Toll-like receptor agonists and conjugates thereof

Abstract

The invention relates to compounds and immunoconjugates of Formula (IV) and pharmaceutically acceptable salts thereof, to the use of the compounds and immunoconjugates in medicine, to compositions containing the compounds and immunoconjugates; to processes for preparing the compounds and immunoconjugates, and to intermediates used in such processes. The compounds and immunoconjugates of the invention may be useful in the treatment of cancer.

Description

[0001] TOLL-LIKE RECEPTOR AGONISTS AND CONJUGATES THEREOF

[0002] Background of the Invention

[0003] Toll-like receptors (TLRs) are a family of transmembrane proteins that recognize structurally conserved molecules that are derived from and unique to pathogens, referred to as pathogen-associated molecular patterns (PAM PS). As such, TLRs function in the mammalian immune system as front-line sensors of pathogen-associated molecular patterns, detecting the presence of invading pathogens (Takeuchi and Akira 2010 Cell 140:805-820). TLR engagement in sentinel immune cells causes biosynthesis of selected cytokines (e.g., type I interferons), induction of costimulatory molecules, and increased antigen presentation capacity. These are important molecular mechanisms that activate innate and adaptive immune responses. Accordingly, agonists and antagonists of TLRs find use in modulating immune responses. TLR agonists are typically employed to stimulate immune responses, whereas TLR antagonists are typically employed to inhibit immune responses (Gosu et al 2012. Molecules 17:13503-13529).

[0004] The human genome contains 10 known TLRs, of these TLR3, TLR7, TLR8, and TLR9 recognize nucleic acids and their degradation products. The distribution of TLR7, TLR8, and TLR9 is restricted to the endosomal compartments of cells and they are preferentially expressed in cells of the immune system. In the activated dimeric receptor configuration TLR7 and TLR8 recognize single strand RNA at one ligand binding site and the ribonucleoside degradation products guanosine and uridine, respectively, (as well as small molecule ligands with related structural motifs) at a second ligand binding site (Zhang et al 2016 Immunity 45(4); 737-748: Tanji et al 2015 Nat Struct Mol Biol 22: 109-115).

[0005] Some small-molecule TLR7 or TLR8 agonists have been identified. Those agonists can be grouped into purine-like molecules, such as 7-thia-8-oxoguanosine (TOG, isatoribine) or the imidazoquinoline-based compounds such as imiquimod. Imiquimod is so far the only approved TLR7 agonist, marketed as a 5% cream (Aldara). It generates approximately 80% 5-year clearance of superficial basal cell carcinomas, which is the most common cancer worldwide, thus demonstrating the importance of TLR7 agonists in cancer immunotherapy.

[0006] Small molecule TLR agonists have also been investigated for use as vaccine adjuvants (Dowling, ImmunoHorizons 2018, 2(6) 185-197).

[0007] There are several advantages to engaging both TLR7 and TLR8 pathways instead of just one pathway. First, activation of each pathway can induce various cytokines with complementary functions. For example, engagement of TLR7 leads to the induction of interferon a / p, which plays essential functions in the control of the adaptive immune response (Bao and Liu 2013 Protein Cell 4:40-5). On the other hand, engagement of TLR8 induces a prominent pro-inflammatory cytokine profile, characterized by increased production of tumor necrosis factor-a, interleukin-12, and IL-18 (Eigenbrod et al J Immunol, 2015, 195,1092-1099).

[0008] In addition, agonizing both TLR7 and TLR8 engages different subsets of immune cells, due to distinct expression pattern of these two receptors. For example, TLR7 is mainly expressed in plasmacytoid dendritic cells, and to a lesser extent, in monocyte and macrophages. TLR8 is highly expressed in myeloid dendritic cells, macrophages, monocytes, and monocyte-derived dendritic cells.

[0009] Thus, a TLR7 / TLR8 (TLR7 / 8) small molecule agonist with dual bioactivity may provide further benefit over a more selective TLR7 agonist and would cause innate immune responses in a wider range of antigen presenting cells and other key immune cell types, including plasmacytoid and myeloid dendritic cells, monocytes, and B cells (van Haren et al 2016 J Immunol 197:4413-4424; Ganapathi et al 2015 Pios One 10(8). e0134640). As a result, TLR7 / 8 dual agonist can repolarize tumor associated macrophages from immunosuppressive M2 phenotype to immunostimulatory M1 phenotype, activate dendritic cell subsets and facilitate T cell priming. These activated T cells then migrate back, infiltrate to more tumors, further disrupt their growth, and therefore facilitate cancer-immunity cycle (Chen and Mellman, Immunity, 2013, 39, 1-10). Therefore, such potent dual TLR7 / 8 agonists may also be effective in stimulating effective anti-tumor responses in cancer (Singh et al 2014 J. Immunol 193 4722- 4731 : Sabado et al 2015 Cancer Immunol Res 3278-287, Spinetti et al 2016 Oncoimmunol 9;5(11):e1230578: Patil et al 2016 Mini Rev Med Chem 16:309-322).

[0010] However, untargeted TLR7 / 8 agonists may present toxicity if delivered via systemic administration routes. The nonspecific cellular uptake of small molecule in peripheral blood may lead to excessive systemic effect to increase the cytokine storm risk.

[0011] To overcome systemic toxicity of untargeted small molecule TLR7 / 8 agonists, a strategy has been developed, referred as immunoconjugates, by combining the properties of antibodies targeting tumor cells or immune cells in the tumor microenvironment and TLR7 / 8 agonists as payloads. Immunoconjugates guide TLR7 / 8 agonists to the antigen-expressing tumor cells or immune cells, where immunoconjugates are internalized into endosome of associated cells where TLR7 and TLR8 are present. Consequently, immunoconjugates can offer reduced systemic toxicity relative to small molecule TLR7 / 8 agonists alone, while enhancing the antitumor immunity induced by TLR7 / 8 agonists.

[0012] Despite the success of Imiquimod (Aldera) in treating superficial basal cell carcinoma, there remains a need for not only more potent TLR7 agonists, but also potent, dual TLR7 / 8 agonists to expand treatment options for patients for various cancers as well as immunoconjugates comprising a TLR7 / 8 dual agonist conjugated to antibodies targeting tumor cells or tumor associated immune cells. The present invention relates to novel TLR7 and TLR8 dual agonist compounds as well as drug-linker compounds comprising TLR7 / 8 agonists, cysteine linked drug compounds comprising TLR7 / 8 agonists, and immunoconjugates comprising TLR7 / 8 agonists. The invention also relates to the preparation of the compounds, including the drug-linker compounds and cysteine linked compounds, the immunoconjugates, and intermediates used in the preparation, compositions comprising the compounds and immunoconjugates, and methods of using the compounds and immunoconjugates alone or in combination with additional anticancer therapeutic agents.

[0013] Summary of the Invention

[0014] The present invention provides, in part: compounds of Formula (I), including Formula (l-a) [(l-a(i)), (l-a(ii)) , and l-a(iii))], Formula (l-b) [(l-b(i)) and (l-b(ii))], Formula (l-c) [(l-c(i)), (l-c(ii)), and (l-c(iii))], and Formula (l-d) [(l-d(i)) and (l-d(ii))], and pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers thereof, collectively, a compound of the invention; drug-linker compounds of Formula (II), including Formula (ll-a) [(ll-a(i)), (ll-a(ii)), (ll-b(i)), and (ll-b(ii))], and pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers thereof, collectively, a drug-linker compound of the invention; cysteine linked drug compounds of Formula (V), including Formulae (V-a), (V-b), (V-c), (V-d), (V-e), (V-f), (V-g), and (V-h), Formula (V’), including Formulae (V’-a), (V’-b), (V’-c), (V’-d), (V’-e), (V’-f), (V’-g), and (V’-h), and pharmaceutically acceptable salts, solvates, tautomers, and stereoisomers thereof, collectively, a cysteine linked drug compound of the invention; and immunoconjugates of Formula (IV), including Formulae (IV-a), (IV-b), (IV-c), (IV-d), (IV- e), (I V-f), (IV-g), and (IV-h), and tautomers and stereoisomers thereof, collectively immunoconjugates of the invention.

[0015] Such compounds and immunoconjugates activate the human TLR7 (hTLR7) and activate the human TLR8 (hTLR8), thereby affecting biological functions. In some embodiments, the invention provides compounds and immunoconjugates that are dual agonists for both TLR7 and TLR8 (TLR7 / 8 agonists). In another embodiment, the invention provides compounds and immunoconjugates that are agonists selective for TLR7.

[0016] Also provided are pharmaceutical compositions comprising the compounds or salts of the invention, alone or in combination with additional anticancer therapeutic agents. The present invention also provides, in part, methods for preparing such compounds, including the drug-linker compounds and cysteine linked drug compounds, pharmaceutically acceptable salts thereof, immunoconjugates, and the compositions of the invention.

[0017] This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0018] In one aspect, the present invention provides a compound of Formula (I): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: ring A is a 5- to 7-membered carbocyclic ring or a 5- to 6- membered heterocyclic ring in which at least one of the ring carbon atoms has been replaced by a heteroatom selected from O, N, and S, and fused to a side a; ring B is phenyl, an N-containing heteroaryl, or an N-containing heterocycloalkyl, wherein the N-containing heteroaryl and N-containing heterocycloalkyl are attached to R1through a ring N atom;

[0019] Y is a single bond or a divalent linking group selected from Ci-C8alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C(=O), Ci-C8alkylene-C(=O), C(=O)-Ci-C8alkylene, C(=O)-O-Ci-C8alkylene, Ci-C8alkylene-O-C(=O), C1-C3 alkylene-O- C1-C3 alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=O)-Ci-C3 alkylene-O-Ci-Cs alkylene;

[0020] R1is selected from the group consisting of

[0021] -H,

[0022] -C1-C20 alkyl,

[0023] - C1-C20 aminoalkyl,

[0024] - C1-C20 haloalkyl,

[0025] - C1-C20 hydroxyalkyl,

[0026] -C(=O)-Ci-C20alkyl, -C(=0)-Ci-C2o alkyl-NH2, -C(=O)-Ci-C20alkyl-OH, -C(=O)-Ci- C2o alkyl-0-Ci-Ce alkyl, -C(=0)-Ci-C2o alkyl-0-Ci-C6 alkyl-OH, which C1-C20 alkyls may be unsubstituted or substituted with one or more halogen atoms up to the available valence number,

[0027] -C(=O)-C2-C8alkenyl,

[0028] -C(=O)-C2-C8alkynyl,

[0029] -(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 and the Ci-Ce alkyl may be unsubstituted or substituted with one or more OH, azide, or NH2,

[0030] -C(=O)-O-(CH2CH2O)P-CI-C6alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 and the Ci-Ce alkyl may be unsubstituted or substituted with one or more OH, azide, or NH2,

[0031] -C(=O)-O-Ci-C6 hydroxyalkyl,

[0032] -Ci-C6alkyl-NH-C(=O)-Ci-Ce alkyl,

[0033] -Ci-C6alkyl-NH-C(=O)-O-Ci-Ce alkyl, and

[0034] -S(=O)2-Ci-C6alkyl;

[0035] R2is H, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy, wherein the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy are each unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from OH and C1-C3 alkoxy;

[0036] R3is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy;

[0037] R4is H, C1-C3 alkyl, or C1-C3 haloalkyl; and

[0038] R5is Ci-Ce alkyl, Ci-Ce haloalkyl, or (CH2)n-O-(CH2)m-CH3 optionally substituted with one or more halogen atoms up to the available valence number, where m is 0, 1 , or 2 and n is 1 , 2, or 3.

[0039] The present invention also provides, in part, a drug-linker compound of Formula (II): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0040] D is a drug unit of Formula (lll-A) or (lll-B): wherein the wave line represents the point of attachment to L, R2is H, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy, wherein the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy are each unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from OH and C1-C3 alkoxy,

[0041] R3is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy,

[0042] R4is H, C1-C3 alkyl, or C1-C3 haloalkyl, and

[0043] R5is Ci-Ce alkyl, Ci-Ce haloalkyl, or (CH2)n-O-(CH2)m-CH3 optionally substituted with one or more halogen atoms up to the available valence number, where m is 0, 1 , or 2 and n is 1 , 2, or 3, and

[0044] L is a linking group of Formula (a), (b), (c), (d), (e), (f), (g), or (h): where, in Formulae (a)-(h): the asterisk * represents the point of attachment to the N atom of the maleimide and the wave line represents the point of attachment to the drug unit, n1 is 2, 3, 4, 5, 6, 7, or 8, n2 is 1, 2, 3, 4, 5, or 6, n3 is 0, 1, 2, 3, 4, 5, or 6, n4 is 1, 2, 3, 4, 5, or 6, ml is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is H, Ci-Ce alkyl, or Ci-Ce haloalkyl.

[0045] The present invention also provides, in part, immunoconjugates comprising TLR7 / 8 agonists. In some embodiments, an immunoconjugate provided herein comprises (i) an antibody that specifically binds to an antigen on an immune cell (e.g. macrophage or dendritic cell) and (ii) one or more of the above compounds or drug-linker compounds. In some embodiments, an immunoconjugate provided herein comprises (i) an antibody that specifically binds to an antigen on an immunosuppressive tumor-associated immune cell (e.g. immunosuppressive tumor-associated macrophage) and (ii) one or more of the above compounds or drug-linker compounds. In some embodiments, an immunoconjugate provided herein comprises (i) an antibody that specifically binds to CD163 (“anti-CD163 antibody”) and (ii) one or more of the above compounds or drug-linker compounds.

[0046] In some embodiments, the immunoconjugate has Formula (IV): wherein:

[0047] Ab is an antibody;

[0048] L is a linking group of Formula (a), (b), (c), (d), (e), (f), or (g) above;

[0049] D is a drug unit of Formula (lll-A) or (Formula (lll-B) above; and r, which represents a drug-to-antibody ratio, is a number from 2 to 12, preferably r is a number from 2 to 8, more preferably r is a number from 2 to 6.

[0050] The present invention also provides, in part, a cysteine linked drug compound of Formula (V) or Formula (V’): wherein:

[0051] L is a linking group of Formula (a), (b), (c), (d), (e), (f), (g), or (h) above; and D is a drug unit of Formula (lll-A) or Formula (lll-B) above.

[0052] In another aspect, the invention provides pharmaceutical compositions comprising a compound, a drug-linker compound, a cysteine linked drug compound, or an immunoconjugate of the invention, according to any of the formulae described herein, and at least one pharmaceutically acceptable excipient.

[0053] Another aspect of the invention provides pharmaceutical compositions and medicaments comprising a compound, a drug-linker compound, a cysteine linked drug compound, or an immunoconjugate of the invention, alone or in combination with additional anticancer therapeutic agents.

[0054] In another aspect, the invention also provides therapeutic methods and uses comprising administering a compound, a drug-linker compound, a cysteine linked drug compound, or an immunoconjugate of the invention.

[0055] In another aspect, the invention provides a method for the treatment of abnormal cell growth, in particular, cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, a drug-linker compound, a cysteine linked drug compound, or an immunoconjugate of the invention. Compounds and immunoconjugates of the invention may be administered as single agents or may be administered in combination with other anti-cancer therapeutic agents, including standard of care agents appropriate for the particular form of cancer. This also includes use of a compound, a drug-linker compound, a cysteine linked drug compound, or immunoconjugate of the invention, in the manufacture of a medicament for treating abnormal cell growth, in particular, cancer, in a subject in need thereof.

[0056] In another aspect, the invention provides a compound, a drug-linker compound, a cysteine linked drug compound, or an immunoconjugate, for use as a medicament, in particular a medicament for the treatment of abnormal cell growth, such as cancer.

[0057] In yet another aspect, the invention provides the use of a compound, a drug-linker compound, a cysteine linked drug compound, or an immunoconjugate, for the manufacture of a medicament for the treatment of abnormal cell growth, such as cancer, in a subject.

[0058] In another aspect, the invention includes within its scope the pharmaceutically acceptable salts of the compounds, drug-linker compounds, cysteine linked drug compounds. Accordingly, the phrase “or a pharmaceutically acceptable salt thereof’ is implicit in the description of all compounds described herein unless explicitly indicated to the contrary.

[0059] Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) is identical to the embodiment of Formula (I) provided above, Embodiment 20 (E20) is identical to the embodiment of Formula (II) provided above, Embodiment 46 (E46) is identical to the embodiment of Formula (IV) provided above, and Embodiment 73 (E73) is identical to the embodiments of Formula (V) and Formula (V’) provided above.

[0060] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0061] Brief Description of the Drawings

[0062] Fig. 1 shows the expression of CD163 on parental HEK hTLR7 reporter cells (left) and CD163-expressing HEK hTLR7 reporter cells (right), examined by flow cytometry.

[0063] Fig. 2 shows the functional outcome indicated by luminescence induced by CD163- targeting TLR7 / 8 immunoconjugate or isotype control TLR7 / 8 immunoconjugate in parental HEK hTLR7 reporter cells (left) and CD163-expressing HEK hTLR7 reporter cells (right).

[0064] Fig. 3 shows the expression of CD163 on parental HEK hTLR8 reporter cells (left) and CD163-expressing HEK hTLR8 reporter cells (right), examined by flow cytometry.

[0065] Fig. 4 shows the functional outcome indicated by luminescence induced by CD163- targeting TLR7 / 8 immunoconjugate or isotype control TLR7 / 8 immunoconjugate in parental HEK hTLR8 reporter cells (left) and CD163-expressing HEK hTLR8 reporter cells (right).

[0066] Detailed Description of the Invention

[0067] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0068] E1 A compound of Formula (I): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as defined above.

[0069] E2 A compound of embodiment E1 , or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R3is methyl and R4is H.

[0070] E3 A compound of embodiment E1 , having Formula (l-a(i)) or Formula (l-a(ii)): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0071] R1, R2, and R5are as defined in Formula (I); ring B is the N-containing heteroaryl or the N-containing heterocycloalkyl attached to R1through a ring N atom; and

[0072] Y is a single bond or a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, C(=O), C1-C3 alkylene-C(=O), C(=O)-Ci-Cs alkylene, C(=O)-O-Ci-Cs alkylene, C1-C4 alkylene-O-C(=O), C1-C3 alkylene-O- C1-C3 alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=O)-Ci-C3 alkylene-O-Ci-Cs alkylene.

[0073] E4 A compound of embodiment E1 , having Formula (l-b(i)) or Formula (l-b(ii)) : or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0074] R1, R2, and R5are as defined in Formula (I); ring B is the N-containing heteroaryl or the N-containing heterocycloalkyl attached to R1through a ring N atom; and

[0075] Y is a single bond or a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, C(=O), C1-C3 alkylene-C(=O), C1-C4 alkylene-O- C(=O), C(=O)-Ci-Cs alkylene, C(=O)-O-Ci-Cs alkylene, C1-C3 alkylene-O-Ci-Cs alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=O)-Ci-C3 alkylene-O- C1-C3 alkylene.

[0076] E5 A compound of embodiment E1 , having Formula (l-c(i)) or Formula (l-c(ii)) : or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: ring B, R1, R2, and R5are as defined in Formula (I); and

[0077] Y is a single bond or a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, C(=O), C1-C3 alkylene-C(=O), C1-C4 alkylene-O- C(=O), C(=O)-Ci-C3 alkylene, C(=O)-O-Ci-C3 alkylene, C1-C3 alkylene-O-Ci-Cs alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=O)-Ci-C3 alkylene-O- C1-C3 alkylene.

[0078] E6 A compound of embodiment E1 , having Formula (l-d(i)) or Formula (l-d(ii)) : or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0079] R1, and R5are as defined in Formula (I); ring B is the N-containing heteroaryl or the N-containing heterocycloalkyl attached to R1through a ring N atom; and

[0080] Y is a single bond or a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, C(=O), C1-C3 alkylene-C(=O), C1-C4 alkylene-O- C(=O), C(=O)-Ci-Cs alkylene, C(=O)-O-Ci-Cs alkylene, C1-C3 alkylene-O-Ci-Cs alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=O)-Ci-C3 alkylene-O- C1-C3 alkylene.

[0081] E7 A compound of any one of embodiments E1 to E5, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R2is H.

[0082] E8 A compound of any one of embodiments E1 to E7, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring B is selected from the group consisting of: wherein the asterisk * represents the point of attachment to R1and the wave line w represents the point of attachment to Y.

[0083] E9 A compound of embodiment E8, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring B is

[0084] E10 A compound of any one of embodiments E1 to E7, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring B is selected from the group consisting of: wherein the asterisk * represents the point of attachment to R1and the wave line represents the point of attachment to Y.

[0085] E11 A compound of any one of embodiments E1 to E10, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5is Ci-Ce alkyl, preferably R5is a C3-C5 alkyl, and more preferably R5is CH2CH2CH2CH3.

[0086] E12 A compound of any one of embodiments E1 to E10, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5is (CH2)n-O-(CH2)m-CH3, where m is 1 or 2 and n is 1 , 2, or 3, preferably R5is (CH2)n-O-(CH2)m-CH3, where m is 1 and n is 1 , 2, or 3, more preferably R5is -CH2OCH2CH3.

[0087] E13 A compound of any one of embodiments E1 to E12, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Y is a Ci-Ce alkylene, a C2-C6 alkenylene, or a C2-C6 alkynylene, preferably Y is a Ci-Ce alkylene.

[0088] E14 A compound of embodiment E1 or embodiment E3, having Formula (l-a(iii)): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0089] X is -CH2- or -O-;

[0090] Y is a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, and C2- C4 alkynylene; and

[0091] R1is selected from the group consisting of -H, -C1-C20 alkyl, -C1-C20 aminoalkyl, - C(=0)-Ci-C2o alkyl, -C(=0)-Ci-C2o haloalkyl, -C(=O)-C2-C8 alkynyl, -C(=0)-Ci-C2o alkyl-OH, -C(=O)-Ci-C20alkyl-O-Ci-C6alkyl, -C(=O)-C2-C8alkynyl, -(CH2CH2O)P- Ci-C6alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, or 6 and the C1-C6 alkyl may be unsubstituted or substituted with azide, -C(=O)-O-Ci-Ce hydroxyalkyl, -C(=O)-O-(CH2CH2O)P-CI-C6 hydroxyalkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-O-(CH2CH2O)P-CI- C6aminoalkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -Ci-C6alkyl-NH-C(=O)-Ci-C6alkyl, -Ci-C6alkyl-NH-C(=O)-O-Ci-C6alkyl, and -S(=O)2-Ci-Ce alkyl.

[0092] E15 A compound of embodiment E1 or embodiment E5, having Formula (l-c(iii)): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0093] X is -CH2- or -O-;

[0094] Y is C(=O)-O-Ci-Cs alkylene; and

[0095] R1is selected from the group consisting of -H, -C1-C20 alkyl, -C1-C20 aminoalkyl, - C(=0)-Ci-C2o alkyl, -C(=0)-Ci-C2o haloalkyl, -C(=O)-C2-C8 alkynyl, -C(=0)-Ci-C2o alkyl-OH, -C(=O)-Ci-C20alkyl-O-Ci-C6alkyl, -C(=O)-C2-C8alkynyl, -(CH2CH2O)P- Ci-C6alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, or 6 and the Ci-Ce alkyl may be unsubstituted or substituted with azide, -C(=O)-O-Ci-Ce hydroxyalkyl, -C(=O)-O-(CH2CH2O)P-CI-C6 hydroxyalkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-O-(CH2CH2O)P-CI- C6aminoalkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -Ci-C6alkyl-NH-C(=O)-Ci-C6alkyl, -Ci-C6alkyl-NH-C(=O)-O-Ci-C6alkyl, and -S(=O)2-Ci-Ce alkyl.

[0096] E16 A compound of embodiment E1 , which is selected from the group consisting of: 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;

[0097] 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0098] 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;

[0099] 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1-yl)methyl)-2- methylpropane-1 ,3-diol;

[0100] 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethan-1-one;

[0101] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethan-1-one;

[0102] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-5-hydroxypentan-1-one;

[0103] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)propan-1-one;

[0104] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)oct-7-yn-1-one;

[0105] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)hexadecan-1-one;

[0106] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)octadecan-1-one;

[0107] 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)octadecan-1-one;

[0108] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2-methoxyethan-1-one; 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2-methoxyethan-1-one;

[0109] 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-methylpiperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0110] 2-((4-amino-2-butyl-7-(3-(4-methylpiperazin-1-yl)propyl)-1H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1,3-diol;

[0111] 2-((4-amino-2-butyl-7-(3-(4-butylpiperazin-1-yl)propyl)-1H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1,3-diol;

[0112] 2-((4-amino-7-(3-(4-butylpiperazin-1-yl)propyl)-2-(ethoxymethyl)-1H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0113] 2-((4-amino-2-butyl-7-(3-(4-pentylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1,3-diol;

[0114] 2-((4-amino-2-butyl-7-(3-(4-octadecylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1,3-diol;

[0115] 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-octadecylpiperazin-1-yl)propyl)-1H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0116] 2-((4-amino-2-butyl-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propyl)-1H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0117] 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propyl)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0118] 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-1 / 7- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0119] 3-hydroxypropyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0120] 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1 -carboxylate;

[0121] 2-(2-(2-aminoethoxy)ethoxy)ethyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)- 2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1-carboxylate;

[0122] 2-((4-amino-2-butyl-7-(3-(4-(butylsulfonyl)piperazin-1-yl)propyl)-1H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0123] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide;

[0124] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide;

[0125] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3-(2-azidoethoxy)propan-1-one; benzyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1, 6,8,9- tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0126] 1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;

[0127] 2-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;

[0128] 3-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;

[0129] 4-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;

[0130] 2-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-

[0131] 2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7- carboxylate;

[0132] 3-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-

[0133] 2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;

[0134] 4-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-

[0135] 2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;

[0136] 2-(piperidin-4-yl)ethyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0137] 1.6.8.9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; and

[0138] 2-(piperazin-1-yl)ethyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0139] 1.6.8.9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0140] E17 A compound of embodiment E1 , which is selected from the group consisting of:

[0141] 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1,3-diol;

[0142] 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;

[0143] 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;

[0144] 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2- methylpropane-1 ,3-diol;

[0145] 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethan-1-one;

[0146] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethan-1-one; 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)octadecan-1-one;

[0147] 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)octadecan-1-one;

[0148] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2-methoxyethan-1-one;

[0149] 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2-methoxyethan-1-one;

[0150] 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-methylpiperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0151] 2-((4-amino-2-butyl-7-(3-(4-methylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;

[0152] 2-((4-amino-2-butyl-7-(3-(4-butylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;

[0153] 2-((4-amino-7-(3-(4-butylpiperazin-1-yl)propyl)-2-(ethoxymethyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0154] 2-((4-amino-2-butyl-7-(3-(4-octadecylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;

[0155] 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-octadecylpiperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0156] 2-((4-amino-2-butyl-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0157] 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propyl)-1 H- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0158] 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-1 / 7- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;

[0159] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide;

[0160] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide;

[0161] 1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3-(2-azidoethoxy)propan-1-one; benzyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 , 6,8,9- tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 ,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; 2-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;

[0162] 3-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate; and

[0163] 2-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-

[0164] 2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;

[0165] 3-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-

[0166] 2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7- carboxylate;

[0167] 4-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-

[0168] 2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;

[0169] 2-(piperidin-4-yl)ethyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0170] 1.6.8.9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; and

[0171] 2-(piperazin-1-yl)ethyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0172] 1.6.8.9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0173] E18 A compound of embodiment E1 , which is 2-((4-amino-2-butyl-7-(3-(piperazin-1- yl)propyl)-1 H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol.

[0174] E19 A compound of embodiment E1, which is pharmaceutically acceptable salt of 2-((4- amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1-yl)methyl)-2- methylpropane-1 ,3-diol.

[0175] Any of the compounds described in embodiments E16 to E19, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, may be claimed individually or grouped together with one or more other compounds of embodiments E1 to E15, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof.

[0176] E20 A drug-linker compound of Formula (II): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as defined above.

[0177] E21 A drug-linker compound of embodiment E20, having Formula (I l-a(i)) , (ll-a(ii)), (I l-b(i)), or or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0178] E22 A drug-linker compound of embodiment E20 or embodiment E21 , or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R2is H.

[0179] E23 A drug-linker compound of any one of embodiments E20 to E22, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R3is C1-C3 alkyl, preferably methyl. E24 A drug-linker compound of any one of embodiments E20 to E23, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R4is H.

[0180] E25 A drug-linker compound of any one of embodiments E20 to E24, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5is Ci-Ce alkyl, preferably R5is a C3-C5 alkyl, and more preferably R5is CH2CH2CH2CH3.

[0181] E26 A drug-linker compound of any one of embodiments E20 to E24, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5is (CH2)n-O- (CH2)m-CH3, where m is 1 or 2 and n is 1 , 2, or 3, preferably R5is (CH2)n-O-(CH2)m-CH3, where m is 1 and n is 1 , 2, or 3, more preferably R5is -CH2OCH2CH3.

[0182] E27 A drug-linker compound of any one of embodiments E20 to E24, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R5is - CH2CH2CH2CH3 or -CH2OCH2CH3.

[0183] E28 A drug-linker compound of any one of embodiments E20 to E27, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formulae (a) to (h), n4 is an integer from 1 to 4, preferably n4 is an integer 1 to 3, and more preferably n4 in Formulae (a) to (g) is 3 and n4 in Formula (h) is 1.

[0184] E29 A drug-linker compound of any one of embodiments E20 to E28, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formulae (a) to (h), n1 is an integer from 2 to 5, preferably n1 is an integer from 2 or 5, and more preferably n1 is 2.

[0185] E30 A drug-linker compound of any one of embodiments E20 to E29, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formulae (a), (b), (c), (e), (f), and (g), n3 is 0.

[0186] E31 A drug-linker compound of any one of embodiments E20 to E29, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formulae (d), (e), (f), and (h), R is H.

[0187] E32 A drug-linker compound of any one of embodiments E20 to E30, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the linking group L has Formula (b):

[0188] E33 A drug-linker compound of embodiment E32, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formula (b), n3 is 0 and ml is an integer from 1 to 14, preferably from 1 to 11 , more preferably from 1 to 7, more preferably from 1 to 3, and most preferably 1.

[0189] E34 A drug-linker compound of any one of embodiments E20 to E29 and E31 , or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, the linking group L has Formula (d):

[0190] E35 A drug-linker compound of embodiment E34, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formula (d), n2 is an integer from 1 to 5, preferably from 2 to 5, and more preferably 4, and ml is an integer from 1 to 12, preferably from 3 to 8, more preferably from 4 to 8, more preferably from 6 to 8, and most preferably 8.

[0191] E36 A drug-linker compound of any one of embodiments E32 to E35, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, in Formulae (b) and (d), n1 is 2 and n4 is 3.

[0192] E37 A drug-linker compound of any one of embodiments E20 to E30, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, the linking group L has Formula wherein n3 is 0 and ml is an integer from 1 to 12, more preferably from 4 to 8, more preferably from 6 to 8, and most preferably 8.

[0193] E38 A drug-linker compound of any one of embodiments E20 to E30, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, the linking group L has Formula (a): wherein n3 is 0.

[0194] E39 A drug-linker compound of any one of embodiments E20 to E29 and E31 , or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein, the linking group L has Formula (h): wherein: n1 is 2; ml is an integer from 1 to 12, preferably from 3 to 8; n2 is an integer from 1 to 5, preferably from 1 to 3, and more preferably 1 ; and n4 is an integer from 1 to 5, preferably from 1 to 3, and more preferably 1.

[0195] E40 A drug-linker compound of embodiment E20, which is selected from the group consisting of: N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15,18,21 ,24-octaoxaheptacosan-27-amide;

[0196] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-3-(2-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol-1-yl)ethoxy)propanamide;

[0197] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-3-(2-(2-(2-(2,5-dioxo-2,5- dihydro-1 H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propenamide; N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-3-(2-(2-(2-(2,5-dioxo-2,5- dihydro-1 H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propenamide;

[0198] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-amide;

[0199] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol-1-yl)-3,6,9,12-tetraoxapentadecan-15-amide;

[0200] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15-pentaoxaoctadecan-18-amide;

[0201] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol-1-yl)-3,6,9,12,15-pentaoxaoctadecan-18-amide;

[0202] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15,18-hexaoxahenicosan-21-amide;

[0203] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)-3,6,9,12,15,18-hexaoxahenicosan-21-amide;

[0204] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol-1 -y l)-3 , 6 , 9 , 12,15,18,21 ,24-octaoxaheptacosan-27-amide;

[0205] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39-amide;

[0206] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol-1-yl)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39- amide;

[0207] 1-(2-(3-(4-(3-(4-Amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3- oxopropoxy)ethyl)-1 / 7-pyrrole-2, 5-dione;

[0208] 1-(27-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-27-oxo-3,6,9,12,15,18,21 ,24- octaoxaheptacosyl)-1H-pyrrole-2, 5-dione; 1-(6-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-6-oxohexyl)-1 H-pyrrole-2, 5-dione;

[0209] 1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1H-pyrrole-2, 5-dione;

[0210] 1-(2-(2-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1H- pyrrole-2, 5-dione;

[0211] 1-(2-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethoxy)ethyl)-1 H-pyrrole-2,5- dione;

[0212] 1-(2-(2-(2-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethoxy)ethoxy)ethyl)-1H-pyrrole-2, 5-dione;

[0213] 1-(2-(2-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1 H- pyrrole-2, 5-dione;

[0214] 1-(2-(2-(2-(2-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethoxy)ethoxy)ethoxy)ethyl)-1 H-pyrrole-2, 5-dione;

[0215] 1-(23-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9,12,15,18,21- heptaoxatricosyl)-1 H-pyrrole-2, 5-dione;

[0216] 1-(23-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0217] 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9, 12, 15, 18,21 - heptaoxatricosyl)-1 H-pyrrole-2, 5-dione;

[0218] 1-(32-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9,12,15,18,21,24,27,30- decaoxadotriacontyl)-1H-pyrrole-2, 5-dione;

[0219] 1-(32-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0220] 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9, 12, 15, 18,21 ,24,27,30- decaoxadotriacontyl)-1H-pyrrole-2, 5-dione;

[0221] 1-(35-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9,12,15,18,21,24,27,30,33- undecaoxapentatriacontyl)-1H-pyrrole-2, 5-dione;

[0222] 1-(35-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9,12,15,18,21 ,24,27,30,33- undecaoxapentatriacontyl)-1H-pyrrole-2, 5-dione; 1-(44-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-

[0223] 3,6,9, 12,15, 18,21 ,24,27,30,33,36,39,42-tetradecaoxatetratetracontyl)-1 H-pyrrole- 2, 5-dione;

[0224] 1-(44-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-

[0225] 3,6,9, 12, 15, 18,21 ,24,27,30,33,36,39,42-tetradecaoxatetratetracontyl)-1 H-pyrrole- 2, 5-dione; and

[0226] / V-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-4-oxobutyl)-1-(2,5-dioxo-2,5- dihydro-1 / 7-pyrrol-1-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0227] E41 A drug-linker compound of embodiment E20, which is selected from the group consisting of: N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide;

[0228] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-3-(2-(2-(2-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)ethoxy)ethoxy)ethoxy)propenamide;

[0229] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol- 1 -y I) -3 , 6 , 9, 12-tetraoxapentadecan- 15-am ide;

[0230] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15-pentaoxaoctadecan-18-amide;

[0231] N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15,18-hexaoxahenicosan-21-amide;

[0232] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1 H-pyrrol-1 -yl)-3,6,9, 12, 15,18,21 ,24-octaoxaheptacosan-27-amide;

[0233] N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxanonatriacontan-39- amide; 1-(2-(3-(4-(3-(4-Amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3- oxopropoxy)ethyl)-1 / 7-pyrrole-2, 5-dione;

[0234] 1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1 H-pyrrole-2, 5-dione;

[0235] 1-(2-(2-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1 H- pyrrole-2, 5-dione;

[0236] 1-(2-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethoxy)ethyl)-1 H-pyrrole-2, 5- dione;

[0237] 1-(2-(2-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethoxy)ethoxy)ethyl)-1 H- pyrrole-2, 5-dione;

[0238] 1-(23-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9,12,15,18,21- heptaoxatricosyl)-1 H-pyrrole-2, 5-dione;

[0239] 1-(32-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9, 12, 15, 18,21 ,24,27,30- decaoxadotriacontyl)-1 H-pyrrole-2, 5-dione; and

[0240] 1-(35-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3,6,9,12,15,18,21 ,24,27,30,33- undecaoxapentatriacontyl)-1 H-pyrrole-2, 5-dione, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0241] E42 A drug-linker compound of embodiment E20, which is N-(4-(4-(3-(4-amino-2-butyl-1-(3- hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-7- yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H-pyrrol-1-yl)- 3,6,9, 12,15, 18,21 ,24-octaoxaheptacosan-27-amide.

[0242] E43 A drug-linker compound of embodiment E20, which is a pharmaceutically acceptable salt of N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1 H- pyrrol-1-yl)-3,6,9,12,15,18,21 ,24-octaoxaheptacosan-27-amide. E44 A drug-linker compound of embodiment E20, which is 1-(2-(2-(4-(3-(4-amino-2-butyl-1- (3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7- yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1H-pyrrole-2, 5-dione.

[0243] E45 A drug-linker compound of embodiment E20, which is a pharmaceutically acceptable salt of 1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1 H-pyrrole-2, 5-dione.

[0244] Any of the drug-linker compounds described in embodiment E40, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, may be claimed individually or grouped together with one or more other drug-linker compounds of embodiments E20 to E39, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof.

[0245] E46 An immunoconjugate of Formula (IV): or tautomer or stereoisomer thereof, as defined above.

[0246] E47 An immunoconjugate of embodiment E46, or tautomer or stereoisomer thereof, wherein the drug unit of Formula (lll-A) is a drug unit of Formula (I I l-a(i)) or Formula (I I l-a(ii)) and the drug unit of Formula (lll-B) is a drug unit of Formula (I I l-b(i)) or Formula (lll-b(ii)): E48 An immunoconjugate of embodiment E46 or embodiment E47, or tautomer or stereoisomer thereof, wherein R2is H.

[0247] E49 An immunoconjugate of any one of embodiments E46 to E48, or tautomer or stereoisomer thereof, wherein R3is C1-C3 alkyl, preferably methyl.

[0248] E50 An immunoconjugate of any one of embodiments E46 to E49, or tautomer or stereoisomer thereof, wherein R4is H.

[0249] E51 An immunoconjugate of any one of embodiments E46 to E50, or tautomer or stereoisomer thereof, wherein R5is Ci-Ce alkyl, preferably R5is a C3-C5 alkyl, and more preferably R5is CH2CH2CH2CH3.

[0250] E52 An immunoconjugate of any one of embodiments E46 to E50, or tautomer or stereoisomer thereof, wherein R5is (CH2)n-O-(CH2)m-CH3, where m is 1 or 2 and n is 1 , 2, or 3, preferably R5is (CH2)n-O-(CH2)m-CH3, where m is 1 and n is 1 , 2, or 3, more preferably R5is -CH2OCH2CH3.

[0251] E53 An immunoconjugate of any one of embodiments E46 to E50, or tautomer or stereoisomer thereof, wherein R5is -CH2CH2CH2CH3 or -CH2OCH2CH3.

[0252] E54 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein the linking group L has Formula (b):

[0253] E55 An immunoconjugate of embodiment E54, or tautomer or stereoisomer thereof, wherein, in Formula (b), n3 is 0 and ml is an integer from 1 to 14, preferably from 1 to 11 , more preferably from 1 to 7, more preferably from 1 to 3, and most preferably 1.

[0254] E56 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein, the linking group L has Formula (d):

[0255] E57 An immunoconjugate of embodiment E56, or tautomer or stereoisomer thereof, wherein, in Formula (d), n2 is an integer from 1 to 5, preferably from 2 to 5, and more preferably 4, and ml is an integer from 1 to 12, preferably from 3 to 8, more preferably from 4 to 8, more preferably from 6 to 8, and most preferably 8.

[0256] E58 An immunoconjugate of any one of embodiments E54 to E57, or tautomer or stereoisomer thereof, wherein, in Formulae (b) and (d), n1 is 2 and n4 is 3.

[0257] E59 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein, in Formulae (a) to (h), n1 is an integer from 2 to 5, preferably 2 or 5, and more preferably 2.

[0258] E60 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein, in Formulae (a) to (h), n4 is an integer from 1 to 4, preferably 1 to 3, and more preferably n4 in Formulae (a) to (g) is 3 and n4 in Formula (h) is 1.

[0259] E61 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein, the linking group L has Formula (c): wherein n3 is 0 and ml is an integer from 1 to 12, more preferably from 4 to 8, more preferably from 6 to 8, and most preferably 8.

[0260] E62 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein, the linking group L has Formula (a): wherein n3 is 0.

[0261] E63 An immunoconjugate of any one of embodiments E46 to E53, or tautomer or stereoisomer thereof, wherein, the linking group L has Formula (h): wherein: n1 is 2; ml is an integer from 1 to 12, preferably from 3 to 8; n2 is an integer from 1 to 5, preferably from 1 to 3, and more preferably 1; and n4 is an integer from 1 to 5, preferably from 1 to 3, and more preferably 1.

[0262] E64 An immunoconjugate of embodiment E46 or embodiment E47, having Formula (IV-a), or tautomer or stereoisomer thereof.

[0263] E65 An immunoconjugate of embodiment E64, wherein, in Formulae (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (I V-f), (IV-g), and (IV-h):

[0264] X is -CH2- or -O-;

[0265] R is H, C1-C6 alkyl, or Ci-Ce haloalkyl, preferably H or C1-C3 alkyl; n1 is 2, 3, 4, 5, or 6, preferably n1 is 2, 3, 4, or 5, more preferably n1 is 2 or 5, and even more preferably n1 is 2; n2 is 1 , 2, 3, 4, 5, or 6; n4 is 1 , 2, 3, 4, or 5, preferably n4 is 1 , 2, 3, or 4, and more preferably n4 in Formulae (IV-a) to (IV-g) is 3 and n4 in Formula (IV-h) is 1 ; ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, preferably ml is 1 , 2, 3, 4, 5, 6, 7,

[0266] 8, 9, 10, 11 , or 12, more preferably m 1 is 1 , 2, 3, 4, 5, 6, 7, or 8; and r is a number from 2 to 10, preferably r is a number from 2 to 8, more preferably r is a number from 2 to 6.

[0267] E66 An immunoconjugate of embodiment E65, having Formula (IV-b): or tautomer or stereoisomer thereof, wherein: n1 is 2; n4 is 3; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, preferably ml is 1 , 2, 3, 7, 10, 11 , or 14, more preferably ml is 1 , 2, or 3, and most preferably ml is 1. E67 An immunoconjugate of embodiment E66, having Formula (I V-b(i)): or tautomer or stereoisomer thereof.

[0268] E68 An immunoconjugate of embodiment E65, having Formula (IV-d): or tautomer or stereoisomer thereof, wherein: n1 is 2; n2 is 4; n4 is 3; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, preferably ml is 1 , 3, 4, 5, 6, 8, or 12, more preferably ml is 6, 8, or 12, most preferably ml is 8.

[0269] E69 or tautomer or stereoisomer thereof.

[0270] E70 An immunoconjugate of embodiment E65, having Formula (IV-h): or tautomer or stereoisomer thereof, wherein: n1 is 2; n2 is 1; n4 is 1; ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and R is H.

[0271] E71 An immunoconjugate of any one of embodiments E46 to E70, wherein Ab is an antibody that specifically binds to an antigen on an immunosuppressive tumor-associated myeloid cell.

[0272] E72 An immunoconjugate of any one of embodiments E46 to E70, wherein Ab is antibody that specifically binds to CD163.

[0273] E73 A cysteine linked drug compound of Formula (V) or Formula (V’): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as defined above.

[0274] E74 A cysteine linked drug compound of embodiment E73, having Formula (V-a), (V-b), (V- c), (V-d), (V-e), (V-f), (V-g), (V-h), (V’-a), (V’-b), (V’-c), (V’-d), (V’-e), (V’-f), (V’-g), of (V’- h):

[0275] or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

[0276] X is -CH2- or -O-;

[0277] R is H, C1-C6 alkyl, or Ci-Ce haloalkyl preferably R is H or C1-C3 alkyl, more preferably H; n1 is 2, 3, 4, 5, or 6, preferably n1 is 2, 3, 4, or 5, more preferably n1 is 2 or 5, and even more preferably n1 is 2; n2 is 1 , 2, 3, 4, 5, or 6; n4 is 1 , 2, 3, 4, or 5, preferably n4 is 1 , 2, 3, or 4, and more preferably n4 in Formulae (V-a) to (V-g) and Formulae (V’-a) to (V’-g) is 3 and n4 in Formula (V- h) and Formula (V’h) is 1 ; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, preferably ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, more preferably m 1 is 1 , 2, 3, 4, 5, 6, 7, or 8. E75 A cysteine linked drug compound of embodiment E73 or embodiment E74, having or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n1 is 2; n4 is 3; and ml is an integer from 1 to 14, preferably m is an integer from 1 to 10.

[0278] E76 A cysteine linked drug compound of embodiment E73 or embodiment E74, having

[0279] Formula (V-d) or Formula (V’-d): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n1 is 2; n2 is 4; n4 is 3; and ml is an integer from 1 to 12, preferably 1, 3, 4, 5, 6, 8, or 12, more preferably 6, 8, or 12, most preferably 8.

[0280] E77 A cysteine linked drug compound of embodiment E73 or embodiment E74, having

[0281] Formula (V-h) or Formula (V’-h): or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: n1 is 2; n2 is 1; n4 is 1; and ml is an integer from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12; and

[0282] R is H.

[0283] E78 A cysteine linked drug compound of embodiment E76, which is selected from the group consisting of: S-(1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-2,5-dioxopyrrolidin-3- yl)-L-cysteine;

[0284] (3F?)-6-(2-((2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)amino)-2-oxoethyl)- 5-oxothiomorpholine-3-carboxylic acid; S-(1-(32-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-27-oxo-3,6,9,12,15,18,21 ,24- octaoxa-28-azadotriacontyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine;

[0285] (3R)-6-(35-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21,24,27- octaoxa-3,31-diazapentatriacontyl)-5-oxothiomorpholine-3-carboxylic acid; and S-((RS)-1-(32-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)- 3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine, or pharmaceutically acceptable salt, solvate, or tautomer, or stereoisomer thereof.

[0286] E79 A cysteine linked drug compound of embodiment E78, which is S-(1-(2-(2-(4-(3-(4-amino- 2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7- yl)propyl)piperazin-1-yl)ethoxy)ethyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine.

[0287] E80 A cysteine linked drug compound of embodiment E78, which is S-(1-(32-(4-(3-(4-amino- 2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7- yl)propyl)piperazin-1-yl)-27-oxo-3,6,9,12,15,18,21 ,24-octaoxa-28-azadotriacontyl)-2,5- dioxopyrrolidin-3-yl)-L-cysteine.

[0288] E81 A cysteine linked drug compound of embodiment E78, which is (3R)-6-(2-((2-(2-(4-(3-(4- amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5- c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)amino)-2-oxoethyl)-5- oxothiomorpholine-3-carboxylic acid.

[0289] E82 A cysteine linked drug compound of embodiment E78, which is (3R)-6-(35-(4-(3-(4- amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H-imidazo[4,5- c]quinolin-7-yl)propyl)piperazin-1-yl)-2,30-dioxo-6,9,12,15,18,21 ,24,27-octaoxa-3,31- diazapentatriacontyl)-5-oxothiomorpholine-3-carboxylic acid.

[0290] Any of the cysteine linked drug compounds described in embodiment E78, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, may be claimed individually or grouped together with one or more other cysteine linked drug compounds of embodiments E73 to E77, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof. E83 A pharmaceutical composition comprising a compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0291] E84 A pharmaceutical composition comprising an immunoconjugate of any one of embodiments E46 to 72, or tautomer or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0292] E85 A method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0293] E86 A method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, as a single agent.

[0294] E87 A method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of: a compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof; and a therapeutically effective amount of an additional anti-cancer therapeutic agent.

[0295] E88 A method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount an immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof.

[0296] E89 A method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof, as a single agent.

[0297] E90 A method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of: an immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof; and a therapeutically effective amount of an additional anti-cancer therapeutic agent. E91 A compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for use as a medicament.

[0298] E92 A compound of any one embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for use in the treatment of cancer.

[0299] E93 Use of a compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0300] E94 Use of a drug-linker compound of any one of embodiments E20 to E45, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0301] E95 An immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof, for use as a medicament.

[0302] E96 An immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof, for use in the treatment of cancer.

[0303] E97 Use of an immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0304] E98 Use of a cysteine linked drug compound of any one of embodiments E73 to E82, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0305] E99 A method for the treatment of a disorder mediated by TLR7 or TLR8 in a subject, comprising administering to the subject in need thereof a compound of any one of embodiments E1 to E19, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount that is effective for treating the disorder.

[0306] E100 A method for the treatment of a disorder mediated by TLR7 or TLR8 in a subject, comprising administering to the subject in need thereof an immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof, in an amount that is effective for treating the disorder. E101 A pharmaceutical combination comprising: a compound of any one of embodiments E1 to E19 or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof; and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof.

[0307] E102 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E101 and at least one excipient.

[0308] E103 A pharmaceutical combination comprising: an immunoconjugate of any one of embodiments E46 to E72, or tautomer or stereoisomer thereof; and at least one additional therapeutic agent or a pharmaceutically acceptable salt thereof.

[0309] E104 A pharmaceutical composition comprising the pharmaceutical combination of embodiment E103 and at least one excipient.

[0310] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. In addition, any of the compounds, including the drug-linker compounds and cysteine linked compounds, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, and immunoconjugates, or tautomers or stereoisomers thereof, described in the Examples, may be claimed individually or grouped together with one or more other compounds, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, or immunoconjugates, or tautomers or stereoisomers thereof, of the Examples, for any of the embodiment(s) described herein.

[0311] Furthermore, each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts, solvates, tautomers, and stereoisomer of the compounds described herein, including the drug-linker compounds and cysteine linked compounds, and tautomers and stereoisomers of the immunoconjugates described herein.

[0312] Definitions

[0313] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0314] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. “Compounds of the invention” include compounds of Formula (I), drug-linker compounds of Formula (II), cysteine linked compounds of Formula (V), and the novel intermediates used in the preparation thereof. One of ordinary skill in the art will appreciate that compounds of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate that compounds of the invention include solvates, esters, salt forms, and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0315] As used herein, the term “immunoconjugate” means a conjugation body in which two substances are covalently linked. In the immunoconjugate, the two substances may be linked directly or may be linked via a linker. In the present invention, one of the two substances is an antibody or antigen-binding fragment thereof, and the other is an agonist for TLR7 or a dual agonist for TLR7 and TLR8. In the present invention, the linker may be a cleavable linker or may be a non-cleavable linker.

[0316] “Immunoconjugates of the invention” include immunoconjugates of Formula (IV). One of ordinary skill in the art will appreciate that immunoconjugates of the invention include conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, tautomers thereof, where they may exist. One of ordinary skill in the art will also appreciate the immunoconjugates of the invention include esters and isotopically labelled versions thereof (including deuterium substitutions), where they may be formed.

[0317] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0318] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of the TLR7 or TLR8 agonists, compounds, or immunoconjugates) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5% ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.

[0319] If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

[0320] "Consists essentially of," and variations such as "consist essentially of' or "consisting essentially of," as used throughout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion of other elements, of similar or different nature than the recited elements, that do not materially change the basic or novel properties of the specified dosage regimen, method, or composition. “Optional" or "optionally" means that the subsequently described event or circumstance may, but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

[0321] The terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e. , unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different. Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense to one of ordinary skill in the art.

[0322] “Halogen” or “halo” refers to fluoro, chloro, bromo, and iodo (F, Cl, Br, I).

[0323] "Hydroxy" refers to an -OH group.

[0324] "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-C12 alkyl”), 1 to 8 carbon atoms (“Ci-Cs alkyl”), 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

[0325] "Alkylene" refers to a straight or branched divalent aliphatic hydrocarbon radical containing no unsaturation. Alkylene groups may contain, but are not limited to 1-12 carbon atoms (“C1-C12 alkylene”), 1 to 8 carbon atoms (“Ci-Cs alkylene”), 1 to 6 carbon atoms (“Ci-Ce alkylene”), 1 to 3 carbon atoms (“C1-C3 alkylene”), or 1 to 2 carbon atoms (“C1-C2 alkylene”). Examples include, but are not limited to, ethylene, propylene, n-butylene, and the like.

[0326] “Alkenyl” refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, as used herein, the term "C2- Ce alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, 2- methylpropenyl, pentenyl, hexenyl, and the like.

[0327] “Alkenylene” refers to a straight or branched divalent hydrocarbon radical containing one or more carbon-carbon double bonds. Alkenylene groups may contain, but are not limited to, 2 to 12 carbon atoms (“C2-C12 alkenylene”), 2 to 8 carbon atoms (“Ci-Cs alkenylene”), 2 to 6 carbon atoms (“Ci-Ce alkenylene”), 2 to 5 carbon atoms (“C2-C5 alkenylene”), 2 to 4 carbon atoms (“C2-C4 alkenylene”), or 2 to 3 carbon atoms (“C2-C3 alkenylene”). Examples include, but are not limited to, ethene-1 ,2-diyl, propene-1 ,3-diyl, methylene-1 ,1-diyl, and the like.

[0328] “Alkynyl” refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, pentynyl, hexynyl, and the like.

[0329] “Alkynylene” refers to a straight or branched divalent hydrocarbon radical containing one or more carbon-carbon triple bonds. Alkynylene groups may contain, but are not limited to, 2 to 12 carbon atoms (“C2-C12 alkynylene”), 2 to 8 carbon atoms (“Ci-Cs alkynylene”), 2 to 6 carbon atoms (“Ci-Ce alkynylene”), 2 to 5 carbon atoms (“C2-C5 alkynylene”), 2 to 4 carbon atoms (“C2-C4 alkynylene”), or 2 to 3 carbon atoms (“C2-C3 alkynylene”). Examples include, but are not limited to, ethyne-1 ,2-diyl, propyne-1 ,3-diyl, and the like.

[0330] “Haloalkyl” refers to an alkyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkyl groups man contain, but are not limited to, 1-6 carbon atoms (“Ci-Ce haloalkyl”), 1-4 carbon atoms (“C1-C4 haloalkyl”), or 1-2 carbon atoms (“C1-C2 haloalkyl”). More specifically, fluorinated alkyl groups may be specifically referred to as “fluoroalkyl.”

[0331] “Fluoroalkyl” refers to an alkyl group, as defined herein, wherein from one to all of the hydrogen atoms of the alkyl group are replaced by fluoro atoms. Examples include, but are not limited to, fluoromethyl, difluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and tetrafluoroethyl. Examples of fully substituted fluoroalkyl groups (also referred to as perfluoroalkyl groups) include trifluoromethyl (-CF3) and pentafluoroethyl (-C2F5).

[0332] “Alkoxy” refers to an alkyl group, as defined herein, that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as alkyl-O-. Alkoxy groups may contain, but are not limited to, 1 to 8 carbon atoms (“Ci-Cs alkoxy”), 1 to 6 carbon atoms (“Ci-Ce alkoxy”), 1 to 4 carbon atoms (“C1-C4 alkoxy”), or 1 to 3 carbon atoms (“C1-C3 alkoxy”). Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isobutoxy, pentoxy, hexyloxy, and the like.

[0333] “Haloalkoxy” refers to an alkoxyl group as defined above containing the specified number of carbon atoms wherein at least one hydrogen atom has been replaced by halogen. Haloalkoxy groups may contain, but are not limited to, 1-6 carbon atoms, (“Ci-Ce haloalkoxy”), 1-4 carbon atoms (“C1-C4 haloalkoxy”), or 1-2 carbon atoms (“C1-C2 haloalkoxy”). More specifically, fluorinated alkoxyl groups may be specifically referred to as “fluoroalkoxy.” “Alkoxyalkyl” refers to an alkyl group, as defined herein, that is substituted by an alkoxy group, as defined herein. Examples include, but are not limited to, CH3OCH2- and CH3CH2OCH2-.

[0334] “Aminoalkyl” refers to an alkyl group, as defined above, that is substituted by 1 , 2, or 3 amino (-NH2) groups.

[0335] “Hydroxyalkyl” refers to an alkyl group, as defined above, that is substituted by 1 , 2, or 3 hydroxy (-OH) groups.

[0336] “5- to 7-membered carbocyclic ring" refers to a cyclic group containing 5 to 7 carbon atoms where the ring may be aromatic or non-aromatic, and where a substituent can occur on any carbon of sufficient valency. Examples include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, and the like.

[0337] “5- to 6-membered heterocyclic ring" refers to a 5- to 6- membered carbocyclic group in which at least one of the ring carbon atoms has been replaced by a heteroatom selected from oxygen, nitrogen, and sulfur, where the ring may be aromatic or non-aromatic, and where a substituent can occur on any atom of sufficient valency. In certain embodiments, the 5- to 6- membered heterocyclic ring contains 1 , 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In certain embodiments, the 5- to 6-membered heterocyclic ring contains 1 or 2 nitrogen atoms.

[0338] “N-containing heteroaryl” refers to a monocyclic ring system containing 5 to 10 ring atoms with at least one nitrogen as a ring member, and optionally further containing oxygen and sulfur as a ring members in a ring in which all carbon atoms in the ring are of sp2hybridization and in which the pi electrons are in conjugation. Such a heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring heteroatom atom. Nonlimiting examples include imidazolyl, pyrazolyl, or pyrrolyl, wherein the N of the heteroaryl is substituted with R1. Non-limiting examples of such N-containing heteroaryl include: where the can attach to the heteroaryl at any atom of sufficient valency and provides the point of attachment within ring B.

[0339] “N-containing heterocycloalkyl” as used herein, refers to a fully saturated cycloalkyl ring system in which one or more of the ring methylene groups (-CH2-) has been replaced with -NR- (in which R is replaced by a bond through which the group is attached to bond to Y or ring A or is R1) and optionally a further ring methylene group is replaced with a heteroatom selected from oxygen and sulfur. Non-limiting examples of N-containing heterocycloalkyl include pyrazolidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein the N of the heterocycloalkyl is substituted with R1. Non-limiting examples of such N-containing heterocycloalkyl include: where the v / vw* can attach to the heterocycloalkyl at any atom of sufficient valency and provides the point of attachment within ring B.

[0340] “Amino” refers to a group -NH2, which is unsubstituted. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NR’R”, where each of R’ and R” is defined as further described herein. For example, “alkylamino” refers to a group -NR’R”, wherein one of R’ and R” is an alkyl moiety and the other is H, and “dialkylamino” refers to -NR’R” wherein both of R’ and R” are alkyl moieties, where the alkyl moieties have the specified number of carbon atoms (e.g., -NH(CI-C4 alkyl) or -N(Ci-C4 alkyl^).

[0341] “Deuterium enrichment factor” as used herein means the ratio between the deuterium abundance and the natural abundance of deuterium, each relative to hydrogen abundance. An atomic position designated as having deuterium typically has a deuterium enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). The term “pharmaceutically acceptable” means the substance (e.g., the compounds and immunoconjugates described herein) and any salt thereof, or composition containing the substance or salt of the invention is suitable for administration to a subject or patient.

[0342] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof as an active ingredient, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients. In some embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent. In some such embodiments, the combination provides an additive, greater than additive, or synergistic anticancer effect.

[0343] "Excipient" as used herein describes any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0344] As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0345] “Biotherapeutic agent” means a biological molecule, such as an antibody or fusion protein, that blocks ligand I receptor signaling in any biological pathway that supports tumor maintenance and / or growth or suppresses the anti-tumor immune response.

[0346] “Chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Chemotherapeutic agents useful in the treatment methods of the present invention include cytostatic and / or cytotoxic agents. Chemotherapeutic agents include the agent itself or any pharmaceutically acceptable salt, co-crystal, or solvate thereof.

[0347] “Cytotoxic agent” refers to an agent that has a cytotoxic and / or cytostatic effect on a cell and a “cytostatic effect” refers to the inhibition of cell proliferation.

[0348] “Cytostatic agent” refers to an agent that has a cytostatic effect on a cell, thereby inhibiting the growth and / or expansion of a specific subset of cells (i.e. , tumor cells).

[0349] “Immunomodulating agent” refers to an agent that stimulates the immune response though the production of cytokines and / or antibodies and / or modulating myeloid and / or T cell function thereby inhibiting or reducing the growth of a subset of cells (i.e., tumor cells) either directly or indirectly by allowing another agent to be more efficacious.

[0350] “Additional anti-cancer therapeutic agent,” “additional chemotherapeutic agent,” and “additional therapeutic agent” are used interchangeably and mean any one or more therapeutic agent, other than a compound or immunoconjugate of the invention, that is or may be used in the treatment of cancer. A biotherapeutic agent and a chemotherapeutic agent are both examples of an additional anti-cancer therapeutic agent.

[0351] “Additive” means that the result of the combination of two compounds, components, or targeted agents is no greater than the sum of each compound, component, or targeted agent individually.

[0352] “Synergy” or “synergistic” mean that the result of the combination of two compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent individually. This improvement in the disease, condition or disorder being treated is a “synergistic” effect. A “synergistic amount” is an amount of the combination of the two compounds, components or targeted agents that results in a synergistic effect, as “synergistic” is defined herein.

[0353] “Treat” or “treating” a cancer means to administer a compound or an immunoconjugate of the present invention to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0354] “Treatment,” unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.

[0355] The terms “subject, “individual,” and or “patient,” used interchangeably and refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development.

[0356] As used herein, “effective dosage” or “effective amount” of drug, compound, immunoconjugate, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired, including biochemical, histological and I or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.

[0357] The phrase “therapeutically effective amount” refers to the amount of active compound, immunoconjugate, or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which, in reference to cancer, may include one or more of the following: (1) reducing the size of the tumor; (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness; (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer; (5) decreasing the dose of other medications required to treat the disease; and / or (6) enhancing the effect of another medication; and (7) delaying the progression of the disease in a patient.

[0358] An effective dosage may be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, compound, immunoconjugate, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound, immunoconjugate, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, immunoconjugate, or pharmaceutical composition.

[0359] “Tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0360] “Tumor burden” or “tumor load,” refers to the total amount of tumorous material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone marrow. Tumor burden may be determined by a variety of methods known in the art, such as, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scans.

[0361] “Tumor size” refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CR or MRI scans.

[0362] For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in several ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1:1S-10S (2009). For example, with respect to tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) standards, a T / C less than or equal to 42% is the minimum level of anti-tumor activity. A T / C <10% is considered a high anti-tumor activity level, with T / C (%) = median tumor volume of the treated I median tumor volume of the control x 100.

[0363] In some embodiments, the treatment achieved by a compound of the invention is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression free survival (PFS), disease free survival (DFS) and overall survival (OS). PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or patients. In some embodiments, response to a combination of the invention is any of PR, CR, PFS, DFS, OR or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.

[0364] The treatment regimen for a compound of the invention that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the invention may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi2-test the ll-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere- Terpstrat- testy and the Wilcon on-test.

[0365] The terms “treatment regimen”, “dosing protocol,” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each compound of the invention, alone or in combination with another therapeutic agent.

[0366] “Ameliorating” means a lessening or improvement of one or more symptoms upon treatment with a combination described herein, as compared to not administering the combination. “Ameliorating” also includes shortening or reduction in duration of a symptom.

[0367] “Abnormal cell growth”, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous).

[0368] The terms “cancer” and “cancerous” refer to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancer includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a patient with a history of previous cancer of a different type from the second primary cancer. Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include leukemia, lymphoma and myeloma. Additional examples of cancer include blastomas and an actinic keratosis. Cancer also includes primary cancer or metastases of a site selected from the group consisting of oral cavity, digestive system, respiratory system, skin, breast, genital system, urinary system, ocular system, nervous system, endocrine system, and lymphoma.

[0369] Salts

[0370] Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds of this invention which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compounds of the invention that is suitable for administration to a subject or patient.

[0371] In addition, the compounds of Formula (I), the drug-linker compounds of Formula (II), and the cysteine linked drug compounds of Formula (V) (i.e. , the compounds of the invention) may also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, which may be useful as intermediates for one or more of the following: 1) preparing compounds of the invention); 2) purifying compounds of the invention; 3) separating enantiomers of compounds of the invention; or 4) separating diastereomers of compounds of the invention.

[0372] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acid and xinofoate salts.

[0373] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0374] Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

[0375] For a review on suitable salts, see Paulekun, G. S. et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J. Med. Chem. 2007; 50(26), 6665-6672.

[0376] Pharmaceutically acceptable salts of compounds of the invention may be prepared by methods well known to one skilled in the art, including but not limited to the following procedures

[0377] (i) by reacting a compound of the invention with the desired acid or base;

[0378] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0379] (iii) by converting one salt of a compound of the invention to another. This may be accomplished by reaction with an appropriate acid or base or by means of a suitable ion exchange procedure. These procedures are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.

[0380] Solvates

[0381] The compounds of the invention, and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, may exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.

[0382] In addition, the compounds of the invention may also include other solvates of such compounds which are not necessarily pharmaceutically acceptable solvates, which may be useful as intermediates for one or more of the following: 1) preparing compounds of the invention); 2) purifying compounds of the invention; 3) separating enantiomers of compounds of the invention; or 4) separating diastereomers of compounds of the invention.

[0383] A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical

[0384] Solids by K. R Morris (Ed H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

[0385] When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

[0386] Solid form

[0387] The compounds of the invention may exist in a continuum of solid states ranging from amorphous to crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

[0388] The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution) and consists of two dimensional order on the molecular level. Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO'Na+, -COO'K+, or -SOs'Na+) or non-ionic (such as -N’N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0389] Stereoisomers

[0390] Compounds and immunoconjugates of the invention may exist as two or more stereoisomers. Stereoisomers of the compounds and immunoconjugates may include c / s and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atropisomers, and conformational isomers. For example, compounds and immunoconjugates of the invention containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. Where a compound or an immunoconjugate of the invention contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[0391] The pharmaceutically acceptable salts of compounds of the invention may also contain a counterion which is optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl- arginine).

[0392] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0393] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where a compound of the invention contains an acidic or basic moiety, a base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography, fractional crystallization, or by using both of said techniques, and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein).

[0394] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two crystal forms are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[0395] Tautomerism

[0396] Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) may occur. This may take the form of proton tautomerism in compounds of the invention containing, for example, an imino / amino, keto / enol, or oxime / nitroso group, lactam / lactim or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. For instance, compounds and immunoconjugates of the invention may include the following amino / imino tautomers: imidic acid / amide tautomers, such as:

[0397] It must be emphasized that while, for conciseness, the compounds of the invention have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.

[0398] Isotopes

[0399] The present invention includes all pharmaceutically acceptable isotopically-labeled compounds and immunoconjugates of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0400] Examples of isotopes suitable for inclusion in the compounds of the invention may include isotopes of hydrogen, such as2H (D, deuterium) and3H (T, tritium), carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, and oxygen, such as150,17O and18O.

[0401] Certain isotopically-labelled compounds of the invention, for example those incorporating a radioactive isotope, are useful in one or both of drug or substrate tissue distribution studies. The radioactive isotopes, such as, tritium and14C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with positron emitting isotopes, such as,11C,18F,15O and13N, may be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Substitution with deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time dependent), or an improvement in therapeutic index or tolerability. In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds, salts, and immunoconjugates where the formula and variables of such compounds and salts are each and independently as described herein. “Deuterated” means that at least one of the atoms in the compound is deuterium in an abundance that is greater than the natural abundance of deuterium (typically approximately 0.015%). A skilled artisan recognized that in chemical compounds with a hydrogen atom, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of the deuterium incorporated into the deuterium-labeled compounds and salt of the invention may be defined by the deuterium enrichment factor. It is understood that one or more deuterium may exchange with hydrogen under physiological conditions.

[0402] In some embodiments, one or more hydrogen atoms on certain metabolic sites on the compounds or immunoconjugates of the invention are deuterated.

[0403] Isotopically-labeled compounds and immunoconjugates of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0404] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, de- DMSO.

[0405] Metabolites

[0406] Also included within the scope of the invention are active metabolites of compounds and immunoconjugates of the invention, that is, compounds formed in vivo upon administration of the drug or immunoconjugate, often by oxidation or dealkylation. Some examples of metabolites in accordance with the invention include, but are not limited to:

[0407] (i) where the compound or immunoconjugate of the invention contains an alkyl group, a hydroxyalkyl derivative thereof (-CH — > -COH);

[0408] (ii) where the compound or immunoconjugate of the invention contains an alkoxy group, a hydroxy derivative thereof (-OR — > -OH);

[0409] (iii) where the compound or immunoconjugate of the invention contains a tertiary amino group, a secondary amino derivative thereof (-NRR’ — > -NHR or -NHR);

[0410] (iv) where the compound or immunoconjugate of the invention contains a secondary amino group, a primary derivative thereof (-NHR ^ -NH2); (v) where the compound or immunoconjugate of the invention contains a phenyl moiety, a phenol derivative thereof (-Ph — > -PhOH);

[0411] (vi) where the compound or immunoconjugate of the invention contains an amide group, a carboxylic acid derivative thereof (-CONH2 — > COOH);

[0412] (vii) where the compound contains a hydroxy or carboxylic acid group, the compound may be metabolized by conjugation, for example with glucuronic acid to form a glucuronide. Other routes of conjugative metabolism exist. These pathways are frequently known as Phase 2 metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, may also be subject to conjugation.

[0413] In certain embodiments, the cysteine linked drug compounds of Formula (V) may be formed in vivo from the administration of the immunoconjugates of Formula (IV).

[0414] Pharmaceutical Compositions

[0415] In another embodiment, the invention comprises pharmaceutical compositions. For pharmaceutical composition purposes, the compound per se, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, will simply be referred to as the compounds of the invention. Likewise, the immunoconjugate per se, or tautomer or stereoisomer thereof, will simply be referred to as the immunoconjugate of the invention.

[0416] In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth in a subject in need thereof, which pharmaceutical composition comprises: a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or a tautomer, or stereoisomer thereof; and a pharmaceutically acceptable carrier or excipient.

[0417] The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0418] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound or the immunoconjugate is administered by intravenous infusion or injection. In yet another embodiment, the compound or immunoconjugate is administered by intramuscular or subcutaneous injection.

[0419] Oral administration of a solid dosage form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound or immunoconjugate of the invention. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dosage form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds and immunoconjugate of the invention are ordinarily combined with one or more adjuvants. Such capsules or tablets may comprise a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

[0420] In another embodiment, oral administration may be in a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as one or more of wetting, emulsifying, suspending, flavoring (e.g., sweetening), or perfuming agents.

[0421] In another embodiment, the invention comprises a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e. , sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using one or more of suitable dispersing, wetting agents, or suspending agents.

[0422] For intranasal administration, the compounds and immunoconjugate of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1 , 1,1, 2, 3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0423] In another embodiment, the invention comprises a rectal dosage form. Such rectal dosage form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[0424] Other excipients and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well- known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams &

[0425] Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago,

[0426] Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of

[0427] Pharmaceutical Salts: Selection and Use New York: Wiley-VCH, 2011 and

[0428] Brittain, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare

[0429] USA, Inc., 2016.

[0430] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0431] For oral administration, the compositions may be provided in the form of tablets or capsules containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Dosing regimens may depend on the route of administration, dose scheduling, and use of flat-dose, body surface area or weight-based dosing. For example, for weight-based dosing, intravenously doses may range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0432] Liposome containing compounds of the invention may be prepared by methods known in the art (See, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49- 60). Particularly useful liposomes may be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

[0433] Compounds and immunoconjugates of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0434] Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing a compound of the invention, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in leuprolide acetate for depot suspension (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0435] The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds and immunoconjugates of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0436] Suitable emulsions may be prepared using commercially available fat emulsions, such as a lipid emulsions comprising soybean oil, a fat emulsion for intravenous administration (e.g., comprising safflower oil, soybean oil, egg phosphatides and glycerin in water), emulsions containing soya bean oil and medium-chain triglycerides, and lipid emulsions of cottonseed oil. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion may comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0. For example, the emulsion compositions may be those prepared by mixing a compound of the invention with a lipid emulsions comprising soybean oil or the components thereof (soybean oil, egg phospholipids, glycerol and water).

[0437] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

[0438] A drug product intermediate (DPI) is a partly processed material that must undergo further processing steps before it becomes bulk drug product. Compounds and immunoconjugates of the invention may be formulated into drug product intermediate DPI containing the active ingredient in a higher free energy form than the crystalline form. One reason to use a DPI is to improve oral absorption characteristics due to low solubility, slow dissolution, improved mass transport through the mucus layer adjacent to the epithelial cells, and in some cases, limitations due to biological barriers such as metabolism and transporters. Other reasons may include improved solid state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains a compound of the invention isolated and stabilized in the amorphous state (for example, amorphous solid dispersions (ASDs)). There are many techniques known in the art to manufacture ASD’s that produce material suitable for integration into a bulk drug product, for example, spray dried dispersions (SDD’s), melt extrudates (often referred to as HME’s), co-precipitates, amorphous drug nanoparticles, and nano-adsorbates. In one embodiment amorphous solid dispersions comprise a compound of the invention and a polymer excipient. Other excipients as well as concentrations of said excipients and the compound of the invention are well known in the art and are described in standard textbooks. See, for example, “Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0439] Administration and Dosing

[0440] Typically, a compound or immunoconjugate of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, the compounds may be administered as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention. The immunoconjugate of the invention may also be administered as immunoconjugates per se

[0441] The compounds and immunoconjugates of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the invention may be administered orally, rectally, vaginally, parenterally (including subcutaneously and intraveneously), topically, intranasally or by inhalation. The immunoconjugates of the invention may be administered orally, rectally, vaginally, parenterally (including subcutaneously and intraveneously), topically, intranasally or by inhalation.

[0442] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

[0443] In another embodiment, the compounds of the invention may also be administered parenterally, for example directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0444] In another embodiment, the compounds and immunoconjugates of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds and immunoconjugates of the invention may also be administered intranasally or by inhalation. In another embodiment, the compounds and immunoconjugates of the invention may be administered rectally or vaginally. In another embodiment, the compounds and immunoconjugates of the invention may also be administered directly to the eye or ear.

[0445] The dosage regimen for the compounds and immunoconjugates of the invention or compositions containing said compounds and immunoconjugates is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. In one embodiment, the total daily dose of an immunoconjugate of the invention is typically from about 0.01 to about 100 mg / kg (i.e., mg compound of the invention per kg body weight) for the treatment of the indicated conditions discussed herein. In another embodiment, total daily dose of the compound of the invention is from about 0.01 to about 100 mg / kg, and in another embodiment, from about 0.5 mg / kg to about 30 mg / kg, preferably about 5 mg / kg to about 20 mg / kg. For a 70 kg human, the amount may range from about 0.05 mg / day to about 7,000 mg / day, preferably about 10 mg to about 2,500 mg / day, more preferably from about 25 mg to 1,000 mg / day.

[0446] It is not uncommon that the administration of the compounds of the invention will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.

[0447] Therapeutic Methods and Uses

[0448] The compounds and immunoconjugates of the invention may agonize the activity of TLR7 or both TLR7 and TL78 and may be useful in the treatment of cancer or other proliferative diseases, disorders and conditions mediated by TLR7 or TLR8. In particular, such compounds and immunoconjugates show a dual affinity for TLR7 and TLR8.

[0449] In some embodiments, the methods provided result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.

[0450] In one aspect, the invention provides a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, in an amount effective to inhibit cell proliferation.

[0451] In another aspect, the invention provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, in an amount effective to inhibit cell invasiveness.

[0452] In another aspect, the invention provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, in an amount effective to induce apoptosis.

[0453] In another aspect, the invention provides a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, in an amount effective to inhibit cell metastasis.

[0454] In another aspect, the invention provides a method of inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, in an amount effective to inhibit angiogenesis.

[0455] In another aspect, the invention provides a method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof. Said method also includes administering the compound of the invention with at least one additional therapeutic agent.

[0456] In one aspect, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof.

[0457] In a further aspect, the invention provides the use of a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a an immunoconjugate of the invention, or tautomer or stereoisomer thereof, for the treatment of abnormal cell growth in a subject.

[0458] In another aspect, the invention provides a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, for use as a medicament, in particular a medicament for the treatment of abnormal cell growth.

[0459] In yet another aspect, the invention provides the use of a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.

[0460] In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer.

[0461] Cancers to be treated include squamous cell carcinoma, basal cell carcinomas, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, nonHodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, uterine cancer, bladder cancer, including non-muscular invasive bladder cancer, hepatoma, breast cancer, and head and neck cancer. More particular examples of cancers to be treated include basal cell carcinomas, small-cell lung cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, ovarian cancer, colorectal cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, pancreatic cancer, bladder cancer (non-muscular invasive bladder cancer), hepatoma, breast cancer, and head and neck cancer.

[0462] Another embodiment of the invention concerns treatment of cancers selected from basal cell carcinomas, ovarian cancer, melanoma, non-muscular invasive bladder cancer, breast cancer, and head and neck cancer.

[0463] Another embodiment of the invention concerns treatment melanoma, gastrointestinal (tract) cancer, breast cancer, ovarian cancer, and head and neck cancer.

[0464] Another embodiment of the invention concerns treatment cancers of the gastrointestinal tract. Such gastrointestinal cancers include cancer of the mouth, esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum, and anus.

[0465] Another embodiment of the invention concerns treatment of non-muscular invasive bladder cancer.

[0466] In some embodiments, the compound or immunoconjugate of the invention is administered as first line therapy. In other embodiments, the compound or immunoconjugate of the invention is administered as second (or later) line therapy.

[0467] Co-administration

[0468] The compounds of the invention may be used alone, or in combination with one or more other therapeutic agents, for instance, and anti-cancer therapeutic agent.

[0469] The efficacy of the compounds and immunoconjugates of the invention in certain tumors may be enhanced by combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents, such as PD 1 or PD L1 antagonists and the like.

[0470] The invention provides any of the uses, methods or compositions as defined herein wherein a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, is used in combination with one or more other therapeutic agent discussed herein.

[0471] In another aspect, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, in combination with an amount of an additional therapeutic agent (e.g., an anti-cancer therapeutic agent), which amounts are together effective in treating said abnormal cell growth. In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer and a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, is administered in combination with other anti-cancer therapeutic agents, in particular with standard of care agents appropriate for the particular cancer.

[0472] The administration of two or more compounds “in combination” means that all of the compounds or immunoconjugates are administered closely enough in time to affect treatment of the subject. The two or more compounds or immunoconjugates may be administered simultaneously or sequentially, via the same or different routes of administration, on same or different administration schedules and with or without specific time limits depending on the treatment regimen. Additionally, simultaneous administration may be carried out by mixing the compounds or immunoconjugates prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration. Examples of “in combination” include, but are not limited to, “concurrent administration,” “co-administration,” “simultaneous administration,” “sequential administration” and “administered simultaneously”.

[0473] A compound or immunoconjugate of the invention and the one or more other therapeutic agents may be administered as a fixed or non-fixed combination of the active ingredients. The term "fixed combination" means a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, and the one or more therapeutic agents, are both administered to a subject simultaneously in a single composition or dosage. The term "nonfixed combination" means that a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, and the one or more therapeutic agents are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously or at different times with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject.

[0474] In one embodiment, the compounds and immunoconjugates of this invention are administered in combination with additional chemotherapeutic agents including the pharmaceutically acceptable salts of the additional chemotherapeutic agents and the pharmaceutically acceptable solvates of said agents and salts.

[0475] Such additional chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists; IL-2 receptor agonist (recombinant cytokines or agonists for cytokine receptors); and anti-sense oligonucleotides or oligonucleotides derivatives that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth.

[0476] Other additional chemotherapy agents include not only taxanes or platinum agents but also HER2 targeted agents, e.g., trastuzumab.

[0477] In one embodiment, the compounds and immunoconjugates of this invention are administered in combination with anti-cancer therapeutic agents including the pharmaceutically acceptable salts of the anti-cancer therapeutic agents and the pharmaceutically acceptable solvates of said agents and salts.

[0478] Such additional anti-cancer therapeutic agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, spindle poison plant alkaloids, KRAS inhibitors; MCT4 inhibitors; MAT2a inhibitors; alk / c-Met / ROS inhibitors (including crizotinib or lorlatinib); mTOR inhibitors (including temsirolimus or gedatolisib); src / abl inhibitors (including bosutinib); cyclin-dependent kinase (CDK) inhibitors (including palbociclib, PF-06873600); erb inhibitors (including dacomitinib); PARP inhibitors (including talazoparib); SMO inhibitors (including glasdegib); EGFR T790M inhibitors; PRMT5 inhibitors; TGFPR1 inhibitors; growth factor inhibitors; cell cycle inhibitors, biological response modifiers; enzyme inhibitors; and cytotoxics.

[0479] In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from an anti-angiogenesis agent, including for example tyrosine kinase I vascular endothelial growth factor (VEGF) receptor (VEGFR) inhibitors (including sunitinib, axitinib, sorafenib, and tivozanib), TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCp inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MM P-9 (matrix-metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (Inlyta™), Sil 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenesis agents include vatalanib (CGP 79787), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), Sil 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Yet further anti-angiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

[0480] In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from hormonal agents and antagonists. Examples include where anti- hormonal agents act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), and a selective estrogen receptor degrader (SERD) including tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifene (Fareston), and fulvestrant. Examples also include aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, and include compounds like 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, fluridil, apalutamide, enzalutamide, cimetidine and goserelin.

[0481] In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases: a signal transduction inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1 R inhibitors, MEK (including binimetinib (Mektovi™)), c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, BRAF (including encorafenib (Braftovi™)), Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and multi-targeted kinase inhibitors. In another embodiment, such additional anti-cancer therapeutic agents include docetaxel, paclitaxel, paclitaxel protein-bound particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine or vinorelbine.

[0482] In another embodiment, such additional anti-cancer therapeutic agents include compounds derived from an epigenetic modulator, where examples include an inhibitor of EZH2 (including PF-06821497), SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2 or BCL6.

[0483] In another embodiment, such additional anti-cancer therapeutic agents include compounds that are immuno-oncology agents, including immunomodulatory agents.

[0484] In another embodiment, combinations with pattern recognition receptors (PRRs) are contemplated. PRRs are receptors that are expressed by cells of the immune system and that recognize a variety of molecules associated with pathogens and / or cell damage or death. PRRs are involved in both the innate immune response and the adaptive immune response. PRR agonists may be used to stimulate the immune response in a subject. There are multiple classes of PRR molecules, including toll-like receptors (TLRs), RIG-l-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (CLRs), and Stimulator of Interferon Genes (STING) protein.

[0485] The STING protein functions as both a cytosolic DNA sensor and an adaptor protein in Type 1 interferon signaling. The terms “STING” and “stimulator of interferon genes” refer to any form of the STING protein, as well as variants, isoforms, and species homologs that retain at least a part of the activity of STING. Unless indicated differently, such as by specific reference to human STING, STING includes all mammalian species of native sequence STING, e.g. human, monkey, and mouse STING is also known as - TMEM173.

[0486] “STING agonist” as used herein means, any molecule, which upon binding to STING, (1) stimulates or activates STING, (2) enhances, increases, promotes, induces, or prolongs an activity, function, or presence of STING, or (3) enhances, increases, promotes, or induces the expression of STING. STING agonists useful in the any of the treatment method, medicaments and uses of the present invention include, for example, nucleic acid ligands which bind STING.

[0487] Examples of STING agonists that are useful in the treatment methods, medicaments, and uses of the present invention include various immunostimulatory nucleic acids, such as synthetic double stranded DNA, cyclic di-GMP, cyclic-GMP-AMP (cGAMP), synthetic cyclic dinucleotides (CDN) such as MK-1454 and ADU-S100 (MIW815), and small molecules such as WO2019027858, WO20180093964, WO2017175156, WO2017175147.

[0488] Therapeutic antibodies may have specificity against a variety of different antigens. For example, therapeutic antibodies may be directed to a tumor associated-antigen, such that binding of the antibody to the antigen promotes death of the cell expressing the antigen. In other example, therapeutic antibodies may be directed to an antigen on an immune cell, such that binding of the antibody prevents downregulation of the activity of the cell expressing the antigen (and thereby promotes activity of the cell expressing the antigen). In some situations, a therapeutic antibody may function through multiple different mechanisms (for example, it may both i) promote death of the cell expressing the antigen, and ii) prevent the antigen from causing down-regulation of the activity of immune cells in contact with the cell expressing the antigen).

[0489] In another embodiment, such additional anti-cancer therapeutic agents include antibodies that would be blocking or inhibitory at the target: CTLA-4 (including ipilimumab or tremelimumab), PD-1 or PD-L1 (including atezolizumab, avelumab, cemiplimab, durvalumab, nivolumab, or pembrolizumab), LAG-3, TIM-3, or TIGIT.

[0490] In another embodiment, such additional anti-cancer therapeutic agents include antibodies that are agonists of 4-1 BB, 0X40, GITR, ICOS, or CD40.

[0491] In another embodiment the anti-cancer therapy may be a CAR-T-cell therapy.

[0492] Examples of a therapeutic antibody include: an anti-OX40 antibody, an anti-4-1 BB antibody, an anti-HER2 antibody (including an anti-HER2 antibody-drug conjugate (ADC)), a bispecific anti-CD471 anti-PD-L1 antibody, and a bispecific anti-P-cadherin I anti-CD3 antibody. Examples of cytotoxic agents that may be incorporated in an ADC as a therapeutic antibody include an anthracycline, an auristatin, a dolastatin, a combretastatin, a duocarmycin, a pyrrolobenzodiazepine dimer, an indolino-benzodiazepine dimer, an enediyne, a geldanamycin, a maytansine, a puromycin, a taxane, a vinca alkaloid, a camptothecin, a tubulysin, a hemiasterlin, a spliceostatin, a pladienolide, and stereoisomers, isosteres, analogs, or derivatives thereof. Exemplary immunomodulating agents that may be incorporated in an ADC include gancyclovier, etanercept, tacrolimus, sirolimus, voclosporin, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolgate mofetil, methotrextrate, glucocorticoid and its analogs, cytokines, stem cell growth factors, lymphotoxins, tumor necrosis factor (TNF), hematopoietic factors, interleukins (e.g., interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, and IL-21), colony stimulating factors (e.g., granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF)), interferons (e.g., interferons- .alpha., -.beta, and -.gamma), the stem cell growth factor designated "S 1 factor," erythropoietin and thrombopoietin, or a combination thereof.

[0493] Additional examples of therapeutic antibodies may include the following antigens where exemplary antibodies directed to the antigen are also included below (in brackets I parenthesis after the antigen). The antigens as follow may also be referred to as “target antigens” or the like herein. Target antigens for therapeutic antibodies herein include, for example: 4-1 BB (e.g. utomilumab); 5T4; A33; alpha-folate receptor 1 (e.g. mirvetuximab soravtansine); Alk-1; BCMA [e.g. see US9969809]; BTN1A1 (e.g. see WO2018222689); CA-125 (e.g. abagovomab); Carboanhydrase IX; CCR2; CCR4 (e.g. mogamulizumab); CCR5 (e.g. leronlimab); CCR8; CD3 [e.g. blinatumomab (CD3 / CD19 bispecific), CD3 / P-cadherin bispecific, CD3 / BCMA bispecific] CD19 (e.g. blinatumomab, MOR208); CD20 (e.g. ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, ublituximab); CD22 (inotuzumab ozogamicin, moxetumomab pasudotox); CD25; CD28; CD30 (e.g. brentuximab vedotin); CD33 (e.g. gemtuzumab ozogamicin); CD38 (e.g. daratumumab, isatuximab), CD40; CD-40L; CD44v6; CD47 (e.g. Hu5F9-G4, CC-90002, SRF231, B6H12); CD52 (e.g. alemtuzumab); CD56; CD63; CD79 (e.g. polatuzumab vedotin); CD80; CD123; CD276 / B7-H3 (e.g. omburtamab); CDH17; CEA; ClhCG; CTLA-4 (e.g. ipilimumab, tremelimumab), CXCR4; desmoglein 4; DLL3 (e.g. rovalpituzumab tesirine); DLL4; E-cadherin; EDA; EDB; EFNA4; EGFR (e.g. cetuximab, depatuxizumab mafodotin, necitumumab, panitumumab); EGFRvlll; Endosialin; EpCAM (e.g. oportuzumab monatox); FAP; Fetal Acetylcholine Receptor; FLT3 (e.g. see WO2018 / 220584); GD2 (e.g. dinutuximab, 3F8); GD3; GITR; GloboH; GM1; GM2; HER2 / neu [e.g. margetuximab, pertuzumab, trastuzumab; ado-trastuzumab emtansine, trastuzumab duocarmazine, [see US8828401]; HER3; HER4; ICOS; IL-10; ITG-AvB6; LAG-3 (e.g. relatlimab); Lewis-Y; LG; Ly-6; M-CSF [see US7326414]; MCSP; mesothelin; MUC1; MUC2; MUC3; MUC4; MUC5AC; MUC5B; MUC7; MUC16; Notchl; Notch3; Nectin-4 (e.g. enfortumab vedotin); 0X40 [see US7960515]; P-Cadherein [see WO2016 / 001810]; PCDHB2; PDGFRA (e.g. olaratumab); Plasma Cell Antigen; PolySA; PSCA; PSMA; PTK7 [see US9409995]; Ror1; SAS; SCRx6; SLAMF7 (e.g. elotuzumab); SHH; SIRPa (e.g. ED9, Effi-DEM); STEAP; TGF-beta; TIGIT; TIM- 3; TMPRSS3; TNF-alpha precursor; TROP-2 (e.g sacituzumab govitecan); TSPAN8; VEGF (e.g. bevacizumab, brolucizumab); VEGFR1 (e.g. ranibizumab); VEGFR2 (e.g. ramucirumab, ranibizumab); Wue-1.

[0494] Exemplary imaging agents that may be included in an ADC include fluorescein, rhodamine, lanthanide phosphors, and their derivatives thereof, or a radioisotope bound to a chelator. Examples of fluorophores include, but are not limited to, fluorescein isothiocyanate (FITC) (e.g., 5-FITC), fluorescein amidite (FAM) (e.g., 5-FAM), eosin, carboxyfluorescein, erythrosine, Alexa Fluor® (e.g., Alexa 350, 405, 430, 488, 500, 514, 532, 546, 555, 568, 594, 610, 633, 647, 660, 680, 700, or 750), carboxytetramethylrhodamine (TAMRA) (e.g., 5,- TAMRA), tetramethylrhodamine (TMR), and sulforhodamine (SR) (e.g., SR101). Examples of chelators include, but are not limited to, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 1 ,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1 ,4,7-triazacyclononane, 1- glutaric acid-4, 7-acetic acid (deferoxamine), diethylenetriaminepentaacetic acid (DTPA), and 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) (BAPTA).

[0495] Exemplary therapeutic proteins that may be included in an ADC include a toxin, a hormone, an enzyme, and a growth factor. Exemplary biocompatible polymers that may be incorporated in an ADC include water- soluble polymers, such as polyethylene glycol (PEG) or its derivatives thereof and zwitterioncontaining biocompatible polymers (e.g., a phosphorylcholine containing polymer).

[0496] Exemplary biocompatible polymers that may be incorporated in an ADC include antisense oligonucleotides.

[0497] The invention also concerns the use of radiation in combination with any anti-cancer therapeutic agent administered herein. More specifically, compounds and immunoconjugates of the invention may be administered in combination with additional therapies, such as radiation therapy and / or chemotherapy.

[0498] These agents and compounds and immunoconjugates of the invention may be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e. , dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

[0499] The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of the invention, or pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or an immunoconjugate of the invention, or tautomer or stereoisomer thereof, as defined above, in combination with one or more (preferably one to three) additional anti-cancer therapeutic agents.

[0500] Kits

[0501] Another aspect of the invention provides kits comprising the compound or immunoconjugate of the invention or pharmaceutical compositions comprising the compound or immunoconjugate of the invention. A kit may include, in addition to the compound or immunoconjugate of the invention or pharmaceutical composition thereof, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the compound or a pharmaceutical composition thereof and one or more therapeutic agents, such as an anticancer therapeutic agent.

[0502] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds or immunoconjugates of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more compounds or immunoconjugates of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage and a container for the dosage.

[0503] The invention also concerns the compounds of the present invention functioning as TLR7 / 8 agonists conjugated, directly or via a linker, to an antibody. Conjugation of drugs to antibodies, either directly or via linkers, involves a consideration of a variety of factors, including the identity and location of the chemical group for conjugation of the drug, the mechanism of drug release, the structural elements providing drug release, and the structural modification to the released free drug. In addition, if the drug is to be released after antibody internalization, the mechanism of drug release must be consonant with the intracellular trafficking of the immunoconjugate.

[0504] An “antibody” refers to an immunoglobulin molecule capable of specific binding to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., through at least one antigen binding site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” can encompass any type of antibody (e.g. monospecific, bispecific), and includes portions of intact antibodies that retain the ability to bind to a given antigen (e.g. an “antigen-binding fragment”), and any other modified configuration of an immunoglobulin molecule that comprises an antigen binding site. An exemplary antibody comprises i) a variable region of the light chain, heavy chain or both and ii) a constant region of the heavy chain comprising three sequential immunoglobulin domains (CH1, CH2, and CH3) and of the light chain comprising a single immunoglobulin domain (CL).

[0505] An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains (HC), immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, I g E, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, lgG3, lgG4, I gAi and lgA3. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0506] Examples of antibody antigen-binding fragments and modified configurations include (i) a Fab fragment (a monovalent fragment consisting of the VL, VH, CL and CH1 domains); (ii) a F(ab')2 fragment (a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region); and (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody. Furthermore, although the two domains of an Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)); see e.g., Bird et al., Science 1988; 242:423-426 and Huston et al., Proc. Natl. Acad. Sci. 1988 USA 85:5879-5883. Other forms of single chain antibodies, such as diabodies are also encompassed.

[0507] In addition, further encompassed are antibodies that are missing a C-terminal lysine (K) amino acid residue on a heavy chain polypeptide (e.g. human IgG 1 heavy chain comprises a terminal lysine). As is known in the art, the C-terminal lysine is sometimes clipped during antibody production, resulting in an antibody with a heavy chain lacking the C-terminal lysine. Alternatively, an antibody heavy chain may be produced using a nucleic acid that does not include a C-terminal lysine.

[0508] As noted above, the term "antibody" (or “A”, “Ab” or “AB”) herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. In addition, while certain aspects of the invention described herein refer to immunoconjugates, it is further envisioned that the antibody portion of the immunoconjugate might be replaced with anything that specifically binds or reactively associates or complexes with a receptor, antigen or other receptive moiety associated with a given target cell population. For example, instead of containing an antibody, an immunoconjugate of the invention could contain a targeting molecule that binds to, complexes with, or reacts with a receptor, antigen or other receptive moiety of a cell population sought to be therapeutically or otherwise biologically modified. Example of such molecules include smaller molecular weight proteins, polypeptide or peptides, lectins, glycoproteins, non peptides, vitamins, nutrient transport molecules (such as, but not limited to, transferrin), or any other cell binding molecule or substances. In certain aspects, the antibody or other such targeting molecule acts to deliver a drug to the particular target cell population with which the antibody or other targeting molecule interacts.

[0509] As noted above, the term "antibody" herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. In addition, while certain aspects of the invention described herein refer to immunoconjugates, it is further envisioned that the antibody portion of the immunoconjugate might be replaced with anything that specifically binds or reactively associates or complexes with a receptor, antigen or other receptive moiety associated with a given target cell population. For example, instead of containing an antibody, immunoconjugates of the invention could contain a targeting molecule that binds to, complexes with, or reacts with a receptor, antigen or other receptive moiety of a cell population sought to be therapeutically or otherwise biologically modified. Example of such molecules include smaller molecular weight proteins, polypeptide or peptides, lectins, glycoproteins, non-peptides, vitamins, nutrient transport molecules (such as, but not limited to, transferrin), or any other cell binding molecule or substances. In certain aspects, the antibody or other such targeting molecule acts to deliver a drug to the particular target cell population with which the antibody or other targeting molecule interacts.

[0510] In some embodiments, an immunoconjugate provided herein may comprise a compound of the present invention conjugated to a therapeutic antibody described herein.

[0511] In some embodiments, an immunoconjugate provided herein may comprise a compound of the present invention conjugated to an antibody that specifically binds to an antigen on an immune cell (e.g. macrophage or dendritic cell). Optionally, the antigen may be on an immunosuppressive tumor-associated immune cell (e.g. immunosuppressive tumor-associated macrophage). In some embodiments, an antigen on an immune cell is CD163.

[0512] Synthetic Methods

[0513] Compounds and immunoconjugates of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources or may be prepared using methods well known to those skilled in the art. Many of the compounds used herein, are related to, or may be derived from compounds in which one or more of the scientific interest or commercial need has occurred. Accordingly, such compounds may be one or more of 1) commercially available, 2) reported in the literature, or 3) prepared from other commonly available substances by one skilled in the art using materials which have been reported in the literature.

[0514] For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds and immunoconjugates of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds and immunoconjugates. Although specific starting materials and reagents are discussed below, other starting materials and reagents may be substituted to provide one or more of a variety of derivatives or reaction conditions. In addition, many of the compounds and immunoconjugates prepared by the methods described below may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0515] The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds and immunoconjugates of the invention. It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compounds and immunoconjugates of the invention.

[0516] In the preparation of compounds and immunoconjugates of the invention it is noted that some of the preparation methods useful for the preparation of the compounds and immunoconjugates described herein may require protection of remote functionality (e.g., a primary amine, secondary amine, carboxyl, etc. in a precursor of a compound of the invention). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.

[0517] For example, if a compound or immunoconjugates contains an amine or carboxylic acid functionality, such functionality may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group (PG) which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as / V-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- fluorenylmethylenoxycarbonyl (Fmoc) for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and may typically be removed without chemically altering other functionality in a compound of the invention.

[0518] General Experimental Details

[0519] In executing the synthesis of the compounds of the invention, one skilled in the art will monitor reactions with common methods that include thin-layer chromatography (TLC), liquid chromatography / mass spectroscopy (LCMS), and nuclear magnetic resonance (NMR).

[0520] In the non-limiting Examples and Preparations that illustrate the invention and that are set out in the description, and in the following Schemes, the following the abbreviations, definitions and analytical procedures may be referred to:

[0521] Except where otherwise noted, reactions were run under an atmosphere of nitrogen. Chromatography on silica gel was carried out using 250-400 mesh silica gel using pressurized nitrogen (-10-15 psi) to drive solvent through the column (“flash chromatography”). Where indicated, solutions and reaction mixtures were concentrated by rotary evaporation under vacuum.

[0522] 1H and19F Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures.1H NMR spectra were recorded on a Bruker XWIN-NMR (400 MHz) spectrometer. Characteristic chemical shifts (5) are given in parts-per-million referenced to residual peaks from the deuterated solvents employed (for1H-NMR) using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDC , deuterochloroform; de-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol. Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible.

[0523] Mass spectra, MS (m / z), were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Where relevant and unless otherwise stated, the m / z data provided are for isotopes19F,35CI,79Br and127l.

[0524] Abbreviations

[0525] AcOH is acetic acid; aq is aqueous; Boc is terf-butoxycarbonyl; Bn is benzyl; br is broad; °C is degrees Celsius; CH3OH is methanol; CO2 is carbon dioxide; CS2CO3 is cesium carbonate;

[0526] DCE is dichloroethane; DCM is dichloromethane or methylene chloride; DIH is 1 ,3-Diiodo-5,5’- dimethylhydantoin; DIPEA / DIEA is N-ethyldiisopropylamine, N,N-diisopropylethylamine; DMA is dimethylacetamide; DMF is N,N-dimethylformamide; DMSO is dimethyl sulphoxide; ee is enantiomeric excess; EtOAc is ethyl acetate; EtOH is ethanol; Et3N is triethylamine; g is gram; HCI is hydrochloric acid; HPLC is high pressure liquid chromatography; H2O is water; Hr or hr is hour; IPA / iPrOH is isopropanol; KOH is potassium hydroxide; K2CO3 is potassium carbonate; L is litre; LCMS is liquid chromatography mass spectrometry; M is molar; m-CPBA is 3- chloroperbenzoic acid; MeCN is acetonitrile; MeOH is methanol; mg is milligram; MHz is mega Hertz; min is minutes; mL is millilitre; mmol is millimole; mol is mole; MS m / z is mass spectrum peak; NaHCOs is sodium hydrogencarbonate; NaOH is sodium hydroxide; Na2COs is sodium carbonate; Na2SO4 is sodium sulphate; NH3 is ammonia; NH4OH is ammonium hydroxide; NMR is nuclear magnetic resonance; Pd(PPHs)4 is tetrakis(triphenylphosphine)palladium; Pd / C is palladium on carbon; Pt / C is platinum on carbon; pH is power of hydrogen; ppm is parts per million; psi is pounds per square inch; Rt is retention time; RT is room temperature; STAB is sodium triacetoxyborohydride; TBME / MTBE is tert-butyl dimethyl ether; TEA is triethylamine;

[0527] TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; THF is tetra hydrofuran; TLC is thin layer chromatography; TsCI is p-toluenesulfonyl chloride; TsOH is p-Toluenesulfonic acid; Zn is zinc; pL is microlitre; pmol is micromole.

[0528] The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds and immunoconjugates of the present invention.

[0529] In the following Schemes, the general methods for the preparation of the compounds are shown either in racemic or enantioenriched form. It will be apparent to one skilled in the art that all of the synthetic transformations may be conducted in a precisely similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature. These isomers can be separated by standard chromatographic techniques, such as normal phase chromatography on silica gel, reverse phase preparative high pressure liquid chromatography or supercritical fluid chromatography. One skilled in the art will also recognize that some compounds of the invention are chiral and thus may be prepared as racemic or scalemic mixtures of enantiomers. Several methods are available and are well known to those skilled in the art for the separation of enantiomers.

[0530] When absolute stereochemistry is known, (R,S) labels are used and bonds are illustrated as and — . When absolute stereochemistry is not known, the unknown stereochemistry at a chiral center is illustrated with .

[0531] Wherein preparative TLC or silica gel chromatography have been used, one skilled in the art may choose any combination of solvents to purify the desired compound.

[0532] General Methods:

[0533] Unless stated otherwise, the variables in Schemes I (including IA and IB), II, III, IV, and V have the same meanings as defined herein.

[0534] All of the derivatives of Formula (I) can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the derivatives of Formula (I), in addition to any novel intermediates used therein. The person skilled in the art will appreciate that the following reactions may be heated thermally or under microwave irradiation or under flow chemistry conditions.

[0535] It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention. Starting materials and reagents are generally commercially available or routinely obtained from chemistry known by those of ordinary skill in the art.

[0536] According to a first process, compounds of Formula (I) may be prepared from compounds of intermediate (i) as illustrated by Scheme IA for synthesis of Template A for compounds of Formula (I), particularly compounds of Formula (I) in which Ring B is an N- containing heteroaryl or an N-containing heterocycloalkyl attached to R1through a ring N atom.

[0537] Scheme IA

[0538]

[0539] In step (1) of Reaction Scheme I, 7-bromo-4-chloro-3-nitroquinoline Intermediate (i) is reacted with amine Intermediate (ii) (R3= CH3, synthesis is described in Biomacromolecules, 2018, 19(12), 4677-4690)) in the presence of a tertiary amine, such as triethylamine, in DCM to provide 7-bromo-3-nitro-N-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]quinolin-4-amine (Intermediate (iii)). This synthetic process is described where R3is CH3, where routine modifications can be used to prepare other Intermediate (ii).

[0540] In step (2), the nitro group of Intermediate (iii) is reduced to provide 7-bromo-N-[(2,2,5- trimethyl-1,3-dioxan-5-yl)methyl]quinoline-3,4-diamine (Intermediate (iv)). Preferably, the reaction is performed using platinum on carbon, in the presence of hydrogen, in tetrahydrofuran.

[0541] In step (3), Intermediate (iv) is reacted with an acid chloride of structure (v), such as 2- ethoxyacetyl chloride in DCM, to provide N-(7-bromo-4-{[(2,2,5-trimethyl-1,3-dioxan-5- yl)methyl]amino}quinolin-3-yl)-2-ethoxyacetamide (Intermediate (vi)). This synthetic process is described where R5is -CH2-O-CH2CH3, where routine modifications can be used to prepare other Intermediate (vi) from reagent (v).

[0542] In step (4), Intermediate (vi) is reacted with a base, such as sodium hydroxide, in an alcoholic solvent, such as ethanol, to provide the dehydrated imidazole containing compound 7- bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]-1 H-imidazo[4,5-c]quinoline (Intermediate (vii)).

[0543] In step (5), Intermediate (vii) was is reacted with a suitable oxidant, such as 3- chloroperoxybenzoic acid, in DCM to provide 7-bromo-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3- dioxan-5-yl)methyl)-1H-imidazo[4,5-c]quinoline 5-oxide (Intermediate (viii)).

[0544] In step (6), Intermediate (viii) was is sequentially reacted with first ammonium hydroxide and then tosyl chloride in DCM to provide 7-bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3- dioxan-5-yl)methyl]-1 H-imidazo[4,5-c]quinolin-4-amine (Intermediate (ix)).

[0545] In step (7), Intermediate (ix) was is reacted with an alkyne like Intermediate (x), such as tert-butyl 4-(prop-2-yn-1-yl)piperazine-1 -carboxylate, in the presence of a palladium catalyst, such as tetrakis(triphenylphosphine)palladium, a copper catalyst, such as copper iodide, and a tertiary amine, such as triethylamine, in dimethylformamide, to provide tert-butyl 4-(3-{4-amino- 2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]-1 H-imidazo[4,5-c]quinolin-7-yl}prop- 2-yn-1-yl)piperazine-1-carboxylate (Intermediate (xi)).

[0546] In step (8), Intermediate (xi) is reduced to provide tert-butyl 4-(3-{4-amino-2- (ethoxymethyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]-1 H-imidazo[4,5-c]quinolin-7- yl}propyl)piperazine-1-carboxylate (Intermediate (xii)). The reduction was performed using a suitable palladium catalyst, such as Pd / C, in the presence of hydrogen, in a mixture of tetrahydrofuran and methanol.

[0547] In step (9), Intermediate (xii) is reacted with hydrochloric acid in DCM to provide 2-({4- amino-2-(ethoxymethyl)-7-[3-(piperazin-1-yl)propyl]-1 H-imidazo[4,5-c]quinolin-1-yl}methyl)-2- methylpropane-1,3-diol hydrochloride (Template A, the linking group Y is a propylene group (C3 alkyl) and ring B is a heterocycloalkyl that is a piperazinyl group). Using the appropriate alkynyl reagent (x) and making non-critical changes, other compounds of Formula (I) can be obtained.

[0548] According to another process, compounds of Formula (I) may be prepared from compounds of intermediate (xiii) as illustrated by Reaction Scheme IB for synthesis of intermediate (xii) (preceding Template A) for compounds of Formula (I).

[0549] Scheme IB e p Pd

[0550] In Reaction Scheme II, Template A produced from Scheme IA or Scheme IB is reacted with an acid chloride, in the presence of a base such as sodium bicarbonate or potassium carbonate, in THF to provide compound of Formula A-(i) where R1is C(=O)H, C(=O)Ci-Ce alkyl,

[0551] -C(=O)-Ci-C6alkyl-NH2, or -C(=O)-Ci-C6alkyl-OH, for instance.

[0552] Scheme II - Method A

[0553] In Reaction Scheme III, Template A is reacted with an aldehyde, such as paraformaldehyde, in the presence of a reducing agent, such as sodium triacetoxyborohydride, in methanol to provide compounds of Formula B-(i), where R1is Ci-Ce alkyl, for instance.

[0554] Scheme III - Method B CH3OH

[0555] Template A B-(i) In Reaction Schemes IV and V, Template A is reacted to provide drug-linker compounds of Formula (II):

[0556] Scheme IV - Method C

[0557] Scheme V - Method D

[0558]

[0559] According to another process, compounds of Formula (I) may be prepared from compounds of intermediate (xxiii) as illustrated by Scheme VIA for synthesis of Template B for compounds of Formula (I).

[0560] Scheme VIA

[0561] (xxiii) Step 1 (xxiv) Step 2 (xxvi)

[0562] POCI3

[0563] Step 3

[0564] Brr Step 5

[0565] (xxix) (xxviii) Step 4 (xxvii)

[0566] HCI DCM Step 6

[0567] Step 13

[0568] (xxxvi i) Template B In step (1) of Reaction Scheme VIA, ethyl 1-benzyl-3-oxopiperidine-4-carboxylate

[0569] Intermediate (xxiii) is reacted ammonium acetate in methanol to provide ethyl 5-amino-1-benzyl- 1,2,3,6-tetrahydropyridine-4-carboxylate (Intermediate (xxiv)). In step (2), Intermediate (xxiv) is reacted with methyl 3,3-dimethoxypropanoate (xxv), in the presence of a base, such as potassium tert-butoxide, in THF to provide methyl 7-benzyl-4- hydroxy-5,6,7,8-tetrahydro-1 ,7-naphthyridine-3-carboxylate (Intermediate (xxvi)).

[0570] In step (3), Intermediate (xxvi) is chlorinated with POC to provide methyl 7-benzyl-4- chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridine-3-carboxylate (Intermediate (xxvii)).

[0571] In step (4), ester hydrolysis of Intermediate (xxvii) using KOTMS, in THF provides 7- benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridine-3-carboxylic acid (Intermediate (xxviii)).

[0572] In step (5), the Curtius rearrangement of Intermediate (xxviii) using DPPA in DMF, in the presence of tert-BuOH, at 95 °C, provides tert-butyl (7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7- naphthyridin-3-yl)carbamate (Intermediate (xxix)).

[0573] In step (6) Intermediate (xxix) is reacted with hydrochloric acid in DCM to provide 7- benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3-amine (Intermediate (xxx)).

[0574] In step (7), Intermediate (xxx) is reacted with an acid chloride of structure (v), such as 2- ethoxyacetyl chloride in DCM, to provide / \ / -(7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7- naphthyridin-3-yl)-2-ethoxyacetamide (Intermediate (xxxi)). This synthetic process is described where R5is -CH2-O-CH2CH3, where routine modifications can be used to prepare other Intermediates (xxxi) from reagent (v).

[0575] In step (8), Intermediate (xxxi) is reacted with amine Intermediate (ii) (R3= CH3, synthesis is described in Biomacromolecules, 2018, 19(12), 4677-4690)) in the presence of a palladium catalyst, such as RuPhos Pd G3, a base, such as potassium phosphate in dioxane at 90 °C to provide / V-(7-benzyl-4-(((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)amino)-5,6,7,8-tetrahydro-1 ,7- naphthyridin-3-yl)-2-ethoxyacetamide (Intermediate (xxxii)). This synthetic process is described where R3is CH3, where routine modifications can be used to prepare other Intermediates (ii).

[0576] In step 9, Intermediate (xxxii) is reacted with a base, such as sodium hydroxide, in an alcoholic solvent, such as ethanol, to provide the dehydrated imidazole containing compound 7- benzyl-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7- imidazo[4,5-c][1 ,7]naphthyridine (Intermediate (xxxiii)).

[0577] In step 10, Intermediate (xxxiii) is reacted with 10% Pd / C in an alcoholic solvent, such as methanol, under an atmosphere of hydrogen, to provide 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine (Intermediate (xxxiv)).

[0578] In step 11 , Intermediate (xxxiv) is reacted with benzyl carbonochloridate (xxxv), in the presence of a base, such as sodium carbonate, in THF to provide benzyl 2-(ethoxymethyl)-1- ((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine- 7-carboxylate (Intermediate (xxxvi)).

[0579] In step 12, Intermediate (xxxvi) is reacted with a suitable oxidant, such as 3- chloroperoxybenzoic acid, in DCM to provide 7-((benzyloxy)carbonyl)-2-(ethoxymethyl)-1-((2,2,5- trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-c / [1 ,7]naphthyridine 5-oxide (Intermediate (xxxvii)).

[0580] In step 13, Intermediate (xxxvii) is sequentially reacted with ammonium hydroxide and then tosyl chloride in DCM to provide 7-bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl]-1 H-imidazo[4,5-c]quinolin-4-amine (Template B).

[0581] According to another process, compounds of Formula (I) may be prepared from compounds of intermediate (xxxviii) as illustrated by Reaction Scheme VIB for synthesis of intermediate (xxxiv) (preceding Template B) for compounds of Formula (I).

[0582] Scheme VIB (xli) ,2-diamino- cyclohexane

[0583] Cul, CS2CO3

[0584] Step 3 In step (1) of Reaction Scheme VIB, 4-chloro-1 ,7-naphthyridine (xxxviii) is reacted with amine Intermediate (ii) (R3= CH3, synthesis is described in Biomacromolecules, 2018, 19(12), 4677-4690)) in the presence of a tertiary amine, such as DIEA, to provide / V- ((2,2, 5-tri methyl- 1 ,3- dioxan-5-yl)methyl)-1 ,7-naphthyridin-4-amine (Intermediate (xxxix)). This synthetic process is described where R3is CH3, where routine modifications can be used to prepare other Intermediate (ii).

[0585] In step 2, Intermediate (xxxix) is reacted with a halogenating reagent, such as / V- iodosuccinamide, in DCM to provide 3-iodo- / V-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,7- naphthyridin-4-amine (Intermediate (xl)).

[0586] In step 3, Intermediate (xl) is reacted with an amide of structure (xli), such as pentanamide, in the presence of a base, such as cesium carbonate, a ligand, such as (1 R,2R)- (-)-1 ,2-diaminocyclohexane and Cui in dioxane, to provide / V-(4-(((2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl)amino)-1 ,7-naphthyridin-3-yl)pentanamide (Intermediate (xlii)).

[0587] In step 4, Intermediate (xlii) is reacted with a base, such as sodium hydroxide, in an alcoholic solvent, such as isopropanol, to provide the dehydrated imidazole containing compound 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine (Intermediate (xliii)).

[0588] In step 5, Intermediate (xliii) is reduced to provide 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine, where R5is n-butyl (xxxiv). The reduction was performed using a suitable catalyst, such as 5% Rh / C, in the presence of hydrogen, at 8 atm and 70 °C in a mixture of 2,2,2-trifluoroethanol and water.

[0589] In Reaction Scheme VII, Template B produced from Scheme VIA or Scheme VIB is reacted with an acid, such as HCI, in a mixture of dioxane and DCM, to provide compounds of Formula E:

[0590] Scheme VII In Reaction Scheme VIII, Intermediate xxxiv is reacted to provide drug-linker compounds of Formula (II):

[0591] Scheme VIII In step 1, an alcohol, such as tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate, is reacted with 4-nitrophenyl carbonochloridate (xlv), in the presence of a base, such as / V- methylmorpholine in DCM to provide tert-butyl 4-(2-(((4- nitrophenoxy)carbonyl)oxy)ethyl)piperidine-1 -carboxylate (Intermediate (xlvi)). In step 2, Intermediate (xlvi) is reacted with Intermediate (xxxiv) in the presence of a base, such as DIEA, in acetonitrile to provide 2-(((tert-butoxycarbonyl)amino)methyl)benzyl 4- amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7- imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (Intermediate (xlvii)).

[0592] In step 3, Intermediate (xlvii) is reacted with an acid, such as HCI, in a mixture of EtOAc and DCM to provide 2-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate as the HCI salt.

[0593] EXAMPLES

[0594] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0595] The compounds and intermediates described below were named using the naming convention provided with PerkinElmer Chemdraw® Version 20.1.1.125. The naming convention provided with Chemdraw® Version 20.1.1.125 is well known by those skilled in the art and it is believed that the naming convention provided with Chemdraw® Version 20.1.1.125 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0596] Example 1 : 2-((4-Amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-1H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol

[0597] Step 1 : Preparation of 7-bromo-3-nitro- / V-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]quinolin- 4-amine (3).

[0598] To a suspension of 7-bromo-4-chloro-3-nitroquinoline (1) (750 mg, 2.6 mmol) and triethylamine (0.72 mL, 5.2 mmol) in DCM (25 mL) was added 1-(2,2,5-trimethyl-1 ,3-dioxan-5- yl)methanamine (2) (415 mg, 2.6 mmol). The mixture was stirred at room temperature for 4 days. The crude reaction mixture was concentrated giving 1.5 g of a yellow solid. The crude product was purified using silica gel column chromatography and eluted with 1 :1

[0599] EtOAc: petroleum ether. The product (3) was obtained as a yellow solid (900 mg, 84% yield).1H NMR (400 MHz, DMSO-cfe) d 9.22 (br s, 1 H), 9.14 (s, 1 H), 8.50 (d, J = 9.1 Hz, 1 H), 8.12 (d, J = 2.1 Hz, 1 H), 7.77 (dd, J = 2.1 , 9.0 Hz, 1 H), 3.94 (d, J = 5.3 Hz, 2H), 3.67 (d, J = 12.0 Hz, 2H), 3.57 (d, J = 12.0 Hz, 2H), 1.36 (s, 3H), 1.23 (s, 3H), 0.92 (s, 3H). LCMS (ESI) m / z 410 / 412 (M+H). Rf 0.5 (1 :1 , EtOAc: petroleum ether).

[0600] Step 2: Preparation of 7-bromo- / V-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]quinoline-3,4- diamine (4).

[0601] To a suspension of 7-bromo-3-nitro- / V-[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]quinolin-4- amine (3) (200 mg, 0.49 mmol) in THF (10 mL) was added 5% platinum on carbon (Pt / C) (20 mg). The mixture was evacuated, purged with hydrogen and stirred at 1 atm for 16 hours. The crude reaction mixture was filtered through a pad of Celite® and the cake was washed with methanol. The filtrate was concentrated under reduced pressure and gave the product (4) as a yellow solid (180 mg, 97% yield).1H NMR (400 MHz, DMSO-d6) d 8.40 (s, 1 H), 8.03 (d, J = 9.2 Hz, 1 H), 7.91 (d, J = 2.0 Hz, 1 H), 7.46 (dd, J = 2.1 , 9.0 Hz, 1 H), 5.29 (s, 2H), 4.68 - 4.55 (m, 1 H), 3.69 (d, J = 11.6 Hz, 2H), 3.58 (d, J = 11.6 Hz, 2H), 3.25 (d, J = 7.3 Hz, 2H), 1.38 (s, 3H), 1.30 (s, 3H), 0.95 - 0.84 (m, 3H). LCMS (ESI) m / z 380 / 382 (M+H). Rf0.6 (EtOAc).

[0602] Step 3: Preparation of A / -(7-bromo-4-{[(2,2,5-trimethyl-1,3-dioxan-5- yl)methyl]amin

[0603] To a solution of 7-bromo- / V-[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]quinoline-3,4- diamine (4) (200 mg, 0.53 mmol) in DCM (10 mL) was added 2-ethoxyacetyl chloride (5) (64 mg, 0.53 mmol). The mixture was stirred at 0 to 10 °C for 0.5 hour. The yellow crude reaction mixture was poured into saturated NaHCOs (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The resultant yellow gummy residue was purified using silica gel column chromatography and eluted with EtOAc. The product (6) was obtained as a yellow gum (200 mg, 82% yield).1H NMR (400 MHz, DMSO-d6) d 9.57 (s, 1 H), 8.37 (s, 1 H), 8.26 (d, J = 9.0 Hz, 1 H), 8.03 (d, J = 2.0 Hz, 1 H), 7.62 (dd, J = 2.1 , 9.1 Hz, 1 H), 5.83 - 5.74 (m, 1 H), 4.11 (s, 2H), 3.70 - 3.49 (m, 8H), 1 .34 (s, 3H), 1.26 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 0.81 (s, 3H). LCMS (ESI) m / z 466 / 468 (M+H). Rf0.5 (EtOAc).

[0604] Step 4: Preparation of 7-bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5- y I )methy I] -1 H-imidazo[4,5-c]quinoline (7).

[0605] To a solution of / V-(7-bromo-4-{[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]amino}quinolin-3-yl)-2- ethoxyacetamide (6) (500 mg, 1.1 mmol) in ethanol (5 mL) was added NaOH (64 mg). The resultant mixture was stirred at 90 °C (reflux) for 2 hours, cooled to 20 °C and stirred for 16 hours. The crude reaction mixture was diluted with EtOAc (50 mL) and washed with brine (10 mL), dried using sodium sulfate, filtered and concentrated. The resultant yellow gum (700 mg) was purified using silica gel column chromatography and eluted with EtOAc and provided a yellow solid (500 mg). The product (7) was further purified using C18 reverse phase chromatography (YMC Triart C18, 250 x 50 mm, 7 micron, gradient using 0.05% ammonia hydroxide / acetonitrile) and the product (7) was isolated as a yellow solid (235 mg, 49% yield).1H NMR (400 MHz, DMSO-d6) d 9.22 (s, 1 H), 8.68 (d, J = 9.0 Hz, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 7.77 (dd, J = 1.9, 9.0 Hz, 1 H), 5.17 (br s, 1 H), 5.12 - 4.95 (m, 2H), 4.72 (br s, 1 H), 3.88 (br s, 1 H), 3.73 (br s, 1 H), 3.56 (br s, 4H), 1.41 (s, 3H), 1.39 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H), 0.57 (s, 3H). LCMS (ESI) m / z 448 / 450 (M+H). Rf0.5 (EtOAc).

[0606] Step 5: Preparation of 7-bromo-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5- yl)methyl)-1 H-imidazo[4,5-c]quinoline 5-oxide (8). To a solution of 7-bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]-1 / 7- imidazo[4,5-c]quinoline (7) (212 mg, 0.47 mmol) in DCM (10 mL) was added 3- chloroperoxybenzoic acid (106 mg, 85% purity, 0.52 mmol). The resultant solution was stirred at 20 °C for 16 hours. LCMS showed starting material (7) remained and the desired product (8). Additional 3-chloroperoxybenzoic acid (41 mg, 85% purity, 0.20 mmol) was added and the mixture stirred at 15 °C for 5 hours. The solution was diluted with DCM (50 mL), washed with saturated aqueous sodium bicarbonate (10 mL), dried over sodium sulfate, filtered and concentrated to give the crude product as a yellow gum (250 mg). The crude product was purified using silica gel column chromatography and eluted with methanol / EtOAc (1 / 10) and the product (8) was isolated as a yellow solid (150 mg, 68% yield).1H NMR (400 MHz, DMSO-ck) d 9.11 (s, 1 H), 8.95 (d, J = 2.1 Hz, 1 H), 8.73 (d, J = 9.0 Hz, 1 H), 7.93 (dd, J = 2.1 , 9.0 Hz, 1 H), 5.13 (br s, 1 H), 5.00 (br s, 2H), 4.81 - 4.58 (m, 1 H), 3.85 (br s, 1 H), 3.72 (br. s, 1 H), 3.57 (br. s, 4H), 1.41 (s, 3H), 1.38 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H), 0.60 (s, 3H). LCMS (ESI) m / z 464 / 466 (M+H). Rf0.5 (MeOH / EtOAc; 1 / 10).

[0607] Step 6: Preparation of 7-bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5- yl)methyl]-1 H-imidazo[4,5-c]quinolin-4-amine (9).

[0608] To a solution of 7-bromo-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)- 1 H-imidazo[4,5-c]quinoline 5-oxide (8) (200 mg, 0.43 mmol) in DCM (5 mL) at 0 °C was sequentially added ammonium hydroxide (16 M, 0.5 mL, 8.0 mmol) and p-toluenesulfonyl chloride (TsCI) (98 mg, 0.52 mmol). The mixture was stirred at 15 °C for 16 hours. The resultant white crude reaction mixture was diluted with DCM (30 mL), washed with saturated sodium bicarbonate (15 mL), dried using sodium sulfate, filtered and concentrated. The resultant white solid (300 mg) was purified using silica gel column chromatography and eluted with 10% MeOH / DCM. The product (9) was obtained as a white solid (150 mg, 75% yield).1H NMR (400 MHz, DMSO-cfe) 6 8.32 (d, J = 8.9 Hz, 1 H), 7.72 (d, J = 1.8 Hz, 1 H), 7.31 (dd, J = 1.6, 8.8 Hz, 1 H), 6.86 (br s, 2H), 5.11 (br s, 1 H), 4.97 (br s, 1 H), 4.86 (br s, 1 H), 4.63 (br s, 1 H), 3.86 (br s, 1 H), 3.72 (br s, 1 H), 3.55 (br s, 4H), 1.42 (s, 3H), 1.40 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H), 0.58 (s, 3H). LCMS (ESI) m / z 463 / 465 (M+H). Rf0.5 (methanol / DCM; 1 / 10).

[0609] Step 7: Preparation of tert-butyl 4-(3-{4-amino-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3- dioxan-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-7-yl}prop-2-yn-1-yl)piperazine-1- carboxylate (11).

[0610] To a solution of 7-bromo-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]- 1 / 7-imidazo[4,5-c]quinolin-4-amine (9) (150 mg, 0.32 mmol) in dimethylformamide (5 mL) was sequentially added tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (10) (182 mg, 0.81 mmol), triethylamine (0.22 mL, 1.6 mmol), Cui (12 mg, 0.06 mmol), and tetrakis(triphenylphosphine)palladium (37 mg, 0.03 mmol). The resultant mixture was degassed and purged with argon (3 times) and stirred at 110 °C for 16 hours. The brown crude reaction mixture was diluted with water (10 mL), and some brown solids formed. The brown solids were collected by filtration and washed with water (2 x 15 mL) and dried to give a brown solid (200 mg). The resultant brown solid was purified using silica gel column chromatography and eluted with methanol / DCM (1 / 10). The product (11) was obtained as a light brown solid (82 mg, 48% yield).1H NMR (400 MHz, DMSO-d6) d 8.34 (d, J = 8.5 Hz, 1 H), 7.59 (s, 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 6.77 (br s, 2H), 5.12 (br s, 1 H), 4.98 (br s, 1 H), 4.86 (br s, 1 H), 4.62 (br s, 1 H), 3.96 - 3.81 (m, 1 H), 3.81 - 3.66 (m, 1 H), 3.66 - 3.43 (m, 8H), 1.45 - 1.37 (m, 15H), 1.14 (t, J = 6.9 Hz, 3H), 0.58 (s, 3H). Some protons are presumably under the DMSO peak. The H-NMR was acquired in CDCh and all the protons were revealed.1H NMR (400 MHz, CDCh) d 8.13 (d, J = 8.5 Hz, 1 H), 7.91 (d, J = 1.3 Hz, 1 H), 7.34 (dd, J = 1.4, 8.7 Hz, 1 H), 5.53 (br s, 2H), 5.34 - 5.05 (m, 2H), 4.78 (br s, 2H), 3.89 - 3.39 (m, 12H), 2.64 (br s, 4H), 1.55 (s, 3H), 1.51 (s, 3H), 1.49 (s, 9H), 1.27 (t, J = 7.0 Hz, 3H), 0.65 (s, 3H). LCMS (ESI) m / z 607 (M+H). Rf0.5 (methanol / DCM; 1 / 10).

[0611] Step 8: Preparation of tert-butyl 4-(3-{4-amino-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1,3- dioxan-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-7-yl}propyl)piperazine-1 -carboxylate (12).

[0612] To a mixture of tert-butyl 4-(3-{4-amino-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl]-1 / 7-imidazo[4,5-c]quinolin-7-yl}prop-2-yn-1-yl)piperazine-1-carboxylate (11) (2.8 g, 4.6 mmol) in methanol (100 mL) was added 10% palladium on carbon (491 mg) and hydrogen. The resultant mixture was stirred at 20 °C at 1 atm for 4 hours. To the crude reaction mixture was added tetrahydrofuran (20 mL) and stirred for 20 hours. The mixture was filtered, and the filter cake was washed with CH3OH-DCM (1 :10). The filtrate was concentrated under reduced pressure and the resultant residue was purified using thin layer silica gel chromatography and eluted with CHsOH-EtOAc (1 :5). The product (12) was obtained as a yellow solid (2.1 g, 91% yield).1H NMR (400 MHz, CDCh) d 8.11 (d, J = 8.5 Hz, 1 H), 7.62 (d, J = 1.5 Hz, 1 H), 7.17 (dd, J = 8.5, 1.8 Hz, 1 H), 5.53 (br s, 2H), 5.15 (br s, 2H), 4.79 (br s, 2H), 3.82 (br s, 2H), 3.64 (br s, 4H), 3.49 - 3.39 (m, 4H), 2.80 (t, J = 7.6 Hz, 2H), 2.47 - 2.35 (m, 6H), 1.93 (br t, J = 7.4 Hz, 2H), 1.55 (s, 3H), 1.51 (s, 3H), 1.47 (s, 9H), 1.29 - 1.25 (m, 3H), 0.68 (s, 3 H). LCMS (ESI) m / z 611 (M+H). Rf 0.1 (CH3OH / DCM; 1 / 10).

[0613] Step 9: Preparation of 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-1H- imidazo[4,5-c]quinolin-1 -yl)methyl)-2-methyl propane-1 ,3-diol (Example 1, isolated as the hydrochloride).

[0614] To a solution of tert-butyl 4-(3-{4-amino-2-(ethoxymethyl)-1-[(2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl]-1 / 7-imidazo[4,5-c]quinolin-7-yl}propyl)piperazine-1-carboxylate (12) (180 mg, 0.29 mmol) in DCM (3.0 mL) at -78 °C was added HCI (8.0 mL, 4M in dioxane, 32 mmol). The resultant solution was stirred at 20 °C for 1.5 hours. The light yellow suspension was concentrated under reduced pressure until ~5 mL remained and the product (Example 1) was isolated by filtration. The filter cake was washed with DCM (3 x 2 mL), dissolved in DCM- CH3OH (5 mL / 5 mL), and concentrated under reduced pressure. The resultant yellow solid was dissolved in water (10 mL) and lyophilized for 18 hours and provided Example 1 as a hydrochloride that was a light yellow solid (170 mg). The crude product was further purified using C18 reverse phase chromatography (Boston Green ODS, 150 x 30 mm, 5 micron, gradient using 0.05% HCI / acetonitrile) and Example 1 was isolated as a yellow solid, as the hydrochloride (100 mg, 67% yield).1H NMR (400 MHz, D2O) d 8.43 (d, J = 8.8 Hz, 1 H), 7.47 (s, 1 H), 7.41 - 7.33 (m, 1 H), 5.00 - 4.75 (m, 3H), 4.65 - 4.48 (m, 1 H), 3.72 - 3.27 (m, 14H), 3.26 - 3.17 (m, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.26 - 1.92 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H), 0.58 (s, 3H). LCMS (ESI) m / z 471 (M+H). Example 2: Preparation of 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)prop-1-yn-1- yl)-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol, isolated as the HCI salt. Example 2

[0615] Example 2 was prepared according to the procedure used to prepare Example 1 , starting from Intermediate 11. The product was isolated as a white solid (13 mg, 34% yield).1H NMR (400 MHz, DMSO-d6) d 14.16 (br s, 1 H), 9.75 (br s, 2 H), 8.76 (d, J = 8.8 Hz, 1 H), 7.98 (d, J = 1.1 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 5.11 - 5.08 (m, 1 H), 4.94 - 4.79 (m, 1 H), 4.73 - 4.70 (m, 2H), 4.42 (s, 2H), 1.15 (t, J = 6.9 Hz, 3H), 0.56 (s, 3H). LCMS (ESI) m / z 467 (M+H).

[0616] Example 3: 2-((4-Amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1,3-diol

[0617] Step 1 : Preparation of 7-chloro- / V-[(3-methyloxetan-3-yl)methyl]quinolin-4-amine (13).

[0618] To a solution of 4,7-dichloroquinoline (26 g, 130 mmol) in dimethylacetamide (100 mL) was added (3-methyloxetan-3-yl)methanamine (26.6 g, 263 mmol), DI PEA (68 g, 525 mmol) and water (32.3 mL, 1790 mmol). The mixture was stirred at 110 °C for 36 hours, then cooled to room temperature and allowed to stir for an additional 3 hours. The resulting mixture was added dropwise to 300 mL of stirring water, then filtered. The solid residue was washed with water (3 x 100 mL) to afford the product (13) as a light yellow solid (27 g, 78% yield).1H NMR (400 MHz, DMSO-ds) d 8.38 (dd, J = 15.4, 7.2 Hz, 2H), 7.80 (t, J = 2.4 Hz, 1 H), 7.48 (dd, J = 9.0, 2.3 Hz, 1 H), 7.26 (t, J = 5.7 Hz, 1 H), 6.59 (d, J = 5.5 Hz, 1 H), 4.51 (d, J = 5.8 Hz, 2H), 4.27 (d, J = 5.8 Hz, 2H), 3.50 (d, J = 5.8 Hz, 2H). LCMS (ESI+) m / z 263 (M+H).

[0619] Step 2: Preparation of 2-{[(7-chloroquinolin-4-yl)amino]methyl}-2-methylpropane-1,3-diol (14).

[0620] To a flask containing 7-chloro- / V-[(3-methyloxetan-3-yl)methyl]quinolin-4-amine (13) (35.0 g, 133.2 mmol) was added water (210 mL), and the mixture was cooled in an ice bath. TFA (140 mL) was added slowly over 15 min. Then the mixture was stirred for 10 minutes on ice followed by 10 minutes at room temperature. The flask was placed in an oil bath and heated to 60 °C. After 1 hour, the mixture was cooled to room tempeature and the TFA was removed under reduced pressure. After the volume was condensed to - 200 mL, CH3OH (70 mL) was added, and the concentration was repeated. CH3OH was again added (70 mL) and the crude concentrated to a volume of -200 mL. The mixture was transferred to a 2 L round bottom flask and 5% NaHCOs aq. solution (350 mL) was added. After 10 minutes, an additional portion of 5% NaHCOs aq. solution (200 mL) was added slowly, and the resulting mixture was allowed to stir overnight. In the morning, another portion of 5% NaHCOs aq. solution (30 mL) was added. The mixture was filtered and the solids were allowed to dry at room temperature for 2 days. Water (500 mL) was then added to the solids and the mixture was stirred overnight before it was again filtered and dried open to air. The material was further dried under reduced pressure at 65 °C overnight to afford the product (14) as a white solid, which was carried forward without further purification (37.8 g, quant, yield).1H NMR (400 MHz, DMSO-d6) d 13.70 (br s, 1H), 9.05 (br t, J = 6.0 Hz, 1 H), 8.55 (d, J = 7.2 Hz, 1 H), 8.44 (d, J = 9.1 Hz, 1 H), 7.93 (d, J = 2.0 Hz, 1 H), 7.81 (dd, J = 9.0, 2.1 Hz, 1 H), 7.05 (d, J = 7.2 Hz, 1H), 4.84 (br s, 2H), 3.53 (d, J = 6.1 Hz, 2H), 3.41 - 3.33 (m, 3H), 0.88 (s, 3H). LCMS (APCI) m / z 281 (M+H).

[0621] Step 3: Preparation of 7-chloro- / V-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]quinolin-4- amine (15).

[0622] To a round bottom flask was added 2-{[(7-chloroquinolin-4-yl)amino]methyl}-2- methylpropane-1,3-diol (14) (30.5 g, 108.7 mmol), p-toluenesulfonic acid (20.6 g, 120 mmol), and anhydrous acetone (725 mL). The mixture was sealed and stirred at RT overnight. The mixture was then filtered and the solids were washed with anhydrous acetone (200 mL). The solids were added to DCM (700 mL) and sat. NaHCOs solution (700 mL) and stirred at room temperature for 2 hours. The layers were separated and the organic layer was extracted with DCM, then washed with water and brine. The crude was dried over Na2SO4 and filtered, then concentrated under reduced pressure to afford the product (15) as an off-white solid (24.7 g, 71% yield).1H NMR (400 MHz, DMSO-d6) d 8.40 (d, J = 4.0 Hz, 1 H), 8.38 (s, 1 H), 7.79 (d, J = 2.3 Hz, 1 H), 7.46 (dd, J = 9.0, 2.3 Hz, 1H), 7.21 (br t, J = 6.3 Hz, 1H), 6.76 (d, J = 5.6 Hz, 1 H), 3.61 (s, 4H), 3.47 (d, J = 6.5 Hz, 2H), 1.39 (s, 3H), 0.87 (s, 3H). LCMS (APCI) m / z 321 (M+H).

[0623] Step 4: Preparation of 7-chloro-3-iodo- / V-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]quinolin- 4-amine (16).

[0624] To a flask containing 7-chloro- / V-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]quinolin-4- amine (15) (12.7 g, 39.6 mmol) was added 1,3-diiodo-5,5-dimethyl-2,4-imidazolidinedione (17.2 g, 43.5 mmol) and AcOH (132 mL). The mixture was stirred at 50 °C for 2.5 hours, then cooled to room temperature. Separately, NaOH (100 mL, 19 M) was diluted with water (700 mL). This mixture was placed in an ice bath, and while stirring, the crude reaction was slowly added in 1 mL portions. The combined mixture was stirred at room temperature and additional NaOH (20 mL, 19 M) diluted with water (50 mL) was added to basify to pH ~ 8. The mixture was filtered with filter paper and orange solids were collected and washed with water (100 mL). The solids were further dried under reduced pressure overnight. The next day, the solids were dissolved in EtOAc and washed with 10% sodium thiosulfate solution (2 x 100 mL) and brine. The resulting mixture was dried over Na2SO4, filtered, and concentrated under reduced pressure for 2 hours before slurrying in DCM (100 mL). The mixture was allowed to sit at room temperature for 30 minutes and the resulting solids were collected by filtration. The solids were washed with DCM (50 mL) and dried under reduced pressure before undergoing purification by silica gel column chromatography (ISCO, EtOAc: Heptane, 0-40%) to afford the product (16) as a pale cream solid (13.5 g, 84% yield).1H NMR (400 MHz, DMSO-d6) d 8.82 (s, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 9.1 , 2.3 Hz, 1H), 5.26 (t, J = 6.4 Hz, 1H), 3.76 (d, J= 6.4 Hz, 2H), 3.65 - 3.53 (m, 4H), 1.34 (s, 3H), 1.22 (s, 3H), 0.92 (s, 3H). LCMS (APCI) m / z 447 (M+H).

[0625] Step 5: Preparation of A / -(7-chloro-4-{[(2,2,5-trimethyl-1,3-dioxan-5- yl)methyl]amino}quinolin-3-yl)pentanamide (17).

[0626] To a flask was added 7-chloro-3-iodo- / V-[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]quinolin- 4-amine (16) (16.3 g, 36.5 mmol), n-valeramide (6.3 g, 62.0 mmol), cesium carbonate (23.8 g, 73.0 mmol), and dioxane (243 mL). The mixture was degassed and purged with nitrogen before adding copper(l) iodide (1.18 g, 6.20 mmol). The mixture was degassed and purged again with nitrogen. Trans-N, / V'-dimethyl-1 ,2-cyclohexanediamine (1.04 g, 7.30 mmol, 1.15 mL) was added through the septa and the mixture was placed in a pre-heated oil bath at 75 °C overnight. The crude reaction mixture was then allowed to cool to room temperature and the volatiles were removed under reduced pressure. To the crude residue was sequentially added water (400 mL) and MTBE (400 mL). The layers were separated and the aqueous layer was extracted with MTBE (20 mL). The combined organic layers were washed with water (200 mL), 1% sodium ethylenediaminetetraacetic acid (200 mL) and brine (200 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated and the resulting solids were transferred to a flask, where EtOAc (200 mL) and DCM (200 mL) were added. The mixture was filtered, the layers were separated, and the combined organic layers were concentrated under reduced pressure. To the solid was added MTBE (85 mL) and the mixture was stirred overnight. In the morning, the solids were collected by filtration and washed with MTBE to afford the product (18) as a white solid (11.6 g, 74% yield).1H NMR (400 MHz, DMSO-d6) d 9.65 (s, 1 H), 8.36 (s, 1 H), 8.32 (d, J = 9.1 Hz, 1 H), 7.87 (d, J = 2.1 Hz, 1 H), 7.49 (dd, J = 9.0, 2.2 Hz, 1 H), 5.62 (t, J = 6.3 Hz, 1 H), 3.72 - 3.45 (m, 6H), 2.40 (t, J = 7.5 Hz, 2H), 1.67 - 1.62 (m, 2H), 1.46 - 1.36 (m, 2H), 1.34 (s, 3H), 1.26 (s, 3H), 0.93 (t, J = 7.3 Hz, 3H), 0.80 (s, 3H). LCMS (APCI) m / z 420 (M+H).

[0627] Step 6: Preparation of 2-butyl-7-chloro-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]-1H- imidazo[4,5-c]quinoline (18).

[0628] To a flask was added / V-(7-chloro-4-{[(2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl]amino}quinolin-3-yl)pentanamide (17) (15.8 g, 37.6 mmol) and IPA (150 mL) followed by an aq. potassium hydroxide solution (3 M, 117 mL). The resulting solution was placed in a pre-heated oil bath at 90 °C overnight. The mixture was then cooled to room temperature and poured into water (1.0 L) and allowed to stir at room temperature overnight. In the morning, the solids were collected by filtration to afford the product (18) as an off-white solid (14.8 g, 98% yield).1H NMR (400 MHz, DMSO-d6) d 9.18 (s, 1 H), 8.73 (d, J = 9.1 Hz, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 9.1 , 2.3 Hz, 1 H), 4.89 (br s, 2H), 3.87 - 3.41 (m, 4H), 3.12 (t, J = 7.6 Hz, 2H), 1.83 (br s, 2H), 1 .49 - 1.41 (m, 8H), 0.96 (t, J = 7.3 Hz, 3H), 0.58 (s, 3H). LCMS (APCI) m / z 402 (M+H).

[0629] Step 7: Preparation of 2-butyl-7-chloro-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1H- imidazo[4,5-c]quinoline 5-oxide (19).

[0630] To a mixture of 2-butyl-7-chloro-1-[(2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl]-1 / 7- imidazo[4,5-c]quinoline (18) (14.6 g, 36.3 mmol) in DCM (363 mL) was added meta- chloroperoxybenzoic acid (12.2 g, 54.5 mmol) at 0 °C, and the resulting solution was stirred at 0 °C for 30 minutes. The mixture was warmed to room temperature and allowed to stir overnight. To the mixture was added 5% NaHCCh (200 mL) and the mixture was stirred for 2 hours. The layers were separated and the organic layer was washed with 5% NaHCCh (2 x 200 mL) followed by brine, then dried over Na2SC>4, filtered, and concentrated under reduced pressure. To the crude residue was added EtOAc and the mixture was concentrated under reduced pressure to a foam. MTBE was added and the residue was concentrated to a solid. To the solid was again added MTBE (50 mL) and the resulting mixture was stirred overnight. In the morning, the solids were collected by filtration to afford the product (19) as a light beige solid (12.9 g, 85% yield).1H NMR (400 MHz, DMSO-d6) d 9.06 (s, 1 H), 8.84 - 8.74 (m, 2H), 7.79 (dd, J = 9.0, 2.4 Hz, 1 H), 4.88 - 4.84 (m, 2H), 3.89 - 3.75 (m, 1 H), 3.75 - 3.51 (m, 2H), 3.51 - 3.36 (m, 1 H), 3.14 - 3.04 (m, 2H), 1.81 (br s, 2H), 1.51 - 1.34 (m, 8H), 0.95 (t, J = 7.3 Hz, 3H), 0.61 (s, 3H). LCMS (APCI) m / z 418 (M+H).

[0631] Step 8: 2-Butyl-7-chloro-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]-1H-imidazo[4,5- c]quinolin-4-amine (20).

[0632] To a flask was added 2-butyl-7-chloro-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 / 7- imidazo[4,5-c]quinoline 5-oxide (19) (12.9 g, 30.9 mmol) and DCM (515 mL). The mixture was placed in an ice bath and stirred, then 28% NH4OH solution (97.2 mL) was added, followed by tosyl chloride (7.07 g, 37.1 mmol). The mixture was sealed and a nitrogen line was attached. The mixture was stirred at 0 °C until the ice bath melted and the reaction was allowed to warm to room temperature overnight. In the morning, the reaction was diluted with DCM and washed with sat. sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was slurried in I PA (14 mL) overnight before filtering and collecting the white solids, which were washed with minimal I PA. The solids were dried under reduced pressure at 60 °C for 2 days to yield the product (20) as a white solid (11.7 g, 91 % yield).1H NMR (400 MHz, DMSO-cfe) d 8.36 (d, J = 9.0 Hz, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 7.18 (dd, J = 8.8, 2.3 Hz, 1 H), 6.67 (s, 2H), 4.78 (br s, 2H), 3.94 - 3.34 (m, 4H), 3.21 - 2.91 (m, 2H), 1.77 (br d, J = 1.0 Hz, 2H), 1.49 - 1.31 (m, 8H), 0.95 (t, J = 7.4 Hz, 3H), 0.58 (s, 3H). LCMS (APCI) m / z 417 (M+H).

[0633] Step 9: Preparation of tert-butyl 4-(prop-2-en-1-yl)piperazine-1-carboxylate (21)

[0634] To a flask was added tert-butyl piperazinecarboxylate (30 g, 160 mmol), potassium carbonate (64.8 g, 469 mmol) and anhydrous THF (488 mL), followed by allyl bromide (20.7 g, 166 mmol, 14.8 mL). The mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The crude product was slurried in heptane (250 mL) for 30 minutes, then filtered. The collected filter cake was washed with heptane. The filtrate was concentrated under reduced pressure to obtain the product (21) as a pale yellow oil (36.7 g, 95% yield).1H NMR (400 MHz, DMSO-d6) 5 5.89 - 5.73 (m, 1 H), 5.24 - 5.09 (m, 2H), 3.31 (t, J = 5.3 Hz, 4H), 2.94 (td, J = 1 .3, 6.4 Hz, 2H), 2.30 (t, J = 5.0 Hz, 4H), 1.40 (s, 9H).

[0635] LCMS (APCI) m / z 227 (M+H). Step 10: Preparation of tert-butyl 4-[3-(10-borabicyclo[4.3.1]decan-10- yl)propyl]piperazine-1 -carboxylate (22).

[0636] To a flask was added tert-butyl 4-(prop-2-en-1-yl)piperazine-1 -carboxylate (21) (5.0 g, 20 mmol). The flask was sealed and anhydrous THF was added (30 mL) before degassing and backfilling with nitrogen. 9-Borabicyclo[3.3.1]nonane in THF (3 g, 20 mmol, 0.5 M, 40 mL) was added and the mixture was stirred at 50 °C for 1 hour. The solution was cooled to room temperature and afforded the product (22), which was used in the next step without further purification (8 g, quant, yield).

[0637] Step 11 : Preparation of tert-butyl 4-(3-{4-amino-2-butyl-1-[(2,2,5-trimethyl-1,3-dioxan-5- yl)methyl]-1H-imidazo[4,5-c]quinoline-7-yl}propyl)piperazine-1 -carboxylate (23).

[0638] To a flask was added 2-butyl-7-chloro-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methyl]-1 / 7- imidazo[4,5-c]quinoline-4-amine (20) (5.00 g, 12.0 mmol), 2-dicyclohexylphosphino-2’,6’- diisopropoxy-1 ,T-biphenyl)[2-(2’-amino-1 ,T-biphenyl)]palladium(ll) methanesulfonate (2.00 g, 2.39 mmol), sodium carbonate (4.00 g, 3.15 mmol), DMF (150 mL) and water (20 mL). The mixture was sealed, degassed, and backfilled with nitrogen. Tert-butyl 4-[3-(10- borabicyclo[4.3.1]decan-10-yl)propyl]piperazine-1-carboxylate (22) (6.3 g, 17 mmol) was added as a solution in THF (0.29 M, 60 mL). A condenser was attached to the round bottom flask, and the crude reaction mixture was degassed, and backfilled with nitrogen. The mixture was stirred at 90 °C for 1 hour before cooling to room temperature and allowing to sit overnight. The next day, the mixture was diluted with water (600 mL) and extracted with MTBE. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (ISCO, 120 g silica gel, EtOAc: heptane, 0-100% followed by CHsOH:DCM hold at 10% over 20 column volumes). The solvent was removed under reduced pressure before being re-diluted with MTBE (140 mL) and stirred at room temperature for two days. The solids were collected by filtration and washed with MTBE, then dried under reduced pressure to afford the product (23) as a white solid (5.5 g, 76% yield).1H NMR (400 MHz, DMSO-d6) d 8.23 (d, J = 8.5 Hz, 1 H), 7.39 (d, J = 1.5 Hz, 1 H), 7.07 (dd, J = 8.4, 1.6 Hz, 1 H), 6.34 (s, 2H), 4.78 (br s, 2H), 3.59 (br s, 4H), 3.11 - 2.92 (m, 2H), 2.69 (br t, J = 7.4 Hz, 2H), 2.37 - 2.25 (m, 6H), 1.85 - 1.72 (m, 4H), 1.46 - 1.35 (m, 18H), 0.95 (t, J = 7.4 Hz, 3H), 0.59 (s, 3H). LCMS (APCI) m / z 609 (M+H).

[0639] Step 12: Preparation of 2-((4-Amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1H-imidazo[4,5- c]quinolin-1 -yl)methyl)-2-methylpropane-1,3-diol (Example 3, isolated as the hydrochloride). p

[0640] To a flask was added tert-butyl 4-(3-{4-amino-2-butyl-1-[(2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl]-1 / 7-imidazo[4,5-c]quinolin-7-yl}propyl)piperazine-1-carboxylate (23) (5.5 g, 9.1 mmol), DCM (74 mL), and CH3OH (74 mL). The mixture was placed in an ice bath and a solution of HCI in dioxane was added (4 M, 114 mL). The reaction was stirred overnight as the ice melted. The material was concentrated under reduced pressure, followed by drying in a vacuum oven at 70 °C overnight to afford the product (Example 3) as a light gray solid (5.42 g, 95% yield).1H NMR (400 MHz, D2O) d 8.53 (d, J = 8.8 Hz, 1 H), 7.58 (d, J = 1.6 Hz, 1 H), 7.48 (dd, J = 8.6, 1.6 Hz, 1 H), 4.98 - 4.84 (m, 1 H), 4.61 - 4.46 (m, 1 H), 3.69 - 3.56 (m, 8H), 3.46 (br s, 2H), 3.38 - 3.29 (m, 2H), 3.06 (br d, J = 5.1 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H), 2.23 - 2.13 (m, 2H), 1.89 - 1.74 (m, 2H), 1.49 - 1.37 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.67 (s, 3H). LCMS (APCI) m / z 469 (M+H).

[0641] Table 1 provides a further example prepared according to Scheme IA with acid catalyzed deprotection of intermediate (xi) and the procedure used to prepare Examples 1-3, made with non-critical changes or standard substitutions to the exemplified procedure used to prepare Examples 1-3 that someone of ordinary skill in the art would be able to realize.

[0642] Table 1

[0643] Example 4: Preparation of 1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-

[0644] (hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethan-1-one.

[0645] Example 1 Example 4

[0646] To a solution of Example 1 , as the HCI salt (40 mg, 0.08 mmol) in tetrahydrofuran (4.0 mL), was sequentially added a solution of sodium bicarbonate (13 mg, 0.16 mmol) in water (1.0 mL) and acetyl chloride (6.2 mg, 0.08 mmol) in tetra hydrofuran (0.2 mL) at 0 °C. The reaction was stirred at 0 to 10 °C for 1 hour. The crude reaction mixture was diluted with EtOAc and water (5 mL each). LCMS gave only product in the aqueous layer. The aqueous layer was concentrated under reduced pressure until ~2 mL remained and the crude product was purified by reverse phase chromatography (Phenomenex Gemini-NX, 80 x 40 mm, 3 pM column; mobile phase gradient using 0.05% ammonium hydroxide / acetonitrile). Example 4 was isolated as a white solid (25 mg, 62% yield).1H NMR (400 MHz, DMSO-d6) d 8.42 (d, J = 8.5 Hz, 1 H), 7.40 (s, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 6.53 (s, 2H), 5.08 - 5.01 (m, 3H), 4.83 - 4.75 (m, 1 H), 4.70

[0647] - 4.54 (m, 2H), 3.54 - 3.47 (m, 2H), 3.42 - 3.41 (m, 5H), 3.30 - 3.24 (m, 2H), 3.21 - 3.13 (m, 1 H), 2.70 (t, J = 7.5 Hz, 2H), 2.36 - 2.33 (m, 4H), 2.31 - 2.28 (m, 2H), 1.98 (s, 3H), 1.89 - 1.73 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H), 0.55 (s, 3H). LCMS (ESI) m / z 513 (M+H). Table 2 provides Examples prepared according to Scheme II - Method A and the procedure used to prepare Example 4, made with non-critical changes or standard substitutions to the exemplified procedure used to prepare Examples 1 or 4 that a person of ordinary skill in the art would be able to realize. Table 2

[0648] Example 5: Preparation of 2-((4-amino-2-(ethoxymethyl)-7-(3-(4-methylpiperazin-1- yl)propyl)-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol.

[0649] A solution of Example 1 , as the HCI salt (30 mg, 0.06 mmol) and paraformaldehyde (9.3 mg, 0.31 mmol) in CH3OH (5.0 mL) was stirred at 10 °C for 60 hours. To the solution was added sodium triacetoxyborohydride (26 mg, 0.12 mmol) and the mixture was stirred at 15 °C for 3 hours. The crude reaction mixture was quench with 2 drops of water and the solvent was removed under reduced pressure to provide a white solid. The crude product was purified by reverse phase chromatography (Phenomenex Gemini-NX, 80 x 40 mm, 3 pM column; mobile phase gradient using 0.05% ammonium hydroxide / acetonitrile). Example 5 was isolated as a white solid (16 mg, 53% yield).1H NMR (400 MHz, DMSO-d6) d 8.42 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 1.5 Hz, 1 H), 7.07 (dd, J = 8.5, 1.7 Hz, 1 H), 6.51 (s, 2H), 5.13 - 5.04 (m, 1 H), 4.99 (t, J = 4.7 Hz, 2H), 8.81 - 4.72 (m, 1 H), 4.68 - 4.55 (m, 2H), 3.51 (br s, 2H), 3.41 (br s, 2H), 3.21 - 3.12 (m, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.45 - 2.17 (m, 10H), 2.14 (s, 3H), 1.78 (quin, J = 7.3 Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H), 0.56 (s, 3H). LCMS (ESI) m / z 485 (M+H).

[0650] Table 3 provides additional Examples prepared according to Scheme II - Method B and the procedure used to prepare Example 5, made with non-critical changes or standard substitutions to the exemplified procedure used to prepare Examples 1 or 5 that a person of ordinary skill in the art would be able to realize.

[0651] Table 3

[0652] Example 6: 2-((4-Amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-6,7,8,9-tetrahydro- 1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol.

[0653] Step 1 : Preparation of tert-butyl 4-(3-(4-amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3- dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1- carboxylate (24).

[0654] To a solution of Intermediate 11 (600 mg, 1 mmol) in isopropanol (20 mL) was added 10% Pd / AhOs (600 mg, 100 w / w%) in one portion. The 250 mL stainless steel reaction vessel was sealed before over-head stirring (1000 rpm) was initiated. The vessel was pressurized with nitrogen three times (0 to 8 Bar) and then hydrogen (20 Bar). The reaction as heated 130 °C at which point the pressure reached 30 Bar. The reaction was heated at 130 °C under 30 Bar of hydrogen for 72 hours. After 72 hours, the vessel was cooled to room temperature, and purged with nitrogen three times (0 to 8 Bar). LCMS gave -50% product to starting material. The crude product (24) was filtered, and the solids washed with isopropanol. The filtrate was collected and concentrated under reduced pressure and gave a yellow solid. The crude product (24) was purified by SFC (Regis (R,R) Whelk-01 , 21.1 x 250 mm column at 35 °C, 30% methanol + 10 mM NHs:70% CO2, 100 bar, 80 mL / min) which gave 142 mg of a beige solid (24% yield). LCMS (ESI) m / z 615 (M+H).

[0655] Step 2: Preparation of 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-6,7,8,9- tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol (Example 6, isolated as the hydrochloride). To a solution of tert-butyl 4-(3-(4-amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1-carboxylate (24) (25 mg, 0.04 mmol) in tetrahydrofuran (0.16 mL) was added HCI (0.07 mL, 6 M aqueous HCI). The amber solution was stirred for 18 hours at room temperature, followed by the addition of 70 L 6 M HCI and warming to 50 °C for 30 minutes. The solvent was removed under reduced pressure, and the product (Example 6) was isolated as an amber residue (20 mg, 100% yield). LCMS (APCI) m / z 475 (M+H).

[0656] Example 7: A / -(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)-1-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide

[0657] Step 1 : Preparation of tert-butyl {4-[4-(3-{4-amino-2-butyl-1-[3-hydroxy-2- (hydroxymethyl)-2-methylpropyl]-1H-imidazo[4,5-c]quinolin-7-yl}propyl)piperazin-1- yl]

[0658] To a vial was added 2-({4-amino-2-butyl-7-[3-(piperazin-1-yl)propyl]-1 / 7-imidazo[4,5- c]quinolin-1-yl}methyl)-2-methylpropane-1 ,3-diol (Example 3) (250 mg, 0.433 mmol), 1 ,1 -dimethylethyl 2-hydroxy-1-pyrrolidinecarboxylate (648 mg, 3.5 mmol), and 4.33 mL anhydrous DCE. After the mixture was sealed, sonicated, and stirred at room temperature for 5 minutes, sodium triacetoxyborohydride was added (733 mg, 3.46 mmol). The mixture was sealed, sonicated, and stirred at room temperature. The sides of the vial were washed with DCE (0.5 mL). After 1 hour, the reaction was quenched with NaHCOs solution. The mixture was diluted with water and extracted with 15% IPA:DCM, then the combined organic layers were washed with brine and dried over Na2SO4. The mixture was concentrated under reduced pressure to obtain a clear oil, which turned pink after standing overnight. The crude residue was purified by reverse phase chromatography (Phenomenex Gemini NX C18 150 x 21.2 mm, 5 urn column; phase A, water + 10 mM ammonium acetate; phase B, acetonitrile; 25 - 60% B in 5.2 minutes mobile phase gradient, 40 mL / min flow rate). The resulting material was further purified by preparatory SFC (Princeton HA-Morpholine 150 x 21.2 mm, 5 urn column; mobile phase A: CO2, mobile phase B: CH3OH 12 - 32% B over 4 minutes, 80 mL / min flow rate) to afford the product (25) as an off white solid (117 mg, 43% yield).1H NMR (400 MHz, DMSO-d6) d 8.38 (d, J = 8.4 Hz, 1 H), 7.43 (s, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 6.55 - 6.36 (m, 1 H), 6.03 (s, 2H), 4.66 (t, J = 4.9 Hz, 2H), 4.64 - 4.60 (m, 1 H), 3.37 (br d, J = 4.1 Hz, 4H), 3.02 (t, J = 7.6 Hz, 2H), 2.94 (q,

[0659] J = 6.3 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.39 (s, 8H), 2.34 (t, J = 7.1 Hz, 2H), 2.27 (br t, J = 6.1 Hz, 2H), 1.82 (quin, J = 7.4 Hz, 4H), 1.51 - 1.41 (m, 6H), 1.39 (s, 9H), 0.97 (t, J = 7.4 Hz, 3H), 0.61 (s, 3H). LCMS (APCI) m / z 640 (M+H).

[0660] Step 2: Preparation of 2-[(4-amino-7-{3-[4-(4-aminobutyl)piperazin-1-yl]propyl}-2-butyl- 1H-imidazo[4,5-c]quinolin-1-yl)methyl]-2-methylpropane-1,3-diol (26).

[0661] To a vial containing terf-butyl {4-[4-(3-{4-amino-2-butyl-1-[3-hydroxy-2-(hydroxymethyl)- 2-methylpropyl]-1 / 7-imidazo[4,5-c]quinolin-7-yl}propyl)piperazin-1-yl]butyl}carbamate (25) (117 mg, 0.18 mmol) dissolved in 0.92 mL anhydrous CH3OH was added 0.92 mL HCI in dioxane (4 M, 133 mg, 3.66 mmol). The mixture was sealed and stirred at room temperature for 20 minutes, then 5 mL CH3OH was added. After 1 hour, the mixture was concentrated under reduced pressure to afford the product (26) as a white solid (140 mg, 95% yield).1H NMR (400 MHz, D2O) d 8.57 (d, J = 8.6 Hz, 1 H), 7.59 (d, J = 1.5 Hz, 1 H), 7.49 (dd, J = 8.6, 1 .6 Hz, 1 H), 5.01 - 4.86 (m, 1 H), 4.58 (br s, 1 H), 3.74 - 3.60 (m, 8H), 3.59 (br s, 2H), 3.49 (br d, J = 10.9 Hz, 2H), 3.30 (br s, 2H), 3.07 (br d, J = 7.5 Hz, 2H), 3.05 - 2.99 (m, 2H), 2.91 (t, J = 7.6 Hz, 2H), 2.23 - 2.13 (m, 2H), 1.88 - 1.78 (m, 4H), 1.77 - 1.67 (m, 2H), 1.47 - 1.37 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H), 0.69 (s, 3H). LCMS (APCI) m / z 540 (M+H).

[0662] Step 3: Preparation of / V-{4-[4-(3-{4-amino-2-butyl-1-[3-hydroxy-2-(hydroxymethyl)-2- methylpropyl]-1H-imidazo[4,5-c]quinolin-7-yl}propyl)piperazin-1-yl]butyl}-1-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide (Example 7).

[0663] Example 7 To a vial containing 2-[(4-amino-7-{3-[4-(4-aminobutyl)piperazin-1-yl]propyl}-2-butyl-1 / 7- imidazo[4,5-c]quinolin-1-yl)methyl]-2-methylpropane-1 ,3-diol (26) was added DMF (1.7 mL) and DIPEA (168 mg, 1.30 mmol). After sonicating, 1-{27-[(2,5-dioxopyrrolidin-1-yl)oxy]-27-oxo- 3,6,9,12,15,18,21 ,24-octaoxaheptacosan-1-yl}-1 / 7-pyrrole-2,5-dione (160 mg, 0.259 mmol) was added in DMF. The mixture was sealed and stirred at room temperature for 1 hour before cooling in an ice bath and adding TFA (100 uL, 1.30 mmol). The mixture was sealed and stirred in the ice bath for 5 minutes, then refrigerated overnight. The crude product was purified by reverse phase chromatography (YMC-Actus Triart C18 150 x 21.2 mm, 5 urn column; mobile phase A: water + 0.05% TFA, mobile phase B: acetonitrile 10 - 50% B in 8.0 minutes, 25 mL / min flow rate) to provide the product (Example 7) as a colorless gum (150 mg, 41% yield).1H NMR (400 MHz, DMSO-d6) d 13.41 (br dd, J = 4.6, 3.3 Hz, 1 H), 8.94 - 8.71 (m, 1 H), 8.67 (br d, J = 8.6 Hz, 1 H), 7.89 - 7.78 (m, 1 H), 7.60 (s, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.01 (s, 2H), 5.16 - 4.96 (m, 1 H), 4.81 (br s, 1 H), 4.59 - 4.45 (m, 1 H), 3.62 - 3.54 (m, 4H), 3.53 - 3.46 (m, 29H), 3.09 - 3.02 (m, 4H), 2.79 (br t, J = 7.8 Hz, 3H), 2.34 - 2.26 (m, 3H), 1.80 (br dd, J = 11.4, 5.8 Hz, 2H), 1.63 - 1.49 (m, 2H), 1 .47 - 1 .35 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H), 0.56 (s, 3H). LCMS (APCI) m / z 1044 (M+H).

[0664] Table 4 provides additional Examples prepared with non-critical changes or standard substitutions to the exemplified procedure used to prepare Example 7 that a person of ordinary skill in the art would be able to realize.

[0665] Table 4

[0666] Example 8: 1-(2-(2-(4-(3-(4-Amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1H- pyrrole-2, 5-dione Step 1 : Preparation of [2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethoxy]acetaldehyde (27).

[0667] To a vial was added 1-[2-(2-hydroxyethoxy)ethyl]-1 / 7-pyrrole-2, 5-dione (66 mg, 0.36 mmol) dissolved in 3.6 mL anhydrous DCM. Dess- Martin periodinane (226 mg, 0.533 mmol) was added and the mixture was stirred at room temperature for 2.5 hours. The mixture was filtered through a syringe tip Teflon filter, which was washed with 0.6 mL MTBE. The filtrate was concentrated under reduced pressure to obtain the product (27) as a clear oil.

[0668] Step 2: Preparation of 11-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1H- pyrrole-2, 5-dione (Example 8).

[0669]

[0670] Example 8

[0671] To a vial containing 2-({4-amino-2-butyl-7-[3-(piperazin-1-yl)propyl]-1 / 7-imidazo[4,5- c]quinolin-1-yl}methyl)-2-methylpropane-1,3-diol (Example 3) (82 mg, 0.135 mmol) and sodium cyanoborohydride (17.0 mg, 0.271 mmol) was added [2-(2,5-dioxo-2,5-dihydro-1 / 7-pyrrol-1- yl)ethoxy]acetaldehyde (27) (62 mg, 0.34 mmol) dissolved in 2.7 mL CH3OH. The mixture was sealed and allowed to stir at room temperature overnight. The reaction was quenched with TFA (0.104 mL, 154 mg, 1.35 mmol) and stirred open to air for 1 hour. The mixture was filtered using a syringe tip Teflon filter, which was washed with 1 mL CH3OH. The filtrate was purified by reverse phase chromatography (Phenomenex Gemini C18 150 x 21.2 mm, 5 urn column, mobile phase A: Water + 0.05% TFA, mobile phase B: Acetonitrile 10 - 40% B in 8.0 minutes, 25 mL / min) to afford the product (Example 8) as a white powder (50 mg, 33% yield).1H NMR (400 MHz, D2O) 5 8.57 (d, J = 8.6 Hz, 1 H), 7.59 (d, J = 1.3 Hz, 1 H), 7.53 - 7.44 (m, 1 H), 6.84 (s, 2H), 5.06 - 4.85 (m, 1 H), 4.61 - 4.46 (m, 1 H), 3.78 - 3.73 (m, 2H), 3.71 - 3.67 (m, 2H), 3.66 - 3.62 (m, 2H), 3.59 (br s, 2H), 3.46 (br s, 2H), 3.42 (br s, 3H), 3.39 - 3.32 (m, 3H), 3.22 - 3.15 (m, 4H), 3.14 - 3.01 (m, 2H), 2.90 (br t, J = 7.5 Hz, 2H), 2.21 - 2.08 (m, 2H), 1.81 (br t, J = 7.6 Hz, 2H), 1.49 - 1.34 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H), 0.69 (s, 3H). LCMS (APCI) m / z 636 (M+H).

[0672] Table 5 provides additional Examples prepared with non-critical changes or standard substitutions to the exemplified procedure used to prepare Example 8 that a person of ordinary skill in the art would be able to realize.

[0673] Table 5

[0674] Example 9: Preparation of S-(1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethoxy)ethyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine TFA salt.

[0675] Example 9 To a vial was added 1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)-1 / 7-pyrrole-2,5- dione TFA salt (Example 8) (49 mg, 0.077 mmol), L-cysteine (28 mg, 0.23 mmol), and DMF (1 mL). The mixture was stirred at 40°C for 22.5 hours and cooled to room temperature. The mixture was filtered through a PTFE syringe filter and the filter was rinsed with 0.5 mL DMF. The filtrate was purified by reverse phase chromatography (YMC-Actus Triart C18 HPLC, 21.2 mm x 150 mm, 5 pm column; 5-35% ACN in water + 0.05% TFA over 8 minutes mobile phase gradient; 25 mL / min flow rate) and lyophilized to afford S-(1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3- hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethoxy)ethyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine TFA salt (Example 9) as a faint yellow oil (46.5 mg, 55% yield).1H NMR (400 MHz, METHANOL-^ ) 5 8.77 (dd, J = 8.8, 1.6 Hz, 1 H), 7.74 (dd, J = 8.0, 1.5 Hz, 1 H), 7.51 - 7.43 (m, 1 H), 5.07 - 4.91 (m, 1 H), 4.75 - 4.61 (m, 1 H), 4.26 - 4.02 (m, 2H), 3.80 - 3.72 (m, 4H), 3.72 - 3.66 (m, 3H), 3.53 - 3.37 (m, 4H), 3.30 - 3.12 (m, 11 H), 3.07 (dt, J = 9.1 , 4.8 Hz, 2H), 3.01 - 2.90 (m, 4H), 2.60 (ddd, J = 18.7, 11.1 , 4.3 Hz, 1 H), 2.18 - 2.04 (m, 2H), 1.98 - 1.85 (m, 2H), 1.61 - 1.48 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H), 0.69 (s, 3H). LCMS (ESI) m / z 757.1 (M+H).

[0676] Table 6 provides additional Examples prepared with non-critical changes or standard substitutions to the exemplified procedure used to prepare Example 9 that a person of ordinary skill in the art would be able to realize.

[0677] Table 6

[0678] Example 10: Preparation of (3 / ?)-6-(2-((2-(2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-

[0679] (hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethoxy)ethyl)amino)-2-oxoethyl)-5-oxothiomorpholine-3-carboxylic acid TFA salt.

[0680] Example 10

[0681] To a vial was added 0.875 mL of a 0.016 M S-(1-(2-(2-(4-(3-(4-amino-2-butyl-1-(3- hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)ethoxy)ethyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine TFA salt (Example 9) in methanol stock solution (10.6 mg, 0.014 mmol). The methanol was evaporated at room temperature with a nitrogen line. To the vial was added 0.933 L of a pH 7.4 monobasic and dibasic potassium phosphate solution. The solution was stirred at room temperature for 22.5 hours. The crude reaction solution was purified by Phenomenex Kinetex 5 urn Biphenyl HPLC (4.6 mm x 50 mm, 2-80% ACN in water + 0.05% TFA over 5 min, 2 mL / min) and lyophilized to afford (3F?)-6-(2-((2- (2-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5- c]quinolin-7-yl)propyl)piperazin-1-yl)ethoxy)ethyl)amino)-2-oxoethyl)-5-oxothiomorpholine-3- carboxylic acid TFA salt (Example 10) as a clear gum (10.2 mg, 69% yield).1H NMR (600 MHz, METHANOL-^) 5 8.72 (d, J = 8.7 Hz, 1 H), 7.67 (s, 1 H), 7.45 (br d, J = 8.2 Hz, 1 H), 4.94 (br s, 1 H), 4.63 (br s, 1 H), 4.43 (br s, 1 H), 3.86 (br t, J = 6.6 Hz, 1 H), 3.79 (br t, J = 4.6 Hz, 2H), 3.71 - 3.63 (m, 1 H), 3.60 - 3.55 (m, 3H), 3.51 - 3.42 (m, 6H), 3.40 - 3.30 (m, 6H), 3.28 (br s, 2H), 3.24 (br dd, J = 4.3, 13.7 Hz, 1 H), 3.15 (br t, J = 6.4 Hz, 2H), 3.13 - 3.08 (m, 1 H), 3.08 (br s, 2H),

[0682] 2.90 (br s, 2H), 2.91 - 2.85 (m, 1 H), 2.63 (dd, J = 7.6, 15.1 Hz, 1 H), 2.13 (quin, J = 7.6 Hz, 2H),

[0683] 1.91 (br s, 2H), 1.52 (br d, J = 6.9 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.66 (s, 3H). LCMS (ESI) m / z 757 (M+H).

[0684] Table 7 provides additional Examples prepared with non-critical changes or standard substitutions to the exemplified procedure used to prepare Example 10 that a person of ordinary skill in the art would be able to realize.

[0685] Table 7

[0686] Example 11 : A / -(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-4-oxobutyl)-1-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide Step 1 : Tert-butyl (4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-4-oxobutyl)carbamate

[0687] (28).

[0688] To a white mixture of the acid (70 mg, 0.34 mmol) and Example 1 (200 mg, 0.34 mmol) in DMF (1.7 mL) was added TEA (0.24 mL, 1.7 mmol). To the resultant cloudy solution was added HATLI (131 mg, 0.34 mmol). The cloudy yellow solution was placed in an oil bath preheated to 50 °C. After 70 minutes, LCMS of the orange mixture gave only product. The crude reaction mixture was cooled to room temperature and allowed to stand at room temperature overnight. The crude reaction mixture was diluted with 30 mL of water and extracted with 20 mL MTBE. Not much uv activity was observed in the organic layer. The aqueous layer was extracted with 3 x 15 mL EtOAc and the combined MTBE and EtOAc extracts were washed with 10 mL of brine, dried over Na2SC>4, filtered and concentrated to an orange oil (308 mg). TLC (10% CH3OH-DCM with 5 drops NHs (7N in methanol) / 10 mL mobile phase) gave mostly Rf 0.6. The crude product was purified over silica gel (2 mm chromatotron plate) and eluted with 3-12% CH3OH-DCM with 0.5 mL NH3 (7M in methanol) per 100 mL of eluent, to provide tert- butyl (4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)- 2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-4-oxobutyl)carbamate (28) as an orange oil (110 mg, 49% yield).1H NMR (400 MHz, DMSO-d6) 5 8.46 (d, J = 8.5 Hz, 1 H), 7.45 (s, 1 H), 7.14 (d, = 8.1 Hz, 1 H), 6.77 (br t, J = 5.3 Hz, 1 H), 5.06 (br s, 1 H), 4.97 (t, J = 4.8 Hz, 2H), 4.79 (br s, 1 H), 4.67 (br s, 2H), 4.07 (q, J = 5.3 Hz, 2H), 3.54 (br s, 2H), 3.43 (br s, 5H), 2.92 (q, J = 6.7 Hz, 2H), 2.73 (br t, J = 7.6 Hz, 2H), 2.44 - 2.25 (m, 8H), 1.96 - 1.76 (m, 2H), 1.61 - 1.57 (m, 2H), 1.37 (s, 9H), 1.31 - 1.26 (m, 3H), 1.14 (t, J = 7.0 Hz, 3H), 0.57 (s, 3H). LCMS (APCI) m / z 656.6 (M+H). Step 2: 4-Amino-1 -(4-(3-(4-amino-2-(ethoxymethyl)-1 -(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butan-1-one HCI salt (29). To a solution of tert-butyl (4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-

[0689] (hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-4- oxobutyl)carbamate (28) (110 mg, 0.17 mmol) in methanol (1.7 mL) was added HCI-dioxane (0.84 mL, 2.4 mmol, 4M) and the amber solution was stirred at room temperature. After 4 hours, LCMS gave >90% product. The solvent was removed under reduced pressure and provided 4- amino-1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butan-1-one HCI salt (29) as an oil (118 mg, 100% yield). LCMS (APCI) m / z 556.3 (M+H).

[0690] Step 3: A / -(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-4-oxobutyl)-1-(2,5- dioxo-2,5-dihydro-1 H-pyrrol-1 -yl)-3,6,9, 12, 15, 18,21 ,24-octaoxaheptacosan-27-amide

[0691] (Example 11).

[0692]

[0693] To 4-amino-1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butan-1-one HCI salt (29) (118 mg, 0.17 mmol) was added 0.5 mL of DMF and DIEA (0.15 mL, 0.84 mmol) which gave a light amber solution, followed by the activated ester (104 mg, 0.17 mmol) in 0.20 mL of DMF. An additional 0.4 mL of DMF was added. The light amber solution was stirred at room temperature for 15 minutes. LCMS of the crude reaction mixture gave >90% product and no starting material. The crude reaction mixture was cooled in an ice bath and 100 uL of TFA was added. The crude product was purified by reverse phase chromatography (Phenomenex Gemini 5 urn NX-C18 150 x 21.2 mm column; water + 0.05% trifluoroacetic acid and acetonitrile 10-40% in 8.0 minutes; 25 mL / min flow rate). / \ / -(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3- hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)-4-oxobutyl)-1-(2,5-dioxo-2,5-dihydro-1 / 7-pyrrol-1-yl)-3,6,9,12,15,18,21 ,24- octaoxaheptacosan-27-amide (Example 11) was isolated as a yellow gum (112 mg, 47% yield).1H NMR (400 MHz, D2O) 5 8.58 (d, J = 8.6 Hz, 1 H), 7.60 (d, J = 1.4 Hz, 1 H), 7.51 (dd, J = 8.7, 1.4 Hz, 1 H), 6.81 (s, 2H), 5.11 - 4.82 (m, 3H), 3.81 - 3.70 (m, 5H), 3.70 - 3.41 (m, 41 H), 3.31 - 3.16 (m, 5H), 3.16 - 2.96 (m, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.51 - 2.41 (m, 4H), 2.27 - 2.11 (m, 2H), 1.79 - 1.72 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.70 (s, 3H). LCMS (APCI) m / z 1059.4 (M+H).

[0694] Example 12: 3-Hydroxypropyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1 -carboxylate.

[0695] Step 1 : 3-((7ert-butyldimethylsilyl)oxy)propyl (4-nitrophenyl) carbonate (30).

[0696] To a solution of 3-((tert-butyldimethylsilyl)oxy)propan-1-ol (30) (500 mg, 2.63 mmol) and TEA (531 mg, 5.25 mmol) in DCM (10 mL) was added 4-nitrophenyl carbonochloridate (31) (582 mg, 2.89 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. LCMS showed 3-((tert-butyldimethylsilyl)oxy)propan-1-ol was consumed and desired mass was detected. The mixture was diluted with water (20 mL), extracted with ethyl acetate (3 x 30 mL). The combined organic layer was dried over with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and eluted with petroleum ether / ethyl acetate (100:1 to 10:1). 3-((Terf-butyldimethylsilyl)oxy)propyl (4-nitrophenyl) carbonate (32) (875 mg, 2.46 mmol, 93% yield) was obtained as colorless oil.1H NMR (400 MHz, CDCh) 6 8.18 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 4.31 (t, J = 6.3 Hz, 2H), 4.02 (q, J = 7.1 Hz, 1 H), 3.66 (t, J = 5.9 Hz, 2H), 1.86 (quin, J = 6.1 Hz, 2H), 1.16 (t, = 7.1 Hz, 2H), 0.81 (m, 9H) -0.03 (s, 6H).

[0697] Step 2: 3-((7ert-butyldimethylsilyl)oxy)propyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1- carboxylate (33).

[0698] Example 3 33

[0699] To a solution of 3-((tert-butyldimethylsilyl)oxy)propyl (4-nitrophenyl) carbonate (32) (50 mg, 0.14 mmol) and 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 / 7-imidazo[4,5-c]quinolin- 1-yl)methyl)-2-methylpropane-1 ,3-diol hydrochloride (Example 3) (72 mg, 0.15 mmol) in dioxane (2 mL) was added TEA (28 mg, 0.28 mmol) and DMF (0.2 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 2 hours. LCMS showed the carbonate (32) was consumed and the desired product mass was detected. The mixture was diluted with water (20 mL), and extracted with DCM (3 x 30 mL). The combined organic layers were dried over with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and eluted with DCM:CHsOH (100:1 to 10:1 , TLC (DCM:CHsOH, 10:1 , Rf = 0.4) and provided 3-((tert-butyldimethylsilyl)oxy)propyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1-carboxylate (33) (75 mg, 0.11 mmol, 78% yield) as colorless oil.1H NMR (400 MHz, DMSO-cfe) d 8.45 (d, J = 8.5 Hz, 1 H), 7.42 (s, 1H), 7.11 (d, J = 7.9 Hz, 1 H), 4.97 (t, J = 4.31 Hz, 2H), 4.97 - 4.68 (m, 1 H), 4.47 - 4.38 (m, 1 H), 4.08 - 3.95 (m, 3H), 3.62 (t, J = 6.1 Hz, 2H), 3.09 - 3.02 (m, 1 H), 2.98 - 2.92 (m, 1 H), 2.70 - 2.65 (m, 3H), 2.31 (br s, 6H), 1.80 - 1.69 (m, 8H), 1.42 - 1.38 (m, 3H), 1.22 (s, 3H), 1.16 (t, J = 7.1 Hz, 2H), 0.92 (t, J = 7.4 Hz, 4H), 0.83 (s, 13H), 0.00 (6H).

[0700] Step 3: 3-Hydroxypropyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1 -carboxylate (Example 12).

[0701] 33 Example 12

[0702] To a solution of 3-((tert-butyldimethylsilyl)oxy)propyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1-carboxylate (33) (70 mg, 0.10 mmol) in DCM (1 mL) was added a solution of TFA (1 mL) in DCM (9 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 2 hours. LCMS showed the TBS ether was consumed and the desired product mass was detected. The mixture was concentrated in vacuum. The crude product was purified by reverse phase chromatography (column: Welch Ultimate C18 150 x 25 mm, 5 urn; mobile phase: Water (formic acid)-ACN: 0%-30%,10 min). The desired fraction was lyophilized and provided 3-hydroxypropyl 4-(3-(4-amino-2-butyl-1-(3- hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1- carboxylate formic acid salt (Example 12) (14 mg, 23% yield) as a white solid.1H NMR (400 MHz, DMSO-d6+ D2O) d 8.46 (d, J = 8.6 Hz, 1 H), 8.18 (s, 2H), 7.44 (s, 1 H), 7.15 (dd, J = 8.6, 1.5 Hz, 1 H), 4.79 - 4.72 (m, 1 H), 4.46 - 4.41 (m, 1 H), 4.02 (t, J = 6.4 Hz, 2H), 3.46 - 3.35 (m, 8H), 3.26 - 3.21 (m, 1 H), 3.19 - 3.13 (m, 1 H), 3.08 - 3.02 (m, 1 H), 3.00 - 2.93 (m, 1 H), 2.71 - 2.67 (m, 2H), 2.36 - 2.34 (m, 6H), 1.84 - 1 .66 (m, 6H), 1.43 - 1.33 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.53 (s, 3H). LCMS (ESI) m / z 571.5 (M+H).

[0703] Example 13: 2-(2-(2-Aminoethoxy)ethoxy)ethyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1- carboxylate.

[0704] Step 1 : (9H-fluoren-9-yl)methyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (36).

[0705] To a stirred solution of 2-(2-(2-aminoethoxy)ethoxy)ethanol (34) (500 mg, 3.35 mmol) and / V-methyl morpholine (407 mg, 4.02 mmol) in dioxane (13 mL) was added (9 / 7-fluoren-9- yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (35) (1240 mg, 3.69 mmol) in dioxane (5 mL) at 5- 10 °C. The mixture was stirred at 20 °C for 16 hours. LCMS showed the starting material was consumed and the main peak was the desired compound. The mixture was concentrated under reduced pressure to remove dioxane and the resultant residue was diluted with water (20 mL), then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with NaHCOs (2 x 20 mL), brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product as a colorless oil (1.4 g). The crude product was purified by silica gel chromatography (Biotage 20 g) and eluted with ethyl acetate / DCM (0% to 50% for 8 minutes, keep 50% for 10 minutes, then from 50% to 90% for 6 minutes, and kept at 90% for 30 minutes) to give (9 / 7-fluoren-9-yl)methyl (2-(2-(2- hydroxyethoxy)ethoxy)ethyl)carbamate (36) as a clear gum (1.2 g, >99% yield).1H NMR (400 MHz, CDCh) 6 7.79 (d, J = 7.5 Hz, 2H), 7.63 (d, J = 7.5 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.43 - 7.32 (m, 2H), 5.48 (br s, 1 H), 4.45 (d, J = 7.0 Hz, 2H), 4.35 (t, J = 6.6 Hz, 1 H), 3.78 - 3.59 (m, 10H), 3.51 (s, 2H), 3.43 (q, J = 5.3 Hz, 1 H). LCMS (ESI) m / z 372.1 (M+H).

[0706] Step 2: (9H-fluoren-9-yl)methyl (2-(2-(2-(((4- nitrophenoxy)carbonyl)oxy)ethoxy)ethoxy)ethyl)carbamate (37).

[0707] FmocN^^O

[0708] A stirred solution of 4-nitrophenyl carbonochloridate (989 mg, 4.91 mmol) in DCM (20 mL) was cooled to 0 °C. A mixture of (9 / 7-fluoren-9-yl)methyl (2-(2-(2- hydroxyethoxy)ethoxy)ethyl)carbamate (36) and TEA (1.7 g, 16.4 mmol) in DCM (20 mL) was added dropwise and stirred for 30 minutes at 0 °C and three hours at room temperature. LCMS showed the alcohol (36) was consumed and the main peak had the desired molecular weight. The crude reaction mixture was quenched with H2O (10 mL), washed with brine (2 x 30 mL), dried over Na2SC>4, filtered and concentrated to give the crude product (1950 mg) as yellow oil. The crude product was purified by silica gel chromatography (Biotage 20 g) and eluted with ethyl acetate / petroleum ether (0% to 50% for 8 minutes, and kept at 50% for 10 minutes, from 50% to 80% for 6 minutes) to give (9 / 7-fluoren-9-yl)methyl (2-(2-(2-(((4- nitrophenoxy)carbonyl)oxy)ethoxy)ethoxy)ethyl)carbamate (37) as a light yellow gum (1300 mg, 74% yield).1H NMR (400 MHz, DMSO-d6) d 8.33 - 8.28 (m, 2H), 7.89 (d, J = 7.5 Hz, 2H), 7.69 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H), 7.41 (t, J = 7.0 Hz, 2H), 7.37 - 7.30 (m, 3H), 4.39 - 4.34 (m, 2H), 4.30 (d, J = 6.8 Hz, 2H), 4.24 - 4.16 (m, 1 H), 3.74 - 3.68 (m, 2H), 3.61 - 3.52 (m, 4H), 3.46 - 3.40 (m, 2H), 3.15 (q, J = 5.8 Hz, 2H). LCMS (ESI) m / z 537.1 (M+H).

[0709] Step 3: 2-(2-(2-Ami noethoxy )ethoxy)ethyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-

[0710] (hydroxymethyl)-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1- carboxylate

[0711] Example 13

[0712] To a solution of 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 / 7-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol hydrochloride (Example 3) (577 mg, 1.00 mmol) in DMF (4 mL) was added (9 / 7-fluoren-9-yl)methyl (2-(2-(2-(((4- nitrophenoxy)carbonyl)oxy)ethoxy)ethoxy)ethyl)carbamate (37) (600 mg, 0.95 mmol) followed by dioxane (4 mL). The mixture was cooled to 0 °C and TEA (0.77 mg, 7.60 mmol) was added. The resultant mixture was stirred at 20 °C for 16 hours under nitrogen. LCMS gave mostly product and the crude reaction mixture was purified by reverse phase chromatography (YMC- Triart Prep C18 150 x 40 mm, 7 urn column; water with formic acid and acetonitrile mobile phase; 60 mL min-1flow rate) and provided 2-(2-(2-aminoethoxy)ethoxy)ethyl 4-(3-(4-amino-2- butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7- yl)propyl)piperazine-1-carboxylate formic acid salt (Example 13) as a white solid (290 mg, 47% yield).1H NMR (400 MHz, DMSO-d6) 5 8.43 (d, J = 8.4 Hz, 1 H), 8.27 (s, 3H), 7.41 (s, 1 H), 7.08 (d, J = 7.0 Hz, 1 H), 4.75 (br s, 1 H), 4.44 (br s, 1 H), 4.13 - 4.08 (m, 2H), 3.64 - 3.51 (m, 9H), 3.48 - 3.31 (m, 7H), 3.31 - 3.00 (m, 3H), 2.93 (t, J = 5.3 Hz, 2H), 2.75 - 2.66 (m, 2H), 2.33 (br s, 4H), 1.88 - 1.67 (m, 5H), 1.46 - 1.35 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.54 (s, 3H). LCMS (ESI) m / z 644.5 (M+H). Example 14: 2-((4-Amino-2-butyl-7-(3-(4-(butylsulfonyl)piperazin-1-yl)propyl)-1H- imidazo[4,5-c]quinolin-1 -yl)methyl)-2-methylpropane-1 ,3-diol.

[0713] Example 3 Example 14

[0714] To a stirred mixture of 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 / 7-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol hydrochloride (Example 3) (70.0 mg, 0.16 mmol) and K2CO3 (90 mg, 0.65 mmol) in a mixture of THF (1.0 mL) and water (1.0 mL) was added butane- 1 -sulfonyl chloride (31 mg, 0.19 mmol) at 20 °C. The mixture was stirred for 18 hours at 20 °C. LCMS gave mostly product. The solvent was removed under reduced pressure and the crude product was purified by reverse phase chromatography (Phenomenex Luna C18 150 x 25 mm, 10 urn column; water with formic acid and acetonitrile mobile phase) and provided 2-((4-amino-2-butyl-7-(3-(4-(butylsulfonyl)piperazin-1-yl)propyl)-1 / 7-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol formic acid salt (Example 14) as a white solid (35 mg, 37% yield).1H NMR (400 MHz, CDOD3) d 8.74 (d, J = 8.4 Hz, 1 H), 8.44 (s, 2H), 7.58 (s, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 4.69 - 4.60 (m, 3H), 3.72 - 3.63 (m, 1 H), 3.60 - 3.40 (m, 3H), 3.20 - 3.13 (m, 5H), 3.05 - 3.01 (m, 2H), 2.87 (t, J = 7.6 Hz, 2H), 2.65 - 2.59 (m, 4H), 2.53 - 2.50 (m, 2H), 2.01 - 1.87 (m, 4H), 1.80 - 1.73 (m, 2H), 1.58 - 1.44 (m, 4H), 1.04 (t, J = 7.4 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H), 0.68 (s, 3H). LCMS (ESI) m / z 589.2 (M+H).

[0715] Example 15: A / -(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-

[0716] 1 / - / -imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide

[0717] Example 3 Example 15

[0718] A solution of 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 / 7-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol (Example 3) (80 mg, 0.14 mmol) and / \ / -(4- oxobutyl)acetamide (179 mg, 1.38 mmol) in methanol (5 mL) and acetic acid (0.1 mL) was stirred at 50 °C for 3 hours, then sodium cyanoborohydride (17.4 mg, 0.28 mmol) was added at 10 °C. The mixture was stirred at 55 °C for 16 hours. LCMS showed Example 3 remained, therefore, more / V-(4-oxobutyl)acetamide (120 mg, 0.93 mmol) and sodium cyanoborohydride (17.4 mg, 0.28 mmol) were added at 10 °C. The mixture was stirred at 55 °C for another 16 hrs. LCMS showed Example 3 was consumed, and the main peak was the desired product. The crude reaction mixture was quenched with water (1 mL), concentrated and the crude product was purified by reverse phase chromatography (Phenomenex Gemini-NX, 80 x 40 mm, 3 micron column; water with 0.05% ammonium hydroxide and acetonitrile mobile phase; 25 mL min-1flow rate). The product / \ / -(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide (Example 15) was isolated as a white solid (15 mg, 20% yield).1H NMR (400 MHz, DMSO-ck + D2O) d 8.39 (d, J = 8.6 Hz, 1 H), 7.39 (s, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 4.78 - 4.73 (m, 1 H), 4.42 - 4.41 (m, 1 H), 3.40 (br s, 2H), 3.30 - 3.09 (m, 2H), 2.99 (m, 4H), 2.72 - 2.60 (m, 2H), 2.46 - 2.15 (m, 12H), 1.85 - 1.67 (m, 7H), 1.36 - 1.35 (m, 6H), 0.90 (t, J = 7.4 Hz, 3H), 0.52 (s, 3H). LCMS (ESI) m / z 582.3 (M+H).

[0719] Example 16: A / -(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide

[0720] Example 16

[0721] To a solution of 2-((4-amino-7-(3-(4-(4-aminobutyl)piperazin-1-yl)propyl)-2- (ethoxymethyl)-1 / 7-imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol hydrochloride salt (prepared using the procedure described to make compound 26, 120 mg, 0.17 mmol) and acetic acid (10.5 mg, 0.17 mmol) in DMF (4 mL) was added DIEA (158 mg, 1.22 mmol) and HATU (79.6 mg, 0.21 mmol). The crude reaction mixture was stirred at 18 °C for 2 hours. LCMS gave mostly product and the crude reaction mixture was diluted with water (0.5 mL). The solvent was removed under reduced pressure and to the yellow gum was added 1 N NaOH (3 mL). The mixture was stirred for 30 minutes at 20 °C and purified by reverse phase chromatography (YMC Triart C18, 250 x 50 mm, 7 micron column; water with 0.05% ammonium hydroxide and acetonitrile mobile phase; 60 mL min-1flow rate), and gave a white solid (50 mg, 49% yield).1H NMR (400 MHz, DMSO-d6, t = 75 °C) d 8.31 (d, J = 8.4 Hz, 1 H), 7.48 (br s, 1 H), 7.34 (s, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.14 (br s, 2H), 4.77 (br s, 1 H), 4.64 (s, 2H), 3.48 (q, J = 7.0 Hz, 2H), 3.35 - 3.19 (m, 4H), 2.96 - 2.95 (m, 3H), 2.65 - 2.58 (m, 2H), 2.29 (s, 8H), 2.25 (t, J = 7.1 Hz, 3H), 2.17 (t, J = 6.4 Hz, 2H), 1.77 - 1.69 (m, 5H), 1.33 (br s, 4H), 1.07 (t, J = 7.0 Hz, 3H), 0.53 (s, 3H). LCMS (ESI) m / z 584.5 (M+H).

[0722] Example 17: 1-(4-(3-(4-Amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3-(2-azidoethoxy)propan-1-one.

[0723] Example 3 Example 17

[0724] To a vial was sequentially added 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 / 7- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol (Example 3) (30 mg, 0.052 mmol), 3-(2-azidoethoxy)propanoic acid (12 mg, 0.08 mmol) in DMF (0.35 mL), DIEA (0.05 mL, 0.31 mmol) and HATLI (30 mg, 0.08 mmol). The solution turned light yellow after addition of HATLI. After 2 hours, LCMS gave a ~9:1 ratio of product to Example 3. The crude reaction mixture was purified by reverse phase chromatography (Phenomenex Gemini 5 urn NX-C18 150 x 21.2 mm column; water + 10 mM ammonium acetate (phase A) and acetonitrile (phase B), 15-40% B in 8.0 minutes mobile phase; 40 mL min-1flow rate). The product, 1-(4-(3-(4-amino-2-butyl-1-(3- hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 / 7-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1- yl)-3-(2-azidoethoxy)propan-1-one (Example 17), was isolated as an off-white solid (32 mg, 61 % yield). LCMS (APCI) m / z 610.3 (M+H).

[0725] Example 18: Benzyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate

[0726] Step 1 : Preparation of A / -((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1,7-naphthyridin-4- amine (39).

[0727] 38 39

[0728] To a vial was sequentially added 4-chloro-1 ,7-naphthyridine (38) (1.9 g, 11.5 mmol), (2,2,5-trimethyl-1 ,3-dioxan-5-yl)methanamine (2) (3.7 g, 23.1 mmol) and DIEA (4.0 mL, 23.1 mmol). The tan mixture was placed in a pre-heated sand bath at 110 °C and became a black solution within a minute. The mixture was stirred at 110 °C for 48 hours. The crude reaction mixture was diluted with 5 mL of methanol. The brown methanol solution was added to 50 mL of water and extracted with 3 x 30 mL EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated which gave a dark brown solid (3.6 g). LCMS gave only product. To the crude product was added 15 mL of MTBE and the dark brown mixture was stirred at room temperature overnight. / V-((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-1 ,7-naphthyridin-4-amine (39) was collected by filtration as a brown solid (2.2 g, 66% yield).1H NMR (400 MHz, DMSO-d6) 5 9.11 (s, 1 H), 8.50 (d, J = 5.5 Hz, 1 H), 8.45 (d, J = 5.8 Hz, 1 H), 8.24 (d, J = 5.4 Hz, 1 H), 7.24 (t, J = 6.5 Hz, 1 H), 6.89 (d, J = 5.5 Hz, 1 H), 3.64 - 3.58 (m, 4H), 3.49 (d, J = 6.5 Hz, 2H), 1.40 (s, 3H), 1.39 (s, 3H), 0.87 (s, 3H). LCMS m / z (APCI) 288.2 (M+H). TLC (2% CH3OH-DCM with 0.1% NH3) Rf0.4.

[0729] Step 2: Preparation of 3-iodo- / V-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1,7- naphthyridin-4-amine (40).

[0730] To a solution of / V-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,7-naphthyridin-4-amine

[0731] (39) (11.0 g, 38.3 mmol) in DCE (170 mL) was added NIS (12.1 g, 53.6 mmol) and the mixture was stirred at 80 °C for 12 hours. The crude reaction mixture was diluted with saturated Na2SO3 and extracted with ethyl acetate. The organic layer was washed with saturated Na2COs, brine, dried, and filtered. The filtrate was concentrated to give the crude product (15 g) which was combined with another lot done on a 3.0 g scale. The crude product was purified over silica gel and eluted with 0-10% CH3OH-DCM and provided 12 g of the crude product. The crude product was purified again over silica gel using 0-5% EtOH-EtOAc (2 times), and 0-100% EtOAc- petroleum ether which provided 4.8 g of a yellow solid. The solid was diluted with ethyl acetate (30 mL) and stirred at room temperature (12 °C) for 30 min. The mixture was filtered and gave 3-iodo- / V-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1 ,7-naphthyridin-4-amine (40) (2.7 g, 17%) as a white solid.1H NMR (400 MHz, CDCI3) d 9.41 (s, 1H), 8.96 (s, 1H), 8.56 (d, J = 6.0 Hz, 1H), 8.15 (d, J = 6.0 Hz, 1H), 4.82 (br t, J = 6.3 Hz, 1 H), 3.88 (d, J = 6.6 Hz, 2H), 3.76 (s, 4H), 1.49 (s, 3H), 1.43 (s, 3H), 1.00 (s, 3H). LCMS m / z (ESI) 414.0 (M+H). TLC (10% CH3OH-DCM) Rf0.5.

[0732] Step 3: Preparation of A / -(4-(((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)amino)-1,7- naphthyridin-3-yl)pentanamide (42).

[0733] To a flask was added 3-iodo- / V-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1,7- naphthyridin-4-amine (40) (1.8 g, 4.1 mmol), pentanamide (41) (750 mg, 7.4 mmol), cesium carbonate (2.8 g, 8.3 mmol) and dioxane (29 mL), followed by cuprous iodide (141 mg, 0.74 mmol) and (1R,2R)-(-)-1 ,2-diaminocyclohexane (124 mg, 0.87 mmol). The mixture was degassed and purged with nitrogen and placed in an oil bath pre-heated at 75 °C. The brown mixture was heated overnight. LCMS gave ~1:1 starting material to product. The temperature was increased to 80 °C for 18 hours. The crude reaction mixture was concentrated under reduced pressure to a volume of about 20 mL, which was then added to 5% NaHCOs (200 mL). The mixture was extracted with 3 x 75 mL of EtOAc. The combined organic extracts were washed with 50% brine (25 mL), 1% NaEDTA solution (25 mL), and brine (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified over silica gel (25 g Biotage) and eluted with 0-10% CH3OH-DCM which gave / V-(4-(((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)amino)-1,7- naphthyridin-3-yl)pentanamide (42) as a light brown solid (1.2 g, 71% yield).1H NMR (400 MHz, DMSO-d6) 6 9.75 (s, 1 H), 9.18 (br s, 1 H), 8.46 (s, 2H), 8.19 (d, J = 5.6 Hz, 1 H), 5.83 (t, J = 6.4 Hz, 1 H), 3.74 - 3.46 (m, 6H), 2.42 (t, J = 7.5 Hz, 2H), 1.64 (quin, J = 7.5 Hz, 2H), 1.47 - 1.31 (m, 5H), 1.26 (s, 3H), 0.93 (t, J = 7.3 Hz, 3H), 0.79 (s, 3H). LCMS m / z (APCI) 387.5 (M+H). TLC (10% CH3OH-DCM) Rf 0.4.

[0734] Step 4: Preparation of 2-butyl-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1H-imidazo[4,5- c][1,7]naphthyridine (43).

[0735] To a flask was added / V-(4-(((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)amino)-1 ,7- naphthyridin-3-yl)pentanamide (42) (1.5 g, 3.8 mmol), I PA (15.2 mL) and an aqueous potassium hydroxide solution (12.8 mL, 3M, 38.3 mmol). The resulting light amber solution was placed in a pre-heated oil bath at 90 °C for 1 hour and allowed to stir at room temperature overnight. The crude reaction mixture was poured into water (250 mL). The light amber solution was stirred over the weekend. A white solid was collected by filtration and it was washed with 25 mL of water, which gave 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 / 7-imidazo[4,5- c][1 ,7]naphthyridine (43) as an off-white solid (780 mg). The filtrate was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated and provided 400 mg of an amber oil. The amber oil was purified over silica gel (2 mm chromatotron plate) and eluted with 0-5% CH3OH-EtOAc which gave a light amber oil that crystallized upon standing overnight and provided more 2-butyl-1-((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine (43) as an off-white solid (280 mg, combined 75% yield).1H NMR (400 MHz, DMSO-d6) 6 9.41 (s, 1 H), 9.29 (s, 1 H), 8.62 (d, J = 5.9 Hz, 1 H), 8.56 (d, J = 5.6 Hz, 1 H), 4.92 (br s, 2H), 4.02 - 3.36 (m, 4H), 3.15 (t, J = 7.7 Hz, 2H), 1.96 - 1.73 (m, 2H), 1.49 - 1.42 (m, 5H), 1 .39 (s, 3H), 0.96 (t, J = 7.40 Hz, 3H), 0.61 (s, 3H). LCMS m / z (APCI) 369.6 (M+H). TLC (10% CH3OH-EtOAc) Rf0.5.

[0736] Step 6: Preparation of 2-butyl-1 -((2,2, 5-trimethyl-1,3-dioxan-5-yl)methyl)-6, 7,8,9- tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridine (44).

[0737] A stainless steel vessel was charged with 2,2,2-trifluoroethanol (7.5 mL), water (2.5 mL), 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine (43) (1.0 g, 2.7 mmol), TEA (0.37 mL, 2.7 mmol) and 5% Rh / C (0.4 g, 1.1 mmol). The vessel was quickly sealed before being rapidly pressurized from 1 to 4 bar purges of nitrogen then hydrogen (0.55 g, 0.27 mol) and the mixture was allowed to stir at 70 °C under 8 atm of hydrogen. After 6 hours, the vessel was purged with three 1.5 to 8 bar purges of nitrogen before being depressurized. LCMS gave 90% desired product. The crude reaction mixture was filtered through a glass fiber filter, and the solids were washed with methanol. The filtrate was concentrated which provided 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7- imidazo[4,5-c][1 ,7]naphthyridine (44) as a brown solid (1.0 g, -85% pure, 79% yield). LCMS m / z (APCI) 373.8 (M+H).

[0738] Step 7: Preparation of benzyl 2-butyl-1 -((2,2, 5-trimethyl-1,3-dioxan-5-yl)methyl)-1, 6,8,9- tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (46).

[0739] To 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5- c][1 ,7]naphthyridine (44) (1.0 g, 2.7 mmol) was added THF (13 mL) and TEA (0.41 mL, 3.0 mmol). To the resultant black solution was added benzyl carbonochloridate (45) (0.42 mL, 3.0 mmol) and a brown solid formed. After 1 hour, LCMS gave -9:1 product to starting material. To the crude reaction mixture was sequentially added 40 uL of TEA and 40 uL of the chloroformate. After 30 minutes, LCMS gave no change in the reaction profile. The crude reaction mixture was poured into 200 mL of 5% NaHCCh and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SC>4, filtered and concentrated to a black oil. The crude product was purified over silica gel (2 mm chromatotron plate) and eluted with 0-5% CHsOH-EtOAc (Rf 0.5; 5% CHsOH-EtOAc) and the Rf0.5 spot was isolated and provide benzyl 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (46) as a light amber oil (1.1 g, 84% yield).1H NMR (400 MHz, DMSO-d6) 6 8.65 (s, 1 H), 7.49 - 7.26 (m, 5H), 5.15 (s, 2H), 4.69 (br s, 2H), 4.53 (br s, 2H), 3.63 - 3.54 (m, 6H), 3.27 (br s, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.76 - 1.73 (m, 2H), 1.46 - 1.37 (m, 5H), 1 .35 (s, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.53 (s, 3H). LCMS m / z (APCI) 507.9 (M+H).

[0740] Step 8: Preparation of 7-((benzyloxy)carbonyl)-2-butyl-1-((2,2,5-trimethyl-1,3-dioxan-5- yl)methyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridine 5-oxide (47).

[0741] To benzyl 2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7- imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (46) (1.1 g, 2.2 mmol) was added DCM (22 mL) followed by 3-chlorobenzperoxoic acid (0.94 g, 4.3 mmol, 80%). The clear solution was stirred at room temperature for 1 hour. LCMS gave >90% product and no starting material. The crude reaction mixture was washed with 5% NaHCCh (3 x 20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated which gave an amber oil (1 g). TLC (5% CH3OH-DCM) gave a major spot at Rf 0.5. The crude product was purified over silica gel (2 mm chromatotron plate) and eluted with 0-10% CH3OH-DCM. The Rf0.5 spot was isolated as an amber oil (920 mg). TLC (10% CHsOH-EtOAc) Rf 0.3 and some minor impurities. The crude product was re-purified over silica gel (2 mm chromatotron plate) and eluted with 2-10% CHsOH-EtOAc. The Rf 0.3 spot was isolated as a light amber oil. To the amber oil was added 5 mL of MTBE. The mixture was stirred at room temperature and a white solid formed within 30 minutes. LCMS of the white mixture gave >95% product. The MTBE was removed under reduced pressure and gave 7- ((benzyloxy)carbonyl)-2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7- imidazo[4,5-c][1 ,7]naphthyridine 5-oxide (47) as a white solid (680 mg, 60% yield).1H NMR (400 MHz, DMSO-d6) 6 8.62 (s, 1 H), 7.44 - 7.32 (m, 5H), 5.16 (s, 2H), 4.66 (br s, 2H), 4.52 (br s, 2H), 3.64 - 3.61 (m, 2H), 3.52 (br s, 2H), 3.28 (s, 2H), 2.99 (t, J = 7.6 Hz, 2H), 1.78 - 1.70 (m, 2H), 1.44 - 1.36 (m, 5H), 1.33 (s, 3H), 0.93 (t, J = 7.4 Hz, 3H), 0.55 (s, 3H). LCMS m / z (APCI) 523.8 (M+H).

[0742] Step 9: Preparation of benzyl 4-amino-2-butyl-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)- 1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (48).

[0743] To 7-((benzyloxy)carbonyl)-2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9- tetrahydro-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine 5-oxide (47) was added acetonitrile (12 mL), pyridine (0.49 mL, 6.0 mmol) and trifluoroacetic anhydride (0.42 mL, 3.0 mmol) at 0 °C. The clear solution became a light amber solution after TFAA was added. The light amber solution was warmed to room temperature after 10 minutes. After 2 hours, LCMS gave only the pyridinium ion intermediate and no / V-oxide. To the crude reaction mixture was added ethanolamine (0.73 mL, 12.1 mmol) and the solution became dark amber. After 20 hours, LCMS gave a ~1 :1 ratio of the product to the pyridinium ion intermediate. To the crude reaction mixture was added ethanolamine (0.35 uL, 6.0 mmol). The crude reaction mixture was stirred four hours at room temperature and one hour at 80 °C. LCMS gave >95% product. The crude reaction mixture was cooled to room temperature and poured into 120 mL of 5% NaHCOs. The aqueous layer was extracted with EtOAc (3 x 40 mL) and the combined organic layers were washed with 5% NaHCCh (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to a brown oil. TLC (5% CHsOH-EtOAc) RF 0.5 only. The brown oil was dissolved in DCM and purified over silica gel (2 mm chromatotron plate) and eluted with 1-6% CHsOH-EtOAc. The Rf 0.5 spot was isolated and provided benzyl 4-amino-2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (48) as a light yellow solid from MTBE (579 mg, 92% yield).1H NMR (400 MHz, DMSO-d6) 6 7.44- 7.28 (m, 5H), 5.91 (br s, 2H), 5.13 (s, 2H), 4.43 (br s, 4H), 3.91 - 3.36 (m, 6H), 3.03 (br s, 2H), 2.92 (br s, 2H), 1.71 - 1.67 (m, 2H), 1.42 - 1.33 (m, 8H), 0.92 (t, J = 7.4 Hz, 3H), 0.52 (s, 3H). Step 10: Preparation of benzyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (Example 18).

[0744] To a solution of benzyl 4-amino-2-butyl-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)- 1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (48) (50 mg, 0.1 mmol) in DCM (3 mL) was added HCI in dioxane (1 mL, 4M, 4 mmol). After 30 minutes, LCMS gave product and starting material. Additional HCI was added (0.5 mL, 4M, 2 mmol) and the solution was stirred at 25°C for 20 minutes. LCMS gave mostly product. The mixture was concentrated and purified by prep HPLC (Boston Prime C18, 150 x 30 mm, 5 micron; aqueous ammonium hydroxide and acetonitrile; 25 mL / min) and gave benzyl 4-amino-2-butyl-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate (Example 18) as a white solid (29 mg, 63% yield).1H NMR (400 MHz, DMSO-ds) 6 7.41 - 7.38 (m, 4H), 7.34 - 7.31 (m, 1 H), 5.86 (s, 2H), 5.13 (s, 2H), 4.83 (m, 2H), 4.58 - 4.23 (m, 4H), 3.89 - 3.46 (m, 2H), 3.31 - 3.20 (m, 5H), 3.00 - 2.81 (m, 3H), 1.74 - 1.61 (m, 2H), 1.41 - 1.30 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.44 (s, 3H). LCMS m / z (ESI) 482.1 (M+H).

[0745] Example 19: Benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate

[0746] Stepl : Preparation of ethyl 5-amino-1-benzyl-1,2,3,6-tetrahydropyridine-4-carboxylate (50). To a solution ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (49) (100 g, 0.38 mol) in methanol (1.0 L) was added ammonium acetate (147 g, 1.9 mol). The crude reaction mixture was stirred at 15 °C for 20 h. LCMS gave the desired peak as the major product. The yellow solution was concentrated to remove the methanol. The residue was diluted with ethyl acetate (400 mL), and the pH adjusted to 8 using a solution of saturated NaHCOs. The resultant suspension was filtered and the solids washed with ethyl acetate (2 x 50 mL) and dried to provide ethyl 5-amino-1-benzyl-1 ,2,3,6-tetrahydropyridine-4-carboxylate (50) as a white solid (67 g, 67% yield). The filtrate was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a yellow gum (20 g) which was diluted with EtOAc (50 mL), petroleum ether (150 mL), and stirred at 15 °C for 30 minutes. During the stirring, some solids formed. The suspension was filtered and the solids were collected and dried which provided additional ethyl 5-amino-1-benzyl-1 ,2,3,6-tetrahydropyridine-4-carboxylate (50) as a yellow solid (14 g, 14% yield).1H NMR (400 MHz, CDCh) d 7.42 - 7.29 (m, 5H), 5.85 (br s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 3.03 (s, 2H), 2.63 (t, J = 5.9 Hz, 2H), 2.39 (t, J = 5.9 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0747] Step 2: Synthesis of methyl 7-benzyl-4-hydroxy-5,6,7,8-tetrahydro-1,7-naphthyridine-3- carboxylate (52).

[0748] A suspension of KOf-Bu (105 g, 0.93 mol) in THF (750 mL) was added to a mixture of ethyl 5-amino-1-benzyl-1 ,2,3,6-tetrahydropyridine-4-carboxylate (50) (81 g, 0.31 mol) and methyl 3,3-dimethoxypropanoate (51) (922 g, 0.62 mol) in THF (250 mL) at 5 - 15 °C. The mixture was stirred for 18 hours at 15 °C. LCMS gave mostly product. The mixture was concentrated to remove most of the THF and diluted with ice water (1000 mL), then extracted with ethyl acetate (3 x 200 mL). The aqueous phase was acidified to pH 6~7 using a solution of 2M HCI. The suspension was filtered and the solids were washed with water to provide methyl 7-benzyl-4-hydroxy-5,6,7,8-tetrahydro-1 ,7-naphthyridine-3-carboxylate (52) as a yellow solid (47 g, 50% yield).1H NMR (400 MHz, DMSO-d6) d 8.16 (s, 1 H), 7.43 - 7.21 (m, 5H), 3.64 (s, 2H), 3.34 (s, 2H), 2.64 (s, 2H), 2.39 (s, 2H). LCMS m / z (ESI) 299.2 (M+H). Step 3: Preparation of methyl 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3- carboxylate (53):

[0749] To POCh (300 mL, 3.2 mol) was added methyl 7-benzyl-4-hydroxy-5,6,7,8-tetrahydro- 1,7-naphthyridine-3-carboxylate (52) (47 g, 0.16 mol) and the mixture was stirred at 85 °C for 20 hours. LCMS of the crude reaction mixture gave mostly the desired product. The mixture was cooled to 15 °C and most of the POCh was removed under reduced pressure. The residue was slowly added to a solution of saturated Na2COs (1500 mL). The black mixture (pH ~ 8) was diluted with ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (500 mL), dried over Na2SO4 and concentrated to give a black gum (70 g). The black residue was filtered through a pad of silica gel (~ 300 g), and washed with petroleum ether / EtOAc (2 / 1, ~ 3 L) until no desired product was detected in the filtrate. The filtrate was concentrated to give methyl 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3- carboxylate (53) as an orange solid (47 g, 94% yield).1H NMR (400 MHz, DMSO-ch) d 8.75 (s, 1 H), 7.41 - 7.40 (m, 4H), 7.34 - 7.33 (m, 1 H), 3.93 (s, 3H), 3.76 (s, 2H), 3.69 (s, 2H), 2.88 - 2.87 (m, 2H), 2.83 - 2.80 (m, 2H). LCMS m / z (ESI) 317.0 (M+H).

[0750] Step 4: Preparation of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3- carboxylic acid (54):

[0751] To a mixture of methyl 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridine-3- carboxylate (53) (47.0 g, 0.15 mol) in THF (350 mL) was KOTMS (22.0 g, 0.17 mol) and the mixture was stirred for 2 hours at 15 °C. TLC (1:1 petroleum ether / ethyl acetate) showed the starting material was consumed. The white slurry was concentrated to remove most of the THF. The residue was diluted with water (350 mL), and washed with ethyl acetate (150 mL). The organic layer was discarded. The aqueous layer was acidified with aqueous HCI (2 M) to pH ~ 6, and the mixture was stirred at 15 °C for 1 hour. Some white solids formed. The suspension was filtered, and the solids were washed with water (2 x 30 mL). The solids were collected, dried and provided 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridine-3-carboxylic acid (54) (40 g, 89% yield) as an off white solid.1H NMR (400 MHz, DMSO-rt6) d 8.66 (s, 1 H), 7.42 - 7.34 (m, 4H), 7.34 - 7.26 (m, 1 H), 3.72 (s, 2H), 3.64 (s, 2H), 2.90 - 2.82 (m, 2H), 2.81 - 2.74 (m, 2H). LCMS m / z (ESI) 303.2 (M+H).

[0752] Step 5: Preparation of tert-butyl (7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-3- yl)carbamate (55).

[0753] To a mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridine-3-carboxylic acid (54) (10.0 g, 33.0 mmol) in DMF (150 mL) was added tert-butanol (24.5 g, 330 mmol), DPPA (13.6 g, 49.5 mmol) and triethylamine (16.7 g, 165 mmol). The mixture was stirred at 95 °C for 36 hours. The crude reaction mixture was combined with another reaction that was done at the same scale. The mixture was diluted with water (1 L) and stirred for 30 minutes. The suspension was filtered and the solids dissolved in DCM (250 mL), dried over Na2SO4, filtered and concentrated. The resultant residue was purified over silica gel (50% petroleum ether / ethyl acetate, Rf 0.5) and gave tert-butyl (7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3- yl)carbamate (55) as an off-white solid (4.4 g, 17% yield).1H NMR (400 MHz, DMSO-d6) d 8.92 (s, 1 H), 8.37 (s, 1 H), 7.40 - 7.34 (m, 4H), 7.30 - 7.27 (m, 1 H), 3.70 (s, 2H), 3.56 (s, 2H), 2.79 - 2.78 (m, 2H), 2.76 - 2.74 (m, 2H), 1.45 (s, 9H). LCMS m / z (ESI) 373.9 (M+H).

[0754] Step 6: Preparation of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-3-amine (56).

[0755] To a mixture of tert-butyl (7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3- yl)carbamate (55) (4.4 g, 9.2 mmol) in DCM (50 mL) was added HCI in ethyl acetate (150 mL, 4 M, 600 mmol) at 0 °C. The suspension was stirred at 25 °C for 5 hours. The mixture was concentrated and gave an off-white solid (5.0 g, HCI salt). The crude product was combined with another batch (2.4 g) and dissolved in water (100 mL). The pH was adjusted to ~8 using a solution of saturated sodium bicarbonate. The mixture was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated which gave 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3-amine (56) as an off-white solid (4.2 g, 83% yield). LCMS m / z (ESI) 274.1 (M+H).

[0756] Step 7: Preparation of A / -(7-benzyl-4-chloro-5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-2- ethoxyacetamide (58).

[0757] To a solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3-amine (56) (4.2 g, 15.4 mmol) and TEA (4.7 g, 46.0 mmol) in DCM (150 mL) was added 2-ethoxyacetyl chloride (57) (2.8 g, 23.0 mmol) dropwise at 0 °C. The mixture was stirred at 15 °C for 2 hours. TLC (EtOAc) showed most of the starting material (X) was consumed, and a new main spot was detected. The yellow solution was diluted with DCM (150 mL), washed with brine (100 mL), dried over Na2SO4, filtered and concentrated which provided a yellow gum (5 g). The residue was purified over silica gel (ethyl acetate, Rf~ 0.5) and gave / \ / -(7-benzyl-4-chloro-5, 6,7,8- tetrahydro-1 ,7-naphthyridin-3-yl)-2-ethoxyacetamide (58) as a yellow solid (3.7 g, 67% yield).1H NMR (400 MHz, CDCh) d 9.29 (s, 1 H), 8.76 (s, 1 H), 7.34 - 7.16 (m, 5H), 4.04 (s, 2H), 3.73 - 3.58 (m, 6H), 2.86 - 2.79 (m, 2H), 2.77 - 2.69 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H). LCMS m / z (ESI) 360.2 (M+H).

[0758] Step 8: Preparation of A / -(7-benzyl-4-(((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)amino)- 5,6,7,8-tetrahydro-1,7-naphthyridin-3-yl)-2-ethoxyacetamide (59).

[0759] The reaction was set up on 4 batches (each reaction used 900 mg of the amide). To a solution of / \ / -(7-benzyl-4-chloro-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3-yl)-2-ethoxyacetamide (58) (900 mg, 2.5 mmol), (2,2,5-trimethyl-1 ,3-dioxan-5-yl)methanamine (2) (597 mg, 3.8 mmol), and K3PO4 (1.1 g, 5.0 mmol) in dioxane (15 mL) was added RuPhos Pd G3 (1.3 g, 1.5 mmol) under an argon atmosphere. The mixture was stirred at 90 °C for 16 hours. TLC (EtOAc) showed the amide (58) was consumed and a new main spot was detected. The four batches were combined and filtered through a pad of Celite. The Celite was washed with DCM / CH3OH (10 / 1 , 200 mL). The filtrate was concentrated and the resultant brown gum (5.5 g) was purified over silica gel (DCM / CH3OH, 10 / 1 , Rf~ 0.5) and gave / V-(7-benzyl-4-(((2,2,5-trimethyl-1 ,3- dioxan-5-yl)methyl)amino)-5,6,7,8-tetrahydro-1 ,7-naphthyridin-3-yl)-2-ethoxyacetamide (59) as a yellow gum (3.3 g, 68% yield).1H NMR (400 MHz, DMSO-d6) d 9.26 (s, 1 H), 7.89 (s, 1 H), 7.41 - 7.33 (m, 4H), 7.32 - 7.24 (m, 1 H), 4.53 (t, J = 6.3 Hz, 1 H), 4.05 - 4.02 (m, 2H), 3.66 (s, 2H), 3.62 - 3.56 (m, 2H), 3.55 - 3.48 (m, 4H), 3.45 (s, 2H), 3.32 - 3.28 (m, 2H), 2.73 - 2.63 (m, 4H), 1.34 (s, 3H), 1.28 (s, 3H), 1.22 - 1.16 (m, 3H), 0.79 (s, 3H). LCMS m / z (ESI) 483.3 (M+H).

[0760] Step 9: Preparation of 7-benzyl-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5- yl)methyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridine (60).

[0761] To a solution of / V-(7-benzyl-4-(((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)amino)-5,6,7,8- tetrahydro-1 ,7-naphthyridin-3-yl)-2-ethoxyacetamide (59) (2.7 g, 5.6 mmol) in ethanol (28 mL) was added NaOH (2.8 mL of 3 M aqueous solution, 8.4 mmol). The mixture was stirred at 90 °C for 8 hours. LCMS showed (59) was consumed, and the desired product was detected.

[0762] The brown solution was concentrated to remove most of the EtOH and the resultant residue was diluted with water (20 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give a brown gum (2.5 g). The residue was purified over silica gel and eluted with 0-10% methanol-EtOAc and 7-benzyl-2- (ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5- c][1,7]naphthyridine (60) was isolated as a yellow gum (1.9 g, 73% yield). LCMS m / z (ESI) 465.3 (M+H). Rf0.5 (10% CH3OH-DCM).

[0763] Step 10: Preparation of 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)- 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridine (61).

[0764] To a mixture of 7-benzyl-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)- 6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-c][1,7]naphthyridine (60) in methanol (30 mL) was added 10% Pd / C (600 mg, 50% wet) and the mixture was degassed and purged with hydrogen (3 times). The mixture was stirred under an atmosphere of hydrogen for 16 hours. LCMS showed most of (60) was consumed and the desired product was detected. The mixture was filtered through a pad of Celite, and the solids were washed with methanol (150 mL). The filtrate was concentrated and gave 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-6,7,8,9- tetrahydro-1 / 7-imidazo[4,5-c][1 ,7]naphthyridine (61) as a white foam (1.4 g, 96% yield). LCMS m / z (ESI) 375.2 (M+H).

[0765] Step 11 : Preparation of benzyl 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5- yl)methyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (62).

[0766] To an ice bath cooled solution of 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-c][1,7]naphthyridine (61) (1.4 g, 3.7 mmol) in THF (50 mL) was added a solution of sodium carbonate (400 mg, 3.7 mmol) in water (5 mL), followed by the portion-wise addition of benzyl carbonochloridate (638 mg, 3.7 mmol). The crude reaction mixture was warmed to room temperature after the addition of the chloroformate and the mixture was stirred for 16 hours. LCMS showed (61) was consumed, and the desired product was detected. The mixture was combined with a reaction done on a 3.2 mmol scale, and poured in saturated NaHCCh (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (35 mL), dried over Na2SO4, filtered and concentrated which gave a yellow gum (3.5 g). The crude product was purified over silica gel and eluted with 10% methanol in ethyl acetate which gave benzyl 2-(ethoxymethyl)-1- ((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1,7]naphthyridine- 7-carboxylate (62) as a white soid (2.8 g, 79% yield).1H NMR (400 MHz, DMSO-d6) d 8.74 (s, 1H), 7.39 - 7.38 (m, 4H), 7.34 - 7.28 (m, 1 H), 5.15 (s, 2H), 4.71 (br s, 6H), 3.63 (br s, 3H), 3.56 - 3.51 (m, 4H), 3.30 - 3.29 (m, 3H), 1.40 (s, 3H), 1.34 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H), 0.53 (s, 3H). LCMS m / z (ESI) 509.3 (M+H). Rf0.5 (10% CH3OH-EtOAc).

[0767] Step 12: Preparation of 7-((benzyloxy)carbonyl)-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3- dioxan-5-yl)methyl)-6,7,8,9-tetrahydro-1 H-imidazo[4,5-cJ[1 ,7]naphthyridine 5-oxide (63). To a solution of benzyl 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)- 1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (62) (2.8 g, 5.5 mmol) in DCM (50 mL) was added m-CPBA (2.4 g, 11.0 mmol). The mixture was stirred at room temperature for 1 hour. TLC (EtOAc) showed (62) was consumed, and a new main spot was detected. The mixture was diluted with DCM (50 mL) and washed with saturated NaHCOs (2 x 25 mL). The organic layer was concentrated and gave a yellow gum (3.6 g). The crude product was purified over silica gel and eluted with 10% methanol in DCM and provided 7- ((benzyloxy)carbonyl)-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9- tetrahydro-1 / 7-imidazo[4,5-c / [1 ,7]naphthyridine 5-oxide (63) as a white solid (2.7 g, 94% yield).1H NMR (400 MHz, DMSO-d6) d 8.72 (s, 1 H), 7.40 - 7.39 (m, 4H), 7.37 - 7.30 (m, 1 H), 5.16 (s, 2H), 4.67 (br s, 6H), 3.63 (br s, 3H), 3.57 - 3.52 (m, 4H), 3.30 - 3.29 (m, 3H), 1.40 (s, 3H), 1.32 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H), 0.56 (s, 3H). LCMS m / z (ESI) 525.1 (M+H). Rf0.1 (EtOAc).

[0768] Step 13: Preparation of benzyl 4-amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5- yl)methyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (64).

[0769] To a solution of 7-((benzyloxy)carbonyl)-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan- 5-yl)methyl)-6,7,8,9-tetrahydro-1 / 7-imidazo[4,5-cJ[1 ,7]naphthyridine 5-oxide (63) (2.7 g, 5.1 mmol) in DCM (50 mL) was added ammonium hydroxide (10 mL, 28%) at 0 °C, followed by TsCI (1 .2 g, 6.2 mmol). After the addition, the mixture was stirred at 25 °C for 16 hours. LCMS showed (63) remained, and the desired product was detected. Additional TsCI (1.2 g, 6.2 mmol) was added, and the mixture was stirred at 15 °C for 2 hours. LCMS showed most of (63) was consumed, and the desired product was detected. The yellow mixture was diluted with DCM (30 mL), washed with saturated NaHCCh (25 mL), dried over Na2SO4, filtered and concentrated to give a yellow solid (3.4 g). The crude product was purified over silica gel and eluted with 0-10% CH3OH-DCM and provided benzyl 4-amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (64) as a white solid (1.4 g, 51 % yield).1H NMR (400 MHz, DMSO-d6) d 7.44 - 7.37 (m, 4H), 7.34 - 7.31 (m, 1 H), 6.11 (br s, 2H), 5.13 (s, 2H), 4.47 (br s, 6H), 3.61 (br s, 4H), 3.53 - 3.44 (m, 4H), 3.04 (br s, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.13 (t, J = 6.9 Hz, 3H), 0.53 (s, 3H). LCMS m / z (ESI) 524.3 (M+H). Rf0.5 (10% methanol-DCM).

[0770] Step 14: Preparation of benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine- 7-carboxylate (Example 19).

[0771] To a solution of benzyl 4-amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5- yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate (64) (30 mg, 0.06 mmol) in DCM (2 mL) was added HCI (1 mL, 4M HCI in dioxane, 4.0 mmol) at 0 °C. The mixture was stirred for 60 minutes at room temperature. The mixture was concentrated and the crude product (40 mg) was purified by reverse phase chromatography (Boston Green ODS, 150 x 30 mm, 5 micron; 0.05% aqueous HCI-acetonitrile, 30 mL / min) and provided benzyl 4-amino- 2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 ,6,8,9-tetrahydro-7 / 7- imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate HCI (Example 19) as a white solid (20 mg, 63% yield).1H NMR (400 MHz, DMSO-d6+ D2O, 75 °C) d 7.44 - 7.26 (m, 5H), 5.15 (s, 2H), 4.80 (br s, 2H), 4.64 (s, 2H), 4.46 (s, 2H), 3.70 (br s, 2H), 3.60 - 3.54 (m, 2H), 3.35 - 3.29 (m, 2H), 3.26 - 3.12 (m, 4H), 1.20 - 1.07 (m, 3H), 0.54 (s, 3H). LCMS mZz (ESI) 484.1 (M+H).

[0772] Example 20: 2-(Aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine- 7-carboxylate

[0773] Step 1 : Preparation of tert-butyl (2-((((4- nitrophenoxy)carbonyl)oxy)methyl)benzyl)carbamate (66).

[0774] To a solution of tert-butyl (2-(hydroxymethyl)benzyl)carbamate (65) (200 mg, 0.84 mmol) in DCM (15 mL) was added 4-nitrophenyl carbonochloridate (31) (255 mg, 1.26 mmol) in one portion at 0 - 5 °C, followed by a solution of TEA (0.18 mL, 1.26 mmol) in DCM (3 mL) added drop-wise. The crude reaction mixture was warmed to 40 °C for 16 hours. The crude reaction mixture was diluted with DCM (20 mL) and H2O (30 mL). The aqueous layer was separated and extracted with DCM (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtrated and concentrated and gave a light yellow solid (400 mg). The crude product was purified over silica gel and eluted with petroleum ether and ethyl acetate (3:1) and provided tert-butyl (2-((((4-nitrophenoxy)carbonyl)oxy)methyl)benzyl)carbamate (66) as a yellow oil (200 mg, 59% yield).1H NMR (400 MHz, CDCI3) d 8.32 - 8.27 (m, 2H), 7.47 (d, J = 7.3 Hz, 1 H), 7.45 - 7.39 (m, 4H), 7.39 - 7.33 (m, 1 H), 5.41 (s, 2H), 4.92 (br s, 1 H), 4.49 (br d, J = 5.6 Hz, 2H), 1.48 (s, 9H).

[0775] Step 2: Preparation of 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)- 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (67).

[0776] To a mixture of benzyl 4-amino-2-(ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5- yl)methyl)-1,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (64) (1.4 g, 2.7 mmol) in THF (50 mL) was added 10% Pd / C (400 mg, 0.38 mmol, 50% wet). The mixture was degassed and purged with hydrogen (3 times). The mixture was stirred under an atmosphere of hydrogen for 24 hours. LCMS gave no starting material and mostly the desired product. The mixture was filtered and the solids were washed with methanol (150 mL). The filtrate was concentrated and provided 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9- tetrahydro-1 / 7-imidazo[4,5-c][1 ,7]naphthyridin-4-amine (67) as a grey solid (1.0 g, 96% yield).1H NMR (400 MHz, DMSO-d6; 75 °C) d 5.69 - 5.61 (m, 2H), 4.74 (s, 2H), 4.53 (s, 2H), 3.77 (s, 2H), 3.65 - 3.51 (m, 7H), 2.97 (d, J = 5.0 Hz, 2H), 2.92 (d, J = 5.1 Hz, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H), 0.71 - 0.59 (m, 3H). LCMS m / z (ESI) 390.2 (M+H).

[0777] Step 3: Preparation of 2-(((tert-butoxycarbonyl)amino)methyl)benzyl 4-amino-2- (ethoxymethyl)-1-((2,2,5-trimethyl-1,3-dioxan-5-yl)methyl)-1,6,8,9-tetrahydro-7H- imidazo[4,5-c][1,7]naphthyridine-7-carboxylate (68).

[0778] To a solution of 2-(ethoxymethyl)-1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-6,7,8,9- tetrahydro-1 / 7-imidazo[4,5-c][1 ,7]naphthyridin-4-amine (67) (50 mg, 0.13 mmol) in DCM (6 mL) was added tert-butyl (2-((((4-nitrophenoxy)carbonyl)oxy)methyl)benzyl)carbamate (66) (62 mg, 0.15 mmol) in one portion at 0 - 5 °C, then TEA (0.053 mL, 0.38 mmol). The crude reaction mixture was warmed to room temperature and stirred for 16 hours. LCMS gave ~ 60% of the desired product (68). The crude reaction mixture was combined with another crude reaction mixture that was done on a 0.3 mmole scale. The combined crude reaction mixtures were quenched with methanol (2 mL) and concentrated under reduced pressure and provided a yellow gum. The crude product was purified by reverse phase chromatography (Boston Prime C18, 150 x 30 mm, 5 micron; aqueous ammonia hydroxide-acetonitrile gradient; 25 mL / minute flow rate) and provided 2-(((tert-butoxycarbonyl)amino)methyl)benzyl 4-amino-2-(ethoxymethyl)- 1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5- c][1 ,7]naphthyridine-7-carboxylate (68) as a white solid (50 mg, 49% yield).1H NMR (400 MHz, DMSO-ds) d 7.44 - 7.19 (m, 5H), 6.11 (br s, 2H), 5.19 (s, 2H). 4.43 (br s, 2H), 4.23 (br, 2H), 3.61(br s, 2H), 3.51 - 3.49 (m, 2H), (br s, 2H), 1.44 - 1.29 (m, 15H), 1.12 (t, J = 7.0 Hz, 3H), 0.52 (br s, 3H). LCMS m / z (ESI) 653.5 (M+H).

[0779] Step 4: Preparation of 2-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine- 7-carboxylate (Example 20).

[0780] To a solution of 2-(((ferf-butoxycarbonyl)amino)methyl)benzyl 4-amino-2-(ethoxymethyl)- 1-((2,2,5-trimethyl-1 ,3-dioxan-5-yl)methyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5- c][1 ,7]naphthyridine-7-carboxylate (68) (35 mg, 0.05 mmol) in DCM (3 mL) was added HCI in EtOAc (3 mL). The crude reaction mixture was stirred for one hour at 25 °C. The crude reaction mixture was purified by reverse phase chromatography (Boston Green ODS, 150 x 30 mm, 5 micron; aqueous HCI-acetonitrile gradient; 30 mL / minute flow rate) and provided 2- (aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate HCI (Example 20) as a white solid (16 mg, 54% yield).1H NMR (400 MHz, DMSO-cfe + D2O, 75 °C) d 7.48 - 7.39 (m, 4H), 5.24 (s, 2H), 4.81 - 4.75 (m, 2H), 4.61 (s, 2H), 4.44 (s, 2H), 4.16 (s, 2H), 3.67 (br s, 2H), 3.55 - 3.51 (m, 2H), 3.33 - 3.27 (m, 2H), 3.24 - 3.18 (m, 2H), 3.13 (br s, 2H), 1.12 (t, J = 7.0 Hz, 3H), 0.52 (s, 3H). LCMS m / z (ESI) 513.2 (M+H).

[0781] Table 8 provides additional Examples prepared according to (Scheme II - Method B) and the procedure used to prepare Example 20, made with non-critical changes or standard substitutions to the exemplified procedure used to prepare Example 20 that a person of ordinary skill in the art would be able to realize.

[0782] Table 8

[0783] Example 21 : 2-(Acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2- (hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine- To a solution of 2-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-

[0784] (hydroxymethyl)-2-methylpropyl)-1 ,6,8,9-tetrahydro-7 / 7-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate HCI (Example 20) (50 mg, 0.085 mmol) and acetic acid (5 uL, 0...

Claims

CLAIMSWe claim:

1. A compound of Formuor pharmaceutically acceptable salt thereof, wherein: ring A is a 5- to 7-membered carbocyclic ring or a 5- to 6- membered heterocyclic ring in which at least one of the ring carbon atoms has been replaced by a heteroatom selected from O, N, and S, and fused to a side a; ring B is phenyl, an N-containing heteroaryl, or an N-containing heterocycloalkyl, wherein the N-containing heteroaryl and N-containing heterocycloalkyl are attached to R1through a ring N atom;Y is a single bond or a divalent linking group selected from Ci-C8alkylene, C2-C6 alkenylene, C2-C6 alkynylene, C(=O), Ci-C8alkylene-C(=O), C(=O)-Ci-C8alkylene, C(=O)-O-Ci-C8alkylene, Ci-C8alkylene-O-C(=O), C1-C3 alkylene-O- C1-C3 alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=O)-Ci-C3 alkylene-O-Ci-Cs alkylene;R1is selected from the group consisting of-H,-C1-C20 alkyl,- C1-C20 aminoalkyl,- C1-C20 haloalkyl,- C1-C20 hydroxyalkyl,-C(=O)-Ci-C20alkyl, -C(=0)-Ci-C2o alkyl-NH2, -C(=O)-Ci-C20alkyl-OH, -C(=O)-Ci- C2o alkyl-0-Ci-Ce alkyl, -C(=0)-Ci-C2o alkyl-0-Ci-C6 alkyl-OH, which C1-C20 alkyls may be unsubstituted or substituted with one or more halogen up to the available valence number,-C(=O)-C2-C8alkenyl,-C(=O)-C2-C8alkynyl,-(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20,-C(=O)-(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 and the Ci-Ce alkyl may be unsubstituted or substituted with 1 , 2, or 3 substituents selected from OH, azide, and NH2,-C(=O)-O-(CH2CH2O)P-CI-C6alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 and the Ci-Ce alkyl may be unsubstituted or substituted with 1 , 2, or 3 substituents selected from OH, azide, and NH2,-C(=O)-O-Ci-C6 hydroxyalkyl,-Ci-C6alkyl-NH-C(=O)-Ci-Ce alkyl,-Ci-C6alkyl-NH-C(=O)-O-Ci-Ce alkyl, and-S(=O)2-Ci-C6alkyl;R2is H, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy, wherein the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy are each unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from OH and C1-C3 alkoxy;R3is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy;R4is H, C1-C3 alkyl, or C1-C3 haloalkyl; andR5is Ci-Ce alkyl, Ci-Ce haloalkyl, or (CH2)n-O-(CH2)m-CH3 optionally substituted with one or more halogen atoms up to the available valence number, where m is 0, 1 , or 2 and n is 1 , 2, or 3.

2. A compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein R3is methyl and R4is H.

3. A compound of claim 1 , having Formula (l-a(i)), Formula (l-a(ii)), Formula (l-b(i)), Formula (l-b(ii)), Formula (l-c(i)), Formula (l-c(ii)), Formula (l-d(i)), or Formula (l-d(ii)):or pharmaceutically acceptable salt thereof, wherein: ring B in Formulae (l-a(i)), (l-a(ii), (l-b(i)) , (l-b(ii)), (l-d(i)), and (l-d(ii)) is the N- containing heteroaryl or the N-containing heterocycloalkyl attached to R1through a ring N atom, and ring B in Formula (l-c(i)) and (l-c(ii)) is as defined in Formula (I);R1, R2, and R5are as defined in Formula (I); andY is a single bond or a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, C(=O), C1-C3 alkylene-C(=O), C(=O)-Ci-Cs alkylene, C(=O)-O-Ci-Cs alkylene, C1-C4 alkylene-O-C(=O), C1-C3 alkylene-O- C1-C3 alkylene, C1-C3 alkylene-O-Ci-Cs alkylene-C(=O), and C(=0)-Ci-C3 alkylene-O-Ci-Cs alkylene.

4. A compound of any one of claims 1 to 3, or pharmaceutically acceptable salt thereof, wherein R2is H.

5. A compound of any one of claims 1 to 4, or pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:wherein the asterisk * represents the point of attachment to R1and the wave line represents the point of attachment to Y.

6. A compound of claim 5, or pharmaceutically acceptable salt thereof, wherein ring B is7. A compound of any one of claims 1 to 6, or pharmaceutically acceptable salt thereof, wherein R5is Ci-Ce alkyl or (CH2)n-O-(CH2)m-CH3, where m is 1 or 2 and n is 1 , 2, or 3.

8. A compound of claim 7, or pharmaceutically acceptable thereof, wherein R5is - CH2CH2CH2CH3 or -CH2OCH2CH3.

9. A compound of any one of claims 1 to 8, or pharmaceutically acceptable salt thereof, wherein Y is a Ci-Ce alkylene, a C2-C6 alkenylene, or a C2-C6 alkynylene.

10. A compound of claim 1 , having Formula (l-a(iii)):or pharmaceutically acceptable salt thereof, wherein:X is -CH2- or -O-;Y is a divalent linking group selected from C1-C4 alkylene, C2-C4 alkenylene, and C2- C4 alkynylene; andR1is selected from the group consisting of -H, -C1-C20 alkyl, -C1-C20 aminoalkyl, - C(=0)-Ci-C2o alkyl, -C(=0)-Ci-C2o haloalkyl, -C(=O)-C2-C8 alkynyl, -C(=0)-Ci-C2o alkyl-OH, -C(=O)-Ci-C20alkyl-O-Ci-C6alkyl, -C(=O)-C2-C8alkynyl, -(CH2CH2O)P- Ci-C6alkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-(CH2CH2O)P-CI-C6 alkyl, where p is 1 , 2, 3, 4, 5, or 6 and the C1-C6 alkyl may be unsubstituted or substituted with azide, -C(=O)-O-Ci-Ce hydroxyalkyl, -C(=O)-O-(CH2CH2O)P-CI-C6 hydroxyalkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -C(=O)-O-(CH2CH2O)P-CI- C6aminoalkyl, where p is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, -Ci-C6alkyl-NH-C(=O)-Ci-C6alkyl, -Ci-C6alkyl-NH-C(=O)-O-Ci-C6alkyl, and -S(=O)2-Ci-Ce alkyl.11 . A compound of claim 1 , which is selected from the group consisting of: 2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1-yl)methyl)-2- methylpropane-1 ,3-diol;1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethan-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)ethan-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-5-hydroxypentan-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)propan-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)oct-7-yn-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)hexadecan-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)octadecan-1-one;1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)octadecan-1-one;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2-methoxyethan-1-one;1-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-2-methoxyethan-1-one;2-((4-amino-2-(ethoxymethyl)-7-(3-(4-methylpiperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(4-methylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(4-butylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-7-(3-(4-butylpiperazin-1-yl)propyl)-2-(ethoxymethyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(4-pentylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(4-octadecylpiperazin-1-yl)propyl)-1 H-imidazo[4,5-c]quinolin-1- yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-(ethoxymethyl)-7-(3-(4-octadecylpiperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-butyl-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propyl)-1 H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-(ethoxymethyl)-7-(3-(4-(2-methoxyethyl)piperazin-1-yl)propyl)-1 H- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1 ,3-diol;2-((4-amino-2-(ethoxymethyl)-7-(3-(piperazin-1-yl)propyl)-6,7,8,9-tetrahydro-1 / 7- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;3-hydroxypropyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1 -carboxylate;2-(2-(2-aminoethoxy)ethoxy)ethyl 4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)- 2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazine-1-carboxylate;2-((4-amino-2-butyl-7-(3-(4-(butylsulfonyl)piperazin-1-yl)propyl)-1H-imidazo[4,5- c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol;N-(4-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1 H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide;N-(4-(4-(3-(4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)- 1 H-imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)butyl)acetamide;1-(4-(3-(4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1H- imidazo[4,5-c]quinolin-7-yl)propyl)piperazin-1-yl)-3-(2-azidoethoxy)propan-1-one; benzyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1, 6,8,9- tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;2-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;3-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;4-(aminomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2- methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate;2-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;3-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;4-(acetamidomethyl)benzyl 4-amino-2-(ethoxymethyl)-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1,6,8,9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7- carboxylate;2-(piperidin-4-yl)ethyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1.6.8.9-tetrahydro-7H-imidazo[4,5-c][1 ,7]naphthyridine-7-carboxylate; and2-(piperazin-1-yl)ethyl 4-amino-2-butyl-1-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-1.6.8.9-tetrahydro-7H-imidazo[4,5-c][1,7]naphthyridine-7-carboxylate,or a pharmaceutically acceptable salt thereof.

12. A compound of claim 1 , which is 2-((4-amino-2-butyl-7-(3-(piperazin-1-yl)propyl)-1H- imidazo[4,5-c]quinolin-1-yl)methyl)-2-methylpropane-1,3-diol.

13. A compound of claim 1 , which is a pharmaceutically acceptable salt of 2-((4-amino-2- butyl-7-(3-(piperazin-1-yl)propyl)-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2- methylpropane-1 ,3-diol.

14. An immunoconjugate of Formula (IV):wherein:Ab is an antibody;L is a linking group of Formula (a), (b), (c), (d), (e), (f), (g), or (h):where, in Formulae (a)-(h): the asterisk * represents the point of attachment to the N atom of the maleimide and the wave line represents the point of attachment to the drug unit, n1 is 2, 3, 4, 5, 6, 7, or 8, n2 is 1 , 2, 3, 4, 5, or 6, n3 is 0, 1 , 2, 3, 4, 5, or 6, n4 is 1 , 2, 3, 4, 5, or 6, ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20, andR is H, Ci-Ce alkyl, or Ci-Ce haloalkyl;D is a drug unit of Formula (lll-A) or (lll-B):wherein the wave line represents the point of attachment to L,R2is H, halo, OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy, wherein the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 haloalkoxy are each unsubstituted or substituted with 1 , 2, or 3 substituents independently selected from OH and C1-C3 alkoxy,R3is C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy,R4is H, C1-C3 alkyl, or C1-C3 haloalkyl, andR5is Ci-Ce alkyl, Ci-Ce haloalkyl, or (CH2)n-O-(CH2)m-CH3 optionally substituted with one or more halogen, where m is 0, 1 , or 2 and n is 1 , 2, or 3; and r is a number from 2 to 12, preferably r is a number from 2 to 8, more preferably r is a number from 2 to 6.

15. An immunoconjugate of claim 14, wherein the drug unit of Formula (lll-A) is a drug unit of F(lll-a(ii)).

16. An immunoconjugate of claim 14, wherein the drug unit of Formula (lll-B) is a drug unit of Formula (lll-b(i)) or Formula (lll-b(ii)):(lll-b(ii)).

17. An immunoconjugate of any one of claims 14 to 16, wherein R2is H.

18. An immunoconjugate of any one of claims 14 to 17, wherein R3is C1-C3 alkyl, preferably methyl.

19. An immunoconjugate of any one of claims 14 to 18, wherein R4is H.

20. An immunoconjugate of any one of claims 14 to 19, wherein R5is Ci-Ce alkyl or (CH2)n- O-(CH2)m-CH3, where m is 1 or 2 and n is 1 , 2, or 3.

21. An immunoconjugate of claim 20, wherein R5is -CH2CH2CH2CH3 or -CH2OCH2CH3.

22. An immunoconjugate of any one of claims 14 to 21 , wherein the linking group L has Formula (b):wherein: n3 is 0; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, preferably ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 , more ml is preferably 1 , 2, 3, 4, 5, 6, or 7, more preferably from ml is 1 , 2, or 3, and most preferably ml is 1.

23. An immunoconjugate of any one of claims 14 to 21 , wherein, the linking group L has Formula (d):wherein: n2 is 1 , 2, 3, 4, or 5, preferably n2 is 2, 3, 4, or 5, and more preferably n2 is 4; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, preferably ml is 3, 4, 5, 6, 7, or 8, more preferably ml is 4, 5, 6, 7, or 8, more preferably ml is 6, 7, or 8, and most preferably ml is 8.

24. An immunoconjugate of claim 22 or claim 23, wherein, in Formulae (b) and (d), n1 is 2 and n4 is 3.

25. An immunoconjugate of any one of claims 14 to 21 , wherein, the linking group L hasFormulawherein: n1 is 2; n2 is 1 , 2, 3, 4, or 5, preferably n2 is 1 , 2, or 3, and more preferably n2 is 1 ; n4 is 1 , 2, 3, 4, or 5, preferably n4 is 1 , 2, or 3, and more preferably n4 is 1 ; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, preferably ml is 3, 4, 5, 6, 7, or 8.

26. An immunoconjugate of claim 14, having Formula (IV-a), (IV-b), (IV-c), (IV-d), (IV-e), (IV-27. An immunoconjugate of claim 26, wherein, in Formulae (IV-a), (IV-b), (IV-c), (IV-d), (IV- e), (I V-f), (IV-g), and (IV-h):X is -CH2- or -O-;R is H, C1-C6 alkyl, or Ci-Ce haloalkyl, preferably R is H or C1-C3 alkyl; n1 is 2, 3, 4, 5, or 6, preferably n1 is 2, 3, 4, or 5, more preferably n1 is 2 or 5, and even more preferably n1 is 2; n2 is 1 , 2, 3, 4, 5, or 6; n4 is 1 , 2, 3, 4, or 5, preferably n4 is 1 , 2, 3, or 4, and more preferably n4 in Formulae (IV-a) to (IV-g) is 3 and n4 in Formula (IV-h) is 1 ; ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, preferably ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, more preferably ml is 1 , 2, 3, 4, 5, 6, 7, or 8; and r is a number from 2 to 10, preferably r is a number from 2 to 8, more preferably r is a number from 2 to 6.

28. An immunoconjugate of claim 27, having Formula (IV-b):wherein: n1 is 2;n4 is 3; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14, preferably ml is 1 , 2, 3, 7, 10, 11 , or 14, more preferably ml is 1 , 2, or 3, and most preferably ml is 1.

29. An immunoconjugate of claim 28, having Formula (I V-b(i)) :wherein: n1 is 2; n2 is 4; n4 is 3; and ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12, preferably ml is 1 , 3, 4, 5, 6, 8, or 12, more preferably ml is 6, 8, or 12, most preferably ml is 8.

31. An immunoconjugate of claim 30, having Formula (IV-d(i)):

32. An immunoconjugate of claim 27, having Formula (IV-h):wherein: n1 is 2; n2 is 1 ; n4 is 1 ; ml is 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably ml is 1, 2, 3, 4, 5, 6, 7, or 8.

33. An immunoconjugate of any one of claims 14 to 32, wherein Ab is an antibody that specifically binds to an antigen on an immunosuppressive tumor-associated myeloid cell.

34. An immunoconjugate of any one of claims 14 to 33, wherein Ab is antibody that specifically binds to CD163.

35. A pharmaceutical composition comprising: a compound of any one of claims 1 to 13 or pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising: an immunoconjugate of any one of claims 14 to 34; and at least one pharmaceutically acceptable excipient.

37. A method for treating cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 13, or pharmaceutically acceptable salt thereof.

38. A method for treating cancer, the method comprising: administering to a subject in need thereof a therapeutically effective amount an immunoconjugate of any one of claims 14 to 34.

39. A method for the treatment of a disorder mediated by TLR7 or TLR8 in a subject, comprising administering to the subject in need thereof a compound of any one of claims 1 to 13, or pharmaceutically acceptable salt thereof, in an amount that is effective for treating the disorder.

40. A method for the treatment of a disorder mediated by TLR7 or TLR8 in a subject, comprising administering to the subject in need thereof an immunoconjugate of any one of claims 14 to 34 in an amount that is effective for treating the disorder.

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