Conjugates containing TOLL-like receptor agonists

Abstract

Disclosed herein are compounds that are Toll-like receptor (TLR) agonists, conjugates comprising these compounds and cell targeting moieties, pharmaceutical compositions thereof, methods of activating toll-like receptors 7 and / or 8, and methods for the treatment of diseases or disorders mediated by toll-like receptors 7 and / or 8, particularly proliferative disorders such as viral infections and cancer.

Description

[Technical field]

[0001]

[0001] The present disclosure relates generally to compounds that are Toll-like receptor (TLR) agonists, conjugates comprising these compounds, pharmaceutical compositions thereof, methods for activating toll-like receptors 7 and / or 8, and methods for the treatment of diseases or disorders mediated by toll-like receptors 7 and / or 8, particularly proliferative disorders such as viral infections and cancer. [Background technology]

[0002] Toll-like receptors (TLRs) are key proteins that recognize pathogen-associated molecular patterns (PAMPs), sense and initiate innate immune responses, and promote the development of adaptive immune responses. In humans, more than 10 TLRs are thought to have distinct functions. These include TLR1, 2, 4, 5, and 6, which are localized to the cell surface, and TLR3, 7, 8, and 9, which are expressed in endosomes. The association of TLRs with their specific ligands activates two major signaling pathways mediated by the adaptor protein myeloid differentiation primary response gene 88 (MyD88) or TIR domain-containing adaptor-inducing interferon-β (TRIF). The signaling cascades mediated by these pathways lead to the activation of transcription factors such as nuclear factor-kappa-B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factors (IRFs), leading to the transcription of various genes for the production of inflammatory and anti-inflammatory cytokines, chemokines, and costimulatory molecules. Thus, the engagement of TLRs with their specific ligands leads to the activation of the innate immune response and initiates the adaptive immune response through the activation of antigen-presenting cells (APCs) and by amplifying B- and T-cell effector cells.

[0003] One benefit of TLR7 / 8 agonists as immune response enhancers is that they stimulate several cell types simultaneously. TLR7 and TLR8 are mainly expressed on immune cells, such as antigen-presenting cells including plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs), as well as natural killer cells and macrophages. TLR7 / 8 activation on pDCs and mDCs leads to the induction and release of type I interferons (IFNs), tumor necrosis factor alpha (TNFα), and interleukin 12 (IL-12), which are important steps in initiating innate and adaptive immunity to kill cancer cells. TLR7 and TLR8 also play a major role in antiviral responses during viral infections by their ability to recognize single-stranded RNA PAMPs. Thus, there is a need to develop small molecule agonists of TLR7 and TLR8 as both antiviral and anticancer compounds.

[0004]

[0004] Cell-binding agent-drug conjugates, including antibody-drug conjugates (ADCs), have emerged as a powerful class of drugs with efficacy across a variety of abnormal cell proliferation or proliferative diseases or disorders (e.g., cancer). Cell-binding agent-drug conjugates (e.g., ADCs) are generally composed of three separate elements: a targeting moiety, a linker, and a payload unit. Therefore, there is also a need for TLR agonist conjugates to enhance bioavailability, targeted delivery, and efficacy. Summary of the Invention [Means for solving the problem]

[0005]

[0005] The present disclosure relates to compounds capable of activating toll-like receptors 7 and / or 8, linker-payload compounds and ADCs comprising these compounds, and the use of such compounds or ADCs for the treatment of cancer or viral infections.

[0006] In one aspect, the present disclosure provides a compound according to formula (I): A-(LD)p (I) (In the formula, A is a targeting moiety, L is a linker, p is an integer from 1 to 8; D is of formula (II):

[0007] [ka] is the payload unit, X is -O-, -S-, -NH-, -(CH 2 ) i -, -(X 1 )NC(O)-, -(X 1 )NS(O) 2 -, -C(O)N(X 1 )- and -S(O) 2 N(X 1 )-, -NH- and -(CH 2 ) i - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; each X 1 are independently hydrogen, alkyl, alkenyl, or haloalkyl; Ring A is cycloalkyl, heterocyclyl, aryl or heteroaryl; W is a direct bond, alkyl, cycloalkyl, heterocyclyl, * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 -alkyl-, selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, and * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 The alkyl in -alkyl is halogen, hydroxyl, cyano, amino, alkyl, and -C(O)OR. aand W is optionally substituted with one or more groups independently selected from * The end is connected to ring A, W 1 -O-, -NR a -, -C(O)-, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and Each R a are independently hydrogen, alkyl, or haloalkyl; R 1 is hydrogen, -N(R b ) 2 , hydroxyl or SH; Each R b are independently hydrogen, alkyl, or haloalkyl; The Two R's b together with the nitrogen atom to which they are attached form a heterocyclyl, R 2 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR e , -OC(O)R e , -SR e , -B(OH) 2 , -NO 2 , -CHO, -C(=NOR e )(R e ), -R 2-1 -N(R e ) 2 , -R 2-1 -N(R e )C(O)R e , -R 2-1 -N(R e )S(O) 2 R e , -R 2-1 -N(R e )P(O) 2 R e , -R 2-1 -C(O)OR e , -R2-1 -C(O)N(R e ) 2 , -R 2-1 -S(O) 2 N(R e ) 2 , -R 2-1 -P(O) 2 N(R e ) 2 , -OC(O)NR e or -NC(O)NR e and Each R 2-1 is independently absent or alkyl; Each R e are independently hydrogen, alkyl, or haloalkyl; Y is -Y 1 -Y 2 -Y 3 and Y 1 is a direct bond or -(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 1 of * Ends with Y 2 is connected to Y 2 is a direct bond or -(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and -(CH 2 ) s - and -(CH 2 ) t - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 of** Ends with Y 3 is connected to Y 3 is hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R b ) 2 , -C(O)-alkyl, -C(O)-alkyl-N(R b ) 2 , and -S(O) 2 -alkyl, Q 1 and Q 2 are each independently selected from a direct bond, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; R c is hydrogen or alkyl, or R c and Y 3 together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from one or more R d and is optionally replaced by R d is selected from the group consisting of halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, and -O-cycloalkyl; i is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3, 4 or 5) or a pharma- ceutically acceptable salt thereof.

[0008] In another embodiment, a compound of formula (Ia): L'-D(Ia) (In the formula, L' is a linker precursor, D is of formula (II):

[0009] [ka] is the payload unit, X is -O-, -S-, -NH-, -(CH 2 ) i -, -(X 1 )NC(O)-, -(X 1 )NS(O) 2 -, -C(O)N(X 1 )- and -S(O) 2 N(X 1 )-, -NH- and -(CH 2 ) i - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; each X 1 are independently hydrogen, alkyl, alkenyl, or haloalkyl; Ring A is cycloalkyl, heterocyclyl, aryl or heteroaryl; W is a direct bond, alkyl, cycloalkyl, heterocyclyl, * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 -alkyl-, selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, and * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1The alkyl in -alkyl is halogen, hydroxyl, cyano, amino, alkyl, and -C(O)OR. a and W is optionally substituted with one or more groups independently selected from * The end is connected to ring A, W 1 -O-, -NR a -, -C(O)-, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and Each R a are independently hydrogen, alkyl, or haloalkyl; R 1 is hydrogen, -N(R b ) 2 , hydroxyl or SH; Each R b are independently hydrogen, alkyl, or haloalkyl; The Two R's b together with the nitrogen atom to which they are attached form a heterocyclyl, R 2 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR e , -OC(O)R e , -SR e , -B(OH) 2 , -NO 2 , -CHO, -C(=NOR e )(R e ), -R 2-1 -N(R e ) 2 , -R 2-1 -N(R e )C(O)R e , -R 2-1 -N(R e )S(O) 2 R e , -R 2-1 -N(R e )P(O)2 R e , -R 2-1 -C(O)OR e , -R 2-1 -C(O)N(R e ) 2 , -R 2-1 -S(O) 2 N(R e ) 2 , -R 2-1 -P(O) 2 N(R e ) 2 , -OC(O)NR e or -NC(O)NR e and Each R 2-1 is independently absent or alkyl; Each R e is independently hydrogen, alkyl, or haloalkyl; Y is -Y 1 -Y 2 -Y 3 and Y 1 is a direct bond or -(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 1 of * Ends with Y 2 is connected to Y 2 is a direct bond or -(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 2 of ** Ends with Y 3 is connected to Y 3 is hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R b ) 2 , -C(O)-alkyl, -C(O)-alkyl-N(R b ) 2 , and -S(O) 2-alkyl, Q 1 and Q 2 are each independently selected from a direct bond, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; R c is hydrogen or alkyl, or R c and Y 3 together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from one or more R d and is optionally replaced by R d is selected from the group consisting of halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, and -O-cycloalkyl; i is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3, 4 or 5) or a pharma- ceutically acceptable salt thereof.

[0010] In another embodiment, the compound of formula (II'):

[0011] [ka] (In the formula, X is -O-, -S-, -NH-, -(CH2 ) i -, -(X 1 )NC(O)-, -(X 1 )NS(O) 2 -, -C(O)N(X 1 )- and -S(O) 2 N(X 1 )-, -NH- and -(CH 2 ) i - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; each X 1 are independently hydrogen, alkyl, alkenyl, or haloalkyl; Ring A is cycloalkyl, heteroalkyl, aryl or heteroaryl; W is a direct bond, alkyl, cycloalkyl, heterocyclyl, * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 -alkyl-, selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, and * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 The alkyl in -alkyl is halogen, hydroxyl, cyano, amino, alkyl, and -C(O)OR. a and W is optionally substituted with one or more groups independently selected from * The end is connected to ring A, W 1 -O-, -NR a -, -C(O)-, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and Each Ra are independently hydrogen, alkyl, or haloalkyl; R 1 is hydrogen, -N(R b ) 2 , hydroxyl or SH; Each R b are independently hydrogen, alkyl, or haloalkyl; The Two R's b together with the nitrogen atom to which they are attached form a heterocyclyl, R 2 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR e , -OC(O)R e , -SR e , -B(OH) 2 , -NO 2 , -CHO, -C(=NOR e )(R e ), -R 2-1 -N(R e ) 2 , -R 2-1 -N(R e )C(O)R e , -R 2-1 -N(R e )S(O) 2 R e , -R 2-1 -N(R e )P(O) 2 R e , -R 2-1 -C(O)OR e , -R 2-1 -C(O)N(R e ) 2 , -R 2-1 -S(O) 2 N(R e ) 2 , -R 2-1 -P(O) 2 N(R e ) 2 , -OC(O)NR e or -NC(O)NR e and Each R 2-1 is independently absent or alkyl; Each R e are independently hydrogen, alkyl, or haloalkyl; Y is -Y 1 -Y 2 -Y 3 and Y 1 is a direct bond or -(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 1 of * Ends with Y 2 is connected to Y 2 is a direct bond or -(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 2 of ** Ends with Y 3 is connected to Y 3 is hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R b ) 2 , -C(O)-alkyl, -C(O)-alkyl-N(R b ) 2 , and -S(O) 2 -alkyl, Q 1 and Q 2 are each independently selected from a direct bond, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; R c is hydrogen or alkyl, or R c and Y 3together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from one or more R d and is optionally replaced by R d is selected from the group consisting of halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, and -O-cycloalkyl; i is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3, 4 or 5) or a pharma- ceutically acceptable salt thereof.

[0012] In a further embodiment, the compound of formula (IIa'):

[0013] [ka] A payload compound is provided having the formula:

[0014]

[0010] In another aspect, the present disclosure is directed to a pharmaceutical composition comprising one or more conjugate compounds, linker-payload compounds or payload compounds of the present disclosure, and one or more pharma- ceutically acceptable carriers.

[0015]

[0011] In a further aspect, the present disclosure is directed to a method for treating a disease mediated by toll-like receptors 7 and / or 8 in a subject in need of such treatment, the method comprising administering to the subject an effective amount of one or more conjugate compounds, linker-payload compounds or payload compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, or a pharmaceutical composition of the present disclosure.

[0016]

[0012] In a further aspect, the present disclosure is directed to a method for activating toll-like receptors 7 and / or 8 in a subject in need of activation of toll-like receptors 7 and / or 8, the method comprising the step of administering to the subject one or more conjugate compounds, linker-payload compounds or payload compounds of the present disclosure, or pharmaceutical compositions of the present disclosure.

[0017]

[0013] In a further aspect, the present disclosure is directed to a method for stimulating an immune response in a subject in need thereof, the method comprising the step of administering to the subject one or more conjugate compounds, linker-payload compounds or payload compounds of the present disclosure, or pharmaceutical compositions of the present disclosure.

[0018]

[0014] In another aspect, the present disclosure is directed to the use of one or more conjugate compounds, linker-payload compounds or payload compounds of the present disclosure, or pharmaceutical compositions of the present disclosure, in the manufacture of a medicament for treating a viral infection or cancer. [Brief description of the drawings]

[0019] [Figure 1]

[0015] Figure 1(a) shows the DAR measurement by MS of an exemplary conjugate containing a payload compound 16. Figure 1(b) shows the DAR measurement by MS of an exemplary conjugate containing a payload compound 16. [Figure 2(a)]FIG. 1 is a graph showing induction of TNF-α production by Balb / c mouse BMDM (bone marrow derived macrophages) of conjugates 1-5 and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(b)] FIG. 1 is a graph showing induction of TNF-α production by conjugates 6, 8, 9, 11, and a control anti-Her2 antibody (Herceptin) by Balb / c mouse BMDMs (bone marrow derived macrophages) in the presence of tumor cells. [Figure 2(c)] FIG. 1 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 7, 10, 12, 13, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(d)] FIG. 1 is a graph showing induction of TNF-α production by conjugates 9, 13, 14, 26, 27, and a control anti-Her2 antibody (Herceptin) by Balb / c mouse BMDMs (bone marrow derived macrophages) in the presence of tumor cells. [Figure 2(e)]

[0020] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 13, 16, 18, 19, 28, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(f)]

[0021] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 13, 21, 23, 25, 29, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(g)]

[0022] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDM (bone marrow derived macrophages) of conjugates 13, 17, 36, 37, 39, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(h)]

[0023] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 17, 20, 22, 24, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(i)]

[0024] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 30, 31, 32, 35, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(j)]

[0025] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 15, 33, 34, 38, 41, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 2(k)]

[0026] FIG. 13 is a graph showing induction of TNF-α production by Balb / c mouse BMDMs (bone marrow derived macrophages) of conjugates 31, 40, 42, 43, and a control anti-Her2 antibody (Herceptin) in the presence of tumor cells. [Figure 3(a)]

[0027] 1 is a graph showing the anti-tumor efficacy of conjugates 1-2 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 3(b)] 1 is a graph showing the anti-tumor efficacy of conjugates 1-2 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 4(a)]

[0028] FIG. 13 is a graph showing the antitumor efficacy of conjugates 4-5 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 4(b)] FIG. 13 is a graph showing the antitumor efficacy of conjugates 4-5 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 5(a)]

[0029] FIG. 13 is a graph showing the antitumor efficacy of conjugates 6-9 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 5(b)] FIG. 13 is a graph showing the antitumor efficacy of conjugates 6-9 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 6(a)]

[0030] 1 is a graph showing the antitumor efficacy of conjugates 10-13 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 6(b)] 1 is a graph showing the antitumor efficacy of conjugates 10-13 against the EMT6-hHER2 model in Balb / c mice compared to the vehicle control group. [Figure 7(a)]

[0031] 1 is a graph showing the antitumor efficacy of conjugates 9, 13, 14, 16, 18, 19, 21, 23, 25, 26, 27, 28, and 29 against HCC1954 model in SCID Beige mice compared to the vehicle control group. [Figure 7(b)] 1 is a graph showing the antitumor efficacy of conjugates 9, 13, 14, 16, 18, 19, 21, 23, 25, 26, 27, 28, and 29 against HCC1954 model in SCID Beige mice compared to the vehicle control group. [Figure 8(a)]

[0032] 1 is a graph showing the antitumor efficacy of conjugates 15, 17, 20, 22 and 24 (5 mg / kg, iv) against HCC1954 model in SCID Beige mice compared to the vehicle control group. [Figure 8(b)] 1 is a graph showing the antitumor efficacy of conjugates 15, 17, 20, 22 and 24 (5 mg / kg, iv) against HCC1954 model in SCID Beige mice compared to the vehicle control group. [Figure 9(a)]

[0033] 1 is a graph showing the antitumor efficacy of conjugates 15, 17, 20, 22 and 24 (2.5 mg / kg, iv) against HCC1954 model in SCID Beige mice compared to the vehicle control group. [Figure 9(b)] 1 is a graph showing the antitumor efficacy of conjugates 15, 17, 20, 22 and 24 (2.5 mg / kg, iv) against HCC1954 model in SCID Beige mice compared to the vehicle control group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020]

[0034] Reference will now be made in detail to certain specific embodiments of the invention, examples of which are shown in the accompanying structures and formulas. Although the invention will be described with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to encompass all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that can be used in the practice of the invention. The invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials, including but not limited to defined terms, term usage, described techniques, etc., differ or conflict with this application, this application will take precedence.

[0021]

[0035] It will be understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be described in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be described separately or in any suitable subcombination.

[0022]

[0036] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms, unless the context clearly indicates otherwise. Thus, for example, a reference to a "compound" includes a plurality of compounds. In this specification and the following claims, reference will be made to certain terms that will be defined to have the following meanings, unless a contrary intention is apparent. definition

[0037] The definitions of specific functional groups and chemical terms are described in more detail below.For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein.In addition, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989;Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987, the entire contents of each of which are incorporated herein by reference.

[0023]

[0038] At various points in this disclosure, linking substituents are described. Where a structure clearly requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, where a structure requires a linking group and the Markush group definition for that variable lists "alkyl," it is understood that "alkyl" represents a linking alkylene group.

[0024]

[0039] Any variable group (e.g., R i When any radical R occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, a group R i When indicated to be substituted with a moiety, the group may have up to two R i Each occurrence of R i are independently i Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0025]

[0040] As used herein, a dash "-" at the front or end of a chemical group is used for convenience to indicate the point of attachment of a substituent. For example, -OH is attached through a carbon atom, and chemical groups may be represented with or without one or more dashes without losing their normal meaning. A wavy line drawn with a single line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which the chemical groups are written or named. As used herein, a solid line emanating from the center of a ring indicates that the point of attachment of a substituent on the ring may be at any ring atom. When a substituent is listed without indicating the atom through which the substituent is attached to the remainder of the compound of a given formula, the substituent may be attached through any atom in the formula. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0026]

[0041] Any variable group (e.g., Ri When any radical R occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, a group R i When indicated to be substituted with a moiety, the group may have up to two R i Each occurrence of R i are independently i Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0027]

[0042] As used herein, the term "about" refers to the value or parameter itself and includes the indicated amount ±10%, ±5%, or ±1%. Also, the term "about X" includes the description "X."

[0028]

[0043] As used herein, the terms "compounds provided herein" or "compounds disclosed herein" or "compounds of the disclosure" refer to compounds of Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (II'), Formula (IIa'), and specific compounds disclosed herein.

[0029]

[0044] As used herein, the term "C i~j " denotes a range of carbon atoms, where i and j are integers, and the range of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, where j is greater than i. For example, C 1~6 indicates a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. 1~12 " denotes 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3 or particularly 1 to 2 carbon atoms. Similarly, the term "m- to n-membered" ring, where m and n are integers and n is greater than m, refers to a ring containing m to n atoms.

[0030]

[0045] As used herein, the term "alkyl," whether as part of another term or used independently, refers to a saturated straight or branched chain hydrocarbon group that may be independently optionally substituted with one or more of the substituents described below. i~j "Alkyl" refers to a straight or branched chain alkyl having i to j carbon atoms. For example, an alkyl group may contain 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. 1~6 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 2-ethyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0031]

[0046] As used herein, the term "alkylaryl" refers to an alkyl linked to an aryl, including -alkyl-aryl and alkyl-aryl-. In some embodiments, alkylaryl refers to -alkyl-aryl.

[0032]

[0047] As used herein, the term "alkylcycloalkyl" refers to an alkyl linked to a cycloalkyl, including -alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to -alkyl-cycloalkyl.

[0033]

[0048] As used herein, the term "alkylheterocyclyl" refers to an alkyl linked to a heterocyclyl, including -alkyl-heterocyclyl and alkyl-heterocyclyl-. In some embodiments, alkylheterocyclyl refers to -alkyl-heterocyclyl.

[0034]

[0049] As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a straight or branched chain hydrocarbon group having at least one carbon-carbon double bond, which may be independently and optionally substituted with one or more substituents described herein, including groups having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In some embodiments, an alkenyl group contains 2-12 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms. In some embodiments, an alkenyl group contains 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, an alkenyl group contains 2 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethylenyl (or vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2 buten-1-yl, 5-hexenyl, and the like.

[0035]

[0050] As used herein, the term "alkynyl," whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond, which may be independently and optionally substituted with one or more substituents described herein. In some embodiments, an alkenyl group contains 2-12 carbon atoms. In some embodiments, an alkynyl group contains 2-11 carbon atoms. In some embodiments, an alkynyl group contains 2-11 carbon atoms, 2-10 carbon atoms, 2-9 carbon atoms, 2-8 carbon atoms, 2-7 carbon atoms, 2-6 carbon atoms, 2-5 carbon atoms, 2-4 carbon atoms, 2-3 carbon atoms, and in some embodiments, an alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and the like.

[0036]

[0051] As used herein, the term "alkoxyl," whether as part of another term or used independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. i~j "Alkoxyl" means that the alkyl portion of the alkoxyl group has i to j carbon atoms. For example, the alkoxy group can contain 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. 1~6 Examples of "alkoxyl" include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), t-butoxy, neopentoxy, n-hexoxy, and the like.

[0037]

[0052] As used herein, the term "amino" refers to the group -NR a R b R a and R b is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, each of which may be optionally substituted.

[0038]

[0053] As used herein, the term "aryl", whether as part of another term or used independently, refers to monocyclic and polycyclic ring systems having a total of 5-20 ring members, where at least one ring in the system is aromatic, and where each ring in the system contains 3-12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. As used herein, the term "aryl" also includes within its scope groups in which an aromatic ring is fused to one or more additional rings. In the case of polycyclic ring systems, only one of the rings need be aromatic (e.g., 2,3-dihydroindole), but all of the rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl include, but are not limited to, benzofuranyl, indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0039]

[0054] As used herein, the term "arylalkyl" refers to an aryl bound to an alkyl, including -aryl-alkyl and aryl-alkyl-. In some embodiments, arylalkyl refers to -aryl-alkyl.

[0040]

[0055] As used herein, the term "cyano" refers to --CN.

[0056] As used herein, the term "cycloalkyl", whether as part of another term or used independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon and contain at least three ring-forming carbon atoms. In some embodiments, cycloalkyl groups can contain 3-12 ring-forming carbon atoms, 3-10 ring-forming carbon atoms, 3-9 ring-forming carbon atoms, 3-8 ring-forming carbon atoms, 3-7 ring-forming carbon atoms, 3-6 ring-forming carbon atoms, 3-5 ring-forming carbon atoms, 4-12 ring-forming carbon atoms, 4-10 ring-forming carbon atoms, 4-9 ring-forming carbon atoms, 4-8 ring-forming carbon atoms, 4-7 ring-forming carbon atoms, 4-6 ring-forming carbon atoms, 4-5 ring-forming carbon atoms. Cycloalkyl groups can be saturated or partially unsaturated. In some embodiments, cycloalkyl groups can be saturated cyclic alkyl groups. In some embodiments, cycloalkyl groups can be partially unsaturated cyclic alkyl groups containing at least one double or triple bond in their ring system.

[0041]

[0057] In some embodiments, the cycloalkyl group can be a saturated or partially unsaturated monocyclic carbocyclic ring system, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0042]

[0058] In some embodiments, cycloalkyl groups may be saturated or partially unsaturated polycyclic (e.g., bicyclic and tricyclic) carbocyclic ring systems that may be arranged as fused, spiro or bridged ring systems. As used herein, the term "fused ring" refers to a ring system having two rings that share two adjacent atoms, the term "spiro ring" refers to a ring system having two rings that are connected through one single common atom, and the term "bridged ring" refers to a ring system having two rings that share three or more atoms. Examples of fused carbocyclyls include, but are not limited to, naphthyl, benzopyrenyl, anthracenyl, acenaphthenyl, fluorenyl, and the like. Examples of spirocarbocyclyls include, but are not limited to, spiro[5.5]undecanyl, spiro-pentadienyl, spiro[3.6]-decanyl, and the like. Examples of bridged carbocyclyls include, but are not limited to, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.3]undecanyl, and the like.

[0043]

[0059] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl linked to an alkyl, including -cycloalkyl-alkyl and cycloalkyl-alkyl-. In some embodiments, cycloalkylalkyl refers to -cycloalkyl-alkyl.

[0044]

[0060] As used herein, the terms "halo" or "halogen" refer to an atom selected from fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), and iodine (or iodo).

[0045]

[0061] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, in which one or more hydrogen atoms have been replaced with a halogen. When a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted with two ("di") or three ("tri") halo groups, which may, but are not necessarily, the same halogen. Some examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ) are mentioned.

[0046]

[0062] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of nitrogen, sulfur, or phosphorus, and any quaternized form of a basic nitrogen.

[0047]

[0063] As used herein, the term "heteroalkyl" refers to an alkyl in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. A heteroalkyl may be a carbon or heteroatom group (i.e., the heteroatom may occur at the middle or end of the group), and may be independently optionally substituted with one or more substituents described herein. The term "heteroalkyl" encompasses alkoxyl and heteroalkoxy groups.

[0048]

[0064] As used herein, the term "heteroalkenyl" refers to an alkenyl in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. The heteroalkenyl may be a carbon or heteroatom group (i.e., the heteroatom may occur at the middle or end of the group), which may be independently optionally substituted with one or more substituents described herein.

[0049]

[0065] As used herein, the term "heteroalkynyl" refers to an alkynyl in which at least one of the carbon atoms is replaced with a heteroatom selected from N, O, or S. The heteroalkynyl may be a carbon or heteroatom group (i.e., the heteroatom may occur at the middle or end of the group), which may be independently optionally substituted with one or more substituents described herein.

[0050]

[0066] As used herein, the term "heteroaryl" refers to an aryl group that has one or more heteroatoms in addition to carbon atoms, whether as part of another term or used independently. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryls include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. Heteroaryl groups also include polycyclic groups in which an aromatic heterocycle is fused with one or more aryl, heteroaryl, alicyclic, or heterocyclyl rings, and the group or point of attachment is on the aromatic heterocycle. Examples of polycyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0051]

[0067] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more ring atoms may be optionally substituted independently with one or more substituents. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl with one or more double bonds in its ring system. In some embodiments, the heterocyclyl may contain any oxidized form of carbon, nitrogen, or sulfur, and any quaternized form of a basic nitrogen. The heterocyclyl group may be carbon-linked or nitrogen-linked, where possible. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Additionally, the imidazole derived groups can be imidazol-1-yl (nitrogen linked) or imidazol-3-yl (carbon linked).

[0052]

[0068] Heterocyclyl groups can be monocyclic. Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, azetidinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, pyrrolidinyl, triazinonyl, and the like.

[0053]

[0069] Heterocyclyl groups may be polycyclic, including fused, spiro and bridged ring systems. Fused heterocyclyl groups include groups in which a heterocyclyl group is fused to a saturated, partially unsaturated, or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Examples of fused heterocyclyls include, but are not limited to, phenyl-fused and pyridinyl-fused rings, such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolidinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, furo[3,4-d]pyrimidinyl, pyrrolo[3,4-d]pyrimidinyl, dihydrofuro[3,4-b]pyridinyl groups, and the like. Examples of spiroheterocyclyls include, but are not limited to, spiropyranyl, spirooxazinyl, 5-aza-spiro[2.4]heptanyl, 6-aza-spiro[2.5]octanyl, 6-aza-spiro[3.4]octanyl, 2-oxa-6-aza-spiro[3.3]heptanyl, 2-oxa-6-aza-spiro[3.4]octanyl, 6-aza-spiro[3.5]nonanyl, 7-aza-spiro[3.5]nonanyl, 1-oxa-7-aza-spiro[3.5]nonanyl, 3,8-dioxa-1-azaspiro[4.5]dec-1-enyl, and the like. Examples of bridged heterocyclyls include, but are not limited to, 3-aza-bicyclo[3.1.0]hexanyl, 8-aza-bicyclo[3.2.1]octanyl, 1-aza-bicyclo[2.2.2]octanyl, 2-aza-bicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[2.2.2]octanyl, and the like.

[0054]

[0070] As used herein, the term "heterocyclylalkyl" refers to a heterocyclyl linked to an alkyl, including -heterocyclyl-alkyl and heterocyclyl-alkyl-. In some embodiments, heterocyclylalkyl refers to a -heterocyclyl-alkyl.

[0055]

[0071] As used herein, the term "hydroxyl" refers to --OH.

[0072] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where said event or circumstance occurs and cases where said event or circumstance does not occur.

[0056]

[0073] As used herein, the term "partially unsaturated" refers to a group that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings that have multiple sites of unsaturation, but is not intended to include aromatic (i.e. fully unsaturated) moieties.

[0057]

[0074] As used herein, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is in accordance with the allowed valence of the substituted atom and results in a stable or chemically feasible compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Substituents may include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. It will be understood by those skilled in the art that the substituents may themselves be substituted, where appropriate. Unless expressly stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, references to an "aryl" group or moiety implicitly include both substituted and unsubstituted variants.

[0058]

[0075] As used herein, the term "targeting moiety" refers to a molecule, complex, or aggregate that specifically or selectively binds to a target molecule, cell, particle, tissue, or aggregate. Examples of targeting moieties include, but are not limited to, antibodies, antibody-binding fragments, bispecific antibodies, immunoglobulins, or other antibody-based molecules or compounds. However, other examples of targeting moieties, such as aptamers, avimers, receptor-binding ligands, nucleic acids, biotin-avidin binding pairs, peptides, small molecules, nanoparticles, or proteins, are known in the art and can be used. The terms "targeting moiety" and "binding moiety" are used interchangeably herein.

[0059]

[0076] As used herein, the term "antibody" includes any immunoglobulin, monoclonal, polyclonal, multivalent, multispecific, or bispecific (bivalent) antibody or functional portion thereof that binds to a specific antigen. A natural intact antibody comprises two heavy (H) and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a variable region (VH) and a first, second, and third constant region (CH1, CH2, and CH3, respectively), while each light chain consists of a variable region (VL) and a constant region (CL). Mammalian heavy chains are classified as α, δ, ε, γ, and μ, and mammalian light chains are classified as λ or κ. The variable regions of the light and heavy chains are responsible for antigen binding. The variable regions in both chains are generally subdivided into three regions of hypervariability called complementarity determining regions (CDRs) (light (L) chain CDRs comprising LCDR1, LCDR2, and LCDR3; heavy (H) chain CDRs comprising HCDR1, HCDR2, and HCDR3). The CDR boundaries of the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the Kabat, Chothia, or Al-Lazikani conventions (Al-Lazikani, B., Chothia, C., Lesk, AM, J. Mol. Biol., 273(4), 927 (1997); Chothia, C. et al., J Mol. Biol. Dec. 5; 186(3):651-63 (1985); Chothia, C. and Lesk, AM, J. Mol. Biol., 196, 901 (1987); Chothia, C. et al., Nature. Dec. 21-28; 342(6252):877-83 (1989); Kabat EA et al., National Institutes of Health, Bethesda, Md. (1991)). The three CDRs are sandwiched between adjacent stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold supporting the hypervariable loops. Thus, each VH and VL comprises three CDRs and four FRs in the following order (amino acid residues N-terminal to C-terminal): FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions.Antibodies are divided into five major classes based on the amino acid sequence of the constant region of their heavy chains: IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Some subclasses of the major antibody classes are, for example, IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

[0060]

[0077] As used herein, the term "antigen-binding fragment" refers to an antibody fragment formed from a fragment of an antibody that contains one or more CDRs, or any other antibody portion that binds to an antigen but does not contain an intact native antibody structure. Examples of antigen-binding fragments include, but are not limited to, diabodies, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds diabodies), single-chain antibody molecules (scFv), scFv dimers (bivalent diabodies), multispecific antibodies, camelized single domain antibodies, nanobodies, domain antibodies, isolated CDRs, and bivalent domain antibodies.

[0061]

[0078] As used herein, the term "Fab" with respect to an antibody refers to a monovalent antigen-binding fragment of an antibody consisting of a single light chain (both variable and constant regions) linked by disulfide bonds to the variable region and first constant region of a single heavy chain. Fab can be obtained by papain digestion of an antibody at residues proximal to the N-terminus of the inter-heavy chain disulfide bond of the hinge region.

[0062]

[0079] As used herein, the term "Fab'" refers to a Fab fragment containing a portion of the hinge region, obtainable by pepsin digestion of an antibody at the residues proximal to the C-terminus of the inter-heavy chain disulfide bond of the hinge region, and thus differs from Fab in a small number of residues in the hinge region, including one or more cysteines.

[0063]

[0080] As used herein, the term "F(ab') 2 " refers to a Fab' dimer containing two light chains and portions of two heavy chains.

[0081] As used herein, the term "Fc" with respect to an antibody refers to the portion of an antibody consisting of the second and third constant regions of a first heavy chain bound to the second and third constant regions of a second heavy chain via disulfide bonds. The Fc region of IgG and IgM contains three heavy chain constant regions (the second, third, and fourth heavy chain constant regions in each chain). It can be obtained by papain digestion of an antibody. The Fc portion of an antibody is responsible for various effector functions such as ADCC and CDC, but does not function in antigen binding.

[0064]

[0082] As used herein, the term "Fv" refers to the smallest fragment of an antibody that has a complete antigen-binding site. An Fv fragment consists of a single light chain variable region bound to a single heavy chain variable region. "dsFv" refers to a disulfide-stabilized Fv fragment in which the link between a single light chain variable region and a single heavy chain variable region is a disulfide bond.

[0065]

[0083] As used herein, the term "single chain Fv antibody" or "scFv" refers to an engineered antibody consisting of a light chain variable region and a heavy chain variable region connected to each other directly or via a peptide linker sequence (Huston JS et al., Proc Natl Acad Sci USA, 85:5879 (1988)). An "scFv dimer" refers to a single chain containing two heavy chain variable regions and two light chain variable regions together with a linker. An "scFv dimer" refers to a single chain containing two heavy chain variable regions and two light chain variable regions together with a linker. H is the other part's V L and another V to form two binding sites that can target the same antigen (or epitope) or different antigens (or epitopes). H -V L The V dimerized with the moiety H -V LThe term "scFv dimer" may also refer to a bivalent diabody or a bivalent ScFv (BsFv) comprising a V H1 and V L1 In cooperation with V H2 and V L2 V cooperates with each other, such that each cooperated pair has a different antigen specificity. L1 -V H2 (linked by a peptide linker) H1 -V L2 (also linked by a peptide linker).

[0066]

[0084] As used herein, the term "single chain Fv-Fc antibody" or "scFv-Fc" refers to an engineered antibody consisting of an scFv linked to the Fc region of an antibody.

[0085] As used herein, the term "camelized single domain antibody", "heavy chain antibody", "nanobody" or "HCAb" refers to a camelized single domain antibody having two V HIt refers to antibodies that contain heavy chain domains and do not contain light chains (Riechmann L. and Muyldermans S., J Immunol Methods. Dec. 10;231(1-2):25-38 (1999); Muyldermans S., J Biotechnol. Jun.;74(4):277-302 (2001); WO94 / 04678; WO94 / 25591; U.S. Patent No. 6,005,079). Heavy chain antibodies were originally derived from the Camelidae family (camels, dromedaries, and llamas). Although lacking light chains, camelized antibodies have a robust antigen-binding repertoire (Hamers-Casterman C. et al., Nature. June 3;363(6428):446-8 (1993); Nguyen VK. et al., "Heavy-chain antibodies in Camelidae; a case of evolutionary innovation", Immunogenetics. April;54(1):39-47 (2002); Nguyen VK. et al., Immunology. May;109(1):93-101 (2003)). The variable domain of heavy-chain antibodies (VHH domain) represents the smallest known antigen-binding unit generated by the adaptive immune response (Koch-Nolte F. et al., FASEB J. November;21(13):3490-8. Epub 2007 June 15 (2007)). "Diabodies" refer to small antibody fragments that have two antigen-binding sites, and the fragments are bound to each other in a single polypeptide chain. L V connected to the domain H Domain Included (V H -V L or V L -V H ) (see, e.g., Holliger P. et al., Proc Natl Acad Sci USA. July 15; 90(14):6444-8 (1993); EP404097; WO93 / 11161). Because the linker is too short, the two domains on the same chain cannot pair, so the domains are forced to pair with complementary domains on another chain, thereby creating two antigen-binding sites. The antigen-binding sites may target the same or different antigens (or epitopes).

[0067]

[0086] As used herein, the term "domain antibody" refers to an antibody fragment that contains only the variable region of a heavy chain or the variable region of a light chain. In some embodiments, two or more V H The domains are covalently linked with peptide linkers to form bivalent or multivalent domain antibodies. H The domains may target the same or different antigens.

[0068]

[0087] As used herein, the term "(dsFv) 2 " is made up of three peptide chains: one connected by a peptide linker and two V L Two V's attached to the moiety H An antigen-binding fragment consisting of a portion of the antibody.

[0069]

[0088] As used herein, the term "bispecific ds diabody" refers to a V H1 and V L1 V via a disulfide bridge between L1 -V H2 V bound to (linked by a peptide linker) H1 -V L2 (which are also linked by a peptide linker).

[0070]

[0089] As used herein, the term "bispecific dsFv" or "dsFv-dsFv'" refers to a bispecific dsFv comprising three peptide chains: heavy chains linked by a peptide linker (e.g., a long flexible linker) and V, ... L1 and V L2 V paired with part H1 -V H2 An antigen-binding fragment consisting of a portion of each disulfide-paired heavy and light chain has a different antigen specificity.

[0071]

[0090] In some embodiments, the antibody or antigen-binding fragment thereof is chimeric or humanized.

[0091] As used herein, the term "chimeric" refers to an antibody or antigen-binding fragment having a portion of a heavy and / or light chain derived from one species and the remainder of the heavy and / or light chain derived from a different species. Illustratively, a chimeric antibody can contain a constant region derived from a human and a variable region derived from a non-human species, such as a mouse.

[0072]

[0092] As used herein, the term "cell interaction molecule" refers to a molecule that can interact with a cell surface material of a target cell to cause or promote the specific binding of a conjugated compound containing such a cell interaction molecule to the cell, cause or promote the endocytosis of the conjugated compound by the target cell, and / or cause or promote the enrichment of the conjugated compound around and / or the entry of the conjugated compound into the target cell. The cell interaction molecule can be a small chemical molecule, a linear or macrocyclic peptide, or a large biological molecule. For example, the cell interacting molecule is a small molecule compound or polypeptide containing, but not limited to, 2-50, 2-40, 2-30, 2-25, 2-22, 2-20, 2-18, 2-15, 2-12, 2-10, 2-8, 4-50, 5-50, 5-40, 5-30, 5-25, 5-22, 5-20, 5-18, 5-15, 5-12, 5-10, 6, 7, 8, or 9 amino acids.

[0073]

[0093] As used herein, the term "humanized" in relation to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that comprises CDRs derived from a non-human animal (e.g., rodent, rabbit, dog, goat, horse, or chicken), FR regions derived from a human, and, if applicable, a constant region derived from a human. In some embodiments, the constant region derived from a human antibody is fused with a non-human variable region. A humanized antibody or antigen-binding fragment is useful as a human therapeutic. In some embodiments, it has reduced immunogenicity or is less likely to induce an immune response in humans compared to non-human species antibodies. In some embodiments, the non-human animal is a mammal, such as a mouse, rat, rabbit, goat, sheep, guinea pig, hamster, or non-human primate (e.g., a monkey (e.g., a cynomolgus or rhesus monkey) or ape (e.g., a chimpanzee, gorilla, simian, or affen)). In some embodiments, the humanized antibody or antigen-binding fragment is composed of substantially all human sequences, except for the CDR sequences, which are non-human. In some embodiments, the humanized antibody or antigen-binding fragment is modified to improve antibody performance, such as binding or binding affinity. For example, one or more amino acid residues in one or more non-human CDRs are altered to reduce potential immunogenicity in humans, and the altered amino acid residues are not critical for immunospecific binding, or the alterations are conservative changes, such that binding of the humanized antibody to the antigen is not significantly affected. In some embodiments, the FR region derived from a human may contain the same amino acid sequence as the human antibody from which it is derived, or it may contain some amino acid changes, for example, no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid changes. In some embodiments, such changes in amino acids may be present only in the heavy chain FR region, only in the light chain FR region, or in both chains. In some preferred embodiments, the humanized antibody comprises human FR1-3 and human JH and Jκ.

[0074]

[0094] As used herein, the term "ligand" refers to a variety of chemical or biological molecules that can have specific binding affinity for a selected target, which can be, for example, a cell surface receptor, a cell surface antigen, a cell, a tissue, an organ, etc. In some embodiments, a ligand can specifically bind to a protein or marker expressed on the surface of a target cell. In some embodiments, the ligands of the present disclosure can be 10 -6 ~10 -11 M(K d In some embodiments, the ligands of the present disclosure bind to cell surface proteins or markers with an affinity of at least 10 -7 , at least 10 -8 and at least 10 -9 M(K d In some embodiments, the ligands of the present disclosure bind to cell surface proteins or markers with an affinity of 10 -6 Less than 10 -7 Less than and 10 -8 Less than M (K d In some embodiments, the ligand of the present disclosure binds to a cell surface protein or marker with an affinity of at least 2, 3, 4, 5, 6, 8, 10, 20, 50, 100 or more times that of the affinity of the ligand to a target cell surface protein or marker to a non-target cell surface protein or marker. In some embodiments, the expression of the cell surface protein or marker of the present disclosure in a target cell (e.g., a cancer cell) is significantly higher than that in a normal cell. As used herein, the term "significantly" refers to a statistically significant difference, or a significant difference that can be recognized by a person skilled in the art.

[0075]

[0095] In some embodiments, the expression level of a cell surface protein or marker of the present disclosure in a target cell (e.g., a cancer cell) is 2-1,000,000 times higher than the expression level in a normal cell, for example, the expression level in a target cell (e.g., a cancer cell) is 2-10, 2-100, 2-1,000, 2-10,000, 2-100,000, or 2-1,000,000 times higher than the expression level in a normal cell (which may be equal to any value within the numerical ranges recited above, including the end values ​​of the ranges). In some embodiments, the expression level of a cell surface receptor in a target cell (e.g., a cancer cell) is at least 10 times, or 100 times, or 1,000 times, or 10,000 times, or 100,000 times higher than the expression level in a normal cell. In some embodiments, the level of a cell surface receptor on a normal cell is reduced by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the level of a cell surface protein or marker on a target cell (e.g., a cancer cell). In some embodiments, a cell surface protein or marker described in this disclosure is undetectable in a normal cell.

[0076]

[0096] As used herein, the term "nanoparticle" refers to any particle having a diameter of less than 1000 nm. For example, nanoparticles may have a diameter of, but is not limited to, 1-990 nm, 10-950 nm, 10-900 nm, 10-800 nm, 10-700 nm, 10-600 nm, 10-500 nm, 10-400 nm, 10-300 nm, 10-200 nm, 10-100 nm, 50-900 nm, 100-800 nm, 200-700 nm, 300-600 nm, or 400-500 nm.

[0077]

[0097] As used herein, the term "nucleic acid" refers to any polynucleotide that binds to an organ, tissue, cell, extracellular matrix component, and / or component associated with an intracellular compartment (target). In some embodiments, the nucleic acid targeting moiety is an aptamer. Aptamers are polynucleotide molecules that are selected (e.g., from a random or mutagenized pool) based on their ability to bind to another molecule. In some embodiments, the aptamer comprises a DNA polynucleotide. In some embodiments, the aptamer comprises an RNA polynucleotide. In some embodiments, the aptamer comprises one or more modified nucleic acid residues. Methods for generating and screening nucleic acid aptamers for binding to proteins are well known in the art. See, for example, U.S. Pat. No. 5,683,867, U.S. Pat. No. 6,344,321, U.S. Pat. No. 7,329,742, and International Patent Publication No. WO03 / 070984, each of which is incorporated herein by reference in its entirety.

[0078]

[0098] As used herein, the term "polypeptide", "protein" or "peptide" may be a single amino acid or a polymer of amino acids. A polypeptide, protein or peptide as described in this disclosure may contain naturally occurring and non-naturally occurring amino acids, or analogs and mimetics thereof. A polypeptide, protein or peptide may be obtained by any method well known in the art, including, but not limited to, isolation and purification from natural materials, recombinant expression, chemical synthesis, etc.

[0079]

[0099] As used herein, the term "small molecule" refers to a compound having a molecular weight of about 2 kDa or less. For example, but not limited to, a small molecule compound has a molecular weight of about 1.5 kDa, 1 kDa, 800 Da, 700 Da, 600 Da, or 500 Da or less.

[0080]

[0100] As used herein, the terms "specific binding" or "specifically binds" refer to a non-random binding reaction between two molecules, such as, for example, between an antibody and an antigen. In some embodiments, the antibodies or antigen-binding fragments provided herein have a binding affinity (K) of about 0.01 nM to about 100 nM, about 0.1 nM to about 100 nM, 0.01 nM to about 10 nM, about 0.1 nM to about 10 nM, 0.01 nM to about 1 nM, about 0.1 nM to about 1 nM, or about 0.01 nM to about 0.1 nM at pH 7.4. D ) specifically binds to the target antigen. D is the ratio of the dissociation rate to the association rate (k off / k on ) and can be determined, for example, using surface plasmon resonance techniques using instruments such as Biacore.

[0081]

[0101] As used herein, the term "tumor antigen" refers to an antigenic substance produced in tumor cells, i.e., it causes an immune response in the host. Normal proteins in the body are not antigenic due to self-tolerance, a process in which autoreactive cytotoxic T lymphocytes (CTLs) and autoantibody-producing B lymphocytes are selected "centrally" in primary lymphoid tissues (BM) and "peripherally" in secondary lymphoid tissues (mainly the thymus for T cells and the spleen / lymph nodes for B cells). Thus, any protein that is not exposed to the immune system will cause an immune response. This may include normal proteins that are well isolated from the immune system, proteins that are usually produced in very small amounts, proteins that are usually produced only at certain stages of development, or proteins whose structure is modified by mutation. Payload Compounds

[0102] In one embodiment, the compound of formula (II'):

[0082] [ka] (In the formula, X is -O-, -S-, -NH-, -(CH 2 ) i -, -(X 1 )NC(O)-, -(X1 )NS(O) 2 -, -C(O)N(X 1 )- and -S(O) 2 N(X 1 )-, -NH- and -(CH 2 ) i - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; each X 1 are independently hydrogen, alkyl, alkenyl, or haloalkyl; Ring A is cycloalkyl, heteroalkyl, aryl or heteroaryl; W is a direct bond, alkyl, cycloalkyl, heterocyclyl, * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 -alkyl-, selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, and * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 The alkyl in -alkyl is halogen, hydroxyl, cyano, amino, alkyl, and -C(O)OR. a and W is optionally substituted with one or more groups independently selected from * The end is connected to ring A, W 1 -O-, -NR a -, -C(O)-, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and Each R a are independently hydrogen, alkyl, or haloalkyl; R1 is hydrogen, -N(R b ) 2 , hydroxyl, or -SH; Each R b are independently hydrogen, alkyl, or haloalkyl; The Two R's b together with the nitrogen atom to which they are attached form a heterocyclyl, R 2 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR e , -OC(O)R e , -SR e , -B(OH) 2 , -NO 2 , -CHO, -C(=NOR e )(R e ), -R 2-1 -N(R e ) 2 , -R 2-1 -N(R e )C(O)R e , -R 2-1 -N(R e )S(O) 2 R e , -R 2-1 -N(R e )P(O) 2 R e , -R 2-1 -C(O)OR e , -R 2-1 -C(O)N(R e ) 2 , -R 2-1 -S(O) 2 N(R e ) 2 , -R 2-1 -P(O) 2 N(R e ) 2 , -OC(O)NR e or -NC(O)NR e and Each R 2-1 is independently absent or alkyl; Each R eare independently hydrogen, alkyl, or haloalkyl; Y is -Y 1 -Y 2 -Y 3 and Y 1 is a direct bond or -(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 1 of * Ends with Y 2 is connected to Y 2 is a direct bond or -(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and -(CH 2 ) s - and -(CH 2 ) t - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 of ** Ends with Y 3 is connected to Y 3 is hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R b ) 2 , -C(O)-alkyl, -C(O)-alkyl-N(R b ) 2 , and -S(O) 2 -alkyl, Q 1 and Q 2are each independently selected from a direct bond, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; R c is hydrogen or alkyl, or R c and Y 3 together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from one or more R d and is optionally replaced by R d is selected from the group consisting of halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, and -O-cycloalkyl; i is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3, 4 or 5) or a pharma- ceutically acceptable salt thereof.

[0083]

[0103] In some embodiments, ring A is

[0084] [ka] is selected from the group consisting of:

[0085]

[0104] In some embodiments, X is -O-, -NH-, or -(CH 2 ) i-, -NH- and -(CH 2 ) i - is optionally substituted with one or more halogen or alkyl.

[0086]

[0105] In certain embodiments, X is -O-, -N(CH 3 )-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -C(CH 3 ) 2 -or- CF 2 -It is.

[0087]

[0106] In some embodiments, R 1 is hydrogen, -N(R b ) 2 Or hydroxyl.

[0107] In some embodiments, W is a direct bond.

[0088]

[0108] In certain embodiments, W is a direct bond and R 1 is hydrogen, -N(R b ) 2 or hydroxyl, and each R b are independently hydrogen or alkyl, or two R b together with the nitrogen atom to which they are attached form a heterocyclyl.

[0089]

[0109] In some embodiments, W is -C(O)OR a In certain embodiments, W is alkyl optionally substituted with -C(O)OR a Optionally replaced by C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 In certain embodiments, each W is -C(O)ORa In certain embodiments, R a is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0090]

[0110] In certain embodiments, W is -C(O)OR a is alkyl optionally substituted with R 1 is hydrogen, hydroxyl or -N(R b ) 2 And each R b are independently hydrogen or alkyl, or two R b taken together with the nitrogen atom to which they are attached form a heterocyclyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is hydroxyl. In certain embodiments, R 1 -N(R b ) 2 And each R b are independently hydrogen, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 In certain embodiments, R 1 -N(R b ) 2 And each R b is independently hydrogen or methyl. In certain embodiments, R 1 -N(R b ) 2 and two R b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 3- to 9-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 3- to 7-membered heterocyclyl, a 3- to 6-membered heterocyclyl, or a 3- to 5-membered heterocyclyl.

[0091]

[0111] In some embodiments, W is * -W 1 In certain embodiments, W is * -W 1 -C 1~6 Alkyl-, * -W 1 -C 1~5 Alkyl-, * -W 1 -C 1~4 Alkyl-, * -W 1 -C 1~3 Alkyl-, or * -W 1 -C 1~2 It is alkyl-.

[0092]

[0112] In certain embodiments, W is * -W 1 -alkyl-, W 1 -O-, -NR a -, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and each R a is independently hydrogen, alkyl, or haloalkyl.

[0093]

[0113] In certain embodiments, W is * -W 1 -alkyl-, and R 1 is -NH 2 or -NH-CH 3 It is.

[0114] In some embodiments, W is * -Alkyl-W 1 In certain embodiments, W is * -C 1~6 Alkyl-W 1 -, * -C 1~5 Alkyl-W 1 -, * -C1~4 Alkyl-W 1 -, * -C 1~3 Alkyl-W 1 -,or * -C 1~2 Alkyl-W 1 -It is.

[0094]

[0115] In certain embodiments, W is * -Alkyl-W 1 - and W 1 is -C(O)-.

[0116] In certain embodiments, W is * -Alkyl-W 1 - and W 1 is -C(O)- and R 1 Ha-NH 2 It is.

[0095]

[0117] In some embodiments, W is * -Alkyl-W 1 In certain embodiments, W is -alkyl-. * -Alkyl-W 1 -alkyl-, each alkyl in W is independently selected from the group consisting of 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0096]

[0118] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- or -OC(O)NR a - and R a is hydrogen, alkyl, or haloalkyl.

[0097]

[0119] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NRa C(O)- and R 1 Ha-NH 2 It is.

[0120] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- and R 1 is hydroxyl.

[0098]

[0121] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -OC(O)NR a - and R 1 -NH-CH 3 It is.

[0122] In some embodiments, W is cycloalkyl. In certain embodiments, W is C 3~10 Cycloalkyl, C 3~9 Cycloalkyl, C 3~8 Cycloalkyl, C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 It is cycloalkyl.

[0099]

[0123] In certain embodiments, W is cycloalkyl and R 1 Ha-NH 2 It is.

[0124] In some embodiments, W is heterocyclyl. In certain embodiments, W is 3-10 membered heterocyclyl, 3-9 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, or 3-5 membered heterocyclyl.

[0100]

[0125] In certain embodiments, W is heterocyclyl and R 1 is hydrogen.

[0126] In some embodiments, R 2is hydrogen, halogen, cyano, alkyl, or alkoxyl. In certain embodiments, R 2 is hydrogen.

[0101]

[0127] In some embodiments, Y 1 is a direct bond.

[0128] In certain embodiments, Y 1 is a direct bond, and Y 2 is a direct bond.

[0129] In certain embodiments, Y 1 is a direct bond, and Y 2 is a direct bond, and Y 3 is -alkyl-aryl.

[0102]

[0130] In certain embodiments, Y 1 is a direct bond, and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** In certain embodiments, Q 2 is a direct bond, cycloalkyl, or aryl, where cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogen or alkyl. In certain embodiments, R c is hydrogen.

[0103]

[0131] In certain embodiments, Y 1 is a direct bond, and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 3 is hydrogen, -alkyl-NH 2 , or -S(O) 2 In certain embodiments, -alkyl-NH 2and -S(O) 2 The alkyl in -alkyl is independently selected from the group consisting of C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0104]

[0132] In some embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl. In certain embodiments, Q 1 is a direct bond, cycloalkyl, or aryl, where cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogen or alkyl.

[0105]

[0133] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 is a direct bond. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0106]

[0134] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 is a direct bond, and Y 3 is hydrogen. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n- is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0107]

[0135] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** In certain embodiments, Q 2 is a direct bond. In certain embodiments, R c is hydrogen. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m- and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0108]

[0136] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 3 is hydrogen, -C(O)-alkyl or -C(O)-alkyl-N(R b ) 2 In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl. In certain embodiments, R c and Y 3 together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more halogens.

[0109]

[0137] In some embodiments, Z is one or more R d In certain embodiments, Z is selected from the group consisting of alkyl, alkenyl, alkynyl, and heteroalkyl, optionally substituted with one or more R d Optionally replaced by C 1~6 Alkyl, C 1~6 Alkenyl, C 1~6 Alkynyl and C 1~6 heteroalkyl.

[0110]

[0138] In certain embodiments, R d is selected from the group consisting of halogen, acyl, alkyl, cycloalkyl, and -O-cycloalkyl. d is halogen, acyl, C 1~6 Alkyl, C 3~6 Cycloalkyl and -OC 3~6 cycloalkyl.

[0111]

[0139] In some embodiments, the present disclosure provides a compound of formula (IIa'):

[0112] [ka] The present invention provides a payload compound having the formula:

[0113]

[0140] In another aspect, the present disclosure provides a method for producing a method for manufacturing a pharmaceutical composition comprising:

[0114] [Table 1-1]

[0115] [Table 1-2]

[0116] [Table 1-3]

[0117]

Table 1-4

[0118]

Table 1-5

[0119]

Table 1-6

[0120]

Table 1-7

[0121]

Table 1-8

[0122]

Table 1-9

[0123]

Table 1-10

[0124]

Table 1-11

[0125]

Table 1-12

[0126]

Table 1-13

[0127]

Table 1-14

[0128]

Table 1-15

[0129]

Table 1-16

[0130]

Table 1-17

[0131]

Table 1-18

[0132]

Table 1-19

[0133]

Table 1-20

[0134]

Table 1-21

[0135]

Table 1-22

[0136]

Table 1-23

[0137]

Table 1-24

[0138]

Table 1-25

[0139]

[0141] A payload compound provided herein can be further attached to a linker provided herein to form a linker-payload compound.

[0142] The payload compounds provided herein are described with reference to both general formula and specific compound.In addition, the payload compounds of the present disclosure may exist in several different forms or derivatives, all of which are within the scope of the present disclosure.These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, solvates, amorphous forms, different crystalline forms or polymorphs.

[0140]

[0143] The payloads provided herein or pharma- ceutically acceptable salts thereof may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or with respect to amino acids as (D)- or (L)-. The present disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved by conventional techniques such as chromatography and fractional crystallization. Traditional techniques for the preparation and isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When compounds provided herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, these compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Whenever compounds are represented in their chiral form, it is understood that the embodiment includes, but is not limited to, the specific diastereomer or enantiomer-enriched form. In situations where chirality is not specified but exists, it is understood that the embodiment is intended to include either the specific diastereomer or enantiomer-enriched form, or a racemic or scalemic mixture of such compounds. A "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0141]

[0144] The term "stereoisomer" refers to compounds that contain the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0142]

[0145] The term "enantiomer" refers to a pair of stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalomic" mixture.

[0143]

[0146] The term "diastereoisomers" refers to stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0147] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compound provided herein.

[0144]

[0148] Some payload compounds provided herein exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and the nature of the equilibrium between tautomers, it is understood by those skilled in the art that the compound includes both amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0145]

[0149] Any formula or structure provided herein also represents unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the same structure as shown by the formula provided herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes include, but are not limited to, hydrogen ( 2 H (deuterium, D), 3 H (tritium), carbon ( 11 C. 13 C. 14 C), nitrogen ( 15 N), oxygen ( 17 O. 18 O), Phosphorus ( 31 P, 32 P), fluorine ( 18F), Chlorine ( 36 Cl), and iodine ( 125 Isotopically labeled compounds may be used in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) in drug or substrate tissue distribution assays or radioactive treatment of patients.

[0146]

[0150] The payload compounds of the present disclosure may be formulated as or may be in the form of a pharma- ceutically acceptable salt.Unless specified to the contrary, the compounds provided herein include pharma- ceutically acceptable salts of such compounds.

[0147]

[0151] As used herein, the term "pharmacologically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the subject being treated therewith.

[0148]

[0152] The term "subject" as used herein refers to an animal, preferably a mammal, more preferably a human, who has been the object of treatment, observation or experiment.

[0153] As used herein, the term "pharmaceutical acceptable salts" includes salts that retain the biological effectiveness of the free acids and bases of the specified compound, and are not biologically or otherwise undesirable, unless otherwise indicated. Contemplated pharmaceutical acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts may facilitate pharmacological use by altering the physical characteristics of a compound without preventing the compound from exerting its physiological effects. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administering higher concentrations of the drug.

[0149]

[0154] Pharmaceutically acceptable salts include those containing acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid.

[0150]

[0155] When an acidic functional group such as carboxylic acid or phenol is present, pharma- ceutically acceptable salts include base addition salts, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamines, and zinc.See, for example, Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, vol. 2, p. 1457, 1995; "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0151]

[0156] Pharmaceutically acceptable salts can be prepared by standard techniques.For example, the free base form of a compound can be isolated by dissolving in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then evaporating the solution.Thus, when a particular compound is a base, the desired pharma-ceutically acceptable salt can be prepared by treating the free base with any suitable method available in the art, such as with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids, such as glucuronic acid or galacturonic acid, alpha-hydroxy acids, such as citric acid or tartaric acid, amino acids, such as aspartic acid or glutamic acid, aromatic acids, such as benzoic acid or cinnamic acid, sulfonic acids, such as p-toluenesulfonic acid or ethanesulfonic acid, etc.

[0152]

[0157] Similarly, if a particular compound is an acid, the desired pharma- ceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as hydroxyethylpyrrolidine, piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0153]

[0158] It should also be understood that the payload compounds of the present disclosure can exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., amorphous, crystalline or polymorphic forms), and the present disclosure is intended to encompass all such forms.

[0154]

[0159] As used herein, the term "solvate" or "solvate form" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance, where the water is H 2 It retains its molecular state as O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0155]

[0160] As the payload compounds provided herein are intended for pharmaceutical use, they are preferably provided in substantially pure form, e.g., at least 60% pure, more suitably at least 75% pure, particularly at least 98% pure (percentages being on a weight to weight basis).

[0156]

[0161] The payload compounds provided herein exhibit effective agonist ability against TLR7 and / or TLR8. In some embodiments, the payload compounds provided herein exhibit effective agonist ability against both TLR7 and TLR8. In some embodiments, the payload compounds provided herein exhibit selective agonist ability against TLR7 over TLR8. In some embodiments, the payload compounds provided herein exhibit selective agonist ability against TLR8 over TLR7.

[0157]

[0162] The payload compounds provided herein are particularly suitable for forming ADCs with TLR agonist activity, which are stable before administration to a subject.The targeting moiety and linker moiety useful for forming ADCs with the payload compounds provided herein can be any targeting moiety and linker moiety known in the art. Synthesis of payload compounds

[0163] The synthesis of the payload compounds provided herein, including their pharma- ceutically acceptable salts, is shown in the synthetic schemes in the examples. The payload compounds provided herein can be prepared using any known organic synthesis technique and can be synthesized according to any of a number of possible synthetic routes, and therefore these schemes are merely illustrative and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in the schemes are for better illustration and can be varied accordingly. The payload compound embodiments in the examples were synthesized for research and potentially regulatory submission purposes.

[0158]

[0164] The reaction for preparing the payload compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0159]

[0165] The preparation of the payload compounds of the present disclosure may include the protection and deprotection of various chemical groups.The necessity of protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art.The chemical nature of protecting groups can be found, for example, in TW Greene and P G M Huts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003, and Peter G M Huts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0160]

[0166] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization," Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety), and normal phase silica chromatography.

[0161]

[0167] Known starting materials of this disclosure may be synthesized by or according to methods known in the art or may be purchased from commercial suppliers. Analytical grade solvents and commercially available reagents were used without further purification unless otherwise noted.

[0162]

[0168] Unless otherwise specified, all reactions in this disclosure were carried out under a positive pressure of nitrogen or argon or in anhydrous solvents using drying tubing and reaction flasks were typically fitted with rubber septa for introduction of substrates and reagents via syringe. Glassware was oven-dried and / or heat-dried.

[0163]

[0169] For illustrative purposes, the following example section shows the synthetic route for preparing the payload compounds and key intermediates of the present disclosure. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are shown, other starting materials and reagents can be easily substituted to provide various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. Linker

[0170] In one embodiment, the compound of formula (III): -L 1 -(L 2 ) j -(L 3 ) k -(III) (In the formula, L 1 is a Stretcher unit covalently attached to a targeting moiety, L 2 is an optional peptide unit of 2 to 12 amino acid residues, L 3 is an optional spacer unit covalently attached to the payload unit, j and k are independently selected from 0 and 1. A linker L is provided having the following structure:

[0164]

[0171] In some embodiments, L 1 is the expression:

[0165] [ka] (In the formula, each R 3 are independently alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylheterocyclyl, heterocyclylalkyl, -alkyl-C(O)N(R a )-Alkyl-N(R a ), -N(R a )-alkyl-, and -(CH 2 CH 2 O) r -CH 2 -, R a is H or alkyl, r is an integer ranging from 1 to 10, and v is an integer ranging from 0 to 5.

[0166]

[0172] In certain embodiments, each R 3 are independently 1~10 Alkyl, C 1~8 Heteroalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, (C 1~10 Alkyl)aryl, aryl(C 1~10 Alkyl), (C 1~10 Alkyl)(C 3~8 Cycloalkyl), (C 3~8 Cycloalkyl)(C 1~10 Alkyl), (C 1~10 alkyl)(3-8 membered heterocyclyl), (3-8 membered heterocyclyl)(C 1~10 alkyl), -(C 2~6 alkyl)-C(O)N(R a )-(C 2~6 Alkyl)-N(R a ), -N(R a )-(C2~6 alkyl)-, and -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 It is an alkyl.

[0167]

[0173] In certain embodiments, v is 1 and R 3 (CH 2 ) 5 It is.

[0174] In some embodiments, j is 0 and k is 0.

[0175] In some embodiments, j is 0 and k is 1.

[0168]

[0176] In some embodiments, L 1 is the expression:

[0169] [ka] (In the formula, R 4 is alkyl, -alkyl-O-, -N(R a )-Alkyl-N(R a )-, -N(R a )-alkyl-, and (CH 2 CH 2 O) r -CH 2 R a is H or alkyl, and r is an integer ranging from 1 to 10.

[0170]

[0177] In certain embodiments, L 1 is the expression:

[0171] [ka] (In the formula, R 4 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6Alkyl)-N(R a )-, -N(R a )-(C 2~6 alkyl)-, and -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl).

[0172]

[0178] In some embodiments, L 1 is the expression:

[0173] [ka] (In the formula, R 5 is alkyl, -alkyl-O-, aryl, -N(R a )-Alkyl- or -(CH 2 CH 2 O) r -CH 2 - selected from R a is H or alkyl, and r is an integer ranging from 1 to 10.

[0174]

[0179] In certain embodiments, L 1 is the expression:

[0175] [ka] (In the formula, R 5 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6 Alkyl)- or -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl, and r is an integer ranging from 1 to 10.

[0176]

[0180] In certain embodiments, L 1 is the expression:

[0177] [ka] (In the formula, R 5 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6 Alkyl)- or -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl, and r is an integer ranging from 1 to 10.

[0178]

[0181] In certain embodiments, the linker L forms a thioether bond with a cysteine ​​amino acid of the targeting moiety, L 1 is the expression:

[0179] [ka] R 5 Ha-(C 2~6 alkyl)-O-, C 2~6 Alkyl is F, OH, O(C 1~6 alkyl), NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1~6 Optionally substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more F.

[0180]

[0182] In certain embodiments, the linker L forms an amide bond with a lysine amino acid of the targeting moiety, L 1 is the expression:

[0181] [ka] R 5 Ha-(C 2~6 alkyl)-O-, C 2~6 Alkyl is F, OH, O(C 1~6 alkyl), NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1~6 Optionally substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more F.

[0182]

[0183] In some embodiments, j is 1 and k is 1.

[0184] In some embodiments, j is 1 and L 2 contains 2 or 12 amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

[0183]

[0185] In certain embodiments, L 2 is valine-citrulline.

[0186] In some embodiments, k is 1 and L 3 includes para-aminobenzyl or para-aminobenzyloxycarbonyl.

[0184]

[0187] In certain embodiments, the linker L has the formula:

[0185] [ka] (wherein AA1 and AA2 are independently selected from amino acid side chains, and p is an integer from 1 to 8). has.

[0186]

[0188] In certain embodiments, the amino acid side chains are independently selected from H, -CH 3 , -CH 2 (C6 H 5 ), -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , -CHCH(CH 3 )CH 3 , and -CH 2 CH 2 CH 2 NHC(O)NH 2 is selected from.

[0187]

[0189] In certain embodiments, the linker L has the formula:

[0188] [ka] has.

[0189]

[0190] In certain embodiments, the linker L has the formula:

[0190] [ka] has.

[0191] In certain embodiments, the linker L has the formula:

[0192] [ka] has.

[0193] In certain embodiments, the linker L has the formula:

[0194] [ka] has.

[0195] In certain embodiments, the linker L has the formula:

[0196] [ka] has.

[0197] In certain embodiments, the linker L has the formula:

[0198] [ka] has.

[0199] In certain embodiments, the linker L has the formula:

[0200] [ka] has.

[0201] In certain embodiments, the linker L has the formula:

[0202] [ka] has.

[0203] In certain embodiments, the linker L is

[0204] [ka]

[0205] [ka]

[0206] [ka] (In the formula, R is

[0207] [ka] is selected from the group consisting of R ’ and R ’’ each is independently hydrogen or methyl. is selected from the group consisting of: targeting part

[0201] In one aspect, a targeting moiety is provided that comprises an immunoglobulin, a protein, a peptide, a small molecule, a nanoparticle, or a nucleic acid.

[0208]

[0200] In some embodiments, the targeting moiety comprises an antibody or an antigen-binding fragment thereof. In certain embodiments, the antibody is selected from the group consisting of BMPR1B, E16, STEAP1, MUC16, MPF, Napi2b, Sema5b, PSCA The antibody specifically binds to one or more tumor-associated antigens or cell surface receptors selected from hlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD79b, FcRH2, HER2, NCA, MDP, IL20Ra, brevican, EphB2R, ASLG659, PSCA, GEDA, BAFF-R, CD22, CD79a, CXCR5, HLA-DOB, P2X5, CD72, LY64, FcRHl, FcRH5, TENB2, PMEL17, TMEFF1, GDNF-Ral, Ly6E, TMEM46, Ly6G6D, LGR5, RET, LY6K, GPR19, GPR54, ASPHD1, tyrosinase, TMEM118, GPR172A, CD33, and CLL-1.

[0209]

[0201] In certain embodiments, the antibody specifically binds to HER2 or B7-H4.

[0202] In certain embodiments, the antibody specifically binds to HER2.

[0210]

[0203] In some embodiments, the antibody is selected from the group consisting of Rituxan (rituximab), Herceptin (trastuzumab), Erbitux (cetuximab), Vectibix (panitumumab), Arzerra (ofatumumab), Benlysta (belimumab), Yervoy (ipilimumab), Perjeta (pertuzumab), tremelimumab, nivolumab, dacetuzumab, urelumab, MPDL3280A, lambrolizumab, and blinatumomab.

[0211]

[0204] In certain embodiments, the antibody is Herceptin (trastuzumab).

[0205] In certain embodiments, the antigen-binding fragment is a Fab, Fab', F(ab')2, single domain antibody, T and Abs dimer, Fv, scFv, dsFv, ds-scFv, Fd, linear antibody, minibody, diabody, bispecific antibody fragment, bibody, tribody, sc-diabody, kappa (lambda) body, BiTE, DVD-Ig, SIP, SMIP, DART, polymer or aptamer.

[0212]

[0206] In some embodiments, the targeting moiety comprises a protein or peptide.

[0207] In certain embodiments, the peptide contains 2 to 100, 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 25, 2 to 22, 2 to 20, 2 to 18, 2 to 15, 2 to 12, 2 to 10, 2 to 8, 4 to 50, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 22, 5 to 20, 5 to 18, 5 to 15, 5 to 12, 5 to 10, 6, 7, 8, or 9 amino acids.

[0213]

[0208] In some embodiments, the targeting moiety comprises a small molecule.

[0209] In certain embodiments, the small molecule targeting moiety is folic acid or an analog thereof.

[0214]

[0210] Folic acid is useful for forming chemical bonds with other groups due to its small molecular weight, non-immunogenicity, and good stability. Folic acid can associate with folic acid receptors expressed on cell surface with high affinity to mediate cellular uptake of folic acid. Folic acid receptors are expressed at very low levels in most normal cells, but are expressed at high levels in many cancer cells to meet the high folic acid demand of rapidly dividing cells under low folic acid conditions (see Kelemen LE, Int J Cancer, 2006;119:243-50; Kane MA et al., J Clin Invest. 1988;81:1398-406; Matsue H et al., Proc Natl Acad Sci USA. 1992;89:6006-9; Zhao R et al., Annu Rev Nutr. 2011;31:177-201). The folic acid can specifically bind to a folate receptor on the cell surface and can also mediate endocytosis of the conjugated compound, or a pharma- ceutically acceptable salt thereof, into the target cell.

[0215]

[0211] In certain embodiments, the analog of folic acid is selected from the group consisting of 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid, methotrexate, and 5,10-methylenetetrahydrofolic acid.

[0216] In some embodiments, the targeting moiety comprises a nanoparticle, preferably a targeted nanoparticle, bound to a targeting molecule that can specifically or preferably bind to a target. In some embodiments, the targeted nanoparticle itself directs the compound of the present invention (such as by enrichment in tumor cells or tissues) to which there is no additional targeting molecule bound.

[0217]

[0213] In some embodiments, the targeting moiety comprises a nucleic acid.

[0214] In some embodiments, the targeting moiety comprises a cell-interacting molecule.

[0215] In some embodiments, the targeting moiety comprises a ligand capable of binding to a cell surface receptor or other molecule.

[0218]

[0216] In certain embodiments, a cell surface protein or marker of the present disclosure is a cell surface receptor.

[0217] In certain embodiments, the cell surface receptor of the present disclosure is selected from the group consisting of Toll-like receptors (TLR), transferrin receptors (TFR), low density lipoprotein receptors (LDLR), folate receptors (FR), growth hormone inhibitory hormone receptors, urate kinase receptors, tumor necrosis factor receptors (TNFR), integrin receptors (LFA-1), SST-14 receptors (SSTR2), GNRH receptors (GNRHR), TRPV6 and integrin alpha receptors.

[0219]

[0218] In certain embodiments, a cell surface protein or marker of the present disclosure is a cell surface antigen.

[0219] In some embodiments, the targeting moiety is capable of binding to a tumor antigen.

[0220] In certain embodiments, the targeting moiety is CD2, CD19, CD20, CD22, CD27, CD28, CD33, CD37, CD38, CD40, CD40L, CD44, CD47, CD52, CD56, CD70, CD79, CD86 / 80, CD113, CD122, CD137, CD155, CD160, CD206, 4-1BB, 5T4, AGS-5, AGS-16, Angiopoietin 2, B7.1, B7.2, B7DC, B7H1, B7H2, B7H3, BT-062, BTLA, CAIX, carcinoembryonic antigen, CTLA4, Cripto, ED-B, ErbBl, ErbB2, ErbB3, ErbB4, EGFL7, EpCAM, EphA2, EphA3, EphB2, FAP, fibronectin, folate receptor, ASGPR, ganglioside GM3, GD2, g pl00, gpA33, GPNMB, ICOS, IGF1R, integrin αν, integrin ανβ, KIR, LAG-3, Lewis Y, mesothelin, c-MET, RON, PRLR, MN carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NKGD2, NOTCH, OX40, OX40L, PD-1, PDL1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC4 4A4, syndecan-1, TACI, TAG-72, tenascin, TIM3, TREM-1, TREM-2, MACRO, Ly6E, TRAILR1, TRAILR2, VEGFR-1, VEGFR-2, VEGFR-3, FOLR1, TRPV6, FOLH1(PMSA), GNRHR, Trop2, NECTIN4, LRP1, GLUT1, EGFR1, AXL, CA9, claudin 18.2, CLDN6, APN, DLL3, DLL4, CEACAM5, FZD10, TFRC, MET, SSTR2, CCKBR, LFA1, ICAM, GPR87, GM-CSF, GM-CSFR, CSF -1R, TLR family, GITRL, GITR, 4-BBL, ICOSL, MHCII antigen, TCR, FLT3, c-KIT, CTLA-4, IGIT, galectin-9, HVEM, VISTA, B7 -H4, phosphatidylserine, HHLA2, galectin-3, LILRB2, LILRB3, LILRB4, SIGLEC15, CLEC5a, TIGIT, TfR, NKG2A, NKG2D, SLAMF7, KIR2DL1, KIR2DL2, KIR2DL3, FGFR1, FGFR2, FGFR4, NeuGcGM3, CXCR4 and variants thereof. Linker-Payload Compounds

[0221] In another embodiment, the compound of formula (Ia): L'-D(Ia) (In the formula, L' is a linker precursor, D is of formula (II):

[0221] [ka] is the payload unit, X is -O-, -S-, -NH-, -(CH 2 ) i -, -(X 1 )NC(O)-, -(X 1 )NS(O) 2 -, -C(O)N(X 1 )- and -S(O) 2 N(X 1 )-, -NH- and -(CH 2 ) i - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; each X 1 are independently hydrogen, alkyl, alkenyl, or haloalkyl; Ring A is cycloalkyl, heterocyclyl, aryl or heteroaryl; W is a direct bond, alkyl, cycloalkyl, heterocyclyl, * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 -alkyl-, selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, and * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 The alkyl in -alkyl is halogen, hydroxyl, cyano, amino, alkyl, and -C(O)OR. a and W is optionally substituted with one or more groups independently selected from * The end is connected to ring A, W 1 -O-, -NR a -, -C(O)-, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and Each R a are independently hydrogen, alkyl, or haloalkyl; R 1 is hydrogen, -N(R b ) 2 , hydroxyl or SH; Each R b are independently hydrogen, alkyl, or haloalkyl; The Two R's b together with the nitrogen atom to which they are attached form a heterocyclyl, R 2 is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -ORe , -OC(O)R e , -SR e , -B(OH) 2 , -NO 2 , -CHO, -C(=NOR e )(R e ), -R 2-1 -N(R e ) 2 , -R 2-1 -N(R e )C(O)R e , -R 2-1 -N(R e )S(O) 2 R e , -R 2-1 -N(R e )P(O) 2 R e , -R 2-1 -C(O)OR e , -R 2-1 -C(O)N(R e ) 2 , -R 2-1 -S(O) 2 N(R e ) 2 , -R 2-1 -P(O) 2 N(R e ) 2 , -OC(O)NR e or -NC(O)NR e and Each R 2-1 is independently absent or alkyl; Each R e are independently hydrogen, alkyl, or haloalkyl; Y is -Y 1 -Y 2 -Y 3 and Y 1 is a direct bond or -(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n- is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 1 of * Ends with Y 2 is connected to Y 2 is a direct bond or -(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and -(CH 2 ) s - and -(CH 2 ) t - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 of ** Ends with Y 3 is connected to Y 3 is hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R b ) 2 , -C(O)-alkyl, -C(O)-alkyl-N(R b ) 2 , and -S(O) 2 -alkyl, Q 1 and Q 2 are each independently selected from a direct bond, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; R c is hydrogen or alkyl, or R c and Y 3 together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from one or more R d and is optionally replaced by R d is selected from the group consisting of halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, and -O-cycloalkyl; i is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3, 4 or 5) or a pharma- ceutically acceptable salt thereof.

[0222] In some embodiments, ring A is

[0223] [ka] is selected from the group consisting of:

[0224] In some embodiments, X is -O-, -NH-, or -(CH 2 ) i -, -NH- and -(CH 2 ) i - is optionally substituted with one or more halogen or alkyl.

[0225] In certain embodiments, X is -O-, -N(CH 3 )-, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -C(CH 3 ) 2 -or- CF2 -It is.

[0226] In some embodiments, R 1 is hydrogen, -N(R b ) 2 Or hydroxyl. In some embodiments, W is a direct bond.

[0227] In certain embodiments, W is a direct bond and R 1 is hydrogen, -N(R b ) 2 or hydroxyl, and each R b are independently hydrogen or alkyl, or two R b together with the nitrogen atom to which they are attached form a heterocyclyl.

[0228] In some embodiments, W is -C(O)OR a In certain embodiments, W is alkyl optionally substituted with -C(O)OR a Optionally replaced by C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 In certain embodiments, each W is -C(O)OR a In certain embodiments, R a is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0229] In certain embodiments, W is -C(O)OR a is alkyl optionally substituted with R 1 is hydrogen, hydroxyl or -N(R b ) 2And each R b are independently hydrogen or alkyl, or two R b taken together with the nitrogen atom to which they are attached form a heterocyclyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is hydroxyl. In certain embodiments, R 1 -N(R b ) 2 And each R b are independently hydrogen, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 In certain embodiments, R 1 -N(R b ) 2 And each R b is independently hydrogen or methyl. In certain embodiments, R 1 -N(R b ) 2 and two R b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 3- to 9-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 3- to 7-membered heterocyclyl, a 3- to 6-membered heterocyclyl, or a 3- to 5-membered heterocyclyl.

[0230] In some embodiments, W is * -W 1 In certain embodiments, W is * -W 1 -C 1~6 Alkyl-, * -W 1 -C 1~5 Alkyl-, * -W 1 -C 1~4 Alkyl-, * -W 1 -C 1~3 Alkyl-, or * -W 1 -C 1~2 It is alkyl-.

[0231] In certain embodiments, W is * -W 1 -alkyl-, W 1 -O-, -NR a -, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and each R a is independently hydrogen, alkyl, or haloalkyl.

[0232] In certain embodiments, W is * -W 1 -alkyl-, and R 1 is -NH 2 or -NH-CH 3 It is.

[0233] In some embodiments, W is * -Alkyl-W 1 In certain embodiments, W is * -C 1~6 Alkyl-W 1 -, * -C 1~5 Alkyl-W 1 -, * -C 1~4 Alkyl-W 1 -, * -C 1~3 Alkyl-W 1 -,or * -C 1~2 Alkyl-W 1 -It is.

[0233]

[0234] In certain embodiments, W is * -Alkyl-W 1 - and W 1 is -C(O)-.

[0235] In certain embodiments, W is * -Alkyl-W 1- and W 1 is -C(O)- and R 1 Ha-NH 2 It is.

[0234]

[0236] In some embodiments, W is * -Alkyl-W 1 In certain embodiments, W is -alkyl-. * -Alkyl-W 1 -alkyl-, each alkyl in W is independently selected from the group consisting of 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0235]

[0237] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- or -OC(O)NR a - and R a is hydrogen, alkyl, or haloalkyl.

[0236]

[0238] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- and R 1 Ha-NH 2 It is.

[0239] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- and R 1 is hydroxyl.

[0237]

[0240] In an embodiment, W is * -Alkyl-W 1 -alkyl-, W 1 -OC(O)NR a- and R 1 -NH-CH 3 It is.

[0241] In some embodiments, W is cycloalkyl. In certain embodiments, W is C 3~10 Cycloalkyl, C 3~9 Cycloalkyl, C 3~8 Cycloalkyl, C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 It is cycloalkyl.

[0238]

[0242] In certain embodiments, W is cycloalkyl and R 1 Ha-NH 2 It is.

[0243] In some embodiments, W is heterocyclyl. In certain embodiments, W is 3-10 membered heterocyclyl, 3-9 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, or 3-5 membered heterocyclyl.

[0239]

[0244] In certain embodiments, W is heterocyclyl and R 1 is hydrogen.

[0245] In some embodiments, R 2 is hydrogen, halogen, cyano, alkyl, or alkoxyl. In certain embodiments, R 2 is hydrogen.

[0240]

[0246] In some embodiments, Y 1 is a direct bond.

[0247] In certain embodiments, Y 1 is a direct bond, and Y 2 is a direct bond.

[0248] In certain embodiments, Y 1 is a direct bond, and Y 2 is a direct bond, and Y 3 is -alkyl-aryl.

[0241]

[0249] In certain embodiments, Y 1 is a direct bond, and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** In certain embodiments, Q 2 is a direct bond, cycloalkyl, or aryl, where cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogen or alkyl. In certain embodiments, R c is hydrogen.

[0242]

[0250] In certain embodiments, Y 1 is a direct bond, and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 3 is hydrogen, -alkyl-NH 2 , or -S(O) 2 In certain embodiments, -alkyl-NH 2 and -S(O) 2 The alkyl in -alkyl is independently selected from the group consisting of C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0243]

[0251] In some embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 )n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl. In certain embodiments, Q 1 is a direct bond, cycloalkyl, or aryl, where cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogen or alkyl.

[0244]

[0252] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 is a direct bond. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n- is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0245]

[0253] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 is a direct bond, and Y 3 is hydrogen. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0246]

[0254] In certain embodiments, Y1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** In certain embodiments, Q 2 is a direct bond. In certain embodiments, R c is hydrogen. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0247]

[0255] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - **and Y 3 is hydrogen, -C(O)-alkyl or -C(O)-alkyl-N(R b ) 2 In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl. In certain embodiments, R c and Y 3 together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more halogens.

[0248]

[0256] In some embodiments, Z is one or more R d In certain embodiments, Z is selected from the group consisting of alkyl, alkenyl, alkynyl, and heteroalkyl, optionally substituted with one or more R d Optionally replaced by C 1~6 Alkyl, C 1~6 Alkenyl, C 1~6 Alkynyl and C 1~6 heteroalkyl.

[0249]

[0257] In certain embodiments, R d is selected from the group consisting of halogen, acyl, alkyl, cycloalkyl, and -O-cycloalkyl.d is halogen, acyl, C 1~6 Alkyl, C 3~6 Cycloalkyl and -OC 3~6 cycloalkyl.

[0250]

[0258] In some embodiments, D has formula (Iia):

[0251] [ka] is the payload unit.

[0252]

[0259] In some embodiments, the payload unit comprises:

[0253] [ka]

[0254] [ka]

[0255] [ka]

[0256] [ka]

[0257] [ka]

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] [ka]

[0262] [ka]

[0263] [ka]

[0264] [ka]

[0265] [ka]

[0266] [ka]

[0267] [ka] (wherein q is 1, 2 or 3);

[0268] [ka] (wherein q is 1, 2 or 3);

[0269] [ka]

[0270] [ka]

[0271] [ka]

[0272] [ka]

[0273] [ka]

[0274] [ka]

[0275] [ka]

[0276] [ka]

[0277] [ka]

[0278] [ka]

[0279] [ka]

[0280] [ka] is selected from the group consisting of:

[0281] In some embodiments, L' has formula (IIIa): L 1’ -(L 2 ) j -(L 3 ) k -(IIIa) (In the formula, L 1’ reacts with the targeting moiety to form a Stretcher unit L that is covalently attached to the targeting moiety 1 wherein the reactive group RG is selected from the group consisting of maleimide, thiol, amino, bromide, bromoacetamide, iodoacetamide, p-toluenesulfonate, iodide, hydroxyl, carboxyl, pyridyl disulfide, and N-hydroxysuccinimide; L 2 is an optional peptide unit of 2 to 12 amino acid residues, L 3 is an optional spacer unit covalently attached to the payload unit, j and k are independently selected from 0 and 1. has.

[0282] In some embodiments, L 1’ teeth,

[0283] [ka] (In the formula, each R 3 are independently a bond, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylheterocyclyl, heterocyclylalkyl, -alkyl-C(O)N(R a )-Alkyl-N(R a ), -N(R a )-alkyl-, and -(CH 2 CH 2 O) r -CH 2-, R a is H or alkyl, r is an integer ranging from 1 to 10, and v is an integer ranging from 0 to 5.

[0284] In certain embodiments, v is 1 and R 3 (CH 2 ) 5 It is.

[0263] In some embodiments, j is 0 and k is 0.

[0264] In some embodiments, j is 0 and k is 1.

[0285] In some embodiments, L 1’ is the expression:

[0286] [ka] (In the formula, R 4 is alkyl, -alkyl-O-, -N(R a )-Alkyl-N(R a )-, -N(R a )-alkyl-, and (CH 2 CH 2 O) r -CH 2 R a is H or alkyl, and r is an integer ranging from 1 to 10.

[0287] In some embodiments, L 1’ is the expression:

[0288] [ka] (In the formula, R 5 is alkyl, -alkyl-O-, aryl, -N(R a )-Alkyl- or -(CH 2 CH 2 O) r -CH 2 - selected from R ais H or alkyl, and r is an integer ranging from 1 to 10. 5 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6 Alkyl)- or -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl, and r is an integer ranging from 1 to 10.

[0289] In some embodiments, L′ reacts with a cysteine ​​amino acid of the targeting moiety to form a thioether bond, and R 5 Ha-(C 2~6 alkyl)-O-, C 2~6 Alkyl is F, OH, O(C 1~6 alkyl), NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1~6 Optionally substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more F.

[0290] In certain embodiments, L′ reacts with a lysine amino acid of the targeting moiety to form an amide bond, and R 5 Ha-(C 2~6 alkyl)-O-, C 2~6 Alkyl is F, OH, O(C 1~6 alkyl), NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1~6 Optionally substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more F.

[0291] In some embodiments, j is 1 and k is 1. In some embodiments, j is 1 and L 2 contains 2 or 12 amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

[0292] In certain embodiments, L 2 is valine-citrulline. In some embodiments, k is 1 and L 3 includes para-aminobenzyl or para-aminobenzyloxycarbonyl.

[0293]

[0273] In certain embodiments, the formula:

[0294] [ka] (wherein AA1 and AA2 are independently selected from amino acid side chains, and p is an integer from 1 to 8). A linker-payload compound is provided having the following structure:

[0295] In certain embodiments, the amino acid side chains are independently H, -CH 3 , -CH 2 (C 6 H 5 ), -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , -CHCH(CH 3 )CH 3 , and -CH 2 CH 2 CH 2 NHC(O)NH 2 is selected from.

[0296]

[0275] In certain embodiments, the formula:

[0297] [ka] A linker-payload compound is provided having the following structure:

[0298]

[0276] In certain embodiments, the formula:

[0299] [ka] A linker-payload compound is provided having the following structure:

[0300]

[0277] In certain embodiments, the formula:

[0301] [ka] A linker-payload compound is provided having the following structure:

[0302]

[0278] In certain embodiments, the formula:

[0303] [ka] A linker-payload compound is provided having the following structure:

[0304]

[0279] In certain embodiments, the formula:

[0305] [ka] A linker-payload compound is provided having the following structure:

[0306]

[0280] In certain embodiments, the formula:

[0307] [ka] A linker-payload compound is provided having the following structure:

[0308]

[0281] In certain embodiments, the formula:

[0309] [ka] A linker-payload compound is provided having the following structure:

[0310]

[0282] In certain embodiments, the formula:

[0311] [ka] A linker-payload compound is provided having the following structure:

[0312] In some embodiments,

[0313] [ka]

[0314] [ka]

[0315] [ka] (In the formula, R ’’’ teeth,

[0316] [ka] R ’ and R ’’ are independently a bond, hydrogen, or methyl. There is provided a linker-payload compound having a formula selected from the group consisting of:

[0317] In some embodiments,

[0318] [ka]

[0319] [ka]

[0320] [ka]

[0321] [ka]

[0322] [ka]

[0323] [ka]

[0324] [ka]

[0325] [ka]

[0326] [ka]

[0327] [ka]

[0328] [ka]

[0329] [ka]

[0330] [ka]

[0331] [ka] or a pharma- ceutically acceptable salt thereof. Conjugate Compounds In another embodiment, a compound of formula (I): A-(LD) p (I) (In the formula, A is a targeting moiety, L is a linker, p is an integer from 1 to 8; D is of formula (II):

[0332] [ka] is the payload unit, X is -O-, -S-, -NH-, -(CH 2 ) i -, -(X 1 )NC(O)-, -(X 1 )NS(O) 2 -, -C(O)N(X 1 )- and -S(O) 2 N(X 1 )-, -NH- and -(CH 2 ) i- is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; Ring A is cycloalkyl, heterocyclyl, aryl or heteroaryl; W is a direct bond, alkyl, cycloalkyl, heterocyclyl, * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 -alkyl-, selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, and * -W 1 -alkyl-, * -Alkyl-W 1 - and * -Alkyl-W 1 The alkyl in -alkyl is halogen, hydroxyl, cyano, amino, alkyl, and -C(O)OR. a and W is optionally substituted with one or more groups independently selected from * The end is connected to ring A, W 1 -O-, -NR a -, -C(O)-, -C(O)NR a -, -NR a C(O)- or -NR a C(O)NR a - and Each R a are independently hydrogen, alkyl, or haloalkyl; R 1 is hydrogen, -N(R b ) 2 , hydroxyl or SH; Each R b are independently hydrogen, alkyl, or haloalkyl; The Two R's b together with the nitrogen atom to which they are attached form a heterocyclyl, R 2is hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR e , -OC(O)R e , -SR e , -B(OH) 2 , -NO 2 , -CHO, -C(=NOR e )(R e ), -R 2-1 -N(R e ) 2 , -R 2-1 -N(R e )C(O)R e , -R 2-1 -N(R e )S(O) 2 R e , -R 2-1 -N(R e )P(O) 2 R e , -R 2-1 -C(O)OR e , -R 2-1 -C(O)N(R e ) 2 , -R 2-1 -S(O) 2 N(R e ) 2 , -R 2-1 -P(O) 2 N(R e ) 2 , -OC(O)NR e or -NC(O)NR e and Each R 2-1 is independently absent or alkyl; Each R e are independently hydrogen, alkyl, or haloalkyl; Y is -Y 1 -Y 2 -Y 3 and Y 1 is a direct bond or -(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 1 of * Ends with Y 2 is connected to Y 2 is a direct bond or -(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and -(CH 2 ) s - and -(CH 2 ) t - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 of ** Ends with Y 3 is connected to Y 3 is hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R b ) 2 , -C(O)-alkyl, -C(O)-alkyl-N(R b ) 2 , and -S(O) 2 -alkyl, Q 1 and Q 2 are each independently selected from a direct bond, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl; R c is hydrogen or alkyl, or R c and Y 3together with the atom to which they are attached form a heterocyclyl optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl; Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, each of which is selected from one or more R d and is optionally replaced by R d is selected from the group consisting of halogen, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, and -O-cycloalkyl; i is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4 or 5; n is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3, 4 or 5) or a pharma- ceutically acceptable salt thereof.

[0333] In some embodiments, ring A is

[0334] [ka] is selected from the group consisting of:

[0335] In some embodiments, X is -O-, -NH-, or -(CH 2 ) i -, -NH- and -(CH 2 ) i - is optionally substituted with one or more halogen or alkyl.

[0336] In certain embodiments, X is -O-, -N(CH 3 )-, -CH 2 -, -(CH 2 ) 2 -, -(CH2 ) 3 -, -(CH 2 ) 4 -, -C(CH 3 ) 2 -or- CF 2 -It is.

[0337] In some embodiments, R 1 is hydrogen, -N(R b ) 2 Or hydroxyl. In some embodiments, W is a direct bond.

[0338] In certain embodiments, W is a direct bond and R 1 is hydrogen, N(R b ) 2 or hydroxyl, and each R b are independently hydrogen or alkyl, or two R b together with the nitrogen atom to which they are attached form a heterocyclyl.

[0339] In some embodiments, W is -C(O)OR a In certain embodiments, W is alkyl optionally substituted with -C(O)OR a Optionally replaced by C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 In certain embodiments, each W is -C(O)OR a In certain embodiments, R a is C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0340] In certain embodiments, W is -C(O)OR a is alkyl optionally substituted with R 1 is hydrogen, hydroxyl or -N(R b ) 2 And each R b are independently hydrogen or alkyl, or two R b taken together with the nitrogen atom to which they are attached form a heterocyclyl. In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is hydroxyl. In certain embodiments, R 1 -N(R b ) 2 And each R b are independently hydrogen, C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 In certain embodiments, R 1 -N(R b ) 2 And each R b is independently hydrogen or methyl. In certain embodiments, R 1 -N(R b ) 2 and two R b together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl, a 3- to 9-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 3- to 7-membered heterocyclyl, a 3- to 6-membered heterocyclyl, or a 3- to 5-membered heterocyclyl.

[0341] In some embodiments, W is * -W 1 In certain embodiments, W is * -W 1 -C 1~6 Alkyl-, * -W 1 -C 1~5 Alkyl-, * -W 1 -C1~4 Alkyl-, * -W 1 -C 1~3 Alkyl-, or * -W 1 -C 1~2 It is alkyl-.

[0342] In certain embodiments, W is * -W 1 -alkyl-, W 1 -O-, -NR a -, -C(O)NR a -, -OC(O)NR a -, -NR a C(O)-, -NR a C(O)O- or -NR a C(O)NR a - and each R a is independently hydrogen, alkyl, or haloalkyl.

[0343] In certain embodiments, W is * -W 1 -alkyl-, and R 1 is -NH 2 or -NH-CH 3 It is. In some embodiments, W is * -Alkyl-W 1 In certain embodiments, W is * -C 1~6 Alkyl-W 1 -, * -C 1~5 Alkyl-W 1 -, * -C 1~4 Alkyl-W 1 -, * -C 1~3 Alkyl-W 1 -,or * -C 1~2 Alkyl-W 1 -It is.

[0344] In certain embodiments, W is * -Alkyl-W1 - and W 1 is -C(O)-. In certain embodiments, W is * -Alkyl-W 1 - and W 1 is -C(O)- and R 1 Ha-NH 2 It is.

[0345] In some embodiments, W is * -Alkyl-W 1 In certain embodiments, W is -alkyl-. * -Alkyl-W 1 -alkyl-, each alkyl in W is independently selected from the group consisting of 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0346] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- or -OC(O)NR a - and R a is hydrogen, alkyl, or haloalkyl.

[0347] In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- and R 1 Ha-NH 2 It is. In certain embodiments, W is * -Alkyl-W 1 -alkyl-, W 1 -NR a C(O)- and R 1 is hydroxyl.

[0348] In an embodiment, W is * -Alkyl-W 1 -alkyl-, W 1 -OC(O)NR a - and R 1 -NH-CH 3 It is. In some embodiments, W is cycloalkyl. In certain embodiments, W is C 3~10 Cycloalkyl, C 3~9 Cycloalkyl, C 3~8 Cycloalkyl, C 3~7 Cycloalkyl, C 3~6 Cycloalkyl, or C 3~5 It is cycloalkyl.

[0349] In certain embodiments, W is cycloalkyl and R 1 Ha-NH 2 It is. In some embodiments, W is heterocyclyl. In certain embodiments, W is 3-10 membered heterocyclyl, 3-9 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, or 3-5 membered heterocyclyl.

[0350] In certain embodiments, W is heterocyclyl and R 1 is hydrogen. In some embodiments, R 2 is hydrogen, halogen, cyano, alkyl, or alkoxyl. In certain embodiments, R 2 is hydrogen.

[0351] In some embodiments, Y 1 is a direct bond. In certain embodiments, Y 1 is a direct bond, and Y 2 is a direct bond. In certain embodiments, Y 1 is a direct bond, and Y2 is a direct bond, and Y 3 is -alkyl-aryl.

[0352] In certain embodiments, Y 1 is a direct bond, and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** In certain embodiments, Q 2 is a direct bond, cycloalkyl, or aryl, where cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogen or alkyl. In certain embodiments, R c is hydrogen.

[0353] In certain embodiments, Y 1 is a direct bond, and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 3 is hydrogen, -alkyl-NH 2 , or -S(O) 2 In certain embodiments, -alkyl-NH 2 and -S(O) 2 The alkyl in -alkyl is independently selected from the group consisting of C 1~6 Alkyl, C 1~5 Alkyl, C 1~4 Alkyl, C 1~3 Alkyl, or C 1~2 It is an alkyl.

[0354] In some embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O-* and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl. In certain embodiments, Q 1 is a direct bond, cycloalkyl, or aryl, where cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogen or alkyl.

[0355] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, alkyl, or haloalkyl; Y 2 is a direct bond. In certain embodiments, -(CH2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0356] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 is a direct bond, and Y 3 is hydrogen. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n- is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0357] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y 2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** In certain embodiments, Q 2 is a direct bond. In certain embodiments, R c is hydrogen. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl.

[0358] In certain embodiments, Y 1 Ha-(CH 2 ) m -Q 1 -(CH 2 ) n -O- * and Y2 Ha-(CH 2 ) s -Q 2 -(CH 2 ) t -NR c - ** and Y 3 is hydrogen, -C(O)-alkyl or -C(O)-alkyl-N(R b ) 2 In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from alkyl or haloalkyl. In certain embodiments, -(CH 2 ) m - and -(CH 2 ) n - one or more C 1~6 Alkyl or C 1~6 In certain embodiments, the -(CH 2 ) m - and -(CH 2 ) n - is optionally substituted with one or more groups independently selected from methyl, ethyl, or trifluoromethyl. In certain embodiments, R c and Y 3 together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more halogens.

[0359] In some embodiments, Z is one or more R d In certain embodiments, Z is selected from the group consisting of alkyl, alkenyl, alkynyl, and heteroalkyl, optionally substituted with one or more R d Optionally replaced by C 1~6 Alkyl, C 1~6 Alkenyl, C 1~6 Alkynyl and C 1~6 heteroalkyl.

[0360] In certain embodiments, R d is selected from the group consisting of halogen, acyl, alkyl, cycloalkyl, and -O-cycloalkyl. d is halogen, acyl, C 1~6 Alkyl, C 3~6 Cycloalkyl and -OC 3~6 cycloalkyl.

[0361] In some embodiments, D has formula (IIa):

[0362] [ka] is the payload unit.

[0363]

[0323] In some embodiments, the payload unit comprises:

[0364] [ka]

[0365] [ka]

[0366] [ka]

[0367] [ka]

[0368] [ka]

[0369] [ka]

[0370] [ka]

[0371] [ka]

[0372] [ka]

[0373] [ka]

[0374] [ka]

[0375] [ka]

[0376] [ka]

[0377] [ka]

[0378] [ka] (wherein q is 1, 2 or 3);

[0379] [ka] (wherein q is 1, 2 or 3);

[0380] [ka]

[0381] [ka]

[0382] [ka]

[0383] [ka]

[0384] [ka]

[0385] [ka]

[0386] [ka]

[0387] [ka]

[0388] [ka]

[0389] [ka]

[0390] [ka]

[0391] [ka] is selected from the group consisting of:

[0392] In some embodiments, L has formula (III): -L 1 -(L 2 ) j -(L 3 ) k -(III) (In the formula, L 1 is a Stretcher unit covalently attached to a targeting moiety, L 2 is an optional peptide unit of 2 to 12 amino acid residues, L 3 is an optional spacer unit covalently attached to the payload unit, j and k are independently selected from 0 and 1. has.

[0393] In certain embodiments, L 1 teeth,

[0394] [ka] (In the formula, each R 3 are independently alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylheterocyclyl, heterocyclylalkyl, -alkyl-C(O)N(R a )-Alkyl-N(R a ), -N(R a )-alkyl-, and -(CH 2 CH 2 O) r -CH2 -, R a is H or alkyl, r is an integer ranging from 1 to 10, and v is an integer ranging from 0 to 5. is selected from the group consisting of:

[0395] In certain embodiments, each R 3 are independently 1~10 Alkyl, C 1~8 Heteroalkyl, C 3~8 Cycloalkyl, C 3~8 Heterocyclyl, aryl, heteroaryl, (C 1~10 Alkyl)aryl, aryl(C 1~10 Alkyl), (C 1~10 Alkyl)(C 3~8 Cycloalkyl), (C 3~8 Cycloalkyl)(C 1~10 Alkyl), (C 1~10 Alkyl)(C 3~8 Heterocyclyl), (C 3~8 Heterocyclyl)(C 1~10 alkyl), -(C 2~6 alkyl)-C(O)N(R a )-(C 2~6 Alkyl)-N(R a ), -N(R a )-(C 2~6 alkyl)-, and -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 It is an alkyl.

[0396] In certain embodiments, v is 1 and R 3 (CH 2 ) 5 It is.

[0328] In some embodiments, j is 0 and k is 0. In some embodiments, j is 0 and k is 1.

[0397] In some embodiments, L 1 is the expression:

[0398] [ka] (In the formula, R 4 is alkyl, -alkyl-O-, -N(R a )-Alkyl-N(R a )-, -N(R a )-alkyl-, and (CH 2 CH 2 O) r -CH 2 R a is H or alkyl, and r is an integer ranging from 1 to 10.

[0399] In certain embodiments, L 1 is the expression:

[0400] [ka] (In the formula, R 4 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6 Alkyl)-N(R a )-, -N(R a )-(C 2~6 alkyl)-, and -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl).

[0401] In some embodiments, L 1 is the expression:

[0402] [ka] (In the formula, R 5is alkyl, -alkyl-O-, aryl, -N(R a )-Alkyl- or -(CH 2 CH 2 O) r -CH 2 - selected from R a is H or alkyl, and r is an integer ranging from 1 to 10.

[0403] In certain embodiments, L 1 is the expression:

[0404] [ka] (In the formula, R 5 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6 Alkyl)- or -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl).

[0405] In certain embodiments, L 1 is the expression:

[0406] [ka] (In the formula, R 5 is C 1~10 Alkyl, -(C 1~10 Alkyl)-O-, -N(R a )-(C 2~6 Alkyl)- or -(CH 2 CH 2 O) r -CH 2 -, R a is H or C 1~6 alkyl).

[0407] In certain embodiments, L forms a thioether bond with a cysteine ​​amino acid of the targeting moiety, and L 1 is the expression:

[0408] [ka] R 5 Ha-(C 2~6 alkyl)-O-, C 2~6 Alkyl is F, OH, O(C 1~6 alkyl), NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1~6 Optionally substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more F.

[0409] In certain embodiments, L forms an amide bond with a lysine amino acid of the targeting moiety, and L 1 is the expression:

[0410] [ka] R 5 Ha-(C 2~6 alkyl)-O-, C 2~6 Alkyl is F, OH, O(C 1~6 alkyl), NH 2 , N.H.C.H. 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1~6 Optionally substituted with alkyl, C 1~6 The alkyl is optionally substituted with one or more F.

[0411] In some embodiments, j is 1 and k is 1. In some embodiments, j is 1 and L 2 contains 2 or 12 amino acid residues independently selected from glycine, alanine, phenylalanine, lysine, arginine, valine, and citrulline.

[0412] In certain embodiments, L 2 is valine-citrulline. In some embodiments, k is 1 and L 3 includes para-aminobenzyl or para-aminobenzyloxycarbonyl.

[0413]

[0341] In certain embodiments, the formula:

[0414] [ka] (wherein AA1 and AA2 are independently selected from amino acid side chains, and p is an integer from 1 to 8). A conjugate compound is provided having the following structure:

[0415] In certain embodiments, the amino acid side chains are independently H, -CH 3 , -CH 2 (C 6 H 5 ), -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NHC(NH)NH 2 , -CHCH(CH 3 )CH 3 , and -CH 2 CH 2 CH 2 NHC(O)NH 2 is selected from.

[0416]

[0343] In certain embodiments, the formula:

[0417] [ka] A conjugate compound is provided having the following structure:

[0418]

[0344] In certain embodiments, the formula:

[0419] [ka] A conjugate compound is provided having the following structure:

[0420]

[0345] In certain embodiments, the formula:

[0421] [ka] A conjugate compound is provided having the following structure:

[0422]

[0346] In certain embodiments, the formula:

[0423] [ka] A conjugate compound is provided having the following structure:

[0424]

[0347] In certain embodiments, the formula:

[0425] [ka] A conjugate compound is provided having the following structure:

[0426]

[0348] In certain embodiments, the formula:

[0427] [ka] A conjugate compound is provided having the following structure:

[0428]

[0349] In certain embodiments, the formula:

[0429] [ka] A conjugate compound is provided having the following structure:

[0430] In one particular embodiment,

[0431] [ka]

[0432] [ka]

[0433] [ka]

[0434] [ka] (In the formula, R is

[0435] [ka] R ’ and R ’’ wherein each of is independently hydrogen or methyl.

[0436] In one particular embodiment,

[0437] [ka]

[0438] [ka]

[0439]

change

[0440]

change

[0441]

change

[0442]

change

[0443]

change

[0444]

change

[0445]

change

[0446]

change

[0447]

change

[0448]

change

[0449] [ka]

[0450] [ka]

[0451] [ka] or a pharma- ceutically acceptable salt thereof.

[0452]

[0352] In some embodiments, the targeting moiety comprises an immunoglobulin, a protein, a peptide, a small molecule, a nanoparticle, or a nucleic acid.

[0353] In some embodiments, the targeting moiety comprises an antibody or an antigen-binding fragment thereof.

[0453] In certain embodiments, the antibody is selected from the group consisting of BMPR1B, B7-H4, E16, STEAP1, MUC16, MPF, Napi2b, Sema5b, PSCA The present invention binds to one or more tumor associated antigens or cell surface receptors selected from hlg, ETBR, MSG783, STEAP2, TrpM4, CRIPTO, CD21, CD79b, FcRH2, HER2, NCA, MDP, IL20Ra, brevican, EphB2R, ASLG659, PSCA, GEDA, BAFF-R, CD22, CD79a, CXCR5, HLA-DOB, P2X5, CD72, LY64, FcRHl, FcRH5, TENB2, PMEL17, TMEFF1, GDNF-Ral, Ly6E, TMEM46, Ly6G6D, LGR5, RET, LY6K, GPR19, GPR54, ASPHD1, tyrosinase, TMEM118, GPR172A, CD33, and CLL-1.

[0454]

[0355] In certain embodiments, the antibody binds to HER2 or B7-H4.

[0356] In certain embodiments, the antibody binds to HER2.

[0357] In certain embodiments, the antibody is trastuzumab.

[0455]

[0358] In another embodiment, the antigen-binding fragment is a Fab, Fab', F(ab')2, single domain antibody, T and Abs dimer, Fv, scFv, dsFv, ds-scFv, Fd, linear antibody, minibody, diabody, bispecific antibody fragment, bibody, tribody, sc-diabody, kappa (lambda) body, BiTE, DVD-Ig, SIP, SMIP, DART, polymer or aptamer.

[0456]

[0359] In some embodiments, the targeting moiety comprises a cell-interacting molecule.

[0360] In some embodiments, the targeting moiety comprises a ligand.

[0361] In some embodiments, the targeting moiety is capable of binding to a tumor antigen.

[0457] In certain embodiments, the targeting moiety is CD2, CD19, CD20, CD22, CD27, CD28, CD33, CD37, CD38, CD40, CD40L, CD44, CD47, CD52, CD56, CD70, CD79, CD86 / 80, CD113, CD122, CD137, CD155, CD160, CD206, 4-1BB, 5T4, AGS-5, AGS-16, Angiopoietin 2, B7.1, B7.2, B7DC, B7H1, B7H2, B7H3, BT-062, BTLA, CAIX, carcinoembryonic antigen, CTLA4, Cripto, ED-B, ErbBl, ErbB2, ErbB3, ErbB4, EGFL7, EpCAM, EphA2, EphA3, EphB2, FAP, fibronectin, folate receptor, ASGPR, ganglioside GM3, GD2, g pl00, gpA33, GPNMB, ICOS, IGF1R, integrin αν, integrin ανβ, KIR, LAG-3, Lewis Y, mesothelin, c-MET, RON, PRLR, MN carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NKGD2, NOTCH, OX40, OX40L, PD-1, PDL1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC4 4A4, syndecan-1, TACI, TAG-72, tenascin, TIM3, TREM-1, TREM-2, MACRO, Ly6E, TRAILR1, TRAILR2, VEGFR-1, VEGFR-2, VEGFR-3, FOLR1, TRPV6, FOLH1(PMSA), GNRHR, Trop2, NECTIN4, LRP1, GLUT1, EGFR1, AXL, CA9, claudin 18.2, CLDN6, APN, DLL3, DLL4, CEACAM5, FZD10, TFRC, MET, SSTR2, CCKBR, LFA1, ICAM, GPR87, GM-CSF, GM-CSFR, CSF -1R, TLR family, GITRL, GITR, 4-BBL, ICOSL, MHCII antigen, TCR, FLT3, c-KIT, CTLA-4, IGIT, galectin-9, HVEM, VISTA, B7 -H4, phosphatidylserine, HHLA2, galectin-3, LILRB2, LILRB3, LILRB4, SIGLEC15, CLEC5a, TIGIT, TfR, NKG2A, NKG2D, SLAMF7, KIR2DL1, KIR2DL2, KIR2DL3, FGFR1, FGFR2, FGFR4, NeuGcGM3, CXCR4 and variants thereof. Synthesis of conjugate compounds To form the conjugate compounds of the present disclosure, the linker can be first reacted with a payload compound to provide a linker-payload compound having one reactive group, which can then be reacted with a targeting moiety. Alternatively, one end of the linker can be first reacted with a targeting moiety to provide a targeting moiety having a linking moiety with one reactive group attached, which can then be reacted with a payload compound.

[0458] In some embodiments, the targeting moiety is an antibody. In some embodiments, the number of payload compounds attached per antibody molecule may be determined spectrophotometrically. In some embodiments, the average number of payload compounds linked per antibody molecule (DAR) is 2-12. In some embodiments, the DAR value is 2-10. In some embodiments, the DAR value is 2-8. In some embodiments, the DAR value is 2.5-4.0. In some embodiments, the DAR value is 4-8. In some embodiments, the DAR value is 5-8. In some embodiments, the DAR value is 6-8. In some embodiments, the DAR value is 6.5-8. In some embodiments, the DAR value is 7-8. In some embodiments, the DAR value is 7.1-8. In some embodiments, the DAR value is 7.2-8. In some embodiments, the DAR value is 7.3-8. In some embodiments, the DAR value is 7.4-8. In some embodiments, the DAR value is 7.5-8. In some embodiments, the DAR value is 7.6-8. In some embodiments, the DAR value is 7.7-8. In some embodiments, the DAR value is from 7.8 to 8. In some embodiments, the DAR value is from 7.9 to 8. Pharmaceutical Compositions

[0365] For purposes of administration, in some embodiments, the compounds provided herein are administered as the raw chemical or are formulated as pharmaceutical compositions.

[0459]

[0366] Thus, in a further aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds provided herein or pharma- ceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a compound selected from Formula (I), Formula (Ia), Formula (II'), Formula (IIa'), or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present disclosure comprise a first compound selected from Formula (I), Formula (Ia), Formula (II'), Formula (IIa'), or a pharma- ceutically acceptable salt thereof, and one or more additional compounds of the same formula, wherein the first compound and the additional compounds are not the same molecule.

[0460]

[0367] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. Pharmaceutical compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. Pharmaceutical compositions can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.

[0461]

[0368] In some embodiments, the pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of one or more compounds of the present disclosure or a pharma- ceutically acceptable salt thereof.

[0369] As used herein, the term "therapeutically effective amount" refers to an amount of a molecule, compound, or composition containing a molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the discretion of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0462]

[0370] In some embodiments, the pharmaceutical composition comprises one or more compounds of the present disclosure or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier or excipient.

[0463]

[0371] As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable, useful for preparing pharmaceutical compositions, including carriers acceptable for veterinary use and human pharmaceutical use. As used herein, "pharmaceutically acceptable carrier" includes both one and more than one such carrier. The term "pharmaceutically acceptable carrier" also encompasses "pharmaceutically acceptable excipients" and "pharmaceutically acceptable diluents." The particular carrier used in the pharmaceutical compositions of the present disclosure will depend on the means and purpose for which the compounds of the present disclosure are being applied.

[0464]

[0372] The pharma- ceutically acceptable carrier used may be, for example, solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs, and solutions, while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are the preferred oral dosage units where solid pharmaceutical carriers are used because of their ease of administration. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0465]

[0373] Tablets containing the pharmaceutical composition of the present disclosure may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, formulations intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active ingredient, mixed with a suitable and convenient amount of carrier material, which may vary from about 0.05 to about 95 percent of the total composition.

[0466]

[0374] The pharmaceutical composition of the present disclosure suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. A suitable surfactant, such as hydroxypropylcellulose, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, a preservative can be included to prevent the harmful growth of microorganisms.

[0467]

[0375] The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage, and thus should preferably be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0468]

[0376] The pharmaceutical compositions of the present disclosure may be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, dusting powder, and the like. Additionally, the compositions may be in a form suitable for use in transdermal devices. These formulations may be prepared by conventional processing methods utilizing the compound represented by formula I of this invention or a pharma- ceutically acceptable salt thereof. For example, a cream or ointment may be prepared by mixing a hydrophilic material and water together with about 0.05 wt% to about 10 wt% of the compound to create a cream or ointment having a desired viscosity.

[0469]

[0377] The pharmaceutical composition of the present disclosure may be in a form suitable for rectal administration, in which the carrier is a solid. Preferably, the mixture forms unit-dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may be conveniently formed by first mixing the composition with the softened or melted carrier, followed by chilling and shaping in molds.

[0470] In addition to the aforementioned carrier components, the pharmaceutical compositions may optionally include one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). Additionally, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. The compositions containing the compounds provided herein or pharma-ceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.

[0471] In some embodiments, the pharmaceutical composition of the present disclosure can be formulated as a unit dosage form. The term "unit dosage form" refers to a physically separate unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, together with a suitable pharmaceutical carrier. The amount of the compound provided herein in a unit dosage form varies depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of the individual subject), the specific route of administration, the actual compound to be administered and its relative activity, and the severity of the subject's symptoms.

[0472]

[0380] In some embodiments, for oral administration, each dosage unit contains from about 0.01 mg to about 2000 mg of one or more compounds provided herein, e.g., from about 0.01 mg to about 1000 mg, from about 0.02 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 2 mg to about 1000 mg, from about 3 mg to about 1000 mg, from about 4 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 50 0 mg to about 1000 mg, about 1 mg to 500 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg , about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg or about 1000 mg.

[0473] In some embodiments, for parenteral administration, each dosage unit contains from about 0.1 mg to about 100 mg of one or more compounds provided herein, e.g., from about 0.5 mg to about 100 mg, from about 1 mg to about 100 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 20 mg to about 100 mg, from about 30 mg to about 100 mg, from about 40 mg to about 100 mg, from about 50 mg to about 100 mg, from about 60 mg to about 100 mg, from about 70 mg to about 100 mg, from about 80 mg to about 100 mg, from about 90 mg to about 100 mg, from about 100 mg to about 100 mg, from about 150 mg to about 150 mg, from about 100 mg to about 150 mg, from about 150 mg to about 10 ... mg to about 100 mg, about 0.5 mg to about 90 mg, about 0.5 mg to about 80 mg, about 0.5 mg to about 70 mg, about 0.5 mg to about 60 mg, about 0.5 mg to about 50 mg, about 0.5 mg to about 40 mg, about 1 mg to about 90 mg, about 5 mg to about 90 mg, about 10 mg to about 80 mg, about 20 mg to about 70 mg, about 30 mg to about 60 mg, or about 40 mg to about 50 mg.

[0474]

[0382] In some embodiments, the dosage level of the pharmaceutical composition of the present disclosure is between 0.001-1000 mg / kg body weight / day, e.g., 0.01-900 mg / kg body weight / day, 0.01-800 mg / kg body weight / day, 0.01-700 mg / kg body weight / day, 0.01-600 mg / kg body weight / day, 0.01-500 mg / kg body weight / day, 0.01-400 mg / kg body weight / day, 0.01-300 mg / kg body weight / day, 0.05-900 mg / kg body weight / day, 0.0 It may be 5-800 mg / kg body weight / day, 0.05-700 mg / kg body weight / day, 0.05-600 mg / kg body weight / day, 0.05-500 mg / kg body weight / day, 0.1-200 mg / kg body weight / day, 0.1-150 mg / kg body weight / day, 0.1-100 mg / kg body weight / day, 0.5-100 mg / kg body weight / day, 0.5-80 mg / kg body weight / day, 0.5-60 mg / kg body weight / day, 0.5-50 mg / kg body weight / day, or 1-50 mg / kg body weight / day. In some cases, dosage levels below the lower limits of the aforementioned ranges may be more than sufficient, while in other cases even larger doses may be used without causing adverse side effects, provided that such larger doses are initially divided into several smaller doses for administration throughout the day. For further information regarding routes of administration and dosage regimes, see Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, specifically incorporated herein by reference.

[0475] In some embodiments, the pharmaceutical compositions of the present disclosure comprising one or more compounds provided herein or pharma- ceutically acceptable salts thereof further comprise one or more additional therapeutically active agents. Examples of additional therapeutically active agents include, but are not limited to, antiviral agents, chemotherapeutic agents, radiation, antitumor vaccines, antiviral vaccines, cytokine therapy, tyrosine kinase inhibitors, or immuno-oncology agents. Immuno-oncology agents include, but are not limited to, small molecule drugs, antibodies, or other biomolecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the immuno-oncology agent can be an antagonist of a protein that inhibits T cell and / or NK cell activation. In some embodiments, the antibody is a monoclonal antibody. Methods for Treating Disease

[0384] In one aspect, a method is provided for preventing or treating a disease mediated by toll-like receptors 7 and / or 8 in a subject in need of such prevention or treatment, the method comprising administering a therapeutically effective amount of a compound or a pharma- ceutical acceptable salt thereof.

[0476]

[0385] As used herein, the term "treatment" or "treating" refers to the management and care of a patient with the goal of reversing, suppressing, or working to eradicate a disease, condition, or disorder. As used herein, the term "prophylaxis" refers to measures taken to maintain health and prevent the spread of a disease, condition, or disorder.

[0477]

[0386] In some embodiments, the disease mediated by toll-like receptors 7 and / or 8 is cancer.

[0387] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell proliferation. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumor, gastrinoma, and pancreatic islet cell carcinoma), mesothelioma, Schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous cell carcinoma of the lung, cancer of the peritoneal cavity, hepatocellular carcinoma, gastric cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, neuroblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, testicular cancer, esophageal cancer, tumors of the biliary tract, and head and neck cancer.

[0478]

[0388] In certain embodiments, the cancer is selected from breast cancer, bladder cancer, head and neck cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, gastrointestinal stromal, gastroesophageal cancer, renal cell carcinoma, prostate cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, lymphoma, cutaneous T-cell lymphoma, visceral tumors or melanoma.

[0479]

[0389] In some embodiments, the disease mediated by toll-like receptors 7 and / or 8 is a viral infection. As used herein, the term "viral infection" includes, but is not limited to, diseases caused by RNA viruses, DNA viruses, Hepatitis A, Hepatitis B (HBV), Hepatitis C (HCV), Hepatitis D (HDV), Human Immunodeficiency Virus (HIV), Human Papillomavirus (HPV), Respiratory Syncytial Virus (RSV), Severe Acute Respiratory Syndrome (SARS), influenza, parainfluenza, cytomegalovirus, dengue, Herpes Simplex Virus 1, Herpes Simplex Virus 2, Coxsackie (CV), Coronavirus, Epstein-Barr Virus (EBV), Encephalomyocarditis (EMCV), Influenza A (IAV), Measles (MV), Sendai (SV), Vesicular Stomatitis (VSV) Virus, Leishmania infection and Respiratory Syncytial Virus. In certain embodiments, viral infections include diseases caused by, for example, Hepatitis A, Hepatitis B (HBV), Hepatitis D (HDV), HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV), severe acute respiratory syndrome (SARS), influenza, parainfluenza, cytomegalovirus, dengue, herpes simplex virus 1, herpes simplex virus 2, coxsackie (CV), encephalomyocarditis (EMCV), influenza A (IAV), measles (MV), Sendai (SV), vesicular stomatitis (VSV) virus, Leishmania infection, and respiratory syncytial virus.

[0480]

[0391] In certain embodiments, the viral infection is from a virus selected from the group consisting of Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human Immunodeficiency Virus (HIV), Human Papillomavirus (HPV), Coxsackie (CV), Coronavirus, Epstein-Barr Virus (EBV), Encephalomyocarditis (EMCV), Influenza A (IAV), Measles (MV), Sendai (SV), or Vesicular Stomatitis (VSV) virus.

[0481] In some embodiments, the subject may not have previously undergone antiviral treatment (treatment naive). In some embodiments, the subject may have previously undergone antiviral treatment (treatment experienced). In some embodiments, the subject may have previously undergone antiviral treatment and developed resistance to the previously undergone antiviral treatment.

[0482] In some embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or pharmaceutical composition may be administered as the only active agent. In some embodiments, the compound of the present disclosure or its pharma- ceutically acceptable salt or pharmaceutical composition may be administered in combination with one or more additional active ingredients. Those skilled in the art will recognize that various active ingredients may be combined with the compound of the present disclosure. In some embodiments, the additional active ingredients of the pharmaceutical combination formulation or dosing regimen have complementary activities to the compound of the present disclosure so as not to adversely affect each other. Such ingredients are suitably present in combination in amounts effective for the intended purpose.

[0483] In some such embodiments, the compounds provided herein or pharma- ceutically acceptable salts thereof, or the pharmaceutical compositions provided herein, may be used in combination with additional treatments, which may optionally include one or more therapeutic agents, radiation therapy, surgery (e.g., lumpectomy and mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplant, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing.

[0484]

[0395] In some embodiments, a compound provided herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein may be administered simultaneously, sequentially or separately with one or more additional therapeutic agents.

[0485]

[0396] In some embodiments, a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein may be administered to a subject with a therapeutically effective amount of an antiviral agent, a chemotherapeutic agent, radiation, an antitumor vaccine, an antiviral vaccine, a cytokine therapy, and a tyrosine kinase inhibitor prior to, concomitantly with, or following administration of the compound.

[0486]

[0397] In a further aspect, there is provided the use of a compound provided herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein, in the manufacture of a method for treating a viral infection or cancer.

[0487]

[0398] In another aspect, there is provided a method for activating toll-like receptors 7 and / or 8 in a subject in need of activation of toll-like receptors 7 and / or 8, the method comprising administering a compound provided herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0488] The term "agonist" refers to a substance that stimulates its binding partner, typically a receptor. Stimulation may be defined in the context of a particular assay or may be apparent in the literature from a discussion of this specification comparing factors or substances recognized as "agonists" of a particular binding partner under substantially similar circumstances as would be understood by one of skill in the art. Stimulation may be defined in terms of a particular effect or increase in function induced by the interaction of an agonist or partial agonist with a binding partner and may include allosteric effects. "Activating toll-like receptors 7 and / or 8" refers to an increase in TLR7 and / or 8 activity compared to the activity of that enzyme in the absence of a compound of the present disclosure. In some embodiments, such an increase in TLR7 and / or 8 and / or TLR7 and / or 8 variant activity may be a direct or indirect response to the presence of a compound provided herein compared to TLR7 and / or 8 activity in the absence of a compound provided herein. In some embodiments, stimulation of TLR7 and / or 8 activity can be compared in the same subject prior to treatment, or in other subjects not receiving treatment.

[0489]

[0400] In some embodiments, the compounds provided herein or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions provided herein may be utilized to inhibit, block, reduce, or decrease TLR7 and / or 8 activation for reducing tumor growth and modulating dysregulated immune responses, e.g., to prevent immunosuppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy.

[0490]

[0401] In a further aspect, there is provided a method for stimulating an immune response in a subject in need thereof, the method comprising administering a compound provided herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein. EXAMPLES

[0491] For illustrative purposes, the following examples are included. The examples provided herein describe the synthesis of compounds disclosed herein and intermediates used to prepare the compounds. However, it should be understood that these examples do not limit the disclosure and are only intended to suggest a method of practicing the disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare some other compounds of the disclosure, and that alternative methods for preparing compounds of the disclosure are considered to be within the scope of the disclosure. For example, the synthesis of non-exemplified compounds according to the disclosure can be successfully performed by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and components known in the art other than those described, and / or by making routine modifications of reaction conditions. Furthermore, those skilled in the art will also understand that the individual steps described herein or in separate batches of compounds can be combined. Alternatively, other reactions disclosed herein or known in the art will be recognized to have applicability for preparing other compounds of the disclosure. Therefore, the following description is not intended to limit the scope of the disclosure, which is rather defined by the appended claims.

[0492]

[0403] The following abbreviations are used in the examples:

[0493] [Table 2-1]

[0494] [Table 2-2] Example 1 Preparation of 7-bromo-2,4-dichloro-3-nitroquinoline (int-6)

[0495] [ka] Step 1: Preparation of methyl 2-acetamido-4-bromobenzoate To a suspension of methyl 2-amino-4-bromobenzoate (600 g, 2.6 mol) in toluene (6000 mL) was added acetic anhydride (399.2 g, 3.9 mol) at room temperature. The mixture was heated at 80° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and the remaining solid was triturated with PE / EtOAc (4400 mL, 10 / 1) and dried in vacuo to give methyl 2-acetamido-4-bromobenzoate (600 g, 84.8% yield) as a white solid.

[0496]

[0405] C 10 H 10 BrNO 3 LCMS (ESI) calculated value [M+H] + m / z=273.1, actual value 273.0. Step 2: Preparation of 7-bromo-4-hydroxyquinolin-2(1H)-one To a solution of potassium bis(trimethylsilyl)amide in THF (1M, 6.6 L, 6.6 mol) was slowly added a suspension of methyl 2-acetamido-4-bromobenzoate (600 g, 2.2 mol) in excess dry THF (6 L) at −78° C. under nitrogen atmosphere. After stirring at this temperature for 1 h, the mixture was warmed to 10° C. within 1 h. LCMS showed the reaction was complete. The reaction mixture was quenched with water (36 L). The aqueous layer was washed with EtOAc (12 L×2). The separated aqueous layer was cooled to 10° C. and the pH was adjusted to 2.5-3.5 by addition of 5N aqueous HCl to give a yellow precipitate. The solid was collected by filtration, washed with EtOAc (12 L), and evaporated to dryness in vacuo to give 7-bromo-4-hydroxyquinolin-2(1H)-one (400 g, 75.8%) as an off-white solid.

[0497]

[0407] C 9 H 6 BrNO 2 LCMS (ESI) calculated value [M+H] + m / z=240.0, actual value 240.0. Step 3: 7-Bromo-4-hydroxy-3-nitroquinolin-2(1H)-one A suspension of 7-bromoquinoline-2,4-diol (400 g, 1.67 mol) and 70% nitric acid (225 mL, 2.5 mol) in acetic acid (4000 mL) was heated at 60° C. for 2 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with ice water (1000 mL), and evaporated to dryness in vacuo to give 7-bromo-4-hydroxy-3-nitroquinolin-2(1H)-one (350 g, 73.5%) as a yellow solid.

[0498]

[0409] C 9 H 5 BrN 2 O 4 LCMS (ESI) calculated value [M+H] + m / z=284.9, actual value 285.0. Step 4: 7-Bromo-2,4-dichloro-3-nitroquinoline (Int6)

[0410] 7-Bromo-4-hydroxy-3-nitroquinolin-2(1H)-one (350 g, 1.23 mol) of POCl 3 To the solution in (2800 mL) was added TEA (149 g, 1.48 mol) at 0° C. The mixture was heated to reflux for 3 h. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was poured into ice water and extracted with DCM (1000 mL×3). The combined organic phase was washed with brine and added Na 2 SO 4 The mixture was dried at rt, concentrated, and purified by silica gel column chromatography (eluted with EtOAc / PE, 0% to 1%) to give 7-bromo-2,4-dichloro-3-nitroquinoline (300 g, 75.7% yield) as a yellow solid.

[0499]

[0411] 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 8.47 (d, J = 1.9 Hz, 1 H), 8.27 (d, J = 9.0 Hz, 1 H), 8.13 (dd, J = 9.0, 1.9 Hz, 1 H). Example 2 Preparation of 7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (11A)

[0500] [ka] Step 1: 7-Bromo-4-chloro-3-nitroquinolin-2-amine

[0412] NH of 7-bromo-2,4-dichloro-3-nitroquinoline (50 g, 156.25 mmol) 3 The solution in MeOH (100 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (35 g, 74.1% yield) as a yellow solid.

[0501]

[0413] C 9 H 5 BrN 3 O 2 LCMS (ESI) calculated value [M+H] + m / z=301.9, actual value 302. Step 2: 7-Bromo-4-chloroquinoline-2,3-diamine To a solution of 7-bromo-4-chloro-3-nitroquinolin-2-amine (35 g, 115.89 mmol) in AcOH (200 mL) was added Fe (64.9 g, 1.158 mol) at 0° C. The reaction mixture was stirred at room temperature for 10 h. LCMS showed the reaction was complete. It was diluted with DCM, the solution was filtered through Celite, and the filtrate was concentrated to give the crude product. The residue was purified by silica gel column chromatography (PE:EA 1:1) to give the title compound (25 g, 79.3% yield) as a yellow solid.

[0502]

[0415] C 9 H 7 BrClN 3 LCMS (ESI) calculated value [M+H] + m / z=271.9, actual value 272. Step 3: N-(2-amino-7-bromo-4-chloroquinolin-3-yl)-2-ethoxyacetamide To a solution of 7-bromo-4-chloroquinoline-2,3-diamine (25 g, 91.73 mmol) and TEA (27.85 g, 275.20 mmol) in DCM (200 mL) was added 2-ethoxyacetyl chloride (16.86 g, 137.60 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction was diluted with water and extracted with DCM (200 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (28 g, yield 85.2%) as a yellow solid.

[0503]

[0417] C 13 H 13 BrClN 3 O 2 LCMS (ESI) calculated value [M+H] + m / z=358.0, actual value 358. Step 4: 7-Bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (11A)

[0418] N-(2-amino-7-bromo-4-chloroquinolin-3-yl)-2-ethoxyacetamide (28 g, 78.2 mmol) NH 3 The solution in MeOH (60 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (21 g, 83.6% yield) as a yellow solid.

[0504]

[0419] C 13 H 13 BrN 4 LCMS (ESI) calculated value for O [M+H] + m / z=321.0, actual value 321. Example 3 Preparation of 7-bromo-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (11B)

[0505] [ka] Step 1: Preparation of 7-bromo-4-chloro-3-nitroquinolin-2-amine 7-Bromo-2,4-dichloro-3-nitroquinoline (20 g, 0.062 mol) NH 3 The solution in MeOH (40 mL) was stirred at 50° C. for 8 h in a high pressure reactor. LCMS showed the reaction was complete. The resulting mixture was cooled to room temperature and concentrated to give the crude title compound without purification.

[0506]

[0421] C 9 H 5 BrClN 3 O 2 LCMS (ESI) calculated value [M+H] + m / z=301.9, actual value 302. Step 2: Preparation of 7-bromo-4-chloroquinoline-2,3-diamine To a solution of 7-bromo-4-chloro-3-nitroquinolin-2-amine (16 g, 0.053 mol) in AcOH (200 mL) was added Fe (29.6 g, 0.53 mol) at room temperature. The mixture was stirred at room temperature for 6 h. LCMS showed the reaction was complete. It was diluted with DCM and the solution was filtered through Celite. The filtrate was concentrated in vacuo to give the crude product. The residue was diluted with water (100 mL) and extracted with EA (100 mL). The organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by Combi-Flash (PE:EA=1:5) to give 7-bromo-4-chloroquinoline-2,3-diamine (10 g, 69.38% yield) as a yellow solid.

[0507]

[0423] C 9 H 7 BrClN3 LCMS (ESI) calculated value [M+H] + m / z=271.9, actual value 272. Step 3: Preparation of N-(2-amino-7-bromo-4-chloroquinolin-3-yl)-2-methylpentanamide

[0424] 7-Bromo-4-chloroquinoline-2,3-diamine (10 g, 36.7 mmol) and Et 3 To a solution of N (5.58 g, 55.1 mmol) in DCM (20 mL) was added dropwise 2-methylpentanoyl chloride (5.4 g, 40.4 mmol) at 0° C. Then the mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3). The organic phase was washed with brine and Na 2 SO 4 The residue was purified by Combi-Flash (PE:EA=1:1) to give N-(2-amino-7-bromo-4-chloroquinolin-3-yl)-2-methylpentanamide (10 g, 73.52% yield) as a yellow solid.

[0508]

[0425] C 15 H 17 BrClN 3 LCMS (ESI) calculated value for O [M+H] + m / z=370.1, actual value 370. Step 4: Preparation of 7-bromo-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (11B)

[0426] N-(2-amino-7-bromo-4-chloroquinolin-3-yl)-2-methylpentanamide (10 g, 0.027 mol) NH 3 The solution in MeOH (30 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was washed with PE:EA (1:1) to give 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (8 g, 88.9% yield) as a yellow solid.

[0509]

[0427] C 15 H 17 BrN 4 LCMS (ESI) calculated value [M+H] + m / z=333.1, actual value 333.

[0428] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.75 (s, 1H), 7.43 - 7.29 (m, 5H), 3.19 - 3.07 (m, 1H), 1.91 - 1.79 (m, 1H), 1.72 - 1.60 (m, 1H), 1.39 (d, J = 7.0 Hz, 3H), 1.33 - 1.17 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). Example 4 Preparation of di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (13A)

[0510] [ka] Step 1: Preparation of 1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-ol

[0429] 7-Bromo-2,4-dichloro-3-nitroquinoline (30 g, 93.2 mmol) and Et 3 To a solution of N (14.15 g, 139.8 mmol) in DCM (100 mL) was added dropwise 1-amino-2-methylpropan-2-ol (9.14 g, 102.5 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with DCM (60 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product.

[0511]

[0430] C13 H 13 BrClN 3 O 3 LCMS (ESI) calculated value [M+H] + m / z=374.4, actual value 374. Step 2: Preparation of 1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-ol To a solution of 1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-ol (32 g, 0.086 mol) in AcOH (260 mL) was added Fe (48 g, 0.86 mol) at room temperature. The mixture was stirred at room temperature for 6 h. LCMS showed the reaction was complete. It was diluted with DCM and the solution was filtered through Celite. The filtrate was concentrated in vacuo to give the crude product. The residue was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 3:1) to give the title compound (20 g, yield 67.96%) as a yellow solid.

[0512]

[0432] C 13 H 15 BrClN 3 LCMS (ESI) calculated value for O [M+H] + m / z=344.3, actual value 344. Step 3: Preparation of N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)-2-ethoxyacetamide

[0433] 1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-ol (20 g, 58.0 mmol) and Et 3To a solution of N (8.8 g, 86.9 mmol) in DCM (40 mL) was added dropwise 2-ethoxyacetyl chloride (7.8 g, 63.9 mmol) at 0° C. Then the mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with DCM (60 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 1:3) to give the title compound (18 g, yield 71.96%) as a yellow solid.

[0513]

[0434] C 17 H 21 BrClN 3 O 3 LCMS (ESI) calculated value [M+H] + m / z=430.1, actual value 430. Step 4: Preparation of 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0435] N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)-2-ethoxyacetamide (18 g, 0.042 mol) NH 3 The solution in MeOH (50 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the resulting mixture was concentrated in vacuo. The residue was washed with PE:EA (1:1) to give 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (16 g, 97.28% yield) as a yellow solid.

[0514]

[0436] C 17 H 21 BrN 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=393.1, actual value 393. Step 5: Preparation of di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (13A)

[0437] A solution of 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (16 g, 0.041 mol) and DMAP (2 g, 0.016 mol) in MeCN (80 mL) was treated with Boc at 75 °C. 2 O (62.18 g, 0.28 mmol) was added. The mixture was stirred at 75° C. for 4 h. The resulting mixture was diluted with water (80 mL) and extracted with EA (100 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (18 g, yield 63.79%) as a yellow solid.

[0515]

[0438] C 32 H 45 BrN 4 O 8 LCMS (ESI) calculated value [M+H] + m / z=693.2, actual value 693.

[0439] 1 H NMR (400 MHz, DMSO) δ 8.60 (d, J = 9.1 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 9.1, 2.1 Hz, 1H), 3.57 (q, J = 7.0 Hz, 2H), 1.99 (s, 2H), 1.56 - 1.35 (m, 5H), 1.28 (s, 18H), 1.21 (s, 9H), 1.19 - 1.12 (m, 6H). Example 5 Preparation of di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (13B)

[0516] [ka] Step 1: Preparation of 1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-ol To a solution of 7-bromo-2,4-dichloro-3-nitroquinoline (50 g, 155.31 mmol) in DCM (500 mL) was added TEA (47.15 g, 465.93 mmol) and 1-amino-2-methylpropan-2-ol (13.84 g, 155.31 mmol) at room temperature. The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction was diluted with DCM, washed with brine and water, and diluted with Na 2 SO 4 The mixture was dried at rt and concentrated in vacuo to give the crude product without purification.

[0517]

[0441] C 13 H 13 BrClN 3 O 3 LCMS (ESI) calculated value [M+H] + m / z=374.4, actual value 374. Step 2: Preparation of 1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-ol (int8) To a solution of 1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-ol (50 g, 133 mmol) in AcOH (600 mL) was added Fe (74.8 g, 1.33 mol) at room temperature. The mixture was stirred at room temperature for 6 h. LCMS showed the reaction was complete. It was diluted with DCM and the solution was filtered through Celite. The filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography (DCM:MeOH 30:1) to give the title compound (35 g, 76.4%) as a white solid.

[0518]

[0443] C 13 H 15 BrClN 3 LCMS (ESI) calculated value for O [M+H] + m / z=344.3, actual value 344. Step 3: N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)-2-methylpentanamide To a solution of 1-[(3-amino-7-bromo-2-chloroquinolin-4-yl)amino-2-methylpropan-2-ol (35 g, 101.56 mmol) and TEA (30.83 g, 304.67 mmol) in DCM (250 mL) was added 2-methylpentanoyl chloride (20.50 g, 152.33 mmol) dropwise at 0° C. The mixture was then stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction was diluted with water and extracted with DCM (50 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at rt and concentrated to give the crude title compound (30 g, 67.2% yield) as a yellow solid.

[0519]

[0445] C 19 H 25 BrClN 3 O 2 LCMS (ESI) calculated value [M+H] + m / z=442.1, actual value 442. Step 4: 1-(4-amino-7-bromo-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0446] N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)-2-methylpentanamide (30 g, 67.8 mmol) NH 3 The solution in MeOH (100 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH 50:1) to give the title compound (18 g, 65.5% yield) as a yellow solid.

[0520]

[0447] C 19 H 25 BrN 4 LCMS (ESI) calculated value for O [M+H] + m / z=405.34, actual value 405. Step 5: Di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (13B)

[0448] To a solution of 1-(4-amino-7-bromo-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (18 g, 44.41 mmol) in ACN (150 mL) was added DMAP (2.17 g, 17.76 mmol) and Boc 2 O (96.92 g, 447.07 mmol) was added. The reaction mixture was stirred at 75° C. for 4 h. It was concentrated, diluted with water (200 mL) and extracted with EtOAc (150 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 25:1) to give the title compound (22 g, yield 70.26%) as a yellow solid.

[0521]

[0449] C 34 H 49 BrN 4 O 7 LCMS (ESI) calculated value [M+H] + m / z=705.6, actual value 705.3. Example 6 Preparation of di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (13C)

[0522] [ka] Step 1: Preparation of 1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-ol

[0450] 7-Bromo-2,4-dichloro-3-nitroquinoline (30 g, 93.2 mmol) and Et 3 To a solution of N (14.15 g, 139.8 mmol) in DCM (160 mL) was added dropwise 1-amino-2-methylpropan-2-ol (9.14 g, 102.5 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (100 mL) and extracted with DCM (60 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product.

[0523]

[0451] C 13 H 13 BrClN 3 O 3 LCMS (ESI) calculated value [M+H] + m / z=374.4, actual value 374. Step 2: Preparation of 1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-ol To a solution of 1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-ol (32 g, 0.086 mol) in AcOH (200 mL) was added Fe (48 g, 0.86 mol) at room temperature. The mixture was stirred at room temperature for 6 h. LCMS showed the reaction was complete. The resulting mixture was filtered and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by Combi-Flash (PE:EA 4:1) to give 1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-ol (20 g, 67.96% yield) as a yellow solid.

[0524]

[0453] C 13 H 15 BrClN 3 LCMS (ESI) calculated value for O [M+H] + m / z=344.3, actual value 344. Step 3: Preparation of N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)pentanamide

[0454] 1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-ol (20 g, 58.0 mmol) and Et 3 To a solution of N (8.8 g, 86.9 mmol) in DCM (40 mL) was added dropwise pentanoyl chloride (7.7 g, 63.9 mmol) at 0° C. The mixture was then stirred at room temperature for 3 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (100 mL) and extracted with DCM (100 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4The residue was purified by Combi-Flash (PE:EA 3:1) to give N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)pentanamide (18 g, 72.32% yield) as a yellow solid.

[0525]

[0455] C 18 H 23 BrClN 3 O 2 LCMS (ESI) calculated value [M+H] + m / z=428.1, actual value 428. Step 4: Preparation of 1-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0456] N-(7-bromo-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-3-yl)pentanamide (18 g, 0.042 mol) NH 3 The solution in MeOH (50 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the resulting mixture was concentrated in vacuo. The residue was washed with PE:EA (1:1) to give 1-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (16 g, 97.3% yield) as a yellow solid.

[0526]

[0457] C 18 H 23 BrN 4 LCMS (ESI) calculated value for O [M+H] + m / z=391.2, actual value 391. Step 5: Preparation of di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (13C)

[0458] A solution of 1-(4-amino-7-bromo-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (16 g, 0.041 mol) and DMAP (2 g, 0.016 mol) in MeCN (120 mL) was treated with Boc at 75 °C. 2 O (62.48 g, 0.286 mmol) was added. The mixture was stirred at 75° C. for 4 h. The resulting mixture was concentrated, then diluted with water (80 mL) and extracted with EA (100 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 5:1) to give di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (18 g, 63.59% yield) as a yellow solid.

[0527]

[0459] C 33 H 47 BrN 4 O 7 LCMS (ESI) calculated value [M+H] + m / z=691.4, actual value 691.

[0460] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (d, J = 9.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 9.1, 2.1 Hz, 1H), 3.02 (s, 2H), 1.90 - 1.79 (m, 2H), 1.52 - 1.41 (m, 4H), 1.38 (s, 3H), 1.29 (s, 21H), 1.21 (s, 9H), 0.94 (t, J = 7.4 Hz, 3H). Example 7 Synthesis of compound 6

[0528] [ka] Step 1: Preparation of di-tert-butyl (7-(4-methoxycarbonyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0461] Di-tert-butyl(7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (693 mg, 1 mmol), Pd(PPh 3 )Cl 2 To a solution of CuI (81 mg, 0.12 mmol) and CuI (43 mg, 0.23 mmol) in DMF (10 mL) was added a solution of (4-(methoxycarbonyl)benzyl)zinc(II) bromide in DMF (0.6 mmol / mL, 15 mL). The mixture was stirred at 50° C. for 1 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EA (40 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA=1:1) to give di-tert-butyl(7-(4-methoxycarbonyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (533 mg, 70% yield) as a yellow solid. Step 2: Preparation of 4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)benzoic acid To di-tert-butyl(7-(4-methoxycarbonyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (553 mg, 0.73 mmol) in MeOH (5 mL) was added 2N NaOH (3 mL). The mixture was stirred at 50° C. for 2 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (20 mL) and extracted with EA (10 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA:HCOOH=1:1:0.01) to give 4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)benzoic acid (519 mg, yield 95%). Step 3: Preparation of di-tert-butyl (7-(4-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate To a solution of 4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)benzoic acid (374 mg, 0.5 mmol), HOBT (81 mg, 0.6 mmol) and DIPEA (130 mg, 1 mmol) in DMF (5 mL) was added EDCI (114 mg, 0.6 mmol) at 0° C. The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The resulting mixture was diluted with water (20 mL) and extracted with EA (10 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4The residue was purified by silica gel column chromatography (PE:EA=1:1) to give di-tert-butyl(7-(4-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (294 mg, 66%). Step 4: Preparation of 4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)-N-(2-aminoethyl)benzamide (compound 6) To a solution of di-tert-butyl(7-(4-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (294 mg, 0.33 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0° C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was adjusted to pH=8 with saturated sodium bicarbonate in water. The resulting mixture was diluted with water (10 mL) and extracted with EA (10 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give 4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)-N-(2-aminoethyl)benzamide (150 mg, 94% yield).

[0529]

[0465] C 27 H 34 N 6 O 3 LCMS (ESI) calculated value [M+H] + m / z=491.3, actual value 491.

[0466] 1H NMR (400 MHz, DMSO-d 6 ) δ 8.49 - 8.27 (m, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.85 - 7.70 (m, 2H), 7.38 (dd, J = 11.2, 4.9 Hz, 3H), 7.06 (d, J = 8.5 Hz, 1H), 6.77 (s, 1H), 6.49 (s, 2H), 4.86 (s, 2H), 4.62 (s, 2H), 4.09 (s, 2H), 3.49 (q, J = 7.0 Hz, 2H), 3.29 - 3.21 (m, 4H), 3.09 (q, J = 6.1 Hz, 1H), 2.67 (t, J = 6.5 Hz, 1H), 1.12 (t, J = 7.0 Hz, 9H). Example 8 Synthesis of compound 7

[0530] [ka] Step 1: Preparation of di-tert-butyl (7-(4-nitro)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0467] Di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (693 mg, 1 mmol), Pd(PPh 3 )Cl 2 To a solution of (81 mg, 0.12 mmol) and CuI (43 mg, 0.23 mmol) in DMF (10 mL) was added a solution of (4-nitro-benzyl)zinc(II) bromide in DMF (15 mL). The mixture was stirred at 50° C. for 1 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EA (40 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4The residue was purified by silica gel column chromatography (PE:EA=1:1) to give di-tert-butyl(7-(4-nitro)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (555 mg, 75% yield) as a yellow solid. Step 2: Preparation of di-tert-butyl (7-(4-amino)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate To di-tert-butyl (7-(4-nitro)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (555 mg, 0.75 mmol) in MeOH (10 mL) was added Pd / C catalyst (20 mg). The reaction was fitted with a hydrogen balloon and stirred at room temperature for 8 h. LCMS showed the reaction to be complete. The resulting mixture was filtered and concentrated to give di-tert-butyl (7-(4-amino)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate without purification. Step 3: Di-tert-butyl (7-(4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)ureido)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate To a solution of di-tert-butyl (7-(4-amino)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (360 mg, 0.5 mmol), tert-butyl (2-aminoethyl)carbamate (96 mg, 0.6 mmol) and triethylamine (76 mg, 0.75 mmol) in DMF (5 mL) was added CDI (97 mg, 0.6 mmol) at 0° C. The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The resulting mixture was diluted with water (20 mL) and extracted with EA (10 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA=1:1) to give di-tert-butyl(7-(4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)ureido)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (288 mg, 64%). Step 4: Preparation of 1-(4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)-3-(2-aminoethyl)urea To a solution of di-tert-butyl(7-(4-(3-(2-((tert-butoxycarbonyl)amino)ethyl)ureido)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (288 mg, 0.32 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0° C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was adjusted to pH=8 with saturated sodium bicarbonate in water. The resulting mixture was diluted with water (10 mL) and extracted with EA (10 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give 1-(4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)-3-(2-aminoethyl)urea (155 mg, 96% yield).

[0531]

[0471] C 27 H 35 N 7 O 3 LCMS (ESI) calculated value [M+H] + m / z=506.3, actual value 506. Example 9 Synthesis of compounds 8, 9 and 10

[0532] [ka] Step 1: Preparation of di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-7-(4-(cyanomethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0472] Di-tert-butyl(7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (480 mg, 0.68 mmol), copper(I) iodide (50.52 mg, 0.26 mmol) and PdCl 2 (PPh 3 ) 2 To a solution of (50.13 mg, 0.0714 mmol) in DMF (4 mL) stirred at room temperature under nitrogen was added (4-(cyanomethyl)benzyl)zinc(II) bromide (4 mL). The mixture was then stirred at 50° C. for 30 min. The reaction was cooled to 5° C. for 30 min. 2 The mixture was quenched with O and extracted with EA. The combined organic phase was washed with brine and 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel column chromatography (PE:EA 10:1) to give the desired product (0.43 g, 79% yield) as a yellow solid.

[0533]

[0473] C 34 H 49 BrN 4 O 7 LCMS (ESI) calculated value [M+H] + m / z=756.43, actual value 756.55. Step 2: Preparation of di-tert-butyl (7-(4-(2-aminoethyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0474] NH of di-tert-butyl(7-(4-(2-aminoethyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (150 mg, 0.20 mmol) and Raney Ni (150 mg). 3A solution of -MeOH (5 mL) was stirred at room temperature under hydrogen. The reaction mixture was stirred at room temperature for 3 hours. The mixture was filtered through Celite and the filtrate was concentrated to give the crude product (0.15 g, 99% yield).

[0534]

[0475] C 43 H 61 N 5 O 7 LCMS (ESI) calculated value [M+H] + m / z=760.46, actual value 760.45. Step 3: Preparation of 1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 8) To a solution of di-tert-butyl(1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-7-(4-(cyanomethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (150 mg, 0.19 mmol) in DCM (5 mL) was added TFA (1.5 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-MeOH (0.05% NH 3 -H 2 O); concentration gradient: 25-60) to obtain compound 8 (79 mg, yield 84%) as a white solid.

[0535]

[0477] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.30, actual value 460.25.

[0478] 1HNMR (400 MHz, MeOD) δ 8.33 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.32 (dd, J = 8.7, 1.7 Hz, 1H), 7.16 (m, 4H), 4.49 (m, 2H), 4.05 (s, 2H), 3.49 - 3.39 (m, 1H), 3.10 - 3.01 (m, 2H), 2.87 - 2.78 (m, 2H), 1.96 - 0.97 (m, 13H), 0.89 - 0.75 (m, 3H). Step 4: Preparation of (R)-1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 9), (S)-1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 10)

[0479] 1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (20 mg) was subjected to SFC (apparatus: LC-30AD SFC; column: DAICEL AS-H 4.6 mml.D. x 250 mmL, 5 μm; mobile phase: CO 2 / MeOH(0.1%NH 3 )=80 / 20; flow rate: 2.0 ml / min; wavelength: UV 214 nm and 254 nm; temperature: 40° C.) to give compound 9 (4 mg, 99% purity) and compound 10 (2 mg, 99% purity). Compound 9:

[0480] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.30, actual value 460.25.

[0536]

[0481] 1 H NMR (400 MHz, DMSO-d 6) δ 8.15 (d, J = 8.6 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.04 (dd, J = 8.6, 1.8 Hz, 1H), 6.27 (s, 2H), 4.87 - 4.23 (m, 3H), 3.98 (s, 2H), 3.52 - 3.45 (m, 1H), 2.73 (t, J = 7.1 Hz, 2H), 2.59 (t, J = 7.2 Hz, 2H), 1.64 - 1.04 (m, 13H), 0.90 - 0.78 (m, 3H). Compound 10:

[0482] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.30, actual value 460.25.

[0537]

[0483] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d, J = 8.6 Hz, 1H), 7.38 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.04 (dd, J = 8.5, 1.7 Hz, 1H), 6.27 (s, 2H), 4.89 - 4.22 (m, 3H), 3.98 (s, 2H), 3.53 - 3.43 (m, 1H), 2.72 (t, J = 7.3 Hz, 2H), 2.58 (t, J = 7.2 Hz, 2H), 1.42 - 1.00 (m, 13H), 0.88 - 0.81 (m, 3H).

[0484] Compounds 1-5, 11-19 and 47 were prepared by the same method as described in Example 9 using the corresponding reagents. Compound 1:

[0538] [ka] 1-(4-amino-7-(4-(aminomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0486] C 25 H 31 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=434.2, actual value 434.0.

[0539]

[0487] 1 H NMR (400 MHz, CD 3 OD, ppm) δ 8.49 (bs, 2 H), 8.28 (d, J = 8.6 Hz, 1 H), 7.53 (s, 1 H), 7.42-7.35 (m, 4 H), 7.28 (d, J = 8.5 Hz, 1 H), 5.00 (bs, 2 H), 4.78 (s, 2 H), 4.15 (s, 2 H), 4.08 (s, 2 H), 3.62 (q, J = 6.9 Hz, 2 H), 1.27-1.22 (m, 9 H). Compound 2:

[0540] [ka] 1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0489] C 26 H 33 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=448.3, actual value 448.0.

[0541]

[0490] 1 H NMR (400 MHz, CD 3OD, ppm) δ 8.47 (s, 2 H), 8.35 (d, J = 8.6 Hz, 1 H), 7.57 (s, 1 H), 7.38 (d, J = 9.6 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.25 (d, J = 8.1 Hz, 2 H), 5.02 (s, 1 H), 4.81 (s, 2 H), 4.15 (s, 2 H), 3.64 (q, J = 7.0 Hz, 2 H), 3.24-3.13 (m, 2 H), 3.03-2.88 (m, 2 H), 1.29-1.24 (m, 9 H). Compound 3:

[0542] [ka] 1-(4-amino-7-(4-(3-aminopropyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0492] C 27 H 35 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=461.6, actual value 462.

[0543]

[0493] 1 H NMR (400 MHz, DMSO-d 6) δ 8.30 (s, 2H), 8.16 (d, J = 8.6 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.1 Hz, 2H), 7.07 (dd, J = 8.5, 1.8 Hz, 1H), 6.57 (s, 2H), 4.87 (s, 2H), 4.63 (s, 2H), 4.00 (s, 2H), 3.50 (q, J = 7.0 Hz, 3H), 2.83 - 2.70 (m, 2H), 2.60 (t, J = 7.7 Hz, 2H), 1.97 - 1.61 (m, 2H), 1.12 (t, J = 7.0 Hz, 8H). Compound 4:

[0544] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0495] C 25 H 31 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=434.3, actual value 434.

[0545]

[0496] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.85 (s, 1H), 8.83 (s, 2H), 8.39 (d, J = 8.5 Hz, 1H), 8.19 (s, 2 H), 7.57 (s, 1H), 7.44 - 7.28 (m, 5H), 4.93 (s, 2H), 4.69 (s, 2H), 4.14 (s, 2H), 4.01 (s, 2H), 3.54 (q, J = 7.0 Hz, 2H), 1.32 - 0.97 (m, 9H). Compound 5:

[0546] [ka] 1-(4-amino-7-(3-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0498] C 26 H 33 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=448.3, actual value 448.

[0547]

[0499] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 2H), 8.37 (d, J = 8.6 Hz, 1H), 7.91 (s, 2H), 7.53 (s, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 - 7.05 (m, 3H), 4.94 (s, 2H), 4.69 (s, 2H), 4.10 (s, 2H), 3.53 (q, J = 7.0 Hz, 2H), 3.07 - 3.00 (m, 2H), 2.89 - 2.79 (m, 2H), 1.31 - 1.05 (m, 9H). Compound 11:

[0548] [ka]

[0500] 1-(4-amino-7-(4-(3-aminopropyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0501] C 29 H 39 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=474.5, actual value 474.

[0549]

[0502] 1H NMR (400 MHz, DMSO-d 6 ) δ 13.65 (s, 1H), 8.79 (s, 2H), 8.42 (d, J = 8.7 Hz, 1H), 7.75 (s, 3H), 7.56 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.19 (m, 4H), 4.79 (s, 1H), 4.09 (s, 2H), 3.58 - 3.44 (m, 1H), 2.78 (m, 2H), 2.67 - 2.55 (m, 2H), 1.81 (m, 2H), 1.64 - 0.54 (m, 16H). Compound 12:

[0550] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0504] C 27 H 35 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=446.3, actual value 446.0.

[0551]

[0505] 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 13.46 (s, 1 H), 8.73 (s, 1 H), 8.42 (d, J = 8.5 Hz, 1 H), 8.14 (s, 3 H), 7.58 (s, 1 H), 7.48-7.27 (m, 5 H), 4.77 (s, 1 H), 4.14 (s, 2 H), 4.01 (s, 2 H), 3.49 (dd, J = 13.8, 7.0 Hz, 1 H), 2.01-0.60 (m, 16 H). Compound 13:

[0552] [ka] 1-(4-amino-7-(3-(2-aminoethyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0507] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.3, actual value 460.0.

[0553]

[0508] 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 8.34 (d, J = 8.1 Hz, 1 H), 7.80 (s, 2 H), 7.51 (s, 1 H), 7.28 (q, J = 7.8 Hz, 2 H), 7.15 (dd, J = 21.9, 8.0 Hz, 3 H), 4.76 (s, 1 H), 4.48 (s, 1 H), 4.08 (s, 2 H), 3.49 (dd, J = 13.7, 6.9 Hz, 1 H), 3.09-2.95 (m, 2 H), 2.90-2.73 (m, 2 H), 1.87-0.67 (m, 16 H). Compound 14:

[0554] [ka] 1-(4-amino-7-(3-(3-aminopropyl)benzyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0510] C 29 H 39 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=474.3, actual value 474.

[0555]

[0511] 1 H NMR (400 MHz, DMSO-d 6) δ 8.20 (d, J = 8.5 Hz, 1H), 8.15 (s, 1H), 7.66 (s, 2H), 7.41 (s, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.16 - 7.04 (m, 4H), 6.71 (s, 2H), 4.73 (s, 1H), 4.48 (s, 2H), 4.02 (s, 2H), 3.48 (dd, J = 13.8, 7.0 Hz, 2H), 2.87 - 2.73 (m, 2H), 2.67 - 2.54 (m, 2H), 1.83 - 1.76 (m, 2H), 1.61 (s, 2H), 1.42 - 1.13 (m, 10H), 0.85 (s, 3H). Compound 15:

[0556] [ka] 1-(4-amino-7-(4-(3-aminopropyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0513] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.3, actual value 460.

[0557]

[0514] 1 H NMR (400 MHz, DMSO-d 6) δ 8.29 (s, 1H), 7.64 (s, 2H), 7.48 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 4.78 (s, 1H), 4.05 (s, 2H), 3.02 (t, J = 7.6 Hz, 2H), 2.78 (s, 2H), 2.60 (t, J = 7.7 Hz, 2H), 1.80 (s, 4H), 1.42 (dd, J = 15.0, 7.7 Hz, 2H), 1.23 (s, 8H), 1.16 (s, 4H), 0.94 (t, J = 7.3 Hz, 3H). Compound 16:

[0558] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0516] C 26 H 33 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=432.3, actual value 432.

[0559]

[0517] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 - 8.14 (m, 2H), 7.45 - 7.29 (m, 5H), 7.09 (d, J = 8.5 Hz, 1H), 6.69 (s, 2H), 4.82 - 4.37 (m, 2H), 4.02 (d, J = 18.9 Hz, 4H), 3.39 (s, 2H), 3.04 - 2.89 (m, 2H), 1.83 - 1.69 (m, 2H), 1.44 - 1.36 (m, 2H), 1.15 (s, 6H), 0.93 (t, J = 7.4 Hz, 3H). Compound 17:

[0560] [ka] 1-(4-amino-7-(3-(2-aminoethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0519] C 27 H 35 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=446.3, actual value 446.0.

[0561]

[0520] 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 8.35 (d, J = 8.7 Hz, 1 H), 7.81 (s, 2 H), 7.52 (s, 1 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.15 (dd, J = 21.2, 8.0 Hz, 3 H), 4.79 (s, 1 H), 4.09 (s, 2 H), 3.17-2.94 (m, 4 H), 2.93-2.73 (m, 2 H), 1.95-1.69 (m, 2 H), 1.42 (dd, J = 14.9, 7.4 Hz, 2 H), 1.17 (s, 5 H), 0.94 (t, J = 7.4 Hz, 3 H). Compound 18:

[0562] [ka] 1-(4-amino-7-(3-(3-aminopropyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0522] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.3, actual value 460.

[0563]

[0523] 1H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.4 Hz, 2H), 7.06 (t, J = 7.7 Hz, 2H), 6.58 (s, 2H), 4.48 (s, 2H), 4.01 (s, 2H), 3.05 - 2.91 (m, 2H), 2.85 - 2.73 (m, 2H), 2.60 (t, J = 7.7 Hz, 2H), 1.79 (m, 4H), 1.49 - 1.30 (m, 2H), 1.15 (s, 6H), 0.93 (t, J = 7.4 Hz, 3H). Compound 19:

[0564] [ka] 1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0525] C 27 H 35 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=446.2, actual value 446.

[0565]

[0526] 1 H NMR (400 MHz, DMSO-d 6) δ 8.18 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 7.73 (s, 2H), 7.40 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 1H), 6.61 (s, 1H), 4.76 (s, 1H), 4.52 (s, 1H), 4.01 (s, 2H), 3.01 (dd, J = 14.4, 7.1 Hz, 4H), 2.90 - 2.73 (m, 2H), 1.87 - 1.69 (m, 2H), 1.50 - 1.35 (m, 2H), 0.99-1.34 (m, 9H). Compound 47:

[0566] [ka] 1-((4-amino-7-(4-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)methyl)cyclopropan-1-ol

[0528] C 26 H 31 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=446.5, actual value 446.

[0567]

[0529] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.08 (s, 1H), 8.07 - 7.68 (m, 4H), 7.60 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 19.7, 8.1 Hz, 4H), 5.74 (s, 2H), 4.77 (s, 2H), 4.11 (s, 2H), 3.38 (dd, J = 13.9, 6.9 Hz, 2H), 3.01 (s, 2H), 2.89 - 2.69 (m, 4H), 1.02 (q, J = 7.2 Hz, 6H). Example 10 Synthesis of compound 20

[0568] [ka] Step 1. Preparation of tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-butyl-7-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)carbamate To a solution of di-tert-butyl(7-(3-(aminomethyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (100 mg, 0.14 mmol) in THF (3 mL) was added NaH (11 mg, 0.27 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Dimethyl sulfate (17.2 mg, 0.14 mmol) was then added to the mixture and allowed to warm to room temperature overnight. LCMS showed TM. The resulting mixture was quenched with water (20 mL) and extracted with EA (20 mL×3). The combined organic phase was washed with brine and Na 2 SO 4 The residue was purified by Combi-Flash (PE:EA 1:1) to give the product (10 mg, 9.6% yield) as a yellow solid.

[0569]

[0531] C 39 H 52 N 4 O 8 LCMS (ESI) calculated value [M+H] + m / z=746.44, actual value 646. Step 2. Preparation of 1-(4-amino-2-butyl-7-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 20) To a solution of di-tert-butyl(1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-butyl-7-(3-((methylamino)methyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (10 mg, 0.015 mmol) in DCM (1 mL) was added TFA (0.3 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuum. The residue was purified by preparative HPLC (column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: ACN-H 2 The mixture was purified by 0 (0.1% FA, concentration gradient: 15 to 45) to obtain compound 20 (1.8 mg, yield 25%) as a white solid.

[0570]

[0533] C 27 H 35 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=446.28, actual value 446.

[0534] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.31-7.99 (m, 1H), 7.52-7.18 (m, 6H), 7.18 (s, 2H), 4.77 (s, 1H), 4.08 (s, 4H), 3.01 (m, 2H), 1.90-1.48 (m, 2H), 1.48 (m, 2H), 1.16 (s, 6H), 0.93 (t, J = 7.3 Hz, 3H).

[0535] Compounds 51-55 and 67-71 were prepared by the same methods as those described in Examples 6 and 9 using the corresponding reagents. The general scheme for preparing compounds 51-55 and 67-71 is shown below.

[0571] [ka] Compound 51:

[0572] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0537] C 26 H 31 F 3 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=486.25, actual value 486.15.

[0573]

[0538] 1 H NMR (400 MHz, MeOD, ppm) δ 8.43 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.40 (m, 5H), 4.67 (s, 2H), 4.23 (s, 2H), 4.11 (s, 2H), 3.19 (s, 2H), 2.54 - 2.39 (m, 2H), 2.32 - 2.16 (m, 2H), 1.31 (s, 6H). Compound 52:

[0574] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-(1,1-difluorobutyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0540] C 26 H 32 F 2 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=468.26, actual value 468.20.

[0575]

[0541] 1 H NMR (400 MHz, DMSO-d 6, ppm) δ 14.21 (s, 1H), 9.26 (s, 2H), 8.56 (d, J = 8.7 Hz, 1H), 8.23 ​​(s, 3H), 7.59 (s, 1H), 7.47- 7.03 (m, 5H), 4.98 (d, J = 15.3 Hz, 1H), 4.58 (d, J = 15.3 Hz, 1H), 4.28-3.87 (m, 4H), 2.58 (m, 2H), 1.68 - 1.39 (m, 2H), 1.28 (s, 3H), 1.01 (m, 6H). Compound 53:

[0576] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-((2,2,2-trifluoroethoxy)methyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0543] C 25 H 29 F 3 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=488.23, actual value 488.20.

[0577]

[0544] 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 13.68 (s, 1H), 8.98 (s, 1H), 8.43 (d, J = 8.6 Hz, 1H), 8.11 (s, 3H), 7.59 (s, 1H), 7.38 (m, 5H), 5.13 (s, 1H), 4.96 (s, 1H), 4.69 (s, 2H), 4.26 (q, J = 9.3 Hz, 2H), 4.19 - 4.08 (m, 2H), 4.01 (d, J = 5.1 Hz, 2H), 1.41-1.02 (m, 6H). Compound 54:

[0578] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-(cyclopropylmethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0546] C 26 H 31 N 5 LCMS (ESI) calculated value for O [M+H] + m / z 430.26, actual value 430.20.

[0579]

[0547] 1 H NMR (400 MHz, DMSO-d 6 , ppm) δ 8.23 ​​(s, 1 H), 8.16 (d, J = 8.6 Hz, 1 H), 7.44-7.26 (m, 5 H), 7.09 (d, J = 8.5 Hz, 1 H), 6.57 (s, 2 H), 4.52 (s, 2 H), 4.01 (d, J = 25.7 Hz, 4 H), 2.99 (s, 2 H), 1.40-0.71 (m, 7 H), 0.49 (d, J = 7.9 Hz, 2 H), 0.25 (d, J = 4.8 Hz, 2 H). Compound 55:

[0580] [ka] 1-(4-amino-7-(3-(aminomethyl)benzyl)-2-(cyclopropoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0549] C 26 H 32 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=446.26, actual value 446.20.

[0581]

[0550] 1H NMR (400 MHz, MeOD) δ 8.32 (d, J = 8.6 Hz, 1H), 7.53 (s, 1H), 7.39- 7.16 (m, 5H), 4.97 (s, 2H), 4.68 (s, 2H), 4.10 (s, 2H), 4.01 (s, 2H), 3.40-3.32 (m, 1H), 1.19 (s, 6H), 0.64 - 0.31 (m, 4H). Compound 67:

[0582] [ka] 1-(4-amino-7-(5-(aminomethyl)-2-fluorobenzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0552] C 26 H 32 FN 5 LCMS (ESI) calculated value for O [M+H] + m / z=450.3, actual value 450.3.

[0583]

[0553] 1 H NMR (400 MHz, DMSO-d6,ppm) δ 13.88 (s, 1H), 8.92 (s, 2H), 8.42 (d, J=8.7 Hz, 1H), 8.21 (s, 3H), 7.59 (s, 1H), 7.50 (dd, J=7.2, 2.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (dd, J=17.9, 8.4 Hz, 2H), 4.82 (s, 2H), 4.15 (s, 2H), 4.01 (s, 2H), 3.04 (t, J=7.7 Hz, 2H), 1.86-1.75 (m, 2H), 1.42 (dd, J=14.9, 7.4 Hz, 2H), 1.18 (s, 6H), 0.94 (t, J=7.4 Hz, 3H). Compound 68:

[0584] [ka] 1-(4-amino-7-(3-(aminomethyl)-4-fluorobenzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0555] C 26 H 32 FN 5 LCMS (ESI) calculated value for O [M+H] + m / z=450.3, actual value 450.2.

[0585]

[0556] 1 H NMR (400 MHz, DMSO-d6,ppm) δ 13.74 (s, 1H), 8.90 (s, 1H), 8.42 (d, J = 8.7Hz, 1H), 8.24 (s, 3H), 7.56 (s, 1H), 7.45 (dd, J=7.2, 2.0 Hz, 1H), 7.42-7.36 (m, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.31-7.23 (m, 1H), 4.82 (s, 2H), 4.12 (s, 2H), 4.05 (d, J=5.3 Hz, 2H), 3.04 (t, J=7.6Hz, 2H), 1.87-1.74 (m, 2H), 1.49-1.36 (m, 2H), 1.18 (s, 6H), 0.94 (t, J=7.4 Hz, 3H). Compound 69:

[0586] [ka] 1-(4-amino-7-((5-(aminomethyl)thiophen-2-yl)methyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0557] C 24 H 31 N 5 LCMS (ESI) calculated values ​​as OS [M+H] + m / z=438.22, measured value 438.3.

[0587]

[0558] 1 H NMR (400 MHz, DMSO-d6,ppm) δ 13.71 (s, 1H), 8.90 (s, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.16 (s, 3H), 7.63 (s, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.07 (d, J=3.4 Hz, 1H), 6.95 (d, J=3.5 Hz, 1H), 4.82 (s, 1H), 4.33 (s, 2H), 4.17 (d, J=5.0 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H), 1.88-1.75 (m, 2H), 1.43 (d, J=7.5 Hz, 2H), 1.19 (s, 6H), 0.95 (t, J=7.4 Hz, 3H). Compound 70:

[0588] [ka] 1-(4-amino-7-(4-(1-amino-2-methylpropan-2-yl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0560] C 29 H 39 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=474.3, actual value 474.3.

[0589]

[0561] 1H NMR (400 MHz, DMSO-d6, ppm) δ 13.79 (s, 1H), 8.91 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 7.67 (s, 3H), 7.59 (s, 1H), 7.37 (d, J = 8.3 Hz, 3H), 7.28 (d, J = 8.3 Hz, 2H), 4.82 (s, 1H), 4.11 (s, 2H), 3.04 (t, J = 6.9 Hz, 4H), 1.86 - 1.74 (m, 3H), 1.42 (dd, J = 14.9, 7.4 Hz, 2H), 1.32 (d, J = 8.1 Hz, 6H), 1.18 (s, 6H), 0.94 (t, J = 7.3 Hz, 3H). Compound 71 was prepared by a method similar to that described in Example 10 using the corresponding reagents. Compound 71:

[0590] [ka] 1-(4-amino-7-(2-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0564] C 26 H 33 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=432.3, actual value 432.2.

[0591]

[0565] 1H NMR (400 MHz, DMSO-d6, ppm) δ 14.05 (s, 1H), 9.02 (s, 2H), 8.45 (d, J = 8.7 Hz, 1H), 8.29 (s, 3H), 7.52 - 7.43 (m, 2H), 7.37 (dd, J = 5.5, 3.6 Hz, 2H), 7.23 (dd, J = 11.1, 7.4 Hz, 2H), 4.59 (d, J = 115.7 Hz, 2H), 4.29 (s, 2H), 4.02 (q, J = 5.4 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 1.91 - 1.73 (m, 2H), 1.43 (dd, J = 14.9, 7.4 Hz, 2H), 1.19 (s, 6H), 0.94 (t, J = 7.3 Hz, 3H). Example 11 Synthesis of compound 22

[0592] [ka] Step 1: Preparation of 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol To a solution of di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (5 g, 7.23 mmol) in DCM (30 mL) was added TFA (10 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was adjusted to pH=8 with saturated sodium bicarbonate in water. The resulting mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (3.6 g).

[0593]

[0568] C 17 H 21 BrN 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=393.1, actual value 393. Step 2: Preparation of 1-(7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0569] 1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (3.6 g, 9.15 mmol), TrtCl (3.8 g, 13.73 mmol) and Et 3 A mixture of N (2.3 g, 22.89 mmol) in MeCN (30 mL) was stirred in a microwave reactor with N 2 The mixture was heated at 100° C. for 0.5 h under an atmosphere of 0.1%. LCMS showed the reaction was complete. The resulting mixture was cooled to 0° C. with ice water. The precipitate was collected by filtration to give 1-(7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (0.6 g, 10.3% yield) as a white solid.

[0594]

[0570] C 36 H 35 BrN 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=635.2, actual value 635. Step 3: Preparation of 2-((1-(7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl hydrogen sulfate To a solution of NaH (190 mg, 4.75 mmol, 60%) in DMF (5 mL) was added 1-(7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (600 mg, 0.95 mmol) in DMF (8 mL). The mixture was stirred at room temperature for 1 h. Then 1,3,2-dioxathiolane 2,2-dioxide (350 mg, 2.84 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (30 mL) and extracted with EA (50 mL x 3). The combined organic phase was washed with brine and Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give a crude product. The residue was purified by silica gel column chromatography (PE:EA=1:1) to give 2-((1-(7-bromo-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl hydrogen sulfate (500 mg, yield 69.74%) as a yellow solid.

[0595]

[0572] C 38 H 39 BrN 4 O 6 LCMS (ESI) calculated value for S [M+H] + m / z=759.2, actual value 759. Step 4: Preparation of di-tert-butyl (7-bromo-1-(2-(2-((tert-butoxycarbonyl)oxy)ethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate 2-((1-(4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethan-1-ol (500 mg, 1.16 mmol), Pd(PPh 3 )Cl 2To a solution of (81 mg, 0.12 mmol) and CuI (43 mg, 0.23 mmol) in DMF (10 mL) was added a solution of (4-(cyanomethyl)benzyl)zinc(II) bromide in DMF (15 mL). The mixture was stirred at 50° C. for 1 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EA (40 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA=1:1) to give tert-butyl (2-((1-(7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)carbamate (550 mg, yield 57.35%) as a yellow solid.

[0596]

[0574] C 52 H 56 N 6 O 4 LCMS (ESI) calculated value [M+H] + m / z=829.4, actual value 829. Step 5: Preparation of 2-(4-((4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile To a solution of tert-butyl (2-((1-(7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)carbamate (200 mg, 0.24 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0° C. The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was adjusted to pH=8 with saturated sodium bicarbonate in water. The resulting mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4The mixture was dried at 40° C. and concentrated to give 2-(4-((4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (100 mg, 85.4% yield).

[0597]

[0576] C 28 H 34 N 6 O 2 LCMS (ESI) calculated value [M+H] + m / z=487.3, actual value 487. Step 6: Preparation of N-(2-((1-(4-amino-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)isobutyramide A solution of tert-butyl (2-((1-(7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)carbamate (80 mg, 0.164 mmol), isobutyric acid (10 mg, 0.12 mmol), HOBT (67 mg, 0.49 mmol), EDCI (95 mg, 0.49 mmol) and DIEA (106 mg, 0.82 mmol) in DMF (3 mL) was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EA (40 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give a crude product. The residue was purified by silica gel column chromatography (PE:EA 2:1) to give N-(2-((1-(4-amino-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)isobutyramide (30 mg, 32.78% yield) as a yellow solid.

[0598]

[0578] C 32H 40 N 6 O 3 LCMS (ESI) calculated value [M+H] + m / z=557.3, actual value 557. Step 7: Preparation of N-(2-((1-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)isobutyramide (compound 22)

[0579] N-(2-((1-(4-amino-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)isobutyramide (30 mg, 0.054 mmol) NH 3 To the solution in MeOH (3 mL) was added an appropriate amount of Raney Ni in MeOH. The mixture was cooled to 5°C. 2 The mixture was stirred at room temperature for 2 hours under reduced pressure. LCMS showed the reaction was complete. The mixture was then filtered through Celite and concentrated under vacuum to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: ACN-H 2 O(0.05%NH 3 ), concentration gradient: 10 to 40) to obtain compound 22 (4.25 mg, yield 14.07%) as a white solid.

[0599]

[0580] C 32 H 44 N 6 O 3 LCMS (ESI) calculated value [M+H] + m / z=561.4, actual value 561.

[0581] 1 H NMR (400 MHz, DMSO-d 6) δ 8.18 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.29 (t, J = 5.5 Hz, 1H), 7.15 (dd, J = 25.6, 7.9 Hz, 4H), 7.07 (dd, J = 8.4, 1.7 Hz, 1H), 6.49 (s, 2H), 4.71 (s, 2H), 4.00 (s, 2H), 3.49 (q, J = 7.0 Hz, 2H), 3.21 (t, J = 5.8 Hz, 2H), 3.00 (d, J = 5.7 Hz, 2H), 2.77 - 2.60 (m, 4H), 2.22 - 2.18(m, 1H), 1.28 - 1.03 (m, 9H), 0.92 (d, J = 6.8 Hz, 6H). Compound 21 was prepared by a method similar to that described in Example 11 using the corresponding reagents. Compound 21:

[0600] [ka]

[0583] C 32 H 45 N 7 O 3 LCMS (ESI) calculated value [M+H] + m / z=576.4, actual value 576.

[0601]

[0584] 1 H NMR (400 MHz, DMSO) δ 8.31 (d, J = 8.6 Hz, 1H), 7.49 (s, 1H), 7.20 (dd, J = 19.4, 8.2 Hz, 5H), 4.09 (s, 2H), 3.63 (q, J = 7.0 Hz, 2H), 3.37 (t, J = 5.4 Hz, 2H), 3.10 (s, 2H), 2.92 (t, J = 7.1 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H), 1.36 - 1.19 (m, 11H), 1.14 (s, 6H). Example 12 Synthesis of compound 23

[0602] [ka] Step 1: Preparation of di-tert-butyl (7-benzyl-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0585] Di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (500 mg, 0.72 mmol), Pd(PPh 3 )Cl 2 To a solution of (152 mg, 0.2159 mmol) and CuI (27 mg, 0.1440 mmol) in DMF (3 mL) was added a solution of benzylzinc(II) bromide in DMF (10 mL). The mixture was stirred at 50° C. for 0.5 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EA (40 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by Combi-Flash (PE:EA 1:2) to give di-tert-butyl (7-benzyl-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (500 mg, 98.42% yield) as a yellow solid.

[0603]

[0586] C 39 H 52 N 4 O 8 LCMS (ESI) calculated value [M+H] + m / z=705.4, actual value 705. Step 2: Preparation of 1-(4-amino-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol To a solution of di-tert-butyl (7-benzyl-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (500 mg, 0.71 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was adjusted to pH=8 with saturated sodium bicarbonate in water. The resulting mixture was extracted with EA (20 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 and concentrated to give the crude title compound.

[0604]

[0588] C 24 H 28 N 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=405.2, actual value 405. Step 3: Preparation of 1-(7-benzyl-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0589] 1-(4-amino-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (180 mg, 0.45 mmol), TrtCl (186 mg, 0.67 mmol) and Et 3 A mixture of N (112 mg, 1.11 mmol) in MeCN (4 mL) was stirred at 40° C. in a microwave reactor. 2The mixture was heated at 100° C. for 0.5 h under an atmosphere of 0.1%. LCMS showed the reaction was complete. The resulting mixture was cooled to 0° C. with ice water. The precipitate was collected by filtration to give 1-(7-benzyl-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (210 mg, 72.97% yield) as a white solid.

[0605]

[0590] C 43 H 42 N 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=467.3, actual value 467. Step 4: Preparation of (2-((1-(7-benzyl-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(tert-butoxycarbonyl)sulfamic acid To a solution of NaH (65 mg, 60% in oil) in DMF (3 mL) was added dropwise a solution of 1-(7-benzyl-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (210 mg, 0.325 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1 h. Then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (217 mg, 0.97 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting mixture was quenched with water (30 mL) and extracted with EA (50 mL x 3). The combined organic phase was washed with brine and Na 2 SO 4After drying at 40° C. and concentration, the crude title compound was obtained. The residue was purified by Combi-Flash (PE:EA 1:2) to give (2-((1-(7-benzyl-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(tert-butoxycarbonyl)sulfamic acid (120 mg, 42.48% yield) as a yellow solid.

[0606]

[0592] C 50 H 55 N 5 O 7 LCMS (ESI) calculated value for S [M+H] + m / z=870.4, actual value 870. Step 5: Preparation of 1-(2-(2-aminoethoxy)-2-methylpropyl)-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 23) To a solution of (2-((1-(7-benzyl-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(tert-butoxycarbonyl)sulfamic acid (120 mg, 0.15 mmol) in DCM (4 mL) was added TFA (1.5 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction was concentrated and purified by preparative HPLC (column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: ACN-H 2 O(0.05%NH 3 ), concentration gradient: 10 to 40) to obtain compound 23 (23 mg, yield 33.88%) as a white solid.

[0607]

[0594] C 26 H 33 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=448.3, actual value 448.

[0595] 1H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.33 - 7.26 (m, 4H), 7.22 - 7.18 (m, 1H), 7.07 (dd, J = 8.5, 1.8 Hz, 1H), 6.49 (s, 2H), 4.72 (s, 4H), 4.04 (s, 2H), 3.50 (q, J = 7.0 Hz, 2H), 3.16 (t, J = 5.7 Hz, 2H), 2.45 (t, J = 5.7 Hz, 2H), 1.89 (s, 2H), 1.15 (s, 3H), 1.12 (t, J = 7.0 Hz, 6H).

[0596] Compounds 28 to 31 were prepared in a similar manner to that described in Example 11 using the corresponding reagents. Compound 28:

[0608] [ka]

[0597] C 28 H 37 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=460.3, actual value 460.0.

[0609]

[0598] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41-8.04 (m, 2 H), 7.39 (s, 1 H), 7.34-7.24 (m, 5 H), 7.23-7.15 (m, 1 H), 7.07 (dd, J = 8.5, 1.7 Hz, 1 H), 6.33 (s, 2 H), 4.50 (s, 1 H), 4.04 (s, 2 H), 3.45 (d, J = 6.4 Hz, 2 H), 2.61 (s, 2 H), 1.70-0.73 (m, 18 H). Compounds 29 and 30:

[0610] [ka] (S)-1-(2-(2-aminoethoxy)-2-methylpropyl)-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 29) and (R)-1-(2-(2-aminoethoxy)-2-methylpropyl)-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 30). Racemic 1-(2-(2-aminoethoxy)-2-methylpropyl)-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (Compound 28, 50 mg, 0.11 mmol) was subjected to SFC (Apparatus: LC-30AD SFC; Column: DAICEL AS-H 4.6 mml.D. × 250 mmL, 5 μm; Mobile phase: CO 2 / MeOH(0.1%NH 3 )=75 / 25; flow rate: 2.0 ml / min; wavelengths: UV 214 nm and 254 nm; temperature: 40° C.) to give (S)-1-(2-(2-aminoethoxy)-2-methylpropyl)-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 29, 10 mg, 99% purity) and (R)-1-(2-(2-aminoethoxy)-2-methylpropyl)-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 30, 8 mg, 99% purity). Compound 31:

[0611] [ka]

[0600] C 27 H 35 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=446.3, actual value 446.

[0612]

[0601] 1 H NMR (400 MHz, DMSO-d 6) δ 8.26 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.33 - 7.25 (m, 4H), 7.24 - 7.16 (m, 1H), 7.08 (dd, J = 8.5, 1.7 Hz, 1H), 6.49 (s, 2H), 4.62 (s, 2H), 4.04 (s, 2H), 3.40 - 3.28 (m, 3H), 3.02 - 2.89 (m, 2H), 2.66 (t, J = 5.5 Hz, 2H), 1.81 - 1.74 (m, 2H), 1.41 (m, 2H), 1.16 (s, 6H), 0.94 (t, J = 7.4 Hz, 3H). Compound 44 was prepared by a method similar to that described in Example 12 using the corresponding reagents. Compound 44:

[0613] [ka]

[0603] C 26 H 32 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=446.26, actual value 446.

[0614]

[0604] 1 H NMR (400 MHz, DMSO-d 6) δ 8.26 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 7.33 - 7.25 (m, 4H), 7.24 - 7.16 (m, 1H), 7.08 (dd, J = 8.5, 1.7 Hz, 1H), 6.49 (s, 2H), 4.62 (s, 2H), 4.04 (s, 2H), 3.40 - 3.28 (m, 3H), 3.02 - 2.89 (m, 2H), 2.66 (t, J = 5.5 Hz, 2H), 1.81 - 1.74 (m, 2H), 1.41 (m, 2H), 1.16 (s, 6H), 0.94 (t, J = 7.4 Hz, 3H). Example 13 Synthesis of compound 24

[0615] [ka] Step 1: Di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0605] Di-tert-butyl(7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (400 mg, 0.57 mmol), PdCl 2 (PPh 3 ) 2 (81 mg, 0.12 mmol) and copper(I) iodide (33 mg, 0.17 mmol) were added to a solution of 2 (4-(cyanomethyl)benzyl)zinc(II) bromide (4 mL, 2 M) was added dropwise. The reaction mixture was stirred at 50° C. for 1 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4The mixture was dried at 400° C., concentrated, and purified by silica gel column chromatography (PE:EA 3:1) to give the title compound (400 mg, yield 83.9%) as a white solid.

[0616]

[0606] C 41 H 53 N 5 O 8 LCMS (ESI) calculated value [M+H] + m / z=744.4, actual value 744. Step 2: Di-tert-butyl (7-(4-(2-aminoethyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0607] Di-tert-butyl(1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (400 mg, 0.54 mmol) NH 3 -MeOH (10 mL) solution was added Raney Ni in MeOH. The reaction mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The resulting mixture was filtered through Celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA 3:1) to give the title compound (350 mg, 87% yield) as a white solid.

[0617]

[0608] C 41 H 57 N 5 O 8 LCMS (ESI) calculated value [M+H] + m / z=748.4, actual value 748. Step 3: Di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate To a solution of di-tert-butyl(7-(4-(2-aminoethyl)benzyl)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (350 mg, 0.4679 mmol) and formaldehyde (3 mL, 33%) in MeOH (10 mL) stirred at 0° C. was added sodium cyanoborohydride (58 mg, 0.93 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the crude product. The residue was purified by flash chromatography (MeOH:DCM 20:1) to give the title compound (300 mg, 82.6% yield) as a white oil.

[0618]

[0610] C 43 H 61 N 5 O 8 LCMS (ESI) calculated value [M+H] + m / z=776.4, actual value 776. Step 4: 1-(4-amino-7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol To a solution of di-tert-butyl(1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (300 mg, 0.38 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The resulting mixture was diluted with NaHCO 3 Adjusted to Ph=8 with aqueous solution and extracted with EA (50mL×3). The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA 1:1) to give the title compound (160mg, 86.9% yield) as a white solid.

[0619]

[0612] C 28 H 37 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=476.2, actual value 476. Step 5: 1-(7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol A solution of 1-(4-amino-7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (160 mg, 0.34 mmol), triphenylmethyl chloride (113 mg, 0.4036 mmol) and TEA (86 mg, 0.841 mmol) in MeCN (6 mL) was stirred at 100° C. for 30 min in a microwave reactor. The mixture was concentrated and purified by combi-flash (PE:EA 2:1) to give the title compound (120 mg, 44.7% yield) as a white solid.

[0620]

[0614] C 47 H 51 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=718.4, actual value 718. Step 6: (tert-butoxycarbonyl)(2-((1-(7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)sulfamic acid 1-(7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (120 mg, 0.1671 mmol) was added to a solution of NaH (6 mg, 0.25 mmol, 60%) in DMF (5 mL) at 0° C. The reaction mixture was then warmed to room temperature and stirred for 30 min. tert-Butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (56 mg, 0.25 mmol) was then added to the mixture at 0° C. The temperature was allowed to warm to room temperature and stirred for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine and Na 2 SO 4 The crude product was purified by silica gel column chromatography (PE:EA 1:1) to give the title compound (45 mg, yield 28.1%) as a white solid.

[0621]

[0616] C 54 H 64 N 6 O 7 LCMS (ESI) calculated value for S [M+H] + m / z=941.4, actual value 941. Step 7: 1-(2-(2-aminoethoxy)-2-methylpropyl)-7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 24) To a solution of (tert-butoxycarbonyl)(2-((1-(7-(4-(2-(dimethylamino)ethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)sulfamic acid (45 mg, 0.05 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-H2 O (0.1% FA); concentration gradient: 5–10–30) to give compound 24 (5.79 mg, yield 21.2%) as a white solid.

[0622]

[0618] C 30 H 42 N 6 O 2 LCMS (ESI) calculated value [M+H] + m / z=519.3, actual value 519.

[0619] 1 H-NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.32 (s, 4H), 4.96 (s, 2H), 4.81 (s, 4H), 4.16 (s, 2H), 3.73 - 3.49 (m, 6H), 3.31 - 3.26 (m, 2H), 3.24 (s, 6H), 3.14 (m, 2H), 1.27 (m, 9H). Example 14 Synthesis of compound 25

[0623] [ka] Step 1: Preparation of ethyl 2-(4-((4-(bis(tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetate

[0620] Di-tert-butyl (7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (1.5 g, 2.2 mmol), CuI (0.08 g, 0.4 mmol) and PdCl 2 (PPh 3 ) 2To a stirred solution of (0.15 g, 0.2 mmol) in DMF (8 mL), 2 A solution of bromo({[4-(2-ethoxy-2-oxoethyl)phenyl]methyl})zinc (1.06 g, 3.3 mmol) in DMF (8 mL) was added under an atmosphere of 0.05%. The reaction mixture was heated at 50° C. for 2 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL×3). The organic phase was washed with brine and diluted with Na 2 SO 4 The extract was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EtOAc=1 / 1) to give ethyl 2-(4-((4-(bis(tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetate (1.26 g, 72.4% yield) as a yellow solid.

[0624]

[0621] C 43 H 58 N 4 O 10 LCMS (ESI) calculated value [M+H] + m / z=791.4, actual value 791.0. Step 2: Preparation of di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-hydroxyethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0622] LiAlH 4To a suspension of (90 mg, 2.4 mmol) in THF (5 mL) was added dropwise a solution of ethyl 2-(4-((4-(bis(tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetate (1.26 g, 1.6 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The mixture was poured into ice water (15 mL) and extracted with EA (20 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The extract was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EtOAc=1 / 2) to give di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-hydroxyethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (600 mg, 50.1% yield) as a yellow solid.

[0625]

[0623] C 41 H 56 N 4 O 9 LCMS (ESI) calculated value [M+H] + m / z=749.4, actual value 749.0. Step 3: Preparation of 4-((4-(bis(tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenethyl methanesulfonate

[0624] Di-tert-butyl(1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-hydroxyethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (600 mg, 0.8 mmol), Et 3To a stirred solution of N (161.6 mg, 1.6 mmol) in DCM (5 mL) was added dropwise a solution of methanesulfonic anhydride (417.6 mg, 2.4 mmol) in DCM (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The organic phase was washed with Na 2 SO 4 Drying at 400 rpm and concentration afforded crude 4-((4-(bis(tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenethyl methanesulfonate (600 mg), which was used in the next reaction without further purification.

[0626]

[0625] C 42 H 58 N 4 O 11 LCMS (ESI) calculated value for S [M+H] + m / z=827.4, actual value 827.0. Step 4: Preparation of di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate A mixture of 4-((4-(bis(tert-butoxycarbonyl)amino)-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenethyl methanesulfonate (500 mg, 0.60 mmol) in pyrrolidine (5 mL) was stirred at room temperature for 8 h. The resulting mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The organic phase was washed with Na 2 SO 4The extract was dried at 400° C., concentrated, and purified by column chromatography on silica gel (DCM / MeOH=50 / 1) to give di-tert-butyl (1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (400 mg, 83.1% yield) as a yellow solid.

[0627]

[0627] C 45 H 63 N 5 O 8 LCMS (ESI) calculated value [M+H] + m / z=802.5, actual value 802.0. Step 5: Preparation of 1-(4-amino-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0628] To a solution of di-tert-butyl(1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (400 mg, 0.5 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was diluted with EtOAc (20 mL) and washed with saturated NaHCO 3 The pH was adjusted to 7-8 with aqueous NaCl. The organic phase was washed with brine and 2 SO 4 Drying at 40° C. and concentration afforded 1-(4-amino-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (200 mg) as a colorless oil, which was used in the next reaction without further purification.

[0628]

[0629] C 30 H39 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=501.3, actual value 501.0. Step 6: Preparation of 1-(2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0630] 1-(4-amino-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (200 mg, 0.4 mmol), TrtCl (166.8 mg, 0.6 mmol) and Et 3 A mixture of N (101 mg, 1 mmol) in MeCN (2 mL) was heated at 100° C. for 30 min in a microwave reactor. LCMS showed the reaction was complete. The resulting mixture was concentrated and purified by silica gel column chromatography (DCM / MeOH=100 / 1) to give 1-(2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (100 mg, 33.6% yield) as a yellow solid.

[0629]

[0631] C 49 H 53 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=744.4, actual value 744.0. Step 7: Preparation of tert-butyl (2-((1-(4-amino-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(trioxidanylsulfonyl)carbamate

[0632] To a stirred suspension of NaH (9.68 mg, 0.40 mmol) in DMF (3 mL) at 0° C., a solution of 1-(2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol in DMF (3 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. Then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (90.01 mg, 0.4 mmol) was added at 0° C. The reaction mixture was stirred at 25° C. for 12 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL×3). The organic phase was washed with brine and Na 2 SO 4 The extract was dried at 40° C., concentrated, and purified by column chromatography on silica gel (DCM / MeOH=50 / 1) to give tert-butyl (2-((1-(4-amino-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(trioxidanylsulfonyl)carbamate (50 mg, 50.8%) as a white solid.

[0630]

[0633] C 37 H 52 N 6 O 9 LCMS (ESI) calculated value for S [M+H] + m / z=757.4, actual value 757.0. Step 8: Preparation of 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 25)

[0634] To a solution of tert-butyl (2-((1-(4-amino-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(trioxidanylsulfonyl)carbamate (50 mg, 0.05 mmol) in DCM (1 mL) at 0° C., TFA (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and purified by preparative HPLC (column: Gemini-C 18 , 150×21.2mm, 5um; Mobile phase: ACN-H 2 Purification by 0 (0.1% FA), concentration gradient: 10% to 40% gave 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-7-(4-(2-(pyrrolidin-1-yl)ethyl)benzyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 25, 4 mg, yield 14.7%) as a white solid.

[0631]

[0635] C 32 H 44 N 6 O 2 LCMS (ESI) calculated value [M+H] + m / z=545.4, actual value 545.0.

[0636] 1 H NMR (400 MHz, CD 3 OD, ppm) δ 8.40 (d, J = 8.6 Hz, 1 H), 7.57 (s, 1 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.32 (q, J = 8.4 Hz, 4 H), 5.01 (s, 2 H), 4.82 (s, 2 H), 4.17 (s, 2 H), 3.85-3.54 (m, 10 H), 3.37 (s, 2 H), 3.15 (dd, J = 10.1, 6.8 Hz, 2 H), 2.26 (s, 4 H), 1.30 (s, 6 H), 1.26 (t, J = 7.0 Hz, 3 H). Example 15 Synthesis of compound 26

[0632] [ka] Step 1: Preparation of 2-(4-((4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile

[0637] To a solution of tert-butyl (2-((1-(7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)carbamate (200 mg, 0.24 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The mixture was purified by tetrahydrofuran (NaHCO 3 The solution was adjusted to pH=8 with 10 mL of DCM. The solution was extracted with DCM (20 mL×3). The organic phase was washed with brine and added with Na 2 SO 4 The residue was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EA=1 / 2) to give 2-(4-((4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (80 mg, yield 85.3%).

[0633]

[0638] C 28 H 34 N 6 O 2 LCMS (ESI) calculated value [M+H] + m / z=487.3, actual value 487. Step 2: Preparation of 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-methyl-2-(2-(pyrrolidin-1-yl)ethoxy)propyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile

[0639] To a solution of 2-(4-((4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (100 mg, 0.20 mmol), succinaldehyde (35.35 mg, 0.4 mmol) in MeOH (10 ml) was added NaBH 3 CN (25.83 mg, 0.41 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. LCMS showed a TM peak. It was concentrated and purified by column chromatography on silica gel (DCM:MeOH 20:1) to give 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-methyl-2-(2-(pyrrolidin-1-yl)ethoxy)propyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (35 mg, 31.4% yield).

[0634]

[0640] C 32 H 40 N 6 O 2 LCMS (ESI) calculated value [M+H] + m / z=541.5, actual value 541. Step 3: Preparation of 7-(4-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1-(2-methyl-2-(2-(pyrrolidin-1-yl)ethoxy)propyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 26)

[0641] NH of 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-methyl-2-(2-(pyrrolidin-1-yl)ethoxy)propyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (50 mg, 0.09 mmol) 3 To the solution in MeOH (5 ml) was added an appropriate amount of Raney Nickel washed with MeOH. The mixture was stirred at room temperature for 3 hours. It was filtered and the filtrate was concentrated to give the crude product. The residue was purified by Combi-Flash (DCM:MeOH 25:1) to give the product as a white solid.

[0635]

[0642] C 32 H 44 N 6 O 2 LCMS (ESI) calculated value [M+H] + m / z=545.5, actual value 545. Example 16 Synthesis of compounds 27 and 73

[0636] [ka] Step 1: 2-(4-((2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetamide

[0643] A solution of 2-(4-((2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (200 mg, 0.29 mmol) in DMSO was added at 0° C. with H 2 O 2 (2mL) and K 2 CO 3 (140 mg) was added. The reaction mixture was warmed to room temperature and stirred for 30 min. LCMS showed the reaction was complete. The solution was diluted with water and extracted with EA (30 mL x 3). The combined organic layers were washed with Na 2 SO 4 The crude product was purified by silica gel column chromatography (PE:EA 1:1) to give the title compound (160 mg, 77.9% yield) as a yellow solid.

[0637]

[0644] C 45 H 45 N 5 O 3 LCMS (ESI) calculated value [M+H] + m / z=704.3, actual value 704. Step 2: 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetamide (compound 73)

[0645] To a solution of 2-(4-((2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetamide (160 mg, 0.23 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-H 2 O (0.1% FA); concentration gradient: 10–35) to give compound 73 (3.45 mg, yield 13.3%) as a white solid.

[0638]

[0646] C 26 H 31 N 5 O 3 LCMS (ESI) calculated value [M+H] + m / z=462.2, actual value 462.

[0647] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.41 (d, J = 14.7 Hz, 2H), 7.23 - 7.16 (m, 4H), 7.08 (d, J = 7.4 Hz, 1H), 6.83 (s, 2H), 4.87 (s, 2H), 4.63 (s, 2H), 4.01 (s, 2H), 3.50 (q, J = 7.0 Hz, 2H), 1.12 (m, 9H). Step 3: (2-((1-(4-amino-7-(4-(2-amino-2-oxoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(tert-butoxycarbonyl)sulfamic acid

[0648] A solution of NaH (33 mg, 1.3 mmol, 60%) in DMF (2 mL) was stirred at 0° C. for 5 min. Then 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetamide (120 mg, 0.2603 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 30 min. tert-Butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (87 mg, 0.3904 mmol) was added to the mixture at 0° C. The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine and Na 2 SO 4 The mixture was dried at rt, concentrated and purified by silica gel column chromatography (PE:EA 1:1) to give the product (50 mg, yield 28.0%) as a white solid.

[0639]

[0649] C 33 H 44 N 6 O 8 LCMS (ESI) calculated value for S [M+H] + m / z=685.2, actual value 685. Step 4: 2-[4-({4-amino-1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)imidazo[4,5-c]quinolin-7-yl}methyl)phenyl]acetamide (compound 27)

[0650] To a solution of (2-((1-(4-amino-7-(4-(2-amino-2-oxoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)ethyl)(tert-butoxycarbonyl)sulfamic acid (50 mg, 0.07 mmol) in DCM (3 mL) was added a solution of TFA (1 mL) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-H 2 O(0.05%NH 3 ); concentration gradient: 30-90) to obtain compound 27 (14.22 mg, yield 38%) as a white solid.

[0640]

[0651] C 15 H 24 N 8 O 2 LCMS (ESI) calculated value [M+H] + m / z=505.2, actual value 505.

[0652] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.19 (s, 4H), 7.08 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 6.65 (s, 1H), 4.75 (s, 2H), 4.02 (s, 2H), 3.51 (q, J = 7.0 Hz, 2H), 3.39 - 3.35 (m, 4H), 3.33 (s, 2H), 2.77 (t, J = 5.4 Hz, 2H), 1.14 (m, 9H). Example 17 Synthesis of compound 32

[0641] [ka] Step 1: Preparation of di-tert-butyl (7-benzyl-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0653] Di-tert-butyl(7-bromo-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (500 mg, 0.71 mmol), Pd(PPh 3 )Cl 2 To a solution of (50 mg, 0.07 mmol) and CuI (27 mg, 0.14 mmol) in DMF (3 mL) was added a solution of benzylzinc(II) bromide in DMF (10 mL). The mixture was stirred at 50° C. for 0.5 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (60 mL) and extracted with EA (40 mL×3). The organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by Combi-Flash (PE:EA 1:1) to give di-tert-butyl (7-benzyl-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (450 mg, 88.58% yield) as a yellow solid.

[0642]

[0654] C 41 H 56 N 4 O 7 LCMS (ESI) calculated value [M+H] + m / z=717.4, actual value 717. Step 2: Preparation of 1-(4-amino-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0655] To a solution of di-tert-butyl (7-benzyl-1-(2-((tert-butoxycarbonyl)oxy)-2-methylpropyl)-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (450 mg, 0.63 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was adjusted to pH=8 with saturated sodium bicarbonate in water. The resulting mixture was extracted with EA (30 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 and concentrated to give the crude title compound.

[0643]

[0656] C 26 H 32 N 4 LCMS (ESI) calculated value for O [M+H] + m / z=417.3, actual value 417. Step 3: Preparation of 1-(7-benzyl-2-(pentan-2-yl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol

[0657] 1-(4-amino-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (200 mg, 0.48 mmol), TrtCl (200 mg, 0.72 mmol) and Et 3 A mixture of N (145 mg, 1.44 mmol) in MeCN (4 mL) was stirred at 40° C. in a microwave reactor. 2 The mixture was heated at 100° C. for 0.5 h under an atmosphere of 0.1%. LCMS showed the reaction was complete. The resulting mixture was cooled to 0° C. The precipitate was collected by filtration to give 1-(7-benzyl-2-(pentan-2-yl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (130 mg, 47.79% yield) as a white solid.

[0644]

[0658] C 45 H 46 N4 LCMS (ESI) calculated value for O [M+H] + m / z=659.4, actual value 659. Step 4: Preparation of (3-((1-(7-benzyl-2-(pentan-2-yl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)propyl)(tert-butoxycarbonyl)sulfamic acid

[0659] To a solution of NaH (40 mg, 60%) in DMF (1 mL) was added dropwise a solution of 1-(7-benzyl-2-(pentan-2-yl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (130 mg, 0.20 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 1 h. Then tert-butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (233 mg, 0.99 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The resulting mixture was quenched with water (20 mL) and extracted with EA (30 mL x 3). The combined organic phase was washed with brine and Na 2 SO 4 After drying at 40° C. and concentration, the crude title compound was obtained. The residue was purified by Combi-Flash (PE:EA 1:2) to give (3-((1-(7-benzyl-2-(pentan-2-yl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)propyl)(tert-butoxycarbonyl)sulfamic acid (70 mg, 39.59% yield) as a yellow solid.

[0645]

[0660] C 53 H 61 N 5 O 6 LCMS (ESI) calculated value for S [M+H] + m / z=896.4, actual value 896. Step 5: Preparation of 1-(2-(3-aminopropoxy)-2-methylpropyl)-7-benzyl-2-(pentan-2-yl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 32)

[0661] To a solution of (3-((1-(7-benzyl-2-(pentan-2-yl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)oxy)propyl)(tert-butoxycarbonyl)sulfamic acid (70 mg, 0.078 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction was concentrated and purified by preparative HPLC (column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: ACN-H 2 The mixture was purified by 0 (0.05% FA, concentration gradient: 10 to 40) to obtain compound 32 (6.23 mg, yield 16.84%) as a white solid.

[0646]

[0662] C 29 H 39 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=474.3, actual value 474.

[0663] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.36 - 7.24 (m, 4H), 7.24 - 7.15 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.36 (s, 2H), 4.61 (d, J = 136.5 Hz, 4H), 4.04 (s, 2H), 3.28 (dd, J = 11.3, 6.1 Hz, 4H), 1.54 - 1.43 (m, 2H), 1.43 - 0.97 (m, 12H), 0.90 - 0.76 (m, 3H).

[0664] Compound 33 was prepared by a method similar to that described in Example 16 using the corresponding reagents. Compound 33:

[0647] [ka]

[0665] C 27 H 35 N 5 O 2 LCMS (ESI) calculated value [M+H] + m / z=462.3, actual value 462.

[0648]

[0666] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.35 - 7.26 (m, 4H), 7.25 - 7.17 (m, 1H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H), 7.06 (s, 2H), 4.88 (s, 2H), 4.64 (s, 2H), 4.06 (s, 2H), 3.50 (dd, J = 14.0, 7.0 Hz, 6H), 1.31 - 0.92 (m, 9H). Example 18 Synthesis of compounds 34 and 35

[0649] [ka] Step 1: Preparation of tert-butyl N-{2-[(7-bromo-2-chloro-3-nitroquinolin-4-yl)amino]ethyl}carbamate

[0667] 7-Bromo-2,4-dichloro-3-nitroquinoline (3 g, 9.32 mmol) and Et 3To a solution of N (1.41 g, 13.95 mmol) in DCM (30 mL) was added tert-butyl N-(2-aminoethyl)carbamate (1.79 g, 11.16 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (20 mL) and extracted with DCM (20 mL×3). The organic phase was washed with Na 2 SO 4 Drying at rt and concentration gave crude tert-butyl (2-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)ethyl)carbamate (2.5 g), which was used in the next reaction without further purification.

[0650]

[0668] C 16 H 18 BrClN 4 O 4 LCMS (ESI) calculated value [M+H] + m / z=445.0, actual value 445.0. Step 2: Preparation of tert-butyl (2-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)ethyl)carbamate

[0669] To a solution of tert-butyl (2-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)ethyl)carbamate (2.5 g, 5.6 mmol) in AcOH (40 mL) was added Fe (3.13 g, 56 mmol). The reaction mixture was stirred at room temperature for 6 h. LCMS showed the reaction was complete. The resulting mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EtOAc=1 / 2) to give tert-butyl (2-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)ethyl)carbamate (2 g, 85.7% yield) as a yellow solid.

[0651]

[0670] C 16 H 20BrClN 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=415.0, actual value 415.0.

[0671] Step 3: Preparation of tert-butyl (2-((7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl)amino)ethyl)carbamate

[0672] To a stirred solution of tert-butyl (2-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)ethyl)carbamate (2 g, 4.8 mmol) in DCM (30 mL) was added dropwise at 0° C. 2-ethoxyacetyl chloride (0.88 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 3 h. The organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EtOAc=1 / 3) to give tert-butyl (2-((7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl)amino)ethyl)carbamate (1.5 g, 62.5% yield) as a yellow solid.

[0652]

[0673] C 20 H 26 BrClN 4 O 4 LCMS (ESI) calculated value [M+H] + m / z=501.1, actual value 501.0. Step 4: Preparation of 1-(2-aminoethyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0674] tert-Butyl (2-((7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl)amino)ethyl)carbamate (1.5 g, 3.2 mmol) NH 3The solution in MeOH (7 M, 20 mL) was heated in a high pressure reactor at 160° C. for 8 h. After cooling to ambient temperature, the reaction mixture was concentrated to give crude 1-(2-aminoethyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (600 mg) as a yellow solid, which was used in the next reaction without further purification.

[0653]

[0675] C 15 H 18 BrN 5 LCMS (ESI) calculated value for O [M+H] + m / z=364.1, actual value 364.0. Step 5: Preparation of di-tert-butyl (1-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0676] A solution of 1-(2-aminoethyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (600 mg, 1.65 mmol) and DMAP (80.5 mg, 0.65 mmol) in MeCN (20 mL) was added to the Boc 2 O (1.8 g, 8.24 mmol) was added. The mixture was heated at 75° C. for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (50 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The extract was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EtOAc=2 / 1) to give di-tert-butyl (1-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (550 mg, 42.7% yield) as a yellow solid.

[0654]

[0677] C 35 H 50 BrN 5 O 9 LCMS (ESI) calculated value [M+H] +m / z=764.3, actual value 764.0. Step 6: Preparation of di-tert-butyl (1-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0678] Di-tert-butyl(1-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (550 mg, 0.72 mmol), Pd(PPh 3 )Cl 2 To a solution of (50.48 mg, 0.072 mmol) and CuI (54.79 mg, 0.14 mmol) in DMF (3 mL) was added benzylzinc(II) bromide (594.38 mg, 2.16 mmol) in DMF (3 mL). The mixture was heated at 50° C. for 2 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed with brine and diluted with Na 2 SO 4 The extract was dried at 40° C., concentrated, and purified by column chromatography on silica gel (PE / EtOAc=1 / 2) to give di-tert-butyl (1-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (300 mg, 52% yield) as a yellow solid.

[0655]

[0679] C 44 H 58 N 6 O 9 LCMS (ESI) calculated value [M+H] + m / z=814.4, actual value 814.0. Step 7: Preparation of 2-(4-((4-amino-1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile

[0680] To a solution of di-tert-butyl(1-(2-(bis(tert-butoxycarbonyl)amino)ethyl)-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (300 mg, 0.37 mmol) in DCM (4 mL) was added TFA (2 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The residue was diluted with EtOAc (20 mL) and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The organic phase was washed with brine and diluted with Na 2 SO 4 Drying at 40° C. and concentration afforded crude 2-(4-((4-amino-1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (140 mg) as a colorless oil, which was used in the next reaction without further purification.

[0656]

[0681] C 24 H 26 N 6 LCMS (ESI) calculated value for O [M+H] + m / z=415.2, actual value 415.0. Step 8: Preparation of N-(2-(4-amino-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)methanesulfonamide (9) and 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-(methylsulfonamido)ethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetamide (compound 35)

[0682] 2-(4-((4-amino-1-(2-aminoethyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetonitrile (140 mg, 0.34 mmol), Et 3To a solution of N (51.28 mg, 0.51 mmol) in DCM (3 mL) was added methanesulfonic anhydride (64.72 mg, 0.37 mmol) in DCM (2 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 30 min. LCMS showed the reaction was complete. The resulting mixture was diluted with water (10 mL) and extracted with DCM (10 mL×3). The organic phase was washed with brine and Na 2 SO 4 The mixture was dried and concentrated by preparative HPLC (column: Gemini-C18, 150 × 21.2 mm, 5 um; mobile phase: ACN-H 2 Purification by 0.1% FA, concentration gradient: 20% to 35% gave N-(2-(4-amino-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)methanesulfonamide (100 mg, yield 59.7%) as a white solid and 2-(4-((4-amino-2-(ethoxymethyl)-1-(2-(methylsulfonamido)ethyl)-1H-imidazo[4,5-c]quinolin-7-yl)methyl)phenyl)acetamide (compound 35, 10 mg, yield 5.76%) as a white solid.

[0657]

[0683] C 25 H 30 N 6 O 4 LCMS (ESI) calculated value for S [M+H] + m / z=511.2, actual value 511.0.

[0684] 1 H NMR (400 MHz, DMSO-d 6) δ 9.76 (s, 1 H), 8.39 (s, 3 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1 H), 7.30 (q, J = 8.4 Hz, 4 H), 7.10 (d, J = 8.5 Hz, 1 H), 6.55 (s, 2 H), 4.71 (s, 4 H), 4.06 (s, 2 H), 3.99 (s, 2 H), 3.69 (s, 3 H), 3.63-3.44 (m, 1 H), 1.16 (t, J = 7.0 Hz, 3 H). Step 9: Preparation of N-(2-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)methanesulfonamide (Compound 34)

[0685] NH of N-(2-(4-amino-7-(4-(cyanomethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)methanesulfonamide (100 mg, 0.2 mmol) obtained from the above step. 3 - Raney NiNH in MeOH (7M, 3 mL) 3 A suspension of -MeOH (7M, 2 mL) was added. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 1 hour. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum and purified by preparative HPLC (column: Gemini-C18, 150×21.2 mm, 5 um; mobile phase: ACN-H 2 Purification by 0.1% FA, concentration gradient: 10% to 45%, gave N-(2-(4-amino-7-(4-(2-aminoethyl)benzyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)methanesulfonamide (compound 34, 20 mg, yield 20.1%) as a white solid.

[0658]

[0686] C 25 H 32 N 6 O 3 LCMS (ESI) calculated value for S [M+H] +m / z=497.2, actual value 497.0.

[0687] 1 H NMR (400 MHz, CD 3 OD, ppm) δ 8.41 (s, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 7.45 (s, 1 H), 7.25 (dd, J = 8.5, 1.5 Hz, 1 H), 7.16 (dd, J = 22.6, 8.1 Hz, 4 H), 4.80 (s, 2 H), 4.71 (t, J = 6.7 Hz, 2 H), 4.03 (s, 2 H), 3.58 (q, J = 7.0 Hz, 2 H), 3.51 (t, J = 6.7 Hz, 2 H), 3.11-2.97 (m, 2 H), 2.91-2.79 (m, 2 H), 2.78 (s, 3 H), 1.17 (t, J = 7.0 Hz, 3 H). Example 19 Synthesis of compounds 36-38

[0659] [ka] Step 1: N-(2-amino-2-methylpropyl)-7-bromo-2-chloro-3-nitroquinolin-4-amine

[0688] To a solution of 7-bromo-2,4-dichloro-3-nitroquinoline (6 g, 18.6 mmol) and TEA (2.82 g, 27.8 mmol) in DCM (60 mL) was added a solution of 2-methylpropane-1,2-diamine (1.64 g, 18.6 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 1:1) to give the title compound (5 g, yield 64.5%) as a yellow solid.

[0660]

[0689] C13 H 14 BrClN 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=373, actual value 373. Step 2: Benzyl (1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-yl)carbamate

[0690] N-(2-amino-2-methylpropyl)-7-bromo-2-chloro-3-nitroquinolin-4-amine (4 g, 10.7 mmol) and Na 2 CO 3 To a solution of (20 mL, 2M) in DCM (30 mL) was added dropwise a solution of CbzCl (2 g, 11.7 mmol) in DCM at 0° C. The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The resulting mixture was diluted with water (100 mL) and extracted with DCM (80 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 5:1) to give the title compound (4 g, yield 66.3%) as a white solid.

[0661]

[0691] C 21 H 20 BrClN 4 O 4 LCMS (ESI) calculated value [M+H] + m / z=507.1, actual value 507. Step 3: Benzyl (1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-yl)carbamate

[0692] To a solution of benzyl (1-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)-2-methylpropan-2-yl)carbamate (4 g, 7.9 mmol) in AcOH (50 mL) was added Fe (4.5 g, 79 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The resulting mixture was diluted with water (100 mL) and extracted with DCM (80 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 3:1) to give the title compound (3.5 g, yield 83.5%) as a yellow solid.

[0662]

[0693] C 21 H 22 BrClN 4 O 2 LCMS (ESI) calculated value [M+H] + m / z=477.1, actual value 477. Step 4: Benzyl (1-((7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl)amino)-2-methylpropan-2-yl)carbamate

[0694] To a solution of benzyl (1-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)-2-methylpropan-2-yl)carbamate (3.5 g, 7.3 mmol) and TEA (0.98 g, 8.0 mmol) in DCM (50 mL) was added a solution of 2-ethoxyacetyl chloride (2.22 g, 21.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (100 mL) and extracted with DCM (80 mL x 3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 3:1) to give the title compound (3.5 g, yield 76.7%) as a white solid.

[0663]

[0695] C 25 H 28 BrClN 4 O 4 LCMS (ESI) calculated value [M+H] + m / z=563.1, actual value 563. Step 5: 1-(2-amino-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0696] Benzyl (1-((7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl)amino)-2-methylpropan-2-yl)carbamate (3.5 g, 6.2 mmol) NH 3 The solution in MeOH (20 mL) was stirred in a high pressure reactor at 160° C. for 8 h. After cooling to ambient temperature, the mixture was concentrated in vacuo to give the crude product without purification.

[0664]

[0697] C 17 H 22 BrN 5 LCMS (ESI) calculated value for O [M+H] + m / z=392.1, actual value 392. Step 6: Di-tert-butyl (1-(2-(bis(tert-butoxycarbonyl)amino)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0698] A solution of 1-(2-amino-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 6.3 mmol) in ACN (25 mL) was treated with DMAP (311 mg, 2.52 mmol) and Boc 2 O (14 g, 63 mmol) was added. The reaction mixture was stirred at 75° C. for 4 h. It was concentrated and diluted with EtOAc. The organic phase was washed with brine and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel column chromatography (PE:EA 3:1) to give the title compound (3 g, yield 60.1%) as a yellow solid.

[0665]

[0699] C 37 H 54 BrN 5 O 9 LCMS (ESI) calculated value [M+H] + m / z=792.3, actual value 792. Step 7: Di-tert-butyl (7-benzyl-1-(2-(bis(tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate

[0700] Zn powder (6.0 g, 93 mmol) and I 2 A mixture of (750 mg, 3 mmol) was placed in a 250 mL three-neck flask with N 2 Evacuate and backfill three times with N 2 I charged it. 2 The flask was carefully heated with a hot air blower until the benzene sublimated. A solution of (bromomethyl)benzene (5 g, 29.6 mmol) in DMF (30 mL) was then added immediately via syringe. The mixture was stirred for 10 min while maintaining the temperature at about 70° C. The heater and stirrer were then removed. The upper clear solution was washed with N 2 Di-tert-butyl(1-(2-(bis(tert-butoxycarbonyl)amino)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (3 g, 3.78 mmol), CuI (300 mg, 1.6 mmol) and Pd(pph 3 ) 2 Cl 2 (400 mg, 0.57 mmol) was added dropwise to a stirred solution of 1,2-dichlorophenyl ether (10 mL) in DMF (10 mL). The mixture was heated at 50° C. for 1 h. The mixture was then quenched with water (150 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water and brine and diluted with Na 2 SO4 The crude product was obtained after drying at 40° C., filtration and concentration. The residue was purified by silica gel column chromatography (PE:EA 5:1) to give the desired product (2 g, 65.8% yield) as a yellow solid.

[0666]

[0701] C 44 H 61 N 5 O 9 LCMS (ESI) calculated value [M+H] + m / z=804.4, actual value 804. Step 8: 1-(2-amino-2-methylpropyl)-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 38)

[0702] To a solution of di-tert-butyl(7-benzyl-1-(2-(bis(tert-butoxycarbonyl)amino)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-yl)iminodicarbonate (100 mg, 0.13 mmol) in DCM (6 mL) was added TFA (2 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-H 2 O(0.1%NH 3 H 2 O); concentration gradient: 10 to 75) to obtain compound 38 (4.4 mg, yield 8%) as a white solid.

[0667]

[0703] C 24 H 29 N 5 LCMS (ESI) calculated value for O [M+H] + m / z=404.2, actual value 404.

[0704] 1 H-NMR (400 MHz, DMSO-d 6) δ 8.29 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.40-7.27 (m, 4H), 7.25-7.16 (m, 2H), 4.86 (m, 4H), 4.10 (s, 2H), 3.56 (s, 2H), 1.48-0.91 (m, 9H). Step 9: tert-Butyl N-[3-({1-[4-amino-7-benzyl-2-(ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-yl}amino)propyl]carbamate

[0705] A solution of NaH (90 mg, 3.72 mmol, 60%) in DMF (3 mL) was stirred at 0° C. for 5 min. Then 1-(2-amino-2-methylpropyl)-7-benzyl-2-(ethoxymethyl)imidazo[4,5-c]quinolin-4-amine (compound 38, 300 mg, 0.74 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 30 min. tert-Butyl 1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (318 mg, 1.33 mmol) was added to the mixture at 0° C. The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine and Na 2 SO 4 The mixture was dried at 40° C., concentrated, and purified by silica gel column chromatography (PE:EA 1:1) to give the title compound (50 mg, yield 28.0%) as a white solid.

[0668]

[0706] C 32 H 44 N 6 O 3 LCMS (ESI) calculated value [M+H] + m / z=561.3, actual value 561. Step 10: N1-(1-(4-amino-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)propane-1,3-diamine (compound 36)

[0707] To a solution of tert-butyl (3-((1-(4-amino-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)amino)propyl)carbamate (50 mg, 0.09 mmol) in DCM (3 mL) was added TFA (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-H 2 O (0.1% FA); concentration gradient: 10–40) to give compound 36 (2 mg, yield 4.6%) as a white solid.

[0669]

[0708] C 27 H 36 N 6 LCMS (ESI) calculated value for O [M+H] + m / z=461.3, actual value 461. Step 11 and Step 12: Preparation of N1-(1-(4-amino-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl)ethane-1,2-diamine (compound 37)

[0709] Compound 37 was synthesized from compound 38 by steps 11 and 12 (the procedures for steps 11 and 12 were similar to those for steps 9 and 10).

[0670]

[0710] C 26 H 34 N 6 LCMS (ESI) calculated value for O [M+H] + m / z=447.2, actual value 447. Example 20 Synthesis of compound 39

[0671] [ka] Step 1: Preparation of tert-butyl (4-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)butyl)carbamate

[0711] To a solution of 7-bromo-2,4-dichloro-3-nitroquinoline (3.5 g, 10.9 mmol) in DCM was added tert-butyl N-(4-aminobutyl)carbamate (2.26 g, 11.9 mmol) and TEA (1.65 g, 16.3 mmol) dropwise at room temperature. The reaction mixture was stirred at 40° C. for 16 h. LCMS showed the reaction was complete. The resulting mixture was diluted with water (50 mL) and extracted with DCM (50 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The residue was purified by silica gel column chromatography (PE:EA 5:1) to give tert-butyl (4-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)butyl)carbamate (4.9 g, yield 85.3%) as a white solid.

[0672]

[0712] C 18 H 22 BrClN 4 O 4 LCMS (ESI) calculated value [M+H] + m / z=473.1, actual value 473. Step 2: Preparation of tert-butyl (4-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)butyl)carbamate

[0713] To a solution of tert-butyl (4-((7-bromo-2-chloro-3-nitroquinolin-4-yl)amino)butyl)carbamate (4.9 g, 10.3 mmol) in AcOH was added Fe (5.8 g, 103 mmol). The reaction mixture was stirred at room temperature for 10 h. LCMS showed the reaction was complete. It was diluted with DCM, the solution was filtered through Celite, and the filtrate was concentrated under vacuum to give the crude product. The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (3.3 g, 65.1% yield) as a white solid.

[0673]

[0714] C 18 H 24 BrClN 4 O2 LCMS (ESI) calculated value [M+H] + m / z=443.1, actual value 443. Step 3: tert-Butyl N-(4-{[7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl]amino}butyl)carbamate

[0715] To a solution of tert-butyl (4-((3-amino-7-bromo-2-chloroquinolin-4-yl)amino)butyl)carbamate (3.3 g, 7.4 mmol) in DCM at 0° C. was added TEA (2.25 g, 22.2 mmol) and 2-ethoxyacetyl chloride (1.36 g, 11.1 mmol). The reaction mixture was allowed to warm to room temperature for 16 h. LCMS showed the reaction was complete. The reaction was diluted with water and extracted with DCM (50 mL×3). The combined organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (1.69 g, 39.1% yield) as a white solid.

[0674]

[0716] C 22 H 30 BrClN 4 O 4 LCMS (ESI) calculated value [M+H] + m / z=529.1, actual value 529. Step 4: tert-Butyl N-{4-[4-amino-7-bromo-2-(ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]butyl}carbamate

[0717] tert-Butyl N-(4-{[7-bromo-2-chloro-3-(2-ethoxyacetamido)quinolin-4-yl]amino}butyl)carbamate (1.69 g, 3.2 mmol) NH 3The solution in MeOH (20 mL) was stirred at 160° C. for 8 h in a high pressure reactor. After cooling to ambient temperature, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (0.9 g, 50% yield) as a yellow solid.

[0675]

[0718] C 22 H 30 BrN 5 O 3 LCMS (ESI) calculated value [M+H] + m / z=492.1, actual value 492. Step 5: tert-Butyl N-{4-[4-amino-7-benzyl-2-(ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]butyl}carbamate

[0719] tert-Butyl N-{4-[4-amino-7-bromo-2-(ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (160 mg, 0.32 mmol), Pd(PPh 3 )Cl 2 To a solution of (54 mg, 0.06 mmol) and copper(I) iodide (138 mg, 0.65 mmol) in DMF was added dropwise a solution of benzyl(bromo)zinc (1.5 mL, 2 M). The reaction mixture was stirred at 50° C. for 3 h. It was concentrated and diluted with EA. The organic phase was washed with brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo The residue was purified by silica gel column chromatography (PE:EA 2:1) to give the title compound (50 mg, 27.5% yield) as a yellow solid.

[0676]

[0720] C 29 H 37 N 5 O 3 LCMS (ESI) calculated value [M+H] + m / z=504.2, actual value 504. Step 6: 1-(4-aminobutyl)-7-benzyl-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (compound 39)

[0721] To a solution of tert-butyl N-{4-[4-amino-7-benzyl-2-(ethoxymethyl)imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (50 mg, 0.10 mmol) in DCM (5 mL) was added TFA (1.5 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give the crude product. The residue was purified by preparative HPLC (column: Gemini-C18 150×21.2 mm, 5 um; mobile phase: ACN-H 2 The mixture was purified by 0 (0.1% FA, concentr...

Claims

1. Equation (I): A-(L-D) ｐ (I) (In the formula, A is the target area, L is Linker, p is an integer from 1 to 8, D is equation (II): 【Chemistry 1】 It is the payload unit, X is selected from the group consisting of -O-, -S-, -NH-, -(CH ２ ), ｉ -, -(X １ ),NC(O)-,-(X １ ),NS(O) ２ -,-C(O)N(X １ )-and-S(O) ２ N(X １ )-; -NH-and -(CH ２ ) ｉ -is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino or alkyl, each X １ These are independently hydrogen, alkyl, alkenyl, or haloalkyl, Ring A is a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring. W is a direct bond, alkyl, cycloalkyl, heterocyclyl, ＊ -W １ -Alkyl-, ＊ -Alkyl-W １ -, and ＊ -Alkyl-W １ Selected from the group consisting of -alkyl-, including alkyl, cycloalkyl, heterocyclyl, and ＊ -W １ -Alkyl-, ＊ -Alkyl-W １ -, and ＊ -Alkyl-W １ -Alkyl in alkyl refers to halogen, hydroxyl, cyano, amino, alkyl and -C(O)OR ａ It is optionally replaced by one or more elements independently selected from W, and ＊ The end is connected to ring A, W １ is -O-, -NR ａ -, -C(O)-, -C(O)NR ａ -, -NR ａ C(O)-, -OC(O)NR ａ -, -NR ａ C(O)O-, or -NR ａ C(O)NR ａ - and Each R ａ These are independently hydrogen, alkyl, or haloalkyl, R １ is hydrogen, -N(R ｂ ) ２ , hydroxyl or -SH, Each R ｂ These are independently hydrogen, alkyl, or haloalkyl, or Two R's ｂ These, together with the nitrogen atoms to which they are bonded, form heterocyclines. R ２ These are hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR ｅ , -OC(O)R ｅ ,-SR ｅ , -B(OH) ２ , -NO ２ , -CHO, -C(=NOR ｅ ) (Caution ｅ ), -R ２－１ -N(R) ｅ ) ２ , -R ２－１ -N(R) ｅ ) C(O)R ｅ , -R ２－１ -N(R) ｅ ) S(O) ２ R ｅ , -R ２－１ -N(R) ｅ ) P(O) ２ R ｅ , -R ２－１ -C(O)OR ｅ , -R ２－１ -C(O)N(R) ｅ ) ２ , -R ２－１ -S(O) ２ N(R) ｅ ) ２ , -R ２－１ -P(O) ２ N(R) ｅ ) ２ , -OC(O)NR ｅ , or -NC(O)NR ｅ And, Each R ２－１ These are independently absent or alkyl, Each R ｅ These are independently hydrogen, alkyl, or haloalkyl, Y is -Y １ -Y ２ -Y ３ And, Y １ is directly bonded or - (CH ２ ) ｍ -Q １ - (CH ２ ) ｎ -O- ＊ and - (CH ２ ) ｍ - and - (CH ２ ) ｎ - are each independently optionally substituted with one or more groups selected from halogen, hydroxyl, alkyl or haloalkyl, and the １ terminal ＊ of Y ２ is connected to Y Y ２ is directly bonded or - (CH ２ ) ｓ -Q ２ - (CH ２ ) ｔ -NR ｃ - ＊＊ and - (CH ２ ) ｓ - and - (CH ２ ) ｔ - are each independently optionally substituted with one or more groups selected from halogen, hydroxyl, alkyl or haloalkyl, and the terminal of Y ２ is ＊＊ connected to Y ３ . Y ３ Hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R ｂ ) ２ -C(O)-alkyl, -C(O)-alkyl-N(R ｂ ) ２ , and -S(O) ２ - Selected from the group consisting of alkyl groups, Q １ and Q ２ Each is independently selected from direct bonds, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with one or more groups independently selected from halogens, hydroxyl, cyano, amino, or alkyl groups. R ｃ is hydrogen or alkyl, or R ｃ and Y ３ Together with the atoms to which they are bonded, they form heterocyclines which are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl groups. Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and each of these is one or more R ｄ It is replaced by an optional selection, R ｄ This is selected from the group consisting of halogens, acyls, alkyls, alkenyls, alkynyls, cycloalkyls, and -O-cycloalkyls. i is 0, 1, 2, 3, 4, 5, or 6. m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, or 5. s is 0, 1, 2, 3, 4, or 5. (t is 0, 1, 2, 3, 4, or 5) A conjugate compound having or a pharmaceutically acceptable salt thereof.

2. Ring A is 【Chemistry 2】 A conjugate compound according to claim 1, selected from the group consisting of the following.

3. X is -O-, -NH-, or -(CH ２ ) ｉ - and -NH- and -(CH ２ ) ｉ - is optionally substituted with one or more halogens or alkyl groups, the conjugate compound according to claim 1.

4. R １ However, hydrogen, -N(R ｂ ) ２ The conjugate compound according to claim 1, or a hydroxyl group.

5. The conjugate compound according to claim 1, wherein W is a direct bond, and / or R1 is hydrogen, -N(Rb)2 or hydroxyl, and each Rb is independently hydrogen or alkyl, or two Rbs together with the nitrogen atom to which they are bonded to form a heterocycline.

6. iW is -C(O)OR ａ The alkyl is optionally substituted, and / or R1 is hydrogen, hydroxyl, or -N(Rb)2, where each Rb is independently hydrogen or alkyl, or two Rbs together with the nitrogen atom to which they are bonded form a heterocycline; or ii W is *-W1-alkyl- and / or W1 is -O-, -NRa-, -C(O)NRa-, -OC(O)NRa-, -NRaC(O)-, -NRaC(O)O-, or -NRaC(O)NRa-, where each Ra is independently hydrogen, alkyl, or haloalkyl, and / or R1 is -NH2 or -NH-CH3; or iii W is *-alkyl-W1- and / or W1 is -C(O)- and / or R1 is -NH2; or iv W is *-alkyl-W1-alkyl- and / or W1 is -NR a C(O)- or -OC(O)NR a-, Ra is hydrogen, alkyl, or haloalkyl, and / or R1 is hydroxyl, -NH2, or -NH-CH3; or v W is cycloalkyl and / or R 1 is -NH 2; or vi W is a heterocycline and / or R 1 is hydrogen, The conjugate compound according to claim 1.

7. R ２ The conjugate compound according to claim 1, wherein the compound is hydrogen, halogen, cyano, alkyl, or alkoxyl.

8. iY １ Y2 is a direct bond, and / or Y3 is an alkylaryl bond; or ii Y1 is a direct bond, and / or Y2 is -(CH2)s-Q2-(CH2)t-NRc-**, and / or Q2 is a direct bond, cycloalkyl or aryl, and the cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogens or alkyls, and / or Rc is hydrogen, and / or Y3 is hydrogen, -alkyl-N(Rb)2, or -S(O)2-alkyl; or iii Y1 is -(CH2)m-Q1-(CH2)n-O-* and / or Q1 is directly bonded, cycloalkyl or aryl, and the cycloalkyl or aryl is optionally substituted with one or more groups independently selected from halogens or alkyls and / or Y2 is directly bonded and / or Y3 is hydrogen or alkyl; or vi Y1 is -(CH2)m-Q1-(CH2)n-O-*, and / or Y2 is -(CH2)s-Q2-(CH2)t-NRc-**, and / or Q2 is a direct bond, and / or Rc is hydrogen, and / or Y3 is hydrogen, -C(O)-alkyl or -C(O)-alkyl-N(Rb)2, or Rc and Y3 together with the atoms to which they are bonded form a heterocycline which is optionally substituted with one or more halogens. The conjugate compound according to claim 1.

9. Z is one or more R ｄ The conjugate compound according to claim 1, wherein R d is optionally selected from the group consisting of alkyl, alkenyl, alkynyl and heteroalkyl elements, and R d is optionally selected from the group consisting of halogen, acyl, alkyl, cycloalkyl and -O-cycloalkyl elements.

10. D is equation (IIa): 【Transformation 3】 It is the payload unit, Optionally, the payload unit is 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 【Chemistry 4-9】 【Chemistry 4-10】 【Chemistry 4-11】 【Chemistry 4-12】 【Chemistry 4-13】 【Chemistry 4-14】 【Chemistry 4-15】 【Chemistry 4-16】 (wherein q is 1, 2, or 3) 【Transformation 5】 (wherein q is 1, 2, or 3) 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 【Chemistry 6-4】 【Transformation 6-5】 【Transformation 6-6】 [Transformation 6-7] [Transformation 6-8] 【Transformation 6-9】 【Chemistry 6-10】 【Chemistry 6-11】 【Chemistry 6-12】 Selected from the group consisting of, The conjugate compound according to claim 1.

11. L is equation (III): -L １ -(L) ２ ) ｊ -(L) ３ ) ｋ -(III) (In the formula, L １ These are stretcher units covalently bonded to the targeting portion. L ２ This is a peptide unit of any choice consisting of 2 to 12 amino acid residues. L ３ This is an optional spacer unit covalently bonded to the payload unit. j and k are independently selected from 0 and 1; and / or L1 is selected from the following group. 【Transformation 7】 (In the formula, each R3 is independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylheterocyclyl, heterocyclylalkyl, -alkyl-C(O)N(Ra)-alkyl-N(Ra), -N(Ra)-alkyl-, and -(CH2CH2O)r-CH2-, where Ra is H or alkyl, r is an integer in the range of 1 to 10, and v is an integer in the range of 0 to 5, and optionally each R3 is independently selected from C1-10 alkyl, C1-8 heteroalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, (C1-10 alkyl)aryl, aryl(C1-10 alkyl), (C1-10 alkyl)(C) Selected from the group consisting of 3-8 cycloalkyl groups, (C3-8 cycloalkyl)(C1-10 alkyl), (C1-10 alkyl)(3-8 membered heterocyclyl), (3-8 membered heterocyclyl)(C1-10 alkyl), -(C2-6 alkyl)-C(O)N(Ra)-(C2-6 alkyl)-N(Ra), -N(Ra)-(C2-6 alkyl)-, and -(CH2CH2O)r-CH2-, where Ra is H or C1-6 alkyl). The conjugate compound according to claim 1, having the following characteristics.

12. formula: 【Transformation 8】 (In the formula, AA1 and AA2 are independently selected from amino acid side chains, p is an integer from 1 to 8, and the amino acid side chain is optionally selected independently from H, -CH3, -CH2(C6H5), -CH2CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, -CHCH(CH3)CH3, and -CH2CH2CH2NHC(O)NH2)) The conjugate compound according to claim 1, having the following characteristics. 【Request Item 13】 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 (In the formula, R is, 【Chemistry 10】 Selected from the group consisting of, where each of R' and R'' is independently a bond, hydrogen, or methyl. A conjugate compound according to claim 1, selected from the group consisting of the following. 【Request Item 14】 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 [Chemistry 11-12] [Chemistry 11-13] [Chemistry 11-14] 【Chemistry 11-15】 A conjugate compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

15. The conjugate compound according to claim 1, wherein the targeting portion comprises an antibody or an antigen-binding fragment thereof, and optionally the antibody is bound to HER2 or B7-H4.

16. Equation (Ia): L'-D(Ia) (In the formula, L' is a linker precursor, D is equation (II): 【Chemistry 12】 It is the payload unit, X is -O-, -S-, -NH-, and -(CH ２ ) ｉ -, -(X １ )NC(O)-,-(X １ )NS(O) ２ -, -C(O)N(X １ ) - and -S(O) ２ N(X) １ Selected from the group consisting of ) and -NH- and -(CH ２ ) ｉ - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl. each X １ These are independently hydrogen, alkyl, alkenyl, or haloalkyl, Ring A is a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring. W is a direct bond, alkyl, cycloalkyl, heterocyclyl, ＊ -W １ -Alkyl-, ＊ -Alkyl-W １ -, and ＊ -Alkyl-W １ Selected from the group consisting of -alkyl-, including alkyl, cycloalkyl, heterocyclyl, and ＊ -W １ -Alkyl-, ＊ -Alkyl-W １ -, and ＊ -Alkyl-W １ -Alkyl in alkyl refers to halogen, hydroxyl, cyano, amino, alkyl and -C(O)OR ａ It is optionally replaced by one or more elements independently selected from W, and ＊ The end is connected to ring A, W １ is -O-, -NR ａ -, -C(O)-, -C(O)NR ａ -, -NR ａ C(O)-, -OC(O)NR ａ -, -NR ａ C(O)O-, or -NR ａ C(O)NR ａ - and Each R ａ These are independently hydrogen, alkyl, or haloalkyl, R １ is hydrogen, -N(R ｂ ) ２ , hydroxyl or SH, Each R ｂ These are independently hydrogen, alkyl, or haloalkyl, or Two R's ｂ These, together with the nitrogen atoms to which they are bonded, form heterocyclines. R ２ These are hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR ｅ , -OC(O)R ｅ ,-SR ｅ , -B(OH) ２ , -NO ２ , -CHO, -C(=NOR ｅ ) (Caution ｅ ), -R ２－１ -N(R) ｅ ) ２ , -R ２－１ -N(R) ｅ ) C(O)R ｅ , -R ２－１ -N(R) ｅ ) S(O) ２ R ｅ , -R ２－１ -N(R) ｅ ) P(O) ２ R ｅ , -R ２－１ -C(O)OR ｅ , -R ２－１ -C(O)N(R) ｅ ) ２ , -R ２－１ -S(O) ２ N(R) ｅ ) ２ , -R ２－１ -P(O) ２ N(R) ｅ ) ２ , -OC(O)NR ｅ , or -NC(O)NR ｅ And, Each R ２－１ These are independently absent or alkyl, Each R ｅ These are independently hydrogen, alkyl, or haloalkyl, Y is -Y １ -Y ２ -Y ３ And, Y １ is a direct bond or -(CH ２ ) ｍ -Q １ - (CH ２ ) ｎ -O- ＊ And, -(CH ２ ) ｍ - and - (CH ２ ) ｎ - is optionally substituted with one or more groups independently selected from halogens, hydroxyls, alkyls, or haloalkyls, Y １ of ＊ The end is Y ２ It is connected, Y ２ is a direct bond or -(CH ２ ) ｓ -Q ２ - (CH ２ ) ｔ -NR ｃ - ＊＊ And, -(CH ２ ) ｓ - and - (CH ２ ) ｔ - is optionally substituted with one or more groups independently selected from halogens, hydroxyls, alkyls, or haloalkyls, Y ２ of ＊＊ The end is Y ３ It is connected, Y ３ Hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R ｂ ) ２ -C(O)-alkyl, -C(O)-alkyl-N(R ｂ ) ２ , and -S(O) ２ - Selected from the group consisting of alkyl groups, Q １ and Q ２ Each is independently selected from direct bonds, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with one or more groups independently selected from halogens, hydroxyl, cyano, amino, or alkyl groups. R ｃ is hydrogen or alkyl, or R ｃ and Y ３ Together with the atoms to which they are bonded, they form heterocyclines which are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl groups. Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and each of these is one or more R ｄ It is replaced by an optional selection, R ｄ This is selected from the group consisting of halogens, acyls, alkyls, alkenyls, alkynyls, cycloalkyls, and -O-cycloalkyls. i is 0, 1, 2, 3, 4, 5, or 6. m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, or 5. s is 0, 1, 2, 3, 4, or 5. (t is 0, 1, 2, 3, 4, or 5) A linker-payload compound having the same property as a pharmaceutically acceptable salt thereof. 【Request Item 17】 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 [Chemistry 13-4] 【Chemistry 13-5】 【Chemistry 13-6】 【Chemistry 13-7】 【Chemistry 13-8】 【Chemistry 13-9】 【Chemistry 13-10】 【Chemistry 13-11】 [Chemistry 13-12] 【Chemistry 13-13】 [Chemistry 13-14] [Chemistry 13-15] A linker-payload compound according to claim 16, selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof.

18. Formula (II'): 【Chemistry 14】 (In the formula, X is -O-, -S-, -NH-, -(CH ２ ) ｉ -, -(X １ )NC(O)-,-(X １ )NS(O) ２ -, -C(O)N(X １ ) - and -S(O) ２ N(X) １ Selected from the group consisting of ) and -NH- and -(CH ２ ) ｉ - is optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl. each X １ These are independently hydrogen, alkyl, alkenyl, or haloalkyl, Ring A is a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring. W is a direct bond, alkyl, cycloalkyl, heterocyclyl, ＊ -W １ -Alkyl-, ＊ -Alkyl-W １ -, and ＊ -Alkyl-W １ Selected from the group consisting of -alkyl-, including alkyl, cycloalkyl, heterocyclyl, and ＊ -W １ -Alkyl-, ＊ -Alkyl-W １ -, and ＊ -Alkyl-W １ -Alkyl in alkyl refers to halogen, hydroxyl, cyano, amino, alkyl and -C(O)OR ａ It is optionally replaced by one or more elements independently selected from W, and ＊ The end is connected to ring A, W １ is -O-, -NR ａ -, -C(O)-, -C(O)NR ａ -, -OC(O)NR ａ -, -NR ａ C(O)-, -NR ａ C(O)O-, or -NR ａ C(O)NR ａ - and Each R ａ These are independently hydrogen, alkyl, or haloalkyl, R １ is hydrogen, -N(R ｂ ) ２ , hydroxyl or SH, Each R ｂ These are independently hydrogen, alkyl, or haloalkyl, or Two R's ｂ These, together with the nitrogen atoms to which they are bonded, form heterocyclines. R ２ These are hydrogen, halogen, hydroxyl, cyano, amino, alkyl, alkenyl, alkynyl, alkoxyl, haloalkyl, -OR ｅ , -OC(O)R ｅ ,-SR ｅ , -B(OH) ２ , -NO ２ , -CHO, -C(=NOR ｅ ) (Caution ｅ ), -R ２－１ -N(R) ｅ ) ２ , -R ２－１ -N(R) ｅ ) C(O)R ｅ , -R ２－１ -N(R) ｅ ) S(O) ２ R ｅ , -R ２－１ -N(R) ｅ ) P(O) ２ R ｅ , -R ２－１ -C(O)OR ｅ , -R ２－１ -C(O)N(R) ｅ ) ２ , -R ２－１ -S(O) ２ N(R) ｅ ) ２ , -R ２－１ -P(O) ２ N(R) ｅ ) ２ , -OC(O)NR ｅ , or -NC(O)NR ｅ And, Each R ２－１ These are independently absent or alkyl, Each R ｅ These are independently hydrogen, alkyl, or haloalkyl, Y is -Y １ -Y ２ -Y ３ And, Y １ is a direct bond or -(CH ２ ) ｍ -Q １ - (CH ２ ) ｎ -O- ＊ And, -(CH ２ ) ｍ - and - (CH ２ ) ｎ - is optionally substituted with one or more groups independently selected from halogens, hydroxyls, alkyls, or haloalkyls, Y １ of ＊ The end is Y ２ It is connected, Y ２ is a direct bond or -(CH ２ ) ｓ -Q ２ - (CH ２ ) ｔ -NR ｃ - ＊＊ And, -(CH ２ ) ｓ - and - (CH ２ ) ｔ - is optionally substituted with one or more groups independently selected from halogens, hydroxyls, alkyls, or haloalkyls, Y ２ of ＊＊ The end is Y ３ It is connected, Y ３ Hydrogen, alkyl, -alkyl-aryl, -alkyl-N(R ｂ ) ２ -C(O)-alkyl, -C(O)-alkyl-N(R ｂ ) ２ , and -S(O) ２ - Selected from the group consisting of alkyl groups, Q １ and Q ２ Each is independently selected from direct bonds, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with one or more groups independently selected from halogens, hydroxyl, cyano, amino, or alkyl groups. R ｃ is hydrogen or alkyl, or R ｃ and Y ３ Together with the atoms to which they are bonded, they form heterocyclines which are optionally substituted with one or more groups independently selected from halogen, hydroxyl, cyano, amino, or alkyl groups. Z is selected from the group consisting of alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl, and each of these is one or more R ｄ It is replaced by an optional selection, R ｄ This is selected from the group consisting of halogens, acyls, alkyls, alkenyls, alkynyls, cycloalkyls, and -O-cycloalkyls. i is 0, 1, 2, 3, 4, 5, or 6. m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, 4, or 5. s is 0, 1, 2, 3, 4, or 5. (t is 0, 1, 2, 3, 4, or 5) A payload compound having the same properties as a pharmaceutically acceptable salt thereof.

19. Formula (IIa'): 【Chemistry 15】 The payload compound according to claim 18, having the following characteristics.

20. A pharmaceutical composition for treating a Toll-like receptor 7 and / or 8-mediated disease in a subject requiring treatment of such disease, comprising a conjugate compound according to any one of claims 1 to 15, a linker-payload compound according to any one of claims 16 to 17, or a payload compound according to claims 18 to 19, and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, wherein the disease mediated by Toll-like receptors 7 and / or 8 is cancer.

22. The pharmaceutical composition according to claim 21, wherein the cancer is selected from breast cancer, bladder cancer, head and neck cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, gastrointestinal stromal cancer, gastroesophageal cancer, renal cell carcinoma, prostate cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, lymphoma, cutaneous T-cell lymphoma, visceral tumor, or melanoma.

23. The pharmaceutical composition according to claim 22, wherein the disease mediated by Toll-like receptors 7 and / or 8 is a viral infection.

24. The pharmaceutical composition according to claim 23, wherein the viral infection is derived from a virus selected from the group consisting of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), coxsackievirus (CV), coronavirus, Epstein-Barr virus (EBV), encephalomyocarditis virus (EMCV), influenza A virus (IAV), measles virus (MV), Sendai virus (SV), or vesicular stomatitis virus (VSV).

25. A pharmaceutical composition for activating the aggregation of Toll-like receptors 7 and / or 8 in a subject requiring activation of aggregation of Toll-like receptors 7 and / or 8, comprising a conjugate compound according to any one of claims 1 to 15, a linker-payload compound according to any one of claims 16 to 17, or a payload compound according to claims 18 to 19, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition for stimulating an immune response in a subject requiring stimulation of an immune response, comprising a conjugate compound according to any one of claims 1 to 15, a linker-payload compound according to any one of claims 16 to 17, or a payload compound according to claims 18 to 19, and a pharmaceutically acceptable carrier.

Images