also useful in the methods and combinations herein are inhibitors of the 26S proteasome, such as lactacystin, bortezomib (PS-341), ritonavir, MG-132 (Z-Leu-Leu-Leu-CHO), MG-115 (Z-LL-Nva-CHO), proteasome inhibitor I (Z-Ile-Glu(OtBu)-Ala-Leu-CHO), and proteasome inhibitor II (Z-LLF-CHO).

Useful E3 ubiquitin ligase inhibitors include proTAME, RITA (5,5'-(2,5-furandiyl)bis-2-thiophenemethanol), HLI 373 (5-[[3-dimethylamino)propyl]amino]-3,10-dimethylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione dihydrochloride), Nutlin-3 ((±)-4-[4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one), SMER 3 (9H-indeno[1,2-e][1,2,5]oxadiazolo[3,4-b]pyrazin-9-one), NSC66811 (2-methyl-7-[phenyl(phenylamino)methyl]-8-hydroxyquinoline), TAME HCl (N ² -[(4-methylphenyl)sulfonyl]-L-arginine methyl ester hydrochloride), Heclin (N-(4-acetylphenyl)-3-(5-ethyl-2-furyl)-2-acrylamide), PRT 4165 (2-(3-pyridylmethylene)-1H-indene-1,3(2H)-dione), NAB2 (N-[(2-chlorophenyl)methyl]-1-(2,5-dimethylphenyl)-1H-benzimidazole-5-carboxamide), SP 141 (6-methoxy-1-(1-naphthyl)-9H-pyrido[3,4-b]indole), SZL P1-41 (3-(2-benzothiazolyl)-6-ethyl-7-hydroxy-8-(1-piperidinylmethyl)-4H-1-benzopyran-4-one), PTC 209 (N-(2,6-dibromo-4-methoxyphenyl)-4-(2-methylimidazo[1,2-a]pyrimidin-3-yl)-2-thiazolamine), SKP C1 (2-[4-bromo-2-[[4-oxo-3-(3-pyridylmethyl)-2-thioxo-5-thiazolidinediyl]methyl]phenoxy]acetic acid), A01 ([4-[[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl]-1-piperazinyl][4-(5-methyl-1H-pyrazol-1-yl)phenyl]methanone), Apcin.

Useful protein kinase C agonists (PKC) include midostaurin (PKC412, CGP41251, 4'-N-benzoylstaurosporine), lubutaurin (LY 333531 HCl, (9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-dimethylenyldibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazolecyclohexadecene-18,20(19H)-dione hydrochloride), solastaurin (AEB071), enzastaurin (LY317615 HCl), solastaurin (AEB071), CGP60474, chelerythrine hydrochloride (HY-12048), fasudil HCl (HY-10341, Go 6983 (HY-13689) and zoledronic acid (CGP 42446). These include phorbol esters such as PMA, prostratin, and 12-deoxyphorbol 13-phenylacetate (DPP) and non-phorbol ester compounds, including bryostatin compounds, including bryostatin-1, diacylglycerol (DAG) analogs such as LMC03 and LMC07, including DAG lactones such as HK654, HK434, HK602, and HK204, ingenol derivatives including ITA, ingenol-3-hexanoate (IngB), and I-3-A, and ingol diterpenes such as 8-methoxyingol 7,12-diacetate, 3-phenylacetate, 8-methoxyingol 7,12-diacetate 3-phenyl acetate (SJ23B), (5aS,7S,8aR,E)-1,1,4,7,10-pentamethyl-2-(((E)-2-methylbut-2-enoyl)oxy)-9-oxo-1,1a,2,3,6,7,8,9,10,10a-decahydro-5a,8a-epoxycyclopenta[a]cyclopropa[e][10]annulene-6,10a-diyl diacetate, and gnidimacrin.

As another example, the following list discloses exemplary HIV antiviral agents and their corresponding US Patent Numbers, the methods for preparing these antiviral agents are incorporated herein by reference, which can be combined with the TLR7 modulating compounds described herein in the methods of the present invention.

Exemplary HIV Antiviral Agents and Patent Numbers

Examples of HIV antiviral agents useful in the combinations and methods herein include Ziagen (abacavir sulfate, US 5,034,394); Epzicom (abacavir sulfate/lamivudine, US 5,034,394); Hepsera (adefovir dipivoxil, US 4,724,233); Agenerase (amprenavir, US 5,646,180); Reyataz (atazanavir sulfate, US 5,849,911); Rescriptor (delaviridine mesylate, US 5,563,142); Hivid (dideoxycytidine; zalcitabine, US 5,028,595); Videx (dideoxyinosine; didanosine, US 4,861,759); Sustiva (steronin, US 5,519,021); Emtriva (emtricitabine, US 6,642,245);

Lexiva (fosamprenavir calcium, US 6,436,989); Virudin; Triapten; Foscavir (foscarnet sodium, US 6,476,009); Crixivan (indinavir sulfate, US 5,413,999); Epivir (lamivudine, US 5,047,407); Combivir (lamivudine/zidovudine, US 4,724,232); Aluviran (lopinavir); Kaletra (lopinavir/ritonavir, US 5,541,206); Viracept (nelfinavir mesylate, US 5,484,926); Viramune (nevirapine, US 5,366,972); Norvir (ritonavir, US 5,541,206); Invirase; Fortovase (saquinavir mesylate, US 5,196,438); Zerit (stavudine, US 4,978,655); (tenofovir disoproxil fumarate/emtricitabine, US 5,210,085); (tenofovir disoproxil fumarate); (emtricitabine/rilpivirine/tenofovir disoproxil fumarate); (efavirenz/emtricitabine/tenofovir disoproxil fumarate); (elvitegravir 150 mg/corbicastat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg); Aptivus (tipranavir); Retrovir (zidovudine; azidothymidine, US 4,724,232) and (emtricitabine/rilpivirine/tenofovir disoproxil fumarate).

In another embodiment, the present application discloses a pharmaceutical composition comprising a TLR7 modulating compound as described herein or a pharmaceutically acceptable salt thereof with at least one additional active agent and a pharmaceutically acceptable carrier or excipient. In another embodiment, the present application provides a combination of two or more therapeutic agents in a single dosage form. Therefore, any compound of the present invention can also be combined with one or more other active agents in a single dosage form.

The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

Co-administration of a compound of the invention with one or more other active agents generally refers to administering the compound of the invention and one or more other active agents simultaneously or sequentially such that therapeutically effective amounts of both the compound of the invention and one or more other active agents are present in the patient's body.

Co-administration is included in the compounds of this invention that administers unit dose before or after one or more other activating agents of administering unit dose, for example, administering the compounds of this invention within a few seconds, minutes or hours of administering one or more other activating agents.For example, the compounds of this invention of unit dose can be first administered, then administer one or more other activating agents of unit dose within a few seconds or minutes. Alternatively, one or more other activating agents of unit dose can be first administered, then administer the compounds of this invention of unit dose within a few seconds or minutes. In some cases, it may be desirable to first administer the compounds of this invention of unit dose, then administer one or more other activating agents of unit dose after a period of time (such as 1-12 hour). In other cases, it may be necessary to first administer one or more other activating agents of unit dose, then after a period of time (such as 1-12 hour), by administering the compounds of this invention of unit dose.

Combination therapy can provide "synergy" and "synergistic effects," i.e., the effect of the active ingredients when taken together is greater than the sum of the effects produced by the compounds taken individually. A synergistic effect can be obtained when the active ingredients are: (1) co-formulated and administered, or delivered simultaneously in a combination formulation; (2) delivered by alternating or concurrent delivery as separate formulations; or (3) delivered by some other regimen. When delivered in alternation therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially—for example, in the form of separate tablets, pills, or capsules—or as different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

Treatment

As used herein, an "agonist" is a substance that stimulates its binding partner (usually a receptor). Stimulation is defined in the context of a specific assay, or as will be clear to one skilled in the art from the literature based on discussions comparing it herein to factors or substances that are accepted as "agonists" or "antagonists" of a particular binding partner under substantially similar circumstances. Stimulation can be defined by an increase in a specific effect or function induced by the interaction of an agonist or partial agonist with a binding partner, and can include allosteric effects.

As used herein, an "antagonist" is a substance that inhibits its binding partner (usually a receptor). Inhibition is defined in the context of a particular assay, or as will be clear to one skilled in the art from the literature based on discussions comparing it herein to factors or substances that are accepted as "agonists" or "antagonists" of a particular binding partner under substantially similar circumstances. Inhibition can be defined by a reduction in a specific effect or function induced by the interaction of the antagonist with the binding partner, and can include allosteric effects.

As used herein, a "partial agonist" or "partial antagonist" is a substance that provides a level of stimulation or inhibition to its binding partner that is incomplete or incomplete agonism or antagonism. It should be recognized that stimulation as well as inhibition are essentially defined as any substance or class of substances that are defined as agonists, antagonists, or partial agonists.

As used herein, "intrinsic activity" or "pharmacodynamics" refers to some measure of the biological effectiveness of a binding partner complex. With respect to receptor pharmacology, the context of intrinsic activity or pharmacodynamics should depend on the context of the binding partner (e.g., receptor/ligand) complex and consider the activity associated with a specific biological outcome. For example, in some cases, intrinsic activity can vary depending on the specific second messenger system involved. It will be clear to one of ordinary skill in the art under what circumstances particular assessments of context are relevant, and the extent to which they are relevant in the context of the present invention.

As used herein, receptor modulation includes receptor agonism, partial agonism, antagonism, partial antagonism, or inverse agonism. TLR7 modulating compounds may also be referred to as TLR7 modulating agents, TLR7 modulators, compounds that modulate TLR7 activity, and the like.

As will be appreciated by those skilled in the art, when treating a viral infection such as HIV, such treatment can be characterized in a variety of ways and measured by a variety of endpoints. The scope of the present invention is intended to include all such characterizations.

In one embodiment, the method can be used for inducing an immune response for the multiple epitopes of human viral infection. The induction of the immune response of resistance virus infection can be assessed using any technology known to those skilled in the art for determining whether an immune response occurs. Suitable methods for detecting the immune response of the present invention include detecting the reduction of viral load or antigen in subject's serum, detecting IFN-γ secretory antigen-specific T cells, and detecting the level of the increase of one or more liver enzymes, such as alanine transferase (ALT) and aspartate transferase (AST). In one embodiment, ELISPOT is used to determine or FACS analysis is used to realize the detection of IFN-γ secretory antigen-specific T cells. Another embodiment includes reducing the viral load relevant to HIV infection, including measuring this reduction by PCR.

TLR7 regulating compounds as described herein can be applied by any useful approach and mode, for example, by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of TLR7 regulating compounds as described herein is from about 0.00001mg/kg body weight/day to about 10mg/kg body weight/day, for example, from about 0.0001mg/kg body weight/day to about 10mg/kg body weight/day, or for example, from about 0.001mg/kg body weight/day to about 1mg/kg body weight/day, or for example, from about 0.01mg/kg body weight/day to about 1mg/kg body weight/day, or for example, from about 0.05mg/kg body weight/day to about 0.5mg/kg body weight/day, or for example, from about 0.3 μg to about 30mg/day, or for example, from about 30 μg to about 300 μg/day.

The frequency of administration of the TLR7 modulating compounds described herein will be determined by the needs of the individual patient and can be, for example, once a day or twice a day or more. Administration of the TLR7 modulating compounds as described herein is continued for the time required to treat HIV infection. For example, the TLR7 modulating compounds described herein can be administered to a person infected with HIV for a period of 20 to 180 days, or for example, a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

Administration can be intermittent, during which the patient receives a daily dose of a TLR7 modulating compound as described herein for one or more days, followed by a few days or more days, during which the patient does not receive a daily dose of a TLR7 modulating compound as described herein. For example, the patient can receive a dose of a TLR7 modulating compound as described herein once every other day, or three times a week, once a week (once every 7 days), once every other week (once every 14 days), once a month, once every other month. For example again, the patient can receive a dose of a TLR7 modulating compound as described herein every day for 1 to 14 days, and then within 7 to 30 days, the patient does not receive the TLR7 modulating compound dosage as described herein, and then the subsequent patient receives the daily dose of a TLR7 modulating compound as described herein again (for example, 1 to 14 days). For other examples, in a separate embodiment, the patient can receive an initial single dose of a TLR7 modulating compound as described herein, then every other day or three times a week, once a week (once every 7 days), once every other week (every 14 days), once a month or once every other month. Alternating administration of a TLR7 modulating compound as described herein, followed by no administration of a TLR7 modulating compound as described herein, can be repeated as clinically necessary to treat the patient.

Each of the TLR7 modulating compounds of Formula II and pharmaceutically acceptable salts thereof represented in Examples 1 to 118 below can be prepared by the methods disclosed in WO 2010/077613 A1 (Desai et al.), which is incorporated herein by reference in its entirety, and by other methods known in the art.

Predictive Example

As examples described herein, the following compounds can be used in the uses, methods of treatment, regimens, pharmaceutical formulations, and kits described herein and can be prepared using synthetic methods similar to those taught in WO 2010/077613 A1 (Desai et al.):

Example 119: 6-amino-2-butoxy-9-(3-(pyrrolidin-1-ylmethyl)benzyl)-9H-purin-8-ol

The compound of Example 119 can be prepared using the method of US Patent No. 7,968,544 (Graupe et al.), where it appears as Compound W.

Example 120: 4-amino-6-(2-methoxyethoxy)-1-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

The compound of Example 120 can be prepared using the methods of WO 2011/049825 and U.S. 8,507,507 (Halcomb et al.), where it appears as Compound AX.

Example 121: 4-amino-7-chloro-6-(2-methoxyethoxy)-1-((4'-(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one

The compound of Example 121 can be prepared using the methods of WO 2011/049825 and U.S. 8,507,507 (Halcomb et al.), where it appears as Compound AY.

Example 122: 6-amino-9-benzyl-2-(2-methoxyethoxy)-9H-purin-8-ol

The compound of Example 122, also known as 1V136, CL 087, and SM 360320, can be prepared as described in US Patent No. 6,329,381, where it appears as Example 88.

Example 123: N-(4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl)methanesulfonamide

The compound of Example 123, also known as R-852, R-852A, and PF-4878691, can be prepared by the method described in US Patent No. 6,677,349, where it appears as Example 236.

Example 124-5-amino-3-((2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)thiazolo[4,5-d]pyrimidine-2,7(3H,4H)-dione

The compound of Example 124 can be prepared as described in US Patent No. 8,097,718, where it appears as Example 122.

Pharmaceutical composition

In one embodiment, the present application discloses a pharmaceutical composition comprising a TLR7 modulating compound as described herein, including a combination of each individual compound selected from Formula II, Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), and Examples 1 to 124, or a pharmaceutically acceptable salt, solvate and/or ester thereof, and at least one other therapeutic agent selected from HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors, HIV integrase strand transfer inhibitors, non-catalytic site integrase inhibitors, HIV gp120/41 inhibitors, CCR5 inhibitors, HIV capsid protein inhibitors, HIV Vif inhibitors, nucleotide HCV inhibitors, nucleoside HCV inhibitors, non-nucleoside HCV inhibitors, and combinations thereof, as well as pharmaceutically acceptable carriers or excipients. Examples include nucleoside-sparing and nucleotide-sparing combinations.

In another embodiment, the present application provides a composition comprising a pharmaceutically effective amount of a TLR7 modulating compound as described herein or a pharmaceutically acceptable salt, solvate and/or ester thereof, and at least one other therapeutic agent selected from amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brenavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), dapoxetine, ... ), JE-2147(AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, AG1859, caravirine, amivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, etravirine, doravirine (MK-1439), GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, TMC-278 (rilpivirine), BILR 355BS, VRX 840773, UK-453061, RDEA806, zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxivir, efavirin, alovudine, MIV-210, racivir (±-FTC), D-d4FC, phosphine azide, fozivudine ester, arithiab AVX754, amdoxivir, KP-1461, and fosivudine ester (formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, CMX-157, adefovir dipivoxil, GS-9131, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives , tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, S-1360, zintevir (AR-177), L-870812, L-870810, MK-0518 (raltegravir), dolutegravir, elvitegravir, GSK1265744, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, enfuvirtide, sifuvirtide, FB006M, TRI-1144, AMD-070, SP01A, BMS-488043, BMS-626529, BMS-663068, BlockAide/CR, immunosin, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, alaviroc, viraviroc and maraviroc, cenicriviroc (TBR-652), cyclosporine, FK-506, rapamycin, paclitaxel, taxotere, clarithromycin, A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343, DMP-323, XM-450, BILA 2011BS, BILA 1096BS, BILA 2185BS, BMS 186,318, LB71262, SC-52151, SC-629 (N,N-dimethylglycyl-N-(2-hydroxy-3-(((4-methoxyphenyl)sulfonyl)(2-methylpropyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide), KNI-272, CGP 53437, CGP 57813 and U-103017, and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of a TLR7 modulating compound described herein or a pharmaceutically acceptable salt, solvate and/or ester thereof, and two, three, four, five or more other therapeutic agents. For example, a TLR7 modulating compound described herein or a pharmaceutically acceptable salt, solvate and/or ester thereof is combined with two, three, four, five or more other therapeutic agents selected from the following categories: HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors, HIV entry inhibitors and HIV integrase inhibitors. The two, three, four, five or more other therapeutic agents may be different therapeutic agents selected from the same therapeutic agent category, or they may be selected from different therapeutic agent categories. In a specific embodiment, the TLR7 modulating compound described herein, or a pharmaceutically acceptable salt, solvate and/or ester thereof, is combined with two, three, four, five or more other therapeutic agents selected from the following categories: HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors and HIV integrase inhibitors. In a more specific embodiment, the pharmaceutical composition of the present invention comprises a compound selected from Example 4, Example 49 (GS-9620), Example 119, Example 120 and Example 121, or a pharmaceutically acceptable salt, solvate and/or ester thereof, in combination with two, three, four, five or more other therapeutic agents selected from the following categories: HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors and HIV integrase inhibitors. For example, such a combination can include a compound selected from the group consisting of Example 4, Example 49 (GS-9620), Example 119, Example 120, and Example 121, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with two, three, four, five, or more other therapeutic agents selected from the group consisting of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), tenofovir alafenamide hemifumarate, abacavir, abacavir sulfate, GS-9131, emtricitabine, lamivudine, elvitegravir, efavirenz, atazanavir, darunavir, raltegravir, dolutegravir, GSK774, corbicistat, ritonavir, and rilpivirine (or a pharmaceutically acceptable salt, solvate, and/or ester thereof).

The combinations and compositions herein include those comprising a pharmaceutically effective amount of TDF and emtricitabine plus a third HIV therapeutic agent, and TAF and emtricitabine plus a third HIV therapeutic agent. Examples of HIV therapeutic agents that can be used with these combinations include HIV protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), integrase strand transfer inhibitors (INSTIs), non-catalytic site integrase inhibitors (NCINIs), capsid protein inhibitors, and the like as listed herein.

Specific embodiments of ternary combinations, which a) can be combined with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical composition, or b) can be used in combination with the methods described herein, include, for example, pharmaceutically effective amounts of each of the compounds listed in the following combinations, or pharmaceutically acceptable salts thereof:

Examples of antiviral agents that can be combined in the pharmaceutical compositions and regimens employed in the uses and methods described herein include TDF, TAF, emtricitabine (FTC), lamivudine (3TC), abacavir (ABC), zidovudine (AZT), efavirenz (EFV), rilpivirine (RPV), etravirine (ETV), atazanavir (ATV), atazanavir + ritonavir (ATV/r), atazanavir + corbicistat (ATV/COBI), tadalafil (tadalafil ... Darunavir (DRV), darunavir + ritonavir (DRV/r), darunavir + corbicistat (DRV/COBI), lopinavir (LPV), lopinavir + ritonavir (LPV/r), lopinavir + corbicistat (LPV/COBI), dolutegravir (DTG), raltegravir (RAL), elvitegravir (EVG), elvitegravir + ritonavir (EVG/r), elvitegravir + corbicistat (EVG/COBI) and maraviroc. Thus, provided herein are separate combinations each comprising a pharmaceutically effective amount of a TLR7 modulator, including a TLR7 modulator of the various formulas and embodiments described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of each of the following separate antiviral combinations: TDF/TAF, TDF/FTC, TDF/3TC, TDF/ABC, TDF/AZT, TDF/EFV, TDF/RPV, TDF/ETV, TDF/ATV, TDFATV/r, TDF/ATV/COBI, TDF/DRV, TDF/DRV/r.TDF/DRV/COBI, TDF/LPV, TDF/LPV/r, TDF/LPV/COBI, TDF/DTG, TDF/RAL, TDF/EVG, TDF/EVG/r, TDF/EVG/COBI, TDF/maraviroc, TAF/FTC, TAF/3TC, TAF/ABC, TAF/AZT, TAF/EFV, TAF/R PV, TAF/ETV, TAF/ATV, TAF/ATV/r, TAF/ATV/COBI, TAF/DRV, TAF/DRV/r, TAF/DRV/COBI, TAF/LPV, TAF/LPV /r, TAF/LPV/COBI, TAF/DTG, TAF/RAL, TAF/EVG, TAF/EVG/r, TAF/EVG/COBI, TAF/Maravero, FTC/3TC, FTC/ABC, FTC/AZT, FTC/EFV, FTC/RPV, FTC/ETV, FTC/ATV, FTC/ATV/r, FTC/ATV/COBI, FTC/DRV, FTC/DRV/r, FTC/DRV /COBI, FTC/LPV, FTC/LPV/r, FTC/LPV/COBI, FTC/DTG, FTC/RAL, FTC/EVG, FTC/EVG/r, FTC/EVG/COBI, FTC/马Ravello, 3TC/ABC, 3TC/AZT, 3TC/EFV, 3TC/RPV, 3TC/ETV, 3TC/ATV, 3TC/ATV/r, 3TC/ATV/COBI, 3TC/DRV, 3TC/D RV/r, 3TC/DRV/COBI, 3TC/LPV, 3TC/LPV/r, 3TC/LPV/COBI, 3TC/DTG, 3TC/RAL, 3TC/EVG, 3TC/EVG/r, 3TC/E VG/COBI, 3TC/Maravero, ABC/AZT, ABC/EFV, ABC/RPV, ABC/ETV, ABC/ATV, ABC/ATV/r, ABC/ATV/COBI, ABC/DRV, ABC/DRV/r, ABC/DRV/COBI, ABC/LPV, ABC/LPV/r, ABC/LPV/COBI, ABC/DTG, ABC/RAL, ABC/EVG, ABC/EVG/r, ABC/EVG/COBI, ABC/Maravero, AZT/EFV, AZT/RPV, AZT/ETV, AZT/ATV, AZT/ATV/r, AZT/ATV/COBI, AZT/DRV, AZT /DRV/r, AZT/DRV/COBI, AZT/LPV, AZT/LPV/r, AZT/LPV/COBI, AZT/DTG, AZT/RAL, AZT/EVG, AZT/EVG/r, AZT /EVG/COBI, AZT/Maravero, EFV/RPV, EFV/ETV, EFV/ATV, EFV/ATV/r, EFV/ATV/COBI, EFV/DRV, EFV/DRV/r, EFV/ DRV/COBI, EFV/LPV,EFV/LPV/r, EFV/LPV/COBI, EFV/DTG, EFV/RAL, EFV/EVG,EFV/EVG/r, EFV/EVG/COBI, EF V/Maravero,RPV/ETV,RPV/ATV,RPV/ATV/r,RPV/ATV/COBI,RPV/DRV,RPV/DRV/r,RPV/DRV/COBI,RPV/LPV,RPV /LPV/r, RPV/LPV/COBI, RPV/DTG, RPV/RAL, RPV/EVG, RPV/EVG/r, RPV/EVG/COBI, RPV/Maravero, ETV/ATV, ETV/ ATV/r, ETV/ATV/COBI, ETV/DRV, ETV/DRV/r, ETV/DRV/COBI, ETV/LPV, ETV/LPV/r, ETV/LPV/COBI, ETV/DTG , ETV/RAL, ETV/EVG, ETV/EVG/r, ETV/EVG/COBI, ETV/Maravero, ATV/r, ATV/COBI, ATV/DRV, ATV/DRV/r, ATV/DR V/COBI, ATV/LPV, ATV/LPV/r, ATV/LPV/COBI, ATV/DTG, ATV/RAL, ATV/EVG, ATV/EVG/r, ATV/EVG/COBI, ATV /Maravero, ATV/r/COBI, ATV/rDRV, ATV/rDRV/COBI, ATV/r/LPV, ATV/r/LPV, ATV/r/LPV/COBI, ATV/r/DTG, ATV /r/RAL, ATV/r/EVG, ATV/r/EVG, ATV/r/EVG/COBI, ATV/r/maravero, ATV/COBI/DRV, ATV/COB/IDRV/r, ATV/COB I/DRV, ATV/COBI/LPV, ATV/COBI/LPV/r, ATV/COBILPV/COBI, ATV/COBI/DTG, ATV/COBI/RAL, ATV/COBI/EVG ,ATV/COBI/EVG/r,ATV/COBI/EVG,ATV/COBI/Maravero,DRV/r,DRV/COBI,DRV/LPV,DRV/LPV/r,DRV/LPV/COBI , DRV/DTG, DRV/RAL, DRV/EVG, DRV/EVG/r, DRV/EVG/COBI, DRV/maravero, DRV/r, DRV/COBI, DRV/r/LPV, DRV/r/ LPV/COBI, DRV/r/DTG, DRV/r/RAL, DRV/r/EVG, DRV/r/EVG/COBI, DRV/Maravero, DRV/COBI/LPV, DRV/COB/ILPV /r, DRV/COBI/LPV/COBI, DRV/COBI/DTG, DRV/COBI/RAL, DRV/COBI/EVG, DRV/COBI/EVG/r, DRV/COBI/EVG/C OBI, DRV/COBI/maraviroc, LPV/r, LPV/COBI, LPV/DTG, LPV/RAL, LPV/EVG, LPV/EVG/r, LPV/EVG/COBI, LPV/maraviroc, LPV/r/LPV/COBI, LPV/r/DTG, LPV/r/RAL, LPV/r/EVG, LPV/r/EVG/COBI, LPV/r/maraviroc, LPV/COBI/DTG, LPV /COBI/RAL, LPV/COBI/EVG, LPV/COBI/EVG/r, LPV/COBI/EVG, LPV/COBI/maraviroc, DTG/RAL, DTG/EVG, DTG/EVG/r, DTG/EVG/COBI, DTG/maraviroc, RAL/EVG, RAL/EVG/r, RAL/EVG/COBI, RAL/maraviroc, EVG/r, EVG/COBI, and EVG/maraviroc. Also provided are separate pharmaceutical compositions, each comprising a pharmaceutically acceptable carrier or excipient, a pharmaceutically effective amount of a TLR7 modulator, each of which in separate embodiments includes those in the formulas and specific embodiments herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of each agent in the separate antiviral combination listed in the previous sentence. It should be understood that the combination of the separate antiviral combination and the separate TLR7 modulator and the pharmaceutically acceptable carrier or excipient constitutes a separate pharmaceutical composition.

Specific embodiments of combinations that a) can be combined with a pharmaceutically acceptable carrier or excipient to prepare a pharmaceutical composition, or b) can be used in combination with the methods described herein include the following separate examples, wherein "TLR7" refers to a TLR7 modulating compound, including the examples described herein. Specific examples within each combination include combinations wherein "TLR7" represents a compound of Formula II. One specific example within each combination includes a combination wherein "TLR7" represents a compound of Example 4. Another specific example within each combination includes a combination wherein "TLR7" represents a compound of Example 49. Yet another specific example within each combination includes a combination wherein "TLR7" represents a compound of Example 119. Yet another specific example within each combination includes a combination wherein "TLR7" represents a compound of Example 120. In each case, reference to a compound should be understood to include the compound or a pharmaceutically acceptable salt thereof.

Combinations include TLR7/TDF/emtricitabine; TLR7/TAF/emtricitabine; TLR7/TDF/elvitegravir; TLR7/TAF/elvitegravir; TLR7/TDF/elvitegravir; TLR7/TAF/elvitegravir; TLR7/TDF/efavirenz;

TLR7/TAF/efavirenz; TLR7/TDF/atazanavir; TLR7/TAF/atazanavir; TLR7/TDF/darunavir;

TLR7/TAF/darunavir; TLR7/TDF/raltegravir; TLR7/TAF/raltegravir; TLR7/TDF/rilpivirine;

TLR7/TAF/rilpivirine; TLR7/emtricitabine/elvitegravir; TLR7/emtricitabine/efavirenz; TLR7/emtricitabine/atazanavir; TLR7/emtricitabine/darunavir;

TLR7/emtricitabine/raltegravir; TLR7/emtricitabine/rilpivirine; TLR7/elvitegravir/efavirenz;

TLR7/elvitegravir/atazanavir; TLR7/elvitegravir/darunavir; TLR7/elvitegravir/raltegravir;

TLR7/elvitegravir/rilpivirine; TLR7/efavirenz/atazanavir; TLR7/efavirenz/darunavir;

TLR7/efavirenz/raltegravir; TLR7/efavirenz/rilpivirine; TLR7/atazanavir/darunavir; TLR7/atazanavir/raltegravir; TLR7/atazanavir/rilpivirine; TLR7/darunavir/raltegravir; TLR7/darunavir/rilpivirine; TLR7/raltegravir/rilpivirine; TLR7/darunavir/ritonavir; TLR7/GSK1265744/rilpivirine; and TLR7/abacavir/lamivudine.

Specific embodiments of quaternary combinations that a) can be combined with pharmaceutically acceptable carriers or excipients to prepare pharmaceutical compositions, or b) can be used in combination with the methods described herein include, for example:

TLR7/TDF/emtricitabine/dolutegravir; TLR7/TAF/emtricitabine/dolutegravir; TLR7/TDF/emtricitabine/elvitegravir; TLR7/TAF/emtricitabine/elvitegravir; TLR7/TDF/emtricitabine/efavirenz; TLR7/TAF/emtricitabine/efavirenz; TLR7/TDF/emtricitabine/atazanavir; TLR7/TAF/emtricitabine/atazanavir;

TLR7/TDF/emtricitabine/darunavir; TLR7/TAF/emtricitabine/darunavir; TLR7/TDF/emtricitabine/raltegravir; TLR7/TAF/emtricitabine/raltegravir; TLR7/TDF/emtricitabine/rilpivirine; TLR7/TAF/emtricitabine/rilpivirine; TLR7/TDF/elvitegravir/efavirenz; TLR7/TAF/elvitegravir/efavirenz;

TLR7/TDF/elvitegravir/atazanavir; TLR7/TAF/elvitegravir/atazanavir;

TLR7/TDF/elvitegravir/darunavir; TLR7/TAF/elvitegravir/darunavir;

TLR7/TDF/elvitegravir/raltegravir; TLR7/TAF/elvitegravir/raltegravir;

TLR7/TDF/elvitegravir/rilpivirine; TLR7/TAF/elvitegravir/rilpivirine;

TLR7/TDF/efavirenz/atazanavir; TLR7/TAF/efavirenz/atazanavir; TLR7/TDF/efavirenz/darunavir; TLR7/TAF/efavirenz/darunavir; TLR7/TDF/efavirenz/raltegravir; TLR7/TAF/efavirenz/raltegravir; TLR7/TDF/efavirenz/rilpivirine; TLR7/TAF/efavirenz/rilpivirine;

TLR7/TDF/atazanavir/darunavir; TLR7/TAF/atazanavir/darunavir; TLR7/TDF/atazanavir/raltegravir; TLR7/TAF/atazanavir/raltegravir;

TLR7/TDF/atazanavir/rilpivirine; TLR7/TAF/atazanavir/rilpivirine; TLR7/TDF/darunavir/raltegravir; TLR7/TAF/darunavir/raltegravir; TLR7/TDF/darunavir/rilpivirine; TLR7/TAF/darunavir/rilpivirine;

TLR7/Emtricitabine/Elvitegravir/Efavirenz; TLR7/Emtricitabine/Elvitegravir/Atazanavir; TLR7/Emtricitabine/Elvitegravir/Darunavir; TLR7/Emtricitabine/Elvitegravir/Raltegravir; TLR7/Emtricitabine/Elvitegravir/Rilpivirine; TLR7/Emtricitabine/Elvitegravir/Atazanavir; TLR7/Emtricitabine/Elvitegravir/Darunavir; TLR7/Emtricitabine/Elvitegravir/Raltegravir; TLR7/Emtricitabine/Elvitegravir/Rilpivirine Virine; TLR7/Emtricitabine/Atazanavir/Darunavir; TLR7/Emtricitabine/Atazanavir/Raltegravir; TLR7/Emtricitabine/Atazanavir/Rilpivirine; TLR7/Emtricitabine/Darunavir/Raltegravir; TLR7I/Emtricitabine/Darunavir/Rilpivirine; TLR7/Emtricitabine/Raltegravir/Rilpivirine; TLR7/Elvitegravir/Efavirenz/Atazanavir; TLR7/Elvitegravir/Efavirenz/Darunavir; TLR7/Elvitegravir/Efavirenz /Raltegravir; TLR7/Elvitegravir/Efavirenz/Rilpivirine; TLR7/Elvitegravir/Azanavir/Darunavir; TLR7/Elvitegravir/Azanavir/Raltegravir; TLR7/Elvitegravir/Raltegravir/Rilpivirine; TLR7/Elvitegravir/Azanavir/Darunavir; TLR7/Elvitegravir/Raltegravir/Rilpivirine; TLR7/Elvitegravir/Azanavir/Darunavir; TLR7/Elvitegravir/Azanavir/Raltegravir; TLR7/Elvitegravir/Azanavir/Rilpivirine; TLR7/Elvitegravir/Darunavir/Raltegravir; TLR7/Elvitegravir/Darunavir TLR7/efavirenz/raltegravir/rilpivirine; TLR7/atazanavir/darunavir/raltegravir; TLR7/atazanavir/darunavir/rilpivirine; TLR7/darunavir/raltegravir/rilpivirine; TLR7/dolutegravir/abacavir/lamivudine; TLR7/raltegravir/darunavir; TLR7/raltegravir/ritonavir/darunavir; TLR7/raltegravir/corbicastat/darunavir; TLR7/raltegravir/atazanavir;

TLR7/Raltegravir/Azanavir/Maraviroc; TLR7/Raltegravir/Maraviroc/Etravirine;

TLR7/Raltegravir/Maraviroc/Rilpivirine; TLR7/Maraviroc/Darunavir/Ritonavir; TLR7/Maraviroc/Darunavir/Corbicistat; TLR7/Raltegravir/Darunavir/Ritonavir/Maraviroc;

TLR7/Raltegravir/darunavir/corbic acid/maraviroc; TLR7/Raltegravir/darunavir/ritonavir/etravirine;

TLR7/raltegravir/darunavir/corbic acid/etravirine; TLR7/atazanavir/ritonavir/efavirenz;

TLR7/atazanavir/corbic acid/efavirenz; TLR7/raltegravir/etravirine; TLR7/ritonavir/lopinavir/raltegravir; TLR7/corbic acid/lopinavir/raltegravir;

TLR7/ritonavir/darunavir/etravirine; TLR7/corbicastat/darunavir/etravirine;

TLR7/ritonavir/lopinavir; and TLR7/ritonavir/lopinavir/maraviroc.

Other specific embodiments include the following combinations: a) a pharmaceutically effective amount of a TLR7 modulating compound, including those of the various formulas and specific examples herein, b) a pharmaceutically acceptable carrier or excipient, and c) a combination of five or more antiviral agents. This combination can be used to prepare a pharmaceutical composition and/or can be used in combination with the various methods described herein. Such combinations include, for example, a pharmaceutically effective amount of a TLR7 modulating compound, including those of the various formulas and specific examples herein, including separate embodiments in each combination in which the TLR7 modulating compound is a compound of Formula II, a compound of Example 4, a compound of Example 49, a compound of Example 119, a compound of Example 120, and an antiviral agent in each of the following separate groups:

TDF/emtricitabine/atazanavir/ritonavir/maraviroc/raltegravir;

TAF/emtricitabine/atazanavir/ritonavir/maraviroc/raltegravir;

TDF/emtricitabine/atazanavir/corbic acid/maraviroc/raltegravir;

TAF/emtricitabine/atazanavir/corbic acid/maraviroc/raltegravir;

TDF/emtricitabine/atazanavir/ritonavir/maraviroc/dolutegravir;

TAF/emtricitabine/atazanavir/ritonavir/maraviroc/dolutegravir;

TDF/emtricitabine/atazanavir/corbic acid/maraviroc/dolutegravir;

TAF/emtricitabine/atazanavir/corbic acid/maraviroc/dolutegravir;

TDF/emtricitabine/darunavir/ritonavir/maraviroc/raltegravir;

TAF/emtricitabine/darunavir/ritonavir/maraviroc/raltegravir;

TDF/emtricitabine/darunavir/corbic acid/maraviroc/raltegravir;

TAF/emtricitabine/darunavir/corbic acid/maraviroc/raltegravir;

TDF/emtricitabine/darunavir/ritonavir/maraviroc/dolutegravir;

TAF/emtricitabine/darunavir/ritonavir/maraviroc/dolutegravir;

TDF/emtricitabine/darunavir/corbic acid/maraviroc/dolutegravir;

TAF/emtricitabine/darunavir/corbic acid/maraviroc/dolutegravir;

TDF/emtricitabine/efavirenz/ritonavir/lopinavir/maraviroc;

TAF/emtricitabine/efavirenz/ritonavir/lopinavir/maraviroc;

TDF/emtricitabine/efavirenz/corbic acid/lopinavir/maraviroc;

TAF/emtricitabine/efavirenz/corbic acid/lopinavir/maraviroc;

TDF/emtricitabine/corbic acid/lopinavir/maraviroc/raltegravir;

TAF/emtricitabine/corbic acid/lopinavir/maraviroc/raltegravir;

TDF/emtricitabine/ritonavir/lopinavir/maraviroc/raltegravir;

TAF/emtricitabine/ritonavir/lopinavir/maraviroc/raltegravir;

TDF/emtricitabine/corbic acid/lopinavir/maraviroc/dolutegravir;

TAF/emtricitabine/corbic acid/lopinavir/maraviroc/dolutegravir;

TDF/emtricitabine/ritonavir/lopinavir/maraviroc/dolutegravir;

TAF/emtricitabine/ritonavir/lopinavir/maraviroc/dolutegravir;

TDF/emtricitabine/corbic acid/fosamprenavir/maraviroc/raltegravir;

TAF/emtricitabine/corbic acid/fosamprenavir/maraviroc/raltegravir;

TDF/emtricitabine/ritonavir/fosamprenavir/maraviroc/raltegravir;

TAF/emtricitabine/ritonavir/fosamprenavir/maraviroc/raltegravir;

TDF/emtricitabine/corbic acid/fosamprenavir/maraviroc/dolutegravir;

TAF/emtricitabine/corbic acid/fosamprenavir/maraviroc/dolutegravir;

TDF/emtricitabine/ritonavir/fosamprenavir/maraviroc/dolutegravir; and

TAF/emtricitabine/ritonavir/fosamprenavir/maraviroc/dolutegravir.

In the separate combinations described above, the specific agents in each combination may be administered in any pharmaceutically effective amount known in the art. In a specific embodiment, the agents are used in the following separate doses in the combination comprising the agent:

Tenofovir disoproxil fumarate (TDF), from about 250 mg to about 350 mg/dose; TAF, from about 5 mg to about 50 mg, emtricitabine, from about 150 mg to about 250 mg/dose; elvitegravir, from about 100 mg to about 200 mg/dose when administered with a booster such as corbicistat or ritonavir, unboosted elvitegravir, from about 800 mg to about 1200 mg; efavirenz, from about 500 mg to about 700 mg/dose; atazanavir, from about 250 mg to about 350 mg/dose; darunavir, from about 700 mg to about 900 mg/dose; raltegravir, from about 350 mg to about 450 mg/dose; rilpivirine, from about 20 mg to about 30 mg/dose (or in the case of rilpivirine HCL, from about 22.5 mg to about 32.5 mg/dose); ritonavir, from about 50 mg to about 150 mg/dose; dolutegravir, from about 30 mg to about 70 mg/dose; abacavir, from about 500 mg to about 700 mg/dose; lamivudine, from about 250 mg to about 350 mg/dose; GSK1265744, from about 10 mg to about 50 mg/dose; colbicistat, from about 100 mg to 200 mg/dose; atazanavir, from about 250 mg to about 350 mg/dose; maraviroc, from about 100 mg to about 200 mg/dose; etravirine, from about 100 mg to about 300 mg/dose; lopinavir, from about 300 mg to about 500 mg/dose; and zidovudine, from about 500 mg to about 750 mg/day.

In other specific embodiments, the agents are used in individual doses in a combination comprising: tenofovir disoproxil fumarate (TDF), from about 275 mg to about 325 mg/dose; TAF, from about 5 mg to about 30 mg; emtricitabine, from about 175 mg to about 225 mg/dose; elvitegravir, from about 125 mg to about 175 mg/dose when administered with a booster such as corbicistat or ritonavir; efavirenz, from about 550 mg to about 650 mg/dose; atazanavir, from about 275 mg to about 325 mg/dose; darunavir, from about 750 mg to about 850 mg/dose; raltegravir, from about 375 mg to about 425 mg/dose; and rilpivirine, from about 22 mg to about 28 mg/dose (or in the presence of rilpivirine HCl). In some cases, from about 24.5 mg to about 30.5 mg/dose); ritonavir, from about 75 mg to about 125 mg/dose; dolutegravir, from about 40 mg to about 60 mg/dose; abacavir, from about 550 mg to about 650 mg/dose; lamivudine, from about 275 mg to about 325 mg/dose; GSK1265744, from about 20 mg to about 40 mg/dose; cobicistat, from about 125 mg to 175 mg/dose; atazanavir, from about 275 mg to about 325 mg/dose; maraviroc, from about 125 mg to about 175 mg/dose; etravirine, from about 150 mg to about 250 mg/dose; lopinavir, from about 350 mg to about 450 mg/dose; and zidovudine, from about 550 mg to about 650 mg/day.

In a further specific embodiment, the agents are used in the following separate doses in a combination comprising: tenofovir disoproxil fumarate (TDF) at about 300 mg/dose; TAF at about 25 mg/dose or about 10 mg per dose in the presence of a booster such as corbicistat or ritonavir, emtricitabine at about 200 mg/dose; elvitegravir at about 150 mg/dose when boosted by corbicistat or ritonavir; efavirenz at about 600 mg/dose; atazanavir at about 300 mg/dose; darunavir at about 800 mg/dose; and raltegravir at about 400 mg/dose. dose; rilpivirine at about 25 mg/dose (or about 27.5 mg/dose as rilpivirine HCL); ritonavir at about 100 mg/dose; dolutegravir at about 50 mg/dose, abacavir at about 600 mg/dose, lamivudine at about 300 mg/dose, GSK1265744 at about 30 mg/dose, colbicistat at about 150 mg/dose, atazanavir at about 300 mg/dose, maraviroc at about 150 mg/dose, etravirine at about 200 mg/dose, lopinavir at about 400 mg/dose, and zidovudine at about 600 mg/day.

The TLR7 modulating compounds in the combination include the TLR7 modulating compounds of Formula II, Examples 4, 49, 119, 120 and 121, and pharmaceutically acceptable salts, which can be delivered in an amount from about 0.1 mg to about 15 mg per dose. Other embodiments of each combination include the TLR7 modulating compound being used in doses of 0.1 mg to 5 mg per dose, 2 mg to 6 mg per dose, 5 mg to 10 mg per dose, and 10 mg to 15 mg per dose.

It should be understood that each dose range of the TLR7 modulating compound can be combined with each dose of the other combination agents discussed above in a pharmaceutical composition or pharmaceutical combination, as well as in each dose regimen. For example, the combination Example 49/TDF/emtricitabine/dolutegravir listed above includes specific combinations containing the following: 0.1 mg to 15 mg per dose of Example 49/from about 250 mg-350 mg per dose of TDF/from about 150 mg to about 250 mg per dose of emtricitabine/from about 30 mg to about 70 mg per dose of dolutegravir; 0.1 mg to 15 mg per dose of Example 49/from about 275 mg-325 mg per dose of TDF/from about 175 mg to about 225 mg per dose of emtricitabine/from about 40 mg to about 60 mg per dose of dolutegravir; 0.1 mg to 15 mg per dose of Example 49/300 mg per dose of TDF/from about 150 mg to about 250 mg per dose of emtricitabine/from about 30 mg to about 70 mg per dose of dolutegravir g per dose of TDF/200 mg per dose of emtricitabine/50 mg per dose of dolutegravir; from 2 mg to 6 mg per dose of Example 49/from about 250 mg-350 mg per dose of TDF/from about 150 mg to about 250 mg per dose of emtricitabine/from about 30 mg to about 70 mg per dose of dolutegravir; 2 mg to 6 mg per dose of Example 49/from about 275 mg-325 mg per dose of TDF/about 175 mg to about 225 mg per dose of emtricitabine/from about 40 mg to about 60 mg per dose of dolutegravir; 2 mg to 6 mg per dose of Example 49/300 mg per dose of TDF/200 mg per dose 5 mg to 10 mg per dose of Example 49 / from about 250 mg to 350 mg per dose of TDF / from about 150 mg to about 250 mg per dose of emtricitabine / from about 30 mg to about 70 mg per dose of dolutegravir; 5 mg to 10 mg per dose of Example 49 / from about 275 mg to 325 mg per dose of TDF / from about 175 mg to about 225 mg per dose of emtricitabine / from about 40 mg to about 60 mg per dose of dolutegravir; 5 mg to 10 mg per dose of Example 49 / 300 mg per dose of TDF / 200 mg per dose of emtricitabine / 50 mg per dose per dose of dolutegravir; 10 mg to 15 mg per dose of Example 49 / from about 250 mg to 350 mg per dose of TDF / from about 150 mg to about 250 mg per dose of emtricitabine / from about 30 mg to about 70 mg per dose of dolutegravir; 10 mg to 15 mg per dose of Example 49 / from about 275 mg to 325 mg per dose of TDF / from about 175 mg to about 225 mg per dose of emtricitabine / from about 40 mg to about 60 mg per dose of dolutegravir; 10 mg to 15 mg per dose of Example 49 / 300 mg per dose of TDF / 200 mg per dose of emtricitabine / 50 mg per dose of dolutegravir. It should be understood that for each combination of agents listed herein, each corresponding dosage range combination is included. It will be understood that for each specific combination in this paragraph, there can also be corresponding combinations in which Example 49 is replaced with another compound of Formula II or other compounds of the formula described herein, or each of Examples 1 to 121, inclusive. It will also be understood that the same range of contemplated combinations applies to each of the formulations listed above that combine a TLR7 modulating compound with an HIV agent, and that there are embodiments in which each combination is used in a method.

In another embodiment, the present application provides a combination pharmaceutical comprising:

a) a first pharmaceutical composition comprising a TLR7 modulating compound as described herein or a pharmaceutically acceptable salt, solvate or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from HIV protease inhibitory compounds, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, HIV capsid protein inhibitors, interferons, immunomodulatory cytokines (IL-7, IL-15), ribavirin analogs, NS3 protease inhibitors, α-glucosidase 1 inhibitors, liver protectants, HCV nucleotide inhibitors, HCV nucleoside inhibitors, HCV non-nucleoside inhibitors, and other drugs used to treat HCV, and combinations thereof. Forms of IL-15 that can be used in the methods herein include human natural and recombinant IL-15, including heterodimeric hetIL-15, and recombinant human IL-15 (rhIL15).

For each embodiment herein comprising "a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof," including uses, methods of treatment, pharmaceutical compositions, dosing regimens, and kits thereof, it is understood that it encompasses separate additional embodiments in which all other components or elements are as defined for the original embodiment, and the "compound of Formula II or a pharmaceutically acceptable salt thereof" in different embodiments is a compound selected from Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), and each of the example compounds of Examples 1 to 124, or a pharmaceutically acceptable salt thereof.

Inducing HIV gene expression in HIV-infected humans

Provided herein are methods of inducing HIV gene expression in a human infected with HIV, wherein active HIV gene expression in the human is suppressed by delivery of antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof.

Provided herein are methods for inducing HIV gene expression in a human infected with HIV, wherein active HIV gene expression in the human is suppressed by administering a combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

Provided herein are methods for inducing HIV gene expression in a human infected with HIV, comprising administering combination antiretroviral therapy until active HIV replication is suppressed, and then administering to the human a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

Provided herein are methods of inducing HIV gene expression in a human infected with HIV undergoing combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

Provided herein is a method for inducing HIV gene expression in HIV-infected cells in a human, comprising administering to the human a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

Also provided herein is a method for inducing HIV gene expression in HIV-infected cells in a human, comprising administering to the human a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

Also provided herein are separate methods for inducing HIV gene expression in HIV-infected cells in humans, each of which comprises administering to a human a pharmaceutically effective amount of a compound selected from Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2), or a pharmaceutically acceptable salt thereof.

Also provided herein are a set of separate methods for inducing HIV gene expression in HIV-infected cells in HIV-infected humans, each of which comprises administering to the HIV-infected human a pharmaceutically effective amount of a compound selected from Examples 1 to 124, or a pharmaceutically acceptable salt thereof. The first of the set of separate methods for inducing HIV gene expression in HIV-infected cells in HIV-infected humans comprises administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 1, or a pharmaceutically acceptable salt thereof; the second method comprises administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 2, or a pharmaceutically acceptable salt thereof; and so forth.

As an example, provided herein is a method of inducing HIV gene expression in HIV-infected cells in a human, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 4, which has the following formula:

or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a human infected with HIV, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 49, which has the formula:

or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a human infected with HIV, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 119, which has the formula:

or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a human infected with HIV, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 120, which has the formula:

or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a human infected with HIV, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of the compound of Example 121 or a pharmaceutically acceptable salt thereof.

latent reservoir

Provided herein are methods of inducing HIV gene expression in a latent HIV reservoir in a human infected with HIV, the methods comprising administering to the human infected with HIV a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in a latent HIV reservoir in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

Also provided herein are twenty separate methods of inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, each separate method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound selected from Formula III, III(a), III(a), III(b), III(c), III(d), III(e), III(f), III(a)(1), III(a)(2), III(b)(1), III(b)(2), III(c)(1), III(c)(2), III(d)(1), III(d)(2), III(e)(1), III(e)(2), III(f)(1), or III(f)(2), or a pharmaceutically acceptable salt thereof. It is understood that one of such methods comprises administering to the human infected with HIV a pharmaceutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof, another method comprises administering to the human infected with HIV a pharmaceutically effective amount of Formula III(a), and so forth.

Also provided herein are a set of separate methods for inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, each of the 120 separate methods comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound selected from one of Examples 1 to 124, or a pharmaceutically acceptable salt thereof. Each of the compounds of Examples 1 to 124 is used in each set of separate methods, wherein the compound of Example 1 or a pharmaceutically acceptable salt thereof is used in the first method, Example 2 or a pharmaceutically acceptable salt thereof is used in the second method, and so on.

For example, provided herein is a method of inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Example 4 or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Example 49 or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Example 119 or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Example 120 or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Example 121 or a pharmaceutically acceptable salt thereof.

For each of the methods discussed above for inducing HIV gene expression in HIV-infected cells in a latent HIV reservoir in a human infected with HIV, there are further embodiments wherein the pharmaceutically effective amount of the compound of Formula II or the compound of Example 4, Example 49, Example 119, Example 120, or Example 121 is 0.1 mg to 15.0 mg of the compound or a pharmaceutically acceptable salt thereof. For each of the methods described above, there are further embodiments wherein the pharmaceutically effective amount of the compound of Formula II or the compound of Example 4, Example 49, Example 119, Example 120, or Example 121 is 4.0 mg to 6.0 mg of the compound or a pharmaceutically acceptable salt thereof. For each of the methods described above, there are further embodiments wherein the pharmaceutically effective amount of the compound of Formula II or the compound of Example 4, Example 49, Example 119, Example 120, or Example 121 is 5.0 mg to 15.0 mg of the compound or a pharmaceutically acceptable salt thereof.

Other embodiments of each of the methods, combinations, and pharmaceutical compositions described herein further comprise the addition of one or more latency reversal agents (LRAs), also known as latency reversal drugs (LRDs), such as: histone deacetylase inhibitors, including hydroxamic acids (or hydroxamates), such as trichostatin A; cyclic tetrapeptides (e.g., trapoxin B) and depsipeptides; benzamides; electrophilic ketones; fatty acid compounds, such as phenylbutyrate and valproic acid, hydroxamic acids, such as vorinostat (suberanoylanilide hydroxamic acid-SAHA), belinostat, LAQ824, panobinostat, benzamides (e.g., entinostat (MS-275), CI994, moxistat, 4SC-202, abestat, ACTR, ACY-12 15. AR-42, CG200745, CHR-2845, CHR-3996, CUDC-101, entinostat, GATA, givisostat, kevetrin, moxistat, panobinostat, resminostat, romidepsin, runx, SB939, sulforaphane, trichostatin A (TSA), trichostatin B, trichostatin C, trapoxin A, trapoxin B, chlamydocin, sodium salt of butyric acid (sodium butyrate), butyric acid, sodium salt of phenylbutyric acid, phenylbutyric acid, scriptaid, FR901228, depudecin, oxamflatin, pyroxamide, apicidin B, apicidin C, Helminthsporium carbonum toxin, 2-amino-8-oxo-9,10-epoxy-decanoyl, 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-acrylamide, suberoylanilide hydroxamic acid, FK228 or m-carboxycinnamic acid bishydroxyamide, ITF2357, MCT-1, MCT-3, NHC-51, and any of the histone deacetylase inhibitor compounds disclosed in Archin MN et al., AIDS 2009; 1799-806, which are incorporated herein by reference;

Akt pathway modulators, such as disulfiram (Doyon et al., AIDS 2013 Jan 14; 27(2): F7-F11);

Methylation inhibitors, such as DNMTi, 5-aza-2'-deoxycytidine (5-aza-dc), decitabine, DL-ethionine, D-methionine, 5-azacytidine, 5-aza-2'deoxycytidine, 5,6-dihydro-5-azacytidine, 5,6-dihydro-5-aza-2'deoxycytidine, 5-fluorocytidine, 5-fluoro-2'deoxycytidine, and short oligonucleotides containing 5-aza-2'deoxycytidine, 5,6-dihydro-5-aza-2'deoxycytidine, and 5-fluoro-2'deoxycytidine, procainamide, zebularine, and (-)-gallocatechin-3-gallate;

Protein kinase C (PKC) modulators, for example, indole lactams, Ingenol and its derivatives such as Ingenol B, prostratin, bryostatin, rottlerin, isoquinolinesulfonamide H-7 and its analogs, phenothiazine agents, tamoxifen, quercetin, verapamil, doxorubicin, polymyxin B, gangliosides, sangivamycin, retinal, staurosporine, aminoacridine, sphingosine and related sphingosine esters;

Cytokine regulators, such as TNF-α, TNF-β, IL-1, IL-6, IL-2, IL-4, IL-6, IL-7, IL-10, IL-15, IL-15SA, Acrp30, AgRP, amphiregulin, angiopoietin-1, AXL, BDNF, bFGF, BLC, BMP-4, BMP-6, b-NGF, BTC, CCL28, Ck beta 8-1, CNTF, CTACK CTAC, Skinkine, Dtk, EGF, EGF-R, ENA-78, eotaxin, eotaxin-2, MPIF-2, eotaxin-3, MIP-4-α, Fas Fas/TNFRSF6/Apo-1/CD95, FGF-4, FGF-6, FGF-7, FGF-9, Flt-3 ligand fms-like tyrosine kinase-3, FKN or FK, GCP-2, GCSF, GDNF Glial, GITR, GITR, GM-CSF, GRO, GRO-a, HCC-4, hematopoietic growth factor, hepatocyte growth factor, I-309, ICAM-1, ICAM-3, IFN-γ, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6, IGF-I, IGF-I SR, IL-1a, IL-1β, IL-1, IL-1 R4, ST2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-11, IL-12p40, IL-12p70, IL-13, IL-16, IL-17, IL-21, 1-TAC, α-chemokine, lymphocyte chemotactic factor, MCP-1, MCP-2, MCP-3, MCP-4, M-CSF, MDC, MIF, MIG, MIP-1, MIP-1β, MIP-1δ, MIP-3a, MIP-3β, MSP-α, NAP-2, NT-3, NT-4, osteoprotegerin, oncostatin M, PARC, PDGF, P1GF, RANTES, SCF, SDF-1, soluble glycoprotein 130, soluble TNF receptor I, soluble TNF receptor II, TARC, TECK, TGF-beta 1, TGF-beta 3, TIMP-1, TIMP-2, TNF-α, TNF-β, thrombopoietin, TRAIL R3, TRAIL R4, uPAR, VEGF, and VEGF-D;

AV6 modulators, HIV-1-responsive protein factor (HRF), quinolin-8-ol, actinomycin, aclarubicin, cytarabine, PKC412, englarin A, oxaliplatin, 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), nordihydroguaiaretic acid (NDGA), and curcumin (Cur);

BRD4 inhibitors, such as JQ1 ([(R,S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-1-thia-5,7,8,9a-tetraaza-cyclopenta[e]azulen-6-yl]-acetic acid tert-butyl ester), GSK525762 (IBET or (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[ 4,3-a][1,4]diazepine-4-yl)-N-ethylacetamide), OTX015 (HY15743-(6S)-4-(4-chlorophenyl)-N-(4-hydroxyphenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide), CPI-0610, and Ten-010; and

Recombinant HIV Tat protein.

Methods for inducing transient HIV viremia

Also provided herein are methods of inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of inducing transient HIV-1 viremia in a virologically suppressed HIV-1 infected human who is receiving combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV is receiving combination antiretroviral therapy and has a plasma HIV-1 RNA concentration of less than 50 HIV-1 RNA copies/mL, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof to increase the human's plasma HIV-1 RNA concentration to greater than 50 HIV-1 RNA copies/mL. Further embodiments include methods wherein the human's plasma HIV-1 RNA concentration is increased to a concentration of 50 HIV-1 RNA copies/mL to at least 500 HIV-1 RNA copies/mL. Further embodiments include methods wherein the human's plasma HIV-1 RNA concentration is increased to a concentration of 50 HIV-1 RNA copies/mL to at least 1000 HIV-1 RNA copies/mL. Further embodiments include such methods wherein the plasma HIV-1 RNA concentration of the human is elevated to a concentration of 50 HIV-1 RNA copies/mL to at least 2000 HIV-1 RNA copies/mL.

Also provided herein is a method of inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV is receiving combination antiretroviral therapy and has maintained a plasma HIV-1 RNA concentration below 50 HIV-1 RNA copies/mL for at least three months, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof to increase the human's plasma HIV-1 RNA concentration to above 50 HIV-1 RNA copies/mL. Further embodiments include methods wherein the human's plasma HIV-1 RNA concentration is increased to a concentration of 50 HIV-1 RNA copies/mL (or lower) to at least 500 HIV-1 RNA copies/mL. Further embodiments include methods wherein the human's plasma HIV-1 RNA concentration is increased to a concentration of 50 HIV-1 RNA copies/mL (or lower) to at least 1000 HIV-1 RNA copies/mL. Further embodiments include methods wherein the plasma HIV-1 RNA concentration of the human is elevated to a concentration of 50 HIV-1 RNA copies/mL (or less) to at least 2000 HIV-1 RNA copies/mL.

Also provided herein is a method of inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV is receiving combination antiretroviral therapy and has maintained a plasma HIV-1 RNA concentration below 50 HIV-1 RNA copies/mL for at least six months, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof to increase the human's plasma HIV-1 RNA concentration to a concentration greater than 50 HIV-1 RNA copies/mL. Further embodiments include methods wherein the human's plasma HIV-1 RNA concentration is increased to a concentration of 50 HIV-1 RNA copies/mL to at least 1000 HIV-1 RNA copies/mL. Further embodiments include methods wherein the human's plasma HIV-1 RNA concentration is increased to a concentration of 50 HIV-1 RNA copies/mL to at least 2000 HIV-1 RNA copies/mL. Still other separate embodiments exist within these methods wherein a viral concentration of 50 HIV-1 RNA copies/mL or less is maintained in a virologically suppressed human infected with HIV-1 for at least a) one month, b) two months, c) three months, d) four months, e) five months, f) six months, g) seven months, h) eight months, i) nine months, j) ten months, k) eleven months, and l) twelve months. Still other separate embodiments exist within these methods wherein a viral concentration of 50 HIV-1 RNA copies/mL or less is maintained in a virologically suppressed human infected with HIV-1 for at least a) from about 1 month to about 3 months, b) from about 2 months to about 3 months, c) from about 3 months to about 6 months, d) from about 6 months to about 9 months, e) from about 6 months to about 1 year, f) from about 9 months to about 1 year, g) from about 10 months to about 1 year, h) from about 1 year to about 1 year and 3 months, i) from about 1 year to about 1 year and 6 months, j) from about 1 year to about 1 year and 9 months, and k) from about 1 year to about 2 years.

In the method of inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1 described above, there is a separate additional embodiment wherein the TLR7 modulating compound comprises a pharmaceutically effective amount of a TLR7 modulating compound selected from one of Formula II, Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), or one of the individual compounds selected from Examples 1 to 124, or a pharmaceutically acceptable salt thereof.

As an example, provided herein is a method for inducing transient HIV-1 viremia in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of a compound of Example 4 or a pharmaceutically acceptable salt thereof.

As another example, provided herein is a method for inducing transient HIV-1 viremia in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof.

Other separate embodiments within each method for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1 include methods wherein the combination antiretroviral therapy is selected from each of the combinations of antiretroviral agents listed herein, wherein each separate combination of antiretroviral agents used constitutes a separate embodiment.

As an example, provided herein is a method for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV-1 is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF, a pharmaceutically effective amount of emtricitabine, and a pharmaceutically effective amount of dolutegravir, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 4 or a pharmaceutically acceptable salt thereof.

As an example, provided herein is a method for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV-1 is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF, a pharmaceutically effective amount of emtricitabine, and a pharmaceutically effective amount of dolutegravir, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof.

Other separate methods include those above, wherein the combination antiretroviral therapy comprises administering to a virologically suppressed human infected with HIV-1 an individual combination listed in each of Tables A, B, C, D, E, F, G, H, I, and J, respectively, together with 0.1 mg to 25 mg of the compound of Example 4. Other separate methods include those above, wherein the combination antiretroviral therapy comprises administering to a virologically suppressed human infected with HIV-1 an individual combination listed in each of Tables A, B, C, D, E, F, G, H, I, and J, respectively, together with 0.1 mg to 25 mg of the compound of Example 49. Other separate embodiments include methods for inducing transient HIV-1 viremia in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-1 infected human is receiving a pharmaceutically effective amount of a combined antiretroviral therapy and a TLR7 modulator as described in Tables 1A, 1B, 2A, 2B, 2A, 2B, 3A, 3B, 4A, 4B, 5A, 5B, 6A, 6B, 7 A, 7B, 8A, 8B, 9A, 9B, 10A, 10B, 11A, 11B, 12A, 12B, 13A, 13B, 14A, 14B, 15A, 15B, 16A, 16B ,17A,17B,18A,18B,19A,19B,20A,20B,21A,21B,22A,22B,23A,23B,24A,24B,25A,25B , 26A, 26B, 26C, 26D, 27A, 27B, 27C, 27D, 28A, 28B, 28C, 28D, 29A, 29B, 29C, 29D, 30A, 30B , 30C, 30D, 31A, 31B, 32A, 32B, 33A, 33B, 34A, 34B, 35A, 35B, 36A, 36B, 37A, 37B, 38A, 38B , 39A, 39B, 40A, 40B, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 (collectively referred to as "Tables 1A to 65" or "Tables 1A-65"), wherein each of the individual combinations in the table is given as a separate method.

Also provided herein is a method of inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF or TAF, a pharmaceutically effective amount of elvitegravir, a pharmaceutically effective amount of cobicistat, and a pharmaceutically effective amount of emtricitabine, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 4 or a pharmaceutically acceptable salt thereof.

Also provided herein is a method of inducing transient HIV-1 viremia in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-infected human is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF or TAF, a pharmaceutically effective amount of elvitegravir, a pharmaceutically effective amount of cobicistat, and a pharmaceutically effective amount of emtricitabine, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof.

Other separate methods include those above, wherein the combination antiretroviral therapy comprises independently administering to a human infected with HIV-1 a combination listed in Combination Antiretroviral Tables A, B, C, D, E, F, G, H, I and J and 0.1 mg to 25 mg of the compound of Example 4. Other separate methods include those above, wherein the combination antiretroviral therapy comprises independently administering to a human infected with HIV-1 a combination listed in Combination Antiretroviral Tables A, B, C, D, E, F, G, H, I and J and 0.1 mg to 25 mg of the compound of Example 49.

Other separate embodiments include methods of inducing transient HIV-1 viremia in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-infected human is receiving a pharmaceutically effective amount of each combined antiretroviral therapy and a TLR7 modulator, which are combined as shown in Tables 1A to 65, wherein each separate combination in the table is administered as a separate method.

Enhanced gene expression in humans/potential reservoirs

Provided herein are methods for enhancing HIV gene expression in HIV-infected cells of an HIV-infected human, the methods comprising administering to the HIV-infected human a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

Provided herein are methods for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV, comprising administering to the human infected with HIV a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein is a method for expressing HIV genes in HIV-infected T cells in a human infected with HIV, the method comprising administering a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, to the human infected with HIV.

Also provided herein are separate methods of: a) enhancing HIV gene expression in HIV-infected cells of a human infected with HIV; b) enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir of a human infected with HIV; and c) enhancing HIV gene expression in HIV-infected T cells of a human infected with HIV, each method independently comprising administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2); or a pharmaceutically acceptable salt thereof. It will be understood that one of these methods comprises administering to a human infected with HIV a pharmaceutically effective amount of Formula III or a pharmaceutically acceptable salt thereof, another method comprises administering to a human infected with HIV a pharmaceutically effective amount of Formula III(a), and so forth.

Also provided herein are separate methods for enhancing HIV gene expression in HIV-infected cells of HIV-infected humans, each of which comprises administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2), or a pharmaceutically acceptable salt thereof.

Also provided herein are separate methods for enhancing HIV gene expression in HIV-infected cells of HIV-infected humans, each comprising administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from one of Examples 1 to 124, or a pharmaceutically acceptable salt thereof. One of each of the compounds of Examples 1 to 124 is used in each separate method for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV, wherein the compound of Example 1 or a pharmaceutically acceptable salt thereof can be used in the first method, the compound of Example 2 or a pharmaceutically acceptable salt thereof can be used in the second method, and so on.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells of an HIV-infected human, comprising administering a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells of an HIV-infected human, the method comprising administering a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells of an HIV-infected human, the method comprising administering a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells of an HIV-infected human, the method comprising administering a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells of an HIV-infected human, the method comprising administering a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein are methods for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

Also provided herein is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, to the HIV-infected human.

Also provided herein are methods for enhancing HIV gene expression in HIV-infected cells in the latent HIV reservoir of a human infected with HIV, the methods comprising administering to the human infected with HIV a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), or Formula III(f)(2); or a pharmaceutically acceptable salt thereof. It is understood that one of these methods comprises administering to the human infected with HIV a pharmaceutically effective amount of Formula III or a pharmaceutically acceptable salt thereof, another method comprises administering to the human infected with HIV a pharmaceutically effective amount of Formula III(a), and the like.

Also provided herein are separate methods for enhancing HIV gene expression in HIV-infected cells in the latent HIV reservoir of a human infected with HIV, each of which comprises administering to a human infected with HIV a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2); or a pharmaceutically acceptable salt thereof.

Also provided herein are a set of methods for enhancing HIV gene expression in HIV-infected cells in the latent HIV reservoir of an HIV-infected human, each separate method comprising administering to the HIV-infected human a pharmaceutically effective amount of a compound selected from one of Examples 1 to 124, or a pharmaceutically acceptable salt thereof. One of each of the compounds of Examples 1 to 124 is used in the set of separate methods for enhancing HIV gene expression in HIV-infected cells in the latent HIV reservoir of an HIV-infected human, wherein the compound of Example 1 or a pharmaceutically acceptable salt thereof can be used in the first method, the compound of Example 2 or a pharmaceutically acceptable salt thereof can be used in the second method, and so on.

For example, one of the methods provided is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 4, or a pharmaceutically acceptable salt thereof.

Also provided is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof.

Also provided is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of a compound of Example 119, or a pharmaceutically acceptable salt thereof.

Also provided is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof.

Also provided is a method for enhancing HIV gene expression in HIV-infected cells in a latent HIV reservoir in an HIV-infected human, the method comprising administering to the HIV-infected human a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof.

Pharmaceutically effective amounts of TLR7 modulating compounds described herein, or pharmaceutically acceptable salts thereof, include individual doses of from about 0.1 mg to about 25 mg, which can be administered daily in a single dose or in divided doses, for example, twice daily, three times daily, or four times daily. Daily dosage ranges include from 0.1 mg to 3 mg, from 2 mg to 6 mg, from 4 mg to 6 mg, from 6 mg to 8 mg, from 8 mg to 10 mg, from 10 mg to 12 mg, from 12 mg to 14 mg, from 14 mg to 16 mg, from 16 mg to 18 mg, from 18 mg to 20 mg, from 20 mg to 22 mg, from 22 mg to 25 mg, from 1 mg to 5 mg, from 2.5 mg to 7.5 mg, from 5 mg to 10 mg, from 7.5 mg to 12.5 mg, from 10 mg to 15 mg, from 12.5 mg to 17.5 mg, from 15 mg to 20 mg, from 17.5 mg to 22.5 mg, and 20 mg to 25 mg. Each of the methods of treatment, pharmaceutical combinations, and pharmaceutical compositions or formulations herein includes 21 further embodiments wherein a pharmaceutically effective amount of a TLR7 modulating compound, including those of each of the formulae and examples herein, in each separate embodiment comprises one of the individual dosage ranges listed in the preceding sentence. A single daily dose of a TLR7 modulating compound described herein, or a pharmaceutically acceptable salt thereof, includes 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg. , 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg, 20 mg, 20.5 mg, 21 mg, 21.5 mg, 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, 24.5 mg and 25 mg of a single dose. Each of the methods of treatment, pharmaceutical combinations and pharmaceutical compositions or formulations herein comprises an additional 49 embodiments wherein a pharmaceutically effective amount of a TLR7 modulating compound, including those of each of the formulae and specific examples herein, comprises, in each separate embodiment, one of the single doses listed in the preceding sentence.

Treatment of HIV infection

Provided is a method for treating HIV infection in a human, comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

Also provided is a method for treating HIV infection in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, sufficient to reduce the level of HIV detected in the human's blood or plasma from a first level to a second level, wherein the second level comprises a concentration of HIV in the human's blood or plasma that is lower than the first level of HIV concentration in the human's blood or plasma.

In each method of treating human HIV infection disclosed herein comprising administering a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof to a person in need thereof, there is a further embodiment comprising the following method, wherein the second level of HIV concentration in the human's blood or plasma comprises a viral load (VL) in plasma of less than 50 HIV RNA copies/mL. Other separate embodiments of each method include the method described herein, and wherein the second level of HIV in the human's blood or plasma comprises a viral load (VL) in plasma of less than: a) less than 40 HIV RNA copies/mL; b) less than 30 HIV RNA copies/mL; c) less than 20 HIV RNA copies/mL; d) less than 10 HIV RNA copies/mL; e) less than 5 HIV RNA copies/mL; f) less than 3 HIV RNA copies/mL; less than 1 HIV RNA copy/mL; and less than 0.5 HIV RNA copies/mL.

In each of the above methods for treating human HIV infection, there are separate additional embodiments wherein the TLR7 modulating compound comprises a pharmaceutically effective amount of a TLR7 modulating compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), or a TLR7 modulating compound selected from one of the individual compounds of Examples 1 to 124; or a pharmaceutically acceptable salt thereof.

HIV treatment combining antiretroviral drugs and TLR7 modulators

Provided are methods for treating HIV-1 infection in a virologically suppressed HIV-1 infected human who is receiving combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

In the above methods for treating HIV-1 infection in virologically suppressed humans infected with HIV-1, there are separate other embodiments wherein the TLR7 modulating compound comprises a pharmaceutically effective amount of a TLR7 modulating compound selected from one of Formula II, Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), or one of the individual compounds selected from Examples 1 to 124; or a pharmaceutically acceptable salt thereof.

As an example, a method of treating HIV-1 infection in a virologically suppressed HIV-1 infected human is provided, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof.

As another example, a method of treating HIV-1 infection in a virologically suppressed HIV-1 infected human is provided, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof.

Separate further embodiments of each of the above methods for treating HIV-1 infection in a virologically suppressed human infected with HIV-1 include methods wherein the combination antiretroviral therapy is selected from the combination of antiretroviral agents listed herein, wherein each separate combination antiretroviral agent is used as a single regimen.

As an example, a method for treating HIV-1 infection in a virologically suppressed HIV-1 infected human is provided, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF, a pharmaceutically effective amount of emtricitabine, and a pharmaceutically effective amount of dolutegravir, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof.

As an example, a method for treating HIV-1 infection in a virologically suppressed HIV-1 infected human is provided, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF, a pharmaceutically effective amount of emtricitabine, and a pharmaceutically effective amount of dolutegravir, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof.

Other separate methods include those above, wherein the combination antiretroviral therapy comprises administering to a human infected with HIV-1 an individual combination listed in Tables A, B, C, D, E, F, G, H, I, and J in combination with 0.1 mg to 25 mg of the compound of Example 4. Other separate methods include those above, wherein the combination antiretroviral therapy comprises administering to a human infected with HIV-1 an individual combination listed in Tables A, B, C, D, E, F, G, H, I, and J in combination with 0.1 mg to 25 mg of the compound of Example 49. Other separate embodiments include methods for treating HIV-1 infection in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV-1 is receiving a pharmaceutically effective amount of each combination antiretroviral therapy as shown in Tables 1A to 65 and a combination of a TLR7 modulator, wherein administration of each individual combination in the table constitutes a separate method.

Also provided is a method for treating HIV-1 infection in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF or TAF, a pharmaceutically effective amount of elvitegravir, a pharmaceutically effective amount of cobicistat, and a pharmaceutically effective amount of emtricitabine, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof.

Also provided is a method for treating HIV-1 infection in a virologically suppressed HIV-1 infected human, wherein the virologically suppressed HIV-1 infected human is receiving combination antiretroviral therapy, wherein the combination antiretroviral therapy comprises a pharmaceutically effective amount of TDF or TAF, a pharmaceutically effective amount of elvitegravir, a pharmaceutically effective amount of cobicistat, and a pharmaceutically effective amount of emtricitabine, the method comprising administering to the human a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof.

Other separate methods include those above, wherein the combination antiretroviral therapy comprises administering to a human infected with HIV-1 an individual combination listed in Tables A, B, C, D, E, F, G, H, I, and J in combination with 0.1 mg to 25 mg of the compound of Example 4. Other separate methods include those above, wherein the combination antiretroviral therapy comprises administering to a human infected with HIV-1 an individual combination listed in Tables A, B, C, D, E, F, G, H, I, and J in combination with 0.1 mg to 25 mg of the compound of Example 49. Other separate embodiments include methods for treating HIV-1 infection in a virologically suppressed human infected with HIV-1, wherein the virologically suppressed human infected with HIV-1 is receiving a pharmaceutically effective amount of each combination antiretroviral therapy as shown in Tables 1A to 65 and a combination of a TLR7 modulator, wherein administration of each individual combination in the table constitutes a separate method.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) administering to a human in need thereof a pharmaceutically effective amount of an antiretroviral agent sufficient to reduce the level of HIV in the human's blood or plasma from a first level to a second level, the second level comprising a lower concentration of HIV in the human's blood or plasma than the first level; and

b) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) administering to a human in need thereof a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma from a first level to a second level, the second level comprising a concentration of HIV in the human's blood or plasma that is lower than the concentration of HIV in the human's blood or plasma at the first level; and

b) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) administering to a human in need thereof a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma from a first level to a second level, the second level comprising a concentration of HIV in the human's blood or plasma that is lower than the concentration of HIV in the human's blood or plasma at the first level; and

b) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a human.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) administering to a person in need thereof a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the person's blood or plasma to a specified level; and

b) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a human.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) First, administering to a person in need thereof a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the person's blood or plasma to a specified level; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) First step: administering to a person in need thereof a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the person's blood or plasma to less than 50 HIV RNA copies/ml; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof.

Provided herein are methods for treating HIV-1 infection in a human, the methods comprising:

a) First, administering to a person in need thereof a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the person's blood or plasma to a specified level; and

b) a second step following the first step, which comprises administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a TLR7 modulating compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), or one of the individual compounds selected from Examples 1 to 124, or a pharmaceutically acceptable salt thereof.

In the methods herein for treating HIV infection in humans, each comprising a first step of administering to a human in need thereof a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy (cART) sufficient to reduce HIV levels in the human's blood or plasma to below detectable levels, and a subsequent second step comprising administering to the human a pharmaceutically effective amount of a combination antiretroviral therapy and a pharmaceutically effective amount of a TLR7 modulating compound, there is a further embodiment wherein the antiretroviral agent or cART regimen and the TLR7 modulating compound are both administered to the human daily. In each of these methods herein for treating HIV infection in humans, there is a further embodiment wherein the antiretroviral agent or cART regimen is administered to the human daily, while the TLR7 modulating compound is administered less than daily. Separate additional embodiments of each of these methods for treating HIV infection in humans include administering an antiretroviral agent or cART regimen to a human daily, and administering a TLR7 modulating compound to a human once or twice every other day, or once or twice every three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, forty-five, or sixty days.

Also provided are separate methods of the above methods, each using a separate compound in the second step, which is one or more compounds selected from the group consisting of: III, III(a), III(a), III(b), III(c), III(d), III(e), III(f), III(a)(1), III(a)(2), III(b)(1), III(b)(2), III(c)(1), III(c)(2), III(d)(1), III(d)(2), III(e)(1), III(e)(2), III(f)(1), and III(f)(2), or pharmaceutically acceptable salts thereof. One such method is as described above, wherein in the second step a pharmaceutically effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof is administered to a human, another method comprises administering a pharmaceutically effective amount of a compound of formula III(a) to a human infected with HIV, and the like.

Also provided are a set of separate methods of the above-described method, each using a separate compound in the second step selected from the compounds of Examples 1 to 124 or pharmaceutically acceptable salts thereof. One such method is as described above, wherein in the second step, a pharmaceutically effective amount of the compound of Example 1 or a pharmaceutically acceptable salt thereof is administered to a human, another method comprises administering a pharmaceutically effective amount of the compound of Example 2 or a pharmaceutically acceptable salt thereof to a human infected with HIV, and so on.

As an example, a method of treating HIV infection in a human is provided, the method comprising:

a) First step: administering to a person in need thereof an antiretroviral agent or combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the person's blood or plasma to a detectable level; and

b) a second step after the first step, the second step comprising administering to the human a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof.

A method of treating HIV infection in a human is provided, the method comprising:

a) a first step of administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a detectable level; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof.

A method of treating HIV infection in a human is provided, the method comprising:

a) a first step of administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a detectable level; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof.

A method of treating HIV infection in a human is provided, the method comprising:

a) a first step of administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a detectable level; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof.

A method of treating HIV infection in a human is provided, the method comprising:

a) a first step of administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a detectable level; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof.

In each of the methods herein for treating HIV infection in a human, wherein the first step comprises administering to a human in need thereof a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to below detectable levels, there is a further embodiment comprising the following method, wherein the level of HIV in the human's blood or plasma below detectable levels comprises a viral load (VL) in the plasma of less than 50 HIV RNA copies/ml. Other separate embodiments of each method include the method described herein, wherein the level of HIV in the human's blood or plasma below detectable levels comprises a viral load (VL) in the plasma of less than: a) less than 40 HIV RNA copies/ml; b) less than 30 HIV RNA copies/ml; c) less than 20 HIV RNA copies/mL; d) less than 10 HIV RNA copies/mL; e) less than 5 HIV RNA copies/mL; f) less than 3 HIV RNA copies/mL; less than 1 HIV RNA copy/mL; and less than 0.5 HIV RNA copies/mL.

Non-limiting tests that can be used to determine the concentration of HIV RNA in blood or plasma include the AMPLICOR HIV-1 MONITOR assay, v1.5 (quantification of HIV-1 RNA from 50 to 750,000 copies/mL), the AmpliPrepHIV-1 assay, v2.0 (quantification of HIV-1 RNA from 20 to 10,000,000 copies/mL), the Abbott RealTime HIV-1 assay (quantification of HIV-1 in human plasma from 40 to 10,000,000 copies/mL), or ultrasensitive single-copy quantitative PCR assays (SCA, iSCA, or gSCA). Other useful assays include the HIV-1 RNA 1.0 assay (kPCR), the NucliSENSHIV-1 v2.0 assay, and HIV-1 RNA qualitative assays.

Combination antiretroviral therapies and compositions that may be included for use in each of the methods herein include commercially available products:

a) Tablets (elvitegravir 150 mg, corbicistat 150 mg, emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) (Gilead Sciences, Inc.);

b) Tablets (emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg) (Gilead Sciences, Inc.);

c) Tablets (efavirenz 600 mg, emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg) (Gilead Sciences, Inc.);

d) tablets (200 mg emtricitabine, 25 mg rilpivirine, 300 mg tenofovir disoproxil fumarate) (Gilead Sciences, Inc.);

e) Tablets (Eq. 600 mg basic abacavir sulfate, 300 mg lamivudine);

f) tablets (150 mg lamivudine, 300 mg zidovudine) (GlaxoSmithKline); and

g) Tablets (Eq. 300 mg basic abacavir sulfate, 150 mg lamivudine, 300 mg zidovudine).

Also included for use in the methods herein are the following antiretroviral combinations:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine; and

d) a pharmaceutically effective amount of tenofovir alafenamide or a pharmaceutically acceptable salt thereof.

Also included for use in the methods herein are the following antiretroviral combinations:

a) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof, such as atazanavir sulfate; and

b) a pharmaceutically effective amount of cobicistat.

Also included for use in the methods herein are the following antiretroviral combinations: a) a pharmaceutically effective amount of TDF, b) a pharmaceutically effective amount of emtricitabine, and c) a pharmaceutically effective amount of a compound selected from efavirenz, rilpivirine, elvitegravir, efavirenz, atazanavir, darunavir, dolutegravir, raltegravir, and tipranavir.

Also included for use in the methods herein are the following antiretroviral combinations: a) a pharmaceutically effective amount of TAF, b) a pharmaceutically effective amount of emtricitabine, and c) a pharmaceutically effective amount of a compound selected from efavirenz, rilpivirine, elvitegravir, efavirenz, atazanavir, darunavir, raltegravir, dolutegravir, and tipranavir.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof to a human in need thereof.

A method of eliminating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

b) administering to the human a pharmaceutically effective amount of one or more antiretroviral agents.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a human in need thereof; and

b) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

c) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a human in need thereof; and

d) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

c) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a human in need thereof;

d) administering a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof, to a human in need thereof.

In each of the methods described above for eliminating HIV infection in a human, there is a further separate embodiment wherein the TLR7 modulating compound is selected from Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2) and a single compound selected from Examples 1 to 124, or a pharmaceutically acceptable salt thereof.

In the methods herein for eliminating HIV infection in a human, which methods comprise administering to a human in need thereof a pharmaceutically effective amount of an antiretroviral agent or a combination antiretroviral therapy (cART) regimen, and administering to the human a pharmaceutically effective amount of a combination antiretroviral therapy regimen and a pharmaceutically effective amount of a TLR7 modulating compound, there is a further embodiment wherein the antiretroviral agent or cART regimen and the TLR7 modulating compound are both administered to the human daily. In each of these methods herein for treating HIV infection in a human, there is a further embodiment wherein the antiretroviral agent or cART regimen is administered to the human daily and the TLR7 modulating compound is administered less than daily. Separate additional embodiments of each of these methods for treating HIV infection in humans include administering an antiretroviral agent or cART regimen to a human daily, and administering a TLR7 modulating compound to a human once or twice every other day, or once or twice every three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, forty-five, or sixty days.

cART combinations and dosing regimens

Each of the above treatment methods may use a combination of antiretroviral compounds (or pharmaceutically acceptable salts thereof). Examples of specific dosage range combinations of antiretroviral agents that can be used in these treatment methods are included in the table below. It should be understood that when practicing the treatment methods herein, the antiretroviral agents listed for each combination can be administered in a single pharmaceutical composition or in separate forms, for example, each dose is a single tablet or oral solution, or in different pharmaceutical compositions that combine different groups of agents. The amount of each agent listed is intended to be the daily dose of each agent, but in the treatment methods herein, the daily dose can be a single daily dose of each agent or can be divided and administered to a person in multiple daily doses, for example, the daily dose is divided into two, three, or four separate doses to be administered in a twice-daily, three-day, or four-times-daily dosing regimen.

The combinations of agents listed in each of the pharmaceutical composition tables below can be used in each of the methods described herein. It should be understood that for each of the individual methods discussed herein, separate methods exist in which each of the drug combinations listed in the pharmaceutical composition tables below is used in each separate method. For example, as described above, eight separate methods for treating HIV infection in humans are provided in Combination Antiretroviral Table A, which comprise administering to a human infected with HIV a combination of Examples A-1, A-2, A-3, A-4, A-5, A-6, A-7, and A-8 and a TLR7 modulating compound described herein.

Combination antiretroviral Table A

Antiviral combinations and dosing regimens comprising elvitegravir, corbicistat, emtricitabine, and TDF or TAF for use in the methods herein include:

Combination antiretroviral schedule B

Antiviral combinations and dosing regimens comprising emtricitabine and TDF or TAF for use in the methods herein include:

Combination Example Emtricitabine TDF TAF B-1 150mg to 250mg 250mg to 350mg 0mg B-2 175mg to 225mg 275mg to 325mg 0mg B-3 200mg 300mg 0mg B-4 150mg to 250mg 0mg 5mg to 30mg B-5 175mg to 225mg 0mg 5mg to 30mg B-6 175mg to 225mg 0mg 25mg B-7 200mg 0mg 25mg

Combination antiretroviral Table C

Antiviral combinations and dosing regimens comprising emtricitabine, TDF or TAF, and raltegravir for use in the methods herein include:

Combination antiretroviral Table D

Antiviral combinations and dosing regimens comprising emtricitabine, TDF or TAF, and dolutegravir for use in the methods herein include:

Combination Example Emtricitabine TDF Dolutegravir TAF D-1 150mg to 250mg 250mg to 350mg 30mg to 70mg 0mg D-2 150mg to 250mg 250mg to 350mg 40mg to 60mg 0mg D-3 175mg to 225mg 275mg to 325mg 40mg to 60mg 0mg D-4 190mg to 210mg 290mg to 310mg 45mg to 55mg 0mg D-5 200mg 300mg 50mg 0mg D-6 150mg to 250mg 0mg 30mg to 70mg 5mg to 30mg D-7 150mg to 250mg 0mg 40mg to 60mg 5mg to 30mg D-8 175mg to 225mg 0mg 40mg to 60mg 5mg to 30mg D-9 190mg to 210mg 0mg 45mg to 55mg 5mg to 30mg D-10 200mg 0mg 50mg 25mg

Combination antiretroviral Table E

Antiviral combinations and dosing regimens comprising rilpivirine HCl, emtricitabine, and TDF or TAF for use in the methods herein include:

Combination Example Rilpivirine HCl Emtricitabine TDF TAF E-1 20mg to 30mg 150mg to 250mg 250mg to 350mg 0mg E-2 22mg to 28mg 175mg to 225mg 275mg to 325mg 0mg E-3 27.5mg 200mg 300 0mg E-4 20mg to 30mg 150mg to 250mg 0mg 5mg to 30mg E-5 22mg to 28mg 175mg to 225mg 0mg 5mg to 30mg E-6 27.5mg 200mg 0mg 25mg

Combination antiretroviral Table F

Antiviral combinations and dosing regimens comprising efavirenz, emtricitabine, and TDF or TAF useful in the methods herein include:

Combination antiretroviral Table G

Antiviral combinations and dosing regimens comprising elvitegravir, emtricitabine, and TAF, with or without corbicistat, for use in the methods herein include:

Combination Example Ivitegravir Emtricitabine Coxistat TAF G-1 100mg to 200mg 150mg to 250mg 100mg to 200mg 5mg to 50mg G-2 600mg to 1200mg 150mg to 250mg 0mg 5mg to 50mg G-3 100mg to 200mg 150mg to 250mg 100mg to 200mg 5mg to 30mg G-4 600mg to 1200mg 150mg to 250mg 0mg 5mg to 30mg G-5 125mg to 175mg 175mg to 225mg 125mg to 175mg 5mg to 30mg G-6 700mg to 1200mg 175mg to 225mg 0mg 5mg to 30mg G-7 125mg to 175mg 175mg to 225mg 125mg to 175mg 5mg to 15mg G-8 700mg to 1200mg 175mg to 225mg 0mg 5mg to 15mg G-9 125mg to 175mg 175mg to 225mg 125mg to 175mg 20mg to 30mg G-10 700mg to 1200mg 175mg to 225mg 0mg 20mg to 30mg G-11 150mg 200mg 150mg 5mg to 30mg G-12 800mg to 1200mg 200mg 0mg 5mg to 30mg G-13 150mg 200mg 150mg 5mg to 15mg G-14 800mg to 1200mg150 200mg 0mg 5mg to 15mg G-15 150mg 200mg 150mg 20mg to 30mg G-16 800mg to 1200mg150 200mg 0mg 20mg to 30mg G-17 150mg 200mg 150mg 25mg G-18 800mg to 1200mg150 200mg 0mg 25mg G-19 150mg 200mg 150mg 10mg G-20 800mg to 1200mg150 200mg 0mg 10mg

Combination antiretroviral Table H

Antiviral combinations and dosing regimens comprising atazanavir sulfate and corbicistat for use in the methods herein include:

Combination Example Atazanavir sulfate Coxistat H-1 250mg to 350mg 100mg to 200mg H-2 275mg to 325mg 125mg to 175mg H-3 290mg to 310mg 140mg to 160mg H-4 300mg 150mg

Combination Antiretroviral Table 1

Antiviral combinations and dosing regimens comprising abacavir (e.g., administered as abacavir sulfate), lamivudine, and optionally dolutegravir for use in the methods herein include:

Combination Example Abacavir Lamivudine Dolutegravir I-1 500mg to 700mg 250mg to 350mg 0mg I-2 275mg to 325mg 125mg to 175mg 0mg I-3 290mg to 310mg 140mg to 160mg 0mg I-4 300mg 150mg 0mg I-5 500mg to 700mg 250mg to 350mg 25 mg to 75 mg I-6 275mg to 325mg 125mg to 175mg 40mg to 60mg I-7 290mg to 310mg 140mg to 160mg 45mg to 55mg I-8 300mg 150mg 50mg I-9 600mg 300mg 50mg

Combination antiretroviral Table J

Antiviral combinations and dosing regimens comprising darunavir (e.g., administered as a tablet or oral solution) and ritonavir or corbicistat for use in the methods herein include:

Combination Example Darunavir Ritonavir Coxistat J-1 50mg to 1000mg 50mg to 150mg 0mg J-2 50mg to 1000mg 0mg 50mg to 200mg J-3 500mg to 900mg 50mg to 150mg 0mg J-4 500mg to 900mg 0mg 50mg to 200mg J-5 500mg to 700mg 75mg to 125mg 0mg J-6 500mg to 700mg 0mg 75mg to 175mg J-7 600mg 100mg 0mg J-9 800mg 100mg 0mg J-10 600mg 0mg 50mg to 150mg J-11 800mg 0mg 100mg to 200mg J-12 600mg 0mg 100mg J-13 800mg 0mg 150mg

In each of the combinations of Tables A to J above for combination antiretrovirals, specific examples are included in each relevant range wherein the elvitegravir and corbicistat components are each independently present at 100 mg, 125 mg, 150 mg, 175 mg, and 200 mg doses; the emtricitabine component is present at 150 mg, 175 mg, 200 mg, 225 mg, and 250 mg doses; the raltegravir component is present at 350 mg, 375 mg, 400 mg, 425 mg, and 450 mg doses; the dolutegravir component is present at 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, and 75 mg doses; the rilpivirine HCl component is present at 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg doses; the efavirenz and abacavir components are each independently present at 500 mg, 525 mg, 550 mg, 575 mg, and 580 mg doses. 5 mg, 600 mg, 625 mg, 650 mg, 675 mg and 700 mg doses; the atazanavir sulfate and lamivudine components are each independently present in doses of 250 mg, 275 mg, 300 mg, 325 mg and 350 mg; darunavir is present in doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg and 1,000 mg; the ritonavir component is present in doses of 50 mg, 75 mg, 100 mg, 125 mg and 150 mg; TDF is present in doses of 150 mg, 175 mg, 200 mg, 250 mg, 275 mg, 300 mg, 325 mg and 350 mg; and TAF is present in doses of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg and 30 mg.

Lowering viremia and chronic set points of HIV viral load

Provided is a method for reducing HIV viremia in a human infected with HIV, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically effective amount thereof.

Also provided is a method of reducing HIV viremia in a human infected with HIV, wherein the human infected with HIV is being treated with one or more antiviral agents, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically effective amount thereof.

A method of lowering the chronic set point of HIV viral load in a human infected with HIV is provided, the method comprising administering to the human a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically effective amount thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising administering to the human a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically effective amount thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV who is receiving combination antiretroviral therapy, the method comprising administering to the human infected with HIV who is receiving combination antiretroviral therapy a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically effective amount thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV who is receiving highly active antiretroviral therapy, the method comprising administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically effective amount thereof, to the human infected with HIV who is receiving highly active antiretroviral therapy.

Also provided are separate methods for reducing HIV viremia in humans infected with HIV and separate methods for lowering the chronic set point of HIV viral load in humans infected with HIV, each of which comprises administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2); or a pharmaceutically acceptable salt thereof.

Also provided are a set of separate methods for reducing HIV viremia in humans infected with HIV and a set of separate methods for lowering the chronic set point of HIV viral load in humans infected with HIV, each of which comprises administering to a human infected with HIV a pharmaceutically effective amount of one compound selected from the group consisting of the 124 compounds of Examples 1 to 124, or a pharmaceutically acceptable salt thereof. One of each compound selected from Examples 1 to 124 is used in each of the set of separate methods for lowering the chronic set point of HIV viral load in humans infected with HIV, wherein the compound of Example 1 or a pharmaceutically acceptable salt thereof is used in the first method, the compound of Example 2 or a pharmaceutically acceptable salt thereof is used in the second method, and so on.

For example, a method for lowering the chronic set point of HIV viral load in a human infected with HIV is provided, comprising administering to the human infected with HIV a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof.

Also provided is a method for lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof.

A method of lowering the chronic set point of HIV viral load in a human infected with HIV is provided, the method comprising:

a) in a first step, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy sufficient to reduce the level of HIV in the human's blood or plasma to undetectable levels; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof.

Also provided is a method of lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising:

a) in a first step, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the chronic set point of HIV in the human's blood or plasma to a first level of less than 50 HIV-1 RNA copies/ml plasma; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof, to reduce the HIV chronic set point in the human's blood or plasma to a second level, wherein the second level is lower than the first level.

A method of lowering the chronic set point of HIV viral load in a human infected with HIV is provided, the method comprising:

a) first, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to undetectable levels; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2); or a pharmaceutically acceptable salt thereof.

Also provided is a method of lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising:

a) in a first step, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the chronic set point of HIV in the human's blood or plasma to a first level of less than 50 HIV-1 RNA copies/ml plasma; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of a compound selected from one of Formula III, III(a), III(a), III(b), III(c), III(d), III(e), III(f), III(a)(1), III(a)(2), III(b)(1), III(b)(2), III(c)(1), III(c)(2), III(d)(1), III(d)(2), III(e)(1), III(e)(2), III(f)(1), or III(f)(2); or a pharmaceutically acceptable salt thereof, to lower the chronic set point of HIV in the human's blood or plasma to a second level, wherein the second level is lower than the first level.

In other separate embodiments of each of the methods described above, wherein each in one embodiment thereof, the each specified method of lowering the chronic set point of HIV viral load in a human infected with HIV comprises the method described, wherein the second level of the chronic set point in the human's blood or plasma is the following concentration in human plasma: a) less than 40 HIV-1 RNA copies/ml plasma; b) less than 30 HIV-1 RNA copies/ml plasma; c) less than 20 HIV-1 RNA copies/ml plasma; d) less than 10 HIV-1 RNA copies/ml plasma; e) less than 5 HIV-1 RNA copies/ml plasma; f) less than 3 HIV-1 RNA copies/ml plasma; g) less than 1 HIV-1 RNA copy/ml plasma; h) less than 0.5 HIV-1 RNA copies/ml plasma; i) less than 0.3 HIV-1 RNA copies/ml plasma; and j) less than 0.1 HIV-1 RNA copies/ml plasma.

Also provided are separate embodiments of each of the methods for lowering the chronic set point of HIV viral load in a human infected with HIV, each of which comprises: in a second step, administering to the human a separate compound selected from one of Formula III, III(a), III(a), III(b), III(c), III(d), III(e), III(f), III(a)(1), III(a)(2), III(b)(1), III(b)(2), III(c)(1), III(c)(2), III(d)(1), III(d)(2), III(e)(1), III(e)(2), III(f)(1), and III(f)(2); or a pharmaceutically acceptable salt thereof. One of the methods is as described above, wherein in a second step, a pharmaceutically effective amount of Formula III or a pharmaceutically acceptable salt thereof is administered to the human; another method comprises administering to the human infected with HIV a pharmaceutically effective amount of Formula III(a), and the like.

Also provided are a set of separate methods of the above method for lowering the chronic set point of HIV viral load in a human infected with HIV, each of which utilizes, in the second step, a compound selected from Examples 1 to 124 or a pharmaceutically acceptable salt thereof. One of the methods is as described above, wherein, in the second step, a pharmaceutically effective amount of the compound of Example 1 or a pharmaceutically acceptable salt thereof is administered to the human; another method comprises administering a pharmaceutically effective amount of the compound of Example 2 or a pharmaceutically acceptable salt thereof to the human infected with HIV, and so on.

For example, a method of lowering the chronic set point of HIV viral load in a human infected with HIV is provided, the method comprising:

a) first, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to below detectable levels; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 4 or a pharmaceutically acceptable salt thereof.

Also provided is a method of lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising:

a) first, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a level below detectable; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof.

Also provided is a method of lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising:

a) first, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to below detectable levels; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 119 or a pharmaceutically acceptable salt thereof.

Also provided is a method of lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising:

a) first, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a level below detectable; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 120 or a pharmaceutically acceptable salt thereof.

Also provided is a method of lowering the chronic set point of HIV viral load in a human infected with HIV, the method comprising:

a) first, administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a level below detectable; and

b) a second step following the first step, the second step comprising administering to the human a pharmaceutically effective amount of a combined antiretroviral therapy regimen and a pharmaceutically effective amount of the compound of Example 121 or a pharmaceutically acceptable salt thereof.

In each of the above listed methods for lowering the chronic set point of HIV viral load in a human infected with HIV, there is a further embodiment wherein the detectable level in the first step is a concentration in human plasma of less than 50 HIV-1 RNA copies/ml plasma.

Enhance immune activity and increase HIV gene expression

Provided is a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV, the method comprising administering a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof to the human infected with HIV.

Also provided is a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV, the method comprising administering a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof to the human infected with HIV.

Also provided is a method for increasing immune cell activity and HIV gene expression in a human infected with HIV, comprising administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2); or a pharmaceutically acceptable salt thereof. It should be understood that one such method comprises administering to a human infected with HIV a pharmaceutically effective amount of Formula III or a pharmaceutically acceptable salt thereof; another method comprises administering to a human infected with HIV a pharmaceutically effective amount of Formula III(a), and the like.

Also provided are separate methods for enhancing immune cell activity and increasing HIV gene expression in humans infected with HIV, each of which comprises administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2); or a pharmaceutically acceptable salt thereof.

Also provided are a set of separate methods for increasing immune cell activity and HIV gene expression in humans infected with HIV, each of which comprises administering to a human infected with HIV a pharmaceutically effective amount of a compound selected from Examples 1 to 124, or a pharmaceutically acceptable salt thereof. One of each of the compounds of Examples 1 to 124 is used in each of the separate methods for increasing immune cell activity and HIV gene expression in humans infected with HIV, wherein the compound of Example 1 or a pharmaceutically acceptable salt thereof is used in the first method, the method of Example 2 or a pharmaceutically acceptable salt thereof is used in the second method, and so on.

For example, a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV is provided, which comprises administering a pharmaceutically effective amount of the compound of Example 4 or a pharmaceutically acceptable salt thereof to the human infected with HIV.

Also provided is a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV, the method comprising administering a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof to the human infected with HIV.

Also provided is a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV, comprising administering a pharmaceutically effective amount of the compound of Example 119 or a pharmaceutically acceptable salt thereof to the human infected with HIV.

Also provided is a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV, comprising administering a pharmaceutically effective amount of the compound of Example 120 or a pharmaceutically acceptable salt thereof to the human infected with HIV.

Also provided is a method for enhancing immune cell activity and increasing HIV gene expression in a human infected with HIV, comprising administering a pharmaceutically effective amount of the compound of Example 121 or a pharmaceutically acceptable salt thereof to the human infected with HIV.

In each of the methods of increasing immune cell activity and increasing HIV gene expression in humans infected with HIV, there are further separate embodiments wherein the immune cell activity is each in each of the further embodiments one of the following activities: a) plasmacytoid dendritic cell (PDC) activity, b) B-cell activity, c) T-cell activity, d) CD4 T-cell activity, e) CD8 T-cell activity, f) natural killer (NK) cell activity, invariant NK T cell activity, monocyte/macrophage activity.

Improve antiviral efficacy

Also provided is a method of increasing the efficacy of an antiviral agent in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a TLR7 modulating compound and a pharmaceutically effective amount of an antiviral agent.

Also provided is a method of increasing the efficacy of two or more antiviral agents in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a TLR7 modulating compound and a pharmaceutically effective amount of each of the two or more antiviral agents.

Separate embodiments of the method of increasing the efficacy of two or more antiviral agents in a human infected with HIV include methods wherein the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof.

Also provided is a method for increasing the efficacy of an antiviral agent in a human infected with HIV, comprising administering to the human infected with HIV a pharmaceutically effective amount of a TLR7 modulating compound, a pharmaceutically effective amount of an antiviral agent, and a pharmaceutically effective amount of cobicistat. Separate embodiments of the method for increasing the efficacy of an antiviral agent in a human infected with HIV include methods wherein the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof.

Also provided is a method for increasing the efficacy of an antiviral agent in a human infected with HIV, the method comprising administering to the human infected with HIV a pharmaceutically effective amount of a TLR7 modulating compound, a pharmaceutically effective amount of an antiviral agent, and a pharmaceutically effective amount of ritonavir. Separate embodiments of the method for increasing the efficacy of an antiviral agent in a human infected with HIV include methods wherein the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof.

Other separate embodiments of the above methods for increasing the efficacy of an antiviral agent in a human infected with HIV include methods wherein the compound of Formula II, or a pharmaceutically acceptable salt thereof, is selected from Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), and Formula III(f)(2); or a pharmaceutically acceptable salt thereof. Other separate embodiments of the above methods for increasing the efficacy of an antiviral agent in a human infected with HIV include methods wherein each of the compounds of Formula II is a compound of Examples 1 to 124, or a pharmaceutically acceptable salt thereof.

Improving the efficacy of an antiviral agent refers to achieving greater antiviral activity in humans infected with HIV by administering an antiviral agent and a TLR7 modulating compound, which is greater than the antiviral activity achieved by administering the same dose or regimen of the antiviral agent alone. Improving the efficacy of an antiviral agent includes achieving a lower viral set point or viral load in humans infected with HIV by administering an antiviral agent and a TLR7 modulating compound, which is lower than the viral set point or viral load achieved by administering the same dose or regimen of the antiviral agent alone, as well as achieving a desired viral set point or viral load in humans by administering a lower dose of the antiviral agent. Improving the efficacy of an antiviral agent also includes achieving elimination of HIV infection in humans infected with HIV.

TLR7 modulating compounds can be used in the methods herein to enhance the efficacy of combination antiviral agents, including those listed in Tables A through J. Combinations of TLR modulating compounds and combination antiviral agents that enhance their activity include those found in Tables 1A through 65.

HIV vaccine

A method of treating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

b) administering a pharmaceutically effective amount of HIV vaccine to a human.

As used herein, the term "HIV vaccine" refers to a vaccine that protects people who are not infected with HIV from contracting the virus, or has a therapeutic effect on people who are infected with HIV or who subsequently come into contact with HIV. Vaccines that can be used to attack the recipient's immune system include HIV DNA vaccines, live vector vaccines, viral protein or viral peptide vaccines, and virus-like particle (VLP) vaccines.

The TLR7 modulating compounds described herein can also be used in the methods herein with HIV vaccines, such as polypeptide vaccines, recombinant subunit protein vaccines (including subunit proteins gp120, gp140 and gp160, live vector vaccines encoding HIV-1 antigens, such as those selected from gag, pol, env, nef, rev, tat, vif, vpr, vpu and antigenic proteins, variants and fusion proteins thereof), inactivated vaccines, modified envelope vaccines, replicons (including Venezuelan equine encephalitis (VEE), Semliki Forest virus (SFV), adenovirus-associated virus (AAV) including self-complementary adeno-associated virus (scAAV) and human papillomavirus (HPV) replicon systems), DNA vaccines, vaccine combinations and virus-like particle vaccines (pseudovirus vaccines). Recombinant HIV vaccines can be produced using vaccine virus vector platforms known in the art, including those from adenoviridae, poxviridae, herpesviridae, or adeno-associated viruses, as well as cytomegalovirus, tobacco-pox, rubella, poliovirus, Venezuelan equine encephalitis virus, lentivirus, Salmonella, Bacillus Calmete-Guerin (BCG), and Sendai vectors.

Examples of HIV vaccines for use in the methods herein include ALVAC-HIV MN120TMG (vCP205), rgp120, monomeric gp120, trimeric gp120, gp120 monomer + gp120 trimer, MN rgp120/HIV-1 and GNE8rgp120/HIV-1, ALVAC-HIV (vCP1521), ALVAC + gp120/MF59, ALVAC-HIV MN120TMG (vCP205), ALVAC (2) 120 (B, MN) GNPs (vCP1452), ALVAC (1) 120 (B, MN) GNPs (vCP1433), ALVAC-HIV + B/E, ALVACVIH 1433, AIDSVAX B/B, AIDSVAX B/E, tgAAC09 (a Gag-PR-RT AAV HIV vaccine), Ad35, Ad35-GRIN/ENV, Ad35-GRIN, Ad35-ENV, SeV-G(NP) vaccine, EN41-FPA2 HIV, EN41-UGR7C, Ad4-EnvC150, GSK 692342, GSK 732461, GSK 732462, MRKAd5 HIV-1Gag, MRKAd5 HIV-1 gag/pol/nef, JS7DNA, pGA2/JS7, Sub C gp140, trimeric gp140, trimeric gp140 + monomeric gp120, trimeric gp140 + trimeric gp120, trimeric gp140 + monomeric gp120 + trimeric gp120, TBC-M4, MVA-nef, rMVA-HIV (env/gag [TBC-M358], tat/rev/nef-RT [TBC-M335]), rFPV-HIV (env/gag [TBC-F357], tat/rev/nef-RT [TBC-F349]), TBC-3B, ADVAX e/g + ADVAX p/Nt(ADVAX), MVA-C+gp140/MF59, DNA-C, DNA-C2, MVA-C, MVAHIV-B(MVATG17401), MVA-mBN120B, MF59, MTP-PE/MF59, DNA-C2+MVA-C, DNA-C2+MVA-C+gp140/MF59, NYVAC, NYVAC-B/rAd5, rAd5/NYVAC-BNYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA+NYVAC+gp120, NYVAC+gp120, Ad26, Ad26.ENVA.01(rAd26), MVA, Ad26/MVA, HIV gp41, HIV gp41 monomer, HIV gp41 trimer, gp120, gp140, gp160, -B HIV vaccine, PENNVAX-G DNA, Salmonella typhi CVD 908-HIV-1LAI gp 120 (VVG 203), HIV-1MN, rgp120/HIV-1MN, VRC4302, VRC-HIVDNA016-00-VP, VRC-HIVDNA009-00-VP, VRC-HIVDNA009-00-VP, VRC-HIVADV014-00-VP, gp160MN/LAI-2, VRC-HIVADV027-00-VP, VRC-HIVADV038-00-VP, VRC-HIVDNA044-00-VP, VRC-HIVADV016-00-VP, VRC rAd5 vaccine (rAd5 gag-pol/env A/B/C), HIV-v, LIPO-4, LIPO-5, LIPO-6T, modified Ankara poxvirus (MVA) vector HIV-1 (ADMVA), CTL MEP/RC529-SE/GM-CSF (CTL MEP), AVX101, HIV-1 immunogen, HIV p24/MF59, HIV-1 p24 (gag), HIV SF2 gp120/MF59, rgp120/HIV-1 SF-2 (gp120), rgp120/HIV-1 SF-2, MVA-CMDR, SCBaL/M9, DNA Nat-B env, NYVAC Nat-B env, DNA CON-S env, NYVAC CON-S env, DNAMosaic env, NYVAC Mosaic env, rAd5 env A, rAd5 env B, rAd5 env C, rAd5 gag-pol, GENEVAX-HIV(APL 400-003), rMVA-HIV(rMVA-HIV env/gag+rMVA-HIV tat/rev/nef-RT), rFPV-HIV(rFPV-HIV env/gag+rFPV-HIV tat/rev/nef-RT), HIV-1 gag DNA plus IL-12 DNA adjuvant, DNA-HIV-PT123, DNA HIVIS, HIVIS 03 DNA, MVA-CMDR, EnvDNA, PolyEnv1, EnvPro, SAAVIDNA-C2, SAAVI MVA-C, HIV-1 C4-V3 multivalent peptide, EP HIV-1043, EP HIV-1090, HIV-MAG, CN54gp140, CN54gp140/GLA-AF, HIV DNA plasmid/recombinant fowlpox vector, HIV62B, MVA/HIV62, pGA2/JS7DNA/MVA/HIV62, VSV-Indiana HIV gag, MRKAd5 (Clade B), Clade B gag DNA/PLG, MRKAd5 HIV-1 gag/pol/nef, env DNA/PLG, GEO-D03 DNA, trivalent MRKAd5 HIV-1 gag/pol/nef, HIVA-1e, MVA.HIVconsv, pSG2.HIVconsv DNA, electroporated pSG2.HIVconsv, pHIS-HIV-AE, rAAV1-PG9DP, Ad5.ENVA.48 HIV-1, Ad26.ENVA.01 HIV-1, NefTat, gp120W61D, ProfectusHIV MAG pDNA, pGA2/JS2 plasmid DNA, ChAdV63.HIVconsv, HIV gp120/NefTat/AS02A, rgp120/HIV-1IIIB, rgp120/HIV-1MN monovalent octameric V3 peptide vaccine, HIV-1 C4-V3 multivalent peptide vaccine, HIV-1 Gag-PolDNA (APL 400-047), AFO-18, NYVAC-C, UBI HIV-1 MN PND peptide immunogen, UBI microparticle monovalent HIV-1 MN branched peptide, HIV p17/p24:Ty-VLP, A244rgp120/HIV-1, Env 2-3, MTP-PE/MF59, P3C541b lipopeptide, rAd5 Gag-Pol Env A/B/C, rAd5Gag-Pol, Ad4-H5-VTN, EP-1233, MVA-mBN32, rVSV, pGA2/JS7DNA, MVA/HIV62, pGA2/JS7(JS7)DNA, MVA62B, HIV-1 Tat/delta-V2 Env binding, HIV-1delta-V2 Env, GTU-multiHIV B. E1M184V peptide, VCR-HIVDNA006-00-VP, HIV LFn-p24, VAC-3S, MYM-V101, DCVax-001, DCVax polyaddition-ICLC, Vacc-4x, TUTI-16, gp120/AS02A, gp120/nef/tat/SIV nef/AS02A, nef/tat/SIV nef/AS02A, gp120/nef/tat/SIV nef, nef/tat/SIVnef/AS06, VICHREPOL, Ad35-ENVA, Ad5HVR48.ENVA.01, ADVAX e/g, ADVAX p/nt, cervicovaginal CN54 gp140-hsp70 conjugate vaccine (TL01), DNA (Gag, Pol, and Env genes from HIV-1 CN54) + Tiantian poxvirus vector, HIV-1 CN54 gag, HIV-1 CN54pol, HIV-1 CN54 env, MV1-F4-CT1, MVA.HIVA, MVA HIV-B, rAd35 and rVSV _IN HIV-1 Gag vaccines, and combinations thereof.

Examples of HIV vaccines and vectors for their preparation that can also be used in the methods herein include those disclosed in US 2008/0199493 A1 (Picker et al.), US 2013/0142823 (Picker et al.), US20040223977 (Diamond), WO2014039840 (Levy), WO2014026033 (Yamamoto), WO2013182660 (Sorensen et al.), WO2013110818 (Brander et al.), WO2013110790 (Bomsel et al.), WO2013059442 (Song et al.), WO2012156750 (Davis et al.), WO2012137072 (Andrieu et al.), WO2012116142 (Podack et al.), US201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), WO201201079 (Valentino et al.), 10 (Liu et al.), WO2012018856 (Rautsola et al.), US20120021000 (Opendra et al.), US20110305749 (Ryttergaard et al.), WO2011117408 (Bourguignon et al.), US20130195904A1 (August et al.), US20110159025 (Littman et al.), US20110123485 (Desrosiers et al.), US20110311585A1 (Berman), US20110159025A1 (Littman et al.), US20110014221 (K ang et al.), US20120263720A1 (Gronvold et al.), US20100304483 (Abulafia-Lapid), US20100215695 (Yu), US20100135994 (Banchereau et al.), US20120045472A1 (Harrison et al.), US20110195083A1 (Anglister et al.), US7612173B2 (Albrecht et al.), US20080199493A1 (Picker et al.), and US7364744B2 (Hovanessian et al.), US20150132332 (S Hao et al.), WO2015073291 (Weiner et al.), WO2015048512 (Haynes et al.), WO2015001128 (Benarous et al.), US20140302080 (Barouch et al.), (WO2014039840 (Levy et al.), WO2014026033 (Yamamoto et al.), WO2015007337 (Hoie et al.), US20150132255 (Birger et al.), US20150050310 (Brander et al.), and US20150004190 (Bomsel et al.), the contents of each of which are incorporated herein by reference.

Also useful in the methods and combinations of vaccines and methods described herein are agents that provide adjuvant activity to the vaccine, such as agonists of TLR3, TLR4, TLR9, NOD-1/2 (NOD-like receptors), and RIG-1 (RIG-I-like receptor).

Also provided is a method for enhancing the effect of an HIV vaccine, the method comprising administering a pharmaceutically effective amount of an HIV vaccine and a pharmaceutically effective amount of a TLR7 modulating compound to a person in need. One method for enhancing the effect of an HIV vaccine comprises a first step of administering a pharmaceutically effective amount of a TLR7 modulating compound to a person in need, and a second step of administering a pharmaceutically effective amount of an HIV vaccine to a person in need. Another method for enhancing the effect of an HIV vaccine comprises a first step of administering a pharmaceutically effective amount of an HIV vaccine to a person in need, and a second step of administering a pharmaceutically effective amount of a TLR7 modulating compound to a person in need. Specific individual embodiments in each of these methods for enhancing the effect of an HIV vaccine include methods wherein the TLR7 modulating compound is respectively: a) a compound of formula II, b) Example 4, c) Example 49, d) Example 119, e) Example 120, and f) Example 121, or a pharmaceutically acceptable salt thereof. Non-limiting examples of HIV vaccines used in these methods include those described herein.

HIV antibodies

A method of treating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

b) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

b) administering to the human a pharmaceutically effective amount of two or more HIV antibodies.

A method of treating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

b) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

b) administering to the human a pharmaceutically effective amount of two or more HIV antibodies.

Twenty-four separate embodiments are also provided, each comprising a method of treating HIV infection in a human by administering a compound of Formula II and an HIV antibody as described above, wherein in each separate embodiment, the compound of Formula II is a compound selected from Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) and Formula III(f)(2), or a pharmaceutically acceptable salt thereof.

Also provided are 124 other separate methods for treating HIV infection in humans by administering a compound of Formula II and an HIV antibody as described above, wherein the compound of Formula II is a compound of Examples 1 to 124 or a pharmaceutically acceptable salt thereof. One of these methods for treating HIV infection in humans by administering a compound of Formula II and an HIV antibody is as described above, wherein in a first step, a pharmaceutically effective amount of the compound of Example 1 or a pharmaceutically acceptable salt thereof is administered to the human, another method comprises administering in a first step a pharmaceutically effective amount of the compound of Example 2 or a pharmaceutically acceptable salt thereof to the human infected with HIV, and so on.

Also provided is a method of treating HIV infection in a human, the method comprising administering to a human in need thereof:

a) a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically effective amount of HIV antibodies.

Also provided is a method of treating HIV infection in a human, the method comprising administering to a human in need thereof:

a) a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically effective amount of HIV antibodies.

Also provided is a method of treating HIV infection in a human, the method comprising administering to a human in need thereof:

a) a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically effective amount of HIV antibodies.

Also provided is a method of treating HIV infection in a human, the method comprising administering to a human in need thereof:

a) a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically effective amount of HIV antibodies.

Also provided is a method of treating HIV infection in a human, the method comprising administering to a human in need thereof:

a) a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof; and

b) a pharmaceutically effective amount of HIV antibodies.

For each of the methods described herein comprising administering to a human in need thereof a pharmaceutically effective amount of a TLR7 modulating compound (including those of Formula II, Examples 1-124, etc.) and a pharmaceutically effective amount of an HIV antibody, there are further embodiments concerning the order in which the agents are administered.

In one embodiment of each method, a TLR7 modulating compound and an HIV antibody can be administered to a human being together, for example, each on the same day. A pharmaceutically effective amount of each agent can be administered in a specific dosing regimen, for example, once a week, once every two weeks, once every three times, once a month, and the like. In another embodiment of each method, an initial dose of a TLR7 modulating compound and an HIV antibody can be administered to a human being together, with subsequent administration being performed at staggered time points. For example, after the initial dose of each agent, the TLR7 compound can be administered to a human being every day or at intervals of 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11, 12-, 13-, 14- or 15 days, wherein the HIV antibody is administered once a week, twice a month, once a month, and the like.

In another embodiment of each method, the TLR7 modulating compound can be administered in the initial administration, wherein the HIV antibody is administered to the human in a subsequent administration, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after the administration of the TLR7 compound. In another embodiment of each method, the HIV antibody can be administered in the initial administration, wherein the TLR7 modulating compound is administered to the human in a subsequent administration, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after the administration of the HIV antibody.

It should be understood that for similar dosing regimens described herein, including administering a pharmaceutically effective amount of a TLR7 modulating compound (including Formula II), those of Examples 1-121, etc., a pharmaceutically effective amount of an HIV antibody, and a method of combining antiretroviral therapy to a person in need, there are other embodiments involving the order in which each agent is administered. For example, in cases where a person in need has been administered an antiretroviral combination therapy (e.g., a cART or HAART regimen), the TLR7 modulating compound and the HIV antibody can be added to the ongoing antiretroviral combination therapy in any of the regimens described above. In another embodiment of each method, the TLR7 modulating compound can be administered as an initial agent, followed by sequential administration of the agent and HIV antibody for the combined antiretroviral therapy. In another embodiment of each method, the TLR7 modulating compound and the HIV antibody can be administered to a person in need in one of the regimens described above, and the agent for the combined antiretroviral therapy can be administered at a later time point.

A method of treating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

A method of treating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof to a person in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided are 19 further separate embodiments, each comprising a method of treating HIV infection in a human by administering a combination antiretroviral therapy, a compound of Formula II, and an HIV antibody as described above, wherein in each separate embodiment, the compound of Formula II is a compound selected from Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), and Formula III(f)(2); or a pharmaceutically acceptable salt thereof.

Also provided are 124 further separate methods of treating a human infected with HIV by administering a combination antiretroviral therapy, a compound of Formula II, and an HIV antibody as described above, wherein the compound of Formula II is a compound of Examples 1 to 124. One of each of the compounds of Examples 1 to 124 is used in each of the separate methods of treating a human infected with HIV by administering a combination antiretroviral therapy, a compound of Formula II, and an HIV antibody, wherein the compound of Example 1, or a pharmaceutically acceptable salt thereof, is used as the compound of Formula II in the first method, Example 2, or a pharmaceutically acceptable salt thereof, is used as the compound of Formula II in the second method, and so on.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of an antiretroviral agent to a person in need thereof;

b) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering to a human in need thereof a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

A method of treating HIV infection in a human is provided, the method comprising:

a) administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy sufficient to reduce the level of HIV in the human's blood or plasma to a specified level; and

b) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Twenty further separate embodiments are also provided, each comprising a method of treating HIV infection in a human by administering a combination antiretroviral therapy regimen sufficient to reduce the level of HIV detected in the human's blood or plasma to a specific value, a compound of Formula II, and an HIV antibody as described above, wherein in each separate embodiment, the compound of Formula II is a compound selected from Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) and Formula III(f)(2), or a pharmaceutically acceptable salt thereof.

Also provided are 124 further separate methods for treating HIV infection in a human by administering a combination antiretroviral therapy regimen sufficient to reduce the level of HIV detected in the human's blood or plasma to a specific value, a compound of formula II, and an HIV antibody as described above, wherein the compound of formula II is a compound of Examples 1 to 124.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering to a human in need thereof a pharmaceutically effective amount of a combination antiretroviral therapy regimen sufficient to reduce the level of HIV in the human's blood or plasma to a specific level;

b) administering a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering to a human in need thereof a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of treating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

HIV antibodies useful in the methods herein include:

Antibodies targeting the CD4-binding site, including those that bind to the CD4 binding site located on gp120, such as VRC01, VRC02, VRC03, VRC04, VROC07, b12, HJ16, NIH45-46, 3BNC60, BNC62, 3BNC117, 12A12, 12A21, 12A30, VRC-PG04, VRC-CH30, VRC-CH31, VRC-CH 32. VRC-CH33, VRC-CH34, VRC-PG04, VRC-PG04b, 8ANC131, 8ANC37, 8ANC134, CH103, CH104, CH105, CH106, 3BNC117, 3BNC60, NIH45, NIH46, 12A12, 12A21, 8ANC131, 8ANC134, 1NC9, 1B2530, 7B2 and A32;

Antibodies targeting Gp-120 variable region 1 and variable region 2 (V1/V2), such as PG9, PG16, CH01-04, PGT141, PGT142, PGT143, PGT144, PGT145, and CAP256-VRC26;

Antibodies targeting glycan V3, such as the PGT121 series of antibodies, including PGT121, PGT122, PGT123, PGT124, PGT 125, PGT126, PGT127, PGT128, PGT130, PGT131, PGT-132, PGT135, PGT136, and PGT137, and 2G12;

Antibodies targeting the membrane proximal external region (MPER), such as 2F5, Z13, 4E10, 10E8, PGT150 series antibodies, M66.6, CAP206-CH12, and 10E81.

PG and PGT antibodies are described in WO 2010/107939 and WO 2012/030904.

Other antibodies for use in the methods herein include PGT-138, PGT-139, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-141, PGT-142, PGT-143, PGT-144, PGT-145, PGT-151, PGT-152, PGT-153, PGT-154, PGT-155, PGT-156, PGT-157, and PGT-158.

Other antibodies used in the methods herein include bispecific antibodies. This bispecific antibody has at least one variable region that recognizes a part of HIV virus, such as gp120 or gp41. In certain embodiments, the bispecific antibody includes a second variable region that recognizes the surface of memory cells, such as CD3 or CD4. Exemplary bispecific antibodies include but are not limited to those that induce the redirected CD8 T cell-dependent lysis of infected HIV cells, such as those of the identification HIVgp120/41 envelope (arm A) and CD3 receptor (arm B) described in WO2013163427A1. In addition, bispecific antibodies can include other platforms, such as BiTE (Amgen), DART (Macrogenics), Duobodies (GenMab) and other platforms (Xencor, Sanofi, etc.). Other examples of bispecific antibodies may include those that induce the lysis of redirected NK cell-mediated infected HIV cells, such as those that recognize HIV gp120/41 envelope (arm A) and NKG2D receptor (arm B) based on the Affimed platform.

Other examples of bispecific antibodies may include those that induce redirected NK cell-mediated lysis of HIV-infected cells, such as those based on the Affimed platform that recognize the HIV gpl20/41 envelope (arm A) and the NKG2D receptor (arm B).

Immunomodulatory antibodies and small molecule reagents

Specific antibodies used also include immunomodulatory monoclonal antibodies:

Inhibitory anti-PD-1 mAbs such as Nivolimumab (BMS-936558 or MDX1106), MK-34775, inhibitory anti-PD-L1 mAb BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, and MDX1105-01; Inhibitory anti-CTLA-4 mAbs such as Ipilimumab and Tremilimumab;

Inhibitory anti-Tim3 mAbs, such as those from Tesaro, Inc; Inhibitory anti-LAG-3 mAbs, such as BMS-986016, IMP321; Inhibitory anti-KIR mAbs, such as Lirilumab (IPH2102/BMS-986015);

Stimulating anti-CD27 mAbs, such as CDX-1127; stimulating anti-CD40 mAbs, such as CP-870,893 and BMS-986090; stimulating anti-CD47 mAbs, such as those described in Tseng et al., Proc Natl Acad Sci U S A. Jul 2, 2013; 110(27):11103-11108; stimulating anti-CD134 (OX40) mAbs, such as MEDI-6469 or those described in WO-2009079335 and WO-2006121810;

Stimulatory anti-CD137 mAbs, such as BMS-663513; PF-05082566; other antibodies against immunomodulatory receptors, such as TIGIT, BTLA, and others, as listed in Chen and Flies, Nat. Rev. Immunol. 13, 227-42 (2013); and nucleic acid-encoded fusion proteins that prevent or inhibit HIV infection, delivered by themselves or via vectors, such as VEE, SFV, AAV, scAAV, or HPV, including US Those described in 2011/0305670A1 (Farzan), such as eCD4-Ig, eCD4-Ig.E, eCD4-Ig.B, CD4-Ig, E1-Ig, E2-Ig, E3-Ig, e3-CD4-Ig, e4-CD4-Ig and CCR5mim-Ig, including AAV-expressed eCD4-Ig and scAAV-expressed eCD4-Ig.

In one embodiment, the specific antibodies used include immunomodulatory monoclonal antibodies:

Inhibitory anti-PD-1 mAbs such as Nivolimumab (BMS-936558 or MDX1106), MK-34775

Inhibitory anti-PD-L1 mAbs BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, and MDX1105-01;

Inhibitory anti-CTLA-4 mAbs, such as ipilimumab and tesimumab;

Inhibitory anti-Tim3 mAbs, such as those from Tesaro, Inc.;

Inhibitory anti-LAG-3 mAbs, such as BMS-986016 and IMP321;

Inhibitory anti-KIR mAbs, such as lirelin (IPH2102/BMS-986015);

Stimulatory anti-CD27 mAbs, such as CDX-1127;

Stimulatory anti-CD40 mAbs, such as CP-870,893 and BMS-986090;

Stimulatory anti-CD47 mAbs, such as Tseng et al., Proc Natl Acad Sci U S A. Jul 2, 2013; 110(27): 11103-11108;

Stimulatory anti-CD134 (OX40) mAbs, such as MEDI-6469 or those found in WO-2009079335 and WO-2006121810;

Stimulatory anti-CD137 mAbs, such as BMS-663513; PF-05082566;

Other antibodies directed against immunomodulatory receptors, such as TIGIT, BTLA, and others, are listed in Chen and Flies, Nat. Rev. Immunol. 13, 227-42 (2013).

Small molecule immunomodulators used in combination with TLR7 agonists include indoleoxygenase inhibitors (also known as inhibitors of IDO, IDO1, indoleamine-2,3-dioxygenase, indoleamine dioxygenase-1, or indoleamine-pyrrole-2,3-dioxygenase), such as INCB024360, 1-methyl-D-tryptophan, NLG919, PI3Kδ inhibitors such as idelalisib, GS-9820, and GS-9901, and other TLR8 agonists such as VTX-1463 or VTX-2337.

A method of eliminating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

b) administering a pharmaceutically effective amount of HIV antibodies to a human.

A method of eliminating HIV infection in a human is provided, the method comprising:

a) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

b) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, to a person in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof, to a human in need thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering to a human in need thereof a pharmaceutically effective amount of the compound of Example 120, or a pharmaceutically acceptable salt thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Also provided is a method of eliminating HIV infection in a human, the method comprising:

a) administering a pharmaceutically effective amount of a combination antiretroviral therapy to a person in need thereof;

b) administering to a human in need thereof a pharmaceutically effective amount of the compound of Example 121, or a pharmaceutically acceptable salt thereof; and

c) administering a pharmaceutically effective amount of HIV antibodies to a human.

Elimination of HIV infection in a human is understood to include elimination of all active HIV virus and HIV-infected cells from the human, including cells that are latent reservoirs of infected cells.

Also provided are separate embodiments comprising the use of a pharmaceutically effective amount of a TLR7 modulating compound as described herein, or a pharmaceutically acceptable salt thereof, for:

a) treatment of HIV infection in humans;

b) treatment of HIV infection in virally suppressed persons;

c) inducing HIV gene expression in humans infected with HIV;

d) inducing HIV gene expression in a human infected with HIV, wherein expression of active HIV genes in the human is suppressed by administration of antiretroviral therapy;

e) inducing HIV gene expression in latent HIV reservoirs in HIV-infected humans;

f) enhancing HIV gene expression in HIV-infected cells of HIV-infected humans;

g) lowering the chronic set point of HIV viral load in HIV-infected humans;

h) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

i) reduce HIV viremia in HIV-infected individuals;

j) enhance immune cell activity and increase HIV gene expression in HIV-infected humans;

k) enhancing the efficacy of antiviral agents in humans infected with HIV;

l) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

m) enhancing the efficacy of HIV vaccines; and

n) Eliminate HIV infection in humans.

Also provided are separate embodiments comprising using a pharmaceutically effective amount of a TLR7 modulating compound as described herein, or a pharmaceutically acceptable salt thereof, to:

a) enhancing HIV gene expression in HIV-infected cells of HIV-infected humans;

b) lowering the chronic set point of HIV viral load in HIV-infected individuals;

c) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

d) reducing HIV viremia in HIV-infected individuals;

e) enhancing immune cell activity and increasing HIV gene expression in HIV-infected humans;

f) enhancing the efficacy of antiviral agents in humans infected with HIV;

g) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

h) enhancing the efficacy of HIV vaccines; and

i) Eliminate HIV infection in humans.

Pharmaceutical composition

Provided herein are pharmaceutical compositions useful in the above-described methods.

Provided herein are pharmaceutical compositions comprising:

a) a pharmaceutically effective amount of a combination antiretroviral therapy;

b) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

Provided herein are pharmaceutical compositions useful in the above-described methods.

Provided herein are pharmaceutical compositions comprising:

a) a pharmaceutically effective amount of a combination antiretroviral therapy;

b) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

Twenty other separate regimens are also provided, each comprising a pharmaceutical composition as defined above, wherein the compound of Formula II is a compound of Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) or Formula III(f)(2), or a pharmaceutically acceptable salt thereof.

Also provided are other separate pharmaceutical compositions as described above, wherein the compound of formula II is a compound of Examples 1 to 124.

As an example, a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of a combination antiretroviral therapy;

b) a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

As another example, a pharmaceutical composition is provided comprising:

a) a pharmaceutically effective amount of a combination antiretroviral therapy;

b) a pharmaceutically effective amount of the compound of Example 49, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

As a further example, provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of a combination antiretroviral therapy;

b) a pharmaceutically effective amount of the compound of Example 119, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

As yet another example, provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of a combination antiretroviral therapy;

b) a pharmaceutically effective amount of the compound of Example 4, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

Elvitegravir/corbic acid/emtricitabine/TDF or TAF/TLR7 modulator combination

A pharmaceutically effective amount of a TLR7 modulating compound, including those of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121, or a pharmaceutically acceptable salt thereof, can be combined with a pharmaceutically effective amount of elvitegravir, corbicistat, emtricitabine, and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective dose of a TLR7 modulating compound can be combined with a tablet containing 150 mg elvitegravir, 150 mg corbicistat, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate (Gilead Sciences, Inc.) in a treatment regimen.

Provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine;

d) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

e) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

f) pharmaceutically acceptable carriers or excipients.

Provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine;

d) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

e) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

f) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine;

d) a pharmaceutically effective amount of tenofovir alafenamide;

e) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

f) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine;

d) a pharmaceutically effective amount of tenofovir alafenamide;

e) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

f) pharmaceutically acceptable carriers or excipients.

Provided herein are a series of tablets and a list of antiviral agents and TLR7 modulating compounds in a series of doses and/or specific dose combinations. Each combination shown is an embodiment, and each embodiment provides a pharmaceutical composition comprising a pharmaceutically effective amount of a combined antiviral agent and a TLR7 modulating compound or a pharmaceutically acceptable salt thereof, alone or in combination with one or more pharmaceutically acceptable carriers or excipients.

Each of these series of doses and/or individual combinations of specific doses also provides a pharmaceutically effective amount of an antiviral agent and a TLR7 modulating compound that can be used in each of the methods described herein. In each of the individual methods described herein, each of these series of doses and/or individual combinations of specific doses described herein for administration to a person in need thereof comprises a separate embodiment for use in the method. For example, the combined use of 1A-a and the first method for treating HIV described above provides a method for treating HIV infection in a human, comprising:

a) administering to a human in need thereof 100 mg to 200 mg of elvitegravir, 100 mg to 200 mg of corbicistat, and 250 mg to 350 mg of TDF to reduce the level of HIV detected in the human's blood or plasma from a first level to a second level, the second level comprising a concentration of HIV in the human's blood or plasma that is lower than the first level of HIV concentration in the human's blood or plasma; and

b) administering to a human 0.1 mg to 15.0 mg of a compound of formula II, or a pharmaceutically acceptable salt thereof.

For each of these separate methods, there are further embodiments concerning the order in which the agents are administered.

In one embodiment of each method, a TLR7 modulating compound (TLR7 modulator) and one or more antiviral agents can be administered to a person together, for example, on the same day. A pharmaceutically effective amount of each agent can be administered according to a specific method of administration, for example, once a day, twice a day, once a week, once every two weeks, once every three weeks, once a month, once every two months, etc. In another embodiment of each method, an initial dose of a TLR7 modulating compound and one or more antiviral agents can be administered to a person together and then administered at staggered time points. For example, after the initial dose of each agent, the TLR7 compound can be administered to a person every other day or every 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14- or 15-day intervals, wherein HIV antibodies are administered once a week, twice a month, once a month, etc., as are each antiviral agent.

In another embodiment of each method, the TLR7 modulating compound can be administered as the initial administration, wherein one or more antiviral agents are administered to the human in a subsequent administration, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after administration of the TLR7 modulating compound. In another embodiment of each method, the antiviral agent can be administered as the initial administration, and the TLR7 compound is administered to the human in a subsequent administration, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days after administration of the antiviral agent. In another embodiment, in each method, administration of the TLR7 modulating compound can be added to an existing antiviral agent regimen.

TLR7 modulators can be administered to a person daily together with an antiviral agent, or in combination with daily antiviral administration, and then the TLR7 modulator can be administered according to a staggered schedule, for example, every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days. In addition, one or more antivirals can be added to the regimen after administering the TLR7 modulator to a person infected with HIV. For example, the TLR7 modulator (compound) can be administered in a single dose, in a series of doses once a day or twice a day, or in a series of doses staggered over a period of time, followed by administration of one or more antivirals to the person.

Tables 1A, 2A, 3A, 4A, 5A, 1B, 2B, 3B, 4B and 5B of pharmaceutical compositions

Provided below are examples of individual pharmaceutical compositions and combinations, each comprising a pharmaceutically acceptable carrier or excipient, and elvitegravir, corbicistat, emtricitabine, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), and an amount of a TLR7 modulating compound described herein, including compounds of Formula II, and Examples 4, 49, 119, and 120, or pharmaceutically acceptable salts thereof (collectively referred to as "TLR7 modulating compounds" in the following tables), the amounts of which are listed in each composition. The pharmaceutical compositions in each pharmaceutical composition table herein include a pharmaceutically effective amount of each agent listed in the composition and a pharmaceutically acceptable carrier or excipient. The pharmaceutical combinations in each pharmaceutical composition table herein include a pharmaceutically effective amount of each agent listed in the composition, which can be used together in the treatment methods described herein, wherein the pharmaceutical agents listed in each composition are administered to a person in need thereof as a single pharmaceutical composition, such as a tablet or oral liquid, or the agents can be administered alone or in any possible combination. For example, a pharmaceutically effective amount of a compound of Formula II and Examples 4, 49, 119 and 120 or pharmaceutically acceptable salts thereof can be administered to a person in need thereof in a first tablet, in combination with a second tablet containing the remaining agents of the combination, e.g., tablet.

Tables 1A, 2A, 3A, 4A, and 5A

The following tables, as Tables 1A, 2A, 3A, 4A and 5A, provide combinations of agents that can be used in the purposes, methods, dosage regimens and pharmaceutical compositions herein. Each of the combinations of agents listed differs only in the TLR7 modulating compound contained in the last column. As shown in Table 1A, the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. As shown in Table 2A, the TLR7 modulating compound is the compound of Example 4 or a pharmaceutically acceptable salt thereof. As shown in Table 3A, the TLR7 modulating compound is the compound of Example 49 or a pharmaceutically acceptable salt thereof. As shown in Table 4A, the TLR7 modulating compound is the compound of Example 119 or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC"). Finally, as shown in Table 5A, the TLR7 modulating compound is the compound of Example 120 or a pharmaceutically acceptable salt thereof. For example, Example 1A-a includes 100 mg to 200 mg of elvitegravir, 100 mg to 200 mg of cobicistat, 150 mg to 250 mg of emtricitabine, 250 mg to 350 mg of TDF, and 0.1 mg to 15.0 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof as a TLR7 modulating compound. Example 2A-a includes the same amounts of the first four agents as in Example 1A-a, except that it also includes 0.1 mg to 15.0 mg of the compound of Example 4 or a pharmaceutically acceptable salt thereof as "TLR7MC." This pattern applies to the five composition examples in each row of the table.

Tables 1B, 2B, 3B, 4B, and 5B

As with Tables 1A to 5A above, Tables 1B, 2B, 3B, 4B, and 5B are combined and presented in the following tables, as Tables 1A, 2A, 3A, 4A, and 5A, providing combination agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Examples of individual pharmaceutical compositions and combinations are provided, wherein each composition includes a pharmaceutically acceptable carrier or excipient and the stated amounts of elvitegravir, corbicistat, emtricitabine, tenofovir alafenamide (TAF), and a TLR7 modulating compound.

As shown in Table 1B, the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. As shown in Table 2B, the TLR7 modulating compound is the compound of Example 4 or a pharmaceutically acceptable salt thereof. As shown in Table 3B, the TLR7 modulating compound is the compound of Example 49 or a pharmaceutically acceptable salt thereof. As shown in Table 4B, the TLR7 modulating compound is the compound of Example 119 or a pharmaceutically acceptable salt thereof. Finally, as shown in Table 5B, the TLR7 modulating compound is the compound of Example 120 or a pharmaceutically acceptable salt thereof. For example, Example 1B-a includes 100 mg to 200 mg of elvitegravir, 150 mg to 250 mg of emtricitabine, 5 mg to 20 mg of TAF, and 0.1 mg to 15.0 mg of the compound of Formula II as the TLR7 modulating compound, or a pharmaceutically acceptable salt thereof. Example 2B-a includes the same amounts of the first four agents as in Example 1B-a, except that it also includes 0.1 mg to 15.0 mg of the compound of Example 4 or a pharmaceutically acceptable salt thereof. This pattern applies to the five composition examples in each row of the table.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

a. a pharmaceutically effective amount of elvitegravir;

b. a pharmaceutically effective amount of TDF;

c. a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof;

d. a pharmaceutically effective amount of cobicistat;

e. a pharmaceutically effective amount of emtricitabine; and

f. a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering the daily dosage of the pharmaceutical composition.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

a. a pharmaceutically effective amount of elvitegravir;

b. a pharmaceutically effective amount of TAF;

c. a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof;

d. a pharmaceutically effective amount of cobicistat;

e. a pharmaceutically effective amount of emtricitabine; and

f. a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering the daily dosage of the pharmaceutical composition.

Further provided is a pharmaceutical kit comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of TDF;

d) a pharmaceutically effective amount of emtricitabine; and

e) a pharmaceutically acceptable carrier or excipient; and

2) a series of second pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and

3) Instructions for administering dosages of the first and second pharmaceutical compositions; wherein the first and second pharmaceutical compositions are both administered once daily.

Another embodiment comprises the above kit, wherein the first and second pharmaceutical compositions are both administered twice daily.

Further provided is a pharmaceutical kit comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of TAF;

d) a pharmaceutically effective amount of emtricitabine; and

e) a pharmaceutically acceptable carrier or excipient; and

2) a series of second pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and

3) Instructions for administering dosages of the first and second pharmaceutical compositions; wherein the first and second pharmaceutical compositions are both administered once daily.

Another embodiment of the kit described above comprises administering both the first and second pharmaceutical compositions twice daily.

Another embodiment within each of the above kits includes kits wherein the first pharmaceutical composition is administered twice daily and the second pharmaceutical composition is administered less than daily. Further embodiments include regimens wherein the first pharmaceutical composition is administered daily and the second pharmaceutical composition is administered every other day or every 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, or 30th day.

In the first embodiment of the above-described pharmaceutical kit comprising pharmaceutically effective amounts of elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate and a compound of formula II, there is a further embodiment comprising the kit described above, wherein the first pharmaceutical composition comprises 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, and the second pharmaceutical composition comprises 0.1 to 25 mg of a compound of formula II or a pharmaceutically acceptable salt thereof.

In the embodiment of the pharmaceutical kit described above, there is a further embodiment comprising the described kit, wherein the first pharmaceutical composition comprises 150 mg of elvitegravir, 150 mg of corbicistat, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, and the second pharmaceutical composition comprises 0.1 to 15 mg of a compound of formula II or a pharmaceutically acceptable salt thereof.

In the second embodiment of the above-described pharmaceutical kit comprising pharmaceutically effective amounts of elvitegravir, costicabtastat, emtricitabine, TAF and a compound of formula II, there is a further embodiment comprising the described kit, wherein the first pharmaceutical composition comprises 150 mg of elvitegravir, 150 mg of costicabtastat, 200 mg of emtricitabine and 10 mg of TAF, and the second pharmaceutical composition comprises 0.1 to 25 mg of a compound of formula II or a pharmaceutically acceptable salt thereof.

In the embodiments of the pharmaceutical kit described above, there are further embodiments comprising the described kit, wherein the first pharmaceutical composition comprises 150 mg of elvitegravir, 150 mg of corbicistat, 200 mg of emtricitabine and 10 mg of TAF, and the second pharmaceutical composition comprises 0.1 to 15 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof.

In each of the above embodiments wherein the kit comprises a first and a second pharmaceutical composition, there are four additional embodiments wherein all other components or elements are as described above, and:

a) In a first additional embodiment, the second pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 4 or a pharmaceutically acceptable salt thereof;

b) In a second additional embodiment, the second pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 49 or a pharmaceutically acceptable salt thereof;

c) In a third additional embodiment, the second pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 119 or a pharmaceutically acceptable salt thereof;

d) In a fourth additional embodiment, the second pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 120 or a pharmaceutically acceptable salt thereof.

Emtricitabine/TDF/TLR7 combination and emtricitabine/TAF/TLR7 modulators

A pharmaceutically effective amount of a TLR7 modulating compound of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121 or a pharmaceutically acceptable salt thereof, can be combined with a pharmaceutically effective amount of emtricitabine and tenofovir disoproxil fumarate (TDF) for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective amount of a TLR7 modulating compound can be combined with a tablet available from Gilead Sciences, Inc. in a treatment regimen containing 200 mg of emtricitabine and 300 mg of TDF.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof; and

d) a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of TAF;

c) a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof; and

d) a pharmaceutically acceptable carrier or excipient.

Tables 6A, 7A, 8A, 9A, 10A, 6B, 7B, 8B, 9B and 10B of the pharmaceutical compositions

Provided are separate pharmaceutical compositions and combinations that can be used in the uses, methods, and dosing regimens herein, wherein each composition comprises a pharmaceutically acceptable carrier or excipient and the amounts of emtricitabine, TDF or TAF, and a TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC" in the table below), the amounts of which are listed for each composition in the table below.

The following tables, Tables 6A, 7A, 8A, 9A, and 10A, provide combinations of agents that can be used in the uses, methods, dosage regimens, and pharmaceutical compositions herein. Each of the listed combinations of agents differs only in the TLR7 modulating compound in the last column. As shown in Table 6A, the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. As shown in Table 7A, the TLR7 modulating compound is the compound of Example 4 or a pharmaceutically acceptable salt thereof. As shown in Table 8A, the TLR7 modulating compound is the compound of Example 49 or a pharmaceutically acceptable salt thereof. As shown in Table 9A, the TLR7 modulating compound is the compound of Example 119 or a pharmaceutically acceptable salt thereof. Finally, as shown in Table 10A, the TLR7 modulating compound is the compound of Example 120 or a pharmaceutically acceptable salt thereof. For example, Example 6A-a comprises a combination of 150 mg to 250 mg of emtricitabine, 250 mg to 350 mg of TDF, and 0.1 mg to 15.0 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof as the TLR7 modulating compound. Example 7A-a contains the same amounts of the first two agents (emtricitabine and TDF) as Example 6A-a, except that it also contains 0.1 mg to 15.0 mg of the compound of Example 4 or a pharmaceutically acceptable salt thereof. This rule applies to the five composition examples in each row of the table.

Tables 6A, 7A, 8A, 9A, and 10A

Tables 6B, 7B, 8B, 9B, and 10B

The following tables, as Tables 6B, 7B, 8B, 9B, and 10B, provide combinations of agents that can be used in the uses, methods, dosage regimens, and pharmaceutical compositions herein. Each of the listed combinations of agents differs only in the TLR7 modulating compound in the last column. As shown in Table 6B, the TLR7 modulating compound is a compound of Formula II or a pharmaceutically acceptable salt thereof. As shown in Table 7B, the TLR7 modulating compound is the compound of Example 4 or a pharmaceutically acceptable salt thereof. As shown in Table 8B, the TLR7 modulating compound is the compound of Example 49 or a pharmaceutically acceptable salt thereof. As shown in Table 9B, the TLR7 modulating compound is the compound of Example 119 or a pharmaceutically acceptable salt thereof. Finally, as shown in Table 10B, the TLR7 modulating compound is the compound of Example 120 or a pharmaceutically acceptable salt thereof. For example, Example 6B-a comprises a combination of 150 mg to 250 mg of emtricitabine, 15 mg to 35 mg of TAF, and 0.1 mg to 15.0 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof as a TLR7 modulating compound. Example 7B-a contains the same amounts of the first two reagents as Example 6B-a, except that it also contains 0.1 mg to 15.0 mg of the compound of Example 4 or a pharmaceutically acceptable salt thereof. This rule applies to the five composition examples in each row of the table.

Emtricitabine/TDF/TLR7 modulator/raltegravir combination

Pharmaceutical combinations and compositions are provided, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of an integrase strand transfer inhibitor; and

e) pharmaceutically acceptable carriers or excipients.

Pharmaceutical combinations and compositions are provided, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of an integrase strand transfer inhibitor; and

e) pharmaceutically acceptable carriers or excipients.

Pharmaceutical combinations and compositions are provided, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir alafenamide;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of an integrase strand transfer inhibitor; and

e) pharmaceutically acceptable carriers or excipients.

Pharmaceutical combinations and compositions are provided, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir alafenamide;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of an integrase strand transfer inhibitor; and

e) pharmaceutically acceptable carriers or excipients.

There are also pharmaceutical combinations and compositions, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of raltegravir; and

e) pharmaceutically acceptable carriers or excipients.

There are also pharmaceutical combinations and compositions, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of raltegravir; and

e) pharmaceutically acceptable carriers or excipients.

There are also pharmaceutical combinations and compositions, each comprising:

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of tenofovir alafenamide;

d) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

e) a pharmaceutically effective amount of raltegravir; and

f) a pharmaceutically acceptable carrier or excipient.

There are also pharmaceutical combinations and compositions, each comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir alafenamide;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of raltegravir; and

e) pharmaceutically acceptable carriers or excipients.

Tables 11A to 15B of pharmaceutical compositions

Consistent with the patterns in the above table, separate pharmaceutical compositions and combinations are provided, comprising a pharmaceutically acceptable carrier or excipient and the amounts of emtricitabine, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), a TLR7 modulating compound (TLR7MC) or a pharmaceutically acceptable salt thereof (collectively referred to as "Formula II" in the following table), and raltegravir, the amounts of which are listed for each composition.

The following tables, Tables 11A, 12A, 13A, 14A, and 15A, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each listed combination of agents contains the stated amounts of emtricitabine, TDF, and raltegravir, differing only in the TLR7 modulating compound contained. In the separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) Formula II in Table 11A, b) the compound of Example 4 in Table 12A, c) the compound of Example 49 in Table 13A, d) the compound of Example 119 in Table 14A, and e) the compound of Example 120 in Table 15A.

Tables 11A, 12A, 13A, 14A, and 15A

Tables 11B, 12B, 13B, 14B, and 15B

The following tables, as Tables 11B, 12B, 13B, 14B and 15B, provide combinations of agents that can be used for the purposes, methods, dosing regimens and pharmaceutical compositions herein. Each of the listed combinations includes the amounts of emtricitabine, TAF and raltegravir, differing only in the TLR7 modulating compound (TLR7MC) included. In each table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) Formula II in Table 11B, b) Example 4 compound in Table 12B, c) Example 49 compound in Table 13B, d) Example 119 compound in Table 14B, and e) Example 120 compound in Table 15B.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

a. a pharmaceutically effective amount of emtricitabine;

b. a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c. a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d. a pharmaceutically effective amount of raltegravir; and

e. a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering the daily dosage of the pharmaceutical composition.

Also provided are separate pharmaceutical kits just described, wherein the pharmaceutical composition comprises one of the above-described pharmaceutical compositions having raltegravir as a component or element in each separate pharmaceutical kit.

A pharmaceutical kit is further provided, comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically acceptable carrier or excipient; and

2) a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of raltegravir and a pharmaceutically acceptable carrier or excipient; and

3) Instructions for administering the dosages of the first and second pharmaceutical compositions; wherein the first and second pharmaceutical compositions are both administered once daily.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically acceptable carrier or excipient; and

2) a series of daily doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of raltegravir and a pharmaceutically acceptable carrier or excipient; and

3) Instructions for administering daily doses of the first and second pharmaceutical compositions; wherein the first and second pharmaceutical compositions are both administered twice daily.

Also provided is a pharmaceutical kit comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically acceptable carrier or excipient; and

2) a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of raltegravir and a pharmaceutically acceptable carrier or excipient; and

3) instructions for administering said dosages of the first and second pharmaceutical compositions; wherein said first pharmaceutical composition is administered once daily and said second pharmaceutical composition is administered twice daily.

Also provided is a pharmaceutical kit comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically acceptable carrier or excipient; and

2) a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of raltegravir and a pharmaceutically acceptable carrier or excipient; and

3) a series of doses of a third pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof; and

4) instructions for administering said dosages of the first and second pharmaceutical compositions; wherein said first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are each administered once daily.

In the embodiments of the above pharmaceutical kits, there are further embodiments comprising a kit as described, wherein the second pharmaceutical composition comprises 10 mg to 500 mg of raltegravir. In the embodiments of the above pharmaceutical kits, there are further embodiments comprising a kit as described, wherein the second pharmaceutical composition comprises 300 mg to 500 mg of raltegravir. In the embodiments of the above pharmaceutical kits, there are further embodiments comprising a kit as described, wherein the second pharmaceutical composition comprises 350 mg to 450 mg of raltegravir. In the embodiments of the above pharmaceutical kits, there are further embodiments comprising a kit as described, wherein the second pharmaceutical composition comprises 400 mg of raltegravir.

A pharmaceutical kit is further provided, comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically acceptable carrier or excipient; and

2) a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of raltegravir and a pharmaceutically acceptable carrier or excipient; and

3) a series of doses of a third pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof; and

4) instructions for administering said dosages of the first and second pharmaceutical compositions; wherein said first and third pharmaceutical compositions are each administered once daily and said second pharmaceutical composition is administered twice daily.

In the embodiment of the pharmaceutical kit described above, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 10 mg to 500 mg raltegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof.

In the embodiment of the pharmaceutical kit described above, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 15 mg to 35 mg raltegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a compound of Formula II, or a pharmaceutically acceptable salt thereof.

In the embodiment of the pharmaceutical kit described above, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 90 mg to 110 mg raltegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a compound of Formula II, or a pharmaceutically acceptable salt thereof.

In the embodiment of the pharmaceutical kit described above, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 375 mg to 425 mg raltegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a compound of Formula II, or a pharmaceutically acceptable salt thereof.

Within each of the above embodiments wherein the kit comprises a first, second, and third pharmaceutical composition, there are four additional embodiments wherein all other combinations or elements are as described above, and:

1) In a first additional embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 4, or a pharmaceutically acceptable salt thereof;

2) In a second additional embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 49, or a pharmaceutically acceptable salt thereof;

3) In a third additional embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 119, or a pharmaceutically acceptable salt thereof;

4) In a fourth additional embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 120, or a pharmaceutically acceptable salt thereof.

Emtricitabine/TDF/TLR7 modulator/dolutegravir combination

A pharmaceutically effective amount of a TLR7 modulating compound, including those of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121 or a pharmaceutically acceptable salt thereof, can be combined with a pharmaceutically effective amount of emtricitabine, TDF or TAF, and dolutegravir for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective dose of a TLR7 modulating compound can be combined with a tablet (200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate) and a tablet (50 mg dolutegravir) in one treatment regimen, the tablet being available from Gilead Sciences and the tablet being available from GlaxoSmithKline.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of dolutegravir; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir alafenamide;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of dolutegravir; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of dolutegravir; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

f) a pharmaceutically effective amount of emtricitabine;

g) a pharmaceutically effective amount of tenofovir alafenamide;

h) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof;

i) a pharmaceutically effective amount of dolutegravir; and

j) a pharmaceutically acceptable carrier or excipient.

Tables 16A, 17A, 18A, 19A, 20A, 16B, 17B, 18B, 19B and 20B

Individual pharmaceutical compositions and combinations are provided, wherein each composition comprises a pharmaceutically acceptable carrier or excipient and the amounts of emtricitabine, TDF or TAF, dolutegravir, and a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, listed for each composition in the table below.

Following the pattern described above, the following tables, Tables 16A, 17A, 18A, 19A, and 20A, provide combinations of agents useful in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each combination of agents listed includes amounts of emtricitabine, TDF, and dolutegravir, differing only in the inclusion of a TLR7 modulating compound. In each separate table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 16A, b) the compound of Example 4 in Table 17A, c) the compound of Example 49 in Table 18A, d) the compound of Example 119 in Table 19A, and e) the compound of Example 120 in Table 20A.

Tables 16A, 17A, 18A, 19A, and 20A

Tables 16B, 17B, 18B, 19B and 20B

As with the above tables, the following tables, as Tables 16B, 17B, 18B, 19B, and 20B, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each combination of listed agents includes the amounts of emtricitabine, TAF, and dolutegravir, differing only in the TLR7 modulating compound contained. In each separate table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC") includes: a) a compound of Formula II in Table 16B, b) a compound of Example 4 in Table 17B, c) a compound of Example 49 in Table 18B, d) a compound of Example 119 in Table 19B, and e) a compound of Example 120 in Table 20B.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically effective amount of dolutegravir; and

e) a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering a daily dose of the pharmaceutical composition.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

f) a pharmaceutically effective amount of emtricitabine;

g) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

h) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

i) a pharmaceutically effective amount of dolutegravir; and

j) a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering a daily dose of the pharmaceutical composition.

Also provided are separate pharmaceutical kits as described above, wherein the pharmaceutical composition comprises one of the above pharmaceutical compositions having dolutegravir as a component or element in each separate pharmaceutical kit.

A pharmaceutical kit is further provided, comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

2) a pharmaceutically acceptable carrier or excipient; and

3) a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of dolutegravir and a pharmaceutically acceptable carrier or excipient; and

4) Instructions for administering the dosages of the first and second pharmaceutical compositions; wherein the first and second pharmaceutical compositions are both administered once daily.

A pharmaceutical kit is further provided, comprising:

A series of daily doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically acceptable carrier or excipient; and

a series of daily doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of dolutegravir and a pharmaceutically acceptable carrier or excipient; and

Instructions for administering daily doses of a first and a second pharmaceutical composition; wherein said first and second pharmaceutical compositions are both administered twice daily.

A pharmaceutical kit is further provided, comprising:

A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof;

d) a pharmaceutically acceptable carrier or excipient; and

a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of dolutegravir and a pharmaceutically acceptable carrier or excipient; and

Instructions for administering said dosages of the first and second pharmaceutical compositions; wherein said first pharmaceutical composition is administered once daily and said second pharmaceutical composition is administered twice daily.

A pharmaceutical kit is further provided, comprising:

1) A series of doses of a first pharmaceutical composition comprising:

a) a pharmaceutically effective amount of emtricitabine;

b) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

c) a pharmaceutically acceptable carrier or excipient; and

2) a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of dolutegravir and a pharmaceutically acceptable carrier or excipient; and

3) a series of doses of a third pharmaceutical composition comprising a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

4) instructions for administering said dosages of the first and second pharmaceutical compositions; wherein said first pharmaceutical composition, second pharmaceutical composition, and third pharmaceutical composition are administered once daily.

In the embodiment of the pharmaceutical kit described immediately above, there is another embodiment comprising the kit as described, wherein the second pharmaceutical composition comprises 30 mg to 70 mg of dolutegravir. In the embodiment of the pharmaceutical kit described immediately above, there is another embodiment comprising the kit as described, wherein the second pharmaceutical composition comprises 40 mg to 60 mg of dolutegravir. In the embodiment of the pharmaceutical kit described immediately above, there is another embodiment comprising the kit as described, wherein the second pharmaceutical composition comprises 45 mg to 55 mg of dolutegravir. In the embodiment of the pharmaceutical kit described immediately above, there is another embodiment comprising the kit as described, wherein the second pharmaceutical composition comprises 50 mg of dolutegravir.

A pharmaceutical kit is further provided, comprising:

A series of doses of a first pharmaceutical composition comprising:

1) a pharmaceutically effective amount of emtricitabine;

2) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

3) a pharmaceutically acceptable carrier or excipient; and

a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of dolutegravir and a pharmaceutically acceptable carrier or excipient; and

a series of doses of a third pharmaceutical composition comprising a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

Instructions for administering said dosages of the first and second pharmaceutical compositions; wherein said first pharmaceutical composition and said third pharmaceutical composition are administered once daily and said second pharmaceutical composition is administered twice daily.

In the above-mentioned pharmaceutical kit embodiment, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 30 mg to 70 mg of dolutegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

In the above-mentioned pharmaceutical kit embodiment, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 40 mg to 60 mg of dolutegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

In the above-described pharmaceutical kit embodiments, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 45 mg to 55 mg of dolutegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

In the above-described pharmaceutical kit embodiments, there is a further embodiment comprising a kit as described, wherein the first pharmaceutical composition comprises 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate, the second pharmaceutical composition comprises 50 mg dolutegravir, and the third pharmaceutical composition comprises 0.1 to 15 mg of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof.

It is to be understood that the descriptions provided herein of kits containing a TLR7 modulating compound each include separate individual kits wherein the TLR7 modulating compound is a compound of each of the Formulas and Examples disclosed herein.

For example, in each of the embodiments described above wherein the kit comprises a first, second, and third pharmaceutical composition, there are five additional embodiments wherein all other components or elements are as described above, and:

a) In a first other embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 4 or a pharmaceutically acceptable salt thereof;

b) In a second other embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 49, or a pharmaceutically acceptable salt thereof;

c) In a third additional embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 119, or a pharmaceutically acceptable salt thereof;

d) In a fourth other embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 120, or a pharmaceutically acceptable salt thereof; and

e) In a fifth further embodiment, the third pharmaceutical composition comprises 0.1 to 15 mg of the compound of Example 121, or a pharmaceutically acceptable salt thereof.

Compositions comprising TDF and a TLR7 modulator

A pharmaceutically effective amount of a TLR7 modulating compound of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121 or a pharmaceutically acceptable salt thereof can be combined with a pharmaceutically effective amount of tenofovir disoproxil fumarate (TDF) for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective dose of a TLR7 modulating compound can be combined with TDF tablets in a treatment regimen, which is available from Gilead Sciences, Inc. in doses of 150 mg, 200 mg, 250 mg, and 300 mg.

A pharmaceutical composition is provided, comprising:

a) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

b) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition is provided, comprising:

a) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

b) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition is provided, comprising:

a) a pharmaceutically effective amount of TAF;

b) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition is provided, comprising:

a) a pharmaceutically effective amount of TAF;

b) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

Specific pharmaceutical compositions and combinations comprise a pharmaceutically acceptable carrier or excipient and a separate amount of TDF or TAF, and a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC"). According to the rules of the above table, the following tables are used as Tables 21A, 22A, 23A, 24A and 25A, providing combinations of agents that can be used for the purposes, methods, dosing regimens and pharmaceutical compositions herein. Each of the listed combinations of agents includes a certain amount of TDF and differs only in the TLR7 modulating compound included. In a separate table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 21A, b) a compound of Example 4 in Table 22A, c) a compound of Example 49 in Table 23A, d) a compound of Example 119 in Table 24A, and e) a compound of Example 120 in Table 25A.

Tables 21A, 22A, 23A, 24A, and 25A

Tables 21B, 22B, 23B, 24B, and 25B

Based on the pattern of the above table, the following tables are used as Tables 21B, 22B, 23B, 24B and 25B to provide combinations of agents that can be used in the uses, methods, dosage regimens and pharmaceutical compositions herein. Each of the listed combinations of agents includes a certain amount of TAF and differs only in the TLR7 modulating compound included. In separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 21B, b) a compound of Example 4 in Table 22B, c) a compound of Example 49 in Table 23B, d) a compound of Example 119 in Table 24B, and e) a compound of Example 120 in Table 25B.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

a) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

b) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering the daily dosage of the pharmaceutical composition.

Also provided is a pharmaceutical kit comprising:

a) a series of daily doses of a first pharmaceutical composition comprising a pharmaceutically effective amount of tenofovir disoproxil fumarate administered daily;

b) a series of doses of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof, which is administered less than daily; and

c) Instructions for administering a daily dose of tenofovir disoproxil fumarate and administering a less than daily dose of a TLR7 modulating compound.

Also provided is a pharmaceutical kit comprising:

1) A series of daily doses of a single pharmaceutical composition comprising:

a. a pharmaceutically effective amount of tenofovir disoproxil fumarate;

b. a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

c. a pharmaceutically acceptable carrier or excipient; and

2) Instructions for administering a daily dose of the pharmaceutical composition.

A series of separate pharmaceutical kits as just described are provided, wherein each separate kit is provided, which contains a pharmaceutically acceptable carrier or excipient set forth in each separate composition example shown in Pharmaceutical Composition Table 21, Pharmaceutical Composition Table 22, Pharmaceutical Composition Table 23, Pharmaceutical Composition Table 24 and Pharmaceutical Composition Table 25, a pharmaceutically effective amount of tenofovir disoproxil fumarate and a compound of Formula II, or a pharmaceutically acceptable salt thereof.

Also provided is a pharmaceutical kit comprising a series of doses of a first pharmaceutical composition comprising a pharmaceutically effective amount of tenofovir disoproxil fumarate and a pharmaceutically acceptable carrier or excipient; a series of doses of a second pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, and instructions for administering the doses of the first and second pharmaceutical compositions; wherein the first and second pharmaceutical compositions are both administered once daily. Also provided is a pharmaceutical kit comprising a series of doses of the first pharmaceutical composition, the second pharmaceutical composition, and the instructions just described, wherein the first and second pharmaceutical compositions are both administered twice daily. Also provided is a pharmaceutical kit comprising a series of doses of the first pharmaceutical composition, the second pharmaceutical composition, and the instructions just described, wherein the first pharmaceutical composition is administered once daily and the second pharmaceutical composition is administered twice daily.

Combination of rilpivirine/emtricitabine/TDF/TLR7 modulator

A pharmaceutically effective amount of a TLR7 modulating compound of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121 or a pharmaceutically acceptable salt thereof can be combined with a pharmaceutically effective amount of emtricitabine/rilpivirine and tenofovir disoproxil fumarate (TDF) for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective amount of a TLR7 modulating compound can be combined with a tablet available from Gilead Sciences, Inc. in one treatment regimen, comprising 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of TDF.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of rilpivirine, or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

d) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of rilpivirine HCl;

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

d) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

e) pharmaceutically acceptable carriers or excipients.

Also provided are a variety of separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of rilpivirine; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound selected from the group consisting of Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), and Formula III(f)(2); or a pharmaceutically acceptable salt thereof. Each separate pharmaceutical composition comprises a formulation, for example, one embodiment comprises: 1) a pharmaceutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof, another embodiment comprises: 1) a pharmaceutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound of formula III(a) or a pharmaceutically acceptable salt thereof, and so on.

Also provided are another set of separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound of Examples 1 to 121. The first of the separate compositions comprises: 1) a pharmaceutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of the compound of Example 1 or a pharmaceutically acceptable salt thereof, and another separate composition comprises: 1) a pharmaceutically effective amount of rilpivirine or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of the compound of Example 2 or a pharmaceutically acceptable salt thereof, and so on.

Tables 26A to 30B

Also provided are specific pharmaceutical compositions and combinations comprising a pharmaceutically acceptable carrier or excipient and separate amounts of: a) rilpivirine or a pharmaceutically acceptable salt thereof; b) emtricitabine; c) TDF or TAF, and b) a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC").

Consistent with the pattern in the table above, separate pharmaceutical compositions and combinations are provided that contain a pharmaceutically acceptable carrier or excipient and the amounts of rilpivirine or rilpivirine HCl, emtricitabine, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF), a TLR7 modulating compound (TLR7MC), or a pharmaceutically acceptable salt thereof, and raltegravir, the amounts of which are listed below for each composition.

The following tables, as Tables 26A, 27A, 28A, 29A, and 30A, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. In separate tables, TLR7 modulating compounds or pharmaceutically acceptable salts thereof include: a) a compound of Formula II of Table 26A, b) a compound of Example 4 of Table 27, c) a compound of Example 49 of Table 28A, d) a compound of Example 119 of Table 29A, and e) a compound of Example 120 of Table 30A.

Tables 26A, 27A, 28A, 29A, and 30A

The following tables, as Tables 26B, 27B, 28B, 29B, and 30B, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. In separate tables, TLR7 modulating compounds or pharmaceutically acceptable salts thereof include: a) a compound of Formula II of Table 26B, b) a compound of Example 4 of Table 27B, c) a compound of Example 49 of Table 28B, d) a compound of Example 119 of Table 29B, and e) a compound of Example 120 of Table 30B.

Tables 26B, 27B, 28B, 29B, and 30B

Tables 26C, 27C, 28C, 29C and 30C

Also provided are specific pharmaceutical compositions and combinations comprising a pharmaceutically acceptable carrier or excipient and a separate amount of a) rilpivirine HCl; b) emtricitabine; c) TDF and b) a pharmaceutically effective amount of a TLR7 modulating compound (TLR7MC) or a pharmaceutically acceptable salt thereof. The following tables, as Tables 26C, 27C, 28C, 29C, and 30C, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. In a separate table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof comprises: a) a compound of Formula II in Table 26C, b) Example 4 in Table 27C, c) a compound of Example 49 in Table 28C, d) a compound of Example 119 in Table 29C, and e) a compound of Example 120 in Table 30C.

Tables 26D, 27D, 28D, 29D and 30D

Also provided are specific pharmaceutical compositions and combinations comprising: a pharmaceutically acceptable carrier or excipient, and a single amount of: a) rilpivirine HCl; b) emtricitabine; c) TAF, and b) a pharmaceutically effective amount of a TLR7 modulating compound (TLR7MC) or a pharmaceutically acceptable salt thereof. The following tables, as Tables 26D, 27D, 28D, 29D, and 30D, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. In separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof comprises: a) a compound of Formula II in Table 26D, b) a compound of Example 4 in Table 27D, c) a compound of Example 49 in Table 28D, d) a compound of Example 119 in Table 29, and e) a compound of Example 120 in Table 30D.

Combination of efavirenz/emtricitabine/TDF/TLR7 modulator

A pharmaceutically effective amount of a TLR7 modulating compound, including those of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121 or a pharmaceutically acceptable salt thereof, can be combined with a pharmaceutically effective amount of efavirenz, emtricitabine, and tenofovir disoproxil fumarate (TDF) for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective dose of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, can be combined in a treatment regimen with a tablet (600 mg efavirenz, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate), which is available from Gilead Sciences, Inc.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of efavirenz;

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

d) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of efavirenz;

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of tenofovir disoproxil fumarate;

d) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of efavirenz;

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of TAF;

d) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

e) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of efavirenz;

b) a pharmaceutically effective amount of emtricitabine;

c) a pharmaceutically effective amount of TAF;

d) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

e) pharmaceutically acceptable carriers or excipients.

Also provided are 19 separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of efavirenz; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound selected from the group consisting of Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1) and Formula III(f)(2); or a pharmaceutically acceptable salt thereof. Each separate pharmaceutical composition comprises a formulation, for example, one embodiment comprises: 1) a pharmaceutically effective amount of efavirenz; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof, another embodiment comprises: 1) a pharmaceutically effective amount of efavirenz; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound of formula III(a) or a pharmaceutically acceptable salt thereof, and so on.

Also provided are separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of efavirenz; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of a compound selected from Examples 1 to 124. The first of the separate compositions comprises: 1) a pharmaceutically effective amount of efavirenz; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of the compound of Example 1, or a pharmaceutically acceptable salt thereof, and another separate composition comprises: 1) a pharmaceutically effective amount of efavirenz; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of tenofovir disoproxil fumarate; 4) a pharmaceutically acceptable carrier or excipient; and 5) a pharmaceutically effective amount of the compound of Example 2, or a pharmaceutically acceptable salt thereof, and so on.

Tables 31A to 35A

Also provided are specific pharmaceutical compositions and combinations comprising a pharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of: a) efavirenz; b) emtricitabine; c) TDF or TAF, and b) a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof (TLR7MC).

Following the pattern in the tables above, the following tables, Tables 31A, 32A, 33A, 34A, and 35A, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each combination of agents listed contains the stated amounts of efavirenz, emtricitabine, and TDF, differing only in the TLR7 modulating compound contained. In separate tablets, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof comprises: a) a compound of Formula II in Table 31A, b) the compound of Example 4 in Table 32A, c) the compound of Example 49 in Table 33A, d) the compound of Example 119 in Table 34A, and e) the compound of Example 120 in Table 35A.

Tables 31A, 32A, 33A, 34A, and 35A

As with the rules in the above table, the following tables, as Tables 31B, 32B, 33B, 34B and 35B, provide uses, methods, dosing regimens and pharmaceutical compositions that can be used in the pharmaceutical compositions herein. Each of the listed combinations of agents contains the stated amounts of efavirenz, emtricitabine and TAF, differing only in the TLR7 modulating compound contained. In a separate table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as TLR7MC) includes: a) a compound of Formula II of Table 31B, b) a compound of Example 4 of Table 32B, c) a compound of Example 49 of Table 33B, d) a compound of Example 119 of Table 34B, and e) a compound of Example 120 of Table 35B.

Tables 31B, 32B, 33B, 34B, and 35B

Combination of elvitegravir/corbic acid/emtricitabine/TAF/TLR7 modulator

A pharmaceutically effective amount of a TLR7 modulating compound, including those of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 4, 49, 119, 120, and 121, or a pharmaceutically acceptable salt thereof, can be combined with a pharmaceutically effective amount of elvitegravir, corbicistat, emtricitabine, and TAF for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective dose of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof, can be combined with 150 mg elvitegravir, 150 mg corbicistat, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate (e.g., tablets, available from Gilead Sciences, Inc.) in a treatment regimen.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine;

d) a pharmaceutically effective amount of tenofovir alafenamide (TAF) or a pharmaceutically acceptable salt thereof;

e) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof; and

f) pharmaceutically acceptable carriers or excipients.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of elvitegravir;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of emtricitabine;

d) a pharmaceutically effective amount of tenofovir alafenamide (TAF) or a pharmaceutically acceptable salt thereof;

e) a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof; and

f) pharmaceutically acceptable carriers or excipients.

Also provided are 19 separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of elvitegravir; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of cobicistat; 4) a pharmaceutically effective amount of tenofovir alafenamide; 5) a pharmaceutically acceptable carrier or excipient; and 6) a pharmaceutically effective amount of a compound selected from the group consisting of Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), and Formula III(f)(2); or a pharmaceutically acceptable salt thereof. Each separate pharmaceutical composition comprises a formulation, for example, one embodiment comprises: 1) a pharmaceutically effective amount of elvitegravir; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of cobicistat; 4) a pharmaceutically effective amount of tenofovir alafenamide; 5) a pharmaceutically acceptable carrier or excipient; and 6) a pharmaceutically effective amount of a compound of formula III or a pharmaceutically acceptable salt thereof, another embodiment comprises: 1) a pharmaceutically effective amount of elvitegravir; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of cobicistat; 4) a pharmaceutically effective amount of tenofovir alafenamide; 5) a pharmaceutically acceptable carrier or excipient; and 6) a pharmaceutically effective amount of a compound of formula III(a) or a pharmaceutically acceptable salt thereof, and so on.

Also provided is another set of separate pharmaceutical compositions, each separate composition comprising: 1) a pharmaceutically effective amount of elvitegravir; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of cobicistat; 4) a pharmaceutically effective amount of tenofovir alafenamide; 5) a pharmaceutically acceptable carrier or excipient; and 6) a pharmaceutically effective amount of a compound selected from Examples 1 to 124. The first of the group of separate compositions comprises: 1) a pharmaceutically effective amount of elvitegravir; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of cobicistat; 4) a pharmaceutically effective amount of tenofovir alafenamide; 5) a pharmaceutically acceptable carrier or excipient; and 6) a pharmaceutically effective amount of the compound of Example 1 or a pharmaceutically acceptable salt thereof, and the next separate composition comprises: 1) a pharmaceutically effective amount of elvitegravir; 2) a pharmaceutically effective amount of emtricitabine; 3) a pharmaceutically effective amount of cobicistat; 4) a pharmaceutically effective amount of tenofovir alafenamide; 5) a pharmaceutically acceptable carrier or excipient; and 6) a pharmaceutically effective amount of the compound of Example 2 or a pharmaceutically acceptable salt thereof, and so on.

Tables 36A, 37A, 38A, 39A, and 40A

Also provided are specific pharmaceutical compositions and combinations comprising a pharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a) elvitegravir; b) emtricitabine; c) corbicistat; d) tenofovir alafenamide (TAF) and e) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC").

Similar to the patterns shown in the above tables, the following tables, Tables 36A, 37A, 38A, 39A, and 40A, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each of the listed combinations contains the stated amounts of elvitegravir, emtricitabine, corbicistat, and TAF, differing only in the TLR7 modulating compound contained. In separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 36A, b) a compound of Example 4 in Table 37A, c) a compound of Example 49 in Table 38A, d) a compound of Example 119 in Table 39A, and e) a compound of Example 120 in Table 40A.

Also provided are pharmaceutical combinations and compositions comprising a pharmaceutically effective amount of a TLR7 modulating compound, a pharmaceutically effective amount of TAF, a pharmaceutically effective amount of emtricitabine, and a pharmaceutically effective amount of one or more antiviral agents selected from the group consisting of:

Non-nucleoside reverse transcriptase inhibitors, such as etravirine, delavirdine, efavirenz, and nevirapine, and pharmaceutically acceptable salts thereof;

Nucleoside reverse transcriptase inhibitors, such as lamivudine, zidovudine, emtricitabine, abacavir, zalcitabine, TDF and stavudine, and pharmaceutically acceptable salts thereof;

protease inhibitors, such as amprenavir, tipranavir, indinavir, saquinavir, lopinavir, ritonavir, fosamprenavir, darunivir, atazanavir, and nelfinavir, and pharmaceutically acceptable salts thereof;

CCR5 antagonists, such as maraviroc and enfuvirtide, and pharmaceutically acceptable salts thereof;

HIV integrase strand transfer inhibitors, such as raltegravir and pharmaceutically acceptable salts thereof;

Non-catalytic site integrase inhibitors, such as BI224436; and

Capsid protein inhibitors.

In each pharmaceutical composition listed herein that contains the component "tenofovir alafenamide or a pharmaceutically acceptable salt thereof" or "TAF", there is another embodiment in which the component contains tenofovir alafenamide fumarate in the amount indicated as "tenofovir alafenamide or a pharmaceutically acceptable salt thereof", and all other components or elements are as listed for the specific composition. In each pharmaceutical composition listed herein that contains the component "tenofovir alafenamide or a pharmaceutically acceptable salt thereof", there is another embodiment in which the component contains tenofovir alafenamide hemifumarate in the amount indicated as "tenofovir alafenamide or a pharmaceutically acceptable salt thereof", and all other components or elements are as listed for the specific composition.

Tables 36B, 37B, 38B, 39B, and 40B

Also provided are specific pharmaceutical compositions and combinations comprising a pharmaceutically acceptable carrier or excipient and a pharmaceutically effective amount of a) elvitegravir; b) emtricitabine; c) corbicistat; d) TDF and e) a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC").

Similar to the patterns shown in the above tables, the following tables, Tables 36B, 37B, 38B, 39B, and 40B, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each of the listed combinations contains the stated amounts of elvitegravir, emtricitabine, TDF, and corbicistat, differing only in the TLR7 modulating compound contained. In separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 36B, b) a compound of Example 4 in Table 37B, c) a compound of Example 49 in Table 38B, d) a compound of Example 119 in Table 39B, and e) a compound of Example 120 in Table 40B.

Also provided are pharmaceutical combinations and compositions comprising a pharmaceutically effective amount of a TLR7 modulating compound, a pharmaceutically effective amount of TDF, a pharmaceutically effective amount of emtricitabine, and a pharmaceutically effective amount of one or more antiviral agents selected from the group consisting of:

Non-nucleoside reverse transcriptase inhibitors, such as etravirine, delavirdine, efavirenz, and nevirapine, and pharmaceutically acceptable salts thereof;

Nucleoside reverse transcriptase inhibitors, such as lamivudine, zidovudine, emtricitabine, abacavir, zalcitabine, TAF and stavudine, and pharmaceutically acceptable salts thereof;

protease inhibitors, such as amprenavir, tipranavir, indinavir, saquinavir, lopinavir, ritonavir, fosamprenavir, darunivir, atazanavir, and nelfinavir, and pharmaceutically acceptable salts thereof;

CCR5 antagonists, such as maraviroc and enfuvirtide, and pharmaceutically acceptable salts thereof;

HIV integrase strand transfer inhibitors, such as raltegravir and pharmaceutically acceptable salts thereof;

Non-catalytic site integrase inhibitors, such as BI224436; and

Capsid protein inhibitors.

Combination of atazanavir sulfate, corbicistat, and TLR7 modulators

A pharmaceutically effective amount of a TLR7 modulating compound of Formula II or a pharmaceutically acceptable salt thereof, and the compounds of Examples 119, 120, and 121 or a pharmaceutically acceptable salt thereof can be combined with a pharmaceutically effective amount of atazanavir sulfate and corbicistat for use in the treatment methods discussed herein. For example, as a separate dosage form, a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof can be combined in a treatment regimen with a pharmaceutically effective amount of corbicistat and 150 mg, 200 mg, or 300 mg of atazanavir sulfate capsules, which are available from Bristol-Meyers Squibb Co. As another example, a dosage unit (e.g., a tablet or capsule) comprising a pharmaceutically effective amount of corbicistat and a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof can be administered to a person in need thereof in coordination with the administration of a pharmaceutically effective amount of atazanavir or atazanavir sulfate (e.g., 150 mg, 200 mg, or 300 mg capsules).

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of a compound that modulates TLR7 activity; and

d) a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of atazanavir sulfate;

b) a pharmaceutically effective amount of cobicistat;

c) a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof; and

d) a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of cobicistat;

b) a pharmaceutically effective amount of a compound that modulates TLR7 activity; and

c) a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of cobicistat;

b) a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of ritonavir;

b) a pharmaceutically effective amount of a compound that modulates TLR7 activity; and

c) a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of ritonavir;

b) a pharmaceutically effective amount of a compound of formula II or a pharmaceutically acceptable salt thereof; and

c) a pharmaceutically acceptable carrier or excipient.

Also provided are 19 separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of cobicistat; 3) a pharmaceutically acceptable carrier or excipient; and 4) a pharmaceutically effective amount of a compound selected from one of Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), and Formula III(f)(2); or a pharmaceutically acceptable salt thereof. Each separate pharmaceutical composition comprises a formulation, for example, one embodiment comprises: 1) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of cobicistat; 3) a pharmaceutically acceptable carrier or excipient; and 4) a pharmaceutically effective amount of a compound selected from one of Formula III or a pharmaceutically acceptable salt thereof; another embodiment comprises: 1) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of cobicistat; 3) a pharmaceutically acceptable carrier or excipient; and 4) a pharmaceutically effective amount of a compound selected from one of Formula III(a) or a pharmaceutically acceptable salt thereof, and so on.

Also provided is another set of separate pharmaceutical compositions, each comprising: 1) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of cobicistat; 3) a pharmaceutically acceptable carrier or excipient; and 4) a pharmaceutically effective amount of a compound selected from Examples 1 to 124 or a pharmaceutically acceptable salt thereof. The first of the separate compositions in the set comprises: 1) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of cobicistat; 3) a pharmaceutically acceptable carrier or excipient; and 4) a pharmaceutically effective amount of the compound of Example 1 or a pharmaceutically acceptable salt thereof, the next of the separate compositions comprises: 1) a pharmaceutically effective amount of atazanavir or a pharmaceutically acceptable salt thereof; 2) a pharmaceutically effective amount of cobicistat; 3) a pharmaceutically acceptable carrier or excipient; and 4) a pharmaceutically effective amount of the compound of Example 2 or a pharmaceutically acceptable salt thereof, and so on.

Tables 41, 42, 43, 44 and 45 of the pharmaceutical compositions

Specific pharmaceutical combinations and compositions are also provided, wherein the designated compositions comprise a pharmaceutically acceptable carrier or excipient and separately a pharmaceutically effective amount of a) atazanavir sulfate; b) cobicistat; and c) a pharmaceutically effective amount of a TLR7 modulating compound, or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC").

Following the pattern described above, the following tables, Tables 41, 42, 43, 44, and 45, provide combinations of agents that can be used in the uses, methods, dosing regimens, and pharmaceutical compositions of the present invention. Each listed combination includes the stated amounts of emtricitabine, TDF, and atazanavir sulfate, differing only in the TLR7 modulating compound present. In separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 41, b) a compound of Example 4 in Table 42, c) a compound of Example 49 in Table 43, d) a compound of Example 119 in Table 44, and e) a compound of Example 120 in Table 45.

Tables 41, 42, 43, 44 and 45

Tables 46 to 55 of the pharmaceutical compositions

Also provided are specific pharmaceutical compositions and combinations comprising a pharmaceutically acceptable carrier or excipient and a separate pharmaceutically effective amount of cobicistat or ritonavir and a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC"), the amounts of which are listed for each separate pharmaceutical composition.

Following the pattern of the above tables, the following tables, Tables 46, 47, 48, 49, and 50, provide combinations of agents useful in the uses, methods, dosing regimens, and pharmaceutical compositions herein. Each listed combination of agents includes the stated amount of cobicistat, differing only in the included TLR7 modulating compound. In separate tables, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof includes: a) a compound of Formula II in Table 46, b) a compound of Example 4 in Table 47, c) a compound of Example 49 in Table 48, d) a compound of Example 119 in Table 49, and e) a compound of Example 120 in Table 50.

Tables 46, 47, 48, 49 and 50

As with the above table, the following tables, as Tables 51, 52, 53, 54, and 55, provide combinations of agents that can be used for the purposes, methods, dosing regimens, and pharmaceutical compositions herein. Each of the listed combinations of agents includes the amount of ritonavir, differing only in the TLR7 modulating compound included. In a separate table, the TLR7 modulating compound or a pharmaceutically acceptable salt thereof (collectively referred to as "TLR7MC") includes: a) a compound of Formula II in Table 51, b) a compound of Example 4 in Table 52, c) a compound of Example 49 in Table 53, d) a compound of Example 119 in Table 54, and e) a compound of Example 120 in Table 55.

Tables 51, 52, 53, 54, and 55

A pharmaceutically effective amount of a TLR7 modulating compound, including each described herein, may also be combined in dosage regimens and pharmaceutical compositions with a pharmaceutically effective amount of a protease inhibitor known in the art, or a pharmaceutically acceptable salt thereof.

Provided is a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of a protease inhibitor;

b) a pharmaceutically effective amount of a TLR7 modulating compound; and

c) a pharmaceutically acceptable carrier or excipient.

For example, combinations useful in pharmaceutical regimens and compositions include:

a) a pharmaceutically effective amount of a protease inhibitor or a pharmaceutically acceptable salt thereof selected from the group consisting of atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, fosamprenavir, ritonavir, amprenavir and telaprevir; and

b) a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of Formula II, Formula III, Formula III(a), Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), Formula III(f)(2), Examples 1 to 12 4 (including compounds of Examples 4, 49, 119, 120 and 121), GSK2245035, Imiquimod, Resiquimod (R848), R-852 (R852A, PF-4878691), ANA773, 5-amino-7-hydroxy-3-((2R,3R,5S)-3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)thiazolo[4,5-d]pyrimidin-2(3H)-one (active metabolite of ANA773), AZD8848 (DSP3025), SM-360320, IMO-8400, CL097, CL075 (3M002), Gardiquimod ^TM (1-(4-amino-2-ethylaminomethylimidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol), etoribine, 6-amino-2-(butylamino)-7,9-dihydro-9-[(6-methyl-3-pyridinyl)methyl]-8H-purin-8-one (SM-276001), 852A (N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide), 3M-854A and 3M-052, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one (S-34240), and loxoribine,

wherein the separate pharmaceutical regimen comprises a pharmaceutically effective amount of each protease inhibitor from group a) individually in combination with a pharmaceutically effective amount of each TLR7 modulating compound represented by the specific compound, agent, or formula of group b), and the separate pharmaceutical compositions each comprise a pharmaceutically acceptable carrier or excipient, a pharmaceutically effective amount of each protease inhibitor from group a), and a pharmaceutically effective amount of each TLR7 modulating compound represented by the specific compound, agent, or formula of group b). It should be understood that the combination of the 11 protease inhibitors from group a) with the 141 TLR7 modulating compounds represented by the specific compound, agent, or formula of group b) provides 1,771 separate combinations of a protease inhibitor and a TLR7 modulating compound.

Examples of combinations of protease inhibitors and TLR7 modulators for use in the methods and pharmaceutical compositions herein include those listed in Tables 57 to 66. The combinations of protease inhibitors and TLR7 modulators listed in Tables 57 to 66, together with pharmaceutically acceptable carriers or excipients, form separate pharmaceutical compositions.

Table 56

Table 57

Table 58

Table 59

Table 60

Example Protease inhibitors TLR7 modulators 60-a Nelfinavir – 100 mg to 2500 mg Formula II – 0.1 mg to 25 mg 60-b Nelfinavir – 100 mg to 2500 mg Example 4 - 0.1 mg to 25 mg 60-c Nelfinavir – 100 mg to 2500 mg Example 49 - 0.1 mg to 25 mg 60-d Nelfinavir – 100 mg to 2500 mg Example 119 - 0.1 mg to 25 mg 60-e Nelfinavir – 100 mg to 2500 mg Example 120 - 0.1 mg to 25 mg 60-f Nelfinavir – 250 mg to 2500 mg Formula II – 0.1 mg to 15 mg 60-g Nelfinavir – 250 mg to 2500 mg Example 4 - 0.1 mg to 15 mg 60-h Nelfinavir – 250 mg to 2500 mg Example 49 - 0.1 mg to 15 mg 60-i Nelfinavir – 250 mg to 2500 mg Example 119 - 0.1 mg to 15 mg 60-j Nelfinavir – 250 mg to 2500 mg Example 120 - 0.1 mg to 15 mg 60-k Nelfinavir – 250 mg to 2500 mg Formula II – 2 mg to 10 mg 60-l Nelfinavir – 250 mg to 2500 mg Example 4 - 2 mg to 10 mg 60-m Nelfinavir – 250 mg to 2500 mg Example 49 - 2 mg to 10 mg 60-n Nelfinavir – 250 mg to 2500 mg Example 119 - 2 mg to 10 mg 60-o Nelfinavir – 250 mg to 2500 mg Example 120 - 2 mg to 10 mg 60-p Nelfinavir – 250 mg to 2500 mg ANA-773 – 200 mg to 2000 mg 60-q Nelfinavir – 250 mg to 2500 mg GSK2245035 – 25mg to 1000mg 60-r Nelfinavir – 250 mg to 2500 mg Imiquimod – 25 mg to 1000 mg 60-s Nelfinavir – 250 mg to 2500 mg Imiquimod – 25 mg to 1000 mg 60-t Nelfinavir – 250 mg to 2500 mg IMO8400–25mg to 1000mg 60-u Nelfinavir – 250 mg to 2500 mg GSK2245035 – 25mg to 1000mg 60-v Nelfinavir – 250 mg to 2500 mg CL075 – 1 mg to 100 mg 60-w Nelfinavir – 250 mg to 2500 mg Gardiquimod – 25 mg to 1000 mg 60x Nelfinavir – 250 mg to 2500 mg Loxoribine – 25 mg to 1000 mg 60-y Nelfinavir – 250 mg Formula II – 0.1 mg to 15 mg 60-z Nelfinavir – 250 mg Example 4 - 0.1 mg to 15 mg 60-aa Nelfinavir – 250 mg Example 49 - 0.1 mg to 15 mg 60-ab Nelfinavir – 250 mg Example 119 - 0.1 mg to 15 mg 60-ac Nelfinavir – 250 mg Example 120 - 0.1 mg to 15 mg 60-ad Nelfinavir – 625 mg Formula II – 0.1 mg to 15 mg 60-ae Nelfinavir – 625 mg Example 4 - 0.1 mg to 15 mg 60-af Nelfinavir – 625 mg Example 49 - 0.1 mg to 15 mg 60-ag Nelfinavir – 625 mg Example 119 - 0.1 mg to 15 mg 60-ah Nelfinavir – 625 mg Example 120 - 0.1 mg to 15 mg

Table 61

Example Protease inhibitors TLR7 modulators 61-a Saquinavir – 200 mg to 1500 mg Formula II – 0.1 mg to 25 mg 61-b Saquinavir – 200 mg to 1500 mg Example 4 - 0.1 mg to 25 mg 61-c Saquinavir – 200 mg to 1500 mg Example 49 - 0.1 mg to 25 mg 61-d Saquinavir – 200 mg to 1500 mg Example 119 - 0.1 mg to 25 mg 61-e Saquinavir – 200 mg to 1500 mg Example 120 - 0.1 mg to 25 mg 61-f Saquinavir – 500 mg to 1000 mg Formula II – 0.1 mg to 15 mg 61-g Saquinavir – 500 mg to 1000 mg Example 4 - 0.1 mg to 15 mg 61-h Saquinavir – 500 mg to 1000 mg Example 49 - 0.1 mg to 15 mg 61-i Saquinavir – 500 mg to 1000 mg Example 119 - 0.1 mg to 15 mg 61-j Saquinavir – 500 mg to 1000 mg Example 120 - 0.1 mg to 15 mg 61-k Saquinavir – 500 mg to 1000 mg Formula II – 2 mg to 10 mg 61-l Saquinavir – 500 mg to 1000 mg Example 4 - 2 mg to 10 mg 61-m Saquinavir – 500 mg to 1000 mg Example 49 - 2 mg to 10 mg 61-n Saquinavir – 500 mg to 1000 mg Example 119 - 2 mg to 10 mg 61-o Saquinavir – 500 mg to 1000 mg Example 120 - 2 mg to 10 mg 61-p Saquinavir – 200 mg to 1500 mg ANA-773 – 200 mg to 2000 mg 61-q Saquinavir – 200 mg to 1500 mg GSK2245035 – 25mg to 1000mg 61-r Saquinavir – 200 mg to 1500 mg Imiquimod – 25 mg to 1000 mg 61-s Saquinavir – 200 mg to 1500 mg Imiquimod – 25 mg to 1000 mg 61-t Saquinavir – 200 mg to 1500 mg IMO8400–25mg to 1000mg 61-u Saquinavir – 200 mg to 1500 mg GSK2245035 – 25mg to 1000mg 61-v Saquinavir – 200 mg to 1500 mg CL075 – 1 mg to 100 mg 61-w Saquinavir – 200 mg to 1500 mg Gardiquimod – 25 mg to 1000 mg 61x Saquinavir – 200 mg to 1500 mg Loxoribine – 25 mg to 1000 mg 61-y Saquinavir – 200 mg Formula II – 0.1 mg to 15 mg 61-z Saquinavir – 200 mg Example 4 - 0.1 mg to 15 mg 61-aa Saquinavir – 200 mg Example 49 - 0.1 mg to 15 mg 61-ab Saquinavir – 200 mg Example 119 - 0.1 mg to 15 mg 61-ac Saquinavir – 200 mg Example 120 - 0.1 mg to 15 mg 61-ad Saquinavir – 500 mg Formula II – 0.1 mg to 15 mg 61-ae Saquinavir – 500 mg Example 4 - 0.1 mg to 15 mg 61-af Saquinavir – 500 mg Example 49 - 0.1 mg to 15 mg 61-ag Saquinavir – 500 mg Example 119 - 0.1 mg to 15 mg 61-ah Saquinavir – 500 mg Example 120 - 0.1 mg to 15 mg

Table 62

Table 63

Table 64

Table 65

Another embodiment includes a kit comprising a pharmaceutically effective amount of an antiviral agent or a pharmaceutically acceptable salt thereof, a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof, and instructions for administering the antiviral agent and the TLR7 modulating compound. Another embodiment includes the kit just described, wherein the antiviral agent and the TLR7 modulating compound are present in the same pharmaceutical composition. Another embodiment includes the kit just described, wherein the antiviral agent and the TLR7 modulating compound are present in separate pharmaceutical compositions.

A series of embodiments are provided within the description of each kit herein, wherein the TLR7 modulating compound is selected from:

Formula II, Formula III, Formula III(a), Formula III(b), Formula III(c), Formula III(d), Formula III(e), Formula III(f), Formula III(a)(1), Formula III(a)(2), Formula III(b)(1), Formula III(b)(2), Formula III(c)(1), Formula III(c)(2), Formula III(d)(1), Formula III(d)(2), Formula III(e)(1), Formula III(e)(2), Formula III(f)(1), and Formula III(f)(2), or a compound selected from Examples 1 to 124, including each of Examples 4, 49, 119 and 120, or a pharmaceutically acceptable salt thereof, and each of the other TLR7 modulating compounds mentioned herein.

Each kit described herein can also include a container and a label or package insert on or associated with the container. The term "package insert" refers to instructions customarily included in commercial packages of therapeutic products, that provide relevant information such as the indications, usage, dosage, administration, contraindications and/or warnings associated with the therapeutic product.

Separate embodiments also include separate kits each comprising a pharmaceutical composition comprising a pharmaceutically effective amount of one or more antiviral agents and a TLR7 modulator as described for each separate combination listed in Tables 1A to 65, and instructions for their administration. It should be understood that each listed combination is presented in a separate kit. Another set of separate embodiments includes the kits just described, wherein the one or more antiviral agents and the TLR7 modulator are present in the same pharmaceutical composition. Another set of embodiments includes the kits just described, wherein the one or more antiviral agents of each combination are in one pharmaceutical composition, and the TLR7 modulator is present in a separate pharmaceutical composition. Another set of embodiments for those combinations having three or more antiviral agents includes the kits just described, wherein two or more antiviral agents of each combination are in one pharmaceutical composition, at least one antiviral agent is in a separate pharmaceutical composition, and the TLR7 modulator is present in another separate pharmaceutical composition. Another set of embodiments includes the kits just described, wherein each antiviral agent of each combination is in a separate pharmaceutical composition, each composition has one antiviral agent, and the TLR7 modulator is present in another separate pharmaceutical composition.

Separate embodiments are also provided which include using a pharmaceutically effective amount of each antiviral compound and a TLR7 modulating compound in each of the separate combinations listed in Tables 1A to 65 for treating HIV in a human. It should be understood that each of the separate combinations in the tables represents a separate embodiment for treating HIV infection in a human. Separate embodiments are also provided which include using a pharmaceutically effective amount of each antiviral compound and a TLR7 modulating compound in each of the separate combinations in the tables listed above for:

a) Treatment of HIV infection in virally suppressed persons;

b) inducing HIV gene expression in humans infected with HIV;

c) inducing HIV gene expression in a human infected with HIV, wherein expression of active HIV genes in the human is suppressed by administration of antiretroviral therapy;

d) inducing HIV gene expression in latent HIV reservoirs in HIV-infected humans;

e) enhancing HIV gene expression in HIV-infected cells of HIV-infected humans;

f) lowering the chronic set point of HIV viral load in HIV-infected individuals;

g) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

h) reducing HIV viremia in humans infected with HIV;

i) Enhances immune cell activity and increases HIV gene expression in HIV-infected individuals;

j) enhancing the efficacy of antiviral agents in humans infected with HIV;

k) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

l) enhancing the efficacy of HIV vaccines; and

m) Elimination of human HIV infection.

Also provided are separate embodiments comprising a pharmaceutically effective amount of each antiviral compound and a TLR7 modulating compound used in each separate combination in the table listed above to prepare a medicament for:

a) Treatment of HIV infection in virally suppressed persons;

b) inducing HIV gene expression in humans infected with HIV;

c) inducing HIV gene expression in a human infected with HIV, wherein expression of active HIV genes in the human is suppressed by administration of antiretroviral therapy;

d) inducing HIV gene expression in latent HIV reservoirs in HIV-infected humans;

e) enhancing HIV gene expression in HIV-infected cells of HIV-infected humans;

f) lowering the chronic set point of HIV viral load in HIV-infected individuals;

g) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

h) reducing HIV viremia in humans infected with HIV;

i) Enhances immune cell activity and increases HIV gene expression in HIV-infected individuals;

j) enhancing the efficacy of antiviral agents in humans infected with HIV;

k) inducing transient HIV-1 viremia in virologically suppressed humans infected with HIV-1;

l) enhancing the efficacy of HIV vaccines; and

m) Elimination of human HIV infection.

Other separate embodiments of each of the kits described herein include the separate kits described, wherein

a) each pharmaceutical composition comprising one or more antiviral agents and a TLR7 modulator is provided separately for daily administration;

b) each pharmaceutical composition comprising an antiviral agent is provided for once-daily administration, and the pharmaceutical composition comprising a TLR7 modulator is provided for less than daily administration; and

c) Each pharmaceutical composition comprising an antiviral agent is provided for administration once or twice daily, and the pharmaceutical composition comprising a TLR7 modulator is provided for administration less than daily.

For each kit wherein the pharmaceutical composition comprising the antiviral agent is provided for administration once or twice daily, and the pharmaceutical composition comprising the TLR7 modulator is provided for administration less than daily, the pharmaceutical composition comprising the TLR7 modulator can be used for administration every other day, or every 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, or 30th day. Another embodiment of each such kit comprises:

a) multiple daily dosage compositions, such as oral tablets or capsules, each daily dosage composition comprising a pharmaceutically effective amount of at least one antiviral agent;

b) multiple less than daily dose compositions, such as oral tablets or capsules, each daily dose composition comprising a pharmaceutically effective amount of at least one antiviral agent and a pharmaceutically effective amount of a TLR7 modulator; and

c) Instructions for administration of the daily dose composition and the less than daily dose composition.

It will be understood that in such a kit, the same number of daily dose composition and less than daily dose composition are present in the kit, wherein the TLR7 modulator is intended for administration every other day, in a kit wherein the TLR7 modulator is intended for administration every third day, the amount of daily dose composition is twice the amount of less than daily dose composition in the kit, etc. Such a kit may further comprise a device for containing the compositions for intended administration, such as a loop pack or blister pack containing the individual compositions contained in separate portions according to the order of their intended administration.

Also provided is a kit comprising:

a) a pharmaceutically effective amount of a TLR7 modulating compound;

b) a pharmaceutically effective amount of an HIV antibody; and

c) Instructions for administering a TLR7 modulating compound and an HIV antibody.

Also provided is a kit comprising:

a) a pharmaceutically effective amount of a TLR7 modulating compound;

b) a pharmaceutically effective amount of an HIV vaccine; and

c) Instructions for administering a TLR7 modulating compound and an HIV vaccine.

Also provided is a kit comprising:

a) a pharmaceutically effective amount of a TLR7 modulating compound;

b) a pharmaceutically effective amount of a latency reversal agent; and

c) Instructions for administering a TLR7 modulating compound and a latency reversing agent.

A separate embodiment is provided, comprising:

Use of a TLR7 modulating compound and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of a TLR7 modulating compound of formula II and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 4 and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 49 and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 119 and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 120 and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;; and

Use of the compound of Example 121 and an antiretroviral agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection.

Separate embodiments are also provided, including:

Use of a TLR7 modulating compound and a latency reversing agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of a TLR7 modulating compound of formula II and a latency reversing agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 4 and a latency reversal agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 49 and a latency reversal agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 119 and a latency reversal agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;

Use of the compound of Example 120 and a latency reversal agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection;; and

Use of the compound of Example 121 and a latency reversal agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection.

Separate embodiments are provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent;

Use of a TLR7 modulating compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent;

Use of the compound of Example 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent;

Use of the compound of Example 49 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent;

Use of the compound of Example 119 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent;

Use of the compound of Example 120 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent; and

Use of the compound of Example 121 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing the efficacy of an antiviral agent.

Separate embodiments are provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of an HIV vaccine;

Use of a modulatory compound of formula II or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of an HIV vaccine;

Use of the compound of Example 4 or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of HIV vaccines;

Use of the compound of Example 49 or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of an HIV vaccine;

Use of the compound of Example 119 or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of an HIV vaccine;

Use of the compound of Example 120 or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of an HIV vaccine; and

Use of the compound of Example 121 or a pharmaceutically acceptable salt thereof in a medicament for enhancing the efficacy of HIV vaccines.

A separate embodiment is provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection;

Use of a TLR7 modulating compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection;

Use of the TLR7 modulating compound of Example 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection;

Use of the TLR7 modulating compound of Example 49 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection;

Use of the TLR7 modulating compound of Example 119 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection;

Use of the TLR7 modulating compound of Example 120 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection; and

Use of the TLR7 modulating compound of Example 121 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for eliminating human HIV infection.

Separate embodiments are provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV;

Use of a TLR7 modulating compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV;

Use of the compound of Example 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV;

Use of the compound of Example 49 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV;

Use of the compound of Example 119 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV;

Use of the compound of Example 120 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV; and

Use of the compound of Example 121 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing HIV gene expression in a human infected with HIV.

Separate embodiments are provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV;

Use of a TLR7 modulating compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV;

Use of the compound of Example 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV;

Use of the compound of Example 49 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV;

Use of the compound of Example 119 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV;

Use of the compound of Example 120 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV;

Use of the compound of Example 121 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for enhancing HIV gene expression in HIV-infected cells of a human infected with HIV.

Separate embodiments are provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1;

Use of a TLR7 modulating compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 49 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 119 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 120, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1; and

Use of the compound of Example 121 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1.

Separate embodiments are provided, including:

Use of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in a virologically suppressed human infected with HIV-1;

Use of a TLR7 modulating compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in virologically suppressed humans infected with HIV-1;

Use of the compound of Example 49 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 119 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in a virologically suppressed human infected with HIV-1;

Use of the compound of Example 120 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in a virologically suppressed human infected with HIV-1; and

Use of the compound of Example 121 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV-1 infection in a virologically suppressed human infected with HIV-1.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound of Formula II or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of the compound of Example 4 or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of the compound of Example 119 or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of the compound of Example 120 or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of the compound of Example 121 or a pharmaceutically acceptable salt thereof in a medicament for inhibiting HIV replication in a human infected with HIV. Also provided is the use of a pharmaceutically effective amount of a compound selected from Examples 1 to 124 herein, or a pharmaceutically acceptable salt thereof, in a medicament for inhibiting HIV replication in a human infected with HIV virus.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound of Formula II or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of the compound of Example 4 or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of the compound of Example 49 or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of the compound of Example 119 or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of the compound of Example 120 or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of the compound of Example 121 or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication. Also provided is the use of a pharmaceutically effective amount of a compound selected from Examples 1 to 124 herein or a pharmaceutically acceptable salt thereof as a research tool for inhibiting HIV replication.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for treating HIV infection in a human in need thereof.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of a combined antiretroviral therapy regimen for treating HIV infection in a human in need thereof.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of a combination antiretroviral therapy regimen for treating HIV infection in a human in need thereof, wherein the combination antiretroviral therapy regimen is sufficient to reduce the level of HIV detected in the human's blood or plasma from a first level to a second level, wherein the first level has a higher concentration than the second level.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of an HIV antibody for treating HIV infection in a person in need thereof.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of a combination antiretroviral therapy regimen for treating HIV infection in a virologically suppressed human infected with HIV-1, wherein the combination antiretroviral therapy regimen is sufficient to reduce the level of HIV detected in the human's blood or plasma from a first level to a second level, wherein the first level has a higher concentration than the second level.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for inducing HIV gene expression in a human infected with HIV whose active HIV gene expression is suppressed by administration of antiretroviral therapy.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for lowering the set point of HIV viral load in a human infected with HIV.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for inducing transient HIV-1 viremia in a virologically suppressed human infected with HIV-1.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for enhancing the efficacy of a pharmaceutically effective amount of an antiviral agent in humans infected with HIV.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for enhancing the efficacy of HIV vaccines.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for eliminating HIV infection in a human.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof for eliminating HIV infection in a human, wherein the human is receiving a pharmaceutically effective amount of a combination antiretroviral therapy.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of a combination antiretroviral therapy regimen for eliminating HIV infection in a human in need thereof, wherein the combination antiretroviral therapy regimen is sufficient to reduce the level of HIV detected in the human's blood or plasma from a first level to a second level, wherein the first level has a higher concentration than the second level.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of an HIV antibody for eliminating HIV infection in a person in need thereof.

Also provided is the use of a pharmaceutically effective amount of a TLR7 modulating compound or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically effective amount of an HIV vaccine to eliminate HIV infection in a person in need thereof.

Biological Examples

Although specific embodiments of the present invention are described and explained in detail herein, the present invention is not limited thereto. The above detailed description is provided as an example of the present invention and should not be construed as constituting any limitation of the present invention. Changes will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present invention are intended to be included within the scope of the appended claims.

Example

Example 201: Formulation of Example 4

Sterile formulations of Example 4 suitable for oral administration were prepared. Initially, a carrier solution was prepared by dissolving propyl gallate in 0.001N HCl (pH 3.0) to achieve a final propyl gallate concentration of 0.005% (w/v). Three solution formulations of Example 4 were prepared by dissolving sufficient Example 4 compound in 0.005% propyl gallate solution to obtain final concentrations of 0.1 mg/mL, 0.2 mg/mL, and 0.3 mg/mL of Example 4 compound. These compositions were frozen at -20°C until use.

Example 202: cART formulation

A cART formulation containing 20 mg/mL tenofovir (TFV, GMP grade), 50 mg/mL emtricitabine (FTC, GMP grade), and 2.5 mg/mL dolutegravir (DTG, 95% purity) was prepared in a solvent containing a final concentration of 25% (v/v) polyethylene glycol 400 (PEG-400, Spectrum Chemical New Brunswick, NJ), 15% (w/v) Captisol (Ligand Pharmaceuticals, LA Jolla, CA), and 0.075 N sodium hydroxide (NaOH, Spectrum Chemical, New Brunswick, NJ) in water. The formulation was prepared by mixing DTG stock solution (10 mg/mL DTG in PEG-400), TFV and FTC stock solutions (80 mg/mL TFV and 200 mg/mL FTC in 0.3 N NaOH), and 30% (w/w) captosil solution in a 1:1:2 (v:v:v) ratio. The final solution was clear with a pH of ~6. It was sterile filtered and then aliquoted into sterile glass and frozen at -20°C until use.

Example 203: TLR7 Modulating Compounds in Chronic Set Point SIV ⁺ Rhesus Monkey Toxemia

In a multiple-dose, dose-escalating, placebo-controlled study, five chronically infected SIV+ rhesus macaques were treated with the compound of Example 4 (n=3 animals) or with the dosing vehicle (placebo, n=2 animals). Rhesus macaques were infected with simian immunodeficiency virus for a sufficient period of time to establish a chronic set point (i.e., a state of sustained viremia, i.e., post-peak viremia, in which host immune control of viral replication is established, but this does not result in complete viral suppression) and then dosed with the compound of Example 4. Animals were not administered combination antiretroviral therapy during any part of the study.

Animals were administered once a week with the compound of Example 4 or placebo by oral gavage (via nasogastric tube). The compound of Example 4 prepared as described in Example 201 was administered to three animals. In the first week, 1 mL/kg of 0.1 mg/mL formulation was administered, corresponding to a dose of 0.1 mg/kg. In the second week, 1 mL/kg of 0.2 mg/mL formulation was administered, corresponding to a dose of 0.2 mg/kg. From the third to the fifth week, 1 mL/kg of 0.3 mg/mL formulation was administered, corresponding to a dose of 0.3 mg/kg. Two animals (placebo group) were given the administration vehicle described in Example 201 at 1 mL/kg per week.

Each formulation of Example 201 or vehicle only (placebo) was used fresh and thawed to room temperature before administration. Quantitative RT-PCR of SIV RNA was performed at different times throughout the study of animals administered the compound of Example 4 and placebo animals to measure gag gene transcripts, thereby determining plasma viral load (expressed as SIV RNA copies per mL of plasma). The data are shown in Figures 1 and 2. Figure 1 describes the absolute viral load of each animal on each study day. Figure 2 describes the change in viral load on each study day compared to baseline (Day 0). In Figures 1 and 2, the dark black data points correspond to the data of animals administered the compound of Example 4, while the gray shaded data points correspond to the data of animals administered the placebo.

In Figures 1 and 2, the dosing days are indicated by arrows on the horizontal x-axis relative to the start of administration of the compound of Example 4.

As shown in Figure 2, three of the three animals administered the compound of Example 4 experienced a reduction in viral load of approximately 0.4 to 1.8 log ₁₀ immediately after the first dose. No reduction in plasma viral load was observed in animals administered placebo. The animal with the highest viral load at the start of the study showed a reduction in viral load after dosing (Figure 2). However, due to SIV-related symptoms, this animal was removed from the study before the fourth and fifth doses.

The animal with the lowest viral load (lowest chronic set point) at the start of the study maintained an undetectable plasma viral load (<50 RNA copies/mL) for at least 100 days after the last dose of the compound of Example 4, as shown in Figure 1. In a second animal dosed with the compound of Example 4, the viral load set point also continued to decrease by approximately 1 log compared to pre-dose (log ₁₀ RNA copies) for at least 100 days after the last dose (Figure 2).

In summary, the data shown in Figures 1 and 2 demonstrate that after the first dose of the study compound, plasma viral load decreased, followed by an increase in circovirus with subsequent doses and a continued maintenance of a new and lower chronic viral set point compared to pre-dosing with the compound of Example 4.

Example 204: TLR7 Modulatory Compounds for Use in cART-Treated SIV ⁺ Rhesus Monkeys with Undetectable Plasma Viremia

In a multiple dose escalation study, a group of 10 Indian rhesus monkeys (Macaca mulatta) were treated with the compound of Example 4 or the dosing vehicle of Example 201 (placebo group). Rhesus monkeys were infected with simian immunodeficiency virus (SIVmac251) by repeated low-dose rectal mucosal attacks. Starting on the 65th day after infection, after establishing the peak viremia and early viral chronic set point, animals were treated with cART at 1 mL/kg by subcutaneous injection for about one year. During cART administration, the plasma viral load was reduced to an undetectable level (SIV gag RNA <50 copies/mL) on the 168th day after infection, and was maintained for about 5 months by daily use of cART before administering the compound of Example 4. In addition, when the compound of Example 4 was administered, the animals were maintained on the same cART dosing regimen. The amount of antiretroviral agent in the cART preparation administered to each animal daily was 20 mg/kg tenofovir, 50 mg/kg emtricitabine (FTC), and 2.5 mg/kg dolutegravir. Beginning approximately day 65 post-infection, animals were administered cART with viral suppression and daily administration of the compound of Example 4 until approximately two weeks after the last administration of the compound of Example 4, at which time cART was stopped to monitor plasma viral load rebound kinetics.

Starting from the 317th day after infection, the animals were administered the compound of Example 4 or the dosing vehicle of Example 201 every other week (placebo group). Four animals were administered the compound of Example 4 prepared as described in Example 201. In the first week, 1 mL/kg of the 0.1 mg/mL formulation was administered, corresponding to a dose of 0.1 mg/kg. In the third week, 1 mL/kg of the 0.2 mg/mL formulation was administered, corresponding to a dose of 0.2 mg/kg. From the 5th to the 13th week, 1 mg/kg of the 0.3 mg/mL formulation was administered, corresponding to a dose of 0.3 mg/kg (a total of 7 doses). The other 6 animals were controls, 3 of which were given saline every two weeks by oral gavage for a total of 7 doses; the remaining three animals were untreated. Approximately two weeks after the last administration of the compound of Example 4, cART was stopped in three saline-administered placebo animals and four animals receiving the compound of Example 4. Approximately one month later, cART was stopped in three untreated control animals. After cART was stopped, viral load was monitored for six months.

Each formulation of the compound of Example 4 or the administration vehicle of Example 201 was thawed at room temperature before administration. Administration to animals was performed by oral gavage through a nasogastric tube.

Plasma viral load (expressed as SIV RNA copies per mL of plasma) was determined by quantitative RT-PCR of SIV RNA measuring gag gene transcripts at various times throughout the study. The viral loads of animals in the compound of Example 4 and placebo groups are shown in Table 1 and Figure 3. The viral load of each animal at the time of administration of the first dose of the compound of Example 4 on each study day is depicted in Figure 3; the days of administration are indicated by arrows on the horizontal x-axis.

As shown in Table 1 and Figure 3, detectable plasma virus was observed in the animals administered the compound of Example 4 approximately 24-72 hours after each of the last three doses of study drug (0.3 mg/kg). In each case, viral levels returned to baseline (<50 copies/mL) before subsequent doses were administered. Viral levels remained undetectable over a total of 13 days after the last administration of the compound of Example 4. Although data are not shown in Figure 3, there was no detectable change in plasma viral expression during administration in the three saline-administered placebo animals and untreated control animals, and the animals maintained <50 SIV RNA copies/mL.

Table 1: Plasma virus levels obtained after administration of the compound of Example 4 to SIV+ rhesus monkeys on cART (4th to 7th doses)

This data from the dose escalation study demonstrates that the compound of Example 4 can reproducibly induce transient plasma viremia in the presence of cART, followed by a return to full plasma SIV RNA suppression. A transient increase in detectable plasma virus occurred after the fourth to fifth dose of the compound of Example 4 administered orally every 14 days.

Two weeks after the last dose of study drug, cART treatment was stopped in all animals that were dosed (including placebo). In the untreated control group animals, cART was stopped after 30 days. Table 2 shows the average chronic viral load set point for days 42-81 after cART cessation for each animal in the study. As shown in Table 2, all animals experienced plasma viral rebound within 7 to 14 days after cART cessation. However, when the pre-cART plasma SIV RNA chronic set point in animals administered the compound of Example 4 was compared with the chronic set point after cART cessation, the value was lower than the change observed in those animals in the placebo group (the average change for all animals administered the dosing vehicle of Example 201) by about ～0.5log ₁₀ (the average change for all animals treated with the compound of Example 4).

Table 2: Changes in Plasma Viral Chronic Set Points in SIV+ Rhesus Monkeys Following Administration of the Compound of Example 4 (Before and After CART Discontinuation)

Example 205. Proviral SIV DNA Assay in Peripheral Blood Mononuclear Cells (PBMCs), Lymph Nodes, and Colon

Whole blood samples, inguinal lymph node samples, and colon clip biopsy samples were taken from animals that received the compound of Example 4 in the study described in Example 204, as well as from animals that received the vehicle (placebo group) of Example 201. These samples were taken before the start of dosing and two weeks after the last dose; these samples were collected when the animals were undergoing cART. Total DNA was isolated from each sample using a commercially available blood and tissue DNA extraction kit. Proviral SIV DNA levels were measured by quantitative PCR (qPCR) using a probe primer set specific for the SIV gag gene and normalized for cell input by measuring glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene levels. When comparing the amount of proviral SIV DNA in PBMC, inguinal lymph node, and colon samples before and after treatment in each animal, the proviral DNA content in all tissues of three of the four animals treated with the compound of Example 4 was significantly reduced. In one compound-treated animal (166-08), there was only a significant decrease in the proviral DNA content in the PBMC, a slight increase in the lymph nodes, and a slight decrease in the colon. However, in placebo-controlled animals dosed with vehicle, proviral SIV DNA was slightly to moderately increased in PBMC and colon samples in two of three animals and was relatively stable in lymph node samples.

Table 3: Proviral SIV DNA in PBMCs, lymph nodes, and colon in SIV+ rhesus macaques undergoing cART

Example 206: Peripheral Lymphocyte Activation

During the treatment with the compound of Example 4 described in Example 204, peripheral lymphocyte activation in the group administered with the compound of Example 4 or the dosing vehicle (placebo) of Example 201 was monitored, and the expression of early activation marker CD69 on various lymphocyte subsets was determined by flow cytometry. This method is used to quantitatively measure the percentage of immune cell subsets expressing early activation markers. Standard data acquisition techniques were used on a flow cytometer, and antibodies conjugated to fluorescent molecules were used, wherein the antibodies recognized rhesus monkey cell surface proteins on various immune cell subsets. In animals administered with the compound of Example 4, whole blood samples were collected at different time points before and after administration of the compound. Total PBMCs in whole blood samples were stained using antibodies selected to be reactive with rhesus monkey CD3, CD4, CD8, NKG2A, CD16, and CD56, each coupled to a different fluorescent probe to depict CD3+CD4+CD8- lymphocytes, CD3+CD4-CD8+ lymphocytes, and CD3-CD8+NKG2A+CD16+CD56+NK cells. The flow cytometry data presented herein were obtained from animals treated with Example 4 compound.

Based on the expression of the early activation marker CD69, peripheral CD4 lymphocytes (CD3+CD4+CD8-) showed transient activation in response to the administration of the compound of Example 4. In cells expressing CD69, the percentage change compared to the pre-dose level increased 24 to 72 hours after administration and returned to near the pre-dose level one week after administration. The percentage change of peripheral activated CD4 lymphocytes was also greatly increased based on the administration of the compound of Example 4). When 0.1 mg/kg of Example 4 was administered, the average maximum percentage change of CD69 expression at any time point on CD4 lymphocytes was 1.1% (range before administration was 0.5-1.7%), at a dose of 0.2 mg/kg, the average maximum percentage change was 1.5% (range before administration was 0.5-2%), and at the first dose of 0.3 mg/kg, the average maximum percentage change was 2.3% (range before administration was 0.6-2.5%). However, all subsequent doses did not achieve similar levels of peripheral CD4 lymphocyte activation; the mean maximum percentage change in CD69 expression was 1.7%.

Based on the expression of CD69, peripheral CD8 lymphocytes (CD3+CD8+CD4-) also showed transient activation in response to the administration of the compound of Example 4. In CD8 lymphocytes expressing CD69, the percentage change compared to the pre-dose level increased 24 to 72 hours after administration and returned to near the pre-dose level one week after administration. The percentage change of peripheral activated CD8 lymphocytes was also greatly increased based on the administration of the compound of Example 4). At a dose of 0.1 mg/kg, the average maximum percentage change of CD69 expression at any time point on CD8 lymphocytes was 7.8% (range before administration was 3.3-12.6%), at a dose of 0.2 mg/kg, the average maximum percentage change was 9.5% (range before administration was 3.0-15.7%), and at the first dose of 0.3 mg/kg, the average maximum percentage change was 17.3% (range before administration was 5.0-14.4%). However, all subsequent doses of 0.3 mg/kg did not achieve similar levels of peripheral CD8 lymphocyte activation; the mean maximum percent change in CD69 expression was 15.5%.

Based on the expression of CD69, total peripheral NK cells (CD3-CD8+NKG2A+CD16+CD56+, including CD16 low/high and CD56 low/high) also showed transient activation in response to the administration of the compound of Example 4. In NK cells expressing CD69, the percentage change compared to the pre-dose level increased 24 to 72 hours after administration and returned to or slightly below the pre-dose level one week after administration. The percentage change of peripheral activated NK cells was based on an increase in only a slight magnitude of the administration of the compound of Example 4). At a dose of 0.1 mg/kg, the average maximum percentage change of CD69 expression on NK cells at any time point was 6.5% (range 89-95% before administration), at a dose of 0.2 mg/kg, the average maximum percentage change was 9.5% (range 83-95% before administration), and at the first dose of 0.3 mg/kg, the average maximum percentage change was 8.3% (range 84-95% before administration). At the second dose of 0.3 mg/kg, the mean maximum percent change was 8.7% (pre-dose range 82-97%). All subsequent 0.3 mg/kg doses achieved similar levels of peripheral NK cell activation; the mean maximum percent change in CD69 expression ranged from 6.1 to 9.2%.

in conclusion

The compound of Example 4 was able to induce transient expression of plasma SIV in a rhesus macaque model of HIV-1 infection. The compound of Example 4 reduced the amount of proviral SIV DNA in PBMC, inguinal lymph nodes, and colon tissue, a marker of reduced viral reservoirs. In addition, administration of the compound of Example 4 produced an immunological response that was measurable in the absence of cART, as evidenced by a lower plasma viral chronic set point (post-cART cessation) after administration of the compound.

In vitro testing

In vitro testing of the compounds disclosed herein was designed to demonstrate similar activation of immune cells in cultures of total PBMCs from virally suppressed HIV-1 infected donors. Both molecules can induce HIV-1 replication in cultures of resting PBMCs obtained from virologically suppressed HIV-1 infected patients. In addition, both molecules exhibited direct antiviral effects in cultures of activated PBMCs exogenously infected with HIV-1.

Example 207: In vitro activation of lymphocyte subsets in PBMC cultures from healthy and HIV-1 infected donors

Total PBMC cultures are derived from the buffy coat obtained from healthy human donors purified through Ficoll, or HIV-1 infected donors (HIV-1 infected donors are patients in cART, and are virologically suppressed, HIV RNA <50 copies/mL, for ≥1 year) leukocyte separation samples. Total PBMC cultures are treated for 24 hours with various concentrations of identified TLR7 regulatory compounds (compounds of embodiment 4 and embodiment 49). After the incubation period, total PBMCs are harvested and stained with antibodies coupled to specific fluorophores to depict human CD4 lymphocytes (CD3+CD4+CD8-) or CD8 lymphocytes (CD3+CD8+CD4-), and co-express early activation marker CD69. Cells are analyzed by flow cytometry, and data are collected on LSR FortessaX20 instrument (BD Biosciences).

The tested TLR7 modulating compounds were able to induce lymphocyte activation in vitro, in particular, to cause activation of CD4+ and CD8+ lymphocytes. The maximum percentage of activated cells was similar for both compounds in each donor.

Table 4: Percentage of CD69 Induction on CD4+ Lymphocytes Induced by TLR7 Modulating Compounds in PBMC Cultures from HIV-1 Infected Donors

Table 5: Percent induction of CD69 on CD8+ lymphocytes by TLR7 modulating compounds in PBMC cultures from healthy and HIV-1 infected donors

Example 208: HIV-1 Expression Induced in PBMC Cultures from HIV-1 Infected Donors on cART Treated with TLR7 Modulating Compounds

In order to evaluate the ability of activating HIV-1 expression in total PBMC cultures, the leukocyte separation sample obtained through Ficoll purification from the donor infected by HIV-1 was determined (the donor infected by HIV-1 was a patient on cART and was virally suppressed, with HIV RNA <50 copies/mL for ≥1 year). The PBMCs isolated were treated with TLR7 regulatory compounds (compounds of Example 4 and Example 49) at different concentrations (0.1, 1, and 10 μM) or treated with dimethyl sulfoxide (DMSO) (carrier control) for 4 to 5 days. The culture was maintained in the presence of antiviral agents (Avitegravir and Efavirenz, each 100 nM) to prevent viral spread and amplification, thereby determining the initial viral production (latency reversal) produced by the TLR7 regulatory compounds. After incubation, the culture supernatant without cells was harvested and the HIV-1 RNA level was quantified by AmpliPrep/TaqMan assay v2.0 (Roche).

In the absence of any other activation stimulus, TLR7 modulating compounds were used to induce HIV-1 expression in PBMC cultures from the tested donors (Table 6). Compared to twice or more activation of the DMSO control, 4 of 6, 3 of 6, and 1 of 4 patient cultures were observed after treatment with 0.1, 1, and 10 μM Example 49 compounds, respectively. A similar frequency of response was observed after treatment with Example 4 compounds. Two-fold or higher HIV-1 expression induction was observed in 6 of 6 donors using at least one TLR-7 agonist (n=2 donors) or two agonists (n=4 donors). Without being bound by any particular theory, it is believed that the lack of consistent dose-responsive viral expression for any agonist within the test concentration range in the tested donors may be the result of the combined net effect of the dual ability of the TLR7 modulating compound to induce viral expression and exert an antiviral effect. While the antiviral effects of TLR7 modulatory compounds were not directly measured in Example 208, additional data from Examples 207 and 209 confirm these potential antiviral activities. Both biological activities can be manifested in a donor-dependent manner at different compound concentrations, resulting in variations in the concentration of TLR7 modulatory compounds that can produce HIV-1 activation. Together, these data demonstrate that TLR7 modulators induce HIV-1 expression in vitro.

Table 5: TLR7 modulating compounds induce HIV-1 expression in PBMC cultures from HIV-1 infected donors on cART

a. Fold induction is expressed as the ratio of HIV-1 RNA copy numbers detected in cell culture supernatants from agonist- and DMSO-treated wells. For each donor and condition, fold activation is the average of three independent wells.

b. Not determined

Tables 7, 8, 9, 10 and 11: Induction of HIV-1 expression in PBMC cultures from HIV-1 infected donors on cART

HIV-1 expression was determined in PBMC cultures from HIV-1 infected donors on cART in the presence of the compounds of Examples 4, 49, 120, 121, 122, 123, 124, resiquimod, and imiquimod using the method described above in Example 208.

Table 7

Table 8

Table 9

Table 10

Table 11

a Induction fold is expressed as the ratio of HIV-1 RNA copy numbers detected in culture supernatants from wells treated with TLR7 agonists and DMSO. Bold values indicate ≥2-fold induction. Supernatants were collected on day 4. For each donor and each condition, the induction fold average was taken from three independent wells. For the data in Table 2, PBMCs were added to the pre-coated compound and immediately transferred to the incubator. This method was used to minimize the possibility of treatment and manipulation effects on the cells. For the data in Table 1, PBMCs were added to the plate, followed by compound addition, and then the plate was transferred to the incubator.

Example 209: Antiviral Activity of TLR7 Modulating Compounds Against HIV-1 Infected PBMC Cultures In Vitro

Antiretroviral activity was determined by testing TLR7 modulatory compounds (compounds of Examples 4 and 49) in total human PBMC cultures that had been treated with nitrogen (phytohemagglutinin A) for two days prior to infection with HIV-1 _BaL . Infected cells were cultured for 6 days in the presence of interleukin-2 and varying concentrations of TLR7 modulatory compounds, or the nucleoside analog HIV-1 reverse transcriptase inhibitor azidothymidine (AZT, positive control). At the end of the incubation period, cell-free culture supernatants were harvested and antiviral activity was determined by measuring HIV-1 Gag p24 production using a commercially available ELISA kit. TLR7 modulatory compounds demonstrated potent, concentration-dependent antiretroviral activity in each of the eight donor cultures tested, with mean EC ₅₀ values of 170 nM and 33 nM, respectively (12). These data demonstrate that TLR7 modulatory compounds possess HIV-1 antiviral activity in the test system.

Table 12: Antiviral activity of TLR7 modulating compounds in HIV-1 infected PBMC cultures

a. Mean ± SD values obtained from at least 8 independent donors

Example 210: Example 49 In vitro activation of HIV in PBMC

PBMCs were isolated from 18 HIV-infected donors (donor IDs 152-169) on suppressive cART as described in Materials and Methods (PBMC isolation) and immediately added to tissue culture plates pre-equilibrated at 37°C in a medium containing DMSO or Example 49 (GS-9620) compound at a concentration of 0.1 uM or 1.0 uM. On day 4 after treatment, cell-free culture supernatants were collected and HIV viral RNA was quantified using the automated AmpliPrep/HIV-1 assay, v2.0 system (Roche Diagnostics, Indianapolis, IN) as previously described in Materials and Methods (HIV-1 activation assay). The geometric mean fold of HIV activation obtained from three independent wells for each donor and condition was expressed as the ratio of HIV-1 RNA copies/ml detected in the culture supernatants of TLR7 agonist-treated and DMSO-treated wells. HIV fold activation values were plotted using GraphPad Prism software (GraphPad, San Diego, CA) and can be seen in Figure 7. Dashed lines indicate > 2-fold induction.

Table 13

Example 211: Example 49 In vitro induction of cytokines/chemokines

PBMCs were isolated from HIV-infected donors on suppressive cART as described above and immediately added to tissue culture plates pre-equilibrated at 37°C in culture medium containing DMSO or Example 49 (GS-9620) compound at a concentration of 0.1 uM or 1.0 uM. On day 2 after treatment, cell-free culture supernatants were collected and frozen at -80°C for subsequent analysis. Frozen supernatants were thawed at room temperature and quantified using a custom multiplex xMAP assay according to the manufacturer's instructions (Thermo Fisher Scientific Inc., Grand Island, NY, custom designed kit).

Example 212: Maximal HIV Activation from Example 49 Depends on IFNα/β Receptor Signaling

PBMCs were isolated from HIV-infected donors on suppressive cART as described above and treated with the indicated doses (10 nM to 10 uM) of the compound of Example 49 (GS-9620) in the presence or absence of a 1:500 dilution of a murine monoclonal antibody (clone MMHAR-2) against human interferon α/β receptor chain 2 (PBL Assay Science, Piscataway, NJ, Cat# 21385-1). On day 4 after treatment, cell-free culture supernatants were collected and HIV viral RNA was quantified using AmliPrep/Assay.

HIV activation in PBMCs from two HIV-infected donors treated with the compound of Example 49 alone and in combination with anti-IFNα/β mAb (IFNAR blocker) is depicted in Figure 8. An average maximum reduction of 85% was seen in the four donors (p<0.05, paired t-test).

Example 213: In vitro activation of HIV by recombinant IFNα

PBMCs were isolated from HIV-infected donors on suppressive cART as described above and treated with human interferon α2a (PBL Assay Science, Piscataway, NJ, Cat# 11100-1) at the indicated concentrations. On day 4 after treatment, cell-free culture supernatants were collected and HIV viral RNA was quantified using the AmliPrep assay. FIG9 depicts HIV fold activation for the four donors.

Example 214: Association with HIV Activation

PBMCs were isolated from 14 HIV-infected donors (donor numbers 152-165) on suppressive cART as described above and immediately added to tissue culture plates pre-equilibrated at 37°C in culture medium containing DMSO or Example 49 (GS-9620) compound at a concentration of 0.1 nM or 10.0 uM. On day 2 after treatment, cell-free culture supernatants were collected and frozen at -80°C for subsequent analysis. The frozen supernatants were thawed at room temperature and the indicated cytokines and chemokines were quantified using a custom multiplex kit assay as described above. On day 4 after treatment, cell-free culture supernatants were collected and HIV viral RNA was quantified using the automated AmpliPrep/HIV-1 assay, v2.0 system (Roche Diagnostics, Indianapolis, IN). To generate the scatter plots, the levels of HIV-1 vRNA induced at GS-9620 concentrations that induced peak IP-10 (CXCL10) or I-TAC (CXCL11) levels were plotted as individual data points for each donor. Graphs were generated, and Spearman rank correlation r and p values were calculated using GraphPad Prism software (GraphPad, San Diego, CA), as shown in FIG10 .

Example 215: HIV-induced reduction

PBMCs were isolated from 4 HIV-infected donors (donor numbers 141-144) on suppressive cART, as described above, and treated with DMSO or 0.1 uM of the compound of Example 49 (GS-9620). On day 7 after treatment, non-adherent cells were collected and total CD4 T cells were isolated using the EasySep ^™ Human T Cell Enrichment Kit (STEMCELL Technologies Inc., Vancouver, BC). CD4 T cells were then stimulated with 1 uM of the protein kinase C (PKC) agonist indole lactam for 3 days, at which point cell-free culture supernatants were collected and HIV viral RNA was quantified using the automated AmpliPrepHIV-1 assay, v2.0 system (Roche Diagnostics, Indianapolis, IN).

HIV-1 RNA copies/ml obtained for DMSO and GS-9620 treatment for each donor were plotted using GraphPad Prism software (GraphPad, San Diego, CA), showing statistically significant differences (*p<0.05, **p<0.01 paired t-test), as shown in FIG11 .

Example 216: Example 49 In vitro induction of HIV-specific multifunctional CD8 T cells

PBMCs were isolated from 5 HIV-infected donors (donor numbers 178-180 and 182-183) on suppressive cART, as described above, and stained with carboxyfluorescein succinimidyl ester (CFSE). PBMC cultures were treated with DMSO or 0.1 or 1 uM of the compound of Example 49 (GS-9620). The cultures were incubated at 37°C for 2 days and treated with 500 ng/ml of a 15-mer peptide library obtained from overlapping HIV gag, pol, nef and env common peptides (JPT Peptide Technologies GmbH). The cells were incubated at 37°C for 8 days. The cultures were divided into two groups and stained in dulbecco's phosphate-buffered saline (DPBS) with LIVE/DEAD fixable dead cell aqueous stain (Life Technologies). The immune recall reaction was performed as follows. One culture group was treated with the same HIV peptide library, and the other group was treated with 500ng/ml of CMV/EBV/Flu/Tetanus (CEFT) peptide (JPT Peptide Technologies GmbH). After 1 hour at 37°C, the cultures were treated with 0.7μl GolgiStop (BD Biosciences) containing monensin and 1μl GolgiPlug (BD Biosciences) containing brefeldin A. The cultures were incubated for another 3 hours at 37°C and stained for 15 minutes with anti-CD4-v450, anti-CD3-AlexaFlour 700, and anti-CD8-APC-H7 (BD Biosciences). The cultures were fixed with IC fixation buffer (eBioscience) and permeabilized with permeabilization buffer (eBioscience). Anti-IFN-γ-APC and anti-TNFα-PerCP-Cy5.5 (BD Biosciences) were used to stain the cytokines produced within the cells. FACS was performed on an LSR Fortessa (BD Biosciences), and data analysis was performed using FlowJo software (TreeStar). The response to the CEFT peptide was subtracted from the response to the HIV peptide. The data were plotted and statistically analyzed using GraphPad Prism software (GraphPad). Treatment with 0.1 uM of Example 49 increased the average level of multifunctional proliferative CD8 T cells (low CFSE, IFNg+, TNFa+) by 9.0 times compared to treatment with DMSO (p<0.05; Student's unpaired two-tailed t-test). Treatment with 1 uM of Example 49 increased the average level of multifunctional proliferative CD8 T cells (low CFSE, IFNg+, TNFa+) by 7.5 times compared to treatment with DMSO (p<0.005; Student's unpaired two-tailed t-test), as shown in Figure 12.

Example 217: Combination of Example 49 and an indoleamine 2,3-dioxygenase (IDO, IDO1) inhibitor enhances the induction of HIV-specific multifunctional CD8 T cells

PBMCs were isolated from four HIV-infected donors (donor numbers 180-183) on suppressive cART and stained with CFSE as described previously. They were treated with 500 ng/ml of a 15-mer peptide pool obtained from overlapping HIV gag, pol, nef, and env consensus peptides (JPTPeptide Technologies GmbH). PBMC cultures were treated with DMSO or 0.1 μM of the compound of Example 49 (GS-9620). In some cultures treated with Example 49, 2 μM of the IDO1 small molecule inhibitor INCB024360 was added. Cultures were incubated at 37°C for 8 days, then divided into two groups and stained in DPBS with LIVE/DEAD fixable dead cell aqueous stain (Life Technologies). Immunorecall reactions were performed as described previously. FACS was performed on an LSR Fortessa (BD Biosciences), and data analysis was performed using FlowJo software (TreeStar). Data were plotted and statistical analysis was performed using GraphPad Prism software (GraphPad). Treatment with Example 49 increased the mean level of polyfunctional proliferative CD8 T cells (low CFSE, IFNg+, TNFa+) by 2.9-fold compared to treatment with DMSO. In this context, inhibition of IDO1 by INCB024360 further increased the mean level of polyfunctional proliferative CD8 T cells by 70% (p=0.05; TLR7 alone versus TLR7+IDO1, using Student's paired one-tailed t-test), as shown in FIG13 .

Example 218: Combination of Example 49 with HIV Antibody PGT121 Enhances Killing of HIV-Infected CD4 T Cells

PBMCs from 2 healthy donors (whole cells: donors ID A4593, A4596, A4606) were isolated as described above. PBMCs were treated with DMSO or 0.1 uM or 1 uM of the compound of Example 49 (GS-9620) in 8 replicate cultures for 5 days. In parallel, total CD4 T cells were isolated from each donor's PBMC using the EasySep Human CD4+ T Cell Enrichment Kit (Stemcell Technologies). CD4 T cells were infected in batches using 50-100 ng p24/million CD4 T cells with HIV-1 clinical isolate HT593 (NIH AIDS reagent program) by spinfecting at 1200 × g for 2 hours. HIV-infected CD4 T cells were incubated at 37°C in RPMI plus 10% FBS containing 30 U/mL IL-2 (Invitrogen) for 5 days. After 5 days in culture, HIV-infected CD4 T cells were washed, counted, and added to PBMCs from an autologous donor at a ratio of 20 PBMCs to 1 CD4 T cell (20:1). HIV antibody PGT121 (Gilead Sciences, Inc.) was added to each co-culture replicate at a concentration of 6.7e-5nM to 6.7e2nM. The co-cultures were incubated at 37°C for 1 day with or without HIV antibodies.

Co-cultures were collected and stained with LIVE/DEAD fixable dead cell aqueous stain (Invitrogen) and PE-Cy7-labeled CD4 antibody (BD Biosciences). Cells were fixed and permeabilized as described above and stained with PE-labeled antibody to HIV Gag protein p24 (Beckman Coulter). FACS was performed on an LSR Fortessa (BD Biosciences), and data analysis was performed using FlowJo software (TreeStar). Data were plotted and statistically analyzed using GraphPad Prism software (GraphPad). The killing rate of HIV-infected CD4 T cells can be calculated as the reduction in CD4+p24+ T cells at each PGT121 concentration compared to cultures without PGT121. For cells treated with DMSO combined with PGT121, the maximum killing rate was 30% or 40%, and the area under the curve (AUC) - which is an integral measure of killing efficacy and maximum killing rate - was 99 or 108, respectively. Relative to the DMSO control, treatment with 0.1 uM of Example 49 (GS-9620) increased the maximum killing rate by 30% or 38% and increased the AUC by 32% or 52%, respectively. Relative to the DMSO control, treatment with 1 uM of Example 49 (GS-9620) increased the maximum killing rate by 50% or 48% and increased the AUC by 52% or 73%, respectively, as shown in Figure 14.

Claims (6)

1. Use of a pharmaceutically effective amount of a TLR7-regulating compound or a pharmaceutically acceptable salt thereof with a broadly neutralizing HIV antibody in the preparation of a medicament for the treatment of virologically suppressed HIV infection in humans. The measurable viral load of the virologically suppressed individuals was less than 200 HIV-1 RNA copies/ml. The broadly neutralizing HIV antibody mentioned above is PGT121. The TLR7 regulating compound or a pharmaceutically acceptable salt thereof is a compound of the following formula: Or its pharmaceutically acceptable salt. 2. The use according to claim 1, wherein the HIV infection is eliminated from the person. 3. The use according to claim 1, wherein the measurable viral load of the person is less than 100, 50, or 20 HIV-1 RNA copies/ml. 4. The use according to claim 3, wherein the virological suppression is caused by administration of a pharmaceutically effective amount of a combination antiretroviral therapy regimen. 5. The use according to claim 4, wherein the combined antiretroviral therapy regimen comprises one or more agents selected from retegvir, aviremil, soltegravir, GSK 1265744, dolutegravir, norinosine, tenofovir disoproxil fumarate, tenofovir alafenamide, emtricitabine, lamivudine, stavudine, zidovudine, abacavir, aviremil, CMX-157, festinavir, nevirapine, epavirenz, ectavirin, rilpivirine, fosvirline, MK-1439, lesvirine, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, telanavir, furazonavir, maraviro, emfuvirtide, BMS-663068, bevirimilima, cocistat, and ritonavir; or pharmaceutically acceptable salts thereof. 6. The use according to claim 1, further comprising the use of a latency reversal agent or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating human HIV infection.