Oxoacridinyl acetic acid derivatives and methods of use thereof

Abstract

Provided are compounds of formula I or pharmaceutically acceptable salts or esters thereof that are capable of binding to and modulating the activity of stimulator of interferon genes (STING). Also provided are methods involving compounds of formula I as effective STING modulators.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 588,820, filed November 20, 2017, U.S. Provisional Application No. 62 / 631,530, filed February 16, 2018, and U.S. Provisional Application No. 62 / 723,660, filed August 28, 2018, the contents of each of which are incorporated herein by reference in their entirety. Background of the Invention

[0004] Modulating innate immune activity through agonistic or antagonistic pattern recognition receptors (PRRs) has enormous potential in clinical applications, either as monotherapy or in combination with other drugs or biopharmaceuticals. Applications range from alleviating autoimmune diseases through immunosuppression to treating solid and hematological cancers by stimulating innate anti-tumor immunity, as well as for antiviral therapy or as vaccine adjuvants.

[0005] One of the PRRs involved in the efficient activation of antigen-presenting cells (APCs) is the stimulator of interferon genes (STING). STING is an evolutionarily conserved cytoplasmic PRR and part of the cGAS-CDN-STING axis. Abnormal dsDNA in the cytoplasm due to cellular stress, viral or intracellular bacterial infection, mitotic failure, or phagocytosis is recognized by the cGAS enzyme, which synthesizes the non-canonical cyclic dinucleotide (CDN), 2'3' cGAMP. 2'3' cGAMP binds to and stabilizes the STING dimer, leading to activation of IRF3 and NFkB and the synthesis of type I interferons. The STING protein plays a crucial role in the innate cell response to viral infection and the accumulation of abnormal cytoplasmic DNA in target cells and reactive innate immune cells. The pleiotropic effects of STING activation depend on the cell type and context. For example, excessive stimulation of T and B cells by STING leads to a pro-apoptotic phenotype, whereas STING activation in myeloid cells elevates type I interferons and proinflammatory cytokines without increasing apoptosis.

[0006] Tumor-derived dsDNA is phagocytosed by resident dendritic cells (DCs), which stimulate the cGAS-CDN-STING axis and activate DCs, leading to lymph node migration and ultimately the proliferation of antigen-specific CD4+ and CD8+ T cells. This process and the accompanying type I IFN response are typically absent in tumors lacking T cell infiltration, highlighting the potential of STING agonism to directly address the escape mechanisms exploited by these tumors. Although several CDN-derived ligands have shown preclinical promise as STING agonists, their relatively large molecular weight and polarity limit their use in intratumoral injection. Moreover, in vivo, binding and activation / inhibition of cytoplasmic STING proteins are limited by cell membrane permeability. In addition, although they have therapeutic efficacy via systemic administration (intravenous or intraperitoneal), previously identified small molecule STING agonists DMXAA and CMA still have species selectivity, which prohibits their use as human therapeutics. Therefore, there is a need for human-active small molecule modulators of STING that are effective therapeutic agents. The present application addresses this need. The novel compounds of this application overcome the limitations of CDN-derived ligands. SUMMARY OF THE INVENTION

[0008] In one aspect, the present application relates to compounds of formula I:

[0009]

[0010] or a pharmaceutically acceptable salt or ester thereof, wherein X, Y, Z, Z1, m and n are each defined herein.

[0011] In another aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

[0012] Another aspect of the present application relates to a method for regulating (e.g., inhibiting or stimulating) a stimulator of interferon genes (STING) protein. The method comprises administering to a subject in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application. In one embodiment, the STING protein is a human STING protein.

[0013] Another aspect of the present application relates to a method for treating or preventing a disease, wherein the disease is caused by or associated with STING expression, activity, and / or function (e.g., dysregulation of STING expression, activity, and / or function). The method comprises administering to a subject in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application.

[0014] Another aspect of the present application relates to a method for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving the STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation). The method comprises administering an effective amount of a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application to a subject in need thereof.

[0015] Another aspect of the present application relates to a kit comprising the compound of the present application or a pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition of the present application.

[0016] Another aspect of the present application relates to a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application, for use in the manufacture of a medicament for regulating (e.g., inhibiting or stimulating) a STING protein, a medicament for treating or preventing a disease, wherein the disease is caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or a medicament for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving a STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0017] Another aspect of the present application relates to the use of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition of the present application in the preparation of a medicament for regulating (e.g., inhibiting or stimulating) the STING protein, a medicament for treating or preventing a disease, wherein the disease is caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or a medicament for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving the STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0018] Another aspect of the present application relates to a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application, for use in regulating (e.g., inhibiting or stimulating) a STING protein, for treating or preventing a disease caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving a STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0019] Another aspect of the present application relates to the use of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition of the present application in regulating (e.g., inhibiting or stimulating) the STING protein, treating or preventing diseases caused by or related to STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or treating or preventing diseases associated with dysregulation of one or more intracellular pathways involving the STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0020] The present application provides a modulator of the STING protein, which is a therapeutic agent for treating or preventing diseases such as cancer and immune diseases.

[0021] The details of the present disclosure are set forth in the following accompanying description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. In the event of a conflict, the present specification, including definitions, shall prevail. In addition, the materials, methods, and examples are illustrative only and are not restrictive. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In the description and the appended claims, the singular also includes the plural, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs.

[0022] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications and co-pending patent applications) are hereby expressly incorporated by reference in their entirety. The references cited herein are not admitted to be prior art to this application. Detailed Description of the Invention

[0024] The present application relates to compounds of formula I, which show effective and selective regulation of STING protein (e.g., human STING protein). In one embodiment, the compound of the present application is represented by formula I:

[0025]

[0026] or a pharmaceutically acceptable salt or ester thereof, wherein

[0027] X is C(R X )2, O, S, CH=CH or not present;

[0028] Each R X are independently H, CH3, CF3, CF2H or F, or two R X Together form =O, =CH2 or =CF2, or two R XTogether with the carbon atom to which they are bonded, they form a cyclopropyl group;

[0029] Z1 is (C(R Z )2) p -T1;

[0030] p is 1, 2, 3, 4, 5, or 6;

[0031] Each R Z are independently H, C1-C4 alkyl, C1-C4 alkyl substituted with one or more halogens, or halogen;

[0032] T1 is CHOR1, C(O)R1, C(O)OR1, C(O)N(R1)2, NR1C(O)R1, C(S)R1, C(S)N(R1)2, NR1C(S)R1, C(O)NHS(O)2R S , C(O)NHOCH3, C(O)NHOH or C(O)NHCN;

[0033] R S is R1, C3-C8 cycloalkyl, a heterocyclic group including a 5-membered or 6-membered ring and 1-2 heteroatoms selected from N, O and S, or a C6-C 10 Aryl, wherein the cycloalkyl, heterocyclyl or aryl group is optionally substituted with one or more groups independently selected from C1-C4 alkyl;

[0034] Each R1 is independently H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more halogens;

[0035] m is 0, 1, 2, 3 or 4;

[0036] each Y is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CN, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl), S(O)2-(C1-C6 alkyl), or QT, wherein the alkyl, alkenyl or alkynyl moiety is optionally substituted with one or more groups independently selected from OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl and N-(C1-C6 alkyl), or two Ys taken together with the two adjacent carbon atoms to which they are bound form a 5- to 7-membered carbocyclic ring or phenyl;

[0037] n is 0, 1, 2, 3 or 4;

[0038] each Z is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CN, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl), S(O)2-(C1-C6 alkyl), or QT, wherein the alkyl, alkenyl, or alkynyl moiety is optionally substituted with one or more groups independently selected from OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl)2;

[0039] each Q is independently a bond, NH, N(C1-C3 alkyl), O, S, S(O), S(O)2, Q', NH-Q', N(C1-C3 alkyl)-Q', O-Q', S-Q', S(O)-Q', or S(O)2-Q';

[0040] Each Q' is independently a compound containing one or more C(R Q )2、C(R Q )2-C(R Q )2.CR Q =CR Q or a carbon linker of C≡C;

[0041] Each R Q are independently H or C1-C3 alkyl;

[0042] Each T is independently C(O)-C1-C6 alkyl, C(O)O-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, a heterocyclic group containing one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, a C6-C 10 Aryl, or heteroaryl containing one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S, wherein the cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R T ;

[0043] Each R T are independently C1-C6 alkyl, C1-C6 haloalkyl, OH, CN, halogen, O-(C1-C6 alkyl), O-(C1-C6 haloalkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, NHS(O)2-(C1-C6 alkyl), (CH2) q -C3-C8 cycloalkyl, (CH2) q -heterocyclic group, (CH2) q -phenyl or (CH2)q - heteroaryl, wherein the heterocyclyl or heteroaryl group comprises one or two 5- or 6-membered rings and 1 to 4 heteroatoms selected from N, O and S; and

[0044] q is 0, 1, 2, or 3,

[0045] When X is C(O) and each R Z When it is H:

[0046] m and n are not both 0; and

[0047] The compound of formula I is not monosubstituted with Cl at the 2- or 7-position; and

[0048] The compounds of the formula I are not disubstituted in the 2- and 8-positions or in the 1- and 7-positions by halogen selected from F and Cl.

[0049] In one embodiment, the compound of formula I is a compound of formula Ia or Ib:

[0050]

[0051] or a pharmaceutically acceptable salt or ester thereof.

[0052] For any compound of Formula I, Ia or Ib, where applicable:

[0053] (a1) In one embodiment, X is C(R X )2.

[0054] (b1) In one embodiment, each R X For H.

[0055] (b2) In one embodiment, at least one R X is CH3, CF3, CF2H or F.

[0056] (b3) In one embodiment, one R X is CH3, CF3, CF2H or F, and other R X For H.

[0057] (b4) In one embodiment, each R X is independently CH3, CF3, CF2H or F. In one embodiment, each R X In one embodiment, each R X In one embodiment, each R X In one embodiment, each R X For F.

[0058] (b5) In one embodiment, two R XTogether they form =O, =CH2 or =CF2.

[0059] (b6) In one embodiment, two R X Together they form =O.

[0060] (b7) In one embodiment, two R X Together they form =CH2.

[0061] (b8) In one embodiment, two R X Together they form =CF2.

[0062] (b9) In one embodiment, two R X Together with the carbon atom to which it is bonded, it forms a cyclopropyl group.

[0063] (a2) In one embodiment, X is O.

[0064] (a3) In one embodiment, X is S.

[0065] (a4) In one embodiment, X is CH=CH.

[0066] (a5) In one embodiment, X is absent.

[0067] (a6) In one embodiment, X is not absent.

[0068] (c1) In one embodiment, p is 1, 2 or 3.

[0069] (c2) In one embodiment, p is 1 or 2.

[0070] (c3) In one embodiment, p is 1.

[0071] (c4) In one embodiment, p is 2, 3, 4, 5 or 6.

[0072] (d1) In one embodiment, each R Z For H.

[0073] (d2) In one embodiment, at least one R Z is C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), C1-C4 alkyl substituted with one or more halogens (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, each substituted with one or more halogens (e.g., F, Cl, Br or I)), or halogen (e.g., F, Cl, Br or I).

[0074] (d3) In one embodiment, at least one R Zis a C1-C4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0075] (d4) In one embodiment, at least one R Z is C1-C4 alkyl substituted with one or more halogens (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, each substituted with one or more halogens (e.g., F, Cl, Br or I)).

[0076] (d5) In one embodiment, at least one R Z is halogen (eg, F, Cl, Br or I).

[0077] (e1) In one embodiment, T1 is CHOR1, C(O)R1, C(O)OR1, C(O)N(R1)2 or NR1C(O)R1.

[0078] (e2) In one embodiment, T1 is C(O)R1, C(O)OR1, C(O)N(R1)2 or NR1C(O)R1.

[0079] (e3) In one embodiment, T1 is C(O)R1, C(O)OR1 or C(O)N(R1)2.

[0080] (e4) In one embodiment, T1 is C(O)OR1 or C(O)N(R1)2.

[0081] (e5) In one embodiment, T1 is C(O)R1 or C(O)OR1.

[0082] (e6) In one embodiment, T1 is C(O)R1, C(O)OR1, C(O)N(R1)2, NR1C(O)R1, C(S)R1, C(S)N(R1)2 or NR1C(S)R1.

[0083] (e7) In one embodiment, T1 is C(O)OR1, C(O)N(R1)2, NR1C(O)R1, C(S)N(R1)2 or NR1C(S)R1.

[0084] (e8) In one embodiment, T1 is C(O)OR1, C(O)N(R1)2 or C(S)N(R1)2.

[0085] (e9) In one embodiment, T1 is C(S)R1, C(S)N(R1)2 or NR1C(S)R1.

[0086] (e10) In one embodiment, T1 is C(O)R1, C(O)OR1, C(O)N(R1)2, NR1C(O)R1, C(O)NHS(O)2R S , C(O)NHOCH3, C(O)NHOH or C(O)NHCN.

[0087] (e11) In one embodiment, T1 is C(O)OR1, C(O)N(R1)2, C(O)NHS(O)2R S , C(O)NHOCH3, C(O)NHOH or C(O)NHCN.

[0088] (f1) In one embodiment, each R1 is H.

[0089] (f2) In one embodiment, at least one R1 is C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), C1-C4 alkyl substituted with one or more halogens (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, each substituted with one or more halogens (e.g., F, Cl, Br or I)), or halogen (e.g., F, Cl, Br or I).

[0090] (f3) In one embodiment, at least one R1 is C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0091] (f4) In one embodiment, at least one R1 is C1-C4 alkyl substituted with one or more halogens (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, each substituted with one or more halogens (e.g., F, Cl, Br or I)).

[0092] (f5) In one embodiment, at least one R1 is halogen (eg, F, Cl, Br or I).

[0093] (g1) In one embodiment, m is 0, 1, 2 or 3.

[0094] (g2) In one embodiment, m is 0, 1 or 2.

[0095] (g3) In one embodiment, m is 0.

[0096] (g4) In one embodiment, m is 1 or 2.

[0097] (g5) In one embodiment, m is 1.

[0098] (g6) In one embodiment, m is 2.

[0099] (h1) In one embodiment, at least one Y is a C1-C6 straight chain or C3-C6 branched chain alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl), optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Y is a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), optionally substituted as described herein. In one embodiment, at least one Y is a C1-C6 straight chain or C3-C6 branched chain alkyl group and is substituted as described herein. In one embodiment, at least one Y is a C1-C6 straight chain or C3-C6 branched alkyl substituted with OH, NH2, N3, halogen, or O-(C1-C6 alkyl). In one embodiment, at least one Y is methyl, optionally substituted as described herein. In one embodiment, at least one Y is ethyl, optionally substituted as described herein. In one embodiment, at least one Y is isopropyl, optionally substituted as described herein. In one embodiment, at least one Y is tert-butyl, optionally substituted as described herein.

[0100] (h2) In one embodiment, at least one Y is a C2-C6 straight chain or C3-C6 branched alkenyl group (e.g., ethenyl, propenyl, butenyl, pentenyl, or hexenyl), optionally substituted with one or more groups independently selected from OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Y is a C2-C6 straight chain or C3-C6 branched alkenyl group substituted with OH, NH2, halogen, or O-(C1-C6 alkyl).

[0101] (h3) In one embodiment, at least one Y is a C2-C6 straight chain or C4-C6 branched alkynyl group (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one or more groups independently selected from OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Y is a C2-C6 straight chain or C4-C6 branched alkynyl group substituted with OH, NH2, halogen, or O-(C1-C6 alkyl).

[0102] (h4) In one embodiment, at least one Y is halogen (e.g., F, Cl, Br, or I). In one embodiment, at least one Y is F. In one embodiment, at least one Y is Cl. In one embodiment, at least one Y is Br.

[0103] (h5-1) In one embodiment, at least one Y is OH or O-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl and N-(C1-C6 alkyl)2. In one embodiment, at least one Y is O-methyl, optionally substituted as described herein. In one embodiment, at least one Y is O-ethyl, optionally substituted as described herein. In one embodiment, at least one Y is O-isopropyl, optionally substituted as described herein.

[0104] (h5-2) In one embodiment, at least one Y is O-(C2-C4 cycloalkenyl) (e.g., ethenyl, propenyl, or butenyl), wherein the alkenyl moiety is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Y is O-vinyl, optionally substituted as described herein. In one embodiment, at least one Y is O-propenyl, optionally substituted as described herein.

[0105] (h5-3) In one embodiment, at least one Y is O-(C2-C4 alkynyl) (e.g., ethynyl, propynyl, or butynyl), wherein the alkynyl moiety is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Y is O-ethynyl, optionally substituted as described herein. In one embodiment, at least one Y is O-propynyl, optionally substituted as described herein.

[0106] (h6-1) In one embodiment, at least one Y is S-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl)2. In one embodiment, at least one Y is S-methyl, optionally substituted as described herein. In one embodiment, at least one Y is S-ethyl, optionally substituted as described herein. In one embodiment, at least one Y is S-isopropyl, optionally substituted as described herein.

[0107] (h6-2) In one embodiment, at least one Y is S(O)-(C1-C6 alkyl) or S(O)2-(C1-C6 alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Y is S(O)2CH3, optionally substituted as described herein.

[0108] (h7) In one embodiment, at least one Y is NH2, NH-C1-C6 straight chain or C3-C6 branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl) or N-(C1-C6 straight chain or C3-C6 branched alkyl)2 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl and N-(C1-C6 alkyl). In one embodiment, at least one Y is N-(C1-C6 alkyl)2, which is optionally substituted as described herein, and the two C1-C6 alkyl groups are the same. In one embodiment, at least one Y is N-(C1-C6 alkyl)2, which is optionally substituted as described herein, and the two C1-C6 alkyl groups are different. In one embodiment, at least one Y is N(CH3)2, which is optionally substituted as described herein. In one embodiment, at least one Y is N(CH3)(CH2CH3), which is optionally substituted as described herein.

[0109] (h8) In one embodiment, at least one Y is QT.

[0110] (h9) In one embodiment, at least one Y is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl) or S(O)2-(C1-C6 alkyl), as described herein.

[0111] (h10) In one embodiment, at least one Y is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2 or S(O)2-(C1-C6 alkyl), as described herein.

[0112] (h11) In one embodiment, at least one Y is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl), or S(O)2-(C1-C6 alkyl), as described herein, and at least another Y is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl), or S(O)2-(C1-C6 alkyl), as described herein.

[0113] (h12) In one embodiment, at least one Y is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, or S(O)2-(C1-C6 alkyl), as described herein, and at least another Y is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, or S(O)2-(C1-C6 alkyl), as described herein.

[0114] (h13) In one embodiment, at least one Y is QT, as described herein, and at least another Y is C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2 or S(O)2-(C1-C6 alkyl), as described herein.

[0115] (h14) In one embodiment, at least one Y is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, as described herein, and at least another Y is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, as described herein.

[0116] (h15) In one embodiment, at least one Y is halogen, as described herein, and at least one other Y is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, as described herein. In one embodiment, at least one Y is Cl, and at least one other Y is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, as described herein. In one embodiment, at least one Y is Cl, and at least one other Y is halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, as described herein. In one embodiment, at least one Y is Cl, and at least one other Y is Cl, O-(C1-C6 alkyl), or S-(C1-C6 alkyl), as described herein. In one embodiment, at least one Y is Cl, and at least another Y is Cl or O-(C1-C6 alkyl), as described herein.

[0117] (h16) In one embodiment, two Y, together with two adjacent carbon atoms to which they are bonded, form cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclopentynyl, cyclohexynyl, or cycloheptynyl. In one embodiment, two Y, together with two adjacent carbon atoms to which they are bonded, form cyclohexyl.

[0118] (h17) In one embodiment, two Y, taken together with the two adjacent carbon atoms to which they are bonded, form a phenyl group.

[0119] (h18) In one embodiment, at least one Y is in the 6 position as shown in Formula I, Ia or Ib.

[0120] (h19) In one embodiment, at least one Y is in the 5 position as shown in Formula I, Ia or Ib.

[0121] (h20) In one embodiment, at least one Y is at position 7, as shown in Formula I, Ia or Ib.

[0122] (h21) In one embodiment, at least one Y is at the 5 position and at least one Y is at the 6 position as shown in Formula I, Ia or Ib.

[0123] (h22) In one embodiment, at least one Y is at the 7 position and at least one Y is at the 6 position as shown in Formula I, Ia or Ib.

[0124] (h23) In one embodiment, one Y is at the 5 position and the other Y is at the 6 position as shown in Formula I, Ia or Ib.

[0125] (h24) In one embodiment, one Y is at the 7 position and the other Y is at the 6 position as shown in Formula I, Ia or Ib.

[0126] (i1) In one embodiment, n is 0, 1, 2 or 3.

[0127] (i2) In one embodiment, n is 0, 1 or 2.

[0128] (i3) In one embodiment, n is 0.

[0129] (i4) In one embodiment, n is 1 or 2.

[0130] (i5) In one embodiment, n is 1.

[0131] (i6) In one embodiment, n is 2.

[0132] (j1) In one embodiment, at least one Z is a C1-C6 straight chain or C3-C6 branched chain alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl), optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl), optionally substituted as described herein. In one embodiment, at least one Z is a C1-C6 straight chain or C3-C6 branched chain alkyl group and is substituted as described herein. In one embodiment, at least one Z is a C1-C6 straight chain or C3-C6 branched alkyl substituted with OH, NH2, N3, halogen, or O-(C1-C6 alkyl). In one embodiment, at least one Z is methyl, optionally substituted as described herein. In one embodiment, at least one Z is ethyl, optionally substituted as described herein. In one embodiment, at least one Z is isopropyl, optionally substituted as described herein. In one embodiment, at least one Z is tert-butyl, optionally substituted as described herein.

[0133] (j2) In one embodiment, at least one Z is a C2-C6 straight chain or C3-C6 branched alkenyl group (e.g., ethenyl, propenyl, butenyl, pentenyl, or hexenyl) optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is a C2-C6 straight chain or C3-C6 branched alkenyl group substituted with OH, NH2, halogen, or O-(C1-C6 alkyl).

[0134] (j3) In one embodiment, at least one Z is a C2-C6 straight chain or C4-C6 branched alkynyl group (e.g., ethynyl, propynyl, butynyl, pentynyl, or hexynyl) optionally substituted with one or more groups independently selected from OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is a C2-C6 straight chain or C4-C6 branched alkynyl group substituted with OH, NH2, halogen, or O-(C1-C6 alkyl).

[0135] (j4) In one embodiment, at least one Z is halogen (e.g., F, Cl, Br, or I). In one embodiment, at least one Z is F. In one embodiment, at least one Z is Cl. In one embodiment, at least one Z is Br.

[0136] (j5-1) In one embodiment, at least one Z is OH or O-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl and N-(C1-C6 alkyl)2. In one embodiment, at least one Z is O-methyl, optionally substituted as described herein. In one embodiment, at least one Z is O-ethyl, optionally substituted as described herein. In one embodiment, at least one Z is O-isopropyl, optionally substituted as described herein.

[0137] (j5-2) In one embodiment, at least one Z is O-(C2-C4 cycloalkenyl) (e.g., ethenyl, propenyl, or butenyl), wherein the alkenyl moiety is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is O-ethenyl, optionally substituted as described herein. In one embodiment, at least one Z is O-propenyl, optionally substituted as described herein.

[0138] (j5-3) In one embodiment, at least one Z is O-(C2-C4 alkynyl) (e.g., ethynyl, propynyl, or butynyl), wherein the alkynyl moiety is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is O-ethynyl, optionally substituted as described herein. In one embodiment, at least one Z is O-propynyl, optionally substituted as described herein.

[0139] (j6-1) In one embodiment, at least one Z is S-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is S-methyl, optionally substituted as described herein. In one embodiment, at least one Z is S-ethyl, optionally substituted as described herein. In one embodiment, at least one Z is S-isopropyl, optionally substituted as described herein.

[0140] (h6-2) In one embodiment, at least one Z is S(O)-(C1-C6 alkyl) or S(O)2-(C1-C6 alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl, and N-(C1-C6 alkyl). In one embodiment, at least one Z is S(O)2CH3, optionally substituted as described herein.

[0141] (j7) In one embodiment, at least one Z is NH2, NH-C1-C6 straight chain or C3-C6 branched alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl) or N-(C1-C6 straight chain or C3-C6 branched alkyl)2 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl), wherein the alkyl portion is optionally substituted with one or more groups independently selected from the group consisting of OH, NH2, N3, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH-C1-C6 alkyl and N-(C1-C6 alkyl). In one embodiment, at least one Z is N-(C1-C6 alkyl)2, which is optionally substituted as described herein, and the two C1-C6 alkyl groups are the same. In one embodiment, at least one Z is N-(C1-C6 alkyl)2, which is optionally substituted as described herein, and the two C1-C6 alkyl groups are different. In one embodiment, at least one Z is N(CH3)2, which is optionally substituted as described herein. In one embodiment, at least one Z is N(CH3)(CH2CH3), which is optionally substituted as described herein.

[0142] (j8) In one embodiment, at least one Z is QT.

[0143] (j9) In one embodiment, at least one Z is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl) or S(O)2-(C1-C6 alkyl), as described herein.

[0144] (j10) In one embodiment, at least one Z is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2 or S(O)2-(C1-C6 alkyl), as described herein.

[0145] (j11) In one embodiment, at least one Z is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl), or S(O)2-(C1-C6 alkyl), as described herein, and at least another Z is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), O-(C2-C4 alkenyl), O-(C2-C4 alkynyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, S(O)-(C1-C6 alkyl), or S(O)2-(C1-C6 alkyl), as described herein.

[0146] (j12) In one embodiment, at least one Z is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, or S(O)2-(C1-C6 alkyl), as described herein, and at least another Z is QT, C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, or S(O)2-(C1-C6 alkyl), as described herein.

[0147] (j13) In one embodiment, at least one Z is QT, as described herein, and at least another Z is C1-C6 alkyl, halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2 or S(O)2-(C1-C6 alkyl), as described herein.

[0148] (j14) In one embodiment, at least one Z is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, as described herein, and at least another Z is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl)2, as described herein.

[0149] (j15) In one embodiment, at least one Z is halogen, as described herein, and at least one other Z is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, as described herein. In one embodiment, at least one Z is Cl, and at least one other Z is halogen, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, as described herein. In one embodiment, at least one Z is Cl, and at least one other Z is halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, as described herein. In one embodiment, at least one Z is Cl, and at least one other Z is Cl, O-(C1-C6 alkyl), or S-(C1-C6 alkyl), as described herein. In one embodiment, at least one Z is Cl, and at least another Z is Cl or O-(C1-C6 alkyl), as described herein.

[0150] (j16) In one embodiment, at least one Z is in the 3 position, as shown in Formula I, Ia or Ib.

[0151] (j17) In one embodiment, at least one Z is in the 4 position as shown in Formula I, Ia or Ib.

[0152] (j18) In one embodiment, at least one Z is in the 3-position and at least one Z is in the 4-position as shown in Formula I, Ia or Ib.

[0153] (j19) In one embodiment, one Z is at the 3-position and the other Z is at the 4-position as shown in Formula I, Ia or Ib.

[0154] (k1) In one embodiment, at least one Q is a bond.

[0155] (k2) In one embodiment, each Q is independently NH, N(C1-C3 alkyl), O, S, S(O), S(O)2, Q', NH-Q', N(C1-C3 alkyl)-Q', O-Q', S-Q', S(O)-Q' or S(O)2-Q'.

[0156] (k3) In one embodiment, each Q is independently NH, O, S or Q'.

[0157] (k4) In one embodiment, each Q is independently Q', NH-Q', O-Q' or S-Q'.

[0158] (k5) In one embodiment, each Q is independently NH, S, Q', NH-Q' or S-Q'

[0159] (k6) In one embodiment, each Q is independently NH, Q' or NH-Q'.

[0160] (k7) In one embodiment, each Q is independently O, Q' or O-Q'.

[0161] (k8) In one embodiment, each Q is independently S, S(O), S(O)2, Q', S-Q', S(O)-Q' or S(O)2-Q'.

[0162] (k9) In one embodiment, at least one Q is Q'.

[0163] (11) In one embodiment, each Q' is independently a Q )2 or C(R Q )2-C(R Q )2 carbon linker. In one embodiment, each Q' is independently a carbon linker comprising one or more C(R Q )2 carbon linker. In one embodiment, each Q' is independently a carbon linker comprising one or more C(R Q )2-C(R Q )2 carbon linking group.

[0164] (12) In one embodiment, each Q' is independently a Q =CR Q carbon linking group.

[0165] (13) In one embodiment, each Q' is independently a carbon linker comprising one or more C≡C.

[0166] (14) In one embodiment, each Q' is independently a Q )2 or C(R Q )2-C(R Q )2 and CR Q =CR Q In one embodiment, each Q' is independently a carbon linker comprising one or more C(R Q )2 and CR Q =CR Q In one embodiment, each Q' is independently a carbon linker comprising one or more C(R Q )2-C(R Q )2 and CR Q =CR Q carbon linking group.

[0167] (15) In one embodiment, each Q' is independently a Q )2 or C(R Q )2-C(R Q )2 and C≡C carbon linker. In one embodiment, each Q' is independently a carbon linker comprising one or more C(R Q )2 and C≡C carbon linker. In one embodiment, each Q' is independently a carbon linker comprising one or more C(R Q )2-C(R Q )2 and C≡C carbon linking group.

[0168] (16) In one embodiment, each Q' is independently a Q =CR Q and a carbon linker with C≡C.

[0169] (17) In one embodiment, each Q' is independently a Q )2、C(R Q )2-C(R Q 2. CR Q =CR Q and a carbon linker with C≡C.

[0170] (m1) In one embodiment, each R Q For H.

[0171] (m2) In one embodiment, at least one R Q is methyl, ethyl or propyl.

[0172] (n1) In one embodiment, at least one T is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, each of which is optionally substituted with one or more RT .

[0173] (n2) In one embodiment, at least one T is cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctyl, each of which is optionally substituted with one or more R T .

[0174] (n3) In one embodiment, at least one T is a heterocyclyl group comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O and S (e.g., pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl), optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 5-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 5-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heterocyclyl group comprising a 6-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T .

[0175] (n4) In one embodiment, at least one T is optionally substituted with one or more R T C6-C 10 In one embodiment, at least one T is optionally substituted with one or more R T of phenyl.

[0176] (n5) In one embodiment, at least one T is a heteroaryl group comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyridinyl, indolyl, purinyl, indolizinyl, quinoxalinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, or benzofuranyl), optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 5-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 5-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 5-membered ring and 1-2 N, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein, which is optionally substituted with one or more R TIn one embodiment, at least one T is a heteroaryl group comprising a 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 6-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein, which is optionally substituted with one or more R T In one embodiment, at least one T is a heteroaryl group comprising a 6-membered ring and 1-2 N, such as those described herein, which is optionally substituted with one or more R T .

[0177] (n6) In one embodiment, at least one T is C(O)-C1-C6 alkyl or C(O)O-C1-C6 alkyl, each optionally substituted with one or more R T .

[0178] (o1) In one embodiment, at least one R T is a C1-C6 straight chain or C3-C6 branched chain alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl). In one embodiment, at least one R T is a C1-C4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0179] (o2) In one embodiment, at least one R T is a C1-C6 haloalkyl group, i.e., a C1-C6 straight chain or C3-C6 branched chain alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl) substituted with one or more halogens (e.g., F, Cl, Br or I). In one embodiment, at least one R T is a C1-C4 haloalkyl group, i.e., a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) substituted with one or more halogens (e.g., F, Cl, Br or I).

[0180] (o3) In one embodiment, at least one R T is OH, CN, halogen or NH2,

[0181] (o4) In one embodiment, at least one R T is halogen (eg, F, Cl, Br or I).

[0182] (o5) In one embodiment, at least one R Tis O-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl). In one embodiment, at least one R T is an O-C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0183] (o6) In one embodiment, at least one R T is O-(C1-C6 haloalkyl) (i.e., wherein the C1-C6 haloalkyl is a C1-C6 straight chain or C3-C6 branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl) substituted with one or more halogens (e.g., F, Cl, Br, or I). In one embodiment, at least one R T is O-(C1-C4 haloalkyl) (i.e., wherein C1-C4 haloalkyl is C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl) substituted with one or more halogens (e.g., F, Cl, Br, or I)).

[0184] (o7) In one embodiment, at least one R T is S-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl). In one embodiment, at least one R T is S-C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0185] (o8) In one embodiment, at least one R T is NH2, NH-(C1-C6 straight chain or C3-C6 branched alkyl), N-(C1-C6 straight chain or C3-C6 branched alkyl)2 or NHS(O)2-(C1-C6 alkyl). In one embodiment, at least one R T is NH-(C1-C6 straight chain or C3-C6 branched alkyl) (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl). In one embodiment, at least one R T is NH-C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). In one embodiment, at least one R Tis NH-(C1-C6 straight chain or C3-C6 branched alkyl)2 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl). In one embodiment, at least one R T is NH-(C1-C4 alkyl)2 (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0186] (o9) In one embodiment, at least one R T (CH2) q -C3-C8 cycloalkyl, (CH2) q -heterocyclic group, (CH2) q -phenyl or (CH2) q -heteroaryl.

[0187] (o10) In one embodiment, at least one R T (CH2) q -C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0188] (o11) In one embodiment, at least one R T (CH2) q -heterocyclyl, wherein the heterocyclyl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl). In one embodiment, the heterocyclyl comprises one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heterocyclyl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heterocyclyl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heterocyclyl comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heterocyclyl comprises one 5-membered ring and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heterocyclyl comprises one 5-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heterocyclyl comprises a 5-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heterocyclyl comprises a 6-membered ring and 1-3 heteroatoms selected from N, O and S, such as those described herein. In one embodiment, the heterocyclyl comprises a 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heterocyclyl comprises a 6-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein.

[0189] (o12) In one embodiment, at least one R T (CH2) q -phenyl.

[0190] (o13) In one embodiment, at least one R T (CH2) q -heteroaryl, wherein the heteroaryl group comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S (e.g., pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyridinyl, indolyl, purinyl, indolizinyl, quinoxalinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, or benzofuranyl). In one embodiment, the heteroaryl group comprises one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heteroaryl group comprises one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heteroaryl group comprises a 5- or 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heteroaryl group comprises a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heteroaryl group comprises a 5-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heteroaryl group comprises a 5-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heteroaryl group comprises a 5-membered ring and 1-2 N, such as those described herein. In one embodiment, the heteroaryl group comprises a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, such as those described herein. In one embodiment, the heteroaryl group comprises a 6-membered ring and 1-3 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heteroaryl group comprises a 6-membered ring and 1-2 heteroatoms selected from N and O, such as those described herein. In one embodiment, the heteroaryl group comprises a 6-membered ring and 1-2 N, such as those described herein.

[0191] (o14) In one embodiment, at least one R T C1-C6 alkyl, C1-C6 haloalkyl, OH, CN, halogen, O-(C1-C6 alkyl), O-(C1-C6 haloalkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl, N-(C1-C6 alkyl)2, (CH2) q -heterocyclic group or (CH2) q-phenyl, as described herein.

[0192] (o15) In one embodiment, at least one R T C1-C6 alkyl, C1-C6 haloalkyl, OH, CN, halogen, O-(C1-C6 alkyl), O-(C1-C6 haloalkyl), S-(C1-C6 alkyl), NH2, (CH2) q -heterocyclic group or (CH2) q -phenyl, as described herein. In one embodiment, at least one R T is methyl, ethyl, propyl, isopropyl, CF3, OH, CN, F, Cl, methoxy, ethoxy, OCF3, SCH3, NH2, (CH2)-morpholinyl or (CH2)-phenyl.

[0193] (p1) In one embodiment, q is 0, 1 or 2.

[0194] (p2) In one embodiment, q is 1, 2 or 3.

[0195] (p3) In one embodiment, q is 0 or 1.

[0196] (p4) In one embodiment, q is 1 or 2.

[0197] (p5) In one embodiment, q is 0.

[0198] (p6) In one embodiment, q is 1.

[0199] (p7) In one embodiment, q is 2.

[0200] (p8) In one embodiment, q is 3.

[0201] (q1) In one embodiment, R S is R1.

[0202] (q2) In one embodiment, R S is a C3-C8 cycloalkyl group, a heterocyclic group containing one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O and S, and or a C6-C 10 Aryl, wherein cycloalkyl, heterocyclyl or aryl is optionally substituted with one or more groups independently selected from C1-C4 alkyl.

[0203] (q3) In one embodiment, R S is C3-C8 cycloalkyl or C6-C 10 aryl groups, each optionally substituted with one or more groups independently selected from C1-C4 alkyl groups.

[0204] (q4) In one embodiment, RS is C3-C6 cycloalkyl or phenyl, each optionally substituted with one or more groups independently selected from C1-C4 alkyl.

[0205] This paper analyzes X, Y, Z, Z1, R1, R Q 、R T 、R X 、R Z 、R S , Q, Q', T1, T, m, n, p and q any of the groups described herein may be combined with any of the groups described herein for X, Y, Z, Z1, R1, R Q 、R T 、R X 、R Z 、R S , Q, Q', T1, T, m, n, p and q, and any combination of the remaining one or more groups.

[0206] (A1) In one embodiment, p is as described in any one of (c1) to (c3), and R Z As described in (d1).

[0207] (A2) In one embodiment, p is as described in any one of (c1) to (c3), and R Z As described in any one of (d2) to (d5).

[0208] (A3) In one embodiment, p is as described in (c3), and R Z As described in (d1).

[0209] (A4) In one embodiment, p is as described in (c3), and R Z As described in any one of (d2) to (d5).

[0210] (A5) In one embodiment, p is as described in (c4), and R Z As described in (d1).

[0211] (A6) In one embodiment, p is as described in (c4), and R Z As described in any one of (d2) to (d5).

[0212] (B1) In one embodiment, p and R Z As described in any one of (A1) to (A6), and T1 is as described in any one of (e1) to (e5).

[0213] (B2) In one embodiment, p and R Z As described in any one of (A1) to (A6), and T1 is as described in any one of (e3) to (e5).

[0214] (B3) In one embodiment, p and R Z As described in any one of (A1) to (A6), and T1 is as described in (e4).

[0215] (B4) In one embodiment, p and R Z As described in any one of (A1) to (A6), and T1 is as described in (e5).

[0216] (B5) In one embodiment, p and R Z As described in any one of (A1) to (A6), and T1 is as described in any one of (e6) to (e9).

[0217] (B6) In one embodiment, p and R Z As described in any one of (A1) to (A6), and T1 is as described in any one of (e10) to (e11).

[0218] (B7) In one embodiment, p and R Z As described in any one of (A3) to (A4), and T1 is as described in any one of (e1) to (e5).

[0219] (B8) In one embodiment, p and R Z As described in any one of (A3) to (A4), and T1 is as described in any one of (e3) to (e5).

[0220] (B9) In one embodiment, p and R Z As described in any one of (A3) to (A4), and T1 is as described in (e4).

[0221] (B10) In one embodiment, p and R Z As described in any one of (A3) to (A4), and T1 is as described in (e5).

[0222] (B11) In one embodiment, p and R Z As described in any one of (A3) to (A4), and T1 is as described in any one of (e6) to (e9).

[0223] (B12) In one embodiment, p and R Z As described in any one of (A3) to (A4), and T1 is as described in any one of (e10) to (e11).

[0224] (B13) In one embodiment, p and R Z As described in (A3), and T1 is as described in any one of (e1) to (e5).

[0225] (B14) In one embodiment, p and R Z As described in (A3), and T1 is as described in any one of (e3) to (e5).

[0226] (B15) In one embodiment, p and R Z As described in (A3), and T1 is as described in (e4).

[0227] (B16) In one embodiment, p and R Z As described in (A3), and T1 is as described in (e5).

[0228] (B17) In one embodiment, p and R Z As described in (A3), and T1 is as described in any one of (e6) to (e9).

[0229] (B18) In one embodiment, p and R Z As described in (A3), and T1 is as described in any one of (e10) to (e11).

[0230] (C1) In one embodiment, m is as described in (g1) or (g2), and Y is as described in any one of (h1)-(h7) and (h18)-(h24).

[0231] (C2) In one embodiment, m is as described in any one of (g4)-(g6), and Y is as described in any one of (h1)-(h7) and (h18)-(h24).

[0232] (C3) In one embodiment, m is as described in (g5), and Y is as described in any one of (h1)-(h7) and (h18)-(h20).

[0233] (C4) In one embodiment, m is as described in (g6), and Y is as described in any one of (h1)-(h7) and (h18)-(h24).

[0234] (C5) In one embodiment, m is as described in (g1) or (g2), and Y is as described in (h8) and (h18)-(h24).

[0235] (C6) In one embodiment, m is as described in any one of (g4) to (g6), and Y is as described in (h8) and (h18) to (h24).

[0236] (C7) In one embodiment, m is as described in (g5), and Y is as described in (h8) and (h18)-(h20).

[0237] (C8) In one embodiment, m is as described in (g6), and Y is as described in (h8) and (h18)-(h24).

[0238] (C9) In one embodiment, m is as described in (g1) or (g2), and Y is as described in any one of (h9)-(h15) and (h18)-(h24).

[0239] (C10) In one embodiment, m is as described in any one of (g4)-(g6), and Y is as described in any one of (h9)-(h15) and (h18)-(h24).

[0240] (C11) In one embodiment, m is as described in (g5), and Y is as described in any one of (h9)-(h15) and (h18)-(h20).

[0241] (C12) In one embodiment, m is as described in (g6), and Y is as described in any one of (h9)-(h15) and (h18)-(h24).

[0242] (D1) In one embodiment, m and Y are as described in any one of (C1) to (C12), and n is as described in (i1) or (i2), where applicable.

[0243] (D2) In one embodiment, where applicable, m and Y are as described in any one of (C1) to (C12), and n is as described in (i3).

[0244] (D3) In one embodiment, where applicable, m and Y are as described in any one of (C1)-(C12), and n is as described in any one of (i4)-(i6).

[0245] (D4) In one embodiment, where applicable, m and Y are as described in any one of (C1) to (C12), and n is as described in (i5).

[0246] (D5) In one embodiment, where applicable, m and Y are as described in any one of (C1)-(C12), and n is as described in (i6).

[0247] (E1) In one embodiment, Y is as described in (h16), and n is as described in (i1) or (i2).

[0248] (E2) In one embodiment, Y is as described in (h16) and n is as described in (i3).

[0249] (E3) In one embodiment, Y is as described in (h16), and n is as described in any one of (i4) to (i6).

[0250] (E4) In one embodiment, Y is as described in (h16), and n is as described in (i5).

[0251] (E5) In one embodiment, Y is as described in (h16), and n is as described in (i6).

[0252] (E6) In one embodiment, Y is as described in (h17), and n is as described in (i1) or (i2).

[0253] (E7) In one embodiment, Y is as described in (h17), and n is as described in (i3).

[0254] (E8) In one embodiment, Y is as described in (h17), and n is as described in any one of (i4) to (i6).

[0255] (E9) In one embodiment, Y is as described in (h17), and n is as described in (i5).

[0256] (E10) In one embodiment, Y is as described in (h17), and n is as described in (i6).

[0257] (F1) In one embodiment, n is as described in (i1) or (i2), and Z is as described in any one of (j1)-(j7) and (j16)-(j19).

[0258] (F2) In one embodiment, n is as described in any one of (i4)-(i6), and Z is as described in any one of (j1)-(j7) and (j16)-(j19).

[0259] (F3) In one embodiment, n is as described in (i5), and Z is as described in any one of (j1)-(j7) and (j16)-(j17).

[0260] (F4) In one embodiment, n is as described in (i6), and Z is as described in any one of (j1)-(j7) and (j16)-(j19).

[0261] (F5) In one embodiment, n is as described in (i1) or (i2), and Z is as described in any one of (j8) and (j16)-(j19).

[0262] (F6) In one embodiment, n is as described in any one of (i4)-(i6), and Z is as described in any one of (j8) and (j16)-(j19).

[0263] (F7) In one embodiment, n is as described in (i5), and Z is as described in any one of (j8) and (j16)-(j17).

[0264] (F8) In one embodiment, n is as described in (i6), and Z is as described in any one of (j8) and (j16)-(j19).

[0265] (F9) In one embodiment, n is as described in (i1) or (i2), and Z is as described in any one of (j9)-(j15) and (j16)-(j19).

[0266] (F10) In one embodiment, n is as described in any one of (i4)-(i6), and Z is as described in any one of (j9)-(j15) and (j16)-(j19).

[0267] (F11) In one embodiment, n is as described in (i5), and Z is as described in any one of (j9)-(j15) and (j16)-(j17).

[0268] (F12) In one embodiment, n is as described in (i6), and Z is as described in any one of (j9)-(j15) and (j16)-(j19).

[0269] (G1) In one embodiment, n and Z are as described in any one of (F1) to (F12), and m is as described in (g1) or (g2), where applicable.

[0270] (G2) In one embodiment, n and Z are as described in any one of (F1) to (F12), and m is as described in (g3), where applicable.

[0271] (G3) In one embodiment, n and Z are as described in any one of (F1)-(F12), and m is as described in any one of (g4)-(g6), where applicable.

[0272] (G4) In one embodiment, n and Z are as described in any one of (F1)-(F12), and m is as described in (g5), where applicable.

[0273] (G5) In one embodiment, n and Z are as described in any one of (F1)-(F12), and m is as described in (g6), where applicable.

[0274] (H1) In one embodiment, where applicable, m, n and Y are as described in any one of (C1)-(D1), (D3)-(E1), (E3)-(E6) and (E8)-(E10), and Z is as described in any one of (j1)-(j7).

[0275] (H2) In one embodiment, where applicable, m, n and Y are as described in any one of (C1)-(D1), (D3)-(E1), (E3)-(E6) and (E8)-(E10), and Z is as described in (j8).

[0276] (H3) In one embodiment, where applicable, m, n and Y are as described in any one of (C1)-(D1), (D3)-(E1), (E3)-(E6) and (E8)-(E10), and Z is as described in any one of (j9)-(j15).

[0277] (I1) In one embodiment, where applicable, m, n and Y are as described in any one of (F1)-(G1) and (G3)-(G5), and Y is as described in any one of (h1)-(h7).

[0278] (I2) In one embodiment, m, n and Z are as described in any one of (F1)-(G1) and (G3)-(G5), and Y is as described in (h8), where applicable.

[0279] (I3) In one embodiment, where applicable, m, n and Z are as described in any one of (F1)-(G1) and (G3)-(G5), and Y is as described in any one of (h9)-(h15).

[0280] (I4) In one embodiment, m, n and Z are as described in any one of (F1)-(G1) and (G3)-(G5), and Y is as described in (h16), where applicable.

[0281] (I5) In one embodiment, m, n and Z are as described in any one of (F1)-(G1) and (G3)-(G5), where applicable, and Y is as described in (h17).

[0282] (J1) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k1).

[0283] (J2) In one embodiment, where applicable, Y, Z, R Z, T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in any one of (k2)-(k9).

[0284] (J3) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k4).

[0285] (J4) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k5).

[0286] (J5) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k6).

[0287] (J6) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k7).

[0288] (J7) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k8).

[0289] (J8) In one embodiment, where applicable, Y, Z, R Z , T1, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5) and (F5)-(I5), and Q is as described in (k9).

[0290] (K1) In one embodiment, where applicable, Y, Z, R Z , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l1).

[0291] (K2) In one embodiment, where applicable, Y, Z, RZ , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l2).

[0292] (K3) In one embodiment, where applicable, Y, Z, R Z , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l3).

[0293] (K4) In one embodiment, where applicable, Y, Z, R Z , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l4).

[0294] (K5) In one embodiment, where applicable, Y, Z, R Z , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l5).

[0295] (K6) In one embodiment, where applicable, Y, Z, R Z , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l6).

[0296] (K7) In one embodiment, where applicable, Y, Z, R Z , T1, Q, m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5) and (J2)-(J8), and Q' is as described in (l7).

[0297] (L1) In one embodiment, where applicable, Y, Z, R Z , T1, Q, Q', m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5), (J1)-(J8) and (K1)-(K7), and T is as described in (n1).

[0298] (L2) In one embodiment, where applicable, Y, Z, R Z, T1, Q, Q', m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5), (J1)-(J8) and (K1)-(K7), and T is as described in (n2).

[0299] (L3) In one embodiment, where applicable, Y, Z, R Z , T1, Q, Q', m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5), (J1)-(J8) and (K1)-(K7), and T is as described in (n3).

[0300] (L4) In one embodiment, where applicable, Y, Z, R Z , T1, Q, Q', m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5), (J1)-(J8) and (K1)-(K7), and T is as described in (n4).

[0301] (L5) In one embodiment, where applicable, Y, Z, R Z , T1, Q, Q', m, n and p are as described in any one of (A1)-(B18), (C5)-(D5), (F5)-(I5), (J1)-(J8) and (K1)-(K7), and T is as described in (n5).

[0302] (M1) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', m, n and p are as described in any one of (A1) to (L5), and X is as described in (a1).

[0303] (M2) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', m, n and p are as described in any one of (A1) to (L5), and X is as described in (a2).

[0304] (M3) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', m, n and p are as described in any one of (A1) to (L5), and X is as described in (a3).

[0305] (M4) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', m, n and p are as described in any one of (A1) to (L5), and X is as described in (a4).

[0306] (M5) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', m, n and p are as described in any one of (A1) to (L5), and X is as described in (a5).

[0307] (N1) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b1).

[0308] (N2) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b2).

[0309] (N3) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b3).

[0310] (N4) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b4).

[0311] (N5) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b5).

[0312] (N6) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b6)

[0313] (N7) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b7).

[0314] (N8) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b8).

[0315] (N9) In one embodiment, where applicable, Y, Z, R Z , T, T1, Q, Q', X, m, n and p are as described in any one of (A1)-(L5) and (M1), and R X As described in (b9).

[0316] (O1) In one embodiment, m is 1 and n is 0.

[0317] (O2) In one embodiment, m is 0 and n is 1.

[0318] (O3) In one embodiment, m is 1 and n is 1.

[0319] (O4) In one embodiment, m is 2 and n is 0.

[0320] (O5) In one embodiment, m is 2 and n is 1.

[0321] (O6) In one embodiment, m is 0 and n is 2.

[0322] (O7) In one embodiment, m is 1 and n is 2.

[0323] (O8) In one embodiment, m is 3 and n is 0.

[0324] (O9) In one embodiment, m is 3 and n is 1.

[0325] (O10) In one embodiment, m is 3 and n is 2.

[0326] (O11) In one embodiment, m is 0 and n is 3.

[0327] (O12) In one embodiment, m is 1 and n is 3.

[0328] (O13) In one embodiment, m is 2 and n is 3.

[0329] (P1) In one embodiment, m and n are as described in any one of (O1), (O3)-(O5), (O7)-(10), (O12) and (O13), and, where applicable, Y is as described in any one of (h1)-(h7) and (h18)-(h24).

[0330] (P2) In one embodiment, m and n are as described in any one of (O1), (O3)-(O5), (O7)-(10), (O12) and (O13), and, where applicable, Y is as described in (h8) and (h18)-(h24).

[0331] (P3) In one embodiment, m and n are as described in any one of (O1), (O3)-(O5), (O7)-(10), (O12) and (O13), and, where applicable, Y is as described in any one of (h9)-(h15) and (h18)-(h24).

[0332] (P4) In one embodiment, m and n are as described in any one of (O1), (O3)-(O5), (O7)-(10), (O12) and (O13), and where applicable, Y is as described in (h16).

[0333] (P5) In one embodiment, m and n are as described in any one of (O1), (O3)-(O5), (O7)-(10), (O12) and (O13), and where applicable, Y is as described in (h17).

[0334] (Q1) In one embodiment, m and n are as described in any one of (O2), (O3), (O5)-(O7) and (O9)-(O13), and, where applicable, Z is as described in (j1)-(j7) and (j16)-(j19).

[0335] (Q2) In one embodiment, m and n are as described in any one of (O2), (O3), (O5)-(O7) and (O9)-(O13), and, where applicable, Z is as described in (j8) and (j16)-(j19).

[0336] (Q3) In one embodiment, m and n are as described in any one of (O2), (O3), (O5)-(O7) and (O9)-(O13), and, where applicable, Z is as described in any one of (j9)-(j15) and (j16)-(j19).

[0337] (R1) In one embodiment, m, n and Y are as described in any one of (P1)-(P5), and where applicable, Z is as described in any one of (j1)-(j7) and (j16)-(j19).

[0338] (R2) In one embodiment, m, n and Y are as described in any one of (P1) to (P5), and where applicable, Z is as described in (j8) and (j16) to (j19).

[0339] (R3) In one embodiment, m, n and Y are as described in any one of (P1)-(P5), and where applicable, Z is as described in any one of (j9)-(j15) and (j16)-(j19).

[0340] (S1) In one embodiment, m, n and Z are as described in any one of (Q1)-(Q3), and where applicable, Y is as described in any one of (h1)-(h7) and (h18)-(h24).

[0341] (S2) In one embodiment, m, n and Z are as described in any one of (Q1)-(Q3), and where applicable, Y is as described in (h8) and (h18)-(h24).

[0342] (S3) In one embodiment, m, n and Z are as described in any one of (Q1)-(Q3), and where applicable, Y is as described in any one of (h9)-(h15) and (h18)-(h24).

[0343] (S4) In one embodiment, m, n and Z are as described in any one of (Q1)-(Q3), and where applicable, Y is as described in (h16) and (h18)-(h24).

[0344] (S5) In one embodiment, m, n and Z are as described in any one of (Q1)-(Q3), and where applicable, Y is as described in (h17) and (h18)-(h24).

[0345] (T1) In one embodiment, m, n, Y and Z are as described in any one of (O1) to (S5), and where applicable, p, R Z and T1 is as described in any one of (A1) to (B18).

[0346] (U1) In one embodiment, where applicable, p, R Z , T1, m, n, Y and Z are as described in any one of (O1) to (T1), and X is as described in (a1).

[0347] (U2) In one embodiment, where applicable, p, R Z , T1, m, n, Y and Z are as described in any one of (O1) to (T1), and X is as described in (a2).

[0348] (U3) In one embodiment, where applicable, p, R Z , T1, m, n, Y and Z are as described in any one of (O1) to (T1), and X is as described in (a3).

[0349] (U4) In one embodiment, where applicable, p, R Z , T1, m, n, Y and Z are as described in any one of (O1) to (T1), and X is as described in (a4).

[0350] (U5) In one embodiment, where applicable, p, R Z , T1, m, n, Y and Z are as described in any one of (O1) to (T1), and X is as described in (a5).

[0351] (V1) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b1).

[0352] (V2) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b2).

[0353] (V3) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b3).

[0354] (V4) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b4).

[0355] (V5) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b5).

[0356] (V6) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b6).

[0357] (V7) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b7).

[0358] (V8) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b8).

[0359] (V9) In one embodiment, p, R Z , T1, m, n, X, Y and Z are as described in any one of (O1)-(T1) and (U1), and R X As described in (b9).

[0360] In one embodiment, the compound of formula I is a compound of formula I1, Ia or Ib:

[0361]

[0362] or a pharmaceutically acceptable salt or ester thereof, wherein R' is H or methyl.

[0363] In one embodiment, the compound of formula I is a compound of formula I2 or I2a:

[0364]

[0365] or a pharmaceutically acceptable salt or ester thereof, wherein R' is H or methyl.

[0366] In one embodiment, the compound of formula I is a compound of formula I3, I3a or I3b:

[0367]

[0368] or a pharmaceutically acceptable salt or ester thereof, wherein R' is H or methyl.

[0369] In one embodiment, the compound of formula I is a compound of formula I4, I4a, I4b, I4c or I4d:

[0370]

[0371] or a pharmaceutically acceptable salt or ester thereof, wherein R' is H or methyl.

[0372] In one embodiment, the compound of Formula I is of Formula I5, I5a1, I5a2, I5a3, I5a4, I5a5, I5a6, I5b1, I5b2, I5b3, I5b4, I5b5, I5b6, I5c1, I5c2, I5c3, I5c4, I5c5, I5c6, I5d1, I5d2, I5d3, I5d4, I5d5, or I5d6:

[0373]

[0374]

[0375] or a pharmaceutically acceptable salt or ester thereof, wherein R' is H or methyl.

[0376] For compounds of any of Formulas II, Ila, Ilb, I2, I2a, I3, I3a, I3b, I4, I4a, I4b, I4c, I4d, I5, I5a1, I5a2, I5a3, I5a4, I5a5, I5a6, I5b1, I5b2, I5b3, I5b4, I5b5, I5b6, I5c1, I5c2, I5c3, I5c4, I5c5, I5c6, I5d1, I5d2, I5d3, I5d4, I5d5, and I5d6, X, Y, Z, R Q 、R T 、R X , Q, Q', T, m and q are respectively as defined in Formula I, for X, Y, Z, R Q 、R T 、R X , Q, Q', T, m and q, each group described herein may be combined as described above.

[0377] For example, where applicable, for compounds of any of Formula I, Ia, Ib, I1, Ila, Ilb, I2, I2a, I3, I3a, I3b, I4, I4a, I4b, I4c, I4d, I5, I5al, I5a2, I5a3, I5a4, I5a5, I5a6, I5b1, I5b2, I5b3, I5b4, I5b5, I5b6, I5c1, I5c2, I5c3, I5c4, I5c5, I5c6, I5d1, I5d2, I5d3, I5d4, I5d5, and I5d6:

[0378] In one embodiment, each Z is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CN, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl), each of which is as described herein.

[0379] In one embodiment, each Z is independently C1-C6 alkyl, halogen, CN, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl), each of which is as described herein.

[0380] In one embodiment, each Z is independently C1-C6 alkyl, halogen, CN, NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, each of which is as described herein.

[0381] In one embodiment, each Z is independently C1-C6 alkyl, halogen, CN, or N-(C1-C6 alkyl)2, each of which is as described herein.

[0382] In one embodiment, each Z is independently methyl, ethyl, n-propyl, isopropyl, CN, F, Cl, Br, I, or N(CH3)2.

[0383] In one embodiment, each Z is independently methyl, F, Cl, Br, CN, or N(CH3)2.

[0384] In one embodiment, each Z is independently F, Cl, or Br.

[0385] In one embodiment, each Z is independently Cl or Br.

[0386] In one embodiment, each Z is Cl.

[0387] In one embodiment, each Z is Br.

[0388] In one embodiment, one Z is Br and the other Z is Cl. In a further embodiment, one Z is Br at the 4-position and the other Z is Cl at the 3-position.

[0389] In one embodiment, X is C(R X )2 and each R X is independently H, CH3, CF3, CF2H or F. In a further embodiment, each R X is independently H or CH3. In another further embodiment, each R X is H. In another further embodiment, each R X For CH3.

[0390] In one embodiment, X is C(R X )2 and two R X Together form =O, =CH2 or =CF2. In a further embodiment, the two R X Together they form =O.

[0391] In one embodiment, R' is H.

[0392] In one embodiment, R' is methyl. In a further embodiment, R' is (S)-methyl. In another further embodiment, R' is (R)-methyl.

[0393] Any of the groups described above for any one of X, Z, and R' may be combined with any of the groups described above for the remainder of X, Z, and R', and, if applicable, the combination of X, Z, and R' may be further combined with any of the groups described herein for Y, Z1, R1, R2, and R3. Q 、R T 、R X 、R Z 、R S , Q, Q', T1, T, m, n, p and q are any combination of one or more of the above groups.

[0394] In one embodiment, the compound of formula I is a compound of formula I5a1, I5b1, I5c1 or I5d1:

[0395]

[0396] or a pharmaceutically acceptable salt or ester thereof, wherein R' is H or methyl.

[0397] For compounds of any of Formulas I5a1, I5b1, I5c1, and I5d1, X, Y, Z, R Q 、R T 、R X , Q, Q', T, m and q are each as defined herein for Formula I, and the for X, Y, Z, R Q 、R T 、R X Each group of any of , Q, Q', T, m and q can be combined as described above.

[0398] For example, where applicable, for compounds of any of Formulas I, Ia, Ib, I5a1, I5b1, I5c1, and I5d1:

[0399] In one embodiment, each Z is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, CN, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl), each of which is as described herein.

[0400] In one embodiment, each Z is independently C1-C6 alkyl, halogen, CN, OH, O-(C1-C6 alkyl), S-(C1-C6 alkyl), NH2, NH-C1-C6 alkyl or N-(C1-C6 alkyl), each of which is as described herein.

[0401] In one embodiment, each Z is independently C1-C6 alkyl, halogen, CN, NH2, NH-C1-C6 alkyl, or N-(C1-C6 alkyl)2, each of which is as described herein.

[0402] In one embodiment, each Z is independently C1-C6 alkyl, halogen, CN, or N-(C1-C6 alkyl)2, each of which is as described herein.

[0403] In one embodiment, each Z is independently methyl, ethyl, n-propyl, isopropyl, CN, F, Cl, Br, I, or N(CH3)2.

[0404] In one embodiment, each Z is independently methyl, F, Cl, Br, CN, or N(CH3)2.

[0405] In one embodiment, each Z is independently F, Cl, or Br.

[0406] In one embodiment, each Z is independently Cl or Br.

[0407] In one embodiment, each Z is Cl.

[0408] In one embodiment, each Z is Br.

[0409] In one embodiment, one Z is Br and the other Z is Cl. In a further embodiment, one Z is Br at the 4-position and the other Z is Cl at the 3-position.

[0410] For any formula described herein, where applicable:

[0411] In one embodiment, one Z is halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), N-(C1-C6 alkyl)2, or QT, each of which is as described herein, and the other Z is Cl. In a further embodiment, Z is Cl at the 3-position, and halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), N-(C1-C6 alkyl)2, or QT is at the 4-position.

[0412] In one embodiment, one Z is halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), or N-(C1-C6 alkyl), each as described herein, and the other Z is Cl. In a further embodiment, Z is Cl at the 3-position and halogen, O-(C1-C6 alkyl), S-(C1-C6 alkyl), or N-(C1-C6 alkyl) is at the 4-position.

[0413] In one embodiment, one Z is halogen and the other Z is Cl. In a further embodiment, Z is Cl at position 3. In a further embodiment, Z is Cl at position 3 and halogen is at position 4. In a further embodiment, halogen is Cl, Br or I. In a further embodiment, halogen is Cl.

[0414] In one embodiment, one Z is O-(C1-C6 alkyl), as described herein. And the other Z is Cl. In a further embodiment, Z is Cl at the 3-position and O-(C1-C6 alkyl) is at the 4-position. In a further embodiment, O-(C1-C6 alkyl) is O-methyl.

[0415] In one embodiment, one Z is S-(C1-C6 alkyl), as described herein. And the other Z is Cl. In a further embodiment, Z is Cl at the 3 position and S-(C1-C6 alkyl) is at the 4 position. In a further embodiment, S-(C1-C6 alkyl) is S-methyl.

[0416] In one embodiment, one Z is N-(C1-C6 alkyl)2, as described herein. And the other Z is Cl. In a further embodiment, Z is Cl at the 3-position and N-(C1-C6 alkyl)2 is at the 4-position. In a further embodiment, N-(C1-C6 alkyl)2 is N(CH3)2 or N(CH3)(CH2CH3).

[0417] In one embodiment, one Z is QT, as described herein. And the other Z is Cl. In a further embodiment, Z is Cl at the 3 position. In a further embodiment, Z is Cl at the 3 position and QT is at the 4 position. In a further embodiment, Q is a bond and T is cycloalkyl, cycloalkenyl, heterocyclyl, C6-C 10 Aryl or heteroaryl, each optionally substituted with one or more R T In a further embodiment, Q is a bond and T is C6-C 10 Aryl, optionally substituted with one or more R T In a further embodiment, T is phenyl, which is optionally substituted with one or more R T .

[0418] In one embodiment, Y is tert-butyl, one Z is S-CH3, and the other Z is Cl. In a further embodiment, one Z is S-CH3 at the 4-position, and the other Z is Cl at the 3-position.

[0419] In one embodiment, Y is tert-butyl, one Z is O-CH3, and the other Z is Cl. In a further embodiment, one Z is O-CH3 at the 4-position, and the other Z is Cl at the 3-position.

[0420] In one embodiment, Y is methyl, isopropyl or tert-butyl, one Z is phenyl, and the other Z is Cl. In a further embodiment, one Z is phenyl at the 4 position, and the other Z is Cl at the 3 position. In a further embodiment, Y is methyl or isopropyl. In a further embodiment, Y is at the 6 position.

[0421] In one embodiment, Y is methyl, isopropyl or tert-butyl, one Z is N(CH3)2, and the other Z is Cl. In a further embodiment, one Z is N(CH3)2 at the 4 position, and the other Z is Cl at the 3 position. In a further embodiment, Y is methyl or tert-butyl. In a further embodiment, Y is at the 6 position.

[0422] In one embodiment, Y is NH-phenyl, one Z is N(CH 3 ) 2 , and the other Z is Cl. In a further embodiment, one Z is N(CH 3 ) 2 at the 4 position, and the other Z is Cl at the 3 position. In a further embodiment, Y is at the 6 position.

[0423] In one embodiment, X is C(R X )2, and each R X is independently H, CH3, CF3, CF2H or F. In a further embodiment, each R X is independently H or CH3. In another further embodiment, each R X is H. In another further embodiment, each R X For CH3.

[0424] In one embodiment, X is C(R X )2, and two R X Together form =O, =CH2 or =CF2. In a further embodiment, the two R X Together they form =O.

[0425] In one embodiment, Y is NH-(phenyl) and one Z is N-(CH3)2, and the other Z is halogen. In a further embodiment, halogen is Cl.

[0426] In one embodiment, Y is C1-C6 alkyl and one Z is phenyl and the other Z is halogen. In a further embodiment, Z is halogen at position 3. In a further embodiment, halogen is Cl. In another further embodiment, Z is Cl at position 3. In another further embodiment, Y is methyl.

[0427] In one embodiment, Y is isopropyl and one Z is N-(CH3)2, and the other Z is halogen. In a further embodiment, Z is halogen at the 3-position. In a further embodiment, halogen is Cl. In another further embodiment, Z is Cl at the 3-position.

[0428] In one embodiment, Y is C1-C6 alkyl and one Z is N-(CH3)2, and the other Z is halogen. In a further embodiment, halogen is Cl. In another further embodiment, Z is Cl at the 3 position. In another further embodiment, Y is methyl. In another further embodiment, Y is methyl at the 6 position.

[0429] In one embodiment, Y is a branched C1-C6 alkyl group and one Z is phenyl and the other Z is halogen. In a further embodiment, Z is halogen at position 3. In a further embodiment, halogen is Cl. In another further embodiment, Y is isopropyl.

[0430] In one embodiment, R' is H.

[0431] In one embodiment, R' is methyl. In a further embodiment, R' is (S)-methyl. In another further embodiment, R' is (R)-methyl.

[0432] Any of the groups described above for any of X, Z, and R' may be combined with any of the groups described above for the remaining X, Z, and R', and where applicable, the combination of X, Z, and R' may be combined with the groups described herein for Y, Z1, R1, R Q 、R T 、R X 、R Z 、R S , Q, Q', T1, T, m, n, p and q, or any combination of one or more of the above.

[0433] Table 1 shows representative compounds of this application.

[0434] Table 1

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] Some of the aforementioned compounds may contain one or more asymmetric centers and therefore may exist in various isomeric forms, for example, stereoisomers and / or diastereomers. Therefore, the compounds of the present application may be in the form of individual enantiomers, diastereomers or geometric isomers or may be in the form of a mixture of stereoisomers. In one embodiment, the compounds of the present application are enantiopure compounds. In another embodiment, a mixture of stereoisomers or diastereomers is provided.

[0464] Another aspect is an isotopically labeled compound of any formula described herein. These compounds have one or more isotopic atoms, which atoms introduced into the compound may be radioactive or non-radioactive (e.g., 3 H. 2 H. 14 C. 13 C. 18 F. 35 S. 32 P. 125 I and 131 I). These compounds are useful in drug metabolism studies and diagnostic as well as therapeutic applications.

[0465] Performance can also be improved through IC 50 Determined under similar conditions, it has a lower IC 50 Compounds with higher IC 50 In some embodiments, substantially similar conditions include determining the binding level of a known STING ligand to a STING protein in vitro or in vivo in the presence of a compound of the present application.

[0466] In one embodiment, the compounds of the present application can be used as therapeutic agents and are thus useful for treating diseases caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function) or diseases associated with one or more intracellular pathways in which STING participates (e.g., regulation of intracellular DNA-mediated type I interferon activation), such as those described herein.

[0467] "Selective STING modulators" can be identified, for example, by comparing the ability of a compound to modulate STING expression / activity / function to its ability to modulate other proteins or STING proteins from other species. In some embodiments, the EC of a compound can be measured. 50 or IC 50In some embodiments, the compounds of the present application are "selective human STING modulators."

[0468] In certain embodiments, the compounds of the present application are STING modulators (e.g., selective human STING modulators) that exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold selectivity over other proteins or STING proteins from other species (e.g., non-human animals such as mice). In various embodiments, the compounds of the present application exhibit 1000-fold selectivity over other proteins or STING proteins from other species.

[0469] The compounds of the present application are defined herein by their chemical structure and / or chemical name. When the chemical structure and chemical name of a compound are mentioned simultaneously, and the chemical structure and chemical name conflict, the chemical structure will determine the identity of the compound.

[0470] The listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment of a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0471] In another aspect, the present application provides a method for synthesizing the compounds disclosed herein. The synthesis of the compounds of the present application can be found herein and in the examples below. Other embodiments are methods for preparing compounds of any formula herein using any one or combination of the reactions described herein. The methods may include the use of one or more intermediates or chemical reagents described herein.

[0472] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

[0473] Another aspect of the present application relates to a kit comprising a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application. In another aspect, the present application provides a kit comprising a compound capable of modulating STING activity, the compound being selected from one or more compounds disclosed herein or a pharmaceutically acceptable salt or ester thereof, optionally in combination with a second agent and instructions for use.

[0474] Another aspect of the present application relates to a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application, for use in the manufacture of a medicament for regulating (e.g., inhibiting or stimulating) a STING protein, a medicament for treating or preventing a disease, wherein the disease is caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or a medicament for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving a STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0475] Another aspect of the present application relates to the use of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition of the present application in the preparation of a medicament for regulating (e.g., inhibiting or stimulating) the STING protein, a medicament for treating or preventing a disease, wherein the disease is caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or a medicament for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving the STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0476] Another aspect of the present application relates to a compound of the present application or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application, for use in regulating (e.g., inhibiting or stimulating) a STING protein, for treating or preventing a disease caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or for treating or preventing a disease associated with dysregulation of one or more intracellular pathways involving a STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0477] Another aspect of the present application relates to the use of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, or the pharmaceutical composition of the present application in regulating (e.g., inhibiting or stimulating) the STING protein, treating or preventing diseases caused by or related to STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function), or treating or preventing diseases associated with dysregulation of one or more intracellular pathways involving the STING protein (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0478] Synthesis methods of compounds

[0479] The compounds of the present application can be prepared in a variety of ways using commercially available starting materials, compounds known in the document, or easily prepared intermediates, by using standard synthetic methods and steps known to those skilled in the art or apparent to those skilled in the art based on the teachings herein. Standard synthetic methods and steps for preparing organic molecules and functional group transformations and manipulations can be obtained from relevant scientific literature or standard textbooks in the field. Although not limited to any one or more sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, incorporated herein by reference, are useful and recognized organic synthesis reference textbooks known to those skilled in the art. The following description of the synthetic method is intended to illustrate but not limit the general procedure for preparing the compounds of the present application. Although in some cases it may be necessary to further convert the compound into a pharmaceutically acceptable salt, ester or prodrug thereof, this method generally provides the desired final compound at or near the end of the overall process. Suitable synthetic routes are described in the schemes below.

[0480] Those skilled in the art will recognize whether there is a stereocenter in the compounds disclosed herein. Therefore, the application includes possible stereoisomers (unless otherwise specified in the synthesis), and not only includes racemic compounds, but also includes independent enantiomers and / or diastereomers. When a compound is required to be a single enantiomer or diastereomer, it can be synthesized by stereospecificity or obtained by splitting the final product or any convenient intermediate. The splitting of the final product, intermediate or starting material may be affected by any appropriate method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Elliel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).

[0481] The compounds of the present application can be prepared by various methods well known to those skilled in the art of organic synthesis. As an example, the compounds of the present application can be synthesized using the methods described below and synthetic methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the following methods.

[0482] The compounds of the present application can be synthesized by following the steps outlined in the following flow chart, which includes the order of different assembly intermediates. The starting materials can be commercially available or prepared by known methods reported in the literature or as shown. As shown in the following scheme, the compounds of the present application can be synthesized by cross-coupling reactions of known compounds catalyzed by transition metals. As shown below, the cross-coupling reactions can provide the compounds or intermediates of the present application, which can be further hydrogenated or deprotected to provide the target compound.

[0483] Options 1a-1d

[0484] 1a-1

[0485]

[0486] 1a-2

[0487]

[0488] 1a'

[0489]

[0490]

[0491] 1d

[0492]

[0493] As shown in Schemes 1a-1d, copper-catalyzed Ullmann coupling between the requisite aniline (B1, B2, B3, or B4) and an appropriately substituted 2-bromobenzoic acid or 2-iodobenzoic acid (A) yields the corresponding diphenylamine (C1, C2, C3, or C4) (1a-1). Alternatively, the diphenylamine (C1, C2, C3, or C4) can be prepared according to 1a-2 or 1a'. Cyclodehydration of the diphenylamine (C1, C2, C3, C4) can provide substituted 10H-acridin-9-ones (D1, D2a, D2b, D3, or D4) (1b). Alkylation of the 10H-acridin-9-ones (D1, D2a, D2b, D3, or D4) followed by saponification yields the target compounds (E1, E2a, E2b, E3, or E4) (1c). Alternatively, 10H-acridin-9-one (D1, D2a, D2b, D3 or D4) is hydrogenated followed by saponification to produce additional target compounds (F1, F2a, F2b, F3 or F4) (1d).

[0494] Option 2

[0495]

[0496] As shown in Scheme 2, the compounds of the present application or their precursors can be prepared by brominating compound F and then saponifying according to the above steps.

[0497] Option 3a

[0498]

[0499] Option 3b

[0500]

[0501] As shown in Schemes 3a and 3b, the compounds of the present application can be prepared by Sonogashira coupling, and the products of the coupling reaction can be hydrogenated to generate other compounds of the present application.

[0502] Option 4

[0503]

[0504] As shown in Scheme 4, the compounds of the present application can be prepared by Suzuki coupling, and the products thereof can be saponified or hydrogenated to produce other compounds of the present application.

[0505] Option 5

[0506]

[0507] Option 6

[0508]

[0509] Options 7a and 7b

[0510] 7a

[0511]

[0512] 7b

[0513]

[0514] Schemes 8a-8f

[0515] 8a

[0516]

[0517] 8b

[0518]

[0519] 8c

[0520]

[0521] 8d

[0522]

[0523] 8e

[0524]

[0525] 8f

[0526]

[0527] Option 9

[0528]

[0529] Plan 10

[0530]

[0531] Plan 11

[0532]

[0533] Option 12a

[0534]

[0535] Plan 12b

[0536]

[0537] Plan 13

[0538]

[0539] Plan 14

[0540]

[0541] Other compounds of the present application can be prepared using the methods of Schemes 5-14.

[0542] The compounds of the present invention can be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, pharmaceutically acceptable base addition salts of the compounds of the present invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Pharmaceutically acceptable salts can include various counterions, for example, counterions of inorganic or organic acids, counterions of inorganic or organic bases, or counterions provided by counterion exchange.

[0543] Acids and bases that can be used in the methods herein are known in the art. An acid catalyst is any acidic chemical substance that can be an inorganic substance (e.g., hydrochloric acid, sulfuric acid, nitric acid, aluminum chloride) or an organic substance (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium trifluoromethanesulfonate). An acid can be used in a catalytic or stoichiometric manner to promote a chemical reaction. A base is any alkaline chemical substance that can be an inorganic substance (e.g., sodium bicarbonate, potassium hydroxide) or an organic substance (e.g., triethylamine, pyridine). A base can be used in a catalytic or stoichiometric manner to promote a chemical reaction.

[0544] Alternatively, the salt form of the present application compound can be prepared using the salt of the raw material or intermediate. The free acid or free base form of the present application compound can be prepared by the corresponding base addition salt or acid addition salt, respectively. For example, the present application compound in the form of an acid addition salt can be converted into the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The present application compound in the form of an alkali addition salt can be converted into the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0545] The nitrogen-containing compounds of the present invention can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (m-CPBA) and / or hydrogen peroxide) to provide other compounds of the present invention. Therefore, when valence and structure permit, all nitrogen-containing compounds shown and claimed are considered to include the compounds shown and their N-oxide derivatives. (Can be represented as N→O or N + -O - ). In addition, in other cases, the nitrogen in the compounds of the present application can be converted into N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidizing the parent amine with an oxidizing agent such as m-CPBA. When valence and structure permit, all nitrogen-containing compounds shown and claimed are also considered to cover the shown compounds and their N-hydroxy (i.e., N-OH) and N-alkoxy derivatives (i.e., N-OR, wherein R is substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-14-membered carbocyclic 3-14-membered heterocyclic).

[0546] Prodrugs of the compounds of the present invention can be prepared by methods known to those of ordinary skill in the art. (For example, see Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985 for further details.) For example, suitable prodrugs can be prepared by reacting the non-derivatized compounds of the present invention with a suitable carbamoylating agent (e.g., 1,1-acyloxyalkyl chloroformate, p-nitrophenyl carbonate, etc.). Specifically, the central N-acetic acid moiety and other similar carboxylic acid groups of the compounds of the present invention can be modified by techniques known in the art to produce effective prodrugs of the present invention.

[0547] Protected derivatives of the compounds of the present invention can be prepared by methods known to those skilled in the art. A detailed description of techniques suitable for creating and removing protecting groups is provided in: TW Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.

[0548] The compounds of the present application can be conveniently prepared or formed into solvates (e.g., hydrates) during administration. Hydrates of the compounds of the present application can be conveniently prepared by recrystallization in a water / organic solvent mixture using an organic solvent such as dioxin, tetrahydrofuran or methanol.

[0549] Optical isomers can be prepared from their respective optically active precursors according to the procedures described herein, or by resolving racemic mixtures. Resolution can be carried out in the presence of a resolving agent by chromatography or by repeated crystallization or some combination of these techniques known to those skilled in the art. For more detailed information on resolution, see Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).

[0550] The synthesized compound can be isolated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. As will be appreciated by those skilled in the art, further methods for synthesizing the compound of the formula herein will be apparent to those of ordinary skill in the art. In addition, various synthesis steps can be performed alternately or sequentially to obtain the desired compound. In addition, the solvents, temperatures, reaction durations, etc. described herein are for illustrative purposes only, and those of ordinary skill in the art will recognize that variations in reaction conditions can produce the desired bridged macrocyclic products of the present application. Synthetic chemistry transformations and protecting group methodology (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions.

[0551] The compounds of the present invention may be modified by attaching various functional groups by any of the synthetic means described herein to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter excretion rate.

[0552] Bioassay

[0553] The biological activity of the compounds of the present application can be measured by various biochemical or cellular assays known to those of ordinary skill in the art. Non-limiting examples of biochemical and cellular assays are listed below.

[0554] SWAT protein FP competition dose-response assay

[0555] A validated STING ligand (e.g., c-di-GMP) is labeled with a readout signal (e.g., a fluorescent signal, such as fluorescein) and then mixed with STING-CTD (e.g., mouse STING-CTD or human STING-CTD) in the presence or absence of a compound of the present invention. Changes in the readout signal are measured (e.g., by fluorescence anisotropy) to determine binding of the compound to STING-CTD.

[0556] Pharmaceutical composition

[0557] In another aspect, a pharmaceutical composition is provided, comprising a therapeutically effective amount of the compound of the present application or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

[0558] The compounds of the present application can be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example, orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions, or topically, for example, in the form of emulsions, gels, ointments or creams, or in the form of nasal preparations or suppositories.

[0559] Pharmaceutical compositions can be prepared in conventional manner by mixing, granulating, or coating methods and comprise a compound of the present invention in free form or in pharmaceutically acceptable salt form in combination with at least one pharmaceutically acceptable carrier or diluent. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient and a) a diluent, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) a lubricant, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol. Tablets may also contain c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired, d) a disintegrant, such as starch, agar, alginic acid, its sodium salt, or an effervescent mixture; and / or e) an absorbent, a colorant, a flavoring, and a sweetener. Injectable compositions can be isotonic aqueous solutions or suspensions, and suppositories can be prepared from fat emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts for regulating osmotic pressure, and / or buffers. Furthermore, they may contain other substances of therapeutic value. Suitable formulations for transdermal application include an effective amount of a compound of the invention and a carrier. The carrier may include an absorbable pharmacologically acceptable solvent to aid passage through the host's skin. For example, a transdermal device may be in the form of a bandage comprising a backing member, a reservoir containing the compound, optionally a carrier, and optionally a rate-controlling barrier to deliver the compound to the host's skin at a controlled and predetermined rate over a prolonged period of time, and to secure the device to the skin. Matrix transdermal formulations may also be used. For example, suitable formulations for topical application, such as to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels as are known in the art. They may include solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0560] The pharmaceutical composition of the present application comprises a therapeutically effective amount of the compound of the present application formulated with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" refers to any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation adjuvant. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polypropylene oxide-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, Ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may be included in the composition according to the judgment of the formulator.

[0561] The pharmaceutical compositions of the present application can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (eg, by powders, ointments or drops), buccally or as an oral or nasal spray.

[0562] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form can also include inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed, peanut, corn, germ, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluent, the oral composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and flavoring agents.

[0563] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injections.

[0564] To prolong the effect of a drug, it is often desirable to slow the absorption of a drug injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The drug's absorption rate then depends on its dissolution rate, which in turn depends on the size and crystalline form of the crystals. Alternatively, delayed absorption of parenteral drugs can be achieved by dissolving or suspending the drug in an oily vehicle.

[0565] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

[0566] Solid compositions of a similar type may also be employed as fillers in hard-filled and soft-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0567] The active compound can also be present in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared by coatings and shells, such as enteric coatings, controlled release coatings and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also conventionally include other substances in addition to inert diluents, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also contain a buffer.

[0568] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if necessary, a preservative or buffer. Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also contemplated within the scope of this application.

[0569] Ointments, pastes, creams and gels may contain, in addition to the active compounds of the present invention, excipients such as animal or vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0570] Powders and sprays may contain, in addition to the compounds of the present application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may also contain customary propellants such as chlorofluorohydrocarbons.

[0571] Another advantage of transdermal patches is the ability to control the release of a compound into the body. This dosage form can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0572] For any compound, the therapeutically effective amount can be estimated initially in cell culture assays (tumor cells) or in animal models (usually rats, mice, rabbits, dogs or pigs). Animal models can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine a dose and route of administration that is useful in humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, ED 50 (the therapeutic dose effective in 50% of the population) and LD 50 (The dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as LD 50 / ED 50 The ratio of . Pharmaceutical compositions with large therapeutic indices are preferred. The dosage may vary within this range depending on the dosage form used, the sensitivity of the patient, and the route of administration.

[0573] The dosage and mode of administration are adjusted to provide adequate levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination, reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, weekly, or biweekly, depending on the half-life and clearance rate of the particular formulation.

[0574] The amount of the active ingredient (e.g., a disclosed compound or a salt thereof, a hydrate, a solvate or an isomer thereof) in a unit dose composition is an effective amount and varies according to the specific treatment involved. It will be appreciated by those skilled in the art that it is sometimes necessary to make routine changes to the dosage according to the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the present invention's compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants required under sterile conditions.

[0575] The pharmaceutical composition comprising the active compound of the present application can be prepared in a conventional manner, for example, by conventional mixing, dissolving, granulating, sugar coating manufacturing, grinding, emulsification, encapsulation, embedding or lyophilizing methods. Pharmaceutical compositions can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or adjuvants, which help to process the active compound into a pharmaceutically useful preparation. Of course, suitable dosage form depends on the selected route of administration.

[0576] Techniques for preparing and administering the compounds disclosed herein can be found in Remington: the Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are combined with a pharmaceutically acceptable carrier or diluent for use in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0577] How to use

[0578] In one aspect, the present application provides a method for regulating (e.g., inhibiting or stimulating) the STING protein. The method comprises administering an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application to a subject in need thereof.

[0579] In some embodiments, by IC 50 Measuring the modulation of STING protein activity. In some embodiments, the EC 50 Measuring the modulation of STING protein activity.

[0580] The compounds of the present application (e.g., compounds of any formula described herein or selected from any compound described herein) can treat or prevent diseases caused by or associated with STING expression, activity and / or function (e.g., dysregulation of STING expression, activity and / or function) or diseases associated with dysregulation of one or more intracellular pathways in which the STING protein participates (e.g., dysregulation of intracellular dsDNA-mediated type I interferon activation).

[0581] In one aspect, the present application provides a method for treating or preventing a disease, wherein the disease is caused by or associated with STING expression, activity, and / or function (e.g., dysregulation of STING expression, activity, and / or function). The method comprises administering to a subject in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application. In one aspect, the disease is a STING-mediated disease.

[0582] In one aspect, the present application provides a method for treating or preventing a disease associated with dysregulation of one or more intracellular pathways in which the STING protein is involved (e.g., dysregulation of type I interferon activation mediated by intracellular dsDNA). The method comprises administering to a subject in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of the present application.

[0583] In one embodiment, the present application provides a method for treating or preventing any disease, disorder, and condition described herein, wherein the subject is a human. In one embodiment, the present application provides a method for treating. In one embodiment, the present application provides a method for preventing.

[0584] As modulators of STING proteins, the compounds and compositions of the present application are particularly useful for treating or alleviating the severity of diseases, disorders, or conditions involving STING proteins or involving one or more intracellular pathways associated with STING. In one embodiment, the present application provides a method of treating or alleviating the severity of diseases, disorders, or conditions using compounds that regulate the binding of atypical cyclic dinucleotides (CDNs) (e.g., 2'3' cGAMP) to STING proteins. In one embodiment, the present application provides a method of treating or alleviating the severity of diseases, disorders, or conditions using compounds that regulate the synthesis of type I interferons and / or type I IFN responses.

[0585] On the one hand, the application also provides a method for treating or preventing cell proliferative diseases such as hyperplasia, dysplasia or precancerous lesions. Atypical hyperplasia is the earliest form of precancerous lesions that pathologists can identify in biopsies. The compounds of the application can be administered to prevent the continued development or canceration of hyperplasia, dysplasia or precancerous lesions. Examples of precancerous lesions may occur in the skin, esophageal tissue, breast and cervical epithelial tissue.

[0586] In one embodiment, the disease or condition includes, but is not limited to, an immune disorder, an autoimmune disorder, a cell proliferative disease or condition, cancer, inflammation, cachexia, a neurodegenerative disease or condition, a neurological disease or condition, a cardiac dysfunction, transplantation, or an infection (e.g., a viral, bacterial, and / or fungal infection or other microbial infection).

[0587] In one embodiment, the disease or disorder is a cell proliferative disease or disorder.

[0588] As used herein, the term "cell proliferative disorder" refers to a condition in which the dysregulation or abnormal growth of cells, or both, leads to the development of an undesirable condition or disease, which may or may not be cancerous. Exemplary cell proliferative disorders or conditions encompass a variety of diseases in which cell division is dysregulated. Exemplary cell proliferative disorders include, but are not limited to, tumors, benign tumors, malignant tumors, precancerous lesions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immune tumors, hematologic tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. As used herein, the term "rapidly dividing cells" is defined as any cell that divides at a rate exceeding or greater than that expected or observed between adjacent or juxtaposed cells in the same tissue. Cell proliferative disorders or conditions include precancerous or precancerous conditions. Cell proliferative disorders or conditions include cancer.

[0589] In one embodiment, the proliferative disease or condition is non-cancerous. In one embodiment, non-cancerous diseases or conditions include, but are not limited to, rheumatoid arthritis; inflammation; autoimmune diseases; lymphoproliferative diseases; acromegaly; rheumatoid spondylitis; osteoarthritis; gout; other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pneumonia; inflammatory bowel disease; Crohn's disease; hyperproliferative diseases associated with the skin; psoriasis Ringworm; eczema; atopic dermatitis; pigmentation disorders; hyperproliferative disorders of the eye; age-related macular degeneration; ulcerative colitis; pancreatic fibrosis; liver fibrosis; acute and chronic kidney disease; irritable bowel syndrome; heartburn (pyrosis); restenosis; cerebral malaria; stroke and ischemic injury; neurotrauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhinitis; allergic conjunctivitis; chronic heart failure; acute coronary syndrome ; cachexia; malaria; leprosy; leishmaniasis; Lyme disease; ReiteR syndrome; acute synovitis; muscle degeneration, bursitis; tendinitis; tenosynovitis; ruptured or herniated disc syndrome; osteosclerosis; thrombosis; restenosis; silicosis; pulmonary sclerosis; osteoporosis and other bone resorption diseases; graft-versus-host disease; fibrofatty hyperplasia; spinocerebellar ataxia type 1; CLOVES syndrome; harlequin ichthyosis; macrodactyly syndrome; Protius syndrome Wiedemann syndrome; LEOPARD syndrome; systemic sclerosis; multiple sclerosis; lupus; fibromyalgia; AIDS and other viral illnesses, such as herpes zoster, herpes simplex type I or II, influenza virus, and cytomegalovirus; diabetes mellitus; hemihyperplasia-polyostotic syndrome; macrocephaly; the rare hypoglycemia Klippel-Trenaunay syndrome; hamartomas; Cowden syndrome; or hyperglycemia due to excessive growth.

[0590] In one embodiment, the proliferative disease is cancer. In one embodiment, the cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, stomach cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma or a solid tumor.

[0591] The term "cancer" includes, but is not limited to, the following cancers: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer, genitourinary tract cancer; esophageal cancer; laryngeal cancer, glioblastoma; neuroblastoma; stomach cancer; skin cancer, keratoacanthoma; lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone cancer; colon cancer; colorectal cancer; pancreatic cancer, adenocarcinoma; thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder cancer; liver cancer and biliary tract cancer; kidney cancer cancer; bone marrow diseases; lymphatic diseases, Hodgkin's disease, hairy cell cancer; buccal and pharyngeal (oral) cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer; small intestine cancer; colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer; chronic myeloid leukemia and leukemia; the term "cancer" includes, but is not limited to, the following cancers: myeloma, lymphoma or stomach cancer, kidney cancer or the following cancers: head and neck cancer or oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma and lung cancer.

[0592] The term "cancer" also refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, tumors, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancer includes, but is not limited to, mesothelioma, leukemias and lymphomas, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotropic virus (HTLV), such as adult T-cell leukemia / lymphoma (ATLL), B-cell lymphomas, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphomas and multiple myeloma, non-Hodgkin's lymphoma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndrome, solid tumors in childhood, such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors and soft tissue sarcomas, common solid tumors in adults, such as head and neck cancer (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer and esophageal cancer), genitourinary tract cancer (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, testicular cancer), lung cancer (e.g., small cell carcinoma and non-small cell carcinoma), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin's syndrome (e.g., medulloblastoma, meningioma, etc.) and liver cancer. Additional examples of cancers that can be treated by the compounds of the present invention include, but are not limited to, bone cancer or smooth muscle cancer, stomach cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer and pituitary cancer.

[0593] Cancer may also include colon cancer, common adenomatous polyposis carcinoma, hereditary non-polyposis colorectal cancer or melanoma. In addition, cancer includes but is not limited to lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gallbladder cancer, bronchogenic carcinoma, multiple myeloma, basal sarcoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngiosarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma.

[0594] Cancers may also include colorectal cancer, thyroid cancer, breast cancer and lung cancer; and myelodysplasia, such as polycythemia vera, thrombocythemia, myelofibrosis with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myeloid leukemia and systemic mast cell disease. In one embodiment, the compounds of the present application can be used to treat hematopoietic system diseases, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia and acute lymphoblastic leukemia (ALL).

[0595] Exemplary cancers may also include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancer, anorectal cancer, anal canal cancer, appendix cancer, childhood cerebellar astrocytoma, childhood cerebellar astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary tract cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brainstem glioma, cerebellar astrocytoma, brain astrocytoma / malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, optic pathway and hypothalamic glioma, breast cancer, bronchial Adenoma / Carcinoid, Carcinoid Tumor, Gastrointestinal Cancer, Nervous System Cancer, Nervous System Lymphoma, Central Nervous System Cancer, Central Nervous System Lymphoma, Cervical Cancer, Childhood Cancer, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Lymphoid Neoplasms, Mycosis Fungoides, Seziary Syndrome, Endometrial Cancer, Esophageal Cancer, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Biliary Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid, Gastrointestinal Stromal Tumor (GIST), Germ Cell Tumor, Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Head and Neck Cancer, Hepatocellular Carcinoma ( Liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), Kaposi's sarcoma, renal cancer, kidney cancer, renal cancer, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, lip and oral cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lymphoma, macroglobulinemia, medulloblastoma, melanoma, intraocular (eye) melanoma, Merkel cell carcinoma, mesothelioma malignant, mesothelioma, metastatic squamous cell carcinoma, oral cancer, tongue cancer, multiple endocrine neoplasia syndrome, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disease Dysplasia / myeloproliferative disorders, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oral cancer, oropharyngeal cancer, ovarian cancer, epithelial ovarian cancer, ovarian low-grade malignant potential tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, blastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasmacytoma / multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing's sarcoma, Kaposi's sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma),Skin cancer (melanoma), Merkel cell skin cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer (gastric epithelial carcinoma), supratentorial primitive neuroectodermal tumor, testicular cancer, pharyngeal cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumor, urethral cancer, endometrial cancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvar cancer and Wilm's tumor.

[0596] "Hematologic cell proliferative disorders" are cell proliferative disorders or conditions involving cells of the hematologic system. Hematologic cell proliferative disorders may include lymphomas, leukemias, myeloid neoplasms, mastocytoma, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granuloma, lymphomatoid papules, polycythemia vera, chronic myeloid leukemia, unexplained extramedullary metaplasia, and essential thrombocythemia. Hematologic cell proliferative disorders may include hyperplasia, dysplasia, and metaplasia of hematologic cells. The compounds and compositions of the present application may be used to treat a cancer selected from a hematologic cancer or a hematologic cell proliferative disorder. Hematologic cancers may include multiple myeloma, lymphomas (including Hodgkin lymphoma, non-Hodgkin lymphoma, childhood lymphoma, and lymphocytic and cutaneous lymphomas), leukemias (including childhood leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, and mast cell leukemia), myeloma, and mast cell tumors.

[0597] "Cell proliferative disease of the lung" is a cell proliferative disease or condition involving lung cells. Cell proliferative disease of the lung may include all forms of cell proliferative disease affecting lung cells. Cell proliferative disease of the lung may include lung cancer, precancerous or early cancerous conditions of the lung, benign growths or lesions of the lung, malignant growths or lesions of the lung, and metastatic lesions of body tissues and organs other than the lung. The compounds and compositions of the present application can be used to treat lung cancer and proliferative diseases of the lung. Lung cancer may include all forms of cancer of the lung. Lung cancer may include malignant lung tumors, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Lung cancer may include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC"), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma. Lung cancer may include "scar carcinoma," bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer may include lung tumors with histological and ultrastructural heterogeneity (e.g., mixed cell types).

[0598] Cell proliferative diseases of the lung can include hyperplasia, metaplasia and dysplasia of the lung.Cell proliferative diseases of the lung can include asbestos-induced hyperplasia, squamous metaplasia and benign reactive mesothelial metaplasia.Cell proliferative diseases of the lung can include stratified squamous epithelial replacement and mucosal dysplasia of columnar epithelium.The risk of individual occurrence of cell proliferative diseases of the lung in those exposed to inhaled harmful environmental substances (such as cigarette smoke and asbestos) may increase.Previous lung diseases that may make individuals easily develop into cell proliferative diseases of the lung can include chronic interstitial lung disease, necrotizing lung disease, scleroderma, rheumatoid arthritis, sarcoidosis, interstitial pneumonia, tuberculosis, recurrent pneumonia, idiopathic pulmonary fibrosis, granuloma, asbestosis, fibrosing alveolitis and Hodgkin's disease.

[0599] A "cell proliferative disorder of the colon" is a cell proliferative disorder involving cells of the colon. A cell proliferative disorder of the colon is colon cancer. The compounds and compositions of the present application can be used to treat colon cancer or a cell proliferative disorder of the colon. Colon cancer can include all forms of cancer of the colon. Colon cancer can include sporadic and hereditary colon cancer. Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors. Colon cancer can include adenocarcinomas, squamous cell carcinomas, and adenosquamous carcinomas. Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis. Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome, and juvenile polyposis.

[0600] Cell proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon, and metachronous lesions of the colon. Cell proliferative disorders of the colon can include adenomas. Cell proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon. Prior colon disease that can predispose an individual to developing a cell proliferative disorder of the colon includes prior colon cancer. Current illness that can predispose an individual to developing a cell proliferative disorder of the colon includes Crohn's disease and ulcerative colitis. Cell proliferative disorders of the colon can be associated with mutations in genes selected from p53, ras, FAP, and DCC. Due to the presence of mutations in genes selected from p53, ras, FAP, and DCC, an individual may have an increased risk of developing a cell proliferative disorder of the colon.

[0601] A "cell proliferative disorder of the pancreas" is a cell proliferative disorder involving pancreatic cells. The compounds and compositions of the present application can be used to treat pancreatic cancer and cell proliferative disorders of the pancreas. Cell proliferative disorders of the pancreas can include all forms of cell proliferative disorders affecting pancreatic cells. Cell proliferative disorders of the pancreas can include pancreatic cancer, precancerous or precancerous conditions of the pancreas, pancreatic hyperplasia and pancreatic dysplasia, benign growths or lesions of the pancreas and malignant growths or lesions of the pancreas, as well as metastatic lesions to tissues and organs other than the pancreas in the body. Pancreatic cancer includes all forms of cancer of the pancreas. Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary tumors, mucinous cystadenoma, papillary cystic tumors, and serous cystadenoma. Pancreatic cancer can also include pancreatic neoplasms with histological and ultrastructural heterogeneity (eg, mixed cell types).

[0602] A "cell proliferative disorder of the prostate" is a cell proliferative disorder involving prostate cells. The compounds and compositions of the present application can be used to treat prostate cancer and cell proliferative disorders of the prostate. Cell proliferative disorders of the prostate can include all forms of cell proliferative disorders that affect prostate cells. Cell proliferative disorders of the prostate can include prostate cancer, precancerous or precancerous conditions of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, as well as metastatic lesions in tissues and organs other than the prostate in the body. Cell proliferative disorders of the prostate can include prostatic hyperplasia, metaplasia, and dysplasia.

[0603] A "cell proliferative disorder of the skin" is a cell proliferative disorder involving skin cells. The compounds and compositions of the present application can be used to treat skin cancer and cell proliferative disorders of the skin. Cell proliferative disorders of the skin can include all forms of cell proliferative disorders affecting skin cells. Cell proliferative disorders of the skin can include precancerous or precancerous conditions of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma, and other malignant growths or lesions of the skin, as well as metastatic lesions to tissues and organs in the body other than the skin. Cell proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia.

[0604] A "cell proliferative disorder of the ovary" is a cell proliferative disorder involving ovarian cells. The compounds and compositions of the present application can be used to treat ovarian cancer and cell proliferative disorders of the ovary. Cell proliferative disorders of the ovary include all forms of cell proliferative disorders affecting ovarian cells. Cell proliferative disorders of the ovary can include precancerous or precancerous conditions of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissues and organs other than the ovary. Cell proliferative disorders of the ovary can include ovarian cell hyperplasia, metaplasia, and dysplasia.

[0605] A "cell proliferative disorder of the breast" is a cell proliferative disorder involving breast cells. The compounds and compositions of the present application can be used to treat breast cancer and cell proliferative disorders of the breast. Cell proliferative disorders of the breast can include all forms of cell proliferative disorders that affect breast cells. Cell proliferative disorders of the breast can include breast cancer, precancerous or precancerous conditions of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, as well as metastatic lesions in tissues and organs other than the breast. Cell proliferative disorders of the breast can include breast hyperplasia, metaplasia, and dysplasia.

[0606] In one embodiment, the disease or condition includes, but is not limited to, diseases or conditions caused by or associated with Entamoeba histolytica, Pneumocystis carinii, Trypanosoma cruzi, Trypanosoma brucei, Leishmania mexicana, Clostridium histolytica, Staphylococcus aureus, foot-and-mouth disease virus, or Crichtonella fabricii, as well as diseases or conditions associated with osteoporosis, autoimmunity, schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, or muscular dystrophy.

[0607] Additional examples of diseases or conditions include, but are not limited to, diseases or conditions caused by or associated with veterinary and human pathogenic protozoa, intracellular motile parasites of the phyla Apicomplexa or Sarcomastigophora, Trypanosoma, Plasmodia, Leishmania, Babesia and Theileria, Cryptosporidia, Sacrocystida, Amoebia, Coccidia and Trichomonadia. For example, the diseases or conditions include, but are not limited to, malaria tropicalis caused by, for example, Plasmodium falciparum, malaria tertiana caused by Plasmodium vivax or Plasmodium ovale; malaria quartana caused by Plasmodium malariae; toxoplasmosis caused by Toxoplasma gondii, coccidiosis caused by Isospora belli, sarcosporidiosis caused by Sarcocystis suihominis, dysentery caused by Entamoeba histolytica, dysentery caused by Cryptosporidium parvum. parvum; Chagas disease caused by Trypanosoma cruzi; sleeping sickness, cutaneous and visceral, and other forms of leishmaniasis caused by Trypanosoma brucei rhodesiense or Trypanosoma gambiense; diseases or conditions caused by zoonotic protozoa, such as Theileria parva, the causative agent of East Coast bovine fever; Trypanosoma congolense congolense or Trypanosoma vivax vivax, and Trypanosoma brucei brucei, the causative agent of African nagana;Trypanosoma brucei evansi, which causes sull's disease; Babesia bigemina, the causative agent of Texas fever in cattle and bison; Babesia bovis, the causative agent of babesiosis in European cattle and babesiosis in dogs, cats, and sheep; Sarcocystis ovicanis in sheep and Endosporium ovifelis in yaks, the causative agents of sarcosporidiosis in sheep, cattle, and pigs; Cryptosporidia, the causative agent of cryptosporidiosis in cattle and birds; Eimeria and Isospora species, the causative agents of coccidiosis in rabbits, cattle, sheep, goats, pigs, and birds, especially chickens and turkeys. Rickettsiae include species such as Rickettsia felis, Rickettsia prowazekii, Rickettsia rickettsii, Rickettsia typhi, Rickettsia conorii, and Rickettsia africana and cause diseases such as typhus, Rickettsialpox, southern European spotted fever, African tick-bite fever, Rocky Mountain spotted fever, Australian tick-borne typhus, Flinders Island tick fever, and Queensland tick-borne typhus.

[0608] In one embodiment, the disease or condition is caused by or is associated with one or more bacteria. Examples of bacteria include, but are not limited to, Gram-positive organisms (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, Streptococcus pneumoniae) and Gram-negative organisms (e.g., Pseudomonas aeruginosa, Burkholderia cepacia, Xanthomonas maltophilia, Escherichia coli, Enterobacter, Klebsiella pneumoniae, and Salmonella).

[0609] In one embodiment, the disease or condition is caused by or associated with one or more fungi. Examples of fungi include, but are not limited to, Candida albicans, Histoplasma neoformans, Coccidioides immitis, and Penicillium marneffei.

[0610] In one embodiment, the disease or disorder is a nervous system disease or disorder. In one embodiment, a nervous system disease or disorder involves the central nervous system (e.g., brain, brainstem, and cerebellum), the peripheral nervous system (e.g., cranial nerves), and / or the autonomic nervous system (e.g., portions thereof located in the central and peripheral nervous systems).

[0611] Examples of neurological disorders include, but are not limited to, acquired epileptic aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger's syndrome; tele-ataxia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Bartter's disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign lesions; amyotrophic lateral sclerosis; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch's disease Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumors; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin-Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorder; Cushing syndrome; cytomegalovirus infection; dancing eyes and feet syndrome; Dandy-Walker syndrome; Dawson disease; Morsier syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; vacuolar sella syndrome; encephalitis; encephalocele; cerebral trigeminal angiomatosis; epilepsy; Erb palsy; essential tremor; Fabry disease; Fahr syndrome; syncope; familial spastic paraplegia; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher disease; Gerstmann syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barré syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis;Herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also a neurologic manifestation of AIDS); holoprosencephaly; Huntington disease and other polyglutamine repeat disorders; hydrocephalus; hydrocortisoneuria; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinence pigmenti; infantile phytanic acid storage disease; infantile spasm disorder; infantile spasms; inflammatory myopathy; intracranial cysts; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel syndrome Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; dementia with Lewy bodies; lissencephaly; locked-in syndrome; Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease—neurological sequelae; Machado-Joseph disease; macroencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-stroke; mitochondrial myopathy; Mobius syndrome; monosomy; motor neuron disease; Moyamoya disease; mucopolysaccharidosis; multiple myopathy Infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating diseases; multiple system atrophy with orthostatic hypotension; muscular dystrophy; myasthenia gravis; diffuse myelin sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurologic manifestations of AIDS; neurologic sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult neuralgia sequence spinal dysraphism sequence); Ohtahara syndrome; olivocerebellar atrophy; oculoclonus and myoclonus; optic neuritis; or cough hypotension; overuse syndrome; paresthesias; Parkinson disease; paramyotonia congenita; paraneoplastic disorders; paroxysmal aggression; Parry-Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disability; light sneeze reflex;Phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumor; polymyositis; pyreneal malformation; postpoliomyelitis syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; orthostatic hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing myelodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen encephalitis; reflex sympathetic dystrophy; Refsum disease; repetitive movement disorder; repetitive stress injury; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; St. Vitus's chorea; Sandhorn syndrome Schizencephaly; Schilder's disease; schizencephaly; intervertebral disc dysplasia; shaken baby syndrome; herpes zoster (shingles); Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham's chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered cord syndrome; Thomsen's disease; thoracic outlet syndrome; trigeminal neuralgia (Tic Douloureux; Todd's palsy; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis complex; vascular dementia (multi-infarct dementia); vasculitis, including temporal arteritis; von Hippel-Lindau disease; Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash; Williams syndrome; Wildon disease; and Zellweger syndrome.

[0612] Examples of neurodegenerative diseases also include, but are not limited to, adrenoleukodystrophy (ALD), Alexander disease, Alper disease, Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, familial fatal insomnia, frontotemporal lobar degeneration, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, dementia with Lewy bodies, osteoporosis, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple system atrophy, multiple sclerosis, narcolepsy, Niemann's Pick disease, Parkinson disease, Pelizaeus-Merzbacher disease, Pick disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, Spielmeyer-Vogt-Sjögren-Batten disease (also called Batten disease), spinocerebellar ataxias (multiple types with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, and toxic encephalopathy.

[0613] In one embodiment, the disease or disorder is an autoimmune disease. Examples of autoimmune diseases include, but are not limited to, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease (IBD) including Crohn's disease (CD), and ulcerative colitis (UC), a chronic inflammatory disease with a polygenic predisposition.

[0614] In one embodiment, the disease or condition is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, systemic lupus erythematosus (SLE), skin-related conditions, psoriasis, eczema, burns, dermatitis, neuroinflammation, allergies, pain, neuropathic pain, fever, lung disease, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, chronic inflammatory lung disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis , congestive heart failure, cardiac reperfusion injury, and complications associated with hypertension and / or heart failure, such as vascular organ damage, restenosis, cardiomyopathy, stroke, including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia, including stroke and cerebral ischemia, and ischemia caused by cardiac / coronary artery bypass surgery, neurodegenerative diseases, liver disease and nephritis, gastrointestinal disorders, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcerative disease, gastric ulcer, viral and bacterial infections, sepsis, septic shock, Gram-negative sepsis, malaria, meningitis Inflammation, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), pneumonia, herpes virus, myalgia caused by infection, influenza, autoimmune diseases, graft-versus-host reaction and allogeneic transplant rejection, treatment of bone resorption diseases, osteoporosis, multiple sclerosis, cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bone cancer, tumors of epithelial cell origin (epithelial cancer), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, oral cancer, esophageal cancer, small Intestinal cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell and / or basal cell carcinoma, prostate cancer, renal cell carcinoma and other cancers known to affect epithelial cells throughout the body, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL), angiogenesis, including neoplasia, metastasis, central nervous system diseases, central nervous system diseases with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury and peripheral neuropathies, or B-cell lymphoma.

[0615] In one embodiment, the disease or disorder is selected from autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In one embodiment, the disease or disorder is selected from proliferative disorders and immune disorders.

[0616] As modulators of the STING protein, the compounds and compositions of the present application can also be used to evaluate, study or test biological samples. One aspect of the present application relates to modulating the activity of the STING protein in a biological sample, comprising contacting the biological sample with a compound or composition of the present application.

[0617] As used herein, the term "biological sample" refers to an in vitro or ex vivo sample, including but not limited to cell culture or extracts thereof; biopsy material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof. Modulation (e.g., inhibition or stimulation) of protein kinase activity in a biological sample can be used for various purposes known to those skilled in the art. Examples of such purposes include but are not limited to blood transfusion, organ transplantation, and biological specimen storage.

[0618] Another aspect of the present application relates to the study of STING proteins in biological and pathological phenomena; and the study of intracellular signal transduction pathways mediated by STING proteins. Examples of such uses include, but are not limited to, biological assays, such as enzyme assays and cell-based assays.

[0619] The activity of the compounds and compositions of the present application as STING modulators can be determined in vitro, in vivo or in cell lines. In vitro assays include determining the regulation (e.g., inhibition or stimulation) of the binding of STING ligands to STING proteins by competitive binding assays. Alternative in vitro assays quantify the ability of modulators (e.g., inhibitors or stimulators) to bind to protein kinases, and can be measured by radiolabeling the modulator (e.g., inhibitor or stimulator) prior to binding, isolating the ligand / protein complex, and determining the amount of radiolabeled binding. The conditions for determining compounds used as modulators or STING proteins in the present application are listed in the following examples.

[0620] In accordance with the foregoing, the present application provides a method for preventing or treating any of the diseases or conditions described herein in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of the present application, or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application. For any of the above uses, the required dosage will vary depending on the mode of administration, the specific condition to be treated, and the desired effect.

[0621] The compounds and compositions of the present application can be administered in combination therapy with one or more therapeutic agents (drug combinations) or treatment modalities in a therapeutically effective amount, including, for example, anti-proliferative, anti-cancer, immunomodulatory (e.g., CTLA-4 and PD-1 pathway antagonists and other immunomodulators), anti-inflammatory, and / or antiviral drugs, and / or non-drug therapies. For example, synergistic effects can be produced with anti-proliferative agents, anti-cancer agents, immunomodulators (e.g., CTLA-4 and PD-1 pathway antagonists and other immunomodulators), anti-inflammatory drugs and / or antiviral substances. When the compounds of the present application are administered in combination with other therapies, the dosage of the co-administered compound will vary depending on the type of co-drug used, the specific drug used, the condition being treated, etc.

[0622] Combination therapy may include further administration of the subject compound of the present invention in combination with one or more other biologically active ingredients (for example, but not limited to, a second STING modulator, a cGAS-CDN-STING axis modulator, or a modulator involved in intracellular dsDNA-mediated type 1 interferon activation). Other biologically active ingredients may also include anti-proliferative agents, anti-cancer agents (for example, chemotherapeutic agents), immunomodulators (for example, CTLA-4 and PD-1 pathway antagonists and other immunomodulators), antibodies, lipids, liposomes, peptides, and the like. For example, the compounds of the present application can be used in combination with other pharmaceutically active compounds, preferably compounds that can enhance the effects of the compounds of the present application. The compounds of the present application can be administered simultaneously (as a single formulation or a separate formulation) or sequentially with another drug therapy or treatment modality. Typically, combination therapy envisions the administration of two or more drugs in one treatment cycle or one course of treatment.

[0623] In one embodiment, the chemotherapeutic agent is an alkylating agent; an antibiotic; an antimetabolite; a detoxifying agent; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an MTOR inhibitor; a multikinase inhibitor; a serine / threonine kinase inhibitor; a tyrosine kinase inhibitor; a VEGF / VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule-targeting drug, a topoisomerase-toxic drug, a molecular target or enzyme inhibitor (e.g., a kinase inhibitor), a cytidine analog drug, or any chemotherapeutic, anti-tumor, or anti-proliferative agent listed at www.cancer.org / docroot / cdg / cdg_0.asp.

[0624] Alkylating agents are non-phase specific agents and strong electrophiles. Generally, alkylating agents form covalent bonds with DNA through nucleophilic moieties (e.g., phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups) of the DNA molecule by alkylation. This alkylation can disrupt nucleic acid function and lead to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards, such as cyclophosphamide (e.g., ), melphalan (e.g., ), and chlorambucil (e.g., ); alkyl sulfonates, such as busulfan (e.g., ); nitrosoureas such as carmustine (e.g., ); and triazenes, such as dacarbazine (eg, DTIC- ).

[0625] Exemplary alkylating agents also include, but are not limited to, busulfan (Busulfex), lomustine (CeeNU), oxaliplatin (Eloxatin), carmustine (Gliadel), ifosfamide (Ifex), nitrogen mustard (Mustargen), busulfan (Myleran), carboplatin Cisplatin (CDDP, ), temozolomide (Temodar), thiotepa (Thioplex), bendamustine (Treanda), streptozotocin (Zanosar), 5-azacytidine (e.g., VIDAZA), decitabine (e.g., DECOGEN), temozolomide (e.g., TEMODAR and TEMODAL), dactinomycin (also known as actinomycin-D, sold under the trade name COSMEGEN), melphalan (also known as L-PAM, L-mylolysin, and melphalan, sold under the trade name ALKERAN), hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trade name HEXALEN), carmustine (e.g., BCNU), bendamustine (e.g., TREANDA), carboplatin (e.g., ), lomustine (also known as CCNU, sold under the trade name Cisplatin (also known as CDDP, sold under the trade name and -AQ), cyclophosphamide (sold under the trade name and Sold), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the trade name Sold), hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trade name sold), ifosfamide (e.g., ), procarbazine (e.g., ), nitrogen mustard (also known as nitrogen mustard, mustine and bischloroethyl methylamine, known as sold), streptozotocin (e.g., ), and thiotepa (also known as thiophosphamide, TESPA and TSPA, and sold under the trade name sell).

[0626] Antibiotic antineoplastic agents are non-stage specific agents that bind to or intercalate with DNA. Typically, this action results in stable DNA complexes or strand breaks, thereby disrupting the normal function of the nucleic acid and leading to cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins, such as actinomycin (e.g., ), anthracyclines such as daunorubicin (eg, in liposome injection form such as or in the form of injections such as ) and doxorubicin (e.g., or ) and bleomycin (e.g., ).

[0627] Exemplary antibiotics also include, but are not limited to, doxorubicin (Adriamycin), liposomal doxorubicin (Doxil), mitoxantrone (Novantrone), bleomycin (Blenoxane), daunorubicin (Cerubidine), liposomal daunorubicin (DaunoXome), actinomycin (Cosmegen), epirubicin (Ellence), idarubicin (Idamycin), plimycin (Mithracin), mitomycin (Mutamycin), pentostatin (Nipent), valrubicin (Valstar), doxorubicin (e.g., and ) Daunorubicin (also known as daunorubicin hydrochloride, daunorubicin and daunorubicin hydrochloride, known under the trade name ), daunorubicin liposomal (daunorubicin citrate liposomal, sold under the trade name DAUNOXOME), mitoxantrone (also known as DHAD, sold under the trade name sold), epirubicin (e.g., ELLENCE TM ), Idabistar (e.g., ) and mitomycin C (e.g., ).

[0628] Antimetabolite antitumor agents are stage-specific agents that act during the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or inhibiting purine or pyrimidine base synthesis, thereby limiting DNA synthesis. As a result, the S phase does not proceed and the cell dies. Examples of antimetabolite antitumor agents include, but are not limited to, fluorouracil and its analogs (e.g., 5-fluorodeoxyuridine (fluridine), 5-fluorodeoxyuridine monophosphate methotrexate), cytarabine (commonly known as Ara-C, which can be CYTOSAR- obtained in the form of) and their analogs (e.g., azacytidine, 2',2'-difluorodeoxycytidine (gemcitabine)), mercaptopurines (e.g., ) and its analogs (e.g., azathioprine), thioguanine (e.g., ) and its analogs (e.g., pentostatin, erythrohydroxy-nonyladenine (EHNA), fludarabine phosphate and cladribine), gemcitabine (e.g., ) and methotrexate.

[0629] Exemplary antimetabolites also include, but are not limited to, fluorouracil (Adrucil), capecitabine (Xeloda), hydroxyurea (Hydrea), mercaptopurine (Purinethol), pemetrexed (Alimta), fludarabine (Fludara), nelarabine (Arranon), cladribine (Cladribine Novaplus, clofarabine (Clolar), cytarabine (Cytosar-U), decitabine (Dacogen), cytarabine liposomal (DepoCyt), hydroxyurea (Droxia), pralatrexate (Folotyn), floxuridine (FUDR), gemcitabine (Gemzar), cladribine (Leustatin), fludarabine (Oforta), methotrexate (MTX, Rheumatrex), methotrexate (Trexall), thioguanine (Tabloid), TS-1 or cytarabine (Tarabine PFS), cladribine (2-chlorodeoxyadenosine, sold under the trade name Sold), 5-fluorouracil (trade name ), 6-thioguanine (trade name Pemetrexed (sold under the trade name sold), cytarabine (also known as cytosine arabinoside (Ara-C), sold under the trade name CYTOSAR- Sold), cytarabine liposomes (also known as liposome Ara-C, sold under the trade name DEPOCYT TM Sold), decitabine (trade name Sold under the trade names DROXIA TM and MYLOCEL TM Sold), fludarabine (sold under the trade name Sold), floxuridine (sold under the trade name Cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trade name LEUSTATIN TM Sold), methotrexate (also known as methotrexate, methotrexate sodium (MTX), sold under the trade name and TREXALL TM Sold under the trade name sell).

[0630] Exemplary antidotes include, but are not limited to, amifostine (Ethyol) and mesna (Mesnex).

[0631] Exemplary interferons include, but are not limited to, interferon alpha-2b (Intron A) and interferon alpha-2a (Roferon-A).

[0632] Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin), ofatumumab (ARZerra), bevacizumab (Avastin), rituximab (Rituxan), cetuximab (Erbitux), panitumumab (Vectibix), tositumomab / iodine 131 Tositumomab (Bexxar), alemtuzumab (Campath), ibritumomab tiuxetan (Zevalin, In-111, Y-90Zevalin), gemtuzumab tuzumab (Mylotarg), eculizumab (Soliris), and / or denosumab.

[0633] Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa), lapatinib (Tykerb), cetuximab (Erbitux), erlotinib (Tarceva), panitumumab (Vectibix), PKI-166, canertinib (CI-1033), matuzumab (Emd7200), and EKB-569.

[0634] Exemplary HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb); and AC-480.

[0635] Exemplary histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza).

[0636] Hormones and hormone analogs are useful compounds for treating cancer where a link exists between the hormone and the growth and / or lack of growth of the cancer. Examples of hormones and hormone analogs that can be used for cancer treatment include, but are not limited to, adrenocortical steroids, such as prednisone and prednisolone; aminoglutethimide and other aromatase inhibitors, such as anastrozole, letrozole, vorozole, and exemestane; progestins, such as megestrol acetate; estrogens and antiestrogens, such as fulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5-reductase inhibitors, such as finasteride and dutasteride; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, idoxifene, and selective estrogen receptor modulators (SERMS), such as those described in U.S. Patents 5,681,835, 5,877,219, and 6,207,716; gonadotropin-releasing hormone (GnRH) and its analogs; and LHRH agonists and antagonists, such as goserelin acetate and luprolide.

[0637] Exemplary hormones also include, but are not limited to, tamoxifen (Soltamox, Nolvadex), raloxifene (Evista), megestrol acetate (Megace), leuprolide (Lupron, Lupron Depot, Eligard, Viadur), fulvestrant (Faslodex), letrozole (Femara), triptorelin (Trelstar LA, Trelstar Depot), exemestane (Aromasin), goserelin (Zoladex), bicalutamide (Casodex), anastrozole (Arimidex), fluoxymesterone (Androxy, Halotestin), medroxyprogesterone acetate (Provera, Depo-Provera), estramustine (Emcyt), flutamide (Eulexin), toremifene (Fareston), degarelix (Firmagon), nilutamide (Nilandron), abarelix (Plenaxis), or testolactone (Teslac).

[0638] Anti-microtubule or anti-mitotic agents or mitotic inhibitors are stage-specific agents that are active against tumor cell microtubules during the M phase or mitotic phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenes and vinca alkaloids. Examples of diterpenes include, but are not limited to, paclitaxel (e.g., ) and its analogs docetaxel (e.g., Examples of vinca alkaloids include, but are not limited to, vinblastine (e.g., ), vincristine (e.g., ), and vinorelbine (e.g., ).

[0639] Exemplary mitotic inhibitors also include, but are not limited to, paclitaxel (Taxol, Onxol, Abraxane), docetaxel (Taxotere), vincristine (Oncovin, Vincasar PFS), vinblastine (Velban), etoposide (Toposar, Etopophos, VePesid), teniposide (Vumon), ixabepilone (Ixempra), nocodazole, epothilone, vinorelbine (Navelbine), camptothecin (CPT), irinotecan (Camptosar), topotecan (Hycamtin), amsacrine, or lamelliposide D (LAM-D).

[0640] Exemplary MTOR inhibitors include, but are not limited to, everolimus (Afinitor) or sirolimus (Torisel), rapamycin, ridaforolimus, or AP23573.

[0641] Exemplary multi-kinase inhibitors include, but are not limited to, sorafenib (Nexavar), sunitinib (Sutent), BIBW 2992, E7080, Zd6474, PKC-412, motesanib, or AP24534.

[0642] Exemplary serine / threonine kinase inhibitors include, but are not limited to, ruboxistaurin, eril / easudil hydrochloride, flavopiridol, seliciclib (CYC202, Roscovitrine), SNS-032 (BMS-387032), Pkc412, bryostatin, KAI-9803, SF1126, VX-680, Azd1152, Arry-142886 (AZD-6244), SCIO-469, GW681323, CC-401, CEP-1347, or PD 332991.

[0643] Inhibitors of serine / threonine kinases also include MAP kinase cascade blockers, including blockers of Raf kinase (rafk), mitogen- or extracellular-regulated kinase (MEK) and extracellular-regulated kinase (ERK); and protein kinase C family member blockers, including PKC (α, β, γ, ε, μ, λ, ι, ζ), IkB kinase family (IKKa, IKKb), PKB family kinases, AKT kinase family members and TGFβ receptor kinase blockers. Inhibitors of serine / threonine kinases are also described in J. Biochem. 126, 799 (1999), Biochem. Pharmacol. 60, 1101 (2000); Cancer Surveys 27, 41 (1996); Cancer Treatment Res. 78, 3 (1995); Bioorg. Med. Chem. Letters 10, 223 (2000); U.S. Pat. No. 6,268,391; and Int. J. Cancer 88, 44 (2000).

[0644] Tyrosine kinases (also known as non-receptor tyrosine kinases) include, but are not limited to, cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Bruton's tyrosine kinase, and Bcr-Abl. Inhibitors of non-receptor tyrosine kinases are described in J. Hematotherapy Stem Cell Res. 8, 465 (1999) and Annual Rev. Immunol. 15, 371 (1997).

[0645] Exemplary tyrosine kinase inhibitors also include, but are not limited to, erlotinib (Tarceva), gefitinib (Iressa), imatinib (Gleevec), sorafenib (Nexavar), sunitinib (Sutent), trastuzumab (Herceptin), bevacizumab (Avastin), rituximab (Rituxan), lapatinib (Tykerb), cetuximab (Erbitux), panitumumab (Vectibix), everolimus (Afinitor), alemtuzumab (Campatuzumab), and seleximab (Sergidoxorubicin). h), gemtuzumab (Mylotarg), sirolimus (Torisel), pazopanib (Votrient), dasatinib (Sprycel), nilotinib (Tasigna), vastatinib (Ptk787, ZK222584), CEP-701, SU5614, MLN518, XL999, VX-322, Azd0530, BMS-354825, SKI-606CP-690, AG-490, WHI-P154, WHI-P131, AC-220, or AMG888.

[0646] Exemplary VEGF / VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent), ranibizumab, pegaptanib and vandetinib, axitinib, brivanibalaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)(propan-2-yl) 2-aminopropanoate, also known as BMS-582664), motesanib (TST-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide), and pasireotide (also known as SO230).

[0647] Inhibitors of members of the phosphatidylinositol 3-kinase family, including blockers of Pekinese, ATM, DNA-PK, and Ku, can also be used in combination with the compounds of the present invention. Such inhibitors are discussed in Curr. Opinion Immunol. 8, 412 (1996); Oncogene 17, 3301 (1998); Int. J. Biochem. Cell Biol. 29, 935 (1997); and Cancer Res. 60, 1541 (2000).

[0648] Exemplary kinase inhibitors also include, but are not limited to, bevacizumab (targeting VEGF), BIBW 2992 (targeting EGFR and Erb2), cetuximab / Erbitux (targeting Erb1), imatinib / Gleevic (targeting Bcr-Abl), trastuzumab (targeting Erb2), gefitinib / Iressa (targeting EGFR), ranibizumab (targeting VEGF), pegaptanib (targeting VEGF), erlotinib / Tarceva (targeting Erb1), nilotinib (targeting Bcr-Abl), lapatinib (targeting Erb1 and Erb2 / Her2), GW-572016 / lapatinib di-toluenesulfonate (targeting HER2 / Erb2), panitumumab / Vectibix (targeting EGFR), vandetanib (targeting RET / VEGFR), E7080 (multi-targeting, including RET and VEGFR), Herceptin (targeting HER2 / Erb2), PKI-166 (targeting EGFR), canertinib / CI-1033 (targeting EGFR), sunitinib / SU-11464 / Sutent (targeting EGFR and FLT3), matuzumab / Emd7200 (targeting EGFR), EKB-569 (targeting EGFR), Zd6474 (targeting EGFR and VEGFR), PKC-412 (targeting V EGR and FLT3), vatalanib / Ptk787 / ZK222584 (targeting VEGR), CEP-701 (targeting FLT3), SU5614 (targeting FLT3), MLN518 (targeting FLT3), XL999 (targeting FLT3), VX-322 (targeting FLT3), Azd0530 (targeting SRC), BMS-354825 (targeting SRC), SKI-606 (targeting SRC), CP-690 (targeting JAK), AG-490 (targeting JAK), WHI-P154 (targeting JAK), WHI-P131 (targeting JAK), Rafenib / Nexavar (targets RAF kinases, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3, and RET), dasatinib / Sprycel (BCR / ABL and Src), AC-220 (targets Flt3), AC-480 (targets all HER proteins, "panHER"), motesanib diphosphonate (targets VEGF1-3, PDGFR, and c-kit), denosumab (targets RANKL, inhibits SRC), AMG888 (targets HER3), and AP24534 (multiple targets, including Flt3).

[0649] Exemplary microtubule-targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristine, vinblastine, nocodazole, epothilone, and navelbine.

[0650] Exemplary topoisomerase toxic drugs include, but are not limited to, teniposide, etoposide, doxorubicin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin, and idarubicin.

[0651] Other topoisomerase toxic drugs include topoisomerase II inhibitors, such as epipodophyllotoxins. Examples of epipodophyllotoxins include, but are not limited to, etoposide (VP-16, ) and teniposide (VM-26, ).

[0652] Examples of taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxel.

[0653] Antibody antagonists that bind to receptor kinase ligands can also act as inhibitors. Examples include Imclone C225 EGFR-specific antibodies (see Cancer Treat. Rev. 26, 269 (2000)), erbB2 antibody (see Breast Cancer Res. 2, 176 (2000)), and 2CB VEGFR2-specific antibody (see Cancer Res. 60, 5117 (2000)).

[0654] Anti-angiogenic therapeutics including non-receptor MEK angiogenesis inhibitors can also be combined with the compounds of the present invention. Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (e.g., bevacizumab [Avastin TM ]) as well as compounds that act through other mechanisms (e.g., linomide, inhibitors of integrin ανβ3 function, endostatin and angiostatin).

[0655] Other therapeutic agents that can be combined with the compounds of the present invention include SH2 / SH3 domain blockers, which disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins, including PI3-K p85 subunits, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. SH2 / SH3 domain blockers are discussed as anticancer drugs in J. Pharm. Toxicol. Methods 34, 125 (1995).

[0656] Other therapeutic agents that can be combined with the compounds of the present invention include inositol signaling inhibitors, such as phospholipase C blockers and inositol analogs. Such signaling inhibitors are described in New Molecular Targets for Cancer Chemotherapy, ed., Paul Workman and David Kerr, CRC press 1994, London.

[0657] Other therapeutic agents that can be combined with the compounds of the present invention include inhibitors of Ras oncogenes, including inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases, as well as antisense oligonucleotides, ribozymes, and immunotherapies. Such inhibitors are discussed in J. Biomed. Sci. 7, 292 (2000); Curr. Opin. Lipidology 9, 99 (1998); and BioChim. Biophys. Acta, 1423, 19 (1989).

[0658] Additional exemplary general chemotherapeutic agents, anti-tumor agents, and anti-proliferative agents include, but are not limited to, hexamethylmelamine (Hexalen), isotretinoin (Accutane, Amnesteem, Claravis, Sotret), tretinoin (Vesanoid), azacitidine (Vidaza), bortezomib (Velcade), asparaginase (Elspar), levamisol (Ergamisol), mitotane (Lysodren), procarbazine (Matulane), pegaspargase (Oncaspar), denileukindiftitox (Ontak), porflin sodium (Photofrin), aldesleukin (Proleukin), lenalidomide (Revlimid), bexarotene (Targretin), thalidomide (Thalomid), sirolimus (Torisel), arsenic trioxide (Trisenox), verteporfin (Visudyne), mimosine (Leucenol), (1M fluazifop-0.4M fluazifop-0.5M fluazifop-1. 5-chloro-2,4-dihydroxypyrimidine-1M oxazolidinone potassium) or lovastatin.

[0659] Other therapeutic agents that can be combined with the compounds of the present application also include antiviral agents, including but not limited to, hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors and human immunodeficiency virus (HIV) inhibitors.

[0660] Other therapeutic agents that can be combined with the compounds of the present invention also include antigens or adjuvants, including but not limited to, B7 co-stimulatory molecules, interleukin 2, interferon gamma, GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligands, CD40 / CD40 ligands, sargramostim, levamisole, vaccinia virus, Bacillus Calmette-Guérin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxin, mineral oil, surfactants (e.g., lecithin), pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. In one embodiment, adjuvants such as aluminum hydroxide or aluminum phosphate can be added to enhance the ability of the vaccine to trigger, enhance, or prolong an immune response. In one embodiment, other substances, such as cytokines, chemokines and bacterial nucleic acid sequences, such as CpG, toll-like receptor (TLR) 9 agonists, and other agonists of TLR 2, TLR 4, TLR 5, TLR7, TLR 8, TLR9, including lipoproteins, LPS, monophospholipid A, lipoteichoic acid, imiquimod, resiquimod, and retinoic acid-inducible gene I (RIG-I) agonists, such as poly I:C, can also be used.

[0661] Other therapeutic agents that can be combined with the compounds of the present invention include cytotoxic agents, including but not limited to arsenic trioxide Asparaginase (also known as L-asparaginase and Erwinia L-asparaginase, sold under the trade name and sell).

[0662] Other therapeutic agents that can be combined with the compounds of the present invention include retinoids, including but not limited to alitretinoin (trade name Sold), retinoic acid (all-trans retinoic acid, also known as ATRA, sold under the trade name Sold), isotretinoin (13-c / s-retinoic acid, sold under the trade name and Sold under the trade name sell).

[0663] Other exemplary chemotherapeutic agents that can be used in combination with the compounds of the present application include, but are not limited to, abiraterone acetate, hexamethylmelamine, vinblastine, auristatin, bexarotene, bicalutamide, BMS184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-L proline-tert-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'deoxy-8'-norvin-caleukoblastine, docetaxel, docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, Dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (Adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea taxanes, ifosfamide, liarole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoctonia soln, sertenef, streptozotocin, mitomycin, methotrexate, taxanes, nilutamide, nivolumab, onapristone, paclitaxel, pembrolizumab, prednimustine, procarbazine, RPR109881, estramustine phosphate, tamoxifen, tazepine, paclitaxel, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.

[0664] Other therapeutic agents that can be combined with the compounds of the present invention include cell cycle signaling inhibitors, pro-apoptotic agents, PARP inhibitors, checkpoint therapeutics, and immunomodulators.

[0665] Cell cycle signaling inhibitors inhibit molecules involved in cell cycle control. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interaction with a family of proteins called cyclins control the progression of the eukaryotic cell cycle. Coordinate activation and inactivation of different cyclin / CDK complexes are essential for the normal progression of the entire cell cycle. Several cell cycle signaling inhibitors are under development. For example, examples of cyclin-dependent kinases include CDK2, CDK4, and CDK6 and their inhibitors are described in Exp. Opin. Ther. Patents 10, 215 (2000).

[0666] Therapeutic agents used in pro-apoptotic regimens (eg, bcl-2 antisense oligonucleotides) can also be used in combination with the compounds of the present invention.

[0667] As used herein, PARP inhibitors refer to pharmacological inhibitors of poly (ADP-ribose) polymerase (PARP). Exemplary PARP inhibitors include, but are not limited to, olaparib (AZD-2281, manufactured by AstraZeneca) and ), Rucaparib (PF-01367338, produced by Clovis Oncology ), niraparib (MK-4827, manufactured by Tesaro ), talazoparib (BMN-673), veliparib (ABT-888), olaparib (AZD-2281), olaparib TOPARP-A, rucaparib (PF-01367338, AG014699), CEP 9722, E7016 (developed by Eisai), BGB-2901, iniparib (BSI 201), and 3-aminobenzamide.

[0668] Drugs used in immunotherapy regimens can also be used in combination with the compounds of the present invention. Immunotherapy includes ex vivo and in vivo methods to increase the immunogenicity of patient tumor cells (e.g., transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte macrophage colony-stimulating factor), methods to reduce T cell energy, methods using transfected immune cells (e.g., cytokine-transfected dendritic cells), methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies.

[0669] As used herein, checkpoint inhibitor therapy refers to a type of cancer treatment immunotherapy that targets immune checkpoints, which are key regulators that stimulate or suppress the immune system's actions, potentially allowing tumors to protect themselves from immune system attack. Checkpoint therapy can block inhibitory checkpoints and restore immune system function.

[0670] As used herein, "immunomodulator" refers to any substance including monoclonal antibodies that affect the immune system. Immunomodulators can be used as anti-tumor drugs to treat cancer. For example, immunomodulators include, but are not limited to, anti-CTLA-4 antibodies, such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo / nivolumab and Keytruda / pembrolizumab). Other immunomodulators include, but are not limited to, ICOS antibodies, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies.

[0671] The CTLA-4 and PD-1 pathways are important negative regulators of the immune response. Activated T cells upregulate CTLA-4, which binds to antigen-presenting cells and inhibits T cell stimulation, IL-2 gene expression, and T cell proliferation. PD-1 binds to activated T cells and inhibits T cell activation. PD-1 antagonists have demonstrated anti-tumor effects. CTLA-4 and PD-1 pathway antagonists that can be used in combination with the compounds of the present invention include ipilimumab, simumab, nivolumab, pembrolizumab, CT-011, AMP-224, and MDX-1106.

[0672] As used herein, PD-1 inhibitors and PD-L1 inhibitors refer to a group of checkpoint inhibitors or immune checkpoint inhibitors that can be used to treat cancer. PD1 and PD-L1 are proteins present on the surface of cells. PD-1 and PD-L1 inhibitors can inhibit the binding of programmed death ligand (PD-L1) to its receptor programmed cell death protein 1 (PD-1). Exemplary PD-1 and / or PD-L1 inhibitors include, but are not limited to, nivolumab (Opdivo), pembrolizumab (MK-3475 or lambrolizumab, Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), pidilizumab (pidilizumab), AMP-224, AMP-514, PDR001, cemiplimab, BMS-936559 and CK-301.

[0673] Anti-PD-L1 antibodies and methods for their preparation are known in the art. Such antibodies to PD-L1 can be polyclonal or monoclonal, and / or recombinant, and / or humanized. Exemplary PD-L1 antibodies are disclosed in U.S. Patents 8,217,149, 8,383,796, 8,552,154, 9,212,224, and 8,779,108 and U.S. Patent Application Publications 20110280877, 20140341902, and 20130045201. Other exemplary antibodies to PD-L1 (also known as CD274 or B7-H1) and methods of use thereof are disclosed in U.S. Patents 7,943,743, 8,168,179, and 7,595,048; WO2014055897, WO2016007235; and U.S. Patent Application Publications 20130034559 and 20150274835. In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105), MPDL3280A (RG7446), MEDI4736, TECENTRIQ TM(atezolizumab), YW243.55.S70, MPDL3280A, BMS-936559, MEDI4736 or MSB0010718C or a V described in WO2013019906 H and V L Antibodies (e.g., SEQ ID NOs: 21 and 24 thereof). Examples of anti-PD-L1 antibodies and methods for preparing them are also described in WO2010077634, WO2007005874, WO2011066389, WO2013019906, WO2010077634, U.S. Patents 8,217,149 and 8,383,796, and U.S. Patent Application Publication 2013034559.

[0674] A PD-1 antagonist or PD-1 inhibitor refers to any compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells). It preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. The human PD-1 amino acid sequence can be found at NCBI site number NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI sites NP_054862 and NP_079515, respectively.

[0675] PD-1 antagonists include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, preferably to human PD-1 or human PD-L1. mAbs can be human antibodies, humanized antibodies, or chimeric antibodies, and can include human constant regions. In some embodiments, the human constant region is selected from IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0676] Examples of mAbs that bind to human PD-1 are described in U.S. Patents 7,488,802, 7,521,051, 8,008,449, 8,354,509, and 8,168,757, WO2004004771, WO2004072286, WO2004056875, and U.S. Patent Application Publication 20110271358. In one embodiment, anti-human PD-1 monoclonal antibodies that can be used as PD-1 antagonists include MK-3475, nivolumab, and humanized antibodies h409A11, h409A16, and h409A17, which are described in WO2008156712 and AMP-514.

[0677] Other PD-1 antagonists that can be used in any aspect and embodiment of the present application include immunoadhesins that specifically bind to PD-1, and preferably specifically bind to human PD-1, for example, a fusion protein comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin molecule). Examples of immunoadhesins that specifically bind to PD-1 are described in WO2010027827 and WO2011066342. In one embodiment, the PD-1 antagonist includes AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein that binds to human PD-1.

[0678] In one embodiment, the anti-PD-1 antibody is KEYTRUDA / pembrolizumab, which is disclosed in U.S. Pat. No. 8,168,757, or Opdivo / nivolumab (also known as BMS-936558, MDX-1106, and ONO-4538, which is disclosed in U.S. Pat. No. 8,008,449.

[0679] In one embodiment, the CTLA-4 antagonist is Yervoy (ipilimumab), which is disclosed in US Patents 6,984,720 and 7,605,238.

[0680] Other examples of other therapeutic agents (anti-tumor agents) that can be combined or co-administered with the compounds of the present invention include antibodies against ICOS. Agonist antibodies against ICOS or ICOS binding proteins are disclosed in WO2012013004, WO2014033327, WO2016120789, U.S. Patent Application Publication Nos. 20160215059 and US20160304610, for example, SEQ ID NOs: 1-6 or their direct equivalents disclosed in WO 2016120789, V H A domain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 7 disclosed in WO2016120789, and / or VL A domain comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 8 disclosed in WO 2016120789.

[0681] Other examples of other therapeutic agents (anti-tumor agents) that can be combined or co-administered with the compounds of the present invention include antibodies against OXO40. Such antibodies are described in WO 2012027328, WO 2013028231 (e.g., an antibody comprising a V sequence having a sequence at least 90% identical to SEQ ID NO: 10). L and / or comprising a V having a sequence at least 90% identical to SEQ ID NO: 4 H ).

[0682] Other examples of other therapeutic agents that are combined or co-administered with the compounds of the present application include immunostimulants. As used herein, an immunostimulant refers to any agent that can stimulate the immune system. As used herein, immunostimulants include but are not limited to vaccine adjuvants, such as Toll-like receptor agonists, T cell checkpoint blockers, such as monoclonal antibodies for PD-1 and CTL4, and T cell checkpoint agonists, such as agonist monoclonal antibodies for OX-40 and ICOS. As used herein, "immunostimulant" refers to any agent that can stimulate the immune system. As used herein, immunostimulants include but are not limited to vaccine adjuvants.

[0683] In one embodiment, TLR agonists include but are not limited to Pam3Cys, a TLR1 / 2 agonist; CFA, a TLR2 agonist; MALP2, a TLR2 agonist; Pam2Cys, a TLR2 agonist; FSL-1, a TLR-2 agonist; Hib-OMPC, a TLR-2 agonist; polyinosinic:polycytidylic acid (Poly I:C), a TLR3 agonist; polyadenosine-polyuridylic acid (poly AU), a TLR3 agonist; polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (Hiltonol), a TLR3 agonist; bacterial flagellin, a TLR5 agonist; imiquimod, a TLR7 agonist; resiquimod, a TLR7 / 8 agonist; loxoribine, a TLR7 / 8 agonist; and unmethylated CpG dinucleotide (CpG-ODN), a TLR9 agonist. Additional TLR agonists include, but are not limited to, aminoalkyl glucosamine phosphates (AGPs). An example of a naturally occurring TLR4 agonist is bacterial LPS. An example of a semisynthetic TLR4 agonist is monophosphoryl lipid A (MPL). Additional AGP derivatives are described in U.S. Patent Nos. 7,129,219, 6,525,028, and 6,911,434.

[0684] In one embodiment, the immunostimulant used in combination with the compounds of the present invention is a TLR4 agonist. In one embodiment, the TLR4 agonist is CRX-601, CRX-527, or CRX547. Other examples include AGPs such as CRX602 or CRX 526.

[0685] In addition, the compounds of the present application can be combined with other therapeutic agents, which, due to their adjuvant properties, can stimulate the immune system to react to cancer antigens present on inactivated tumor cells. Such adjuvants include, but are not limited to, lipids, liposomes, inactivated bacteria that induce innate immunity (e.g., inactivated or attenuated Listeria monocytogenes), compositions that mediate innate immune activation through (NOD)-like receptors (NLRs), (RIG)-I-like receptors (RLRs) based on retinoic acid-induced genes, and / or C-type lectin receptors (CLRs). Examples of PAMPs include lipoproteins, lipopeptides, peptidoglycans, yeast polysaccharides, neisserial proteins, flagellin, actin inhibitory proteins, galactosylceramide, and muramyl dipeptide. Peptidoglycans, lipoproteins, and lipoprotein acids are components of Gram-positive cell walls. Lipopolysaccharides are expressed in most bacteria, of which MPL is an example. Flagellin is a structural component of bacterial flagella secreted by pathogenic and commensal bacteria. rt-galactosylceramide (rt.-GalCer) is an activator of natural killer T cells (NKT). Muramyl dipeptide is a biologically active peptidoglycan motif shared by all bacteria.

[0686] Other examples of other therapeutic agents that can be combined or co-administered with the compounds of the present application include IDO inhibitors (e.g., Epacadostat, as described in U.S. Patent 8,034,953), CD73 inhibitors, and A2a and A2b adenosine antagonists.

[0687] In one embodiment, the compounds may be administered in combination with one or more separate pharmaceutical agents, for example, chemotherapeutic agents, immunotherapeutic agents, or adjunctive therapeutic agents.

[0688] The compounds of the present invention can be used in combination with at least one other therapeutic agent for preventing or treating bacterial and viral infections. Examples of such agents include, but are not limited to, polymerase inhibitors such as those described in WO2004037818 and WO2006045613; JTK-003, JTK-019, NM-283, HCV-796, R-803, R1728, R1626, and those disclosed in WO2006018725, WO2004074270, WO2003095441, U.S. Pat. Publication Nos. 20050176701, WO2006020082, WO2005080388, WO2004064925, WO2004065367, WO2003007945, WO2002004425, WO2005014543, WO2003000254, EP1065213, WO2001047883, WO2002057 287. Those of WO2002057245; replication inhibitors such as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar drugs; protease inhibitors such as the HIV protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, rasinavir, and the HCV protease inhibitor BILN 2061, VX-950, SCH503034, and similar drugs; nucleoside and nucleotide reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, efavirenz, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, alafenamide fumarate) / tenofovir alafenamide hemifumarate and similar drugs; non-nucleoside reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, rilpivirine and similar drugs; entry inhibitors, such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix and similar drugs; integrase inhibitors, such as dolutegravir, elvitegravir, raltegravir L-870, 180 and similar drugs; sprouting inhibitors such as PA-344 and PA-457 and similar drugs;Chemokine receptor inhibitors, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,857), TAK449, and those disclosed in WO2002074769, WO20040054974, WO2004055012, WO2004055010, WO2004055016, WO2004055011 and WO2004054581, and similar drugs; pharmacokinetic enhancement Strong agents such as cobicistat; neuraminidase inhibitors such as CS-8958, zanamivir, oseltamivir, peramivir and similar drugs; ion channel blockers such as amantadine or adamantane, and similar drugs; interfering RNA and antisense oligonucleotides such as ISIS-14803 and similar drugs; and antiviral drugs whose mechanism of action is not yet determined, such as those disclosed in WO2005105761, WO2003085375, WO2006122011, ribavirin and similar drugs. ;

[0689] The compounds of the present application can be used in combination with at least one other therapeutic agent that can be used to treat Kaposi's sarcoma-associated herpesvirus infection (KSHV and KSHV-associated), including but not limited to, chemotherapeutic agents such as bleomycin, vinblastine, vincristine, cyclophosphamide, prednisone, alitretinoin and liposomal anthracyclines such as doxorubicin, daunorubicin, immunotherapies such as rituximab, tocilizumab, siltuximab, and others such as paclitaxel and rapamycin.

[0690] The compounds of the present invention can be used in combination with at least one other therapeutic agent that can be used to treat TB infection (Mycobacterium tuberculosis) and tularemia (Franciscothria tularensis), including but not limited to first-line oral agents including isoniazid, rifampicin, pyrazinamide, ethambutol, streptomycin, rifabutin; injections including kanamycin, amikacin, capreomycin, streptomycin; fluoroquinolones including levofloxacin, moxifloxacin, ofloxacin; oral antibacterial agents including para-aminosalicylic acid, cycloserine, terizidone, thiocarbamate, thiophene, thiabendazole, thiabendazole, thiophene ... amide, prothionamide; SQ-109PNU-100480, rifapentine, linezolid, PA-824AZD5847, gatifloxacin, moxifloxacin, Sirturo (bedaquiline), Delamanid (OPC-67683), and drugs with undefined mechanisms of action in the treatment of drug-resistant TB, including clofazimine, linezolid, amoxicillin / clavulanate thiosemicarbazone, imipenem / cilastatin, high-dose isoniazid, clarithromycin, and ciprofloxacin.

[0691] The compounds of the present application can be used in combination with at least one of the following agents: antimycobacterial agents (such as isoniazid (INH), ethambutol Rifampin and pyrazinamide (PZA)), bactericidal antibiotics (such as rifabutin or rifapentine ), aminoglycosides Fluoroquinolones (levofloxacin, moxifloxacin, ofloxacin), thioamides (ethionamide), cyclosporine para-aminosalicylic acid Cycloserine Kanamycin Streptomycin, viomycin, capreomycin ), Bedaquiline Fumarate Oxazolidinone PNU-100480 or delamanid (OPC-67683).

[0692] The compounds of the present application can be used in combination with at least one other therapeutic agent that can be used for the treatment of Chlamydia, including but not limited to azithromycin, doxycycline, erythromycin, levofloxacin and ofloxacin.

[0693] The compounds of the present application can be used in combination with at least one other therapeutic agent useful for treating Plasmodium infection, including but not limited to chloroquine, atovaquone-proguanil, artemether-lumefantrine, mefloquine, quinine, quinidine, doxycycline, clindamycin, artesunate and primaquine.

[0694] In the treatment of amyotrophic lateral sclerosis (ALS), the compounds of the present application can be used in combination with the following agents: glutamate blockers (riluzole ), quinidine Anticholinergics ( Scopolamine patch ), anesthetics (pseudoephedrine), mucolytics (guaifenesin), or analgesics (tramadol Ketorolac Morphine; or fentanyl patch ).

[0695] In the treatment of multiple sclerosis, the compounds of the present application can be used in combination with the following agents: corticosteroids (prednisone, methylprednisolone), interferon β1-A Peginterferon beta-1A Glatiramer acetate Glatiramer acetate (generic equivalent of Copaxone) ); dimethyl fumarate Fingolimod ); teriflunomide Dalfampridine Daclizumab (Zinbryta); Alemtuzumab Natalizumab or mitoxantrone hydrochloride

[0696] The compound of the present application can be used in combination with one or more vaccines or immunogenic antigens that can be used to prevent or treat viral infections. These vaccines or immunogenic antigens include but are not limited to pathogen-derived proteins or particles, such as attenuated viruses, viral particles, and viral proteins commonly used as immunogenic substances. The example of virus and viral antigen includes but is not limited to poliovirus, Coronaviridae and Coronavirus, rhinovirus (all subtypes), adenovirus (all subtypes), hepatitis A, hepatitis B, hepatitis C, hepatitis D, human papillomavirus (including all subtypes), rabies virus, human T-cell lymphotropic virus (all subtypes), rubella virus, mumps virus, coxsackie virus A (all subtypes), coxsackie B virus (all subtypes), human enterovirus, herpes virus including cytomegalovirus, Epstein-Barr virus, human herpes virus (all subtypes), herpes simplex virus, varicella zoster virus, human immunodeficiency virus ( HIV (all subtypes), Epstein-Barr virus, Reovirus (all subtypes), Filoviruses (including Marburg virus and Ebola virus) (all stains), Arenaviruses including Lymphocytic Choriomeningitis Virus, Lassa virus, Junin virus, and Machupo virus, Arboviruses including West Nile virus, Dengue virus (all serotypes), Zika virus, Colorado Tick Fever virus, Sindbis virus, Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, Orthomyxoviridae, Poxviruses including Orthopoxviruses (Variola virus, Monkeypox virus, Vaccinia virus) virus), cowpox virus), Yatapoxvirus (Tanapoxvirus, Yaba monkey tumor virus), parapoxvirus, molluscumpoxvirus, yellow fever, hantavirus including hantavirus, Seoul virus, multibervavirus, sin nombre virus, Puumala virus and multiberva-like Saaremaa virus, human parainfluenza virus and influenza virus (all types), H1N1 influenza virus and swine influenza virus, respiratory syncytial virus (all subgroups), rotavirus including human rotavirus AE, bovine rotavirus, rhesus rotavirus, polyomavirus including simian virus 40, JC virus, BK virus, tick virus family, eyach virus, calicivirus and parvoviridae family, including dependovirus, parvovirus and erythrovirus genera.

[0697] The compounds of the present application can be used in combination with at least one other therapeutic agent that can be used to prevent or treat viral infections, such as immunotherapy (e.g., interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, and similar drugs); and therapeutic vaccines, anti-fibrotic agents, anti-inflammatory agents, such as corticosteroids or NSAIDs (non-steroidal anti-inflammatory agents), and similar drugs.

[0698] The compounds of the present application can be used in combination with other anti-inflammatory drugs, including oral or topical corticosteroids, anti-TNF drugs, 5-aminosalicylic acid and mesalamine preparations, hydroxychloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologics, including anti-IL6 biologics, anti-Ill agents, anti-IL17 biologics, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologics and other cytokine inhibitors or T cell or B cell receptor or interleukin biologics.

[0699] For example, in the treatment of systemic lupus erythematosus and related lupus diseases, the compounds of the present invention can be used in combination with at least one other therapeutic agent, including a corticosteroid (e.g., prednisolone ( Orapred, Millipred, Omnipred, Econopred, Flo-Pred), immunosuppressants (such as methotrexate Dexamethasone Mycophenolate mofetil B cell therapy (Belimumab B cell inhibitors ( (anti-CD22), SBI-087 (anti-CD20), anti-BAFF antibodies (LY2127399, A623), ), azathioprine Quanxilong ( , Kenalog- ), hydroxychloroquine Thalidomide Immunoglobulin therapy Anti-interferon α therapy ( AGS- IFNKinoid), TLR7 and TLR9 blockers (IMO-3100), anti-cytokine therapy (anti-IL6 (CNTO-136), anti-interferon-γ (AMG811), immunomodulatory therapy (Lupuzor TM , Abatacept, or AMG557, laquinimod, paquinimod, leflunomide, anti-ICOS (Medi-570), anti-CD40 ligand antibody (CDP7657), and / or platelet aggregation inhibitor (aspirin).

[0700] In the treatment of diseases with inflammation of small and medium-sized blood vessels and vasculitis, the compounds of the present application can be used in combination with alkylating agents (cyclophosphamide, ), anti-rheumatic anti-CD20 antibody and anti-TNF inhibitors Use in combination.

[0701] In the treatment of psoriasis, the compounds of the present application can be used in combination with ixekizumab, tildrakizumab (MK-3222) or secukinumab (AIN457).

[0702] In one embodiment, at least one additional therapeutic agent is selected from the group consisting of inhaled corticosteroids, long-acting beta agonists, a combination of inhaled corticosteroids and long-acting beta agonists, short-acting beta agonists, leukotriene modifiers, anti-IgE, methylxanthine bronchodilators, mast cell inhibitors, and long-acting muscarinic antagonists. For example, in the treatment of asthma, the compounds of the present application can be used in combination with the following agents: inhaled corticosteroids (ICS), such as fluticasone propionate Beclomethasone dipropionate Budesonide (Pulmicort), triamcinolone acetonide Flunisolide Mometasone furoate or ciclesonide ), long-acting beta-agonists (LABAs, such as formoterol fumarate Salmeterol xinafoate ), combinations of ICS and LABA (such as fluticasone furoate and vilanterol Formoterol / budesonide inhaler Beclomethasone Dipropionate / Formoterol and fluticasone propionate / salmeterol Short-acting beta-agonists (SABAs), such as albuterol sulfate ( Inhalation solution), levalbutamol tartrate ( HFA), ipratropium bromide / albuterol Ipratropium bromide ( HFA), leukotriene modifiers (e.g., montelukast sodium Zafirlukast or Qiliutong and anti-IgE (eg, omalizumab) ), methylxanthine bronchodilators (such as theophylline ( Quibron- 、Slo- 、Slo- 、 T- 、Theo- 、Theo- 、Uni- 、 ), mast cell inhibitors (such as sodium cromoglycate and nedocromil sodium ), long-acting muscarinic antagonists (LAMAs such as mometasone furoate / formoterol fumarate dihydrate ).

[0703] Other drugs that may be suitable for combination therapy in asthma include protein tyrosine kinase inhibitors (masitinib), CRTH2 / D-prostanoid receptor antagonists (AMG 853), indacaterol Epinephrine inhalation aerosol (E004), fluticasone furoate / fluticasone propionate, vilanterol inhaler / fluticasone furoate powder (Relovair TM ), Fluticasone Propionate / Formoterol Fumarate Reslizumab, salbutamol dry powder inhaler, tiotropium bromide Formoterol / budesonide Fluticasone furoate Vectura's VR506, lebrikizumab (RG3637), and a combination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).

[0704] In one embodiment, at least one other therapeutic agent is selected from a long-acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid long-acting beta agonist, a short-acting beta agonist, and an inhaled corticosteroid. For example, in the treatment of COPD, the compounds of the present application can be used in combination with the following agents: LABA (e.g., salmeterol xinafoate (Serevent), umeclidinium / vilanterol (Anoroglucose), ... ), umeclidinium Formoterol tartrate Formoterol fumarate inhalation powder Indacaterol maleate or fluticasone propionate / formoterol fumarate ), long-acting inhaled sedatives (or muscarinic antagonists such as tiotropium and aclidinium bromide Phosphodiesterase (PDE-r) inhibitors (e.g., roflumilast, ), ICS / LABA combinations (e.g., fluticasone furoate and vilanterol Fluticasone propionate / salmeterol budesonide / formoterol Mometasone / Formoterol Ipratropium bromide / salbutamol sulfate Salbutamol / ipratropium ), SABA (e.g. ipratropium bromide and salbutamol sulfate ) and ICS (eg, budesonide and fluticasone propionate ( ), beclomethasone dipropionate

[0705] Other drugs that may be suitable for combination therapy in COPD include SCH527123 (a CXCR2 antagonist), glycopyrrolate (NVA237) ), glycopyrrolate and indacaterol maleate ((QVA149) ), glycopyrrolate and formoterol fumarate (PT003), indacaterol maleate (QVA149), olodaterol Tiotropium bromide / Odaterol and aclidinium / formoterol inhaler.

[0706] In one embodiment, the at least one additional therapeutic agent is selected from oral corticosteroids, antithymocyte globulin, thalidomide, chlorambucil, calcium channel blockers, topical emollients, ACE inhibitors, serotonin reuptake inhibitors, endothelin-1 receptor inhibitors, antifibrotic agents, proton pump inhibitors, or imatinib, ARG201, and tocilizumab.

[0707] For example, in the treatment of systemic scleroderma, the compounds of the present application can be used in combination with the following agents: oral corticosteroids (such as prednisolone ( Ordnred, Millipred, Omnipred, Econopred, Flo-Pred), immunosuppressants (such as methotrexate Cyclosporine Antithymocyte globulin Mycophenolate mofetil Cyclophosphamide FK506 (tacrolimus), thalidomide Chlorambucil Azathioprine ), calcium channel blockers (such as nifedipine ( ) or nicardipine Topical emollients (nitroglycerin ointment), ACE inhibitors (eg, lisinopril Diltiazem ( ), serotonin reuptake inhibitors (e.g., fluoxetine ), endothelin 1 receptor inhibitors (e.g., bosentan or epoprostenol ) Antifibrotic agents (e.g., colchicine Para-aminobenzoic acid (PABA), dimethyl sulfoxide (DMSO), and D-penicillamine Interferon alpha and interferon gamma (INF-g), proton pump inhibitors (eg, omeprazole Metoclopramide Lansoprazole Esomeprazole Pantoprazole Rabeprazole ) or imatinib ARG201 (arGentis Pharmaceutical), belimumab Tocilizumab

[0708] In the treatment of Sjogren's syndrome, the compounds of the present application can be used in combination with the following agents: anti-rheumatic agents (hydroxychloroquine and ), cholinergic agonists JAK inhibitors and anti-TNF therapy

[0709] In one embodiment of the present invention, at least one other therapeutic agent is ciliary neurotrophic growth factor or a gene transfer agent. For example, in the treatment of retinitis pigmentosa, the compound of the present application can be combined with ciliary nerve growth factor (NT-501-CNTF) or a gene transfer agent. Use in combination.

[0710] In one embodiment of the present invention, at least one other therapeutic agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent or an inactivated influenza vaccine. For example, in the treatment of influenza, the compounds of the present application can be used in combination with the following agents: a trivalent (IIV3) inactivated influenza vaccine (e.g., ), quadrivalent (IIV4) inactivated influenza vaccine (such as Quadrivalent, Quadrivalent, Quadrivalent), trivalent recombinant influenza vaccine (such as ), quadrivalent live attenuated influenza vaccine (such as Quadrivalent), antiviral agents (such as oseltamivir Zanamivir Rimantadine or amantadine )or Fludase, Preflucel or

[0711] In the treatment of staphylococcal infections, the compounds of the present application can be used in combination with the following agents: antibiotics (e.g., β-lactam cephalosporins ( etc.), nafcillin Sulfonamides (sulfamethoxazole and trimethoprim Sulfasalazine Acetylsulfisoxazole etc.) or vancomycin ).

[0712] In one embodiment, at least one other therapeutic agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, interferon gamma, an antihistamine, or an antibiotic. For example, in the treatment of atopic dermatitis, the compounds of the present application can be used in combination with a topical immunomodulator or calcineurin inhibitor (e.g., pimecrolimus) or tacrolimus ointment ), topical corticosteroids (eg, hydrocortisone Betamethasone flurandrenolide Fluticasone Quanxilong Fuceconazole acetate and clobetasol ), oral corticosteroids (eg, hydrocortisone Methylprednisolone or prednisolone Immunosuppressants (eg, cyclosporine or interferon gamma ( Intron A, Roferon- ), antihistamines (for itching, e.g. ), antibiotics (such as the penicillin derivative flucloxacillin or dicloxacillin Erythromycin ( , T- , Erythra- etc.), nonsteroidal immunosuppressants (such as azathioprine ( ), methotrexate Cyclosporine or mycophenolate mofetil ).

[0713] In one embodiment, the compounds may be administered in combination with one or more separate agents, such as chemotherapeutic agents, immunotherapeutic agents, or adjuvant therapeutic agents, as well as one or more other secondary agents described herein.

[0714] As used herein, "combination therapy" or "co-therapy" includes the administration of a compound of the present application, or a pharmaceutically acceptable salt or ester thereof, and at least a second drug, as part of a specific treatment regimen intended to provide the beneficial effects of the combined action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions produced by the combination of therapeutic agents. The combined administration of these therapeutic agents is typically performed over a prescribed time period (usually a few minutes, hours, days or weeks, depending on the selected combination). "Combination therapy" may (but is not usually) intended to cover the administration of two or more therapeutic agents as part of a separate monotherapy regimen and accidentally or arbitrarily leading to the combination of the present application.

[0715] "Combination therapy" is intended to include administering these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at different times, as well as administering these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule of each therapeutic agent or multiple single capsules of each therapeutic agent in a fixed ratio. Each therapeutic agent can be administered sequentially or substantially simultaneously by any appropriate route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. The order in which the therapeutic agents are administered is not strictly specified.

[0716] "Combination therapy" also includes the further administration of a therapeutic agent as described herein in combination with other biologically active ingredients and a non-drug treatment (e.g., surgery or radiation therapy). When the combination therapy also includes a non-drug treatment, the non-drug treatment can be administered at any appropriate time, as long as the beneficial effects of the combined action of the therapeutic agent and the non-drug treatment are achieved. For example, in appropriate circumstances, when the non-drug treatment is temporarily removed from the administration of the therapeutic agent, it may be continued for several days or even weeks and still achieve a beneficial effect.

[0717] As used herein, the term "immune response" refers to any one or more of the following: specific immune response, nonspecific immune response, both specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation and cytokine expression. In one embodiment, the compound of the present application or a pharmaceutically acceptable salt or ester thereof is administered with one or more other therapeutic agents (including antiviral compounds, vaccines intended to stimulate an immune response to one or more predetermined antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulators, lipids, liposomes, peptides, anticancer agents and chemotherapeutic agents, etc.).

[0718] definition

[0719] Listed below are definitions of various terms used in this application. These definitions apply to the terms as they are used in this specification and claims, whether used individually or as part of a larger group, unless otherwise limited in specific instances.

[0720] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group containing, in certain embodiments, 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl groups.

[0721] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety, which, in certain embodiments, contains two to six carbon atoms and has at least one carbon-carbon double bond. The double bond may or may not be a point of attachment to another group. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.

[0722] As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon moiety, which, in certain embodiments, contains two to six carbon atoms and has at least one carbon-carbon triple bond. A triple bond may or may not be a point of attachment to another group. Alkynyl groups include, but are not limited to, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.

[0723] The term "alkoxy" refers to an -O-alkyl group.

[0724] As used herein, the terms "halo," "halo," and "halogen" refer to an atom selected from the group consisting of fluorine, chlorine, bromine, and iodine.

[0725] As used herein, the term "cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic compound. Examples of C3-C8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl; and C3-C8 12 Examples of -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

[0726] As used herein, the term "cycloalkenyl" refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic compound containing at least one carbon-carbon double bond. Examples of C4-C8 cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclopentenyl, and cyclooctyl.

[0727] As used herein, the term "aryl" refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.

[0728] The term "aralkyl" as used herein refers to an alkyl residue as described herein attached to an aryl ring as described herein. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0729] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic or more) fused or non-fused group or ring system having at least one aromatic ring, 5 to 10 ring atoms, wherein 1 ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, indazolyl, cinnolinyl, phthalazinyl, pyridazinyl, indolyl, acridinyl, benzoquinolinyl, pyrimidinyl, purinyl, pyrrolopyrimidinyl, quinoxalinyl, quinazolinyl, indazolinyl, and phthalazinyl, among others.

[0730] As used herein, the term "heteroaralkyl" refers to an alkyl residue as described herein attached to a heteroaryl ring as described herein. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like.

[0731] According to the present application, any aryl, substituted aryl, heteroaryl and substituted heteroaryl described herein can be any aromatic group. Aromatic groups can be substituted or unsubstituted.

[0732] As used herein, the term "heterocyclyl" refers to a non-aromatic monocyclic or polycyclic (e.g., bicyclic, tricyclic, or higher) fused or non-fused group or ring system having 3 to 10 ring atoms, one of which is selected from S, O, and N; zero, one, or two of which are additional heteroatoms selected from S, O, and N; and the remaining ring atoms are carbon. Representative heterocycloalkyl groups include, but are not limited to, [1,3]dioxolanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuranyl, among others.

[0733] The term "alkylamino" refers to a group having -NH(C1-C 12 -NH(C1-C6 alkyl), wherein C1-C6 alkyl is as defined above.

[0734] The term "dialkylamino" refers to a group having -N(C1-C 12 A group having a C1-C6 alkyl)2 structure, for example, -NH(C1-C6 alkyl), wherein the C1-C6 alkyl is as defined above.

[0735] The term "acyl" includes residues derived from acids including, but not limited to, carboxylic acid, carbamic acid, carbonic acid, sulfonic acid, and phosphorous acid. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates, and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxyacetyl, and the like.

[0736] The term "ester" includes compounds or moieties containing a carbon or heteroatom bonded to an oxygen atom bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and the like.

[0737] As described herein, the compounds of the present application and the moieties present in the compounds may be optionally substituted with one or more substituents, such as those generally described above or as exemplified by the specific classes, subclasses and species of the present application. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether or not preceded by the term "optionally", refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise stated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. The terms "optionally substituted", "optionally substituted alkyl", "optionally substituted alkenyl", "optionally substituted alkynyl", "optionally substituted cycloalkyl", "optionally substituted cycloalkenyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted aralkyl", "optionally substituted heteroaralkyl", "optionally substituted heterocyclyl" and any other optionally substituted groups as used herein refer to groups that are substituted or unsubstituted by independently replacing one, two, or three or more hydrogen atoms on the group with substituents including, but not limited to:

[0738] -F, -CI, -Br, -I, -OH, protected hydroxyl, -NO2, -CN, -NH2, protected amino, -NH-C1-C 12 -alkyl, -NH-C2-C 12 -alkenyl, -NH-C2-C 12 -alkenyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 -alkyl, -O-C2-C 12 -alkenyl, -O-C2-C12 -alkenyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -alkyl, -C(O)-C2-C 12 -alkenyl, -C(O)-C2-C 12 -alkenyl, -C(O)-C3-C 12 -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -alkyl, -CONH-C2-C 12 -alkenyl, -CONH-C2-C 12 -alkenyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C 12 -alkenyl, -OCO2-C2-C 12 -alkenyl, -OCO2-C3-C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12 -alkyl, -OCONH-C2-C 12 -alkenyl, -OCONH-C2-C 12 -alkenyl, -OCONH-C3-C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-C1-C 12 -alkyl, -NHC(O)-C2-C 12 -alkenyl, -NHC(O)-C2-C 12 -alkenyl, -NHC(O)-C3-C 12 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1-C 12 -alkyl, -NHCO2-C2-C 12 -alkenyl, -NHCO2-C2-C 12 -alkenyl, -NHCO2-C3-C 12 -cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, NHC(O)NH2, -NHC(O)NH-C1-C 12 -alkyl, -NHC(O)NH-C2-C12 -alkenyl, -NHC(O)NH-C2-C 12 -alkenyl, -NHC(O)NH-C3-C 12 -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH2, -NHC(S)NH-C1-C 12 -alkyl, -NHC(S)NH-C2-C 12 -alkenyl, -NHC(S)NH-C2-C 12 -alkenyl, -NHC(S)NH-C3-C 12 -cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 -alkyl, -NHC(NH)NH-C2-C 12 -alkenyl, -NHC(NH)NH-C2-C 12 -alkenyl, -NHC(NH)NH-C3-C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NHheterocycloalkyl, -NHC(NH)-C1-C 12 -alkyl, -NHC(NH)-C2-C 12 -alkenyl, -NHC(NH)-C2-C 12 -alkenyl, -NHC(NH)-C3-C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -alkyl, -C(NH)NH-C2-C 12 -alkenyl, -C(NH)NH-C2-C 12 -alkenyl, C(NH)NH-C3-C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -S(O)-C1-C 12 -alkyl, -S(O)-C2-C 12 -alkenyl, -S(O)-C2-C 12 -alkenyl, -S(O)-C3-C 12 -cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl-SO2NH2, -SO2NH-C1-C 12 -alkyl, -SO2NH-C2-C 12-alkenyl, -SO2NH-C2-C 12 -alkenyl, -SO2NH-C3-C 12 -cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 -alkyl, -NHSO2-C2-C 12 -alkenyl, -NHSO2-C2-C 12 -alkenyl, -NHSO2-C3-C 12 -cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C 12 -alkyl, -S-C2-C 12 -alkenyl, -S-C2-C 12 -alkenyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl or methylthiomethyl.

[0739] The term "cancer" includes, but is not limited to, the following cancers: epidermoid oral cavity: buccal cavity, lip, tongue, mouth, pharynx; heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, laryngeal carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, pancreatic adenocarcinoma) ), small intestine (adenocarcinoma, lymphoma, carcinoid, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, colon cancer, leiomyoma), colon, colorectal, colorectal, rectum; genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicle (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroma, adenomatous tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), bile duct cancer , hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract cancer; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma, osteochondroma, osteochondroma exostosis, benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas) Gynecological: Uterus (endometrial cancer), Cervix (cervical cancer, preneoplastic cervical dysplasia), Ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant melanoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), Fallopian tube (carcinoma), Breast cancer.Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hair cells; lymphatic diseases; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Thyroid: papillary thyroid carcinoma, follicular thyroid carcinoma; Medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; and Adrenal: neuroblastoma. Thus, the term "cancer cell" as provided herein includes cells afflicted by any of the above conditions.

[0740] As used herein, the term "subject" refers to a mammal. Thus, a subject refers to, for example, a dog, cat, horse, cow, pig, guinea pig, etc. Preferably, the subject is a human. When the subject is a human, the subject may be referred to herein as a patient.

[0741] "Treatment" and "treatment" refer to a method for alleviating or eliminating a disease and / or its attendant symptoms.

[0742] As used herein, "preventing" describes the alleviation or elimination of the symptoms or onset of complications of a disease, disorder or condition.

[0743] Unless the context clearly dictates otherwise, the terms "disease," "disorder," and "condition" are used interchangeably.

[0744] As used herein, the term "therapeutically effective amount of a compound or pharmaceutical composition of the present application" refers to a sufficient amount of a compound or pharmaceutical composition to alleviate the symptoms of a condition in a subject. As is well known in the medical field, a therapeutically effective amount of a compound or pharmaceutical composition of the present application should have a reasonable benefit / risk ratio applicable to any medical treatment. However, it should be understood that the total daily dosage of the compounds and compositions of the present application will be determined by the attending physician within the scope of reasonable medical judgment. The specific adjusted dose (e.g., inhibitory or stimulating) for any particular patient will depend on a variety of factors, including the disease being treated and the severity of the disease; the activity of the specific compound used; the specific composition used; the patient's age, weight, overall health, sex and diet; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used; and other factors well known in the medical field.

[0745] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0746] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds formed by the methods of the present application that are suitable for use in contact with the tissues of humans and lower animals within the scope of reasonable medical judgment. They are free of excessive toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). These salts can be prepared in situ during the final isolation and purification of the compounds of the present application, or they can be prepared separately by reacting the free base or acid functional group with a suitable acid or base.

[0747] Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, maleic, tartaric, citric, succinic, or malonic acids. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbic acid, aspartic acid, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, lauric acid, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, 7-toluenesulfonate, undecanoate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include, where applicable, non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl groups having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0748] As used herein, the term "pharmaceutically acceptable ester" refers to an ester of a compound formed by the methods of the present application that hydrolyzes in vivo and includes those that readily decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids, and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

[0749] As used herein, the term "pharmaceutically acceptable prodrug" refers to those prodrugs of the compounds formed by the methods of the present application that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, have undue toxicity, irritation, allergic response, etc., and have a reasonable benefit / risk ratio, and are effective for their intended use, and where possible, the zwitterionic form of the compounds of the present application is also effective.

[0750] As used herein, "prodrug" refers to a compound that is transformable in vivo by metabolic means (eg, by hydrolysis) to provide any of the compounds depicted by the formulae of the present application. Various forms of prodrugs are known in the art, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug Deliver Reviews, 8: 1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77: 285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer," Hydrolysis In Drug And Those described in "Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

[0751] A "pharmaceutically acceptable excipient" is an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes pharmaceutically acceptable excipients for veterinary use as well as for human use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes one or more such excipients.

[0752] The present application also includes pharmaceutical compositions containing pharmaceutically acceptable prodrugs of compounds of the present application, and methods for treating diseases by administering pharmaceutically acceptable prodrugs of compounds of the present application. For example, compounds of the present application with free amino groups, amide groups, hydroxyl groups or carboxyl groups can be converted into prodrugs. Prodrugs include compounds in which amino acid residues or polypeptide chains of two or more (e.g., two, three or four) amino acid residues are covalently bonded to free amino groups, hydroxyl groups or carboxyl groups of compounds of the present application via amide or ester bonds. Amino acid residues include, but are not limited to, 20 natural amino acids typically represented by three letter symbols, and also include 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, valine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Other types of prodrugs are also included. For example, free carboxyl groups can be derived into amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinate, phosphate, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl, as described in Advanced Drug Delivery Reviews, 1996, 19, 1-15. Also included are carbamate prodrugs of hydroxyl and amino groups, as well as carbonate prodrugs, sulfonates, and sulfates of hydroxyl groups. Hydroxyl groups are derived into (acyloxy)methyl and (acyloxy)ether, wherein the acyl group can be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or where the acyl group is an amino acid ester as described herein. Such prodrugs are described in J.Med.Chem. 1996, 39, 10. Free amines can also be derived into amides, sulfonamides, or phosphonamides. All of these prodrug moieties can be combined with moieties including, but not limited to, ether, amine, and carboxylic acid functional groups.

[0753] The combinations of substituents and variables contemplated herein are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have sufficient stability to allow manufacture and maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., for therapeutic or prophylactic administration to a subject).

[0754] When any variable (e.g., R1) occurs multiple times in any constituent of a compound or in a formula, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R moieties, each occurrence of R is independently selected from the definition of R. Similarly, combinations of substituents and / or variables are permissible, provided that such combinations form stable compounds within the normal valencies of the designated atoms.

[0755] In addition, some compounds of the present application have one or more double bonds or one or more asymmetric centers. Such compounds can exist as racemates, racemic mixtures, single enantiomers, single diastereomers, diastereomeric mixtures and cis or trans or E- or Z-diisomeric forms, as well as other stereoisomeric forms defined according to absolute stereochemistry, such as (R)- or (S)- or (D)- or (L)- configurations of amino acids. When the compounds described herein include olefinic double bonds or other geometric asymmetric centers, unless otherwise indicated, the compound should include both E and Z geometric isomers. The selection of the configuration of any carbon-carbon double bond occurring herein is only for convenience and is not intended to specify a specific configuration, unless otherwise indicated in the text; therefore, any carbon-carbon double bond described herein as trans can be cis, trans or a mixture of the two in any ratio. All these isomeric forms of these compounds are explicitly included in the present application.

[0756] "Isomers" refer to compounds that have the same molecular formula but differ in the order in which their atoms are bonded or how they are arranged in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," while stereoisomers that are non-superimposable mirror images are called "enantiomers," sometimes also called optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0757] A carbon atom bonded to four different substituents is called a "chiral center."

[0758] "Chiral isomer" refers to a compound with at least one chiral center. Compounds with multiple chiral centers can exist as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When a single chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center (e.g., carbon). Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents to be considered attached to the chiral center are ordered according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0759] "Geometric isomers" refer to diastereomers that exist due to hindered rotation about double bonds. The names of these configurations are distinguished by the prefixes cis and trans or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0760] Furthermore, the structures and other compounds discussed in this application include all atropic isomers thereof. An "atropic isomer" is a stereoisomer in which the atoms of the two isomers are arranged differently in space. Atropic isomers exist due to restricted rotation around a central bond, hindered by the presence of bulky groups. Such atropic isomers typically exist as a mixture, but recent advances in chromatographic techniques have made it possible, in some cases, to separate a mixture of two atropic isomers.

[0761] A tautomer is one of two or more structural isomers in equilibrium that readily convert from one isomeric form to another. This conversion results in the formal migration of hydrogen atoms, accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomers in solution. In solid form, one tautomer usually predominates. In solutions where tautomerism is possible, chemical equilibrium among the tautomers is achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerism is called tautomerism.

[0762] Of the various possible tautomerism types, two are generally observed. In keto-enol tautomerism, the displacement of electrons and hydrogen atoms occurs simultaneously. The aldehyde group (-CHO) in the sugar chain molecule reacts with a hydroxyl group (-OH) in the same molecule to form a ring (cyclic) form, thereby producing a ring-chain tautomerism phenomenon, such as that shown in glucose. Common tautomerism pairs are: keto-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocycles (for example, in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine. The compounds of the present application can also be represented in multiple tautomeric forms, in which case the present application explicitly includes all tautomeric forms of the compounds described herein (for example, alkylation of the ring system may result in multiple site alkylation, and the present application explicitly includes all such reaction products).

[0763] In the present application, for convenience, the structural formula of the compound represents a certain isomer in some cases, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, etc.

[0764] In addition, the compounds of the present application, such as salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms or in solvate forms with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0765] "Solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of a solvent. Certain compounds tend to trap fixed molar ratios of solvent molecules in their crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; a hydrate is formed by the combination of one or more molecules of water with one molecule of a substance, where the water remains in its molecular form, HO. Example

[0766] All compounds had a purity exceeding 95% and were analyzed using a Waters LC / MS system. 1 H NMR was obtained at 400 MHz. Chemical shifts are expressed relative to dimethyl sulfoxide (δ = 2.50). Data are reported as (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet).

[0767] The abbreviations used in the following examples and elsewhere herein are:

[0768] AcOH acetic acid

[0769] atm atmosphere

[0770] BOC2O Di-tert-butyl dicarbonate

[0771] br broad peak

[0772] CuSO4 copper sulfate

[0773] CDCl3 deuterated chloroform

[0774] DCM dichloromethane

[0775] DIEA N,N-Diisopropylethylamine

[0776] DMA N,N-dimethylacetamide

[0777] DMAP 4-dimethylaminopyridine

[0778] DMF N,N-dimethylformamide

[0779] DMSO dimethyl sulfoxide

[0780] DMSO-d6 deuterated dimethyl sulfoxide

[0781] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0782] ESI electrospray ionization

[0783] EtOAc

[0784] HCl

[0785] h hour

[0786] HATU bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0787] HPLC high-performance liquid chromatography

[0788] KHMDS Potassium Hexamethyldisilazide

[0789] LCMS liquid chromatography-mass spectrometry

[0790] m multiplet

[0791] mL milliliters

[0792] MeCN Acetonitrile

[0793] MeOH methanol

[0794] mg milligrams

[0795] mmol millimole

[0796] MgSO4 magnesium sulfate

[0797] MHz Megahertz

[0798] min

[0799] MS

[0800] Na2CO3 sodium carbonate

[0801] NaHCO3 sodium bicarbonate

[0802] NMR Nuclear Magnetic Resonance

[0803] Tf triflate

[0804] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0805] Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride

[0806] PhN(SO2CF3)2 N-phenyl-bis(trifluoromethanesulfonamide)

[0807] PMe3 trimethylphosphine

[0808] ppm parts per million

[0809] PTSA p-Toluenesulfonic acid

[0810] rt room temperature

[0811] TBAF Tetra-n-butylammonium fluoride

[0812] t-BuOH tert-Butanol

[0813] TFA trifluoroacetic acid

[0814] TMS trimethylsilane

[0815] THF Tetrahydrofuran

[0816] TLC thin layer chromatography

[0817] μL microliter

[0818] Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0819] Z' Z-factor statistic

[0820] Example 1: Synthesis of Compounds 1-20 and 29-38

[0821] Compounds 1-20 and 29-38 were prepared according to Schemes 1a-1c. The first step is a copper-catalyzed Ullmann-type coupling reaction between the requisite aniline and an appropriately substituted 2-bromobenzoic acid or 2-iodobenzoic acid to form the corresponding diphenylamine. Representative reaction conditions include Cu2O (0.05 eq), Cu (0.1 eq), and K2CO3 (1.2 eq) at reflux in DMF overnight. The base, solvent, and copper source can vary.

[0822] The second step is cyclodehydration in H2SO4:H2O (10:1) at elevated temperature (80°C or higher, overnight) to yield the substituted 10H-acridin-9-one. Other strongly acidic reagents, such as polyphosphoric acid, can also be effective for this purpose. If the diphenylamine is synthesized from a starting aniline without an ortho-substituent, the cyclodehydration yields a mixture of positional isomers (regioisomers). This mixture can be separated using normal-phase silica gel chromatography.

[0823] With ethyl bromoacetate and excess CsCO3 in DMF, heating (80 ℃, 2hr), 10H-acridin-9-one is alkylated.The bromoacetate, alkali and solvent used in this step can be modified as needed.If the inferred mixture of N- and O-alkylated products is produced in the alkylation process, the ratio depends on the 10H-acridin-9-one substituent.Use metal hydroxide (NaOH, LiOH or KOH) in protic solvent (such as methanol or THF / water mixture) to saponify these products into a mixture.By extraction or reverse phase preparative HPLC purification, obtain the required substituted 10-carboxymethyl-9-acridone.

[0824] Example 2: Synthesis of Compound 13

[0825] Step 1: Synthesis of N-(2,3-dichloro-phenyl)-anthranilic acid

[0826] 2-Bromobenzoic acid (4.0 g, 19.9 mmol, 1 eq), 2,3-dichloroaniline (3.55 g, 21.9 mmol, 1.1 eq), Cu2O (849 mg, 5.9 mmol, 0.3 eq), Cu (384 mg, 5.9 mmol, 0.3 eq) and K2CO3 (5.8 g, 41.3 mmol, 2.05 eq) were combined in DMF and heated at 140 ° C for 4 hours. The mixture was cooled to room temperature, poured into ice water, acidified with 2M HCl aqueous solution, and extracted with ethyl acetate (25 mL x 5). The combined organic layer was washed with brine and concentrated to give the crude product, which was triturated with petroleum ether to give 2.9 g of the desired substance as a solid. Calculated value: C 13 H9Cl2NO2+H: 282.0; found: 282.1m / z.

[0827] Step 2: Synthesis of 3,4-dichloroacridone

[0828] 2.9 g of crude N-(2,3-dichloro-phenyl)-o-aminobenzoic acid was mixed with 30 mL of polyphosphoric acid and then heated at 140°C for 4 hours. The mixture was cooled to room temperature and poured into ice water. The pH was neutralized with saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic layer was dried, filtered, and concentrated to give 880 mg of solid 3,4-dichloroacridone crude product. Calculated value: C 13 H7Cl2NO+H: 264.0; found: 264.2 m / z.

[0829] Step 3: Synthesis of ethyl 9-oxoacridine-10-acetate

[0830] The crude 3,4-dichloroacridone (360 mg, 1.36 mmol, 1 eq) was mixed with ethyl bromoacetate (295 mg, 1.8 mmol, 1.3 eq) and Cs2CO3 (886 mg, 2.72 mmol, 2 eq) in acetonitrile (10 mL). The mixture was heated to 80°C overnight with stirring, then cooled to room temperature, filtered and concentrated in vacuo to give 294 mg of crude oil, which was used directly in the next step. Calculated value: C 17 H 13 Cl2NO3+H: 350.0; found: 350.2 m / z.

[0831] Step 4: Synthesis of compound 13

[0832] The crude product 9-oxoacridine-10-ethyl acetate (294 mg, 0.82 mmol, 1 eq) was stirred in THF (5 mL) at room temperature. LiOH (133 mg, 3.28 mmol, 4 eq) was dissolved in 2 mL of H2O and added dropwise to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The reaction mixture was then diluted into water and extracted with ethyl acetate (5 mL × 3). The organic layer was then washed with water (5 mL). The aqueous layers were combined and the pH was adjusted to 40 with 2 M HCl aqueous solution. The organic layer was dried and concentrated to give a residue, which was triturated with petroleum ether:ethyl acetate (3:1, 4 mL) to give the title compound as a yellow solid (37.1 mg, 14%).

[0833] Example 3: Synthesis of Compound 26

[0834] Compound 26 (NaI, 1 eq; CuI, 1 eq; PPh3, 1 eq; Pd(PPh3)4, 0.1 eq; TEA, 75°C overnight; 43%) was prepared from ethyl 3-bromo-4-methyl-9-oxoacridine-10-acetate by Sonogashira coupling, followed by catalytic hydrogenation (Pd / C, MeOH / THF, room temperature overnight, 84%) and saponification in a conventional manner.

[0835] Example 4: Synthesis of Compound 27

[0836] Compound 27 was prepared from ethyl 3-bromo-4-methyl-9-oxoacridine-10-acetic acid by Suzuki reaction, wherein 1-cyclohexen-1-yl-boronic acid pinacol ester was reacted with ethyl 3-bromo-4-methyl-9-oxoacridine-10-acetic acid by Sonogashira coupling (PdCl2(dppf)CH2Cl2, 0.1eq; K2CO3, 2eq; dioxane / water, 15mL / 3mL; 78°C, overnight, 19%), and then the ethyl ester was saponified according to a conventional method.

[0837] Example 5: Synthesis of Compound 21

[0838] Compound 21 was prepared by bromination of 10-carboxymethyl-9-acridone (Br2, 1.3 eq; AcOH, room temperature) to produce a 2:1 mixture of monobrominated and dibrominated products. The mixture was alkylated with ethyl bromoacetate and saponified under standard conditions.

[0839] Example 6: Synthesis of Compound 22

[0840] Compound 22 (NaI, 1 eq; CuI, 1 eq; PPh3, 1 eq; Pd(PPh3)4, 0.1 eq; TEA, 75°C overnight; 22%) was prepared by Sonogashira coupling of phenylacetylene with compound 21, followed by saponification using standard conditions.

[0841] Example 7: Synthesis of Compound 25

[0842] Compound 25 was prepared by Suzuki coupling of 1-cyclohexen-1-ylboronic acid pinacol ester with compound 21 (PdCl2(dppf)CH2Cl2, 0.1 eq; K2CO3, 2 eq; dioxane / water, 15 mL / 3 mL; 78°C; overnight 16%), followed by catalytic hydrogenation over palladium and then saponification in the conventional manner to give the title compound.

[0843] Example 8: Synthesis of Compounds 47-49, 51-53, 55-58, 66, 78, 79, 81-85, 89, 92-94, 96-99, 102, 111, 112, 120, 121, 124, 127, and 128

[0844] Compounds 47-49, 51-53, 55-58, 66, 78, 79, 81-85, 89, 92-94, 96-99, 102, 111, 112, 120, 121, 124, 127 and 128 were synthesized according to the procedure described in Scheme 1 using appropriate starting materials.

[0845] Example 9: Synthesis of Compounds 86 and 90

[0846] Compounds 86 and 90 were prepared according to the procedure described in Scheme 2 using appropriate starting materials.

[0847] Example 10: Synthesis of Compounds 39, 40, 42, 43, 74-76, 80, 88 and 90

[0848] Compounds 39, 40, 42, 43, 74-76, 80, 88 and 90 were prepared according to the procedures described in Scheme 3 using appropriate starting materials.

[0849] Example 11: Synthesis of Compounds 41, 50, 54, 65, 67, 68, 72, 73, 77, 91, 114-116 and 125

[0850] Compounds 41, 50, 54, 65, 67, 68, 72, 73, 77, 91, 114-116 and 125 were prepared according to the procedures described in Scheme 4 using appropriate starting materials.

[0851] Example 12: Synthesis of Compounds 44-46, 59-64, 69, 70, 71, 95, 107, 117-119, 122, 123, 126, and 129

[0852] Compounds 44, 46, 59-61, 69, 71, 95, 117-119, 122, 123, 126 and 129 were prepared from compound 30 by nucleophilic substitution.

[0853] Compounds 70 and 107 were prepared from compound 83 by nucleophilic substitution.

[0854] Compounds 45 and 62-64 were prepared from compound 93 by nucleophilic substitution.

[0855] Example 13: Synthesis of Compound 90

[0856] Compound 90 was prepared according to the procedure described in Scheme 3 using appropriate starting materials.

[0857] Example 14: Synthesis of Compounds 67, 68, 72, 88 and 125

[0858] Compound 88 and compounds 67, 68, 72 and 125 were prepared from compound 89 according to Scheme 3 and Scheme 4, respectively.

[0859] Example 15: Synthesis of Compounds 73, 74 and 80

[0860] Compound 73 and compounds 74 and 80 were prepared from compound 21 according to Scheme 4 and Scheme 3, respectively.

[0861] Example 16: Synthesis of Compounds 75-77

[0862] Compounds 75 and 76 and compound 77 were prepared from compound 78 according to Scheme 3 and Scheme 4, respectively.

[0863] Example 17: Synthesis of Compounds 50, 65, 91 and 114-116

[0864] Compounds 50, 65, 91 and 114-116 were prepared from compound 79 according to Scheme 4.

[0865] Example 18: Synthesis of Compound 87

[0866]

[0867] Step 1

[0868] To a mixture of 1a (880 mg, 4.2 mmol, 1.0 eq) and Cs2CO3 (3.4 g, 10.5 mmol, 2.5 eq) in acetonitrile / THF (5.0 mL / 4.0 mL) was added 1b (1.02 mg, 6.3 mmol, 1.50 eq) at room temperature. The mixture was then stirred at 80°C for 2 days, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE / EtOAc, ) to give 1c (80 mg, 6.4%) as a yellow solid. LC / MS: 296.2 [M+H] + .

[0869] Step 2

[0870] To a mixture of 1c (15.0 mg; 0.05 mmol, 1.0 eq) in THF (3 mL) was added dropwise a solution of NaOH (8.0 mg, 0.2 mmol, 4.0 eq) in H2O (1.0 mL). The reaction mixture was stirred at 35°C overnight, then cooled to room temperature and diluted with ice water (3.0 mL) and extracted with DCM (3.0 mL×3). The aqueous layer was acidified to pH=3 with 2N HCl and extracted with EtOAc (5.0 mL×4). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=3:1) and filtered to give compound 87 (5.0 mg, 37.6%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.43 (m, 2H), 7.18-7.14 (m, 2H), 6.98-6.94 (m, 2H), 6.81 (d, J = 8.0Hz, 2H), 4.68 (s, 2H), 1.51 (s, 6H). LC / MS:268.4[M+H]+ .

[0871] Example 19: Synthesis of Compound 85

[0872]

[0873] Step 1

[0874] A mixture of 2a (5.0 g, 23.25 mmol, 1.0 eq), 2b (4.14 g, 25.58 mmol, 1.1 eq), potassium carbonate (8.02 g, 58.13 mmol, 2.5 eq), copper powder (443.0 mg, 6.98 mmol, 0.3 eq) and cuprous oxide (I) (997.0 mg, 6.98 mmol, 0.3 eq) in DMF (100.0 mL) was stirred at 140 ° C. overnight under an argon atmosphere and then cooled to room temperature. Water (50.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then water (50.0 mL) was added. The resulting mixture was extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with brine (20.0 mL×5), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product 2c (crude product, 4.61 g, 67.0%). LC / MS: 296.1 [M+H] + .

[0875] Step 2

[0876] A mixture of 2c (4.61 g, 15.6 mmol), sulfuric acid (20.0 mL), and H2O (2.0 mL) was heated at 100°C for 2 hours, then cooled and poured into a mixture of ice and water. The suspension was filtered and the filter cake was washed with water (20.0 mL x 3) and dried under vacuum to give the crude product 2d (1.0 g, 20.4%). LC / MS: 278.1 [M+H] + .

[0877] Step 3

[0878] To a mixture of 2d (300.0 mg, 1.08 mmol) in THF (10.0 mL) was added BH3·THF (1 M in THF, 5.5 mL). The mixture was stirred at 70°C for 2 h, diluted with water (30.0 mL), and extracted with EtOAc (15.0 mL x 3). The combined organic layers were concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v = 20:1) and filtered to give 2e (120 mg, 42.0%) as a yellow solid. LC / MS: 264.1 [M+H] + .

[0879] Step 4

[0880] To a mixture of 2e (120.0 mg, 0.46 mmol, 1.0 eq) and Cs2CO3 (446.0 mg, 1.37 mmol, 3.0 eq) in a mixed solvent of acetonitrile / THF (5.0 mL / 5.0 mL) was added 1b (153.0 mg, 0.92 mmol, 2.0 eq). The mixture was stirred at room temperature overnight and then filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=10:1) and filtered to give 2f (40 mg, 25.5%) as a yellow solid. LC / MS: 350.1 [M+H] + .

[0881] Step 5

[0882] To a mixture of 2f (40 mg; 0.12 mmol, 1.0 eq) in THF (20.0 mL), a solution of NaOH (19.0 mg, 0.46 mmol, 4.0 eq) in H o (8.0 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, diluted with ice water (30.0 mL), and extracted with EtOAc (15.0 mL x 3). The aqueous layer was acidified to pH=3 with 2N HCl and extracted with EtOAc (25.0 mL x 3). The combined organic layers were dried over anhydrous Na sO and filtered. The filtrate was concentrated in vacuo to give compound 85 (15.0 mg, 40.8%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.27 (d, J=8.0Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.08 (s, 1H), 7.03 (d, J=7.6Hz, 1H), 6.80 (d, J=7.2Hz, 1H), 4.75 (s, 2H), 3.92 (s, 2H), 2.26 (s, 3H). LC / MS:322.1[M+H] + .

[0883] Example 20: Synthesis of Compound 81

[0884]

[0885] Step 1

[0886] A mixture of 2-amino-3,4-dichlorobenzoic acid (1.0 g, 4.85 mmol, 1.0 eq), 3a (1.93 g, 9.70 mmol, 2.0 eq), potassium carbonate (1.34 g, 9.70 mmol, 2.0 eq), L-proline (0.17 g, 1.46 mmol, 0.3 eq) and copper (I) iodide (0.28 g, 1.46 mmol, 0.3 eq) in 2-pentanol (30 mL) was stirred at 140 ° C. under an argon atmosphere overnight, then cooled to room temperature and water (30.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then water (30.0 mL) was added. The resulting mixture was extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with brine (30.0 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product 3b (1 g, 63.6%). LC / MS: 324.0 [M+H] + .

[0887] Step 2

[0888] A mixture of 3b (1.0 g, 3.09 mmol, 1.0 eq), sulfuric acid (20.0 mL) and H2O (2.0 mL) was heated at 100°C for 2 hours, then cooled and poured into a mixture of ice and water (20.0 mL). The solid was collected by filtration and dried under vacuum to give the crude product 3c (0.3 g, 31.9%). LC / MS: 306.0 [M+H] + .

[0889] Step 3

[0890] To a mixture of 3c (0.3 g, 0.98 mmol, 1.0 eq) and Cs2CO3 (0.96 g, 2.94 mmol, 3.0 eq) in acetonitrile / THF (15.0 mL / 15.0 mL) was added 1b (0.33 g, 1.96 mmol, 2.0 eq). The mixture was stirred at 30°C overnight, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=10:1) and filtered to give 3d (0.05 g, 13.2%) as a yellow solid. LC / MS: 392.1 [M+H] + .

[0891] Step 4

[0892] To a mixture of 3d (50.0 mg; 0.13 mmol, 1.0 eq) in THF (4.0 mL) was added dropwise a solution of NaOH (20.8 mg, 0.52 mmol, 4.0 eq) in H O (1 mL). The reaction mixture was stirred at room temperature overnight, diluted with ice water (20.0 mL) and extracted with EtOAc (15.0 mL x 3). The aqueous layer was acidified to pH=3 with 2N HCl and extracted with EtOAc (25.0 mL x 3). The combined organic layers were dried over anhydrous Na SO and filtered. The filtrate was concentrated in vacuo to give Compound 81 (40.0 mg, 86.9%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ13.11 (br, 1H), 8.21 (d, J=8.8Hz, 1H), 8.12 (d, J=8.4Hz, 1H), 7.62 (d, J= 8.4Hz, 1H), 7.50 (s, 1H), 7.31 (d, J=7.6Hz, 1H), 5.22 (s, 2H), 3.65 (m, 1H), 1.27 (d, J=6.8Hz, 6H). LC / MS: 364.2[M+H] + .

[0893] Example 21: Synthesis of Compound 79

[0894]

[0895] Step 1

[0896] A mixture of 2-amino-3,4-dichlorobenzoic acid (5.0 g, 24.3 mmol, 1.0 eq), 4a (17.2 g, 72.9 mmol, 3.0 eq), potassium carbonate (10 g, 72.9 mmol, 3.0 eq), L-proline (0.84 g, 7.29 mmol, 0.3 eq) and copper (I) iodide (1.39 g, 7.29 mmol, 0.3 eq) in 2-pentanol (50 mL) was stirred at 140 ° C. under an argon atmosphere overnight, then cooled to room temperature and water (50.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then water (50.0 mL) was added. The resulting mixture was extracted with EtOAc (50.0 mL×3). The combined organic layers were washed with brine (30.0 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product 4b (4.0 g, 48.0%). LC / MS: 359.9 [M+H] + .

[0897] Step 2

[0898] A mixture of 4b (4.0 g, 11.1 mmol, 1.0 eq), sulfuric acid (20.0 mL) and H2O (2.0 mL) was heated at 100°C for 2 hours, then cooled and poured into a mixture of ice and water (100.0 mL). The solid was collected by filtration and dried under vacuum to give the crude product 4c (2.5 g, 65.8%). LC / MS: 341.9 [M+H] + .

[0899] Step 3

[0900] To a mixture of 4c (2.5 g, 7.29 mmol, 1.0 eq) and Cs2CO3 (7.13 g, 21.87 mmol, 3.0 eq) in acetonitrile / THF (15.0 mL / 15.0 mL) was added 1b (2.43 g, 14.6 mmol, 2.0 eq). The mixture was stirred at 30°C overnight, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=10:1) and filtered to give 4d (0.2 g, 6.5%) as a yellow solid. LC / MS: 427.9 [M+H] + .

[0901] Step 4

[0902] To a mixture of 4d (0.2 g; 0.47 mmol, 1.0 eq) in THF (4.0 mL) was added dropwise a solution of NaOH (75.2 mg, 1.88 mmol, 4.0 eq) in H O (1 mL). The reaction mixture was stirred at room temperature overnight, diluted with ice water (20.0 mL) and extracted with EtOAc (15.0 mL x 3). The aqueous layer was acidified to pH = 3 with 2N HCl and extracted with EtOAc (25.0 mL x 3). The combined organic layers were dried over anhydrous Na SO and filtered. The filtrate was concentrated in vacuo to give compound 79 (0.18 g, 95%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ13.22 (s, 1H), 8.20 (d, J=8.4Hz, 1H), 8.09 (d, J=8.4Hz, 1H), 7. 96 (d, J=1.6Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.56 (dd, J=8.4Hz, 1.6Hz, 1H), 5.23 (s, 2H). LC / MS: 399.9[M+H]+.

[0903] Example 22: Synthesis of Compound 59

[0904]

[0905] Step 1

[0906] A mixture of 5a (5.0 g, 18.8 mmol, 1.0 eq), 5b (4.60 g, 28.2 mmol, 1.5 eq), potassium carbonate (6.5 g, 47.0 mmol, 2.5 eq), copper powder (360.0 mg, 5.64 mmol, 0.3 eq) and cuprous oxide (I) (810.0 mg, 5.64 mmol, 0.3 eq) in DMF (100.0 mL) was stirred overnight at 140 ° C under an argon atmosphere and then cooled to room temperature. Water (50.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then water (50.0 mL) was added. The resulting mixture was extracted with EtOAc (50.0 mL x 3). The combined organic layers were washed with brine (20.0 mL×5), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product 5c (3.0 g, 54.0%). LC / MS: 300.0 [M+H] + .

[0907] Step 2

[0908] A mixture of 5c (3.0 g, 10 mmol), sulfuric acid (15.0 mL) and H2O (2.0 mL) was heated at 100°C for 2 hours, then cooled and poured into a mixture of ice and water (100.0 mL). The suspension was filtered and the filter cake was washed with water (20.0 mL x 3) and dried under vacuum to give the crude product 5d (1.7 g, 60.0%). LC / MS: 282.0 [M+H] + .

[0909] Step 3

[0910] To a mixture of 5d (1.7 g, 6.05 mmol, 1.0 eq) and Cs2CO3 (5.92 g, 18.15 mmol, 3.0 eq) in a mixed solvent of acetonitrile / THF (15.0 mL / 15.0 mL) was added 1b (2.02 g, 12.1 mmol, 2.0 eq). The mixture was stirred at 65°C overnight, cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=10:1) and filtered to give 5e (1.6 g, 73.0%) as a yellow solid. LC / MS: 368.0 [M+H] + .

[0911] Step 4

[0912] To a mixture of 5e (1.6 g; 4.35 mmol, 1.0 eq) in THF (20.0 mL) was added dropwise a solution of NaOH (696.0 mg, 17.39 mmol, 4.0 eq) in H2O (8.0 mL). The reaction mixture was stirred at room temperature overnight, diluted with ice water (30.0 mL), and extracted with EtOAc (15.0 mL x 3). The aqueous layer was acidified to pH = 3 with 2N HCl and extracted with EtOAc (25.0 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give compound 5f (1.5 g, 95%) as a yellow solid. LC / MS: 340.0 [M+H]+.

[0913] Step 5

[0914] To a mixture of 4f (60 mg, 0.18 mmol, 1.0 eq) in THF (2.0 mL) was added 4g (3 mL). The mixture was stirred at 100° C. for three days, cooled to room temperature, and purified by preparative HPLC to give compound 59 (45 mg, 60.8%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6): δ13.17 (s, 1H), 8.15 (d, J = 8.4Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 6.88 (s, 1H), 6.66 (d, J=9.2Hz, 1H), 6.40 (s, 1H), 5.00 (s, 2H), 1.96 (d, J=12.0Hz, 2H), 1.74 (d, J=12.4Hz, 2H), 1.63 (d, J=12.8Hz, 1H), 1.41-1.18 (m, 6H). LC / MS: 419.1[M+H] + .

[0915] Example 23: Synthesis of Compound 71

[0916]

[0917] A mixture of 5f (20 mg, 0.06 mmol, 1.0 eq) and dimethylamine (2 mL, 2 M in THF) was stirred in a sealed tube at 100 °C overnight, then cooled to room temperature and purified by preparative HPLC to give compound 71 (20 mg, 93.0%) as a yellow solid. 1HNMR (400MHz, DMSO-d6): δ8.16 (d, J=8.0Hz, 1H), 7.98 (d, J=8.0Hz, 1H), 7.57 (d, J=12Hz, 1H), 6.84 (d, J=12Hz, 1H), 6.54 (d, J=2Hz, 1H), 5.14 (s, 2H), 3.09 (s, 6H). LC / MS: 365.1[M+H] + .

[0918] Example 24: Synthesis of Compound 72

[0919]

[0920] Step 1

[0921] A mixture of 2-amino-3,4-dichlorobenzoic acid (3.0 g, 14.56 mmol, 1.0 eq), 7a (10.27 g, 43.69 mmol, 3.0 eq), potassium carbonate (6.03 g, 43.69 mmol, 3.0 eq), cuprous iodide (830.0 mg, 4.37 mmol, 0.3 eq) and L-proline (502.0 mg, 5.64 mmol, 0.3 eq) in 2-pentanol (100.0 mL) was stirred at 140° C. under an argon atmosphere overnight and then cooled to room temperature. Water (50.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then water (50.0 mL) was added. The resulting mixture was extracted with EtOAc (50.0 mL×3). The combined organic layers were washed with brine (20.0 mL x 5), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product 7b (crude product, 4.0 g, 76.0%). LC / MS: 359.9 [M+H] +

[0922] Step 2

[0923] A mixture of 7b (4.0 g, 11.14 mmol), sulfuric acid (20.0 mL) and H2O (2.0 mL) was heated at 100°C for 2 hours, then cooled and poured into a mixture of ice and water (100.0 mL). The suspension was filtered and the filter cake was washed with water (20.0 mL x 3) and dried under vacuum to give the crude product 7c (crude product, 1.0 g, 26.0%). LC / MS: 341.9 [M+H] + .

[0924] Step 3

[0925] To a mixture of 7c (1.0 g, 2.92 mmol, 1.0 eq) and Cs2CO3 (2.90 g, 8.77 mmol, 3.0 eq) in a mixed solvent of acetonitrile / THF (15.0 mL / 15.0 mL) was added 1b (950 mg, 5.85 mmol, 2.0 eq). The mixture was stirred at room temperature overnight, cooled to room temperature and filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=10:1) and filtered to give 7d (crude product, 350 mg, 28.0%) as a yellow solid. The crude product 7d was used in the next step without purification. LC / MS: 427.9 [M+H] + .

[0926] Step 4

[0927] To a mixture of 7d (100 mg, 0.233 mmol) and 7e (38 mg, 0.233 mmol, 1.0 eq) in EtOH / H2O (8.0 mL / 2.0 mL) was added K2CO3 (128 mg, 0.932 mmol, 4 eq) and Pd(PPh3)4 (14 mg, 0.017 mmol, 0.1 eq). The mixture was stirred at 50°C under N2 overnight, then diluted with water (30.0 mL) and extracted with EtOAc (15.0 mL x 3). The extract was concentrated in vacuo. The residue was purified by preparative HPLC to give compound 72 (7.5 mg, 8%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ13.21 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.0Hz, 1H), 8.16-8.14 (d, J=8.0Hz , 1H,), 7.77-7.66 (m, 1H), 7.44 (d, J=8.0Hz, 1H), 5.24 (s, 2H), 3.09 (s, 6H), 1.27 (d, J=2.0Hz, 6H). LC / MS: 440.1[M+H]+.

[0928] Example 25: Synthesis of Compound 68

[0929]

[0930] To a mixture of 7d (100 mg, 0.233 mmol) and 8a (38 mg, 0.233 mmol, 1 eq) in EtOH / H2O (10.0 mL / 2.0 mL) was added K2CO3 (128 mg, 0.932 mmol, 4 eq) and Pd(PPh3)4 (14 mg, 0.017 mmol, 0.1 eq) at room temperature. The mixture was then stirred at 50 ° C under N2 overnight. It was diluted with water (30.0 mL) and extracted with EtOAc (15.0 mL x 3). The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give compound 68 (7 mg, 7%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ13.24 (s, 1H), 8.41 (s, 1H), 8.27 (d, J = 8.8Hz, 1H), 8.15 (d, J = 11.6Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.6 7 (d, J=8.4Hz, 1H), 7.60 (s, 1H), 7.56 (d, J=7.6Hz, 1H), 7.40 (t, J=8.0Hz, 1H), 7.23 (d, J=7.2Hz, 1H), 5.25 (s, 2H), 2.42 (s, 3H). LC / MS: 412.1[M+H]+.

[0931] Example 26: Synthesis of Compound 52

[0932]

[0933] Step 1

[0934] A mixture of 9a (340 mg, 2.47 mmol, 1.0 eq), 9b (1.0 g, 3.70 mmol, 1.5 eq), potassium carbonate (1.03 g, 7.41 mmol, 3.0 eq), cuprous iodide (141.0 mg, 0.74 mmol, 0.3 eq) and L-proline (85.0 mg, 0.74 mmol, 0.3 eq) in 2-pentanol (30.0 mL) was stirred at 140° C. under an argon atmosphere overnight, then cooled to room temperature and water (50.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH=2 with 2N HCl, and then water (50.0 mL) was added. The resulting mixture was extracted with EtOAc (50.0 mL×3). The combined organic layers were washed with brine (20.0 mL×5), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 9c (crude product, 600 mg, 74.5%). LC / MS: 326.0 [M+H] + .

[0935] Step 2

[0936] A mixture of 9c (600 mg, 1.84 mmol), sulfuric acid (15.0 mL) and H2O (2.0 mL) was heated at 100°C for 2 hours, then cooled and poured into a mixture of ice and water (100.0 mL). The solid was collected by filtration and dried under vacuum to give 9d (crude product, 500 mg, 88.4%). LC / MS: 307.9 [M+H] + .

[0937] Step 3

[0938] To a mixture of 9d (300 mg, 0.97 mmol, 1.0 eq) and Cs2CO3 (950 mg, 2.91 mmol, 3.0 eq) in acetonitrile / THF (10.0 mL / 10.0 mL) was added 1b (320 mg, 1.94 mmol, 1.2 eq). The mixture was stirred at 65°C for 2 h, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=10:1) and filtered to give 9e (77 mg, 20.0%) as a yellow solid. LC / MS: 394.0 [M+H] + .

[0939] Step 4

[0940] To a mixture of 9e (70 mg; 0.18 mmol, 1.0 eq) in THF (5.0 mL) was added dropwise a solution of NaOH (28.0 mg, 0.71 mmol, 4.0 eq) in H O (2.0 mL). The reaction mixture was stirred at room temperature overnight, diluted with ice water (10.0 mL), and extracted with EtOAc (15.0 mL×3). The aqueous layer was acidified to pH=3 with 2N HCl and extracted with EtOAc (25.0 mL×3). The combined organic layers were dried over anhydrous Na SO and filtered. The filtrate was concentrated in vacuo to afford compound 52 (61.0 mg, 93.8%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ=13.1 (br, 1H), 8.19 (d, J=8.0Hz, 1H), 8.13 (d, J=8.4Hz, 1H), 7.78-7.85 (m, 2H), 7.68 (d, J=8.4Hz, 1H), 7.39 (t, J=7.2Hz, 1H), 5.18 (s, 2H). LC / MS: 366.0[M+H] + .

[0941] Example 27: Synthesis of Compound 51

[0942]

[0943] Step 1

[0944] A mixture of 10a (3.5 g, 14.1 mmol, 1.0 eq), 10b (2.9 g, 14.1 mmol, 1.0 eq), potassium carbonate (3.9 g, 28.2 mmol, 2.0 eq), copper powder (605 mg, 4.2 mmol, 0.3 eq) and cuprous oxide (I) (267 mg, 4.2 mmol, 0.3 eq) in DMF (100.0 mL) was stirred at 140 ° C under an argon atmosphere for 4.0 h, then cooled to room temperature and water (50.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then additional water (250.0 mL) was added. The resulting mixture was extracted with EtOAc (100.0 mL x 3). The combined organic layers were washed with brine (100.0 mL×3), dried over anhydrous Na SO and filtered. The filtrate was concentrated in vacuo to give the crude product 10c (6.1 g, 100%). LC / MS: 326.0 [M+H] + .

[0945] Step 2

[0946] A mixture of 10c (6.1 g, 18.8 mmol), sulfuric acid (40.0 mL) and H2O (4.0 mL) was heated at 80°C overnight, then cooled and poured into a mixture of ice and water (140.0 mL). The product was collected by filtration and dried under vacuum to give the crude product 10d (2.0 g, 35.0%). LC / MS: 307.9 [M+H] + .

[0947] Step 3

[0948] To a mixture of 10d (2.0 g, 6.5 mmol, 1.0 eq) and Cs2CO3 (6.4 g, 19.5 mmol, 3.0 eq) in acetonitrile / THF (30.0 mL / 30.0 mL) was added 1b (1.3 g, 7.8 mmol, 1.2 eq). The mixture was stirred at 50°C overnight, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v = 10:1) and filtered to give 10f (150 mg, 1%) as a yellow solid. LC / MS: 394.0 [M+H] + .

[0949] Step 4

[0950] To a mixture of 10f (150 mg; 0.38 mmol, 1.0 eq) in THF (15.0 mL) was added dropwise a solution of NaOH (153 mg, 3.80 mmol, 10.0 eq) in H2O (3.0 mL). The reaction mixture was stirred at 50 ° C overnight, diluted with ice water (30.0 mL), and extracted with EtOAc (15.0 mL x 3). The aqueous layer was acidified to pH = 3 with 2N HCl and extracted with EtOAc (25.0 mL × 3). The combined organic layers were concentrated in vacuo and purified by preparative HPLC to give compound 51 (110 mg, 73%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ13.0 (br, 1H), 8.23 ​​(d, J=8.8Hz, 1H), 8.18 (d, J=8.0Hz, 1 H), 7.77-7.80 (m, 2H), 7.64 (d, J=8.4Hz, 1H), 7.37 (t, J=8.0Hz, 1H), 5.29 (s, 2H). LC / MS: 366.0[M+H]+.

[0951] Example 28: Synthesis of Compound 47

[0952]

[0953] Step 1

[0954] A mixture of 2-amino-3,4-dichlorobenzoic acid (1.5 g, 7.3 mmol, 1.0 eq), 11a (3 g, 14.6 mmol, 2.0 eq), potassium carbonate (2.0 g, 14.6 mmol, 2.0 eq), L-proline (252.0 mg, 2.18 mmol, 0.3 eq) and copper (I) oxide (406.0 mg, 2.19 mmol, 0.3 eq) in 2-pentanol (30.0 mL) was stirred at 130° C. under an argon atmosphere overnight, then cooled to room temperature and water (20.0 mL) was added. The mixture was filtered through celite. The filtrate was acidified to pH = 2 with 2N HCl, and then water (50.0 mL) was added. The resulting mixture was extracted with EtOAc (50.0 mL×3). The combined organic layers were washed with brine (20.0 mL×5), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the crude product 11b (1.7 g, 69%). LC / MS: 338.1 [M+H] + .

[0955] A mixture of step 211b (1.7 g, 5.0 mmol) and concentrated H2SO4 / H2O (50 mL / 5 mL) was heated at 80°C overnight, then cooled and poured into an ice-water mixture. The solid was collected by filtration and dried to give the crude product 11c (1.05 g, 65.2%). LC / MS: 320.1 [M+H] +

[0956] Step 3

[0957] To a mixture of 11c (1.05 g, 3.3 mmol, 1.0 eq) and K2CO3 (910.8 mg, 6.6 mmol, 2.0 eq) in acetonitrile / THF (20.0 mL / 40.0 mL) was added 1b (651.0 mg, 3.9 mmol, 1.20 eq). The mixture was stirred at 80°C overnight, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give 11d (97 mg, 7.2%) as a yellow solid. LC / MS: 406.1 [M+H] + .

[0958] Step 4

[0959] To a mixture of 11d (197.0 mg; 0.24 mmol, 1.0 eq) in THF (15 mL) was added dropwise a solution of NaOH (38.0 mg, 0.96 mmol, 4.0 eq) in H2O (4.0 mL). The reaction mixture was stirred at 40°C overnight, cooled to room temperature, diluted with ice water (3.0 mL), and extracted with DCM (3.0 mL×3). The aqueous layer was acidified to pH=3 with 2N HCl and extracted with EtOAc (5.0 mL×4). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was triturated with PE / EtOAc (v / v=3:1) and filtered to give compound 47 (71.0 mg, 78.5%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ8.21 (d, J=8.8Hz, 1H), 8.12 (d, J=8.4Hz, 1H), 7.63 (d , J=8.8Hz, 1H), 7.59 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 5.21 (s, 2H), 1.35 (s, 9H). LC / MS: 378.3[M+H] + .

[0960] Example 29: Synthesis of Compound 102

[0961]

[0962] Step 1

[0963] To a mixture of 1a (500 mg, 2.6 mmol, 1.0 eq) and Cs2CO3 (3.4 g, 10.5 mmol, 2.5 eq) in acetone / THF (20 mL / 10 mL) was added 1b (1.4 g, 7.8 mmol, 3.0 eq) at room temperature. The mixture was then stirred at 40°C overnight, cooled to room temperature, and filtered through celite. The filtrate was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE / EtOAc, v / v=2:1) ​​to give 853 mg of crude product, which was further purified by preparative HPLC to give 1c (182 mg, 24.1%). LC / MS: 296.1 [M+H] + .

[0964] Step 2

[0965] To a mixture of 1c (182 mg; 0.62 mmol, 1.0 eq) in THF (10 mL) was added dropwise a solution of NaOH (98.7 mg, 2.5 mmol, 4.0 eq) in H O (2 mL). The reaction mixture was stirred at 40 ° C overnight, then cooled to room temperature and diluted with ice water (3.0 mL) and extracted with DCM (3.0 mL x 3). The aqueous layer was acidified to pH = 3 with 2N HCl and extracted with EtOAc (5.0 mL x 4). The com...

Claims

1. A compound of the formula: or a pharmaceutically acceptable salt thereof.

2. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

3. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 in the preparation of a medicament for treating or preventing a disease selected from immune disorders, cell proliferative diseases or disorders, inflammation, cachexia, nervous system diseases or disorders, cardiac dysfunction or infection.

6. The use of claim 5, wherein the immune disorder is an autoimmune disorder, wherein the cell proliferative disease or disorder is cancer, and wherein the nervous system disease or disorder is a neurodegenerative disease or disorder.

7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, in the manufacture of a medicament for regulating STING protein, or for treating or preventing a disease caused by or associated with STING expression, activity and / or function, or a disease associated with dysregulation of one or more intracellular pathways in which STING protein participates.

8. A kit comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 4.

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